Studies toward the total synthesis of ristocetin A aglycone using arene-ruthenium complexes as SNAr substrates: construction of an advanced tricyclic intermediate

Article abstract of DOI:10.1016/j.tetlet.2008.01.094

Ruthenium-mediated S_NAr reactions are used to construct the diaryl ether linkages in two key intermediates for a projected total synthesis of the aglycone of ristocetin A.

Full text of DOI:10.1016/j.tetlet.2008.01.094

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1922–1926
Studies toward the total synthesis of ristocetin A aglycone using
arene–ruthenium complexes as SNAr substrates: construction of
an advanced tricyclic intermediate
Anthony J. Pearson *, Diana V. Ciurea, Avdhoot Velankar
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Received 9 November 2007; accepted 24 January 2008
Available online 30 January 2008
Abstract
Ruthenium-mediated SNAr reactions are used to construct the diaryl ether linkages in two key intermediates for a projected total
synthesis of the aglycone of ristocetin A.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
gence of vancomycin resistant strains of infectious bacteria.2
Recent increased activity in searching for new antibacterials
is expected to lead to solutions to this problem.3
Ristocetin A (2) is structurally related to vancomycin,
but possesses different glycoside units, as well as different
Vancomycin (1)1 has captured the interest of synthetic
chemists for a number of years, as a result of its molecular
complexity and, perhaps more importantly, the recent emer-
OH
HO
OH
O
OH
O
OH
OH
O
OH
HO
O
O
O
HO
OH
O
HO
OH
OH
HO
O
O
HO
O
O
O
O
O
O
E
C
NH2
HO NH2
Cl
H
O
O
O
O
D
C
E
O
H
H
D
OH
HO
H
Cl
H
O
OH
O
H
N
H
N
H
H
H
H
O
H
N
N
H
H
H
H
H
N
H
NH
O
N
N
NHMe
H
H
N
N
H
O
O
NH2
H
O
HN
H
MeOOC
H
O
H
H
O
O
F
B
HN
H
HOOC
O
B
HO
O
G
A
O
NH2
Me
OH
A
HO
OH
OH
HO
OH
OH
HO
O
Vancomycin (1)
OH
OH
Ristocetin A (2)
*
Corresponding author. Tel.: +1 216 368 5920; fax: +1 216 368 3006.
E-mail address: ajp4@case.edu (A. J. Pearson).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.094

A. J. Pearson et al. / Tetrahedron Letters 49 (2008) 1922–1926
1923
F and G amino acid residues and an additional ring that is
formed by aryl ether bridging between them. Ristocetin,
teicoplanin (not shown, but structurally related to risto-
cetin), and vancomycin are the three most important mem-
bers of this class of antibiotics, and therefore prime
targets for total synthesis efforts. Several total syntheses
of vancomycin aglycone have been reported,4 and Nico-
laou has completed the synthesis of vancomycin itself.5
Two independent total syntheses of the teicoplanin agly-
cone have been reported,6 and Boger has completed a total
synthesis of ristocetin A aglycone.7 While ristocetin A
exhibits antibiotic activity similar to vancomycin, its clini-
cal use was discontinued owing to fatalities8 that were
likely the result of platelet aggregation caused by the anti-
biotic.9 The aglycone of ristocetin has been shown to be a
useful lead compound for development of new antibiotics
that exhibit activity against vancomycin resistant
bacteria.10
Our approach to the total synthesis of these compounds
rests on the ability of a transition metal, coordinated g6 to
an aromatic ring, to induce nucleophilic attack on the
arene. When the aromatic ligand is a halobenzene deriva-
tive, most commonly a chloroarene (and therefore readily
prepared), the result is nucleophilic substitution. Ruthe-
nium is especially useful for such applications, since it is
strongly activating, can be attached to the aromatic moiety
without detriment to a wide range of functional side chains
(in the present case amino acids), is stable to numerous
chemical transformations, and can be removed in a reus-
able form by non-invasive photochemical methods. This
overall process is illustrated schematically in Figure 1.
Scheme 1) that illustrates the compatibility of arene–ruthe-
nium chemistry with complex molecular synthesis. Our
strategy was to construct the left hand portion first, as
intermediate 4, which would then be coupled to the E–F–
O–G intermediate 5, or a similar building block. The cou-
pling product would then be subjected to SNAr cyclization,
demetallation, and further conversion to the target mole-
cule. A previous report has detailed our synthesis of inter-
mediate 4, which also used arene–ruthenium chemistry to
construct the aryl ether macrocycle connecting rings C
and D.12
Scheme 2 summarizes our approach to the F–O–G
building block 13, which has now been further optimized.13
Amine protection, as Teoc on the F-ring residue, was to be
utilized for intermediate 9 to ensure orthogonality with the
remaining units. While we have successfully carried out
Sharpless aminohydroxylation of the styrene derivative 6
using TeocNH2 as the carbamate partner, which directly
affords the N-Teoc protected amino alcohol,14 this
approach was actually less satisfactory in terms of yield,
enantiomeric purity, and ease of purification of the prod-
uct, than the indirect method shown in Scheme 2. Removal
of the Boc protecting group (7), followed by Teoc re-pro-
tection and chromatographic purification afforded the
required material 8 with high ee (99%). Hydrogenolysis
of the benzyl ethers to give 9, followed by intermolecular
etherification using complex 12, then methylation of
the remaining phenolic OH afforded the F–O–G building
block 13.
The SNAr reaction between 9 and 12 was rather capri-
cious, so we investigated the alternate approach outlined
in Scheme 3.14 The known7 benzyloxycarbonyl derivative
17 (95% ee, prepared as shown) was converted to 18 by
hydrogenolysis followed by Teoc protection of the amine.
Reaction of 18 with 12 also proved somewhat troublesome,
which we tentatively attribute to the sterically congested
2. Results and discussion
Following successful model studies,11 we have focused
on developing a total synthesis of ristocetin aglycone (3,
Cl
X
X
Cl
+
+
Nucleophile
(X )
-
RuCp
RuCp
hν, MeCN
CpRu(MeCN) PF
3
6
CpRu(MeCN) PF
3
-
+
-
6
PF
6
PF
6
solvent, heat
80 - 90 % recovery
Fig. 1. Schematic representation of ruthenium-mediated SNAr chemistry.
Ruthenium-mediated
OH
2
S
Ar Cyclization
N
OMe
RuCpPF6
O
O
O
C
E
Cl
O
O
OH
D
HO
H
H
E
C
O
D
HO
OTBS
OH
O
H
N
H
H
N
H
H
N
H
H
H
Macrolactamization
H
O
N
3
N
NHTeoc
MEMO
N
NH2
HO
NHBoc
N
NH
H
H
H
O
H
H
H
HN
BnO
MeO
O
O
O
O
NH2
H
HN
H
MeOOC
O
B
F
F
B
G
H
MeO
HO
O
A
G
A
OMe
OMe
OH
OH
O
Me
4
Me
HO
OMe
HO
5
Peptide Coupling
1
Ristocetin A aglycon (3)
Scheme 1.

1924
A. J. Pearson et al. / Tetrahedron Letters 49 (2008) 1922–1926
NHTeoc
NHP
HO
HO
BocNH2,
t
-BuOCl,
H2, Pd-C,
MeOH
HO
NaOH, 10 °C
X
NHG
MEMO
1) Na-2,6-di-t-butyl-
phenoxide, THF, 0 °C
HO
(DHQ)2PHAL,
OBn
K2OsO2(OH)4,
NHBoc
95%
OH
BnO
BnO
OBn
Me
2) MeCN, hν
Me
n-PrOH/H2O
Me
9
6
45% (2 steps)
1) HCl, dioxane
2) TeocOC6H4NO2
Et3N, THF, 0 °C
7 P = Boc
58%, 96% e.e.
MeO
8 P = Teoc
O
72%
Me
3) TMSCHN2,
benzene,MeOH
88%
OMe
NHBoc
NHBoc
1) MEMCl,
MEMO
Jones
reagent,
0 °C
13 X = H,H; G = Teoc
14 X = H,H; G = H
15 X = O; G = Teoc
HO
Cl
TBAF, THF
82%
i-Pr2NEt
BocNH2, t-BuOCl,
NaOH, 10 °C
96%
RuCpPF6
12
72%
Cl
(DHQD)2PHAL,
K2OsO2(OH)4,
2) CpRu(MeCN)3PF6
Cl
OMe
1,2-dichloroethane
reflux, 1 h
OMe
OMe
n-PrOH/H2O
10
11
100%
72%, 92-94% e.e.
Scheme 2.
NHTeoc
HO
1) (a) NaH, THF,
-10 °C to rt;
(b) add 12
NHCbz
benzyl carbamate,
NaOH, -BuOCl,
HO
1) H2, Pd-C,
t
13
(DHQ)2PHAL,
K2OsO2(OH)4,
-PrOH/Et2O/H2O
80%, 95% e.e.
MeO
OH
MeO
Me
OBn
2) TeocOSu
OBn
MeO
2) CH3CN, hν
Me
Et3N, dioxane, rt
Me
n
66% over two steps
16
85% over two steps
17
18
Scheme 3.
RuCpPF6
Cl
RuCpPF6
OTBS
Cl
OTBS
NHTeoc
NHBoc
RuCpPF6
OTBS
Cl
Jones reagent, 0
°
C
14, HATU, NaHCO3,
THF, 0
°C
H
O
H
N
NHTeoc
N
40-50%
NHBoc
HO
O
42%
HO
O
MEMO
MEMO
HO
NHTeoc
HATU =
O
N
MeO
MeO
O
19
N
O
20
Me
Me
N
N
OMe
OMe
5
O
C(NMe2)2 PF6
Scheme 4.
nature of the chloroareneRuCp complex. After some
experimentation, it was found that the treatment of 18 with
NaH in THF, followed by the addition of complex 12 in
small portions, then photolytic demetallation, reproducibly
afforded 13 in 66% yield over two steps.
Building block 13 was used in two approaches to the tar-
get molecule (Scheme 515), of which the more convergent
required coupling of 14, from Teoc deprotection of 13, with
complex 19, prepared as described previously.11a This cou-
pling afforded 20 in 42% yield (Scheme 4). Jones oxidation
of 20 was somewhat problematic, affording carboxylic acid
5 in variable yield. Direct coupling between 4 and 5 affor-
ded intermediate 22 in 33% yield.
atic steps in the construction of 5 and the low yield for
its coupling with 4, the less convergent route to 22 via 21
is the preferred one. Cycloetherification of 22, followed
by demetallation and TBS protection of the C-ring second-
ary alcohol afforded the advanced intermediate 23.
In conclusion, we have demonstrated that chloroarene–
ruthenium complexes are versatile intermediates for the
construction of aryl ether linkages in complex molecular
environments. They are easy to prepare, have excellent
shelf life, and the organometallic moiety is stable to numer-
ous organic reaction conditions and can be attached to
and disengaged from the arene substrate without detri-
ment to sensitive functionality. Further transformations
of 23 are required to afford the aglycone of ristocetin A,
and these will be the subject of future work in our
laboratory.
The alternate approach involved coupling of 4 with 15
to afford 21, which was then deprotected and coupled with
complex 19 to afford intermediate 22. Given the problem-

A. J. Pearson et al. / Tetrahedron Letters 49 (2008) 1922–1926
1925
OMe
DEPBT, NaHCO3,
O
OH
O
THF, 0 °C
4 + 15
HO
O
N
O
66%
H
N
H
NHTeoc
MEMO
(EtO)2(O)PO
O
N
N
N
N
NHBoc
H
DEPBT =
H
HN
BnO
MeO
O
H
MeO
O
OMe
OMe
Me
21
OMe
1) TBAF, THF, rt (80%)
2) 19, HATU, TMP, DMF, 0 °C (66%)
RuCpPF6
OMe
H
Cl
OMe
O
O
O
O
OH
OTBS
TBSO
H
H
HO
OTBS
1) Cs2CO3, DMF
2) MeCN, hν
H
DEPBT,
THF, 0 °C
O
O
NHTeoc
NHBoc
H
O
H
H
N
N
O
N
H
N
H
H
H
N
O
N
N
H
H
N
H
NHTeoc
4 + 5
MEMO
40%
O
H
H
HN
BnO
MeO
O
33%
O
O
NHBoc
3) CF3CONMeTBS, HN
MEMO
MeCN
H
H
H
MeO
BnO
O
85%
MeO
OMe
OMe
OMe
OMe
O
Me
Me
OMe
22
MeO
23
MeO
Scheme 5.
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Acknowledgments
We are grateful to the National Institutes of Health
(GM 36925) and the Case Western Reserve University
for financial support.
Supplementary data
Experimental procedures and spectroscopic data for all
new compounds. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.01.094.
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