Ruthenium mediated SNAr reactions in synthetic approaches to ristocetin a aglycon: Preparation of an ABCD ring intermediate

Article abstract of DOI:10.1016/j.tetlet.2005.02.108

A synthesis of an intermediate representing the ABCD ring system of ristocetin A aglycon is described, in which ruthenium-mediated intramolecular etherification is used as a key bond-forming step.

Full text of DOI:10.1016/j.tetlet.2005.02.108

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2639–2642
Ruthenium mediated SNAr reactions in synthetic approaches to
ristocetin A aglycon: preparation of an ABCD ring intermediate
Anthony J. Pearson* and Sheng Cui
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Received 25 January 2005; accepted 14 February 2005
Abstract—A synthesis of an intermediate representing the ABCD ring system of ristocetin A aglycon is described, in which ruthe-
nium-mediated intramolecular etherification is used as a key bond-forming step.
Ó 2005 Elsevier Ltd. All rights reserved.
Vancomycin (1)1 has captured the interest of synthetic
chemists for a number of years, as a result of its molec-
ular complexity and, perhaps more importantly, the
emergence of vancomycin resistant strains of infectious
bacteria.2 Such resistance has triggered alarm because
this compound has been in use for some time as the anti-
biotic of last resort for treatment of methicillin-resistant
infections. Several total syntheses of vancomycin agly-
con have been reported,3 and Nicolaou et al. have com-
pleted the synthesis of vancomycin itself.4
as an additional ring that is formed by aryl ether bridg-
ing between them. In fact, ristocetin is more closely
related to the structure of teicoplanin (structure not
shown here), another important member of this class.
While ristocetin A exhibits antibiotic activity similar to
vancomycin, its clinical use was discontinued owing to
fatalities.5 This is likely the result of platelet aggregation
caused by the antibiotic,6 and it has been shown that
such activity is eliminated when rhamnose is cleaved
from the tetrasaccharide moiety. The aglycone of risto-
cetin is a useful lead compound for development of
new antibiotics that exhibit activity against vancomycin
resistant bacteria.7 At present, the main use of ristocetin
Ristocetin A (2) is structurally related to vancomycin,
but possesses very different F and G residues, as well
OH
HO
OH
OH
OH
HO
O
O
OH
O
OH
O
O
O
E
C
O
OH
O
OH
D
O
O
HO
H
H
O
O
HO
OH
OH
O
HO
O
O
H
N
OH
H
N
HO
H
H
N
NH
H
Cl
HO
H
NH
2
HO
O
O
O
O
E
C
N
O
O
O
O
E
C
NH2
O
H
D
H
H
HO
H
Cl
H
O
O
NH2
H
O
HN
D
O
H
OH
F
B
H
O
OH
H
N
H
O
MeOOC
H
H
N
O
H
H
O
G
H
H
1
H
N
A
4
OH
2
6
HO
N
NHMe
H
N
H
N
H
H
NH
H
N
N
HO
OH
Me
O
5
3
H
H
H
H
N
HO
O
O
O
HN
H
H
H
O
O
O
NH2
7
HN
H
B
3
O
H
F
B
H
HOOC
HO
NH2
A
OH
OH
MeOOC
O
G
HO
OH
A
O
HO
OH
Me
OH
OH
HO
1 Vancomycin
O
2 Ristocetin A
OH
*
Corresponding author. Tel.: +1 216 3685920; fax: +1 216 3683006; e-mail: ajp4@po.cwru.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.108

2640
A. J. Pearson, S. Cui / Tetrahedron Letters 46 (2005) 2639–2642
A is in clinical diagnosis of von WillebrandÕs disease, a
genetic hemorrhagic disorder. Two independent total
syntheses of the teicoplanin aglycon have been
reported,8 and more recently, while our own work was
in progress, Boger et al. have completed a total synthesis
of ristocetin A aglycon (3).9
used for the purposes of ristocetin construction.10 This
letter describes the preparation of an actual intermediate
representing the ABCD ring system of 3.11 The synthesis
demonstrates the viability of using ruthenium promoted
intramolecular SNAr reactions in a very complex molec-
ular environment.12
Our approach to the total synthesis of 3 rests on the
ability of a transition metal, that is g6 coordinated to
an aromatic ring, to induce nucleophilic attack on the
arene. When the aromatic ligand is a halobenzene deriv-
ative, most commonly a chloroarene, the result is nucleo-
philic substitution. The RuCp moiety is well suited for
this particular application, since it is strongly activating,
can be attached to the aromatic moiety without detri-
ment to a wide range of functional side chains (in the
present case amino acids), is stable to numerous chemi-
cal transformations, and can generally be removed in a
reusable form by non-invasive photochemical methods.
This overall process is illustrated schematically in
Figure 1.
Ruthenium complex 4 was required for this effort, and
we examined two approaches for its construction from
the previously prepared10c chlorophenylserine derivative
5 (Scheme 1). One can either remove the Boc protecting
group before, or after conversion to the arene–RuCp
complex. In the event, while deprotection can indeed
be carried out without detriment to the organometallic
moiety (see 7 ! 4), the overall yield is higher when free
amine 6 is used in the complexation step.
We next required intermediate 11 (Scheme 2) for cou-
pling with 4 in an effort to secure an advanced interme-
diate 12 that could be subjected to cycloetherification.
The biaryl 8 was prepared using a known synthesis3a
and was coupled with the D-ring N-protected amino
acid 913 to afford methyl ester 10, which was hydrolyzed
to 11 under standard conditions. It should be noted that
We have described a number of model studies designed
to demonstrate that arene–ruthenium chemistry can be
Cl
X
X
Cl
+
+
Nucleophile
-
RuCp
RuCp
hν, MeCN
CpRu(MeCN) PF
3
(X )
6
CpRu(MeCN) PF
3
+
-
-
6
PF
PF
6
6
solvent, heat
80 - 90 % recovery
Figure 1. Schematic representation of ruthenium-mediated SNAr chemistry.
+
-
Cl
+
-
Cl
+
-
CpRu PF
6
CpRu PF
[CpRu (CH CN) ]PF
3 3 6
+
-
TBSOTf,
CH Cl ,
6
Cl
[CpRu (CH CN) ]PF
6
Cl
3
3
1,2-dichloroethane,
2
2
1,2-dichloroethane,
TFA-CH Cl ,
2
0 °C, 2h2
TBSO
reflux, 3h
TBSO
EtO
TBSO
EtO
0 °C, 2h
TBSO
EtO
reflux, 4h
5
EtO
O
NHBoc
95%
97%
90%
NH
NHBoc
64%
NH
2
2
O
O
O
(or TBSOTf,
5 (84% e.e.)
7
6
4 (84% e.e.)
CH Cl : 61%)
2
2
Scheme 1.
O
OMe
D
OMe
EDCI, HOAt, THF*
-78-0 °C, 24 h
OH
OH
HO
HO
HO
NH2
MeO
N3
4, HOAt, EDCI, THF*
-45-0 °C, 14 h
O
+
B
H
N
95% (9% epimer)
(12% epimers)
85%
RO
N3
BnO
NHBoc
NHBoc
A
OMe
OMe
O
9
O
MeO
LiOH, THF/H2O (1:1),
0 °C, 50 min
8
BnO
10 R = Me
11 R = H
*EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
HOAt = 1-hydroxy-7-azabenzotriazole
OMe
OMe
89%
MeO
CpRu+PF6
-
OMe
OMe
OMe
Cl
HO
+
-
CpRu PF
6
O
OH
O
OH
2 equiv sodium
2,6-di-t-butylphenoxide,
THF, 5 mM,
OH
Hg-lamp,
TBSO
TBSO
EtO
TBSO
EtO
CH3CN, 24 h,
O
O
O
-78-0 °C, 27 h
H
H
EtO
H
N
N
N
N
H
N
H
NHBoc
N
H
NHBoc
NHBoc
(sat. aq. NaNO3
and Pyrex
H
H
O
O
O
O
O
88%
O
N3
N3
N3
sleeve as filter )
BnO
BnO
BnO
OMe
OMe
OMe
OMe
OMe
85%
OMe
MeO
MeO
MeO
13
12
14
Scheme 2.

A. J. Pearson, S. Cui / Tetrahedron Letters 46 (2005) 2639–2642
2641
OMe
OMe
OMe
O
O
OH
OH
O
OH
1.5 equiv TBAF,
THF, -15-0 °C, 5h
HO
HO
O
Et3P, CH3CN/H2O
HO
O
O
O
(4:1), rt, 21h
O
H
N
H
H
FDPP,* i-Pr2NEt
H
14
O
N
RO
N
EtO
N
N
H
NHBoc
NHR
N
H
NHBoc
92%
H
H
88%
H
DMF, 0 °C, 12h
HN
O
O
O
NH2
( two steps )
76%
N3
PO
H
BnO
BnO
OMe
OMe
OMe
OMe
OMe
OMe
MeO
MeO
MeO
15
18 R = Boc, P = Bn
3 R = H, P = Bn
16 R = Et
17 R = H
LiOH, THF/H2O
(1:1), 0 °C, 10 min
HCO2H/CHCl3
rt, 7h (85%)
*(FDPP = pentafluoro-
phenyl diphenylphosphinate)
19 R = H, P = MEM
Scheme 3.
minor epimerization (ca 9%) occurs during the peptide
coupling, but 10 was not subjected to rigorous purifica-
tion to minimize loss of material. Coupling 11 with 4,
using HOAt/EDCI at low temperature afforded the de-
sired ruthenium complex 12 in 85% yield. Several minor
epimeric compounds (12% total) were observed in the
1H NMR spectrum of this material, as expected because
the subunits are not optically pure, but these were not
removed at this stage. Cycloetherification of 12 was car-
ried out by treatment with the weak non-nucleophilic
base, sodium 2,6-di-t-butylphenoxide, to afford 13 in
excellent yield. The reactivity of the chloroarene–ruthe-
nium complexes is sufficiently great that this weak base
can be used, which minimizes the risk of epimerization
of sensitive residues. Removal of the ruthenium from
13 followed the photochemical method used in our ear-
lier work, but with slight modification to control the UV
wavelength (Hanovia reactor using NaNO3 solution as
filter). Also, the [CpRu(CH3CN)3]PF6 that is generated
in this process caused side reactions on the product 14
during its isolation.14 Accordingly, this complex was
destroyed immediately after photolysis, by treating the
reaction mixture with aq ammonia, and intermediate
14 was isolated in 85% yield, after purification by flash
chromatography. It should be noted that minor epimeric
impurities generated during the earlier coupling steps
were removed during this purification.
molecular synthesis. The RuCp moiety is extremely ver-
satile in its ability to withstand numerous chemical
transformations elsewhere in the molecule, and its
attachment to highly functionalized amino acid
derivatives.
Acknowledgements
We are grateful to Mr. Avdhoot Velankar for preparing
intermediate 9, and to the National Institutes of Health
for financial support (GM 36925).
Supplementary data
Spectroscopic data for all new compounds reported
herein. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2005.02.108.
References and notes
1. Structural studies: Sheldrick, G. M.; Jones, P. G.; Ken-
nard, O.; Williams, D. H.; Smith, G. A. Nature (London)
1978, 271, 223–225; Harris, C. M.; Kopecka, H.; Harris,
T. M. J. Am. Chem. Soc. 1983, 105, 6915–6922.
2. Reviews on this topic: Nicolaou, K. C.; Boddy, C. N. C.;
Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38,
2096–2152; Williams, D. H.; Bardsley, B. Angew. Chem.,
Int. Ed. 1999, 38, 1172–1193; Hiramatsu, K. Drug Resist.
Update 1998, 1, 135–150.
Conversion of 14 to the desired ABCD intermediate fol-
lowed tactics similar to those used by Nicolaou et al. in
their synthesis of the vancomycin aglycone (Scheme 3).3a
It is necessary to deprotect the secondary alcohol of
the arylserine C ring residue to ensure high yield in the
subsequent ester hydrolysis step. Treatment of 14 with
excess TBAF at low temperature effects this transforma-
tion without side reactions—at higher temperatures sig-
nificant dehydration and retroaldol-type reaction of the
arylserine C-ring residue occurs. The A-ring azide was
reduced to amine using triethylphosphine, and the ester
was hydrolyzed using LiOH in THF to afford the amino
acid derivative 17, which was used directly in the cyc-
loamidation step to afford 18. Removal of the Boc pro-
tecting group from 18 afforded 3, which differs from
BogerÕs ABCD intermediate (19) only in the nature of
the primary alcohol protecting group.
3. (a) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.;
Hughes, R.; Salomon, M. E.; Ramanjulu, J. M.; Boddy,
C. N. C.; Takayanagi, M. Angew. Chem., Int. Ed. 1998, 37,
2708–2714; Nicolaou, K. C.; Jain, N. F.; Natarajan, S.;
Hughes, R.; Salomon, M. E.; Li, H.; Ramanjulu, J. M.;
Takayanagi, M.; Koumbis, A. E.; Bando, T. Angew.
Chem., Int. Ed. 1998, 37, 2714–2716; Nicolaou, K. C.;
Katayanagi, M.; Jain, N. F.; Natarajan, S.; Koumbis, A.
E.; Bando, T.; Ramanjulu, J. M. Angew. Chem., Int. Ed.
1998, 37, 2717–2719; (b) Evans, D. A.; Wood, M. R.;
Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J.
L. Angew. Chem., Int. Ed. 1998, 37, 2700–2704; Evans, D.
A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.;
Richardson, T. I.; Trotter, B. W.; Katz, J. L. Angew.
Chem., Int. Ed. 1998, 37, 2704–2708; (c) Boger, D. L.;
Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.;
Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 10004–
10011.
In conclusion, this work demonstrates that arene–ruthe-
nium chemistry can be used in the context of complex

2642
A. J. Pearson, S. Cui / Tetrahedron Letters 46 (2005) 2639–2642
4. Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger,
N.; Hughes, R.; Bando, T. Angew. Chem., Int. Ed. 1999,
38, 240–244.
5. Dries, C. P.; Koch, R. J. Pediat. 1960, 56, 498–504;
Herting, R. L.; Lees, B.; Zimmerman, A. J.; Berryman, G.
H. J. Am. Med. Assoc. 1959, 170, 176–178.
10. (a) Pearson, A. J.; Chelliah, M. J. Org. Chem. 1998, 63,
3087–3098; (b) Pearson, A. J.; Heo, J.-Y. Org. Lett. 2000,
2, 2987–2990; (c) Pearson, A. J.; Zigmantas, S. Tetrahe-
dron Lett. 2001, 42, 8765–8768, and references cited
therein.
11. Cui, S. Ph.D. Dissertation, Case Western Reserve Uni-
versity, January, 2004. Cui, S.; Pearson, A. J. 225th
National Meeting of the American Chemical Society, New
Orleans, LA, March 23–27, 2003. Paper ORGN 243.
12. For other uses of Ru-promoted aryl ether formation in
total synthesis, see: Janetka, J. W.; Rich, D. H. J. Am.
Chem. Soc. 1995, 117, 10585–10586; Janetka, J. W.; Rich,
D. H. J. Am. Chem. Soc. 1997, 119, 6488–6495; Pearson,
A. J.; Lee, K. J. Org. Chem. 1994, 59, 2304–2313; Pearson,
A. J.; Zhang, P.; Lee, K. J. Org. Chem. 1996, 61, 6581–
6586.
6. Howard, M. A.; Firkin, B. G. Thromb. Diath. Haemorrh.
1971, 26, 362–369.
7. McComas, C. C.; Crowley, B. M.; Hwang, I.; Boger, D. L.
Bioorg. Med. Chem. Lett. 2003, 13, 2933–2936; Balzarini,
J.; Pannecouque, C.; De Clercq, E.; Pavlov, A. Y.;
Printsevskaya, S. S.; Miroshnikova, O. V.; Reznikova,
M. I.; Preobrazhenskaya, M. N. J. Med. Chem. 2003, 46,
2755–2764; Kobrin, M. B.; Katrukha, H. S.; Fedorova, G.
B. J. Antibiot. 1989, 42, 1441–1442.
8. (a) Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-H.;
Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc.
2001, 123, 1862–1871; (b) Evans, D. A.; Katz, J. L.;
Peterson, G. S.; Hintermann, T. L. J. Am. Chem. Soc.
2001, 123, 12411–12413.
13. Pearson, A. J.; Chelliah, M. V.; Bignan, G. C. Synthesis
1997, 536–540.
14. During isolation of 14 it was found that RuCp becomes
attached to the D-ring arene system, most likely a result of
the electron rich character of this residue. Destruction of
the released [CpRu(CH3CN)3]PF6 by immediate treatment
with aqueous ammonia prevents this.
9. Boger, D. L.; Crowley, B. M.; Mori, Y.; McComas, C. C.;
Tang, D. J. Am. Chem. Soc. 2004, 126, 4310–
4317.