Stereodivergent SN2@P reactions of borane oxazaphospholidines: Experimental and theoretical studies

Article abstract of DOI:10.1021/ja400208t

The stereodivergent ring-opening of 2-phenyl oxazaphospholidines with alkyl lithium reagents is reported. N-H oxazaphospholidines derived from both (+)-cis-1-amino-2-indanol and (-)-norephedrine provide inversion products in a highly stereoselective process. In contrast, N-Me oxazaphospholidines yield ring-opening products with retention of configuration at the P center, as previously reported by Juge and co-workers. As a result, from a single amino alcohol auxiliary, both enantiomers of key P-stereogenic intermediates could be synthesized. Theoretical studies of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H substrates react in a single step via preferential backside S_N2@P substitution with inversion at phosphorus. N-methylated substrates react preferentially via a two-step frontside S_N2@P, yielding a ring-opened product in which the nucleophilic methyl binds to P with retention of configuration. DFT calculations have shown that the BH₃ unit is a potent directing group to which the methyl lithium reagent coordinates via Li in all the reactions studied.

Full text of DOI:10.1021/ja400208t

Article
pubs.acs.org/JACS
Stereodivergent S 2@P Reactions of Borane Oxazaphospholidines:
N
Experimental and Theoretical Studies
†
,⊥
‡,⊥
†
†
‡
Hester Zijlstra,, Thierry Leon
́
,
Abel de Coz
́
ar, Cel
́
ia Fonseca Guerra, Daniel Byrom,
Antoni Riera,*‡,§ Xavier Verdaguer,* and F. Matthias Bickelhaupt*
,‡,§
,†,∥
†Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling (ACMM), VU University Amsterdam, De
Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands
‡
Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri Reixac 10, E-08028 Barcelona, Spain
§
Departament de Química Organ
̀
ica, Universitat de Barcelona, Martí i Franques
Institute of Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, NL-6525 AJ Nijmegen, The Netherlands
S Supporting Information
́
, 1, E-08028 Barcelona, Spain
∥
*
ABSTRACT: The stereodivergent ring-opening of 2-phenyl oxazaphospho-
lidines with alkyl lithium reagents is reported. N-H oxazaphospholidines
derived from both (+)-cis-1-amino-2-indanol and (−)-norephedrine provide
inversion products in a highly stereoselective process. In contrast, N-Me
oxazaphospholidines yield ring-opening products with retention of
configuration at the P center, as previously reported by Juge and co-
́
workers. As a result, from a single amino alcohol auxiliary, both enantiomers
of key P-stereogenic intermediates could be synthesized. Theoretical studies
of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H
substrates react in a single step via preferential backside S 2@P substitution with inversion at phosphorus. N-methylated
N
substrates react preferentially via a two-step frontside S 2@P, yielding a ring-opened product in which the nucleophilic methyl
N
binds to P with retention of configuration. DFT calculations have shown that the BH unit is a potent directing group to which
3
the methyl lithium reagent coordinates via Li in all the reactions studied.
1
. INTRODUCTION
Scheme 1. Synthesis of P-Stereogenic Phosphines Using the
a
Juge−
́
Stephan Method with Ephedrine
Chiral phosphines have played a crucial role in the emergence
of asymmetric metal catalysis as an efficient tool to produce
1
single-enantiomer compounds. One of the historical con-
tributions in this field was the development of the P-stereogenic
phosphine ligands PAMP and DIPAMP and their application in
asymmetric hydrogenation for the synthesis of the anti-
2
alzheimer drug L-DOPA. Today, P-stereogenic phosphines
attract increasing interest from the asymmetric catalysis
community because of their capacity to impart excellent
selectivities. However, the methods for the synthesis of
these compounds are scarce and limited in terms of substrate
scope. One of the most well-established approaches for the
a
Ring-opening of BOP highlighted in blue.
3
,4
group in 1 was a key element for the success of the reaction.
For example, N-methyl oxazaphospholidine 2 did not undergo
ring-opening under the same reaction conditions (Scheme 2).
synthesis of P-stereogenic ligands is the so-called “Juge−
́
Stephan method”, which is based on the nucleophilic ring-
Most noticeably, S
inversion of configuration at the P center, while ring-opening in
Stephan system (Scheme 1) takes place
2@P of 1 took place with unprecedented
N
opening of ephedrine-derived borane oxazaphospholidines
the ephedrine Juge−
́
(
(
BOPs) in an S 2@P process with alkyl lithium reagents
Scheme 1). The main drawback of this strategy is that it is
N
5
5
,6
with retention of configuration.
The opposite stereochemical pathways observed for these
two systems can be attributable to the following: (a) tert-butyl
vs phenyl substitution at the 2 position of the BOP ring; (b)
hydrogen vs methyl substitution at the N atom of the BOP
ring; and (c) the use of distinct 1,2-amino alcohol scaffolds. To
not amenable for the synthesis of bulky phosphines because of
the lack of reactivity of intermediate II.
Recently, we described that oxazaphospholidines are also
7
amenable for the synthesis of bulky P-stereogenic amino-
8
phosphines. tert-Butyl oxazaphospholidine 1 derived from cis-
1-amino-2-indanol (3) reacted stereoselectively with alkyl
lithium or Grignard reagents to furnish the corresponding
ring-opening products (Scheme 2). The presence of a free N-H
Received: January 8, 2013
Published: February 25, 2013
©
2013 American Chemical Society
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Scheme 2. Synthesis of P-Stereogenic Aminophosphines
Using (+)-cis-1-Amino-2-indanol
Table 1. Ring-Opening of (+)-cis-1-Amino-2-indanol-
Derived Phenyl Oxazaphospholidines
a
a
entry
S.M.
R
R′
yield (%)
dr
product
a
Ring-opening of BOP highlighted in red.
c
1
2
3
4
4
5
4
5
H
Me
H
Me
Me
89
89
73
≥95:5
≥95:5
≥95:5
≥95:5
6a (SP)
7a (RP)
d
d
b
b
shed light on these issues, we examined the effect of these three
o-An
o-An
6b (RP)
d
factors on the stereoselective S 2@P reactions of BOPs. Here
Me
88
7b (SP)
N
a
1
b
we report on the ring-opening of 2-phenyl oxazaphospholidines
and how N-substitution allows discrimination between
inversion and retention pathways in a completely stereo-
divergent process. Also, for the first time, we conducted a
Diastereomeric ratio was determined by H NMR spectroscopy. o-
An = ortho-anisyl (2-methoxyphenyl). Absolute configuration of
dimethyl derivative 9 determined by X-ray analysis. Absolute
c
d
configuration determined by analysis of the corresponding meth-
anolysis product, see Table 2.
computational mechanistic exploration of the S 2@P reactions
N
between methyl lithium and various model BOPs to explain the
stereoselectivity observed using relativistic density functional
theory (DFT; see computational details).
2. EXPERIMENTAL RESULTS
2
.1. Ring-Opening Experiments with 2-Phenyl Oxazaphos-
pholidines. Since 2-phenyl BOPs undergo rapid ring-opening with
5
organolithium reagents at low temperatures, we chose 2-phenyl
oxazaphospholidines 4 and 5 derived from (1S, 2R)-(+)-cis-1-amino-2-
indanol (3) to study the process (Scheme 3). Condensation of 3 with
the bis(diethylamino)phenylphosphine provided the corresponding
BOP 4 as a 10:1 mixture of diastereomers in 76% yield. The major
diastereomer with the R configuration at the P center was obtained by
Figure 1. X-ray structure of methyl ether 9 prepared by
permethylation of 6a showing that the configuration at the phosphorus
center is S.
9
crystallization in hexane/CH Cl mixtures. Diastereomerically pure
2
2
(RP)-4 was easily alkylated by deprotonation with MeLi and reaction
with iodomethane to yield the N-Me BOP (R )-5 as a single
P
diastereomer in excellent yield.
With BOPs 4 and 5 in hand, we proceeded to test their ring-
opening with two alkyl lithium reagents, namely methyl lithium and
ortho-anisyl lithium (o-AnLi), which are widely used in this type of
chemistry. The reaction of 4 and 5 took place efficiently at −78 °C for
both MeLi and o-AnLi (Table 1). In all cases, ring-opening occurred
provided the same methyl phosphinite 10 in high enantiomeric excess
but with opposite configurations (Table 2, entries 1 and 2). A similar
outcome was obtained for the methanolysis of phosphinoamines 6b
and 7b. Compound 6b led to dextrorotatory phosphinite 11, while 7b
gave levorotatory phosphinite 11 (Table 2, entries 3 and 4). Therefore,
the methanolysis of compounds 6 and 7 confirmed that the ring-
opening of 4 and 5 occurs with high stereoselectivity but through
opposite mechanistic pathways. Ring-opening of BOP 4, which has a
free N-H group, provides inversion, whereas the same reaction on
BOP 5, which contains an N-Me moiety, leads to retention of the
configuration. As a result, from a single enantiomer of cis-1-amino-2-
indanol auxiliary, both enantiomers of P-stereogenic phosphinites 10
and 11 could be synthesized.
1
with complete stereoselectivity, as determined by H NMR spectros-
copy, to yield substitution compounds as single diastereomers. At this
stage, the stereochemistry of compounds 6a−b and 7a−b could not be
ascertained by X-ray analysis because these compounds either were
oils or did not provide suitable crystals for analysis. However, we were
able to undertake diffraction analysis for the methyl ether 9 obtained
by permethylation of 6a (Figure 1). The X-ray structure of this
derivative (9) showed the P atom with the S configuration, thus
confirming that S 2@P of 4 with MeLi took place with inversion of
configuration at the P center in an analogous fashion, as happens with
the tert-butyl BOP 1 (Scheme 2).
To further confirm that the sole factor governing the stereo-
divergent ring-opening of BOPs is the substitution at the nitrogen
atom and that the chiral auxiliary employed had no influence, we next
studied the stereochemical course of the reaction using norephedrine
derivatives (Scheme 4). Condensation of norephedrine with PhP-
(NEt ) in hot dioxane followed by protection with borane produced a
N
To fully ascertain the stereochemistry in the ring-opening of 4 and
, we next carried out the acid-catalyzed methanolysis of compounds
5
6
a−b and 7a−b (Table 2). It is known that methanolysis of similar
2
2
compounds takes place with inversion at the P center in a highly
stereoselective manner. The methanolysis of compounds 6a and 7a
mixture of diastereomers in an 8:1 ratio. Purification by flash
5a
chromatography yielded the major diastereomer (R )-12 in 39%
P
Scheme 3. Synthesis of N-H and N-Me Phenyl Oxazaphospholidines Derived from (+)-cis-1-Amino-2-indanol
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Table 2. Methanolysis of Aminophosphines 6a−b and 7a−b
a
b
c
d
entry
S.M.
R
R′
yield (%)
[α]D
ee (%)
product
stereochemical course
1
2
2
4
6a
7a
6b
7b
H
Me
H
Me
Me
89
89
73
88
+94.5
−94.4
+26.9
−26.8
98
98
99
99
(+)-10-(RP)
(−)-10-(SP)
(+)-11-(SP)
(−)-11-(RP)
inver./inver.
ret./inver.
e
e
o-An
o-An
inver./inver.
ret./inver.
Me
a
b
Optical rotations were recorded in CHCl at a concentration of 1g/100 mL. Enantiomeric excess calculated on the basis of the optical rotations
and data in the literature (ref 5a). Absolute configuration was determined on the basis of the sign of optical rotation (ref 5a). Stereochemical
pathway observed for the ring-opening and methanolysis steps respectively. o-An = ortho-anisyl (2-methoxyphenyl).
3
c
d
e
Scheme 4. Synthesis of Phosphinite 10 Using Norephedrine
as a Chiral Auxiliary
Scheme 5. Postulated Reaction Pathways for the Ring-
Opening of N-Me and N-H Borane Oxazaphospholidines
and g STOs was used to fit the molecular density and to represent the
Coulomb and exchange potentials accurately in each self-consistent
field cycle. Relativistic effects were taken into account using the zeroth-
9
yield. Treatment of 12 with MeMgBr at room temperature afforded
13
order regular approximation (ZORA).
the ring-opening product in >95:5 stereoselectivity, as determined by
H NMR. Finally, methanolysis of 13 provided dextrorotatory
phosphinite (+)-(R )-10 in 96% enantiomeric excess. These findings
demonstrate that ring-opening for the norephedrine system takes place
with inversion at the P center, as opposed to the known retention
pathway observed for ephedrine.
Reactions were modeled both in the gas phase and in toluene, using
methyl lithium as nucleophilic reagent, and the four borane
oxazaphospholidines (BOPs) are depicted in Figure 2. Solvation in
toluene has been simulated using the conductor-like screening model
1
P
1
4
(COSMO).
Overall, these results show that the only factor that regulates the
stereodivergent ring-opening of oxazaphospholidines is the substitu-
tion at the nitrogen atom of the heterocycle. Thus, BOPs 4 and 12
bearing Ph and H substituents at P and N, respectively, react via
backside S 2@P, which is accompanied by inversion of configuration
N
8
at the P center (Scheme 5A). Methyl substitution at N blocks this
Figure 2. Model BOPs in this computational study.
route and diverts the reaction toward the frontside S 2@P pathway,
N
5b,c,10
which implies the retention of configuration (Scheme 5B).
In the
case of BOP 1 bearing t-Bu (instead of Ph) and H substituents at P
In general, transition states (TSs) were determined by following the
eigen mode with the negative force constant toward the saddle point
on the potential energy surface. The following six TSs were
determined by a linear transit (LT) in which the nucleophile−
substrate C−P bond length varies from its values in the initial
minimum to that in the final minimum, while optimizing all other
and N, respectively, the system still reacts via backside S 2@P, i.e.,
N
with inversion of configuration. This time, however, methylation of N
(2) not only blocks the backside pathway but also leaves the frontside
S 2@P route inaccessible. In this case, backside S 2@P requires two
N
N
equivalents of nucleophile to proceed, whereas frontside S 2@P
N
involves the usual one equivalent of organometallic reagent.
geometry parameters in each LT point: postTS in backside S 2@P of
N
MePh in the gas phase and in toluene; TS in frontside S 2@P of both
N
3
. COMPUTATIONAL MECHANISTIC STUDIES
HPh and of HtBu in the gas phase and in toluene. This procedure was
shown before to yield excellent agreement with reaction profiles from
3
.1. Computational Details. All calculations have been
1
1
1
2
15
performed using the Amsterdam Density Functional (ADF) program
using DFT at OLYP/TZ2P for geometry optimization and energies.
TZ2P is a large uncontracted set of Slater-type orbitals (STOs) of
triple-ζ quality for all atoms and was augmented with two sets of
polarization functions, that is, p and d functions for the hydrogen atom
and d and f functions for the other atoms. An auxiliary set of s, p, d, f,
steepest-descent computations. An LT approach was also used for
determining the TS for the facile lithiation of HPh and HtBu. All
stationary points were verified to be minima (zero imaginary
frequencies) or TSs (one imaginary frequency) through vibrational
analysis. The character of the mode representing the transition vector
was examined, and attention was paid to a correct coupling of C−P
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Figure 3. Reaction profiles of backside and frontside S 2@P reactions of MeLi + HPh, MePh, HtBu, and MetBu in the gas phase and in toluene,
N
computed at (COSMO) ZORA-OLYP/TZ2P.
+
bond formation, P−O bond breaking, and Li migration in the S 2@P
Inspection of the condensed-phase reaction profiles shows that N-
methylation raises the backside but not the frontside S 2@P barriers,
whereas replacing the phenyl substituent at P by t-butyl raises both the
backside and the frontside S 2@P barriers (see Figure 3). This is in
line with earlier findings that increasing steric congestion near the
N
TSs. In a few cases, species had a spurious imaginary frequency
associated with nearly free rotation of methyl groups (see Supporting
Information).
The electronic structure of key species was analyzed using
quantitative Kohn−Sham molecular orbital (MO) theory. Further-
more, the electronic charge density distribution was evaluated using
the Voronoi deformation density (VDD) atomic charge method.
.2. Overview of Mechanistic Pathways. Figure 3 shows our
computed reaction profiles for the backside and frontside S 2@P
reactions of methyl lithium with the four BOP substrates shown in
Figure 2, in the gas phase and in toluene. A complete account of all
structural data can be found in the Supporting Information. Relative
energies of stationary points are specified with respect to the reactant
complex (RC) that is formed prior to the substitution process, which
occurs either in one step via a single TS or in two steps via a stable
intermediate transition complex (TC) that is separated from the RC
and the product complex (PC) by a pre- (preTS) and a post-transition
states (postTS).
In the presence of methyl lithium, substrates HPh and HtBu
undergo facile deprotonation at nitrogen under formation of the N-
lithiated species + methane. For MeLi + HPh, this reaction is
exothermic by −53.6 kcal/mol and proceeds via a barrier of <1 kcal/
mol. A second methyl lithium molecule is then required to enter the
nucleophilic substitution pathways.
N
N
1
6
15
electrophilic center causes higher S
methylation goes for all model systems with a two-step substitution
mechanism that involves a stable S 2@P TC, i.e., a stable
2 barriers. Interestingly, N-
N
1
7
N
pentacoordinate phosphorus intermediate, instead of a labile S 2@P
3
N
TS. On the other hand, when the N atom carries a hydrogen, the
substitution reactions proceed in a concerted (one-step) fashion. We
will return to this later on.
Comparison of our computed reaction profiles with experimental
data reveals that model reactions in toluene that involve TSs >16 kcal/
mol relative to the reactant complex do not occur in the experiments
N
(compare Figure 3 with Schemes 1 and 2). There are three model
reactions in which no TS higher than 16 kcal/mol relative to the
reactant complex occurs: 2 MeLi + HPh via b-S 2@P; 2 MeLi + HtBu
N
via b-S 2@P; and MeLi + MePh via f-S 2@P (see Figure 3). This
N
N
agrees well with the experimental finding that BOP substrates carrying
18
hydrogen at N react via backside S 2@P, N-methylated substrates
N
with phenyl-substitution at P react via frontside S 2@P, and
N
simultaneous N-methylation and t-butyl substitution at P make
substrates unreactive.
3.3. Reactions of MePh. Figure 4 compares the energy profiles of
backside and frontside S 2@P reactions of MeLi + MePh, starting
N
The corresponding lithiation reaction is blocked in the case of the
N-methylated substrates MePh and MetBu in which case already the
first methyl lithium molecule can enter into the nucleophilic
substitution pathways. This finding matches with the experimental
observation that reactions involving N-methylated substrates proceed
with only 1 equiv of methyl lithium, whereas unmethylated substrates
require 2 equiv of methyl lithium.
from the reactant complexes. The energy of stationary points is again
shown relative to the reactant complex. Both pathways show the two-
step mechanism that is usual for S 2 at phosphorus and other third-
N
1
5,19
and higher period electrophilic centers.
The BH group at phosphorus acts as a directing group to which the
3
metal-stabilized nucleophile MeLi coordinates via lithium (see Scheme
1
0
6). In this way, the methyl anion is effectively positioned for
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Figure 4. Backside versus frontside S 2@P reaction profiles for each of our four substrates in the gas phase and in toluene, computed at (COSMO)
N
ZORA-OLYP/TZ2P.
Scheme 6. Computed Backside and Frontside S 2@P
Pathways of MeLi + MePh
nucleophilic attack, both in the backside and frontside S 2@P
mechanism. In the course of the first elementary step, this leads to the
N
N
formation of the pentacoordinate TC, in which the BH group hosts
3
and stabilizes the lithium cation that is released as the methyl anion
forms a new bond with phosphorus.
A critical factor in the second elementary step (i.e., dissociation of
the P−O bond) is the feasibility of stabilizing the evolving alkoxide
leaving group by the lithium cation. In both, backside and frontside
SN2@P pathways, the associated postTS possesses a transition vector
in which Li moves from P toward O, while simultaneously the P−O
bond is dissociating. In the TC of the backside process (b-MePh-TC),
the ∼0.6 Å longer Li−O distance (see Figure 5) leads to a high barrier
in the second reaction step (see Figure 4). In the frontside pathway,
the lithium cation is in closer proximity to oxygen and can assist P−O
bond breaking more effectively by stabilizing the emerging alkoxide
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Figure 5. Computed structure (Li−O distance in Å) of the pentacoordinate TC in backside and frontside S 2@P reactions of MeLi with MePh and
N
MetBu in toluene.
already in an earlier stage. Thus, frontside S 2@P becomes preferred
N
over backside S 2@P in the case of MeLi + MePh.
N
3
.4. Reactions of MetBu. The S 2@P reaction profiles for MeLi
N
+
MetBu are similar to those for MeLi + MePh (see Figure 3). In
particular, the frontside S 2@P pathway remains preferred over the
N
backside one due to the aforementioned closer proximity between
oxygen and lithium, in this case ∼0.8 Å compared to the backside
pathway (see Figure 5). Yet, there is also a striking difference between
the reactions of MePh and MetBu. The barrier heights go up for all
elementary reaction steps along the backside as well as frontside S 2@
Figure 6. Reactant complexes for the frontside (encounter complex)
and backside S 2@P reaction of 2 MeLi + HPh (in toluene, the
former is 10 kcal/mol more stable than the latter).
N
P processes as one goes from phenyl (in MePh) to the sterically more
demanding t-butyl substituent at P (in MetBu). Thus, both pathways
become relatively less viable in the latter case (see Scheme 7). This is
in line with the observation that the corresponding substrates in the
N
experiments do not show S 2@P reactivity (see Scheme 2).
The reason is that here, at variance with the reactions of the N-
methylated substrates, the O atom is at any time, starting from the
reactant complex, in close proximity and coordinating to Li cation.
N
+
Scheme 7. Computed Backside and Frontside S 2@P
N
Consequently, the evolving alkoxide leaving group is directly stabilized
Pathways of MeLi + MetBu
and can dissociate in a concerted manner, without the need of a
+
separate elementary reaction step involving Li migration from BH to
3
O. The result is a single-step S 2@P reaction with lithium-mediated
N
P−O bond breaking for both the frontside pathway and the backside
pathway discussed below.
On the other hand, the backside S 2@P reaction occurs from b-
N
HPh-RC, that is, after the Li−Li bond has already been broken. This
backside reaction involves a sterically somewhat less demanding
configuration in the TS which is 6.3 kcal/mol above to the backside
reactant complex or 17 kcal/mol above the encounter complex f-HPh-
RC. Thus, the backside pathway prevails as it is associated with two
steps with relatively low barriers: (a) a methyl rearrangement from
encounter complex to b-S 2@P reactant complex with a barrier of 13
N
kcal/mol, followed by (b) a favorable S 2@P barrier of some 6 kcal/
N
3
.5. Reactions of HPh. As pointed out above, the BOP substrates
mol (see Figure 4). Note also that now the backside pathway does not
+
HPh and HtBu react with a first methyl lithium molecule via facile
lithiation at nitrogen. In the case of HPh, this lithiation proceeds via a
barrier of <1 kcal/mol and is −53.6 kcal/mol exothermic. The
formation of the encounter complex with a second methyl lithium
molecule is −29.8 kcal/mol exothermic. In this complex, methyl
lithium coordinates via Li to the O atom of the leaving group, while
simultaneously the methyl group is in a bridging position between its
own Li atom and the Li atom coordinated to N. Note that in the
course of this association, the two Li atoms approach each other and
achieve a short Li−Li contact of 2.49 Å (see Figure 6). This encounter
complex serves either as the reactant complex from which the one-step
suffer from a larger distance between Li and O, in contrast to the
situation for the N-methylated substrates. The reason is that the Li+
stemming from the second methyl lithium remains coordinated to BH3
at the side of O, whereas the nucleophilic methyl can coordinate in the
+
backside reactant complex to the other Li that was incorporated in
the earlier lithiation step.
3.6. Reactions of HtBu. The S 2@P mechanistic pathways for the
N
sterically somewhat more crowded HtBu substrate are very similar to
those of HPh (compare Schemes 8 and 9). The main difference is that
all substitution barriers for HtBu are higher by 8−10 kcal/mol (see
Figures 3 and 4). Thus, the backside S 2@P reaction still prevails and,
N
frontside S 2@P reaction proceeds or it can be transformed via a 13
kcal/mol barrier in toluene into the 10 kcal/mol higher-energy
at variance with the frontside process, is observed in the corresponding
experiments.
N
reactant complex for the one-step backside S 2@P reaction by
3.7. Li Coordination to B versus O. An interesting finding of this
N
migrating the nucleophilic methyl group from its bridging position in
between the two Li atoms entirely to the N-coordinated Li atom.
Along this migration, the Li−Li bond dissociates.
study is that, in the reactant complex and preTS of the S 2@P
N
reactions, the lithium of the MeLi reactant always coordinates to the B
atom (or BH group) of the BOP substrate and only in some cases
3
1
0
The frontside S 2@P reaction proceeds via nucleophilic attack of
also to O (see, e.g., Figures 6 and 7).
N
Me at P in a sterically relatively crowded TS at nearly 55 kcal/mol
above the frontside reactant complex. The path of nucleophilic attack
The origin of this coordination behavior is found upon inspection of
the electronic structure of the BOP substrate. In the first place, the
+
−
is blocked by the Li unit which, in the course of this reaction step,
formal charges in the substrate are P −B .This agrees well with the
2
dissociates its relatively soft Li−Li bond (see Figure 6). Note that the
pentacoordinate species is no longer a stable intermediate (or TC).
fact that the highest occupied molecular orbital (HOMO) of this
molecule has a large amplitude on BH , larger than on O.
3
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Scheme 8. Computed Backside and Frontside S 2@P
N
Pathways of MeLi + HPh, Starting from Reactant Complex
after Lithiation
Scheme 9. Computed Backside and Frontside S 2@P
N
Pathways of MeLi + HtBu, Starting from Reactant Complex
after Lithiation
Figure 8. HOMO (left) and VDD atomic charges (in au, right) of
HPh (upper) and HPh with singly methylated boron (lower).
Our DFT computations on model reactions of methyl
lithium with model oxazaphospholidines yield trends in
reactivity that agree well with experimental observations: The
N-methylated substrate MePh reacts preferentially via a two-
step frontside S 2@P yielding a ring-opened product in which
N
the nucleophilic methyl binds to P with retention of
configuration. Likewise MetBu also prefers the frontside
SN2@P pathway, but all barriers involving the sterically more
congested MetBu substrate are higher, and the corresponding
substrate in experiments turns out to be unreactive. On the
other hand, the substrates HPh and HtBu react with a first
methyl lithium molecule via facile N-lithiation. Next, a second
equivalent of methyl lithium reacts in a single step via
preferential backside S 2@P substitution.
N
The origin of the preference for frontside substitution in the
case of the N-methylated substrates MePh and MetBu is the
+
closer proximity, in this pathway, of the Li ion to the O leaving
group. Proceeding from the encounter complex of the frontside
pathway, the Li atom is from the beginning coordinating to
Figure 7. MeLi coordinates via Li to the BH group.
BH on the same side as the leaving-group O atom. Therefore,
3
3
in the second reaction step, the evolving alkoxide leaving group
+
can relatively easily access the Li ion and engage in a stabilizing
interaction. Along the backside pathway, the methyl lithium
reagent coordinates via Li at the opposite side with respect to
the O atom. Consequently, the transfer of Li to the leaving
group involves bridging a larger spatial separation which is
associated with a higher barrier.
The preference for the backside substitution in the case of
the unmethylated HPh and HtBu is the combination of
thermodynamically relatively stable frontside encounter com-
plexes of the second methyl lithium reagent with the lithium-
stabilized but effectively negatively charged substrates in
combination with a sterically less accessible path of approach,
Furthermore, the accumulated charge of the BH group of −0.43 au
3
(
computed from the VDD atomic charges) is significantly more
+
negative than the O atomic charge of −0.17 au (see Figure 8). The
situation in related B-methylated BOP is similar (see Figure 8). In this
scenario, the BH group behaves as a potent directing group that
3
strongly coordinates to the metal center of the approaching
20
organometallic reagent.
4. CONCLUSION
In summary, we have demonstrated that the only factor that
governs the stereodivergent ring-opening in 2-phenyl BOPs is
the substitution at the nitrogen atom of the heterocycle. Thus,
which is blocked by an Li cluster. Furthermore, the backside
BOPs 4 and 12 react with MeLi or o-AnLi via backside S 2@P
2
N
pathway is not hampered anymore by a large distance between
with inversion of configuration at phosphorus. On the other
+
hand, N-methylated BOP (5) reacts via frontside S 2@P, as it
Li and the evolving oxide leaving group to which this cation
N
+
had been previously described by Juge,
configuration at phosphorus.
́
with retention of
must migrate because of the presence of two Li cations, one of
which is always in close proximity to O.
4
489
dx.doi.org/10.1021/ja400208t | J. Am. Chem. Soc. 2013, 135, 4483−4491

Journal of the American Chemical Society
Article
(
5) (a) Juge,
́
S.; Stephan, M.; Laffitte, J. A.; Genet, J. P. Tetrahedron
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, compound characterization data, and
spectra for all new compounds, and CIF file for compound 9.
Structural data and total energies of stationary points. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
Lett. 1990, 31, 6357−6360. (b) Juge,
Genet, J. P.; Halut-Desportes, S. J. Chem. Soc., Chem. Commun. 1993,
31−533. (c) Darcel, C.; Uziel, J.; Juge, S. Synthesis of P-stereogenic
phosphorus compounds based on chiral aminoalcohols as chiral
auxiliary. In Phosphorous Ligands in Asymmetric Catalysis; Borner, A.,
Ed.; Wiley-WCH: Weinheim, 2008; Vol. III, pp 1211−1233.
(6) For other examples of the Juge-Stephan method and related
systems, see: (a) Brown, J. M.; Laing, J. C. P. J. Organomet. Chem.
́ ̀
S.; Stephan, M.; Merdes, R.;
*
S
5
́
̈
́
1
997, 529, 435−444. (b) den Heeten, R.; Swennenhuis, B. H. G.; van
AUTHOR INFORMATION
Corresponding Author
f.m.bickelhaupt@vu.nl; antoni.riera@irbbarcelona.org; xavier.
verdaguer@irbbarcelona.org
■
Leeuwen, P. W. N. M.; de Vries, J. G.; Kamer, P. C. J. Angew. Chem.,
Int. Ed. 2008, 47, 6602−6605. (c) Maienza, F.; Spindler, F.;
Thommen, M.; Pugin, B.; Malan, C.; Mezzetti, A. J. Org. Chem.
2
002, 67, 5239−5249. (d) Yang, H.; Lugan, N.; Mathieu, R.
Author Contributions
These authors contributed equally.
Organometallics 1997, 16, 2089−2095. (e) Leyris, A.; Nuel, D.;
Giordano, L.; Achard, M.; Buono, G. Tetrahedron Lett. 2005, 46,
⊥
8
4
677−8680. (f) Bondarev, O. G.; Goddard, R. Tetrahedron Lett. 2006,
7, 9013−9015. (g) Han, Z. S.; Goyal, N.; Herbage, M. A.; Sieber, J.
Notes
The authors declare no competing financial interest.
D.; Qu, B.; Xu, Y.; Li, Z.; Reeves, J. T.; Desrosiers, J.; Ma, S.; Grinberg,
N.; Lee, H.; Mangunuru, H. P. R.; Zhang, Y.; Krishnamurthy, D.; Lu,
B. Z.; Song, J. J.; Wang, G.; Senanayake, C. H. J. Am. Chem. Soc. 2013,
ACKNOWLEDGMENTS
■
1
35, 2474−2477.
7) Bauduin, C.; Moulin, D.; Kaloun, E. B.; Darcel, C.; Juge,
Chem. 2003, 68, 4293−4301.
8) Leon, T.; Riera, A.; Verdaguer, X. J. Am. Chem. Soc. 2011, 133,
740−5743.
9) In order to avoid steric congestion, the alkyl/aryl groups on
We thank The Netherlands Organization for Scientific
Research (NWO-CW), the National Research School Combi-
nation-Catalysis (NRSC-C), Ikerbasque, MICINN (CTQ2011-
(
́
S. J. Org.
(
5
(
́
2
3620, CTQ2010-16959/BQU), IRB Barcelona, and the
Generalitat de Catalunya (2009SGR-00901) for financial
support. T.L thanks the Generalitat de Catalunya for a FI
fellowship.
phosphorous are placed invariably in a trans disposition with respect to
the other substituents in the oxazaphospholidine ring, see refs 5 and 6.
(
́
10) For N-methylated oxazaphospholidines, Juge and co-workers
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(
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4
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