Asymmetric organocatalytic electrophilic phosphination

Article abstract of DOI:10.1002/anie.201007188

Meeting the challenge: The first asymmetric catalytic C*-P bond formation employing electrophilic phosphorus compounds has been developed using a catalytic amount of a dimeric cinchona alkaloid, and a subsequent one-pot process to deliver high stereoselectivities and good yields of α-quaternary α-phosphino β-amino acids (see scheme). ³¹P-NMR experiments suggest a novel reaction mechanism wherein a cinchona alkaloid nucleophilically activates the phosphorus electrophile. Copyright

Full text of DOI:10.1002/anie.201007188

DOI: 10.1002/anie.201007188
Asymmetric Synthesis
Asymmetric Organocatalytic Electrophilic Phosphination**
Martin Nielsen, Christian Borch Jacobsen, and Karl Anker Jørgensen*
The asymmetric incorporation of phosphorus-containing
groups into target molecules is an important goal in diverse
areas of synthetic chemistry. Organophosphorus compounds
are used in various fields such as the synthesis of natural
products[1] and their analogues,[2] ligands in organometallic
catalysis,[3] organocatalysis,[4] and in general synthetic chemis-
try.[5] Hence, the development of asymmetric organocatalytic
approaches towards optically active organophosphorus mol-
ecules is highly important.[6] A synthetic limitation is that
previously the asymmetric catalytic formation of stereogenic
turned our attention to the use of cinchona alkaloids.
Pleasingly, using a stoichiometric amount of (DHQD)2PYR
(5; Table 1) led to a 77% conversion within 30 minutes under
ambient reaction conditions. However, only traces of 3 were
formed when 0.1 equivalent of 5 was employed, which was
attributed to the protonation of the catalyst. We anticipated
that this problem could be solved by employing a base
capable of scavenging the acid. Indeed, the addition of an
excess of proton sponge (1,8-bis(dimethylamino)naphtha-
lene)[13] when using 10 mol% of 5 led to full conversion after
6 hours under ambient reaction conditions.
Having established a catalytic system, extensive screen-
ing[12] resulted in the development of the reaction shown in
Table 1, in which step a with subsequent oxidative protection
of the phosphine (step b), nitrile reduction, and then N pro-
tection (step c),[14] provided highly enantioenriched 4 (up to
93% ee) in good yields (> 85% for each reaction step). The
scope of this reaction was studied by carrying out a range of
reactions, in which both the R and the ester substituents in 1,
and the aryl substituents in 2 were varied (Table 1). All the
yields reported in Table 1 are for the formation of 4 from 1,
and are thus the result of four steps performed in a one-pot
fashion.
À
carbon centers bonded to phosphorus (C* P) has only been
performed using nucleophilic phosphorus compounds.[7]
À
Herein we present the first asymmetric catalytic C* P bond
formation employing a phosphine electrophile. By reacting a-
substituted cyanoacetates (1)[8] with diaryl phosphine chlo-
rides (2) under organocatalytic conditions,[9] optically active
a-phosphinated cyanoacetates (3), which contain a stereo-
genic quaternary carbon center, are obtained (Scheme 1).
Initially, it was shown that employing either
(DHQD)2PYR (5) or (DHQ)2PYR (dihydroquinine 2,5-
diphenyl-4,6-pyrimidinediyl diether, 5’) as catalysts gave
similar results for the formation of 4a and ent-4a (Table 1,
entries 1 and 2). Therefore both enantiomers of the a-
quaternary a-phosphino b-amino acids (4) are accessible,
thus increasing the synthetic value of this reaction. A careful
investigation of bases and other additives revealed that in
order for the reaction to proceed, the proton sponge is
necessary. An acceptable reaction rate was observed when the
reaction was run using 5 equivalents of the proton sponge at
À408C. The reaction also proceeded with a lower amount of
proton sponge; at À208C the reaction of 1a’ with 2a (in
reference to entry 11 in Table 1) proceeded to full conversion
with 3 equivalents of the proton sponge to provide the adduct
with a slight decrease in enantioselectivity (82% ee, see the
Supporting Information).
These initial observations were followed by an investigat-
ion into the range of different aryl groups in 2 that could be
tolerated in this reaction (Table 1, entries 1, 3, and 4).
Substituents in both the 4- and 3-positions were well tolerated
and the products were isolated with yields ranging from 52 to
55% and enantioselectivities from 88 to 92% ee. Also, the
presence of an electron-donating group, for example in the
form of a methoxy group in the 4-position, led to a smooth
reaction, giving 4c in a 54% yield with an 88% ee (entry 4).
Unfortunately, electron-withdrawing groups were found to be
unsuitable and led to degradation reactions during step b.
Scheme 1. One-pot electrophilic phosphination and formation of a-
quaternary a-phosphino b-amino esters 4 by an asymmetric organo-
catalytic key step. Boc=tert-butoxycarbonyl.
Furthermore, 3 is transformed into protected chiral a-
quaternary a-phosphino b-amino acids[10] (4) by using a one-
pot procedure. This class of compounds might also be
regarded as precursors for novel P,N ligands.[3f]
Initially, we focused on the formation of a-phosphinated
cyanoacetates (3), in which an equivalent of HCl is produced
during the course of the reaction. Previously, phase-transfer
catalysis (PTC) has been shown to be a useful protocol for this
type of reaction.[11] However, several attempts using PTC
failed to produce any traceable amounts of 3.[12] We therefore
[*] Dr. M. Nielsen, C. B. Jacobsen, Prof. K. A. Jørgensen
Center for Catalysis, Department of Chemistry, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
[**] This work was made possible by grants from the Carlsberg
Foundation and OChemSchool. The authors are grateful to Dr.
Jacob Overgaard for X-ray crystallographic analysis and to Erik Daa
Funder for fruitful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007188.
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Table 1: One-pot formation of a-quaternary a-phosphino b-amino acids 4 by
reaction of 1 with 2 catalyzed by 5 and subsequent transformations.[a]
Scheme 2. The reduction of 4a to 4a’ (bottom) and of 4c to 4c’ (top).
Crystal structure analysis was performed on 4c’.
subsequent borane protection of the trivalent phosphine was
performed. This led to 4a’ in a 41% yield over the three steps,
and, more importantly, the enantiomeric excess was main-
tained at 92% ee.
Entry 1 (R)
2 (Ar)
Overall
Yield
ee
[%][c]
We were surprised that the reaction did not proceed under
PTC conditions. This observation led us to speculate whether
the catalyst partially functions by nucleophilic activation of
[%][b]
1
1a (Pr)
1a
1a
2a (Ph)
2a
2b (4-MeC6H4)
55 (4a)
52 (ent-4a) 93
52 (4b)
92
2[d]
3
2,[16] which would lead to an activated intermediate containing
92
88 (R)
87
93
92
92
85
92
90
[17]
À
an ammonium-ion-based N P bond.
4
1a
2c (3,5-Me2-4-MeOC6H2) 54 (4c)
31P NMR measurements were performed to obtain more
information on the reaction mechanism (Figure 1). When the
31P NMR spectrum of 2 (Figure 1, spectrum a) is compared
with those of mixtures of 2 with quinuclidine and with 5
5
6
7
8
1b (Me)
1c (Et)
1d (Hex)
1d
2a
2a
2a
2b
56 (4d)
60 (4e)
53 (4 f)
54 (4g)
46 (4h)
36 (4i)
41 (4j)
9
1e (MeOCH2CH2) 2a
10
1 f (Bn)
2a
2a
11[e]
1a’[e]
[a] All reactions were performed in one pot. Reaction conditions: a) 1
(0.25 mmol), 2 (1.5 equiv), 5 (0.10 equiv), and proton sponge (5.0 equiv) in
CHCl3 (0.25 mL) at À408C; b) tBuO2H (5.5m in decane, 3.9 equiv) at 08C to
RT; c) NiCl2·6H2O (4.0 equiv), Boc2O (2.6 equiv), and NaBH4 (until reaction
is considered complete by thin-layer chromatography) in MeOH at 08C to
RT. [b] Yield of 4 isolated from 1. [c] Determined by HPLC analysis using a
chiral stationary phase. [d] Catalyst: 5’. [e] 1a’ is the corresponding ethyl
ester of 1a (i.e. nBu is replaced by Et). Ar=aryl, Bn=benzyl.
By varying the R substituent in 1, the reaction was shown
to be unaffected by the length of the aliphatic chain, with
enantioselectivities of 87–93% ee and yields of 52–60%
(Table 1, entries 1 and 5–7). The only minor outlier is the
methyl substituent that led to 87% ee (Table 1, entry 5). An
ether group (1e) led to slightly inferior results with 4h being
isolated with an 85% ee and a 46% yield (Table 1, entry 9). A
benzyl group (1 f) led to 4i being isolated in 36% yield
(corresponding to a 77% yield for each reaction step) and a
92% ee (Table 1, entry 10). Changing the n-butyl ester to an
ethyl ester gave 4j in a 41% yield with 90% ee (Table 1,
entry 11), thus showing that the reaction is unaffected by the
aliphatic ester moiety employed.
Figure 1. 31P NMR investigations: a) 2, b) mixture of 2 with quinucli-
dine, c) mixture of 2 with 5, d) standard reaction at room temperature
after 10 min, e) standard reaction at room temperature after 6 h,
f) standard reaction with excess of 1 at room temperature after
10 min, g) standard reaction with excess of 1 at room temperature
after 3 h. All solutions were at 1m concentration.
The absolute configuration was determined to be R by X-
ray crystal structure analysis of the reduced alcohol derivative
of 4c (Scheme 2, top; also see the Supporting Information).[15]
To enhance the developed reaction, the concomitant
reduction of the ester and phosphine oxide in 4, with a
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(Figure 1, spectrum b and c, respectively), two new signals
(d = 36 and 37 ppm) are seen, indicating that a new species is
formed (6). To verify that this species is also present during
the reaction of 1 with 2 when it is catalyzed by 5, 31P NMR
spectra of the crude reaction mixture were measured after
10 minutes and after 6 hours (Figure 1, spectrum d and e,
respectively), by which time the full conversion of 1 was
observed. As expected, over time the signal for 2 decreased in
intensity and the signal for 3 (d = 18 ppm) increased. The
peaks assigned to the intermediate 6 (see Scheme 3 for the
structure) were seen throughout the course of the reaction, as
anticipated when using an excess of 2 (1.5 equiv) in this
reaction. To verify that intermediate 6 is not a “parasitic” or
“benign” species, the reaction between 1 and 2 using an excess
of 1, was performed. Under these conditions, the peaks
assigned to 6 were observed after 10 minutes (Figure 1,
spectrum f). However, as the reaction proceeded these
peaks decreased in intensity and disappeared after 3 hours
(Figure 1, spectrum g) by which time the full conversion of 2
was observed. The fact that this only occurred when using an
excess of 1 suggests that 6 is involved in the catalytic cycle. If 6
was degraded by other mechanisms, its disappearance would
also have been expected under the standard reaction con-
ditions, which use an excess of 2.
mechanism constitutes, according to our knowledge, the first
example of a cinchona alkaloid catalyzed enantioselective
nucleophilic activation of a substituted electrophile directly
on the reactive center.[20]
In conclusion, we have demonstrated the first asymmetric
À
catalytic C* P bond formation employing electrophilic
phosphorus compounds. By applying catalytic amounts of
(DHQD)2PYR) in combination with the proton sponge and a
subsequent one-pot process, a-quaternary a-phosphino b-
amino acids were synthesized with high stereoselectivities and
good yields. These compounds were also subjected to further
transformations. A range of 31P NMR experiments allowed us
to propose a novel reaction mechanism with a cinchona
alkaloid catalyzed nucleophilic activation of the phosphorus
electrophile.
Received: November 16, 2010
Published online: February 21, 2011
Keywords: asymmetric synthesis · organocatalysis ·
.
phosphorus · synthetic methods
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À
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À
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