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Asymmetric Induction in the Replacement of Diastereotopic Bromine Atoms by Lithium Atoms.

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I91 a) S. Ernst, V. Kasack, C. Bessenbacher, W. Kaim, 2. Naturforsch. 8 4 2
(1987)425; b) S. Ernst, P. Hanel, J. Jordanov, W. Kaim, V. Kasack, E.
Roth, submitted for publication; c) S. Ernst, Disseriation, Universitat
Frankfurt 1987.
(101 a) W. Kaim, Coord. Chem. Reu. 76 (1987) 187; b) A. Bencini, D.
Gatteschi, Transition Met. Chem. N. Y. 8 (1982) 1.
[I 11 For the relation between metal/ligand (de)localization and the g factor,
see R. Gross, W. Kaim, Inorg. Chem. 26 (1987) 3596; J . Chem. SOC.
Faraday Trans. 1 83 (1987)3549.
I121 M. Haga, E.S. Dodsworth, A. B. P. Lever, Inorg. Chem. 25 (1986)447.
[If W. Kaim, S. Emst, S . Kohlmann, Chem. Unserer Zeit 21 (1987)SO.
[I41 Cf. R. Gross, W. Kaim, Angew. Chem. 99 (1987)257; Angew. Chem. l n t .
Ed. Engl. 26 (1987)251.
I151 Note added in p r o o f In analogy to organic compounds described recently, 1 may be formulated as a 2,5-acceptor-1,3,4,6-donor-substituted
pentalene K system: F. Closs, R. Gompper, H. Noth, H.-U. Wagner, Angew. Chem. 100 (1988) 875; Angew. Chem. Int. Ed. Engl. 27 (1988)
Asymmetric Induction in the Replacement of
Diastereotopic Bromine Atoms by Lithium Atoms**
By Reinhard W. Hoffmann. * Martin BewersdorKlaus Ditrich, Michael Kriiger, and Rainer Stiirmer
In memoriam Gert Kobrich 1929-1974
The formation of new chiral centers by intramolecular
asymmetric induction is accomplished almost exclusively
by reactions at the diastereotopic sides of a prochiral C=C,
C=N, or C=O group.['] The use of diastereotopic groups in
preparative chemistry, on the other hand, has been reported in only a few special cases.IZ1On cyclic systems, the
selective replacement of one of two diastereotopic bromine
atoms by a metal atom has long been
Herein we
report o n the diastereoselective replacement of one of the
bromine atoms of open-chain, chiral 1,l-dibromoalkanes
1. The investigations were carried out on racemic compounds.
60: 90%; ds = 94 : 6
6b: 71%; ds
8 0 : 78%; ds
> 90 : 10
9a: ds > 90 : 10
9b: ds = 75 : 25
8b: 78%; ds = 70 : 30
a: R = fBu; b: R = iPr
In the series lb,l4' with R = isopropyl, the results were
essentially the same, although the diastereoselectivity (of
6b-9b) was less['] than in the tert-butyl-substituted series
These findings indicate that the halogen-metal exchange
o n la takes place with a diastereoselectivity of ca. 93 :7
(for l b , 75 :25), that the carbenoids 213 are configurationally stable at - 120 to -9O"C, and that they are trapped
stereospecifically by the electrophiles E@to give 4/5. This
interpretation is based on the fact that the ratio of the isomers 415 was independent of the nature of the trapping
electrophile in the examples investigated. For a rapid epimerization of 2 and 3 , on the other hand, the product ratio
415 would be expected to depend on the nature of the
electrophile. Thus, the halogen-metal exchange on 1 is
presumably the product-determining step. Preliminary results from experiments in which the organolithium compounds were varied support this conclusion, as shown by
the reaction of rac-lb to give 6b.
rac- 1 b
roc- 1
7a: 70%; ds = 93 : 7
7b: 80%; ds = 75 : 25
= 75 : 25
= tBu;
b: R = i P r
In a typical experiment, 3.3 mmol of a 1.55 M solution of
n-butyllithium in hexane was added dropwise to a solution
of l a (3 m m ~ l ) ' and
~ ] acetone (6 mmol) as electrophile, E@,
in 25 mL of Trapp mixture[61 at - 120°C. After 1 h a t
< - 90°C, the solution was allowed to reach room temperature and the products were hydrolyzed, affording a 94 :6
mixture of the two diastereomeric epoxides 6a in 90%
yield.[51Similar reaction using the pinacol ester of phenylboronic acid, instead of acetone, gave a 93 :7 mixture of
the diastereomeric boronates 7a.[71Addition of the carbenoids to isobutyraldehyde resulted in a 3 : 1 mixture of the
cis- and trans-epoxides 8a and 9a. Each of these epoxides
had a diastereomeric purity of > 90 :10.
[*I Prof. Dr. R. W. Hoffmann, DipLChem. M. Bewersdorf,
Dr. K. Ditrich, DipLChem. M. Kriiger, R. Stiirmer
Fachbereich Chemie der Universitat
Hans-Meenvein-Strasse, D-3550 Marburg (FRG)
I**] This work was supported by the Fonds der Chemischen Industrie and
the Deutsche Forschungsgemeinschaft (SFB260).
0 VCH VerlagsgesellschaffmbH, D-6940 Weinheim. 1988
R' = t B u
R' = nBu
R' = Me
ds = 81 : 19
ds = 60 : 40
75 : 25
Since the configuration of the product is established
during the halogen-metal exchange, it is of interest to determine which of the diastereotopic bromine atoms in 1 is
exchanged. To this end, the mixture of diastereomers 7a,
as well as 7b, was oxidized with alkaline H 2 0 2 to afford a
mixture of the known d i ~ l s [ ' ~
10/11. The main diastereomer in each case had the threo configuration 11. Thus,
the pro-ul bromine atom[''] in 1 is preferentially exchanged
with formation of the carbenoid 2. The (unproven) notion
that coordination of the organolithium compounds to the
trimethylsiloxy group might play a role in this process[31
was crucial in selecting 1 for these experiments.
Received: May 9, 1988 [Z 2750 IE]
German version: Angew. Chem. 100 (1988) 1232
OS70-0833/88/0909-1176 $ 02.50/0
Angew. Chem. Inr. Ed. Eng!. 27 (1988) No. 9
[ I ] Cf. J. D. Morrison (Ed.): Asymmetric Synthesis, Vol. 1-5. Academic
Press. New York 1983-1985.
[2] For example, diastereotopic protons in chiral sulfoxides: R. Viau, T.
Durst, J. Am. Chem. SOC.95 (1973) 1346; G. Solladie, R. G. Zimmermann, Teerrahedron Left.25 (1984) 5769; diastereotopic chlorine atoms
in chiral dichloromethaneboronic esters: D. S. Matteson, K. M. Sadhu,
M. L. Peterson, J . Am. Chem. SOC.108 (1986) 810.
[3] K. G. Taylor, W. E. Hobbs, M. S. Clark, J. Chaney, J. Org. Chem. 37
(1972) 2436; T. Harada, Y. Yamaura, A. Oku, Bull. Chem. SOC.Jpn. 60
(1987) 1715.
[4] l a was prepared by reaction of tert-butyloxirane with dibromomethyllithium at - 100°C in the presence of BF,-ether, followed by silylation.
l b was obtained by reaction of dibromomethyllithium at -95°C with
prenyl bromide [S], followed by hydroboration, oxidation, and silylation.
[ 5 ] J. Villieras, B. Kirschleger, R. Tarhouni, M. Rambaud, Bull. Soc. Chim.
Fr. 1986. 470, and references cited therein.
[6] G. Kobrich, H. Trapp, Chem. Ber. 99 (1966) 670, 680.
[7] Cf. G. Kobrich, H. R. Merkle, Chem. Ber. 100 (1967) 3371.
[8] The bis(phenylse1eno)acetal corresponding to l b gave a diastereomeric
ratio of 91 :9 upon selenium-lithium exchange and subsequent addition
to acetone.
[9] S. Kiyooka, H. Kuroda, Y. Shimasaki, Tetrahedron Lett. 27 (1986)
[lo] D. Seebach, V. Prelog, Angew. Chem. 94 (1982) 696; Angew Chem. l n l .
Ed. Engl. 21 (1982) 654.
A Synthetic Heparin-like Compound which still
Activates Antithrombin I11 although It Contains an
Open Chain Fragment instead of
a-L-Idopyranuronate* *
By Constant A . A . van Boeckel,* Jan E. M . Basten.
Hans Lucas, and Sjoerd F. van Aelst
The sulfated pentasaccharide la (Scheme l), which is
synthetically available,['] corresponds to a unique antithrombin 111 (AT-111) binding region of the anticoagulant
drug heparin. Ia catalyzes the AT-111-mediated inactivation of coagulation factor X a (anti-Xa activity in an amidolytic assay = 590 U/mg), but not of thrombin. Recently,
it has been e ~ t a b l i s h e d ' ~that
, ~ ~most of the charged groups
in heparin fragment la participate in the AT-111-activation
process. Moreover, the synthetic analogue Ic containing
an extra 3-0-sulfate at unit 6 elicits higher activity (i.e.
anti-Xa activity = 1270 U/mg) than the naturally occurring fragment.[,]
A special role should be ascribed to the rare, flexible
carbohydrate a-t-iduronic acid (unit 5) in compound Ia.[41
For instance, it has been shown[51that the carboxylate
group of the a-L-idopyranuronate moiety of Ia is essential
for AT-I11 activation, while the removal of its 2-0-sulfate
substituent (Scheme 1, compound Ib) leads to a fourfold
reduction of activity.[2b1The crucial question remains
whether the presence of the complex a-L-idopyranuronate
is essential for the biological activity of the heparin fragment.
To answer this question we synthesized a "ring-opened"
analogue (i.e. compound II), in which a-L-iduronic acid
(unit 5) is replaced by a n (R)-glyceric acid -2-0-CH2moiety (2,3 seco-2,3-di-nor-a-~-iduronic
acid). In addition,
compound I1 contains a n extra 3-0-sulfate group at unit 6
[*I Dr. C. A. A. van Boeckel, J. E. M. Basten, H. Lucas, S. F. van Aelst
Organon International B.V.
Scientific Development Group
P.O. Box 20, NL-5340 BH Oss (The Netherlands)
We thank Dr. J:R. Mellema and Mr. G. N . Wagenaars for the 'H-NMR
spectrum of 11, Drs. R . Gebhard for assistance with the syntheses, Mr.
Tl.G . van Drnrher for determining the anti-Xa activities and Dr. H . C . J .
Ottenheijm for discussions.
Angew. Chem. Int. Ed. Engl. 27 (1988) No. 9
Scheme 1. Compound la comprises the antithrombin activating region of
heparin. Compounds Ib and lc are synthetic analogues, which are respectively less and more active than the naturally occurring derivative la. The
synthetic analogue I1 is described in this communication: the a-L-iduronic
acid moiety (unit 5 ) has been replaced by an (R)-glyceric acid-OCH,-moietY
to compensate for the drop in activity caused by the absence of the 2-0-sulfate group at unit 5 (see above).
A key goal in the synthesis of I1 was the preparation of
a suitably protected and activated (R)-glyceric acid building block (i.e. compound 7) that could be coupled via a
2-oxymethylene function to the (low reactive) 4-hydroxy
group of compound 8[3a1
(see Scheme). Since this coupling
reaction is formally identical to a carbohydrate glycosidic
bond formation, we adopt a BF,. OEt,-catalyzed glycosidation with glycosyl fluorides[61for coupling of the ( R ) glyceric acid-2-0-CH2F derivative 7. The synthesis of 7
started from (R)-glyceric acid methyl ester 2, which was
prepared from D-serine (l)."]The primary hydroxy group
of 2 was protected selectively with a D M T group,[*]after
which the secondary hydroxy group was methoxymethylated to give 3 in high yield. Mild acid treatment afforded
compound 4, which was allylated in a two-step procedure
to provide derivative 5 in 58% overall yield. Acetolysis of 5
afforded compound 6 in quantitative yield. The latter was
treated with HF/pyridine['I to give the key building block
7 in 70% yield. Reaction of 7 with 8 , in the presence of
BF, .OEt2 afforded the corresponding coupled product in
84% yield, from which the temporary ally1 protective group
was cleaved by PdCI, treatment to give 9 in 40% yield. The
resultant aglycon 9 was then stereoselectively condensed
with the known glycon
in 65% yield using HgBr2/
Hg(CN)2 as promoter. The a-coupled product 12a was
first de-levulinoylated to give 12b and then coupled to
monosaccharide 11 [91 to give the fully protected pentasaccharide analogue 13 in 50% yield. Compound 13 was converted into the desired analogue II['"] in 22% overall yield
by the following ~ell-established['~~~~~~~~l
reaction sequence: (i) NaOH; (ii) Me3N.S03, DMF; (iii) H2/Pd; (iv)
pyridine .SO,, H 2 0 ; and gel permeation chromatography.
Analogue I1 displayed prominent AT-111-mediated antiXa activity (150 U/mg), thus proving that the biological
activity of a heparin-like fragment is retained when the
complex carbohydrate a-L-iduronic acid has been replaced
by a linear chain that is substituted by a correctly oriented
carboxylate group. Preliminary conformational analysis
studies reveal that the conformational freedom of the linear moiety of I1 is restricted considerably. Thus, vicinal
proton-proton coupling constants and NOE data of com[*I Abbreviations: D M T = 4,4'-dimethoxytrityl: All = Allyl; Lev = levulinOYl: Ac = acetyl; Bz = benzoyl; Bn = benzyl; T H F = tetrahydrofuran;
D M F = N,N-dimethylformamide; MS = molecular sieve.
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim. 1988
0570-0833/88/0909-1177$ 02.5010
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asymmetric, induction, atom, diastereotopic, bromine, replacement, lithium
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