Inversion of Configuration at the Phosphorus Nucleophile in the Diastereoselective and Enantioselective Synthesis of P-Stereogenic syn-Phosphiranes from Chiral Epoxides

Article abstract of DOI:10.1002/anie.201801427

Nucleophilic substitution results in inversion of configuration at the electrophilic carbon center (S_N2) or racemization (S_N1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to

Full text of DOI:10.1002/anie.201801427

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Accepted Article
Title: Inversion of Configuration at the Phosphorus Nucleophile
in Diastereoselective and Enantioselective Synthesis of P-
Stereogenic syn-Phosphiranes from Chiral Epoxides
Authors: Jake Muldoon, Balazs Varga, Meaghan Deegan, Timothy
Chapp, Adam Eordogh, Russell Hughes, David S. Glueck,
Curtis Moore, and Arnold Rheingold
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801427
Angew. Chem. 10.1002/ange.201801427
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10.1002/anie.201801427
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Inversion of Configuration at the Phosphorus Nucleophile in
Diastereoselective and Enantioselective Synthesis of P-
Stereogenic syn-Phosphiranes from Chiral Epoxides
Jake A. Muldoon,[a] Balázs R. Varga,[a] Meaghan M. Deegan,[a] Timothy W. Chapp,[a] Ádám M. Eördögh,[a]
Russell P. Hughes,*[a] David S. Glueck,*[a] Curtis E. Moore,[b] and Arnold L. Rheingold [b]
pyramidal
inversion
••
••
Abstract: Nucleophilic substitution results in inversion of
configuration at the electrophilic carbon (SN2) or racemization
(SN1). Stereochemistry at the nucleophile is rarely considered, but
phosphines, which have a high barrier to pyramidal inversion,
attack electrophiles with retention of configuration at P.
Surprisingly, cyclization of bifunctional secondary phosphine alkyl
tosylates proceeded under mild conditions with inversion of
configuration at the nucleophile to yield P-stereogenic syn-
phosphiranes. DFT studies suggested that the novel
stereochemistry results from acid-promoted tosylate dissociation
to yield an intermediate phosphenium-bridged cation, which
undergoes syn-selective cyclization.
P
P
A
A
C
C
C
B
B
high
barrier
RX
RX
R
P
R
P
X
A
X
A
retention
C
B
B
Scheme 1. Phosphines Undergo Nucleophilic Reactions with Retention of
Configuration at Phosphorus
H
i. LiPHMes*
Mes*
R
P
P
The stereochemistry of nucleophilic substitution provides
ii. TsCl
HOTs
DYKAT
H
R
O
valuable
racemization: SN1).
mechanistic
information
Textbooks do not mention the
(inversion:
SN2;
H
H
1
Mes*
+
OTs
stereochemistry at the nucleophile, which is usually achiral.
However, P-stereogenic phosphines, which have high barriers
to pyramidal inversion,2 undergo nucleophilic reactions, such
as quaternization with alkyl halides, with retention of
configuration at phosphorus (Scheme 1).3 We report here the
first reversal of this paradigm, in which intramolecular
nucleophilic substitution proceeds at room temperature
with inversion of configuration at phosphorus, as the key step
in controlling the diastereo- and enantioselective synthesis of
P-stereogenic syn-phosphiranes.
P
H
H
R
Mes*
R
OTs
syn-
2a-d
1a-d
R = Ph (a), Me (b), Et (c), CH2OMe (d)
Scheme 2. Generation and Cyclization of Diastereomeric Tosylates 1. Both
Intermediates Formed the Same Phosphirane Products syn-2 9
Treatment of chiral epoxides with LiPHMes* (Mes* = 2,4,6-
(t-Bu)3C6H2), followed by tosyl chloride, yielded a ca. 1:1
mixture of diastereomeric tosylates 1 via highly regioselective
ring opening at the less substituted carbon.4,5 As generated,
tosylates 1 cyclized at 25 °C to selectively form syn-
Table 1. Synthesis of syn-Phosphiranes 2a-da
No.
2a
R
time (h)
14
yield (%)
dr
er
Ph
71
74
70
63
>99:1
>99:1
>99:1
>95:5
99:1
>99:1
>99:1
>99:1
phosphiranes
2
in
a
dynamic kinetic asymmetric
transformation (DYKAT, Scheme 2, Table 1). 6 The syn-
stereochemistry and inversion of configuration at the epoxide
carbon were established by X-ray crystal structures of syn-2a
and -2c and of anti-2a,7 which were consistent with NMR data.8
2b
2c
Me
24
Et
38
2d
CH2OMe
110
a
In THF at ambient temperature, isolated yields; see the Supporting
Information for details
[a]
[b]
J. A. Muldoon, Dr. B. R. Varga, M. M. Deegan, Dr. T. W. Chapp, A.
M. Eördögh, Prof. R. P. Hughes, Prof. D. S. Glueck
Department of Chemistry, Dartmouth College, 6128 Burke
Laboratory, Hanover, New Hampshire 03755, United States
E-mail: rph@dartmouth.edu, glueck@dartmouth.edu
Dr. C. E. Moore, Prof. A. L. Rheingold
Changes in reaction conditions or epoxide and phosphine
substituents switched this DYKAT to a kinetic resolution (KR),
in which one diastereomer (1-fast) formed syn-2, leaving
unreacted 1-slow (Scheme 3). The reactivity of 1b was
particularly sensitive to conditions, including its method of
generation and the presence of added chloride- or tosylate-
containing salts. When 1b was formed, along with LiCl, from
propylene oxide (Scheme 3, route A), DYKAT occurred as in
Department of Chemistry, University of California, San Diego, 9500
Gilman Drive, La Jolla, California, 92093, United States
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/anie.201801427
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Scheme 2. However, 1b underwent a slower KR when it was
generated, along with LiOTs, from chiral ditosylate 3 (Scheme
3, route B). Adding LiOTs, NBu4OTs, or LiCl to the epoxide-
derived reaction mixtures (route A) caused KR, while DYKAT
proceeded normally in the presence of NBu4PF6. Adding LiCl
or NBu4Cl to the 1b/LiOTs mixture (route B) promoted KR,
which with LiCl now occurred in 1 d instead of 3 d. When
propylene oxide was replaced with epichlorohydrin (1e, R =
CH2Cl, route A), very slow DYKAT (50% conversion, 17 d)
changed to KR on addition of 0.1 equiv of LiOTf and heating to
60 °C for 24 h. Finally, epichlorohydrin and the less bulky
nucleophile LiPHIs (Is = 2,4,6-(i-Pr)3C6H2) formed secondary
phosphine diastereomers 4, whose KR gave syn-phosphirane
5 and 4-slow; this cyclization was also faster with added LiCl.
extension, those of the fast diastereomers, which have the
opposite P-configuration, as shown in Scheme 3.
Cyclization with the usual retention at P, as evident from
arrow-pushing for nucleophilic attack of the P lone pair at the
tosylate-bearing carbon, would yield anti-2 from 1-fast and
syn-2 from 1-slow, contradicting the experimental
observations. Therefore, cyclization occurred with inversion of
configuration at the P-nucleophile. Consistent with this
conclusion, isolated 1b-slow very slowly formed anti-
phosphirane 2b, but added HCl caused epimerization to an
equilibrium mixture of 1b-fast and 1b-slow, which quickly
formed syn-2b (Scheme 4). These observations suggest
Curtin-Hammett behavior in the DYKAT of Scheme 2,10 where
acid-mediated interconversion of the P-epimeric secondary
phosphine diastereomers 1-fast and 1-slow is faster than their
cyclization, 11 and syn-2 forms more quickly than anti-2
(Scheme 5).
Me
H
TsO OTs
R
H
1b-slow
O
Mes*
H
HCl
1b-fast +
1b-slow
P
3
Me
H
i. LiPHAr
ii. TsCl
– LiCl
LiPHMes*
– LiOTs
A
B
OTs
slow
fast
Mes*
Mes*
H
Ar
H
fast
slow
P
P
P
P
R
H
R
Me
H
Me
Ar
+
H
H
syn-2b
anti-2b
OTs
OTs
Scheme 4. Reactions of 1b-slow.9
R = Me, Ar = Mes* (1b, via A or B)
R = CH2Cl, Ar = Mes* or Is (1e, 4, via A)
kinetic resolution
We used DFT studies (B3LYP-D3/6-311G**++/THF) and
literature precedent to propose a mechanism of cyclization
consistent with the experimental stereochemistry (Scheme 5).
The P-inversion requires cyclization from eclipsed conformers
of 1, which are accessible; the energies of eclipsed and
staggered structures for both fast and slow diastereomers of
1b were the same within the expected error of the calculations,
1 kcal/mol. Direct SN2 displacement of tosylate from 1b with
retention or inversion at P was ruled out by locating the
transition states, with activation energies of ca. 25 kcal/mol,
1b (via A): LiOTs, NBu4OTs, or LiCl
1b (via B): no additive, LiCl or NBu4Cl
1e: LiOTf 4: no additive, or LiCl
O
H2O2
Ar
H
Ar
H
Ar
P
P
+
R
H
OTs
R
H
OTs
P
R
H
6b/e-slow
7-slow
1b/e-slow
4-slow
syn-2b/e, 5
inconsistent
with
the
observed
room-temperature
reactivity. Instead, SN1-like dissociation of tosylate from 1,
promoted by steric crowding and Lewis or Brønsted acids,
could give cation 8.12 Previously, loss of X– from hypothetical
H2PCH2CHMe(X) was predicted to yield a related carbocation
stabilized (23 kcal/mol) by hyperconjugation with the P–C s-
bond; because the eclipsed rotamer was preferred over the
staggered one by 15 kcal/mol,13 Scheme 5 also shows the
Scheme 3. Kinetic Resolution of Diastereomeric Tosylates 1b/e and 4.9 (R
= Me, Ar = Mes* (1b/2b/6b); R = CH2Cl, Ar = Mes* (1e/2e/6e) or Ar = Is
(4/5/7))
Although the origin of these effects of reaction conditions
and substrate substituents on DYKAT vs KR are not clear,
eclipsed geometry for 8. Cyclization of
8 followed by
deprotonation of cation 9 would yield phosphirane 2. Overall
inversion at P would occur by staggered-to-eclipsed rotation of
the PHMes* unit around the P-CH2 bond in 1, followed by
attack at C in 8 by the rear lobe of the P lone pair.
To probe the proposed formation and cyclization of the
key intermediate, cation 8, we computed the effects of tosylate
O-protonation in 1b (Figure 1).14 At equilibrium, the protonated
diastereomer 1b(H+)-fast is preferred over the slow one by 3.7
kcal/mol. Rotation about the P-C bond to give the eclipsed
conformer results in essentially barrierless formation of an
intermediate cation 8b in which HOTs is dissociated and
PHMes* semi-bridges the two carbon atoms; a transition state
for HOTs dissociation could not be located. As in the O-
these
observations
enabled
determination
of
the
stereochemistry of cyclization by correlating the absolute
configurations of the tosylate intermediates and phosphirane
products. After KR processes resulted in complete
consumption of 1b/e-fast or 4-fast, the slow diastereomers
were separated from phosphiranes 2b/e or 5 and isolated
directly (1b-slow), or after oxidation (H2O2) with retention of P-
configuration (6b/e-slow or 7, Scheme 3).3a The crystal
structures of the secondary phosphine oxides 6e-slow and 7-
slow•H2O,7a along with NOESY studies of these oxides and of
1b-slow, established their absolute configurations and, by
2
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10.1002/anie.201801427
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protonated precursors, the cation 8b formed from 1b-fast is
more stable than the slow one.
staggered
eclipsed
H
Mes*
Mes*
H
H
H
Mes*
R
rotate
AX
Mes*
Mes*
P
R
P
P
P
P
R
R
R
H
H
HX
AOTs
H
H
H
1-slow
H
anti-2
X
9
X
OTs
H+-mediated
OTs
SLOW
FAST
HX
HX
8
P-epimerization
Mes*
H
R
Mes*
H
Mes*
R
Mes*
H
P
P
P
P
P
AX
R
R
R
H
Mes*
rotate
H
H
OTs
H
HX
syn-2
H
1-fast
X
X
AOTs
O
S
X A
Ar
hyperconjugation-
stabilized carbocation
(preferred conformation)
P-inversion
1-fast syn-2
1-slow anti-2
O
acid-promoted
tosylate dissociation
O
Scheme 5. Proposed Mechanism and Stereochemistry of syn-Phosphirane Formation (AX = Brønsted/Lewis acid, such as HOTs or LiCl)9
3.4
‡
3.7
0.0
1.4
‡
1b(H+)-fast
cyclization
transition state
-
-
4.1
1b(H+)-fast
staggered
6.5
8b-fast
eclipsed
-
9.2
syn-9b
-
10.9
Figure 1. Structures (for the fast diastereomers) and energies for staggered and eclipsed conformers of 1b(H+)-fast (black) and 1b(H+)-slow (blue) and transition
states for their conversion via cations 8b to syn-9b (black) and anti-9b (blue) with inversion at P. Mes* C-H atoms are omitted.
NBO studies revealed details of the bonding in staggered
and eclipsed cations 8b. The Natural Localized Molecular
Orbitals (NLMOs)15 for the P lone pair (Plp) showed small
delocalization from the NBO reference Lewis structure (Figure
2) into the nominally vacant Cb(p)-orbital (row A), and
significant hyperconjugative delocalization from P-Ca(s) into
Cb(p) (row B), consistent with NBO orbital occupancies and
Wiberg Bond Indices (WBI: row C). Comparison of NBO
occupancies and WBIs for intermediate conformers reveals
less electron depletion of Plp and the P-Ca(s) bond with
correspondingly lower population of Cb(p) in staggered 8b (row
D) than in eclipsed 8b (row C). In addition, small
delocalizations from P-H and P-Mes* s-bonds contribute to the
greater stability of the eclipsed conformer.
the transition states shown in Figures 1-2. The transition state
formed from 8b-fast involves contraction of the Ca-Cb-P angle
(95.1°®77.1°), and opening of the Mes*-P-H angle
(101.8°®117.0°), consistent with evolution of the P lone pair
into the nascent P-Cb s-bond with inversion at P. Loss of HOTs
from phosphiranium cation 9b to give syn-2b is downhill by 7.5
kcal/mol, consistent with experiment, where protonated
phosphiranes 9 were not observed. Finally, the proposed
kinetic origin of syn-selectivity agrees with the computed
energies of the products; both anti-2b and protonated [anti-
9b][OTs] are more stable than the syn- isomers, by 1.3 and 1.7
kcal/mol respectively. The thermodynamic preference for
1b(H+)-fast in the Curtin-Hammett equilibrium (Figure 1),
coupled with a lower energy pathway for its cyclization via the
energetically preferred cation 8b-fast, provides a rationale for
Both eclipsed cations 8b-fast and 8b-slow undergo low
energy ring closure to give the protonated phosphirane 9b via
3
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21
reactions is rare.
Chiral phosphiranes are especially
unusual, 22 so our convenient new one-pot synthesis is
Intermediate
Transition State
23
potentially useful
for expanding their currently limited
24
, 25
applications in asymmetric catalysis.
We are now
investigating this possibility, as well as the intriguing role of Li+
and other Lewis acids in mediating phosphirane formation.
A
B
Acknowledgements
We thank the US National Science Foundation for funding
(CHE-126578, -1562037, and -1011887) and the US
Department of Education (GAANN, TWC and JAM), Dartmouth
College (MMD), and the Rosztoczy Foundation (AME) for
fellowship support.
C
D
Keywords: nucleophilic substitution • stereochemistry •
mechanism • phosphirane • P-stereogenic
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the observed syn-selectivity, which might also be promoted by
dispersive attractions with the Mes* group.16
In conclusion, we have reported stereochemical behavior
new for phosphines, with inversion of configuration at
phosphorus in nucleophilic substitution. The difference from
textbook examples showing retention of configuration at the
nucleophile is the formation of a small ring, for which the
normal linear SN2 transition state is inaccessible, as in the
proposed inversion of configuration at a nitrogen nucleophile
via an unobserved azetidinium intermediate. 17 While inversion
at nitrogen is facile, the high barrier in phosphines makes our
observations remarkable. Figures 1 and 2 show how inversion
can be promoted. Cation 8b is hyperconjugatively stabilized by
[5]
[6]
Quenching with NH4Cl instead of TsCl yielded the alcohols
Mes*HPCH2CH(R)(OH) (10). Styrene oxide gave a second minor set
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of the anti-phosphiranes were observed in some reaction mixtures. c)
Racemic phosphirane 2b (R = Me) was prepared earlier as a syn-anti
mixture: T. Oshikawa, H. Yamashita, Synthesis 1985, 290-291.
a) CCDC 1571673-1571677 (b) Repeating the synthesis of racemic
anti-2a (M. Yoshifuji, K. Toyota, N. Inamoto, Chem. Lett. 1985, 14,
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[7]
[8]
PHMes*
stereochemical information from the chiral epoxide precursor,
which would otherwise be lost in conventional SN1
semi-bridging
both
carbons,
preserving
a
intermediate. The preferred conformation of this cation dictates
evolution of the rear lobe of the P lone pair into the new P–C
bond in the transition state, thereby providing energetic
compensation to circumvent the normally high barrier to
inversion at P.
Besides its fundamental importance, the unusual
stereochemistry of P–C bond formation controls selectivity in
formation of P-stereogenic chiral phosphiranes. 18 Although
phosphiranes have unique stereoelectronic properties, with
smaller cone angles and higher P-inversion barriers than their
acyclic analogs, and are thought to be poorer s-donors and
better π-acceptors,19 their use as ligands20 in metal-catalyzed
[9]
For convenience, epoxides, phosphiranes 2, and intermediates are
drawn with the same absolute configuration. See the Supporting
Information (SI) for details of the absolute configurations of specific
epoxides, intermediates and products.
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Am. Chem. Soc. 2014, 136, 4865–4868. d) Slow P-epimerization
4
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would result in the observed KR. With the high sensitivity of this
process to reaction conditions, we have not attempted to model the
origin of KR and instead focus here on the mechanism and
stereochemistry of the key cyclization step.
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or Lewis acid binding, at O or at P was reversible, but cyclization was
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Lewis acid-base adducts) could evolve to yield the observed products.
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of
4 and IsPCH2CHMe (19:1 syn/anti) from IsPH2. For more
information on the scope of the phosphirane synthesis, see the SI.
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5
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10.1002/anie.201801427
Angewandte Chemie International Edition
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Jake A. Muldoon, Balázs R. Varga,
Meaghan M. Deegan, Timothy W.
Chapp, Ádám M. Eördögh, Russell P.
Hughes,* David S. Glueck,* Curtis E.
Moore, and Arnold L. Rheingold
H
Mes*
P
P
R
H
OTs
inversion at the
P-nucleophile
Mes*
R
H
HOTs
syn
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Nucleophilic substitution results in inversion (SN2) or racemization (SN1) at the
electrophile, but what about the nucleophile? P-stereogenic phosphines act as
nucleophiles with retention of P-configuration. In the first reversal of this paradigm,
we report intramolecular nucleophilic substitution with inversion at phosphorus as the
key step in controlling the diastereo- and enantioselective synthesis of P-stereogenic
syn-phosphiranes.
Inversion of Configuration at the
Phosphorus Nucleophile in
Diastereoselective and
Enantioselective Synthesis of P-
Stereogenic syn-Phosphiranes from
Chiral Epoxides
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