Ansa macrolides as molecular workbenches: Stereocontrolled syn additions to E olefins

Article abstract of DOI:10.1002/(SICI)1521-3773(19980619)37:11<1566::AID-ANIE1566>3.0.CO;2-U

Fixed on an aromatic platform in a conformationally defined way, acyclic (E)-alkenes can be considered gripped on a molecular workbench. The olefinic ansa-macrolides formed in this way are shielded on one face. On epoxidation and dihydroxylation [Eq. (1)] the attack on the double bond takes place diastereoselectively from outside the ring, and the ansa chain can subsequently be cleaved from the workbench by mild hydrogenolysis. Bn = benzyl, NMO = N-methylmorpholin-N-oxide.

Full text of DOI:10.1002/(SICI)1521-3773(19980619)37:11<1566::AID-ANIE1566>3.0.CO;2-U

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minor changes in the cyanide environment.[11, 12] The lack of a
strong solvent dependence for the IR spectra of cyanocup-
rates is most likely due to the interaction of CN , Li , and
[CuMe2] to give 3 (Scheme 1) regardless of solvent. The
structure of 3 is supported by IR measurements and theoret-
ical calculations.[11] The present data suggest that, in the
absence of cyanide, dimethylcuprate is largely dimeric 1 in
Et2O and monomeric 2 in THF.
Trost), Pergamon Press, Oxford, 1991, pp. 169 ± 198; d) B. H. Lipshutz
in Organometallics in Synthesis, (Ed.: M. Schlosser), Wiley, 1994,
pp. 283.
‡
[2] a) B. H. Lipshutz, R. S. Wilhelm, S. T. Nugent, R. D. Little, M. M.
Baizer, J. Org. Chem. 1983, 48, 3306 ± 3308; b) B. H. Lipshutz, J. A.
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G. Dabbagh, X. He, P. P. Power, ibid. 1993, 115, 11640-11641; e) E. M.
Meyer, S. Gambarotta, C. Floriani, A. Chiesi-Villa, C. Guastini,
Organometallics 1989, 8, 1067 ± 1079.
[3] A. Gerold, J. T. B. H. Jastrzebski, C. M. P. Kronenburg, N. Krause, G.
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Engl. 1997, 36, 755 ± 757.
[4] a) R. G. Pearson, C. D. Gregory, J. Am. Chem. Soc. 1976, 98, 4098 ±
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1982, 47, 1472.
[5] This dimer concept has been used to describe the mechanisms of both
substitution and 1,4-addition reactions of diorganocuprates without
regard to the solvent. See a) C. Ullenius, B. Christenson, Pure Appl.
Chem. 1988, 60, 57 ± 64; b) G. H. Posner, An introduction to Synthesis
Using Organocopper Reagents, Wiley, New York, 1980; c) E. Naka-
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119, 4887 ± 4899; d) E. Nakamura, S. Mori, K. Morokuma, ibid. 1997,
119, 4900 ± 4910.
[6] a) T. M. Barnhart, H. Huang, J. E. Penner-Hahn, J. Org. Chem. 1995,
60, 4310 ± 4311; b) T. L. Stemmler, T. Barnhart, J. E. Penner-Hahn,
C. E. Tucker, P. Knochel, M. Böhme, G. Frenking, J. Am. Chem. Soc.
1995, 117, 12489 ± 12497.
[7] The spectra are independent of the cuprous halides (CuI vs. CuBr)
used. Only spectra for CuI are shown.
[8] P. P. Power, Prog. Inorg. Chem. 1991, 39, 75 ± 112.
[9] G. van Koten, S. L. James, J. T. B. H. Jastrzebski in Comprehensive
Organometallic Chemistry, Vol. 3 (Eds.: E. W. Abel, F. Gordon, A.
Stone, G. Wilkinson), Elsevier, New York, 1995, pp. 57 ± 133.
[10] N. P. Lorenzen, E. Weiss, Angew. Chem. 1990, 102, 322 ± 324; Angew.
Chem. Int. Ed. Engl. 1990, 29, 300 ± 302.
[11] H. Huang, K. Alvarez, Q. Cui, T. M. Barnhart, J. P. Snyder, J. E.
Penner-Hahn, J. Am. Chem. Soc. 1996, 118, 8808 ± 8816.
[12] H. Huang, Ph.D. Thesis, The University of Michigan, 1997.
Scheme 1. Structural conversion of dimethylcuprates in THF and Et2O as
well as in the presence of cyanide.
In summary, XAS measurements have revealed solvent-
dependent effects for the structures of dimethylcuprates
derived from CuI. Dimeric (CuMe2Li)2 species are predom-
inant in Et2O and DMS, while a monomeric [CuMe2] , or at
most a weakly associated aggregate, appears to be the main
species in THF. The structures of cyanocuprates are less
susceptible to solvent, probably due to the association of the
‡
cyanide (or the [Li2CN] unit) with the [CuMe2] unit. This
Ansa Macrolides as Molecular Workbenches:
Stereocontrolled syn Additions to E olefins
may account for the higher yield for cuprate reactions with
CuCN as a precursor.
Johann Mulzer,* Karin Schein, Jan W. Bats,
Jürgen Buschmann, and Peter Luger
Experimental Section
Organocuprate samples (0.1m) were prepared under dry N2 using Schlenk
techniques.[11] CuCN (99%), CuBr (99.999%), and CuI (99.999%) were
purchased from Aldrich. Halide-free MeLi (1.4m in Et2O, Aldrich) was
titrated with 2-butanol using 1,10-phenanthroline as an indicator. THF was
freshly distilled from Na/benzophenone; Et2O and DMS were freshly
distilled from CaH2. The solutions in DMS and THF contain 14% Et2O
from MeLi addition. Sample preparation and data collection and analysis
were previously described.[6b] Solutions in THF and Et2O were measured in
the transmission mode, while solutions in DMS were measured in the
fluorescence mode. Data for all samples were evaluated in an identical way.
Stereocontrolled dihydroxylations and epoxidations of
acyclic 1,2-disubstituted E olefins are in favorable cases
carried out catalytically,[1] otherwise with substrate-induced
diastereodifferentiation; this method, however, requires al-
lylic or homoallylic hydroxy or amide groups.[2] In general an
effective face discrimination is difficult because of the high
conformative mobility of the substrate. We herein report a
new approach to solving this problem. In this, the acyclic E
Received: November 27, 1997 [Z11204IE]
German version: Angew. Chem. 1998, 110, 1628 ± 1630
[*] Prof. Dr. J. Mulzer
Institut für Organische Chemie der Universität
Währingerstraûe 38, A-1090 Wien (Austria)
Fax: (‡43)1-31367-2280
Keywords: copper
´ metal ± metal interactions ´ solvent
effects ´ X-ray absorption spectroscopy ´
E-mail: mulzer@felix.orc.univie.ac.at
Dr. K. Schein, Dr. J. W. Bats
Institut für Organische Chemie der Universität Frankfurt
[1] a) G. H. Posner, Org. React. 1972, 19, 1; b) ibid. 1975, 22, 253; c) A.
Kozlowski, Comprehensive Organic Synthesis, Vol. 4 (Ed.: B. M.
Dr. J. Buschmann, Prof. Dr. P. Luger
Institut für Kristallographie der Freien Universität Berlin
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olefin is covalently attached to a benzene ring in the 1,4
positions through appropriate functional groups. This olefin is
then sterically shielded from one side. A crucial problem is the
conformational equilibrium which is to be expected[3] between
the two helical forms 1 and 2(Scheme 1): Even if the double
bond is attacked only from ªthe front sideº, two diastereom-
ers are obtained, for example 3 and 4, after epoxidation. A
stereochemically defined outcome of the reaction is only
possible if one of the two conformers 1 and 2 predominates
under the influence of the arene. The latter then works as a
ªmolecular workbenchº, fixing the substrate in a rigid
conformation.
To put this concept into effect,[4] we chose the easily
accessible olefinic diols 8 as substrates, as they can be bonded
to the arene 9 with the aid of the diol unit and (after
deacylation) of the terminal hydroxy group, to form a cyclic
ketal and an ester, respectively. With these functional groups a
preferred conformational orientation is expected on closure
to form the ansa macrolide ring, as five-membered ring ketals
usually adopt an envelope conformation and the ester group
should line up coplanar to the arene. The compounds 8 were
synthesized stereoisomerically pure according to Scheme 2
from (R)-isopropylidene glyceraldehyde (5). The Claisen ±
Johnson rearrangement of 6 to 7 ensures the E configuration
(>95%) of the alkene unit. The diastereomeric acetals
obtained as a 1:1 mixture in the reaction of 8 with 9 were
separated chromatographically and then transformed into the
Scheme 1. Arenes as ªmolecular workbenchesº.
seco acids 10a,b and 11a,b on a gram scale. These were then
macrolactonized in a 10 4 m solution according to Yamagu-
chiꢁs method[5] in approximately 60% yield.
The macrolides 12, 14, and 15, as well as the methoxy
derivatives 16 and 17 prepared in an analogous fashion, are
Scheme 2. Synthesis of the ansa-macrolide alkenes 12 ± 17. a) Allyl- (for 6a) or 3-butenylmagnesium bromide (for 6b), THF, 308C; removal of the main
isomer; b) NaH, BnCl, imidazole, DMF; c) O3/PPh3, CH2Cl2; d) vinylmagnesium bromide, THF, 08C; 6a 25%, 6b 31%; e) CH3C(OEt)3, cat. EtCO2H,
toluene, reflux; 7a 79%, 7b 79%; f) LiAlH4, THF, 08C; g) n ˆ 1: Ac2O, CH2Cl2/NEt3 (1/1); n ˆ 2: BzCl, pyridine; h) 50% HOAc; 8a 83%, 8b 86%; i) 9, cat.
TsOH, molecular sieve 4 Š, separation by HPLC; j) LiOH, H2O/MeOH/THF; 10a 40%, 10b 38%, 11a 38%, 11b 33%; k) 2,4,6-trichlorobenzoyl chloride,
NEt3, THF, 2 h, then DMAP, toluene, reflux, 20 h; 12 62%, 13 64%, 14 60%, 15 58%. Bn ˆ benzyl, Bz ˆ benzoyl, TsOH ˆ p-toluenesulfonic acid, DMAP ˆ
4-dimethylaminopyridine.
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Figure 1. Structures of the ansa-macrolide olefins 15 (a), 12 (b), and 14 (c) in the crystal.[6j
crystalline and were characterized by single-crystal X-ray
diffraction (examples of the structures are given in Fig-
ure 1).[6] A common feature of all compounds is the antiper-
iplanar arrangement of the C ± O(R) bond and the vicinal C ±
O bond of the ketal, which is probably due to electrostatic
repulsion and acts as a conformational anchor. The benzene
rings are deformed in all five macrolides, with bow and stern
of the boat lifted above the ring plane by about 0.07 Š each,
regardless of the remaining structure. The ªpore sizeº of the
macrocycle and therefore its conformational mobility de-
creases when going from n ˆ 2 to n ˆ 1 and from the cis- to the
trans-ketal; accordingly, the effective shielding of the ªinner
faceº increases. Remarkably, the helicity of the double bond
moiety in 12 and 14 as well as in 16 and 17 is determined by the
configuration of the acetal center: 14 and 17 have the same
helicity as 1, whereas 12 and 16 show the same helicity as 2,
Table 1. Diastereoselectivities for the syn addition to the ansa-alkenes
12 ± 17.
and no definite assignment is possible for 15.
For a conformational analysis of the compounds in solution,
1H NMR measurements were conducted between 75 and
1008C. They show that in the ªlargeº lactones 13 and 15, the
arene rotates around the para axis. The coalescence temper-
atures of the signals for the ortho and meta protons are
about 80 (15) and 108C (13). This effect does not occur in 12
and 14. Nevertheless, the ansa chain should display rapid
helical inversion in the sense of 1 > 2 in all cases. Evidence for
this inversion is obtained from preliminary studies on the
molecular dynamics of 12, 14, 16, and 17, which, however, also
show that the ªhelicamersº observed in the crystal dominate
overall.
Alkene
Diastereoselectivity
Dihydroxylation[b]
Epoxidation[a]
13
15
16
12
17
14
1.6:1 (19b)
2.0:1 (21b)
7.1:1 (19c)
9.5:1 (19a)
> 20:1 (21c)
> 20:1 (21a)
1.5:1 (18b)
2.1:1 (20b)
> 20:1 (18c)
> 20:1 (18a)
> 12:1 (20c)
> 20:1 (20a)
[a] mCPBA, CH2Cl2, 0.5m NaH2PO4/Na2HPO4, 08C !RT, 3h. [b] OsO4,
NMO, acetone, H2O, 08C !RT, 12h. Yields: 76 ± 92%. mCPBA ˆ m-
chloroperbenzoic acid, NMO ˆ N-methylmorpholine-N-oxide.
indeed function as a workbench. The tolerance of the ansa
macrolide ring toward a poor fit is surprisingly low. Thus, one
CH2 unit is already sufficient(compounds 12/13 and 14/15) to
obtain a conformationally
The stereoselectivities for epoxidations and dihydroxyla-
tions (Table 1) are fully in accordance with the expectations
deduced from the structures: They are high for the ªtightº
macrolides 12, 14, 16, and 17 and low for the ªwideº
macrolides 13 and 15. The reagent preferentially attacks from
the ªoutsideº, as expected. This can be gathered from the
structures[6] of the diol derivatives 18a and 20a and of the
epoxide 19c in the crystal. Moreover, superimposition of the
structures 16 and its epoxide 19c shows that the conformation
changes only slightly after the addition and that the arene can
nondetermined structure
instead of
a determined
structure. The fact that the
dihydroxylation and the ep-
oxidation of 22, the acyclic
analogue of 12, show almost
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Crystallographic Data Centre as supplementary publication no.
CCDC-100826. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
int. code ‡ (44)1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
[7] M. Schelhaas, H. Waldmann, Angew. Chem. 1996, 108, 2192 ± 2219;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2056 ± 2083.
no selectivity clearly indicates that the stereogenic centers of
the substrate are unsuitable for acyclic stereocontrol.
Can one dispose of the workbench after the job is done? As
exemplified for the dihydroxylation product 18a, the benzyl
acetal can not be hydrolyzed under mild acid catalysis, but is
easily cleaved hydrogenolytically (Scheme 3). Thus one
Homoleptic Lanthanide Amides as
Homogeneous Catalysts for the Tishchenko
Reaction**
Helga Berberich and Peter W. Roesky*
The Tishchenko reaction (or Claisen ± Tishchenko reac-
tion), that is, the dimerization of aldehydes to form the
corresponding carboxylic ester [Eq. (1)], has been known for
about a century.[1] Its industrial importance is mirrored in the
Scheme 3. Cleavage of the ªworkbenchº. a) 2,2-dimethoxypropane, PPTS,
CH2Cl2, 94%; b) H2/Pd/C, EtOAc; 23 97%, 24 97%. PPTS ˆ pyridinium-
p-toluene sulfonate.
obtains the partially protected hexol derivative 23; the arene
remains bonded to one of the primary hydroxy groups as the
4-methyl benzoate protecting group. Epoxides such as 19a are
transformed into tetrahydrofuran derivatives (e.g. 24) by an
SN2 attack of the hydroxy group liberated after debenzylation.
The arene 9 that is incorporated into the macrolide can
therefore be understood as a polyfunctional protecting group
that amplifies the influence of the substrateꢁs stereogenic
centers. As such it thus represents a new type of ªstereoactive
protective groupº.[7]
great number of patents. Thus the Tishchenko ester of 3-
cyclohexenecarbaldehyde is the precursor for the formation
of epoxy resin, which is durable against environmental
influences.[2] Traditionally aluminum alkoxides[2a, 3] have been
used as homogeneous catalysts for the catalytic variations of
the Tishchenko reaction. More recently other catalysts such as
boric acid[4] and a few transition metal complexes[5] are used.
However, these alternative catalysts are either only reactive
under extreme reaction conditions (e.g. boric acid), difficult to
prepare (e.g. [(C5Me5)2LaCH(SiMe3)2]),[5a] slow (e.g.
[(C5H5)2ZrH2]),[5b] expensive (e.g. [H2Ru(PPh3)2]),[5c] or give
small yields (e.g. K2[Fe(CO)4]).[5d]
Received: December 9, 1997
Revised version: February 6, 1998 [Z11247IE]
German version: Angew. Chem. 1998, 110, 1625 ± 1628
Herein we report that the homoleptic bis(trimethylsilyl)
amides of Group 3 metals and lanthanides, M[N(SiMe3)2]3[6] 1
(M ˆ Sc, Y, Ln (lanthanide)), are high-
Keywords: diastereoselective reactions ´ dihydroxylations ´
epoxidations ´ macrocycles ´ protecting groups
ly active catalysts for the Tishchenko
reaction. Compound 1 belongs to a
class of materials that has been known
for the last 25 years. Recently, in
particular, it has proven to be a
[1] Reviews: Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, New
York, 1993; R. Noyori, Asymmetric Catalysis in Organic Synthesis,
Wiley, New York, 1994; new method of epoxidation: Z.-X. Wang, Y.
Tong, M. Frohn, J.-R. Zhang, Y. Shi, J. Am. Chem. Soc. 1997, 119,
11224 ± 11235.
valuable starting material in lanthanide chemistry through
the easy cleavage of the silylamide group.[7] Compound 1 can
either be prepared from a simple one-step synthesis or it can
be bought (M ˆ Y). Therefore it is even more surprising to
find that up till now there is no known use of 1 as a catalyst.
To compare the reaction rates of 1 with other catalysts the
standard reaction of benzaldehyde to benyzl benzoate was
[2] A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307 ±
1370; R. W. Hoffmann, ibid. 1989, 89, 1841 ± 1860.
[3] Rotational barriers [kJmol 1]: (E)-cyclooctene 149, (E)-cyclononene
84, (E)-cyclodecene 45; A. C. Cope, B. A. Pawson, J. Am. Chem. Soc.
1965, 87, 3649 ± 3651; A. C. Cope, K. Banholzer, H. Keller, B. A.
Pawson, J. J. Whang, H. J. S. Winkler, ibid. 1965, 87, 3644 ± 3649; G.
Binsch, J. D. Roberts, ibid. 1965, 87, 5157 ± 5162.
[4] Additions to ansa alkenes: P. K. Chowdhury, A. Prelle, D. Schomburg,
M. Thielmann, E. Winterfeldt, Liebigs Ann. Chem. 1987, 1095 ± 1099;
summary: E. Winterfeldt, Chimia 1993, 47, 39 ± 45; diastereoselective
addition to double bonds in macrocycles: W. C. Still, L. J. MacPherson,
T. Harada, J. F. Callahan, A. L. Rheingold, Tetrahedron 1984, 40, 2275 ±
2281.
[5] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, Y. Yamaguchi, Bull. Chem.
Soc. Jpn. 1979, 52, 1989 ± 1993.
[6] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
[*] Dr. P. W. Roesky, H. Berberich
Institut für Anorganische Chemie der Universität
Engesserstrasse, Geb. 30.45, D-76128 Karlsruhe (Germany)
Fax: (‡49)721-661921
E-mail: roesky@achibm6.chemie.uni-karlsruhe.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie (Liebig-Stipendium). Prof.
Dr. D. Fenske is also thanked for his support.
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