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Chiral Phosphanyldihydrooxazoles in Asymmetric Catalysis Enantioselective Heck Reactions.

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Nielsen, AIDS 1989.3. 635-~641;
A. Kobata, Alfred Benron Symp. 1994. 36,
246-256,J.-E. S. Hansen, H . Clausen. T. Ssrensen, T. White, H.H.Wandall,
ibid. 1994,36,297-310;J.-E. S.Hansen, B. Hofmann, T. Ssrensen, H . Clausen.
ihirl. 1994. 36. 414-427, and references therein.
[3] T. Mizuochi. M. W. Spellman. M. Larkin. J. Solomon, L. J. Basa, T. Feizi,
Biochern. .I 1988,254, 599-603.
[41 H . Lis, N.Sharon, J. B i d . Cliern. 1978.253,3468:E.Li, S.Kornfeld, [hid. 1979.
254, 1600; L. Dorland, H . Ydn Halbeek, J. F. G. Vliegenthart, H . Lls. N.
Sharon. ibid. 1981,256, 7708.
[51 W E.G.Miiller, H . C. Schroder, P. Reuter, A. Maidhof. G. Uhlenbruck, 1.
Winkler, AIDS 1990,4 , 159- 162.
[61 Synthesis of major segments of high mannose glycoproteins: H. Paulsen,
Angew. Chem. 1990,102. 851 -867; Angew. Chnn. I n t . Ed. Engl. 1990,29,823.
and references therein; J. R. Merritt. E. Naisang, B. Fraser-Reid. .IOrg. Cliem.
[7l a) S. V. Ley, H. W M. Priepke, S. L. Wdrriner. Angew. Cliem. 1994,106,24102412;Angew. Chem. Int. Ed. Engl. 1994.33,2290-2292;b) S. V.Ley, H. W. M.
Priepke. ihid. 1994,106, 2412-2414and 1994.33,2292-2294; c) P. Grice, S. V.
Ley, J. Pietruszka, H . W M. Priepke, E. P. E.Walther. Synlerr 1995,781-784;
d) T. Ziegler, Angew. Chem. 1994,106,2362-2365:Angew Cliern.In(. Ed. Engl.
1994,33. 2212-2275.
[XI Preparation of building blocks with full experimental details will be reported in
due course.
[9] S.Mehtd, B. M. Pinto, J. Org. Cheni. 1993,58,3269-3276; H. M. Zuurmond,
P. H. van der Meer, P. A. M. van der Klein, G . A. van der Marel, J. H . van
Boom. J. Carholvdr. Clrem. 1993, 12, 1091-1103; G.H . Veeneman. J. H. van
Boom, Tetrahedron Lett. 1990, 31, 275-278: G . H. Veeneman. S. H. van
Leeuwen, J. H. van Boom, ibid. 1990,31, 1331-1334.
Y.-M. Zhang. A. Brodzky, P. Sinay, G. Saint-Marcoux, B. Perly. Tetruhedron:
Asjmnwtry 1995,6. 1195%1216.
2: ' H N M R (500 MHz, D,O, 297.3 K): 6 = 5.29 (s, 1 H. I-Ha). 5.22 ( s , 1 H,
I - € l J , 5.19 ( s , 1 H, l-HJ, 5.04 (s, 1 H. I-HJ. 4.93 ( s , 3H. l-Hc. I-H,, 1-HJ,
l a R =CH,
l b R = CH(CH&
1 C R = C(CH3)Z
I d R =C,Hs
l e R = CHZ(C6HS)
R = CHzCH(CH3)z
l g R = CH&(CH&
tested these ligands in intermolecular Heck reactions of cyclic
olefins. The reaction between 2,3-dihydrofuran and l-cyclohexenyl triflate, previously reported by Ozawa, Hayashi et a1.,[2b1
was chosen to screen different ligands and catalyst precursors
and to optimize the reaction conditions (Table 1). The best
enantioselectivity and also the highest catalyst activity was observed with the tert-butyldihydrooxazole derivative 1 c. With
3 mol% of catalyst, prepared in situ from [Pd(dba),]['I and
1.S-2 equivalents of ligand 1c, the 2,s-dihydrofuran derivative
2 was formed in high yield and with excellent enantioselectivity
[Eq. (a), Table 11. The corresponding 2,3-dihydrofuran deriva-
4.76(s,1H,l-H,),4.63(s,1H,l-H,),3.40-4.07(m,54H),3.29(s,3H.OCH,): +
13CNMR (100 MHz, D,O): 6 =102.2, 102.2 (2x). 100.9,100.6 (2x), 100.5.
99.4, 98.0 (anomeric C), 54.74 (OCH,); MALDI-TOF-MS: m / z : 1513
( [ M + Na]'). MALDI = matrix-supported laser desorptioniionkation. TOF
= time of flight.
[Pd(dba),] (3 mol%)
l c (6mol%)
C6H8,30 "C, 3 d
Table I . Enantioselective Heck reaction of 2,3-dihydrofuran to give (R)-2 [Eq. (a)].
re ["h]
Yield ["A] [a]
> 99
98 [bl
Chiral Phosphanyldihydrooxazoles in Asymmetric
Catalysis: Enantioselective Heck Reactions**
Olivier Loiseleur, Peter Meier, and Andreas Pfaltz*
The development of enantioselective variants of the Heck
reaction has added a new dimension to this important method
for C-C bond formation.['. 21 Excellent enantioselectivities
have been achieved and several remarkable applications in the
synthesis of complex natural products have been reported.
So far, the most effective ligand for these reactions has been
BINAP." - 31 However, the application range of Pd(B1NAP)
catalysts seems limited to certain classes of substrates and their
activity is often low. In addition, these catalysts promote C = C
bond migration which sometimes leads to useful products but
unfortunately often results in mixtures of isomers. Therefore, it
i s necessary to search for other ligands and catalysts to enhance
the scoDe of enantioselective Heck reactions.
In the course of our work on phosphanyldihydrooxazoles
1,[4-61 which have proven to be effective ligands for enantioselective Pd-t4"*'1 and W-catalyzed[61allylic substitution, we have
Prof. Dr. A. Pfaltz.[+' Dipl.-Chem. 0. Loiseleur, P. Meier
lnstitut fur Organische Chemie der Universitit
St.-Johanns-Ring 19, CH-4056 Basel (Switzerland)
New address: Max-Planck-Institut fur Kohlenforschung
Kaiser-Wilhelm-Platr I , D-45470 Mulheirn an der Ruhr (Germany)
Fax: Int. code +(208)306-2992
Financial support of this work by the Swiss National Science Foundation and
Hoffmann-La Roche AG. Basel. i s gratefully acknowledged.
VCH Verlugsgesellschuft mbH, 0-69451 Weinheim, 1996
sodium carbonate
sodium acetate
[a] Determined by GC with n-tridecane as internal standard. [b] Yield of purified
product: 92%.
tive was not detected, in contrast to the Pd(B1NAP)-catalyzed
reactionrzb1which yields the thermodynamically more stable
2,3-dihydro isomer as the main product with 5 8 % yield and
87 YO ee. With Pd(B1NAP) catalysts, 1,8-bis(dimethylamino)naphthalene (proton sponge) has to be used as base for optimum results, whereas in our case simpler bases such as triethylamine or N,N-diisopropylethylamineare equally effective. Catalysts derived from analogous ligands with less bulky substituents at the stereogenic center are significantly less reactive
and the resulting ee values are slightly lower [ Y conversion/
% ee: 97/98 for 1 c, 24/90 for 1 e, 18/95 for 1 f; proton sponge,
50 "C, other conditions, see Equation (a)].
Similar results were obtained with phenyl and l-cyclopentenyl triflate (Scheme 1). Arylation of 4,7-dihydro-I ,3-dioxepin,
which leads to a masked hydroxyaldehyde, also proceeds with
good enantioselectivity and satisfactory yield. The corresponding Pd(B1NAP)-catalyzed process[2d1 was reported to give
72 'YO ee and 84 YOyield.
The reaction was found to be highly sensitive to traces of
chloride ions and chloroform. No reaction was observed in the
presence of Et4NC1 o r with [(lc)PdCl,]/BuLi as catalyst precur-
0570-0833196i3502-0200 $ 10.00+ .25/0
Angen. Chem. I n t . Ed. Engl. 1996,35, No. 2
97% ee
THF, 70 "C. 4 d
(87% Yield)
proton sponge
CGH,, 50 "C, 3 d
92% ee
THF, 70 "C. 7 d
Scheme I [cat]
[Pd(dba),] (3 m o l % ) . I c ( 6 m o l % ) .
sor. [Pd,(dba), . CHCI,] as catalyst precursor gave lower conversion than [Pd,(dba);dba], and large fluctuations in yields and
enantiomeric excesses were observed.[8]
The low tendency of (phosphanyldihydrooxazo1e)palladium
catalvsts to Dromote C = C bond migration
allows the use of
substrates such as cyclopentene, which are converted to mixtures of isomers with P ~ ( B I N A P )catalysts (scheme 2). ~h~
product distributions are strongly dependent on the solvent and
the base. However, under optimized conditions, the desired chiral 3-substituted cyclopentene derivatives 6 and 9 are formed in
good yield and with high preference Over the corresponding
achiral isomers 7 and 10. Other isomers are formed only in trace
amounts under these conditions, in contrast to the correspond-
Experimental Procedure
(91% ee)
[Pd,(dbaL.dba] (77.5 mg. 0.135 mmol) and (-)-(S)-lc (104.6 mg, 0.270 mmol)
were placed under Ar in an ampoule equipped with a magnetic stirring bar and a
Young valve and treated with a solution of I-cyclohexenyl triflate (1.048 g,
4.55 mmol)and n-tridecane(424 mg. 2.30 mmol) as internal GC standard in Ar-sdturated benzene (10 mL). followed by 2.3-dihydrofurdn (1.35 mL. 17.9 mmol), N,Ndiisopropylethylamine (1.57 mL, Y.17 mmol), and Ar-saturated benzene (40 mL).
The ampoule was sealed under argon and the mixture stirred at 24 C (red solution.
precipitation of N.N-diisopropylethylammonium triflate) until the reaction was
complete according to GC analysis (65 h; M N Permabond ov 1701 5o m. Yo210 C. 0.7 C min-', 120 kPa: r, = 21.7 min(n-tridecane). 22.3 min(2)). The reaction mixture was diluted with pentane (ca. 150 mL) and
the resulting red suspension was filtered through a 2 cm
layer of silica gel (@ = 7 cm). Further elution with Et,O
and concentration gave a red oil which was purified by
!lash chromatography (silica gel. 4 x 25 cm; n-pentanel
CH,CI, 1 : 1) followed by Kugelrohr distillation (125'C.
12 kPa) lo afford (R)-(+ ) - 2 (629 mg. 9 2 % ) as a colorless
oil[9].[a], = +201 (c =1.06,CHCI,.24 C , 9 9 % e e b y
GC). GC (Chirdldex ;l-CD-TFA; 30 m, 80 140 ' C ,
0.3 ' C min-', 60 kPa) 29.3 min ( S ) . 30.4 min ( R ) .
96 : 4 (85% yield)
(86% ee)
99 : 1 (80%yield)
ing Pd(B1NAP)-catalyzed reactions which give complex mixtures of isomers and low er values due to extensive double bond
migration in the five-membered ring.
A mechanistic interpretation of the observed selectivities will
have to wait until more is known about the structure, relative
stability, and reactivity of the intermediates in the catalytic cycle.['l Unless we can distinguish between two possible pathways,
one involving cis the other trans coordination of the olefin and
the P atom, no meaningful mechanism of enantioselection can
be proposed.
The remarkable selectivities obtained with phosphanyldihydrooxazoles point to a considerable potential of P,N ligands of
this type for enantioselective Heck reactions. Because of the low
extent of C = C bond migration, the product distribution can
differ substantially from analogous Pd(B1NAP)-catalyzed reactions. Phosphanyldihydrooxazoles are attractive ligands because they are readily synthesized from simple precursors[4.
and because their modular structure allows extensive and independent variation of the backbone, the dihydrooxazole ring.
and the phosphane group. Thus it should be possible to improve
the catalysts described here still further by optimizing the steric
and electronic properties of the ligand.
Received: September 18. [Z8409IE]
German version: Angeir. Cheni 1996. 108.218-220
Keywords: asymmetric catalysis . dihydrooxazoles . Heck reactions palladium
catalysts . P,N ligands
(R'-BINAP (6 mol%)
(iPr),NEt. 70 "C, 6-8 d
[Pd(OAc),] (3mol%). C,H,
(6% ee)
46 : 15 : 39
(77% yield)
[Pd(dba),] (3 mol%), THF
(36% ee)
7 3 : 1 5 : 12
(80% yield)
[Pd(dba)2](3 mol%)
1c (6 mol%)
THF, 75 "C
(73% ee)
C,H6. 40 "C
(89% ee)
98 : 2
(70% yield)
Scheme 2. Heck reiictions with cyclopentene. Comparison ofligand lc with BINAP.
Angrii CYIIWI. In/. Ed Engl. 1996. 35. No. 2
VCH Vrrluggesellschufr mhH, 0-69451 Weinheitn. 1996
[I] Reviews: a) H. G Schmalz, Nudir. Cheni. f i d i . Luh.
1994,42,270: b) R. C. Larock, Adv. Met Org. Chem.
1994, 3. 97; c) A de Meijere. F E. Meyer. Angew.
Chrm. 1994. 106, 2473: Angeii.. Chen?. In!. Ed. Eng/.
1994, 33, 2379; d ) W. Cabri. I. Candiani. A < ( . Clien?.
Rex 1995. 28. 2.
[2] See for example a) Y Sato. M. Sodeoka, M.
Shibasaki, J Org Clieni. 1989, 54. 4738; K. Kondo,
M. Sodeoka. M. Mori. M. Shibasaki, Sjnthe.o.5. 1993,
920; K. Kondo. M. SodeoJa. M Shibasaki. J. Org.
Clirm. 1995, 60, 4322: b) F. Orawa, A. Kubo, T.
Hayashi, J An?. Chcni So<. 1991. 113. 1417; F. Ozawa. Y Kobatake. T Hayashi, Tetrttlirdron Letr. 1993,
34. 2505; F. Ozawa, A. Kubo. Y. Matsumoto. T.
Hayashi. E Nishioka. K . Yandgi. K. Moriguchi.
Urgunoinelu//ics 1993. f2. 4188. c.) A Ashimori. T.
Matsuura, L. E. Overman, D J. Poon. J Org Chenr.
1993, 58, 6949. L. E. Overman. Pure &pi. Ciiem.
1994, 66, 1423: d ) Y Koga. M . Sodeoka. M.
Shibasaki, Terruherlron L ~ I /1994.
35. 1227: e) L. F.
Tietze. R. Schimpf, Angeir. C/7m. 1994. 106. 1138;
Angen . C/ieni. in/. Ed. Engl. 1994. 33. 1089
0570-0X33/96/3502-0201S f0.00+.25 0
20 1
[3] BlNAP = ?.~'~bis(diplienylphosphano)-l
.l'-binaphthyl: R. Noyori. H. Takaya.
A r Chi~m.R c 1990. 33, 345
[4] a) P. von Matt. A. Pfaltz. Aiigeii.. Chrri?.1993. 105, 614: Ailgeu.. Chen?.Int. E d
EiigI. 1993. 32, 566. P. von Matt, 0. Loiseleur. G. Koch. A. Pfaltz. C. Lefeber.
T. Feucht. G Helmchen. Terruhedroii: A.?ynmierry 1994, 5, 573; b) G. Koch,
G. C. Lloyd-Jones, 0 . Loiseleur, A Pfaltz, R. PretBt, S. Schaffner, P Schnider.
1995, 114. 206.
P. von Matt, R e d Trm. Chmi. Puy~~-Bos
151 See also: a) J. Spi-inz. M. Kiefer, G. Helmchen, M. Reggelin, G. Huttner. 0.
Walter. L. Zsolnai, Terruherlron Lett. 1994.35. 1523; P. Sennhenn, B. Gabler. G .
Helmchen. ihid. 1994. 35,8595; b) G . J. Dawson. C. G. Frost. J. M. J. Williams,
S. J. Coote, ?hid. 1993, 34. 3149; G. J. Dawson, J. M. J. Williams. ihid. 1995. 36.
461; I C. Baldwin. J. M . J. Williams, R. P. Beckett, Tetruhedron: A.\wiinetry
1995. 6. 679.
[6j G . C. Lloyd-Jones, A. Pfaltz, Angeu.. Chem. 1995. 107. 534: Angel$..Chern. In/.
Ed. Engl. 1995. 34, 462.
171 [Pd,(dba),.dba]: Y. Takahashi. T. Ito, S. Sakai, Y Ishii. J. Chml. Soc Chein.
Commun. 1970,1065: T. Ukai, H. Kawazura, Y. Ishii, J. J. Bonnet, J. A. Ibers. J.
Orgunomel. Chem. 1974. 65, 253.
[XI For the effect of halide ions in Heck reactions, see for example ref. [Id]. Facile
oxidative addition of chloroform to [(diphosphane)(dba)Pd'] complexes has
been reported: W A. Herrmann. W R. Thiel. C. Brossmer. K. Ofele. T. Priermeier. W. Scherer. J Orgunorner. Chern. 1993, 461, 51.
[9] Configurational assignments: 2 and (R)-(-)-2-(l-cyclohexenyl)2.3-dihydrofurdn [2b] were converted to (R)-( +)-2-(l-cyclohexenyl)tetrdhydrofuran. (R)(+)-3:ref.[2b].(R)-(+)-4:CDcomparisonwith(R)-(
+)-2.(R)-(+)-S: ref.[2d].
(R)-(+)-6: H. B Hopps, Diss. Absrr. 1962. 23, 439.
Molecular Recognition of Carboxylate Ions
Based on the Metal-Ligand Interaction and
Signaled through Fluorescence Quenching**
Giancarlo De Santis, Luigi Fabbrizzi,*
Maurizio Licchelli, Antonio Poggi, and Angelo Taglietti
Molecular recognition of a given substrate can be signaled in
a number of ways: the change in the the potential of an electrode, the shift of an NMR signal, an abrupt color change.
However, the most spectacular and easily detectable signaling
effect is probably a change in fluorescence. Fluorescent sensing
procedures have been developed over the last decade for several
metal ions.['] Usually the recognition of the metal center is communicated to the outside through the quenching (for transition
metal ions)r21o r the revival (for alkali and alkaline earth metal
cations)[31of the fluorescence of a light-emitting unit linked to
the receptor. In any case, the variation of the fluorescence emission is related to an intramolecular electron transfer process,
which directly involves the metal center. On the other hand,
fluorescence sensing of anions is a much less developed field,
which may be due to the low energy of the receptor-substrate
interactions (hydrogen bonding, electrostatic effects). A successful case is the binding of hydrogen phosphate to a polyammonium unit, to which an anthracene subunit is appended
as a fluorescent group.r41
We considered that the metal - ligand interaction, which can
be significantly stronger than hydrogen bonding and other van
Prof. Dr. L. Fabbrizzi, Dr. G. De Santis. Dr. M. Licchelli. Prof. Dr. A. Poggi.
Dr. A. Tdglietti
Dipartimento di Chimica Generale. Universita di Pavia
Via Taramelli 12, 1-27100 Pavia (Italy)
Fax: Int. code + (382)528544
This work was supported by the Italian National Council of Research (CNR:
Progetto Strategico: Tecnologie Chimiche Innovative) and by the European
Union (HCM program: Network Contract no. ERBCHRXCT940492).
nibH, 0-69451 Weinheirn. 1996
der Waals interactions, could be conveniently used for anion
recognition. In this connection, we first appended a 9-anthrdcenyl group to a peripheral nitrogen atom of tris(2-aminoethyl)amine (tren). The resulting anthrylamine 1 was reacted
with Zn" to give the corresponding complex. In the two-component system [Zn"(l)]'+, the four-coordinate metal center has a
vacant site for coordination of a solvent molecule or for an
anion to give a trigonal-bipyramidal arrangement. The proximate luminescent unit is in a favorable position to signal the
occurrence of the anion recognition. In methanolic solutions
[Zn'1(l)]2f shows a strong affinity towards anions bearing a
carboxylate group. In particular, a stable 1 :1 adduct is formed
with the benzoate ion, as shown by spectrophotometric titrations. However, parallel titration experiments carried out in the
spectrofluorimetric cuvette indicate that anion binding does not
interfere with the photophysical activity of the proximate anthracene group, whose emission spectrum was not altered even
after the addition of several equivalents of the anion. Thus, in
this case the anthracene subunit is only a "silent witness" of the
anion binding to the Zn" center.
However, when a solution of [Zn"(1)]2f was titrated with the
4-N,N-dimethylaminobenzoateion (X-) , the fluorescence intensity progressively decreased until complete quenching
(Fig. 1). The plot of fluorescence intensity (IF) versus equiva-
100 -
% Q W V
n Fig. 1. Spectrofluorimetric titrations of the [Zn"(l)]z+ receptor in methanolic soluM) with standard methanolic solutions of N,N-dimethylaminobenzoate
(T). acetate (v); N,N-dimethylaminobenzoate t acetate ( 0 ) : n = equivalents of
anion/equivalents of complex.
lents of anion added indicates that the 1 :1 adduct [Zn"(l)X]+ is
formed, and least-squares treatment of the curve gave a IgK
value of 5.45+0.03 for the equilibrium [Zn"(l)]*'
X[Zn"(l)X] .[sl It is suggested that fluorescence quenching is due
to an intramolecular electron transfer (ET) process within the
[Zn"( 1)X]+ adduct, in particular from the Zn"-bound dimethylaminobenzoate subunit D to the photo-excited anthracene unit
*An. The electron donor tendencies of N,N-dimethylaniline
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chiral, asymmetric, hecke, reaction, catalysing, phosphanyldihydrooxazoles, enantioselectivity
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