Synthesis of a key precursor for orienticin C and model study on ruthenium-mediated macrocyclization

Article abstract of DOI:10.1021/jo702245z

(Chemical Equation Presented) A tripeptido-arene-ruthenium complex was prepared as a key precursor for the projected synthesis of orienticin C, demonstrating that the cyclopentadienylruthenium moiety can be attached to a chloroarene in the presence of mul

Full text of DOI:10.1021/jo702245z

ticin C the name bis-dechlorovancomycin, also known as
A82846C. A key structural element for the vancomycin-type
molecules is the diaryl ether, and a variety of approaches have
been developed for construction of this type of linkage.5 Total
syntheses of the aglycones of vancomycin,6 orienticin C,7 and
the related antibiotics teicoplanin8 and ristocetin A9 have been
reported, and a total synthesis of the full vancomycin structure
has been accomplished.10
Synthesis of a Key Precursor for Orienticin C
and Model Study on Ruthenium-Mediated
Macrocyclization
Anthony J. Pearson* and Diana V. Ciurea
Department of Chemistry, Case Western ReserVe UniVersity,
CleVeland, Ohio 44106
ajp4@case.edu
ReceiVed October 17, 2007
Our group has investigated ruthenium-mediated SNAr meth-
odology as a general approach for construction of diaryl ethers,
and this methodology was successfully applied for construction
of an intermediate 3 representing the ABCD ring system of
orienticin C (and ristocetin A).11 For this to be applied in a
synthesis of orienticin C, a chloroarene-ruthenium complex 4
A tripeptido-arene-ruthenium complex was prepared as a
key precursor for the projected synthesis of orienticin C,
demonstrating that the cyclopentadienylruthenium moiety can
be attached to a chloroarene in the presence of multiple
functionality. The ruthenium-mediated intramolecular SNAr
reaction for formation of the required diaryl ether linkage
was successfully tested on a model system.
(4) Sheldrick, G. M.; Jones, P. G.; Kennard, 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.
(5) For a review, see: Sawyer, S. J. Tetrahedron 2000, 56, 5045-5065.
(6) (a) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
T-Y.; Natarajan, S.; Chu, X-J.; Brase, S.; Rubsam, F. Chem.-Eur. J. 1999,
5, 2584-2601. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.;
Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Yue, T-Y.; Brase,
S.; Salomon, M. E. Chem.-Eur. J. 1999, 5, 2602-2621. Nicolaou, K. C.;
Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li,
H.; Hughes, R. Chem.-Eur. J. 1999, 5, 2622-2647. 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.; Loiseleur, O.; Castle, S. L. J. Am.
Chem. Soc. 1999, 121, 3226-3227. 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.
Vancomycin-related glycopeptides constitute a large family
of clinically important antibiotics, used as drugs of last resort
in treating infections caused by methicillin-resistant Staphylo-
coccus aureus.1 However, the frequency of vancomycin resistant
pathogens has increased significantly over the past decade,2
prompting an interest in the development of synthetic and
semisynthetic glycopeptides.3
Members of the vancomycin family have a complex rigid
molecular architecture with a heptapeptide backbone structure,
synthetically challenging components, and numerous stereo-
centers.4 Orienticin C (2) is structurally similar to vancomycin
(1), having one extra vancosamine unit and lacking the chloro-
substituents on the C and E aromatic rings, which gives orien-
(7) Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow,
J. C. J. Am. Chem. Soc. 1997, 119, 3417-3418. Evans, D. A.; Barrow, J.
C.; Watson, P. S.; Ratz, A. M.; Dinsmore, C. J.; Evrard, D. A.; DeVries,
K. M.; Ellman, J. A.; Rychnovsky, S. D.; Lacour, J. J. Am. Chem. Soc.
1997, 119, 3419-3420.
(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.
(9) Boger, D. L.; Crowley, B. M.; Mori, Y.; McComas, C. C.; Tang, D.
J. Am. Chem. Soc. 2004, 126, 4310-4317.
(10) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes,
R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem.-Eur. J. 1999, 5,
2648-2667. Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger, N.;
Hughes, R.; Bando, T. Angew. Chem., Int. Ed. 1999, 38, 240-244.
(11) Pearson, A. J.; Cui, S. Tetrahedron Lett. 2005, 46, 2639-2642.
(1) McCormick, M. H.; Stark, W. M.; Pittenger, G. F.; Pittenger, R. C.;
McGuire, G. M. Antibiot. Annu. 1955-1956, 606.
(2) Recent reviews on this topic: Kahne, D.; Leimkuhler, C.; Lu, W.;
Walsh, C. Chem. ReV. 2005, 105, 425-448. 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. Updates 1998, 1, 135-150.
(3) Crowley, B. M.; Boger, D. L. J. Am. Chem. Soc. 2006, 1218, 2885-
2892. 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.
10.1021/jo702245z CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/23/2007
760
J. Org. Chem. 2008, 73, 760-763

SCHEME 1. Synthesis of Tripeptide Acid 13
SCHEME 2. Synthesis of 16-Membered Macrocycle
the dipeptide 8 in nearly quantitative yield with no detectable
epimerization at the chiral centers. Hydrolysis of the ethyl ester
dipeptide 8 provided subunit 9 with minimal epimerization (ca.
5% by NMR).
The third amino acid needed is an asparagine derivative,
N-Boc-â-cyanoalanine, obtained from commercially available
L-N-Boc-asparagine via amide dehydration, following a known
procedure.14 Evans15 has used the nitrile as a latent carboxamide
of asparagine in his studies toward the vancomycin family of
glycopeptides, and also, Boger6c has exploited the same
protected asparagine in his total synthesis of vancomycin
aglycone. Carboxylic acid 10 was protected as its methyl ester
derivative by treatment with TMSCHN2 in methanol-benzene
mixture (1:4) at room temperature.14 Removal of the Boc
protecting group, using 4 M HCl in dioxane at room temper-
ature, furnished the desired building block 11 in quantitative
yield. Coupling this intermediate with dipeptide 9 was then
investigated. After screening different reaction conditions, the
best result was obtained by using EDCI and HOAt as coupling
reagents, and DIPEA as a base, to afford 12, which was then
hydrolyzed to carboxylic acid 13 under standard conditions.
Ruthenium complexation of 13 followed the standard reaction
procedure, wherein the tripeptide acid was treated with [CpRu-
(CH3CN)3]PF6 in 1,2-dichloroethane under reflux conditions for
8 h to afford complex 14 in 85% yield (Scheme 2). Importantly,
this demonstrates that the complexation reaction is not com-
promised by the multiple functionality of this molecule. With
this complex in hand, we tested the ruthenium-mediated SNAr
reaction for construction of the biaryl ether linkage on a model
system 16, whose synthesis is shown in Scheme 2. The
ruthenium tripeptide 14 was treated with the amine 15 and the
peptide coupling reagents EDCI and HOAt to afford the
pseudotetrapeptide ruthenium complex 16 in 85% yield. Ac-
cording to NMR analysis, a demetalated pseudotetrapeptide was
formed as a byproduct in this reaction but only in 5% yield,
and this is consistent with TLC observation, which showed
formation of a less polar product. It could be formed by in situ
demetalation of the ruthenium pseudotetrapeptide 16 and/or
demetalation of ruthenium tripeptide acid 14 that then underwent
peptide coupling. The macrocyclization proceeded smoothly in
the presence of Cs2CO3 as base, and demetalation of the product
was achieved by irradiating an acetonitrile solution of the
ruthenium complex with UV light (Rayonet apparatus) for 18
is required. Connecting 3 and 4 and further elaboration would
afford the orienticin C core structure. However, ruthenium
attachment to an advanced polyfunctional peptido-arene of this
type has not yet been investigated. Here we describe the
synthesis of 4 as well as a model study on its use in
macrocyclization that is needed for the orienticin C synthesis.
This approach offers maximum recycling potential for the use
of ruthenium, because the metal moiety is not carried through
a multistep sequence. The cyclopentadienyl-ruthenium moiety
is attached to and removed from the aromatic ring under
noninvasive conditions and provides a convenient temporary
activator for the SNAr chemistry that is required for aryl ether
construction.
Construction of 4 involves elaboration of a tripeptide from
the corresponding amino acids via standard peptide coupling
reactions. One of the required amino acids is the arylserine
derivative 6, which was obtained from the azide 5 already
prepared in our laboratory (Scheme 1).12 Protection of the free
alcohol 5, as its TBS derivative, followed by reduction of the
azide functional group13 furnished the desired amine 6 in 92%
overall yield. Coupling 6 with D-N-Boc-N-methylleucine (7),
using EDCI and HOAt as coupling reagents at 0 °C, afforded
(14) (a) Liberek, B.; Buczel, Cz.; Grzunka, Z. Tetrahedron 1966, 22,
2303-2306. (b) Ressler, C.; Ratzkin, H. J. Org. Chem. 1961, 26, 3356-
3360. (c) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T. J. Org.
Chem. 1997, 62, 4721-4736.
(15) Evans, D. A.; Ellman, J. A.; DeVries, K. M. J. Am. Chem. Soc.
1989, 111, 8912-8914.
(12) Pearson, A. J.; Heo, J.-Y. Tetrahedron Lett. 2000, 41, 5991-5996.
Pearson, A. J.; Heo, J.-Y. Org. Lett. 2000, 2, 2987-2990.
(13) Maiti, S. N.; Singh, M. P.; Micetich, R. G. Tetrahedron Lett. 1986,
27, 1423-1424.
J. Org. Chem, Vol. 73, No. 2, 2008 761

benzene-CH3OH (4:1, 15 mL) at room temperature was slowly
added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane,
2 mL, 4.0 mmol, 1.3 equiv), and the mixture was stirred at this
temperature for 4 h. The reaction was quenched by adding glacial
acetic acid (2 mL). The volatiles were removed in Vacuo, and the
residue was dissolved in CH2Cl2 (15 mL), washed with saturated
aqueous NaHCO3 (3 × 4 mL), H2O (10 mL), brine (10 mL), dried
(Na2SO4), and then concentrated in Vacuo. Flash chromatography
(40% EtOAc/hexanes) afforded the methyl ester (687 mg) as a white
h. The desired product 17 was obtained in 76% yield over two
steps and was easily characterized by 1H NMR, which shows a
characteristic pattern where one of the D-ring aromatic protons
is shifted upfield relative to the others due to the shielding effect
of the neighboring E-phenyl ring.16 The minor product present
in the reaction mixture was uncyclized demetalated starting
material.
In conclusion, an arene-tripeptide complex was prepared as
a key building block for the synthesis of orienticin C, followed
by further conversion to a ruthenium complex on which the
metal-driven SNAr reaction was applied to afford the diaryl ether
linkage, thus demonstrating the feasibility of using this meth-
odology for synthesis of orienticin C, a member of the
vancomycin class of antibiotics.
solid (98% yield). Rf ) 0.35 (40% EtOAc/hexanes): mp ) 80-
1
82 °C; [R]25 +36 (c 1.7, CHCl3). H NMR (CD3OD, 400 MHz)
D
δ 4.46 (dd, 1H, J ) 8.4, 5.2 Hz), 3.76 (s, 3H), 3.01 (dd, 1H, JAB
)
17.0, JAX ) 5.2 Hz), 2.90 (dd, 1H, JAB ) 17.0, JBX ) 8.4 Hz), 1.46
(s, 9H). 13C NMR (CD3OD, 100 MHz) δ 171.4, 157.5, 118.2, 81.1,
53.2, 51.5, 28.5, 21.1. FABHRMS (m/z) [MH+] calcd for
(C10H17N2O4) 229.1188, found 229.1191.
A solution of N-Boc-â-cyanoalanine methyl ester (687 mg, 3
mmol) in 4 M HCl-dioxane (30 mL) was stirred at room
temperature for 1 h. The solvent is removed in Vacuo to provide
Experimental Section
Dipeptide (8). A solution of 6 (189.1 mg, 0.532 mmol, 1.0 equiv)
and D-N-Boc-N-methylleucine (7) (130.7 mg, 0.532 mmol, 1.0
equiv) in anhydrous THF (10 mL) was cooled to 0 °C. HOAt (343.9
mg, 1.758 mmol, 3.3 equiv) and EDCI (221.9 mg, 1.598 mmol,
3.0 equiv) were added, and the resulting mixture was stirred
vigorously for 14 h. H2O (5 mL) was added at 0 °C, and after 15
min, the aqueous phase was extracted with EtOAc (3 × 5 mL).
The combined organic layers were washed with aqueous saturated
NaHCO3 solution (3 × 3 mL), H2O (5 mL), brine (5 mL), dried
(Na2SO4), and concentrated, and the residue was purified by flash
column chromatography (15% EtOAc/hexanes) to give the product
8 (306 mg) as a pale-yellow foam, (98% yield). Rf ) 0.35 (15%
EtOAc/hexanes). [R]25D +22 (c 1.0, CHCl3). 1H NMR (CDCl3, 400
MHz) δ 7.35-7.30 (4H), 5.20-4.96 (br, 1H), 4.69 (d, 1H, J ) 7.6
Hz), 4.59 (br, 1H), 4.17 (q, 2H, J ) 7.2 Hz), 2.60-2.40 (br, 3H),
1.60-1.30 (br, 12H), 1.26 (t, 3H, J ) 7.2 Hz), 0.91 (dd, 6H, J )
8.4, 6.4 Hz), 0.85 (s, 9H), 0.05 (s, 3H), -0.18 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ 172.4, 171.2, 157.6, 140.5, 134.8, 129.7,
129.3, 81.5, 75.5, 62.4, 60.0, 56.7, 38.1, 30.0, 28.7, 26.3, 26.1, 25.8,
23.4, 22.1, 18.8, 14.4, -4.4, -4.9. FABHRMS (m/z) [M H+] calcd
for (C29H50ClN2O6Si) 585.3127, found 585.3107.
Dipeptide Acid (9). A solution of ethyl ester 8 (276 mg, 0.472
mmol, 1.0 equiv) in THF (1.2 mL) was cooled to 0 °C, and then a
mixture of 2:1 t-BuOH:H2O (2.4 mL t-BuOH, 1.2 mL H2O) was
added. This solution was treated with LiOH‚H2O (70.6 mg, 0.943
mmol, 2.0 equiv) and stirred for 10 h. When the reaction was
complete, the pH of the solution was adjusted to 3 by the dropwise
addition of 6 N HCl solution, the reaction mixture was diluted with
EtOAc (5 mL), and the layers were separated. The resulting aqueous
phase was extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 solution (3
× 3 mL), H2O (5 mL), brine (10 mL), dried (Na2SO4), and then
concentrated in Vacuo. Flash chromatography (5% MeOH and 1%
AcOH in CH2Cl2) afforded 9 (252.2 mg) as a white foam (96%
yield). Rf ) 0.3 (5% MeOH and 1% AcOH in CH2Cl2). [R]25D +20
(c 0.88, CHCl3). 1H NMR (CD3OD, 400 MHz) δ 7.35-7.29 (4H),
5.30-5.15 (br, 1H), 4.78-4.70 (br, 1H), 4.70-4.58 (br, 1H), 2.80-
2.60 (br, 3H), 1.78-1.44 (br, 12H), 0.94-0.87 (6H), 0.86 (s, 9H),
0.09 (s, 3H), -0.08 (s, 3H). 13C NMR (CD3OD, 100 MHz) δ 173.7,
172.5, 157.6, 140.6, 134.7, 129.7, 129.2, 82.09, 81.5, 75.5, 69.4,
60.4, 58.2, 56.9, 38.0, 31.1, 30.1, 28.6, 26.2, 25.8, 23.5, 22.0, 18.9,
-4.6, -4.9. FABHRMS (m/z) [M H+] calcd for (C27H46ClN2O6-
Si) 557.2814, found 557.2824.
1
the product (498 mg, 100%) as a yellow oil. H NMR (CD3OD,
400 MHz) δ 4.51 (t, 1H, J ) 6.0 Hz), 3.91 (s, 3H), 3.22 (ABX,
2H, J ) 6.0, 4.0, 18.0 Hz). 13C NMR (CD3OD, 100 MHz) δ 168.2,
116.0, 54.5, 50.2, 19.7. FABHRMS (m/z) [MH+] calcd for
(C5H10N2O2Cl) 165.0431, found 165.0444.
Tripeptide (12). A solution of carboxylic acid 9 (338.3 mg, 0.607
mmol, 1.0 equiv) and amine hydrochloride 11 (100 mg, 0.607
mmol, 1.0 equiv) in THF (10 mL) was cooled to 0 °C, and after
15 min, DIPEA (0.22 mL, 1.214 mmol, 2.0 equiv) was added and
the reaction mixture was stirred for 10 min. HOAt (276.8 mg, 2.003
mmol, 3.3 equiv) and EDCI (350.8 mg, 1.821 mmol, 3.0 equiv)
were added, and the resulting mixture was stirred vigorously for
24 h. H2O (5 mL) was added at 0 °C, and after 15 min, the aqueous
phase was extracted with EtOAc (3 × 6 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (3 × 4 mL),
H2O (12 mL), brine (15 mL), dried (Na2SO4), and concentrated to
give 283 mg (70% combined yield) of a mixture of two diastere-
omers (8:1 ratio by NMR analysis), which was further separated
by flash column chromatography (30% EtOAc/hexanes): 252 mg
of 12 (major product), as a yellowish foam and 31 mg of its epimer
as a white foam. For the major isomer: Rf ) 0.35 (30% EtOAc/
hexanes). [R]25D + 31.3 (c 2.0, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ 7.36-7.31 (4H), 5.04 (d, 1H, J ) 8 Hz), 4.70 (t, 2H, J ) 6.4
Hz), 4.62-4.46 (br, 1H), 3.76 (s, 3H), 2.99 (d, 2H, J ) 6.4 Hz),
2.50-2.40 (br, 3H), 1.54-1.40 (br, 12H), 0.90 (dd, 6H, J ) 8.4,
6.4 Hz), 0.84 (s, 9H), 0.04 (s, 3H), -0.15 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ 172.6, 171.7, 170.4, 140.5, 134.7, 130.0, 129.3, 129.1,
117.7, 75.0, 61.3, 59.8, 53.5, 50.3, 37.9, 29.9, 28.6, 26.2, 25.6, 23.5,
21.8, 20.9, 20.6, 18.8, 14.5, -4.4, -4.7. FABHRMS (m/z) [MH+]
calcd for (C32H52ClN4O7Si) 667.3294, found 667.3305. The minor
product results from epimerization at the phenylalanine R-center
(evident from the 1H NMR J couplings) during the coupling reaction
and was not fully characterized.
Tripeptide Acid (13). A solution of methyl ester 12 (159.3 mg,
0.238 mmol, 1.0 equiv) in THF (1.5 mL) was cooled to 0 °C, and
a mixture of t-BuOH/H2O (2:1, 4.5 mL) was added. This solution
was treated with LiOH‚H2O (36 mg, 0.477 mmol) and stirred for
10 h. Upon completion, the pH of the solution was adjusted to 3
by the dropwise addition of 6 N HCl solution. EtOAc (6 mL) was
added to the reaction mixture, and the layers were separated. The
resulting aqueous phase was further extracted with EtOAc (3 × 3
mL). The combined organic layers were washed with saturated
aqueous NaHCO3 (3 × 3 mL), H2O (6 mL), brine (10 mL), dried
(Na2SO4), and then concentrated in Vacuo. Flash chromatography
(10% MeOH in CH2Cl2) afforded 13 (148 mg) as a white foam
(95% yield). Rf ) 0.3 (8% MeOH in CH2Cl2). [R]25D +47 (c 0.58,
CHCl3). 1H NMR (CD3OD, 400 MHz) δ 7.38-7.31 (4H), 5.09 (d,
1H, J ) 7.2 Hz), 4.72 (d, 1H, J ) 8 Hz), 4.64-4.58 (br, 1H), 4.51
(t, 1H, J ) 5.6 Hz), 2.99 (d, 2H, J ) 5.2 Hz), 2.58-2.42 (br, 3H),
Methyl â-Cyanoalanate Hydrochloride (11). To a solution of
L-N-Boc-â-cyanoalanine (10) (658 mg, 3.07 mmol, 1.0 equiv) in
(16) Williams, D. H.; Kalman, J. R. J. Am. Chem. Soc. 1977, 99, 2768-
2774.
(17) Yoshikawa, S. Patent: JP11130739 A2, Jpn. Kokai Tokkyo Koho,
1999.
762 J. Org. Chem., Vol. 73, No. 2, 2008

1.58-1.40 (br, 12H), 0.89 (dd, 6H, J ) 4.8, 6.8 Hz), 0.84 (s, 9H),
0.05 (s, 3H), -0.15 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 172.6,
171.5, 157.6, 157.0, 140.6, 134.8, 130.1, 129.4, 118.3, 81.9, 81.5,
3.87 (s, 3H), 3.11 (dd, 1H, JAB ) 17.2, JAX ) 5.2 Hz), 3.01 (dd,
1H, JAB ) 17.2, JBX ) 8.0 Hz), 2.83 (s, 3H), 1.78 (t, 1H, 6.2 Hz)
1.49 (s, 9H), 0.94 (6H overlapped with s, 9H), 0.30 (s, 3H), 0.16
(s, 3H). 13C NMR (CD3OD, 125 MHz) δ 174.2, 170.6, 170.0, 158.0,
148.4, 147.5, 142.2, 135.6, 119.5, 118.1, 115.4, 112.5, 116.9, 87.7,
87.5, 85.4, 85.2, 83.9, 81.6, 72.6, 65.0, 60.6, 57.3, 56.4, 38.4, 30.9,
30.7, 28.7, 26.4, 26.1, 23.5, 21.7, 20.8, 18.9, -3.8, -4.6. FAB-
HRMS (m/z) [MH - PF6]+ (C44H64ClN5O8SiRu) 955.3265, found
955.3250.
Diaryl Ether Macrocycle (17). To a solution of 16 (10 mg,
0.009 mmol, 1.0 equiv) in DMF (1.8 mL) at 0 °C was added Cs2-
CO3 (14.6 mg, 0.045 mmol, 5.0 equiv). The reaction mixture was
stirred for 8 h at 0 °C and then at rt for 24 h. The mixture was then
diluted with CH2Cl2 (5 mL), and the organic layer was washed
with H2O (3 mL), brine (5 mL), dried (Na2SO4), and concentrated.
The residue was dissolved in CH3CN (4.5 mL) and degassed for 1
h. The solution was photolyzed for 18 h in a Rayonet photoreactor
(350 nm). The reaction mixture was filtered through a Celite pad
and purified by PTLC (0.5 mm, 40% EtOAc/hexanes) to afford
75.1, 60.3, 58.1, 56.9, 51.2, 37.9, 31.1, 29.9, 28.6, 26.3, 26.2, 25.7,
+
23.5, 21.4, 18.9, -4.5, -4.7. FABHRMS (m/z) [(M - H)Na2
]
calcd for (C31H48ClN4O7SiNa2+) 697.2777, found 697.2784.
Ruthenium-Tripeptide Acid Complex (14). A solution of
tripeptide acid 13 (94.2 mg, 0.144 mmol, 1.05 equiv) in dry 1,2-
dichloroethane (20 mL) was degassed with argon at 60 °C for 1 h.
[CpRu(CH3CN)3]PF6 (62.62 mg, 0.137 mmol, 1.0 equiv) was added
to the cooled solution, which was then heated under reflux (90 °C)
for 8 h. The solution was cooled, and the solvent was removed
under reduced pressure. The resulting solid was dried in Vacuo to
give the crude ruthenium complex, which was purified by flash
chromatography (5-30% MeOH in CH2Cl2 gradient elution) to
afford 14 (118 mg, 85%) as a white solid. [R]25 +2.6 (c 0.65,
D
CHCl3). 1H NMR (CD3OD, 400 MHz) δ 6.80 (d, 1H, J ) 6.4 Hz),
6.69 (d, 1H, J ) 6.0 Hz), 6.46 (d, 1H, J ) 6.0 Hz), 6.32 (d, 1H,
J ) 5.2 Hz), 5.50 (s, 5H), 5.38-5.30 (br, 1H), 5.12-5.06 (br, 1H),
4.70 (dd, 2H, J ) 5.2, 10.4 Hz), 4.44 (t, 1H, J ) 5.6 Hz), 3.16-
2.96 (2H), 2.85 (s, 3H), 1.44 (3H overlapped with s, 9H), 0.88
(6H overlapped with s, 9H), 0.35 (s, 3H), 0.20 (s, 3H). 13C NMR
(CD3OD, 125 MHz) δ 174.1, 169.4, 157.7, 119.2, 118.9, 107.0,
106.5, 87.8, 85.3, 83.7, 81.3, 72.8, 60.2, 58.2, 57.1, 52.6, 52.1, 38.4,
30.7, 28.8, 26.5, 26.1, 23.4, 22.0, 21.8, 18.8, -3.8, -4.7. FABMS
(m/z) [M - PF6]+ calcd for (C36H54ClN4O7SiRu) 819.2494, found
819.2500.
5.2 mg of 17 (76% yield over two steps). Rf ) 0.3 (40% EtOAc/
1
hexanes); [R]25 + 15.2 (c 0.6, CHCl3) H NMR (CD3OD, 400
D
MHz) δ 7.36-7.18 (2H), 7.12-6.99 (1H), 6.92-6.78 (2H), 6.01
(d, 1H, J ) 2.0 Hz), 5.57 (d, 1H, J ) 4.4 Hz), 5.12 (d, 1H, J ) 5.6
Hz), 5.16 (d, 1H, J ) 7.2 Hz), 5.01 (d, 1H, J ) 4.8 Hz), 4.70 (d,
1H, J ) 6.6 Hz), 4.52 (s, 2H), 3.93 (s, 3H), 2.97 (d, 2H, J ) 6.4
Hz), 2.88 (s, 3H), 1.56-1.48 (3H), 1.45 (s, 9H), 0.92 (6H,
overlapping s, 9H,), 0.13 (s, 3H), 0.10 (s, 3H). 13C NMR (CD3OD,
100 MHz) δ 179.5, 174.3, 172.0, 171.5, 157.8, 150.2, 142.7, 140.6,
134.8, 129.3, 120.9, 118.3, 114.5, 81.9, 81.5, 75.1, 68.5, 62.3, 60.3,
58.1, 56.9, 51.2, 37.9, 31.1, 29.6, 28.6, 26.3, 26.2, 25.7, 23.5, 21.8,
21.4, 18.9, -4.4, -4.7. HRMS was not determined (the compound
appears to be unexpectedly unstable and undergoes considerable
degradation on standing in CD3OD solution).
Pseudotetrapeptide (16). A solution of ruthenium complex 14
(18.5 mg, 0.019 mmol, 1.0 equiv) and amine 1516 (2.9 mg, 0.019
mmol) in THF (1.4 mL) was cooled to -20 °C. HOAt (8.7 mg,
0.063 mmol, 3.3 equiv) was added, and the reaction mixture was
stirred for 30 min at this temperature. EDCI (11.11 mg, 0.0575
mmol, 3 equiv) was then added, and the reaction was run for 24 h.
H2O (2 mL) and CH2Cl2 (5 mL) were added at 0 °C, and after 10
min, the layers were separated and the aqueous phase was extracted
with CH2Cl2 (2 × 5 mL). The combined organic layers were dried
(Na2SO4) and concentrated, and the residue was first washed with
diethyl ether in order to remove the organic material and purified
by preparative TLC (25% MeOH in EtOAc) affording 16 (17.8
Acknowledgment. We are grateful to the National Institutes
of Health (GM 36925) and Case Western Reserve University
for financial support of this research and to Penny Neisen-Roufs
for preparation of the amine 15.17
Supporting Information Available: Copies of NMR spectra
for all new compounds and details for the preparation of 6. This
material is available free of charge via the Internet at http:
//pubs.acs.org.
mg, 85%) as a white film. Rf ) 0.3 (25% MeOH in EtOAc). [R]25
D
1
+10.4 (c 0.24, CHCl3). H NMR (CD3OD, 400 MHz) δ 6.98-
6.89 (3H), 6.72 (d, 1H, J ) 5.6 Hz), 6.42 (dd, 2H, J ) 5.6, 7.2
Hz), 5.49 (s, 5H), 5.15 (s, 2H), 5.08-5.02 (br, 1H), 4.84-4.76
(br, 1H), 4.70 (dd, 2H, J ) 5.2, 10.4 Hz), 4.64-4.60 (br, 1H),
JO702245Z
J. Org. Chem, Vol. 73, No. 2, 2008 763