Enantioselective synthesis of phospholenes via asymmetric organocatalytic alkene isomerization

Article abstract of DOI:10.1002/adsc.200800226

An asymmetric synthesis of the 2,5-diphenylphosphol-2-ene fragment (≥95% ee) has been realized via enantioselective Cinchona-alkaloid catalyzed double bond isomerization of a meso-2,5-diphenylphosphol-3-ene amide to a 2,5-diphenylphosphol-2-ene amide (up to 83% ee), followed by enantiomeric enrichment to ≥95% ee by crystallization. The 2,5-diphenylphosphol-2-ene amide (a cyclic phosphinic acid amide) was hydrolyzed to the 2,5-diphenylphosphol-2-ene acid (a cyclic phosphinic acid) with retention of configuration at C-5.

Full text of DOI:10.1002/adsc.200800226

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DOI: 10.1002/adsc.200800226
Enantioselective Synthesis of Phospholenes via Asymmetric
Organocatalytic Alkene Isomerization
Lukas Hintermanna,* and Marco Schmitza
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-(0)241-80-92391; phone: (+49)-(0)241-80-90283; e-mail: lukas.hintermann@oc.rwth-aachen.de
Received: April 14, 2008; Published online: June 13, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An asymmetric synthesis of the 2,5-diphe-
nylphosphol-2-ene fragment (ꢀ95% ee) has been
realized via enantioselective Cinchona-alkaloid cat-
alyzed double bond isomerization of a meso-2,5-di-
phenylphosphol-3-ene amide to a 2,5-diphenylphos-
phol-2-ene amide (up to 83% ee), followed by enan-
tiomeric enrichment to ꢀ95% ee by crystallization.
The 2,5-diphenylphosphol-2-ene amide (a cyclic
phosphinic acid amide) was hydrolyzed to the 2,5-
diphenylphosphol-2-ene acid (a cyclic phosphinic
acid) with retention of configuration at C-5.
tion with chiral lithium amides and an electrophilic
quench was possible.[8]
We now present a catalytic asymmetric synthesis of
phospholenes that relies on the new concept of orga-
nocatalytic enantioselective double-bond isomeriza-
tion.[9] This chemistry represents another extension of
organocatalysis towards a reaction type that has pre-
viously been associated with the field of metal cataly-
sis.[10,11] For realizing an efficient asymmetric synthesis
of phospholane acid 1, the catalytic asymmetric iso-
merization of meso-phospholane
4 to enriched
AHCTREUNG
Keywords: alkaloids; alkenes; asymmetric catalysis;
Cinchona alkaloids; isomerization; phosphorus het-
erocycles
since it would convert the existing efficient synthetic
sequence[3] into an asymmetric catalytic one
(Scheme 2, a).
Initial experiments showed that such a process is
difficult to realize because it requires strongly basic
reaction conditions that are difficult to achieve with
usual types of chiral base catalysts.[12] On the other
Enantiopure phospholanes are building blocks in the hand, the meso-phospholene 3, which is the initial
synthesis of chiral 2,5-dialkylphospholane ligands that
find widespread use in asymmetric transition metal-
catalyzed hydrogenation and other reactions.[1] Limi-
tations in synthetic methodology had prevented the
access to 2,5-diarylphospholanes, until Fiaud and co-
workers presented a synthesis and resolution of rac-
2,5-diphenylphospholanic acid (Æ)-1[2,3] via the Mc-
Cormack reaction of 1,4-diphenyl-1,3-butadiene (2)
(Scheme 1).[4] The resolved acid 1 is the starting mate-
rial for the synthesis of a number of 2,5-diphenylphos-
pholane ligands that have already proved successful
in various transition metal-catalyzed asymmetric reac-
tions and other applications.[3,5,6]
The procedure of Scheme 1 requires stoichiometric
quantities of chiral resolving agents and obviously
yields a maximum of 50% for each enantiomer of 1.
An attempt to convert this route to an enantioselec-
tive synthesis via sparteine/sec-BuLi deprotonation/re-
protonation of meso-1,2,5-triphenylphospholane oxide
suffered from low yields or selectivities,[7] even
Scheme 1. Fiaudꢀs route (R=Me) to 2,5-diphenylphospho-
though a corresponding a-alkylation via deprotona- lanic acid 1.[3]
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Lukas Hintermann and Marco Schmitz
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ourable background reaction, which we ascribed to
simple base catalysis. In fact, the isomerization of 3b
to 6 was also catalyzed by the amidine base DBU
(1,8-diazabicycloACHTRE[UNG 5.4.0]undec-7-ene) (Table 2, entry 1).
This observation led to the development of an orga-
nocatalytic enantioselective double-bond shift for the
desymmetrization of phospholene 3b. A screening of
chiral amine bases revealed that amino alcohols and,
among them particularly the Cinchona alkaloids
(Figure 1) were suitable catalysts for the desired
asymmetric catalysis (Table 2, entries 2–8). For con-
venience, initial experiments were carried out in an
NMR tube in CDCl3. The conversion was readily ob-
served by NMR spectroscopy. Even more convenient-
ly, the addition of an excess of quinine to the catalysis
mixture (irrespective of the initial catalyst) gave two
Scheme 2. Desirable desymmetrization reactions of meso-
phosphacycles. a) cis-trans isomerization of a trans-trans-
meso-phospholane. b) Isomerization of a meso-3-phospho-
lene to a chiral 2-phospholene.
product of the McCormack reaction in the Fiaud se- distinct 31P NMR resonances for the enantiomers of
quence (Scheme 1),[3] bears activated allylic C H 6; thus, the quinine served as a chiral shift reagent
À
bonds that should be more susceptible to catalytic (Figure 2, left).[16,17] Presumably, the alkaloid forms
transformations. In fact, we find that the 3-phospho- diastereomeric complexes via hydrogen bonding of its
lene amide 3b undergoes an irreversible double-bond alcoholic hydroxy proton to the P=O double bond
shift to the conjugated chiral 2-phospholenamide 6 (Figure 2, right). Purified samples of 6 were also read-
(Scheme 2. b).[13] This alkene isomerization is cata- ily analyzed by chiral HPLC.[18]
lyzed either by transition metal complexes or Brønst-
An initial screening of catalysts in CDCl3 solution
ed bases (vide infra). In a first set of experiments, 3b (Table 2, entries 2–8) led to identification of cincho-
was submitted to the action of hydride-activated com- nine (CN) as the most selective catalyst. In a second
plexes NiX2(Me-DuPHOS) (Table 1, entries 1 and 2) step, several reaction media were tested (entries 9–
that have already been used as catalysts in asymmet- 13). Dipolar aprotic solvents gave the best results
ric olefin isomerization by Frauenrath and co-work- both in terms of selectivity and activity, and acetoni-
ers.[14] No enantioselectivity was observed in the iso- trile was favoured due to its volatility. The Cinchona
merization to 6 for either the chloride- or iodide-con- alkaloids were more selective catalysts in this solvent
taining catalyst, but when the corresponding hydride (entries 14–17). Additional studies of the reaction
activated complexes NiX
inductions of up to 38% ee were achieved (Table 1, the temperature and the substrate dilution (Table 3).
entries 3–7). Catalyst loadings of 10% were efficient, and even
(JOSIPHOS)[15] were used, conditions included variations of the catalyst loading,
2ACHTREUNG
In the course of these experiments, we noted that loadings of 5% gave satisfactory results (entries 5, 9,
an excess of the hydride activator induced an unfav- 11, 13, 16). The substrate concentration was set to
Table 1. Transition metal-catalyzed asymmetric isomerization of 3b to 6.[a]
Entry
Ligand[b]
X
Solvent
T [8C]
Time [h]
Conversion [%][c]
ee [%][c]
1
2
3
4
5
6
7
C
Cl
I
Cl
Cl
Cl
I
THF
PhMe
THF
THF
THF
THF
THF
r.t.
r.t.
50
50
0
30
5
5
50
5
20
51
33
88
29
58
54
>99
98
0
0
19
12
38
0
-
-
(2R)
(2R)
(2R)
-
50
0
I
0
-
[a]
Conditions: 0.1 mmol 3b, 5 mol% of catalyst, 1 mL solvent. The Ni complex was activated with a co-catalytic (5 mol%)
amount of LiBH(s-Bu)3 solution prior to substrate addition.
See Figure 1 for ligand structures.
Conversion and ee (Æ1%) determined by HPLC (Supporting Information).
AHCTREUNG
[b]
[c]
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Enantioselective Synthesis of Phospholenes
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Table 2. Amine-catalyzed asymmetric isomerization of 3b to 6.[a]
Entry
Catalyst[b]
A
Solvent
T [8C]
Time [h]
Conversion [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
DBU100
QN
QD
CN
CD
(À)-NME
(2S)-DPP
l-proline
CN
CN
CN
CN
CN
QN
QD
CN
CD
55
50
50
50
50
70
70
70
50
50
50
50
50
50
50
50
50
16
16
16
16
16
16
16
18
24
24
24
24
24
16
16
16
16
90
35
47
76
49
6
12
78
3
30
30
30
30
10
10
30
30
30
30
30
20
10
10
10
10
CDCl3
16
31
59
39
33
26
15
44
53
72
50
72
30
40
71
62
(5S)
(5R)
(5R)
(5S)
(5S)
(5R)
(5S)
(5R)
(5R)
(5R)
(5R)
(5R)
(5S)
(5R)
(5R)
(5S)
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CD3CN
PhMe
PhCl
9
98
10
11
12
13
14
15
16
17
>99
>99
>99
>99
81
91
98
79
MeCN
THF
DMF
MeCN
MeCN
MeCN
MeCN
[a]
Conditions: 0.1 mmol of 3b, 1 mL solvent (c=0.1M).
CN=cinchonine; CD=cinchonidine; QN=quinine; QD=quinidine; NME=N-methylephedrine; DPP=diphenylproli-
[b]
nol; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
AHCTREUNG
[c]
[d]
1
The conversion was determined by H NMR.
The ee was determined by 31P NMR in CDCl3 with quinine as chiral shift reagent (accuracy Æ5%).
0.1M, since this assures dissolution of the alkaloid 16), but the reaction time was considerably reduced.
catalyst; further dilution had no marked beneficial Under optimized conditions, the pseudo-enantiomeric
effect. It was possible to replace part of the acetoni- catalyst cinchonidine (CD) gave (1S,5S)-6 in similar
trile by dichloromethane to assure dissolution of the enantioselectivity (entry 7).
catalyst in smaller reaction volumes, without loss of
A set of robust reaction conditions emerged from
selectivity (entry 3). The enantioselectivity of the re- this screening (MeCN, 0.05–0.10M, 5–10 mol% of cin-
action was not markedly lowered upon increasing the chonine, 508C) that regularly gave the product
reaction temperature to as high as 908C (entries 8– (1R,5R)-6 in an enantiomeric excess of 82–83% on
preparative scale (5 g). After evaporation of the sol-
vent, the reaction product was separated from the cat-
alyst by a simple acid wash, with no additional purifi-
Figure 2. Left: In situ enantiomer analytics of 6 by 31P NMR
spectroscopy (CDCl3) with quinine in CDCl3 [er=69.6:30.4,
Figure 1. Catalysts and ligands tested in the catalytic isomer-
ization reaction of 3b to 6.
ee=39% (2R)]. Right: Proposed complexation of quinine to
phospholene 6.
Adv. Synth. Catal. 2008, 350, 1469 – 1473
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1471

Lukas Hintermann and Marco Schmitz
Table 3. Chincona alkaloid-catalyzed isomerization of 3b to 6 in MeCN: temperature and concentration effects.[a]
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Entry
Catalyst
[mol%]
Dilution [L·molÀ1]
T [8C][b]
Time [h]
Conversion [%][c]
ee [%][c]
1
2
2a
3[e]
4[f]
5
7
8
9
10
11
12
13
14
15
16
CN
CN
CN
CN
CN
CN
CD
CN
CN
CN
CN
CN
CN
CN
CN
CN
10
10
10
10
10
5
10
10
5
10
5
10
5
10
20
20
50
50
50
50
50
50
50
60
60
70
70
80
80
90
90
90
16
16
16
16
4
22
40
7.5
16
5
6
3
4
1.5
3
>99
>99
>99
>99
59
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
79
80
83[d]
80
78
78
72
78
76
77
75
75
74
73
75
74
(5R)
(5R)
(5R)
(5R)
(5R)
(5R)
(5S)
(5R)
(5R)
(5R)
(5R)
(5R)
(5R)
(5R)
(5R)
(5R)
10+1.6[e]
10
20
10
10
10
10
10
10
10
10
10
5
10
20
20
3.5
[a]
Conditions: 0.1 mmol substrate in MeCN; closed vessels under argon.
Temperature of the oil bath. Reactions at 80 or 908C may build up pressure.
[b]
[c]
[d]
[e]
[f]
Conversion and ee determined by chiral HPLC (accuracy Æ1%), see Supporting Information.
Large scale reaction (5 g of 3b).
Reaction in a mixed solvent MeCN/dichloromethane.
Reaction with microwave heating.
cation needed. Both the acetonitrile solvent and the hydrogenation to Fiaudꢀs cyclic phosphinic acid 1 will
catalyst are readily recycled.[19] Importantly, the enan- be of particular interest.[20]
tiomeric excess of the phospholenamide 6 was in-
In conclusion, we have presented both a metal-cata-
creased to ꢀ95% by a single crystallization from ace- lyzed and a superior organocatalytic asymmetric
tone and hexanes (Scheme 3). Acidic hydrolysis of 6 double-bond isomerization of achiral meso-3-phos-
gave the new 2-phospholenic acid 7. We are currently pholene 3b to the chiral 2-phospholene 6 with high
investigating uses of acid 7 as a chiral Brønsted acid enantioselectivity. This new asymmetric catalytic pro-
catalyst[11] and as a synthetic precursor of phospho- cess opens the way to a catalytic enantioselective syn-
lane ligands; in this connection, the stereoselective thesis of 2,5-diarylphospholane building blocks for ap-
plications as catalysts, chiral auxiliaries or ligands in
transition metal catalysis.
Experimental Section
Typical Procedure
To a solution of meso-phospholene 3b (5.00 g, 15.35 mmol)
in acetonitrile (300 mL) at 508C, cinchonine (0.452 g,
1.535 mmol, 10 mol%) was added and the mixture stirred
for 22 h at 508C. The solvent was evaporated at room tem-
perature, and the residue taken up in EtOAc (200 mL).
After washing with aqueous HCl (2M; 2”30 mL) and water
(50 mL), the organic phase was dried over MgSO4, filtered,
and the solvent evaporated to leave (1R,5R)-6 as slightly
yellow solid; yield: 4.89 g (98%); ee 83% (HPLC).
Scheme 3. Conversion of amide 6 to acid 7. Optical rotation
signs refer to both CH2Cl2 and MeOH solution.
Crystallization: A sample of 6 (0.300 g; 80% ee) was dis-
solved in acetone (20 mL) and the solution overlayered with
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Enantioselective Synthesis of Phospholenes
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hexanes (20 mL). After standing for 16 h at À108C, the
solid (racemate) was filtered off and the filtrate evaporated
to leave (1R,5R)-6; yield: 0.213 g (71%); ee 95% (HPLC).
indenes has been observed: a) M. Aune, A. Gogoll, O.
Matsson, J. Org. Chem. 1995, 60, 1356, and references
cited therein.
[10] Metal-catalyzed asymmetric double bond isomerization
reactions: see ref.[14] and a) G. Fu, in: Modern Rhodi-
um-Catalyzed Organic Reactions, (Ed.: P. A. Evans)
Wiley-VCH, Weinheim, 2005; b) S. Akutagawa, Topics
in Catalysis 1997, 4, 271; c) S. Otsuka, K. Tani, Synthe-
sis 1991, 665.
Supporting Information
Experimental procedures, characterization data and NMR
spectra of compounds 3b, 6, 7. Conditions for chiral HPLC
and NMR analyses are given as Supporting Information.
[11] Other reactions that have been typically associated
with metal catalysis include the hydrogenation of
imines or conjugated alkenes with Hantzsch ester in
the presence of chiral Brønsted acids, see, e.g.: a) M.
Rueping, E. Sugiono, C. Azap, T. Theissmann, M.
Bolte, Org. Lett. 2005, 7, 3781 and subsequent works;
b) S. Hoffmann, A. Seayad, B. List, Angew. Chem.
2005, 117, 7590; Angew. Chem. Int. Ed. 2005, 44, 7424
and subsequent works; c) R. I. Storer, D. E. Carrera, Y.
Ni, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128,
84 and subsequent works.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (Emmy
Noether Programm), the Fonds der Chemischen Industrie
and Prof. Carsten Bolm, RWTH Aachen, for continued sup-
port.
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Adv. Synth. Catal. 2008, 350, 1469 – 1473
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