Synthetic studies on the BCDF ring system of ristocetin A via ruthenium-promoted SNAr reaction

Article abstract of DOI:10.1016/S0040-4039(01)01928-1

Ruthenium-promoted intramolecular S_NAr reaction has allowed the construction of the 16-membered BCD model macrocycle of ristocetin A that incorporates the required arylserine residue as the C ring, and includes a fully functionalized F ring.

Full text of DOI:10.1016/S0040-4039(01)01928-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8765–8768
Synthetic studies on the BCDF ring system of ristocetin A via
ruthenium-promoted SNAr reaction
Anthony J. Pearson* and Sarunas Zigmantas
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Received 13 September 2001; accepted 9 October 2001
Abstract—Ruthenium-promoted intramolecular SNAr reaction has allowed the construction of the 16-membered BCD model
macrocycle of ristocetin A that incorporates the required arylserine residue as the C ring, and includes a fully functionalized F
ring. © 2001 Elsevier Science Ltd. All rights reserved.
OR1
The vancomycin group of antibiotics1 is of contempo-
O
O
O
rary interest to synthetic chemists because of the clinical
importance as well as the structural complexity of these
molecules. Moreover, the recent occurrence of van-
comycin-resistant strains of infectious bacteria2 pro-
vides the impetus for the development of total
syntheses3 of vancomycin. Ristocetin A (1) has struc-
tural features that are similar to vancomycin, but incor-
porates an additional 14-membered biaryl ether
connection between amino acid residues F and G. The
construction of the biaryl ether linkage in these struc-
tures poses a significant challenge due to the presence
of base-sensitive amino acid residues, especially aryl-
glycine derivatives.4 Studies toward the total synthesis
of ristocetin A in our group have focussed on the use of
ruthenium-promoted SNAr reactions to incorporate the
diaryl ethers.5 Complexation of the aromatic subunits
with ruthenium is accomplished under very mild condi-
tions, etherification can be effected without appreciable
racemization of arylglycines as well as phenylalanine
subunits, and demetallation under simple photolytic
conditions allows release of the desired organic struc-
ture as well as recycling of the ruthenium complex
precursor.
E
R2O
O
OH
O
O
H
N
H
N
H
H
H
NH2
N
H
N
H
N
H
H
H
H
O
HN
MeO2C
O
O
G
HO
OH
OR3
Me
OH
HO
R1, R2, R3 = sugars
RISTOCETIN ( 1)
Our synthesis began with the chlorocinnamic esters 2 (a
and b), which were subjected to the Sharpless asymmet-
ric aminohydroxylation7 protocol to afford directly the
N-Boc-protected arylserines 3 (Scheme 1). It should be
noted that the N-Cbz analogue of 3 has previously been
reported,7 but the use of the benzyloxycarbonyl protect-
ing group is precluded for preparation of arene ruthe-
nium complexes because of the competition between
two aromatic rings. The absolute stereochemistry of 3a
was confirmed by conversion to the known Cbz deriva-
tive (CF3CO2H, CH2Cl2, 0°C; CbzCl, Na2CO3) and
comparison of the optical rotation with this compound.
The enantiomeric excess was determined by conversion
to the Mosher amide8 (CF3CO2H, CH2Cl2, 0°C;
MTPA-Cl, TMP, CH2Cl2, 0°C), followed by NMR
analysis. Complexation of 3a under the conditions pre-
viously reported5 afforded complex 4 (R=Me) in excel-
lent yield.
The present study focuses on the use of ruthenium
complexes of chloroarylserine derivatives that represent
the C ring of the ristocetin structure, to determine
whether there are likely to be any problems associated
with this subunit, and if so, their solution. We have
previously reported studies that utilize arylserine–ruthe-
nium systems that represent the E ring, which is
diastereomeric with the C ring.6
At this stage we examined the stability of complex 4 to
the conditions that are required for intramolecular
* Corresponding author. Fax: (+1)216-368-3006; e-mail: ajp4@
po.cwru.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01928-1

8766
A. J. Pearson, S. Zigmantas / Tetrahedron Letters 42 (2001) 8765–8768
+
RuCp
K2OsO2(OH)4,
Cl
Cl
Cl
(DHQD)2AQN (6 mol%),
BocNClNa, PrOH/H2O
CpRu(CH3CN)3PF6
ClCH2CH2Cl, ∆, 5h
HO
RO
-
HO
RO
PF6
RO
25 ˚C, 1.5h
95%
NHBoc
NHBoc
O
O
O
4
3 (a): 35% yield; 67% ee
(b): 48% yield; 95% ee
2 (a) R = Me
(b) R = Et
Base
+
1) TBSOTf,
2,6-lutidine,
CH2Cl2, 0 ˚C
2) LiOH, t-BuOH/H2O, 0 ˚C
3) MeNH2, EDCI, HOBt, CH2Cl2
+
RuCp
RuCp
Cl
Cl
Cl
1) CpRu(CH3CN)3PF6
ClCH2CH2Cl, ∆, 1h
TBSO
MeHN
-
-
TBSO
MeHN
PF6
PF6
2) CF3CO2H,
CH2Cl2, 0 ˚C, 3h
RO
NHBoc
NHBoc
NH2.TFA
O
O
O
5
92%
7
6
80% overall yield from 3b
Scheme 1.
The stereochemical homogeneity of 6 was confirmed
SNAr reaction that would be used later in the
sequence. Treatment of the complex with mild base
(Cs2CO3 or sodium 2,6-di-t-butylphenoxide) resulted
in dehydra- tion to afford 5. This result indicates that
steps must be taken to prevent this elimination reac-
tion if the arene–ruthenium system is to be used for
construction of the ristocetin BCD ring structure. It
may be noted that similar dehydration does not occur
by NMR spectroscopy.
In considering the approach that we would ultimately
use for the total synthesis of the aglycone of ristocetin
A, we focussed on developing a strategy that would be
most efficient in its use of ruthenium. Accordingly, our
preference would be to use as few steps as possible
after the preparation of complex 7, which requires that
we couple this compound with a building block repre-
senting the ABDF sequence of arylamino acids. For
the present study, which was to establish the feasibility
of this approach, we decided to forego the use of the
AB biaryl structure and instead use a tripeptide corre-
sponding approximately to the BDF sequence. Since
methodology for construction of the biaryl is already
known,3 we felt that this approach would lay the nec-
essary groundwork for a final assault on the actual
total synthesis of ristocetin.
with the ruthenium complex of the ring
E
chloroarylserine.6 Logically, one would expect that
lowering the acidity of the proton alpha to the car-
bonyl group, and/or tempering the leaving group
capability of the benzylic oxygen, would ameliorate
the situation. This indeed proved to be the case: use of
either the N-methylamide derivative, or the silyl ether
of 4 produced a system that was quite stable to base.
In order to be assured that a synthesis of the BCD
ring structure of the target molecule could be com-
pleted, we chose to use the silyl ether/N-methylamide
7, for two reasons: the dehydration is prevented by
both measures, and the silyl ether (TBS) renders the
compound soluble in organic solvents that are used
for subsequent coupling reactions. Evans’ group have
reported an efficient procedure for conversion of N-
methylamide to carboxylic acid that is compatible with
the vancomycin system, so one is assured that this will
not present difficulties later in the synthesis.9 (In fact,
we did survey the use of the free hydroxyl derivative
corresponding to 7, as well as the TBS ether of 4 in
the later reactions. In the first case, solubility problems
arose, while in the second we were unable to secure
good yields in the cycloetherification step that is used
for the diaryl ether construction.) Conversion of the
ethyl ester derivative 3b to the fully protected methyl-
amide 6 proceeded uneventfully, and complexation fol-
lowed by N-deprotection afforded 7 in good yield.
Scheme 2 summarizes the successful construction of an
advanced intermediate that represents the BCDF ring
structure of ristocetin. Coupling of the 4-
methoxyphenylglycine methyl ester 8 with the known
D ring precursor 9,10 using standard conditions,
afforded good yield of the dipeptide derivative 10 after
chromatographic purification to remove minor
amounts of epimerized material. Simultaneous removal
of the benzyl ether and Cbz protecting groups, by
standard hydrogenolysis, followed by coupling with
the F ring building block 11, previously reported by
us,6 produced the protected tripeptide 12, again in
good yield. Hydrolysis of the methyl ester of 12
afforded the corresponding carboxylic acid in 73%
yield, with no detectable epimerization of any of the
arylglycine residues (by NMR). The carboxylic acid
was coupled with ruthenium complex 7 under stan-
dard conditions to yield 13, though difficulties with

A. J. Pearson, S. Zigmantas / Tetrahedron Letters 42 (2001) 8765–8768
8767
OMe
BnO
OBn
O
OMe
H
EDCI, HOAt, TMP,
CH2Cl2, 0 ˚C, 2h,
then rt, 14h
NH2
BnO
HO
OBn
MeO
O
H
N
H
MeO
NHCbz
71%
H
O
NHCbz
H
OMe
O
10
9
8
O
OMe
1) H2, 10% Pd-C
H
NHCbz
OBn
HO
2) 11, EDCI, HOAt,
TMP, 0 ˚C, 2h,
then rt, 15h
MeO
OMe
Me
11
+
-
RuCp
HO
OH
PF6
OMe
Cl
HO
OH
1) LiOH, THF/MeOH/H2O
2) 7, EDCI, HOAt, TMP
O
O
H
N
TBSO
MeHN
H
H
NHCbz
OBn
O
O
H
MeO
N
H
H
N
H
H
NHCbz
O
N
H
N
H
H
H
O
O
MeO
OMe
Me
MeO
OBn
12
OMe
Me
13
75% overall from 10
OMe
1) Cs2CO3, DMF, rt, 6h
2) hν, Rayonet reactor,
350 nm, CH3CN, 24h
O
OH
Hb
C
D
TBSO
MeHN
Ha
O
O
H
N
H
H
NHCbz
OBn
N
H
N
31% overall from 12
H
H
H
O
O
B
F
MeO
OMe
Me
14
Scheme 2.
rigorous purification of this compound, without mate-
rial loss, prompted us to use the crude product in the
subsequent etherification/demetallation, which pro-
ceeded smoothly to afford the cyclic compound 14 in
good overall yield (45% from the carboxylic acid; 31%
from 12). We did not observe any evidence for epimer-
ization or elimination from NMR spectroscopy of the
crude product from this sequence of reactions.
Conclusions
A 16-membered BCD model of ristocetin A was pre-
pared by using ruthenium-promoted intramolecular
SNAr reaction under conditions that are sufficiently
mild to avoid epimerization. Application of ruthenium–
arylserine complex 7 was successful for the construction
of the biaryl ether linkage. The chemistry developed in
this study is currently being extended to the total
synthesis of the aglycone of ristocetin A.
Successful formation of the 16-membered ring of 14 is
evidenced by the expected3,5,6 upfield NMR shift of one
of the ring-D protons, as a result of the shielding effect
of the neighboring C ring, underneath which this pro-
ton is situated (see Ha versus Hb in structure 14). In the
present case the observed chemical shifts (600 MHz) are
l 5.88 (Ha) and 6.53 (Hb), which may be compared with
the chemical shifts for the same protons in the cycliza-
tion precursors (e.g. both at l 6.37 for 12).
Acknowledgements
We are grateful to the National Institutes of Health for
financial support of this research (GM-36925).

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Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc.
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