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Synthesis of 3′-substituted-2′,3′-dideoxynucleoside analogs as potential anti-aids drugs
Tetrahedron Letters,Vol.30,No.l5,pa Printed in Great Britain
1955-1958,1989
0040-4039/89 $3.00 Pergamon Press plc
SYNTHESIS OF 3'-SUBSTITUTED-2',3'-DIDEOXYNUCLEOSIDE
+ .oo
ANALOGS
AS POTENTIAL ANTI-AIDS DRUGS Michel
Maillard',
Abdesslem
Fara_i2,
Francois
Frappier’,
David S. Grierson'*, and Claude Institut
de
Chimie
des
Substances
Florent',
Jean-Claude
Monneret’*. CNRS,
Naturelles,
91198
Gif
sur
Yvette,
France. Unite associee
piques,
Universite
des Sciences Pharmaceutiques V, 4 avenue de l’Observatoire, 75006 Paris,
Paris
Faculte
3 '-Aaino-3' -deoxythy.nidine
Abstract: overall for
au CNRS no 484,
yield their
from
Five
rhymidine.
anti-HIV
2
was
derivatives
of
infected
agd1,1 s.
a DNA copy host
1
cell
3’-deoxychymidinr gression These
parently close
vations,
they not
the
.
the
To
enzyme viral
9
and
steps
compound
and 17 --
in
were
67%
tested
have
th+
immune
mode
may indicate
phosphodiester
RNA (reverse
to
sys~zm through
be
action to
they
of
that
it
for
its
is
the
action
antiviral
period
in
of
act
as
these
molecules
almost
devoid
some
aspect
as
of
in
they
are
2
and
Intrigued
reactivity
of
syn-
the
non-
the
the
pro-
administered.
DNA c.hain
However 3
of
the
3’-azido-
retarding
nascent
compounds
in
particular
the
activity.
the
found
agents
terminator’.
chain
during
not
which
RT into
of
is
and
as
development
formation
and
analogs,
effective
the
AZT are
bond
transcription),
during
groups,
of
resemblance
ca’:alyzi‘s
proven
3’-hydroxyl
sol?
virus (HIV), the etiological agent of AIDS,
2’,3’-dideoxynuc:eoside
date,
incorporated
the
structural
which
of
on
are
lack
Thi:;
(AZT)
attack
of
because
a
i
compounds
of
six
CRT) stands out as a prime target for the
tha +2nzyme reverse rranscriptase thesis
in
activity.
In cha fight against the human immunodeficlency c~*mnt t!cl-ap*utic
prepared
et BioloFrance.
3* by
where,
this
is
which these
azidc
ap-
bear obser-
group
L
1
which
activity chemically
is
also
of
a series with
responsible
the
of active
action’,
we
have
3 ‘-amino-3’-deoxythymidine site
of
BT
HO
(or
one
v 0
I
R
1955
prepared
derivatives of
the
earlier
1 R=N, 2 R=CN 1 R=SCN
and
have
which
can
enzymes).
tested potentially
the
anri-HIV interact
in
1956 3'-Amino-3'-deoxythymidine dine
4 by
substantial via
placement, thymidine
derivative
The obtention
me is important
by azide
of a mixture
ted
product.
at the
(silica;
Mesylate
reaction
of -5 with
of a THF
solution
matography mp
removed
for
this
step
achieved
matography
with
without
DOWEX-50
lit12
DBU
of 7
chloride
was
of
under
log scale)
bromide
almost
of the analogs
in methanol
+ 9" (MeOH))
11"
purification the
in THF. 3
at O'C
Introduction
in hot DMF6.
The
5'-deprotection intermediate
after and
AZT.
to remove
of hydrogen
quantitative
isolated
in 85%
(silica)
sodium yield
by reaction
preparation
of
analogs
85%) 7b, and intermediate
[ajD -
(CHC13),
8"
+ 28"
(MeOH),
aside
as
was
protec-
obtained
chromatogra-
1
aside
prepared
silica
yields
flash
were
treatment
of
Pd/C
then
solid
(mp
as follows.
Reaction
chrocar-
compound
8
(0.1 equiv.)
3'-Amino-3'-deoxythymidine
a colorless
was
8 (mp 80-82°C
AZT
of
crystals
at C-3'
by silica
addition
chro-
are obtained
function
steps
by
treatment flash
(colorless
reduction
involved
then
Subsequent
and
Comparable
the resin,
achieved
acetate
after
gave
the
purification
90%).
followed
in CH2C12
150°C
(hexane-acetone);
reaction the
oxidized
of Lwith
3'-hydrazino
of 2
with
15 - and
12,
aqueous the
1_2 (mp 150°C;
containing
Deprotection
90%) whereas
phine
than
work-up
purification
This
overnight.
yield
lo-12 from zwas --
formate l3 in DMF
The
(Y = 95%).
the
interme-
alcohol 10
flash
was
derivative
of
with
of the 3',5'-bis-silyla-
5'-0-thexyldimethylsilyl
in 85% yield
filtration
containing
lorophenyl
Cal,
sche-
group.
after
(acetone))
by normal
cyanamide
(silica;
11 (EtOH)) was prepared by reaction of Ewith - (mp 105-106°C CH2C12 (Y = 48%), and the relatively sensitive aminonitrile
MeOH,
in this
9 was
159-160°C
thus
(EtOH);
160-161°C).
Preparation
For
dis-
in the derived
+ 8" (acetone))
((5%)
in 98% yield'l.
the
1 atm.
+
in pyridine
2h) followed
isolated
1:2).
[a],
This
0-trityl
chloride
amounts
the 2,3'-anhydrothymidine
NaN
with
isolation
in
thymi-
a 3'-O-mesyl-
to work
group.
[a]D
thexyldimethylsilyl
(acetone);
hydride
(CHC13))
and
in
group
it easier
employed
(acetone);
8:2) from minor
(reflux
1:l) gave
sodium
of AZT
pure
MeOH,
96-98°C
(H+) in methanol,
and reaction obtained
(mp
(hexane-EtOAc,
out
from entails
intermediate
by a 0-thexyldimethylsilyl
of 4 with
- 60" (acetone),
+ 39”
group
of the 3'-azido
as a discrete
than the conventionally
methanesulfonyl
by reaction [aID
(EtOH);
ried
2
using
the mesylate
by reduction
2 (mp 178-180°C
CH2C12:
of 6 with
[a],
of
yield
1). This
(scheme
(Y = 50%) h,9 we found
step
5' position
(hexane-EtOAc,
162-164°C.
in 67% overall
of the mesyl group in 6 (when R = trityl) leads to for8 azide products. Although 2,3'-anhydrothymidine itself
of 3'-epimeric
from the reaction
separation
and
sequence'
displacement
is more readily
in 65% yield
steps
intermediate,
followed
ion6
5'-0-"hexyldimethylsilylthymidine
phic
in six
of an established
from 4 in a single
substituted
ting group
prepared
of the 2,3'-anhydronucleoside
as direct
can be prepared diates
was
a 2,3'-anhydrothymidine
product7.
mation
2
amelioration
of
14
imlde
as
(Bu4NF,
the
was
was
to give
THF)
gave
CC14,
of the 5'-hydroxyl
1_1.(mp
gave
acid
hydrazino
followed
gave group
followed
with
194°C
the
in
(MeOH);
(CHCl3-hexane)i
and
triphenylphos-
isonitrile 14 ).
the initially 15
(SnCl2,
2,4,5-trich-
3-amino-3'-deoxythymidine
by loss of nitrogen.
after
by KCN.
reduced
12 (mp 176-178°C
triethylamine,
group
in pyridine-
in 35% yield
reacted
[a]D
Carbamate
95:5).
first
(Y = 72% for the last two steps
hydroxylaminr-O-sulfonic derivative
8
cyanogen
(CHCl3);
chloroformate
and NaHSC3
in
+ 12" (CHCl3))
of 12 with
[a], + 9.5' (CHC13)
to the corresponding
group
with
92°C
12 was obtained
ethyldiisopropylamine
treatment
by liberation
[a],
of 9
(mp
CH2C12:MeOH,
methyl
formaldehyde
azide
10
formed
12
(mp
17 rather product
is
1957
2 R=H
jJ
RskxyldiMeSi.R’=NH~
u
R D ?he.xyldiicSi
u
R=H,R’.NHCHO
xl u
R=CN
u
R=CO&H,
. R’=NIICHO
rlli
lx u
Reagents : i) ‘11e@iiM&iC1,
L
R=CHICN
imidax&, DMF. 0” ; ii) I&Cl, pydine,
J_& R=H,R’=NC
0 *; iii) DBU, THF, reflux; iv) NaN3, DMF, 120’;
v) JXXVEX 50 (l-I+), CH,OH; vi) H,, PdjC, CH,OH; vii) BrCN, NaOAc, CH,OK
20”; viii) ClCO&Hy, Oob
pyridine-CH,Cl,; ix) N&lSC$. H&O, KCN, 60° - 20”; x) SnClz, C&OH; xi) 2,4,S-trkhlorophed
DLEA, DMF, O-20”; xii) (C41-Q4NF, THF. 20’; xiii) CC&, Et@, (P&P, CH&z, BY.
fecal%
1958
Nucleoside 1 in HIV
CEM
analogs
compounds
The
cells.
induced
wdre
I.N.S.E.R.M. and
Institut
These
2
Furman,
are
activity
their
for
were
performed
inactive were
grateful
RhBne-Poulenc
for
cytotoxicity in
compared
by
to Dr Werner for
the
the
the
and of
range
to AZT
supported
Santk,
against
(2 PM)
(Directeur
biological
used
to
Sci.
H; Brcder, P.A.;
4780
J.A.:
St
Boloqnesi, 8333
83,
M.;
S, Nature,
Fyfe,
S.N.;
USA,
Okabe,
Sun,
Herdewijn,
effects
on all
as reference.
de
Recherche
which
Externe and
Drs
were
CNRS)
performed
at
325,
773
Claire,
D.P.;
J.L.;
Freeman,
(1987).
M.H.;
Broder,
Wienhold,
S.;
K.;
Mitsuya,
H.;
Rideout, Barry,
D.W.:
Proc.
R.-C.;
Tam,
S.Y.-ii.:
Todaro,
L.J.;
Coffen,
D.L.;
J.
P.;
Balzarini,
H.: J. Med.
J.;
Chem..
De Clercq,
32, 1270
ACad.
Org.
2,
Chem.,
R.;
Baba,
M.:
297
(19881.
Broder,
Oppenheimer,
Glinski,
R.-P.;
Kha.?. M.S.; KaYal&,ias,R.L. i J. erg. Chelll.,Lg8, 4299 (1973).
Fulmer
Shealy,
N.J.;
6.; Pauwels,
S.;
Vander-
(19871
A.L.;
483
G.A.;
NatI.
11986).
Handlon,
Pharmaceut.
Y_;
Allen
O'Dell,
Singh,
M.P.;
Micetich,
C.;
Res.. 2,
Shannon,
W.M.;Arnett,
G.;
J.
Med.
Chem.,
29, -
(1986).
bj Naiti, c)
HIV-
(1978).
haeghe,
a)
of
100 JJM but
de Recherche
tests
LAV
inhibitory
0.05
u Contrat
a
strain
Paris.
Lehrman,
S.M.;
Mungall,
1659
9
compared
Assays
'I. We
tested
and footnotes.
Mitsuya,
8
were
investigations
n" 882011
Pasteur,
were
to be completely
found
1
4
15-17 --
products
Lemaitre,
References
3
and
cytopathog?niclty.
Aknouledgements;
Zerial
lo-12 --
w.s.;
Greene,
G.L.;
R.G.;
Heavener,
Tetrahedron G.A.;
Letters,
Heitsinger,
27, 1423
R.L.;
J.
(1986).
Org.
them.,
(1975).
Matsuda, Kowollik,
d.;
Watanabe,
10
Wetler,
11
The spectral
12
Lin.
H.; Oertle,
T.-S.:
data
x.;
Prusoff,
.?artinez J.; Laur,
19
!.,?pe 1 R. ; Kleinstuck,
15
Wallace,
16
Dolduras.
R.G.: G.A.;
FOX, J.J.;
P.; Tetrahedron
Tetrahedron
Letters,
w.H.; J. Med.
R.;
Ziehn,
Aldrichimica Kollonitsch,
26,
MS) are in agreement
J.; Synthesis,
in France
J. Org. Chem., e5, 3274 (1988).
K.; Langen,
(IR, NMR,
13
(Received
K.A.;
E.; Gaertner,
Chem.,
979
12
5515
(1985). the assigned
(19691.
structures.
(1978).
(1982). Angew.
Chem.
Internat.
Edn, l-0, 132
(I), 3 (1980).
3,; J. Am.
28 December
3863
with
21, 109
K.-D.;
Acta,
Letters,
Chem.
1988)
Sot.,
100,
341
11978).
(1971).
42,
1955-1958,1989
0040-4039/89 $3.00 Pergamon Press plc
SYNTHESIS OF 3'-SUBSTITUTED-2',3'-DIDEOXYNUCLEOSIDE
+ .oo
ANALOGS
AS POTENTIAL ANTI-AIDS DRUGS Michel
Maillard',
Abdesslem
Fara_i2,
Francois
Frappier’,
David S. Grierson'*, and Claude Institut
de
Chimie
des
Substances
Florent',
Jean-Claude
Monneret’*. CNRS,
Naturelles,
91198
Gif
sur
Yvette,
France. Unite associee
piques,
Universite
des Sciences Pharmaceutiques V, 4 avenue de l’Observatoire, 75006 Paris,
Paris
Faculte
3 '-Aaino-3' -deoxythy.nidine
Abstract: overall for
au CNRS no 484,
yield their
from
Five
rhymidine.
anti-HIV
2
was
derivatives
of
infected
agd1,1 s.
a DNA copy host
1
cell
3’-deoxychymidinr gression These
parently close
vations,
they not
the
.
the
To
enzyme viral
9
and
steps
compound
and 17 --
in
were
67%
tested
have
th+
immune
mode
may indicate
phosphodiester
RNA (reverse
to
sys~zm through
be
action to
they
of
that
it
for
its
is
the
action
antiviral
period
in
of
act
as
these
molecules
almost
devoid
some
aspect
as
of
in
they
are
2
and
Intrigued
reactivity
of
syn-
the
non-
the
the
pro-
administered.
DNA c.hain
However 3
of
the
3’-azido-
retarding
nascent
compounds
in
particular
the
activity.
the
found
agents
terminator’.
chain
during
not
which
RT into
of
is
and
as
development
formation
and
analogs,
effective
the
AZT are
bond
transcription),
during
groups,
of
resemblance
ca’:alyzi‘s
proven
3’-hydroxyl
sol?
virus (HIV), the etiological agent of AIDS,
2’,3’-dideoxynuc:eoside
date,
incorporated
the
structural
which
of
on
are
lack
Thi:;
(AZT)
attack
of
because
a
i
compounds
of
six
CRT) stands out as a prime target for the
tha +2nzyme reverse rranscriptase thesis
in
activity.
In cha fight against the human immunodeficlency c~*mnt t!cl-ap*utic
prepared
et BioloFrance.
3* by
where,
this
is
which these
azidc
ap-
bear obser-
group
L
1
which
activity chemically
is
also
of
a series with
responsible
the
of active
action’,
we
have
3 ‘-amino-3’-deoxythymidine site
of
BT
HO
(or
one
v 0
I
R
1955
prepared
derivatives of
the
earlier
1 R=N, 2 R=CN 1 R=SCN
and
have
which
can
enzymes).
tested potentially
the
anri-HIV interact
in
1956 3'-Amino-3'-deoxythymidine dine
4 by
substantial via
placement, thymidine
derivative
The obtention
me is important
by azide
of a mixture
ted
product.
at the
(silica;
Mesylate
reaction
of -5 with
of a THF
solution
matography mp
removed
for
this
step
achieved
matography
with
without
DOWEX-50
lit12
DBU
of 7
chloride
was
of
under
log scale)
bromide
almost
of the analogs
in methanol
+ 9" (MeOH))
11"
purification the
in THF. 3
at O'C
Introduction
in hot DMF6.
The
5'-deprotection intermediate
after and
AZT.
to remove
of hydrogen
quantitative
isolated
in 85%
(silica)
sodium yield
by reaction
preparation
of
analogs
85%) 7b, and intermediate
[ajD -
(CHC13),
8"
+ 28"
(MeOH),
aside
as
was
protec-
obtained
chromatogra-
1
aside
prepared
silica
yields
flash
were
treatment
of
Pd/C
then
solid
(mp
as follows.
Reaction
chrocar-
compound
8
(0.1 equiv.)
3'-Amino-3'-deoxythymidine
a colorless
was
8 (mp 80-82°C
AZT
of
crystals
at C-3'
by silica
addition
chro-
are obtained
function
steps
by
treatment flash
(colorless
reduction
involved
then
Subsequent
and
Comparable
the resin,
achieved
acetate
after
gave
the
purification
90%).
followed
in CH2C12
150°C
(hexane-acetone);
reaction the
oxidized
of Lwith
3'-hydrazino
of 2
with
15 - and
12,
aqueous the
1_2 (mp 150°C;
containing
Deprotection
90%) whereas
phine
than
work-up
purification
This
overnight.
yield
lo-12 from zwas --
formate l3 in DMF
The
(Y = 95%).
the
interme-
alcohol 10
flash
was
derivative
of
with
of the 3',5'-bis-silyla-
5'-0-thexyldimethylsilyl
in 85% yield
filtration
containing
lorophenyl
Cal,
sche-
group.
after
(acetone))
by normal
cyanamide
(silica;
11 (EtOH)) was prepared by reaction of Ewith - (mp 105-106°C CH2C12 (Y = 48%), and the relatively sensitive aminonitrile
MeOH,
in this
9 was
159-160°C
thus
(EtOH);
160-161°C).
Preparation
For
dis-
in the derived
+ 8" (acetone))
((5%)
in 98% yield'l.
the
1 atm.
+
in pyridine
2h) followed
isolated
1:2).
[a],
This
0-trityl
chloride
amounts
the 2,3'-anhydrothymidine
NaN
with
isolation
in
thymi-
a 3'-O-mesyl-
to work
group.
[a]D
thexyldimethylsilyl
(acetone);
hydride
(CHC13))
and
in
group
it easier
employed
(acetone);
8:2) from minor
(reflux
1:l) gave
sodium
of AZT
pure
MeOH,
96-98°C
(H+) in methanol,
and reaction obtained
(mp
(hexane-EtOAc,
out
from entails
intermediate
by a 0-thexyldimethylsilyl
of 4 with
- 60" (acetone),
+ 39”
group
of the 3'-azido
as a discrete
than the conventionally
methanesulfonyl
by reaction [aID
(EtOH);
ried
2
using
the mesylate
by reduction
2 (mp 178-180°C
CH2C12:
of 6 with
[a],
of
yield
1). This
(scheme
(Y = 50%) h,9 we found
step
5' position
(hexane-EtOAc,
162-164°C.
in 67% overall
of the mesyl group in 6 (when R = trityl) leads to for8 azide products. Although 2,3'-anhydrothymidine itself
of 3'-epimeric
from the reaction
separation
and
sequence'
displacement
is more readily
in 65% yield
steps
intermediate,
followed
ion6
5'-0-"hexyldimethylsilylthymidine
phic
in six
of an established
from 4 in a single
substituted
ting group
prepared
of the 2,3'-anhydronucleoside
as direct
can be prepared diates
was
a 2,3'-anhydrothymidine
product7.
mation
2
amelioration
of
14
imlde
as
(Bu4NF,
the
was
was
to give
THF)
gave
CC14,
of the 5'-hydroxyl
1_1.(mp
gave
acid
hydrazino
followed
gave group
followed
with
194°C
the
in
(MeOH);
(CHCl3-hexane)i
and
triphenylphos-
isonitrile 14 ).
the initially 15
(SnCl2,
2,4,5-trich-
3-amino-3'-deoxythymidine
by loss of nitrogen.
after
by KCN.
reduced
12 (mp 176-178°C
triethylamine,
group
in pyridine-
in 35% yield
reacted
[a]D
Carbamate
95:5).
first
(Y = 72% for the last two steps
hydroxylaminr-O-sulfonic derivative
8
cyanogen
(CHCl3);
chloroformate
and NaHSC3
in
+ 12" (CHCl3))
of 12 with
[a], + 9.5' (CHC13)
to the corresponding
group
with
92°C
12 was obtained
ethyldiisopropylamine
treatment
by liberation
[a],
of 9
(mp
CH2C12:MeOH,
methyl
formaldehyde
azide
10
formed
12
(mp
17 rather product
is
1957
2 R=H
jJ
RskxyldiMeSi.R’=NH~
u
R D ?he.xyldiicSi
u
R=H,R’.NHCHO
xl u
R=CN
u
R=CO&H,
. R’=NIICHO
rlli
lx u
Reagents : i) ‘11e@iiM&iC1,
L
R=CHICN
imidax&, DMF. 0” ; ii) I&Cl, pydine,
J_& R=H,R’=NC
0 *; iii) DBU, THF, reflux; iv) NaN3, DMF, 120’;
v) JXXVEX 50 (l-I+), CH,OH; vi) H,, PdjC, CH,OH; vii) BrCN, NaOAc, CH,OK
20”; viii) ClCO&Hy, Oob
pyridine-CH,Cl,; ix) N&lSC$. H&O, KCN, 60° - 20”; x) SnClz, C&OH; xi) 2,4,S-trkhlorophed
DLEA, DMF, O-20”; xii) (C41-Q4NF, THF. 20’; xiii) CC&, Et@, (P&P, CH&z, BY.
fecal%
1958
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