An enzyme-labile linker group for organic syntheses on solid supports

Article abstract of DOI:10.1002/(SICI)1521-3773(19980504)37:8<1143::AID-ANIE1143>3.0.CO;2-E

Lipases and esterases can be used to fragment the 4-acetyloxybenzyloxy group used as a linker for organic synthesis on solid supports. (A support-bound compound is shown on the right; the enzyme-labile bond is marked with an arrow.) This enzyme-initiated

Full text of DOI:10.1002/(SICI)1521-3773(19980504)37:8<1143::AID-ANIE1143>3.0.CO;2-E

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Vittorelli, H.-J. Hansen, H. Schmid, Helv. Chim. Acta 1975, 58, 1293;
c) R. L. Vance, N. G. Rondan, K. N. Houk, F. Jensen, W. T. Borden, A.
Komornicki, E. Wimmer, J. Am. Chem. Soc. 1988, 110, 2314.
[19] a) G. Büchi, J. E. Powell, J. Am. Chem. Soc. 1970, 92, 3162; b) M. M.
Abelmann, R. F. Funk, J. D. Munger, ibid. 1982, 104, 4030.
[20] The activation energy DG= for the racemization of optically active E-
cyclononene is about 20 kcalmol 1 and the half-life at 08C 4 min: A. C.
Cope, K. Banholzer, H. Keller, B. A. Pawson, J. J. Wang, H. J. S.
Winkler, J. Am. Chem. Soc. 1965, 87, 3644. For comparison, (E)-
Cycloocten: DG=ˆ 35 kcalmol 1, t1/2 bei 1338C: 120 h: A. C. Cope,
B. A. Pawson, ibid. 1965, 87, 3649.
centers in the indolizidinones by means of the ring contrac-
tion. Further investigations into the scope and limitations of
the diastereoselective transannular reaction are in progress.
Received: September 9, 1997 [Z10908IE]
German version: Angew. Chem. 1998, 110, 1178 ± 1181
Keywords: chirality ´ heterocycles ´ lactams ´ rearrange-
ments ´ ring contractions
[21] Synthesis of azoninones without any stereogenic centers: E. D.
Edstrom, J. Am. Chem. Soc. 1991, 113, 6690.
[1] M. Diederich, U. Nubbemeyer, Angew. Chem. 1995, 107, 1095; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1026.
[22] Structural proof: a) Position bridgehead C-8a and PhSe-substituent by
1H/13C HETCOR analysis for 12, 13, and 14: in each case coupling C-1
(Ar) with H-8; C-8 (d, d ꢀ 40) with H-8 ) substituent Se; C-8a (d, d ꢀ
60) with H-8a ) substituent N. 12: NOE analysis: Relative config-
uration of C-2, C-6, C-8 and C-8a ( ) b: H-2, H-8a; a: H-6, H-8): H-
2 ) H-8a (9); H-8a ) H-2 (6), H-7b (8); H-6 ) H-8 (7), H-7a (7); H-
8 ) H-6 (7), H-1a (4); H-1a ) H-8 (8). 13: NOE analysis: Relative
configuration of C-2, C-6, C-8, and C-8a ( ) b: H-2, H-8; a: H-6, H-
8a): H-1b ) H-2 (9), H-8 (10), H-2 ) H-1b (6), H-3b (5); H-8 ) H-1b
(5), H-7b (4); H-6 ) H-7a (4), H-7a ) H-6 (11); H-8a ) H-7a (10),
H-1a (5); H-7a ) H-6 (11), H-8a (5); H-1a ) H-8a (5). 14: NOE
analysis: (irradiation of H-x ) enhancement at H-y [%]) relative
configuration of C-2, C-6, C-8, and C-8a ( ) b: H-6, H-8a; a: H-2, H-
8): H-1b ) H-8a (10); H-5b ) H-7b (3), H-8a (3); H-7b ) H-5b (3),
H-8a (2); H-8a ) H-1b (8), H-5b (7), H-7b (7); H-6 ) H-7b (4); H-
2 ) H-1a (8), H-1a ) H-2 (4), H-8 (11); H-8 ) H-1a (11), H-7a (8).
For IR data see Table 1.
[2] M. Diederich, U. Nubbemeyer, Chem. Eur. J. 1996, 2, 896.
[3] Review on Claisen rearrangements: H. Frauenrath, Methoden Org.
Chem. (Houben-Weyl) 4th ed. 1952 ± , Vol. E21d, p. 3301.
[4] L. F. Tietze, T. Eicher, Reaktionen und Synthesen im Organisch-
Chemischen Praktikum, 2nd ed., Thieme, Stuttgart, 1991, p. 135.
[5] R. N. Icke, B. B. Wisegarver, G. A. Alles, Org. Synth. Coll. Vol. 3 1955,
723; N-Methylproline methyl ester 2: R. L. Elliott, H. Kopeka, N.-H.
Lin, Y. He, D. S. Garvey, Synthesis 1995, 772.
[6] L. F. Tietze, T. Eicher, Reaktionen und Synthesen im Organisch-
Chemischen Praktikum, 2nd ed., Thieme, Stuttgart, 1991, p. 85; N-
Benzylproline methyl ester 3: E. J. Corey, J. O. Link, J. Org. Chem.
1991, 56, 442.
[7] E. J. Corey, A. Venkatesvarlu, J. Am. Chem. Soc. 1972, 94, 6190.
[8] E. Winterfeldt, Synthesis 1975, 617.
[9] A. J. Mancuso, D. Swern, Synthesis 1981, 165.
[10] a) E. J. Corey, R. Greenwald, M. Chaykovsky, J. Org. Chem. 1963, 28,
1128; b) J. A. Marshall, M. T. Pike, R. D. Carroll, ibid. 1966, 31, 2933.
[11] a) J. A. Marshall, W. F. Huffmann, J. A. Ruth, J. Am. Chem. Soc. 1972,
94, 4691; b) G. Magnusson, Tetrahedron Lett. 1977, 2713.
[12] Any epimerization was avoided when the aldehydes trans-4 were
processed immediately after isolation. Example for the partial
epimerization of the aldehydes trans-4 (EtNiPr2, CH2Cl2, RT): The
trans-4:cis-4 ratio is 4:1 after 1 day and 3:2 after 4 days; the
diastereomers were separated after Wittig olefination to form 5; yield
65 ± 68%.
[23] a) D. Y. Curtin, Rec. Chem. Prog. 1954, 15, 111; b) J. I. Seeman, Chem.
Rev. 1983, 83, 83.
[24] 2 (R ˆ Ph): [a]D22
ˆ
51.98 (c ˆ 3.7, CHCl3); 3 (R ˆ Ph): [a]D22
ˆ
44.08
(c ˆ 0.7, CHCl3); trans-5 (R ˆ Ph): [a]D22
ˆ
55.18 (c ˆ 0.8, CHCl3);
trans-11-B (R ˆ Ph): [a]D22
ˆ
122.08 (c ˆ 0.3, CHCl3); trans-11-B
(R ˆ H): [a]2D2 ˆ ‡67.98 (c ˆ 0.6, CHCl3); 12: [a]2D2 ˆ ‡59.48 (c ˆ 0.4,
CHCl3); 13: [a]2D2
ˆ
42.08 (c ˆ 0.4, CHCl3); 14: [a]D22
ˆ
20.08 (c ˆ
0.1, CHCl3).
[13] Usually, allyl chlorides generated by Von-Braun-degradation of the
intermediate acylammonium salts were isolated as side products. J. H.
Cooley, E. J. Evain, Synthesis 1989, 1. For preparative details see
refs. [1] and [2]. Some decrease of the yields had to be taken in
account after HPLC separations.
An Enzyme-Labile Linker Group for
[14] All previously isolated lactams displayed an E-olefin and an ªEº-
amide geometry. Structural proof: cis-11: Olefin (E): 3J(H-5,H-6) ˆ
16 Hz (1H-NMR); NOE analysis (irradiation of H-x ) enhancement
at H-y [%]): H-4a ) H-6 (7); H-6 ) H-4a (4); H-5 ) H-7b (8); H-
7b ) H-5 (10). Amide (ªEº): H-3 ) H-9b (2); H-9b ) H-3 (3).
Relative configuration of C-3 and C-8 (cis): H-3 ) H-5 (3), H-9b
(2); H-5 ) H-3 (2), H-8 (3), H-9b (1); H-8 ) H-5 (5), H-9b (3); H-
9b ) H-3 (2), H-5 (1), H-8 (4). trans-11-A: Olefin (E): 3J(H-5,H-6) ˆ
16 Hz (1H-NMR); NOE analysis: H-4a ) H-6 (7); H-6 ) H-4a (4);
H-5 ) H-7b (6); H-7b ) H-5 (8). Amide (ªEº): H-3 ) H-9a (17); H-
9a ) H-3 (28). Relative configuration of C-3 and C-8 (trans): H-3 )
H-6 (4), H-9a (17); H-6 ) H-3 (3), H-9a (3); H-9a ) H-3 (27), H-6
(6); H-8 ) H-9b (4); H-9b ) H-8 (6). trans-11-B: Olefin (E): 3J(H-
5,H-6) ˆ 16 Hz (1H-NMR); NOE analysis: H-4b ) H-6 (6); H-6 ) H-
4b (5); H-5 ) H-7a (10); H-7a ) H-5 (13). Amide (ªEº): H-3 ) H-9a
(15); H-9a ) H-3 (28). Relative configuration of C-3 and C-8 ( )
trans): H-3 ) H-5 (4), H-9a (15); H-5 ) H-3 (3), H-9a (3); H-9a ) H-
3 (28), H-5 (5); H-8 ) H-6 (3), H-9b (2); H-9b ) H-8 (3).
Organic Syntheses on Solid Supports**
Bernd Sauerbrei, Volker Jungmann, and
Herbert Waldmann*
Combinatorial chemistry has proven to be a new and
valuable method for the rapid identification and further
development of compounds with a predetermined profile of
properties, not only for drug discovery but also for asymmetric
catalysis.[1] In the majority of the cases combinatorial syn-
theses are carried out on solid supports. Once the desired
compounds are constructed they have to be released from the
supports selectively and without attack on the synthesized
structures through cleavage of a suitable anchor group
(linker). Combinatorial synthesis gives access to a multitude
of different classes of compounds with a wide range of
stability under the conditions of the releasing reactions.
Therefore the development of broadly applicable linkers
[15] M. Nagatsuma, F. Shirai, N. Sayo, T. Nakai, Chem. Lett. 1984, 1393.
[16] The relative configuration was not determined, because under the
conditions of measurement ketenes and acylammonium salts were
formed. The protonation and acylation of trans-5 (R ˆ H) with non-
ketene-generating acyl units proceeded diastereoselectively syn with
respect to the vinyl and anti to the TBSO group, which was proved by
NOE experiments.
[17] a) D. A. Evans, J. Bartoli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127; b) W. Richter, W. Sucrow, Chem. Ber. 1971, 104, 3679.
[18] a) W. S. Johnson, V. J. Bauer, J. L. Margrave, M. A. Frisch, L. H.
Dreger, W. N. Hubbard, J. Am. Chem. Soc. 1961, 83, 606; b) P.
[*] Prof. Dr. H. Waldmann, Dr. B. Sauerbrei, Dr. V. Jungmann
Institut für Organische Chemie der Universität
Richard-Willstätter-Allee 2, D-76128 Karlsruhe (Germany)
Fax : (‡ 49)721-608-4825
E-mail: waldmann@ochhades.chemie.uni-karlsruhe.de
[**] This research was supported by the Bundesministerium für Bildung
und Forschung, the Fonds der Chemischen Industrie, and BASF AG.
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allowing for selective cleavage of the synthesized products
from the polymeric support under mild conditions (preferably
at pH 7 and room temperature) is of particular importance. In
many cases biocatalyzed transformations have opened up
advantageous alternatives to classical chemical approaches,
since enzymatic reactions often proceed under very mild
conditions and with pronounced chemo-, regio-, and stereo-
selectivity.[2] The use of enzyme-labile anchor groups could
also provide new opportunities for combinatorial chemistry
and solid-phase synthesis. However, a broadly applicable
enzyme-labile linker has not yet been developed.[3] We now
report that the 4-acyloxy-3-carboxybenzyloxy group can be
employed advantageously as an enzyme-labile linker for
solid-phase syntheses. The compounds built up at this anchor
group can be released by means of an enzyme-initiated
fragmentation.
enzyme-labile
bond
O
O
O
R
O
HN
O
X
X = NH, O, CR2
1
enzyme
–RCOOH
O
O
HN
O
O
X
For the design of an enzyme-labile linker we have drawn
from our experience in the development of enzymatically
removable protecting groups.[4] The anchor group was con-
structed in such a way that a) it contains a functional group
that is recognized and attacked by the biocatalyst, that
b) cleavage of the enzyme-labile bond yields an intermediate
that undergoes a spontaneous fragmentation, thereby releas-
ing the desired compound,[5] and that c) a further functional
group for attaching the linker to the solid support is present.
The realization of this principle is shown in Scheme 1. The
linker is attached through a carboxyl group as an amide to the
solid phase (!1). It contains an acyl group, for example an
acetate, which can be cleaved by lipases or esterases. A
phenolate is thus generated (!2), which fragments to give a
quinone methide 3 and releases the desired compound 4, a
product of, for example, combinatorial synthesis. The quinone
methide remains bound to the solid phase and is trapped there
by water or an additional nucleophile. In this way amines
(bound as urethanes), alcohols (bound as carbonates), and
carboxylic acids (bound as esters) can be detached from the
polymeric carrier. The substrate specificity of the enzyme
guarantees that only the intended ester is cleaved, and the
mild conditions of the biocatalyzed transformations ensure
that the compounds built up on the solid phase remain intact
during the cleavage. Furthermore the linker is constructed in
such a way that the variable part of the substrates is remote
from the site of the biocatalystꢁs attack. This guarantees that
the substrate tolerance of the enzyme in the cleaving reaction
is not restricted by interfering electronic or steric interactions
of the protein with the different substrates generated by
combinatorial synthesis.
2
O
O
O
HN
Nu
+
HO
X
CH2
3
4
X = NH: amines (–CO2)
X = O: alcohols (–CO2)
X = CR2: carboxylic acids
Scheme 1. Principle for the development of the enzyme-labile 4-acyloxy-
benzyloxy linker groups. The solid support is represented by a shaded
sphere; the target compounds constructed by combinatorial synthesis are
shown schematically (rectangles, circles, oblongs, ellipses).
1) AcCl, NEt3, CH2Cl2, 95%
2) 1.25 equiv NBS, AIBN,
O
O
OAc
OH
CCl4, ∆, 58%
HO
HO
3) 0.1N AgNO3/dioxane (1/1),
RT, 62%
CH3
OH
5
6
1) TentaGel S-NH2, DIC,
CH2Cl2, RT
2) COCl2, toluene,
RT
O
O
OAc
O
O
OAc
O
O
O
N
N
Leu-OtBu,
CH2Cl2,
RT
H
H
O
O
O
For the synthesis of the linker, building block 5-methyl-
salicylic acid (5) was first O-acetylated, then the methyl group
was converted into a benzyl bromide with N-bromosuccini-
mide (NBS), and the bromide was finally hydrolyzed to the
benzyl alcohol by treatment with AgNO3 solution (Scheme 2).
The polymeric support selected for the subsequent trans-
formations on the solid phase was TentaGelS-NH2, a poly-
styrene resin onto which terminally NH2-functionalized
oligoethyleneglycol units had been grafted.[6] Its polar surface
and the fact that it is well solvated in aqueous solution are
particularly advantageous properties that should facilitate the
enzymatic cleavage of the linker. After activation with
68
68
Cl
NH
Leu
OtBu
54%
(3 steps)
TentaGel
TentaGel
7
8
Scheme 2. Synthesis of linker 6 and its attachment to TentaGelS-NH2.
AIBN ˆ 2,2'-azobisisobutyronitrile,
DIC ˆ diisopropylcarbodiimide,
Leu ˆ leucine, RTˆ room temperature.
diisopropyl carbodiimide (DIC) the carboxylic acid 6 was
coupled to the polymer, and the benzylic alcohol was then
converted into the chloroformic acid ester 7 by treatment with
phosgene. Thus, an activated intermediate is generated to
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which a broad variety of amines and alcohols can be attached.
Carboxylic acids can already be coupled to the polymer-
bound benzyl alcohol 9 (see Scheme 3). In order to determine
the best conditions for the enzyme-initiated fragmentation of
the anchoring group, leucine tert-butyl ester was linked to 7 to
give the urethane 8.[7] Several commercially available lipases
and esterases were investigated for the enzyme-initiated
fragmentation of the linker. By far the best results were
achieved with lipase RB001-05 (Recombinant Biocatalysis,
Diversa, San Diego, USA). This biocatalyst detaches leucine
tert-butyl ester at pH 5.8 und 408C in 0.05m morpholino-
ethane sulfonic acid (MES) buffer/methanol (60/40), in other
words, under very gentle conditions. The amino acid ester was
isolated in 73% yield. Lipase from Mucor miehei also
catalyzes this reaction under similarly mild conditions (0.1m
NaH2PO4 buffer, pH 6, 378C); however, the product was
obtained in lower yield (50%).
this end, the benzylic OH group of the TentaGelS-NH2 bound
linker 9 was first esterified with Boc-l-tryptophan, and the
Boc group was then removed by treatment with trifluoro-
acetic acid. The support-bound tryptophan 10 was then
condensed with aliphatic and aromatic aldehydes at 508C in
the presence of molecular sieves to give imines 11, which
under these reaction conditions cyclized immediately to the
tetrahydro-b-carbolines. Starting from 9 the heterocyclic
amines 12 were thus formed in 55 ± 85% yield.[7] The
Pictet ± Spengler adducts could also be released from the
polymeric support under very mild conditions by lipase-
initiated fragmentation of the anchor group. Upon treatment
of 12 with lipase RB001-05 at pH 5.8 in an MES buffer/
methanol mixture (60/40) the enzyme selectively attacked the
acetate incorporated into the linker and converted it into the
corresponding phenolate (!13), which then fragmented
spontaneously. By means of this enzyme-mediated dissection
of the anchor group the desired tetrahydro-b-carbolines 14
were released in 70 ± 80% yield.[9] The result that the
enzymatic fragmentation of the linker occurs already at
pH 5.8 is not a foregone one. In the nonenzymatic cleavage of
4-acyloxybenzyloxy groups the pH has to be raised to at least
10 ± 11 to deprotonate the corresponding phenol and thereby
induce its conversion into the quinone methide.[10, 11] Active
participation of the enzyme in the fragmentation, for example
by means of basic amino acid side chains in or close to the
active site, is therefore very probable.
The applicability of the enzyme-labile anchor group to
multistep transformations on the solid phase, which are for
instance relevant to the generation of libraries in pharma-
ceutical research, was proven by the synthesis of tetrahydro-b-
carbolines by means of the Pictet ± Spengler reaction[8] and
their subsequent enzyme-mediated release (Scheme 3). To
O
OAc
O
OAc
O
O
1) Boc-Trp,
DIC, DMAP
N
H
O
To further prove the broad applicability of the enzyme-
labile anchor group the polymer-bound chloroformic acid
ester 7 was coupled with the very acid-labile 5'-O-dimethoxy-
trityl(DMTr)-protected thymidine (NaH, THF). Treatment of
the resulting immobilized nucleoside 15 with lipase RB001-05
2) CF3COOH
RT
68
OH
NH3
N
H
CF3COO
TentaGel
9
10
molecular sieves
50 °C
R-CHO,
CH2Cl2
MeO
O
H3C
OAc
O
OAc
NH
C
O
MeO
N
O
O
O
O
O
HN
N
O
N
N
H
H
C O
O
R
R
O 68
O
12
11
H
N
R = Ph, 4-NO2C6H4, iPr
55–85%
OAc
O
15
lipase
RB 001-05
50mM MES buffer/CH3OH
(60/40), pH 5.8, 30 °C
lipase
50 mM MES buffer/CH3OH
RB 001-05 (80/20), 0.2M NaHSO3,
pH 6.5, 30 °C
O
O
O
MeO
O
O
HO
H3C
HN
HN
NH
N
H
N
H
C O
R
MeO
R
N
O
O
13
14
OH
70–80%
16
Scheme 3. Solid-phase synthesis of tetrahydro-b-carbolines and subse-
quent detachment (!14) by enzyme-initiated fragmentation of the anchor
group. Boc ˆ tert-butyloxycarbonyl, Trp ˆ tryptophan, DMAP ˆ 4-
dimethylaminopyridine.
68%
Scheme 4. Detachment of DMTr-protected thymidine from the polymeric
support by enzyme-initiated fragmentation of the anchor group.
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[11] If an amino group can function intramolecularly as nucleophile, the
fragmentation (in these cases with cyclization) can occur even at pH 8.
This principle can also be employed for the development of an anchor
group that can be cleaved by classical chemical methods: B. Atrash,
M. Bradley, J. Chem. Soc. Chem. Commun. 1997, 1397.
at pH 6.5 initiated the fragmentation of the linker and
released the DMTr-protected thymidine 16 from the solid
support under gentle conditions (Scheme 4).
The results demonstrate that the 4-acetyloxybenzyloxy
linker allows for the detachment of amines (like leucine tert-
butyl ester), carboxylic acids (like the tetrahydro-b-carbolines
14), and alcohols (like the protected nucleoside 16) from the
polymeric support under very mild conditions (pH 5 ± 7, room
temperature) and with complete selectivity. The results are
not only relevant to combinatorial chemistry, they also
indicate that enzymes in general may be valuable reagents
for transformations on solid supports.[12]
[12] For biocatalyzed transformations on solid supports see ref.[3] and
a) R. L. Halcomb, H. Huang, C.-H. Wong, J. Am. Chem. Soc. 1994,
116, 11315; b) S. Köpper, Carbohydr. Res. 1994, 265, 161; c) M. Meldal,
F.-I. Auzanneau, O. Hindsgaul, M. M. Palcic, J. Chem. Soc. Chem.
Commun. 1994, 1849; d) H. Waldmann, A. Reidel, Angew. Chem.
1997, 109, 642; Angew. Chem. Int. Ed. Engl. 1997, 36, 647.
Received: November 12, 1997 [Z11151IE]
German version: Angew. Chem. 1998, 110, 1187 ± 1190
Keywords: cleavage reactions ´ enzyme catalysis ´ combina-
torial chemistry ´ lipases ´ solid-phase synthesis
Novel Distorted Pentagonal-Pyramidal
Coordination of Anionic Oxodiperoxo
Molybdenum and Tungsten Complexes**
[1] Reviews: a) F. Balkenhohl, C. von dem Bussche-Hünnefeld, A.
Lansky, C. Zechel, Angew. Chem. 1996, 108, 2437; Angew. Chem. Int.
Ed. Engl. 1996, 35, 2288; b) J. S. Früchtel, G. Jung, ibid. 1996, 108, 19
and 1996, 35, 17; c) L. A. Thompson, J. A. Ellman, Chem. Rev. 1996,
96, 555.
Jean-Yves Piquemal, Sabine Halut, and
Jean-Marie Bregeault*
Â
There is currently much interest in the preparation of new
polyoxo(peroxo)metalates for homogeneous catalysis[1] and
heterogeneous systems[2] in order to understand the chemistry
of surface species and the nature of the catalytically active
sites of transition metal containing molecular sieves or other
materials. While studying oxidation reactions with mesopo-
rous materials,[1m] which are potentially interesting catalysts
and/or catalyst supports,[3] we became interested in comparing
anionic or neutral oxoperoxo complexes with those that can
be formed on silica and/or alumina. From studies on systems
of aqueous [MoO4]2 and [Mo7O24]6 solutions and silica, it is
known that MoVI uptake by SiO2 is relatively low over the
entire pH range, except for a small increase at pH 2 or lower
owing to the formation of [SiMo12O40]4 ions, which can
partially desorb into solution.[4] Furthermore, silica (BET
[2] Enzyme Catalysis in Organic Synthesis (Eds.: K. Drauz, H. Wald-
mann), VCH, Weinheim, 1995.
[3] The detachment of peptides and carbohydrates from solid supports by
means of a protease or a phosphatase was reported in only few cases:
a) D. T. Elmore, D. J. S. Guthrie, A. D. Wallace, S. R. E. Bates, J.
Chem. Soc. Chem. Commun. 1992, 1033; b) M. Schuster, P. Wang, J. C.
Paulson, C.-H. Wong, J. Am. Chem. Soc. 1994, 116, 1135; c) K.
Yamada, I. Nishimura, Tetrahedron Lett. 1995, 36, 9493.
[4] Reviews: a) T. Kappes, H. Waldmann, Liebigs Ann. 1997, 803; b) M.
Schelhaas, H. Waldmann, Angew. Chem. 1996, 108, 2192; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2056.
[5] For applications of this concept in protecting group chemistry see:
a) H. Waldmann, E. Nägele, Angew. Chem. 1995, 107, 2425; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2259; b) H. Waldmann, M. Schelhaas, E.
Nägele, J. Kuhlmann, A. Wittinghofer, H. Schroeder, J. R. Silvius, ibid.
1997, 109, 2334 and 1997, 36, 2238; c) T. Pohl, H. Waldmann, J. Am.
Chem. Soc. 1997, 119, 6702.
1
specific surface area 263 m2 g ) and molybdenum± (or
[6] W. Rapp. in Combinatorial Peptide and Nonpeptide Libraries (Ed.: G.
Jung), VCH, Weinheim, 1996, p. 425.
tungsten ± ) oxoperoxo species interact in aqueous acidic
medium to form surface peroxo species with characteristic IR
bands nÄO±O near 870 cm 1 (nÄO±O is expected to be in the range
ˆ
[7] Characteristic IR data (FTIR) for 8: nÄ ˆ 1776 (C O, ester), 1724
1
ˆ
ˆ
(C O, urethane), 1666 cm (C O, amide). In order to determine the
loading of the resin leucine tert-butyl ester was cleaved from 8 by
treatment with methanol/0.1n NaOH (1/1). Per gram of resin,
0.154 mmol of the released ester was isolated. Based on the initial
1
of 845 ± 885 cm ).[1] These observations suggest that it might
be possible to synthesize oxoperoxoheterosiloxanes involving
the various functionalities on the silica surface (i.e., lone
1
loading of the resin of 0.29 mmolg this corresponds to an overall
yield of 54% for three steps. The loading of the resin 12 with the
tetrahydro-b-carbolines was determined analogously.
[8] For Pictet ± Spengler reactions on polymeric supports see: a) K.
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[*] Prof. Dr. J.-M. Bregeault, J.-Y. Piquemal
Â
Kaljuste, A. Unden, Tetrahedron Lett. 1995, 36, 9211; b) R. Mohan, Y.-
Á
Á
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Systemes Interfaciaux a lꢁEchelle Nanometrique
ESA 7069 CNRS, Departement de Chimie
Universite Pierre et Marie Curie
L. Chou, M. M. Morrissey, ibid. 1996, 37, 3963; c) S. Hutchins, K.
Chapman, ibid. 1996, 37, 4865; c) L. Yang, L. Guo, ibid. 1996, 37, 5041;
d) J. P. Mayer, D. Bankaitis-Davis, J. Zhang, G. Beaton, K. Bjergarde,
C. M. Andersen, B. A. Goodman, C. J. Herrera, ibid. 1996, 37, 5633.
[9] 14a (R ˆ Ph): 75% yield; 1H NMR (200 MHz, CD3OD, 258C, TMS):
d ˆ 7.28 ± 7.49 (m, 6H, H-7, H-14 ± 18), 7.12 (dd, 1H, H-10, J ˆ 6.8, J' ˆ
1.4 Hz), 6.96 (td, 1H, H-9, J ˆ 6.9, J' ˆ 1.3 Hz), 6.90 (td, 1H, H-8,
J ˆ 6.9, J' ˆ 1.4 Hz), 5.99 (br. s, 1H, H-1 (trans)), 5.84 (br. s, 1H, H-1
(cis)), 4.12 ± 4.26 (m, 1H, H-3), 3.35 ± 3.51 (br. m, 2H, H-4).
Â
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Tour 54, case 196, 4 place Jussieu, F-75252 Paris cedex 05 (France)
Fax: (‡33)1-4427-5536
E-mail: bregeaul@ccr.jussieu.fr
Dr. S. Halut
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Laboratoire de Chimie des Metaux de Transition, URA 419 CNRS
Departement de Chimie, Universite Pierre et Marie Curie, Paris
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[10] G. Le Corre, E. Guibe-Jampel, M. Wakselman, Tetrahedron 1978, 34,
[**] We thank Dr. J. S. Lomas for constructive discussions and for
correcting the manuscript.
3105.
1146
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3708-1146 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 8