Application of ruthenium induced cyclization for construction of strained biaryl ether macrocyclic compounds

Article abstract of DOI:10.1016/S0040-4020(02)00511-2

Synthesis of strained macrocyclic biaryl ethers of type 1 and 2 were accomplished using η⁶-ruthenium-induced macroetherification. This novel application demonstrates the versatility of this method in construction of constrained macrocyclic biar

Full text of DOI:10.1016/S0040-4020(02)00511-2

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5453±5458
Application of ruthenium induced cyclization for construction of
strained biaryl ether macrocyclic compounds
Srikanth Venkatraman,p F. George Njoroge and Viyyoor Girijavallabhan
A 301, MS-3545 Schering Plough Research Institute, K-15, 2015 Galloping Hill road, Kenilworth, NJ 07033, USA
Received 13 March 2002;accepted 16 May 2002
AbstractÐSynthesis of strained macrocyclic biaryl ethers of type 1 and 2 were accomplished using h6-ruthenium-induced macroetheri®-
cation. This novel application demonstrates the versatility of this method in construction of constrained macrocyclic biaryl ether ring
systems. q 2002 Elsevier Science Ltd. All rights reserved.
Isolation and characterization of a wide variety of macro-
cyclic biaryl ether containing glycopeptide antibiotics
such as vancomycin, ristocetin, b-avoparcin, actaplanin,
A33512B has spurred extensive investigation for the syn-
theses of these type of ring systems.1 Chloropeptins,
piperazinomycin, and protease inhibitors K-13, and
OF49491-IV are other bioactive peptides containing macro-
cyclic biaryl ethers.2 Vancomycin is currently the drug
of choice for the treatment of methicillin resistant
staphylococcus infections and is routinely used in bacterial
infections for patients allergic to b-lactam antibiotics.
Moreover, the formation of macrocyclic biaryl ether has
been utilized for the synthesis of HIV, matrix metallo, and
HCV protease inhibitors.3 The incorporation of macrocyclic
biaryl ether in the design of peptidic inhibitors render them
resistant towards proteolytic enzymes and improve oral
bioavailability and plasma pharmacokinetics.4 Synthesis of
these natural products from the corresponding amino acids
require mild conditions in order to avoid potential epimeri-
zation and decomposition. Intensive research in the syn-
theses of natural products has resulted in the development
of new mild methods for the formation of biaryl ethers.
The use of arene ruthenium induced macroetheri®cation,
pioneered by the groups of Pearson and Rich has been
showcased in the syntheses of vancomycin, ristocetin A,
teicoplanin, OF4949III, and K-13.3a,b,5 Yamamura, Evans
and others have reported the oxidative methodology that
utilizes thallium trinitrate for the syntheses of biaryl ethers
in vancomycin and chloropeptin.6 The classical method of
Ullmann allowed the assembly of the diphenylether of the
natural products K-13 and OF4949-III.7 Alternate methods
using triazines, o-nitro¯uoro aromatics have also provided
smooth access to the formation of these biaryl ring systems.8
In connection with our infectious diseases program we
were challenged to synthesize macrocycles represented by
structures 1 and 2 (Fig. 1).
The 16 and 18 member macrocycles 1 and 2 are derived
from cyclization of nonproteinogenic amino acids
(S)-7-hydroxy-1,2,3-tetrahydroisoquinoline-3-carboxylic
acid ((S)-7-hydroxy-Tic), cyclohexylglycine, and phenyl-
propionic acid or phenylpentanoic acid. A comprehensive
Figure 1.
Keywords: macrocyclic biaryl ethers;ruthenium induced cyclization;
macroetheri®cation.
Corresponding author;e-mail: srikanth.venkatraman@spcorp.com
p
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00511-2

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S. Venkatraman et al. / Tetrahedron 58 (2002) 5453±5458
Scheme 2. Reagents andconditions : (a) CpRu(CH3CN)3PF6, ClCH2CH2Cl, re¯ux, 2 h, 73% (b) 4, BOP reagent, HuÈnig's base, 220!258C, 24 h, 63%;(c) 4 M
HCl/ dioxane, (d) 7, EDCI, HOBt, DMF, rt, 24 h, 83%;(e) 5.0 equiv. Cs CO3, DMF;(f) CH 3CN, hn; 350 nm, 48 h, 20%.
2
review of literature revealed a number of biaryl ether
macrocycles synthesized mainly from phenylglycines and
phenylalanines but none were prepared from (S)-7-hydroxy-
Tic. In this communication we report the application of the
arene ruthenium induced macrocylization method for the
construction of the highly strained rings 1 and 2.
10 was accomplished by the photolytic deprotection of
ruthenium at 350 nm.
A similar route to that used in preparation of macrocycle
1 was also used for the synthesis of the 18 membered
homologue 2 (Scheme 3).
As shown in the retrosynthesis of 1 (Scheme 1), our
approach required ligating a cationic ruthenium reagent on
the arene ring of 4-chlorophenylpropionic acid 5 and
inducing a macroetheri®cation using the hydroxyl of
7-hydroxy-Tic 4.
As outlined in Scheme 3, synthesis of the 18 member biaryl
ether macrocycle 2 began with 4-chlorophenyl propionic
acid 5. Reduction of acid 5 with BH3´THF12 followed by
oxidation using Py´SO3 and DMSO13 gave 3-(4-chloro-
phenyl)propanal which was homologated using stabilized
Wittig reagent14 (EtO)2P(O)CH2COOC2H5 to yield 12 as a
colorless oil. Reduction of the double bond by hydro-
genation followed by hydrolysis of the ethyl ester gave
4-chlorophenylpentanoic acid 13. As previously discussed,
the ruthenium reagent was introduced by the reaction of 13
with CpRu(CH3CN)3PF6 and subsequently coupling to the
dipeptide 9 gave rise to the macrocyclic precursor 15.
Macrocyclization and photolytic deprotection of the
arene ruthenium resulted in the formation of the strained
macrocycle 2 in 15% yield.
As outlined in Scheme 2, the synthesis of ruthenium
complex 7 was initiated with 4-chlorophenylpropionic
acid 5. The reaction of 4-chlorophenylpropionic acid 5
with CpRu(CH3CN)3PF6 in re¯uxing dichloroethane
resulted in the smooth formation of the complex 7 in 73%
yield, which crystallized out of the reaction mixture on
cooling.9 We were now ready to couple it to 7-hydroxy-
Tic and cyclohexylglycine.
Dipeptide 8 was synthesized in 63% yield by the coupling of
Boc protected (S)-cyclohexylglycine 6 with 7-OH-Tic
methyl ester 4 using BOP reagent.10 Deprotection of the
Boc group followed by coupling with 7 using EDCI and
HOBt resulted in the formation of macrocyclic precursor
10 in 83% yield. Initial attempts to cyclize 10 using 2,6
di-tert-butylphenoxide11 failed and resulted only in the
recovery of starting material. However treating tripeptide
10 with excess Cs2CO3 resulted in a smooth cyclization to
form the macrocycle 11. Synthesis of 1 in 20% yield from
In conclusion, we have completed the synthesis of the
macrocycles 1 and 2 using the arene ruthenium chemistry.
The composition of these macrocycles clearly extends the
scope of the intramolecular ruthenium-activated cyclization
methodology to generate novel strained macrocyclic
biphenyl ethers derived from 7-hydroxy-Tic. We are
currently exploring the ability to use these arene ruthenium
reagents for the construction of ethers bridged by two
heterocycles.

S. Venkatraman et al. / Tetrahedron 58 (2002) 5453±5458
5455
heated at re¯ux for 2 h. The reaction mixture was cooled
to rt, when colorless crystals of the ruthenium complex 7
precipitated out. The crystals were ®ltered and washed with
a mixture of Et2O/CH2Cl2 (1:1 v/v) and dried in vacuo. The
1
colorless crystals (3.3 g, 73%) were analytically pure: H
NMR (d6-DMSO, 400 MHz,) d 6.64 (d, 2H, Jˆ6.6 Hz),
6.22 (d, 2H, Jˆ6.3 Hz), 5.35 (s, 5H), 2.49 (t, 2H, Jˆ
9.6 Hz), 2.74 (dd, 2H, Jˆ4.3 Hz); 13C NMR 139.6, 131.6,
129.7, 128.6, 128.5, 100.3, 35.5, 28.9;MS (ES) m/z, relative
intensity: 350 [(C14H14ClRu1), M1, 100];Anal. calcd for
C14H14ClF6O2PRu: C, 33.92;H, 2.85;Cl, 7.15, found: C,
34.04;H, 3.04;Cl, 7.09.
1.1.2. (S,S)-(N-tert-Butoxycarbonyl)-cyclohexylglycine-
7-hydroxy-1,2,3-tetrahydroisoquinoline-3-carboxylic
acid methyl ester (8). A solution of Boc-Chg-OH 6 (3.84 g,
14.93 mmol) in CH2Cl2/DMF (1:1, 100 mL) at 2208C was
treated with 4 (3.3 g, 13.57 mmol), HuÈnig's base (4.24 g,
32.84 mmol) and BOP reagent (6.60 g, 14.93 mmol). The
reaction mixture was left in the freezer overnight and
concentrated in vacuo. The residue was diluted with aq.
HCl (1 M, 200 mL) and extracted with EtOAc (3£
100 mL). The combined organic layers were extracted
with saturated NaHCO3, brine, dried (MgSO4), concentrated
in vacuo and puri®ed by chromatography (SiO2, EtOAc/hex
2:3) to yield 3.8 g (63%) of 8 as a colorless ¯uffy solid: 1H
NMR (CDCl3 300 MHz) d 6.85 (d, 1H, Jˆ8.1 Hz), 6.54 (d,
1H, Jˆ2.4 Hz), 6.54 (dd, 1H, Jˆ2.7, 5.7 Hz), 5.48 (d, 1H,
Jˆ9.3 Hz), 5.43 (dd, 1H, Jˆ3.9, 2.1 Hz), 4.73 (d, 1H, Jˆ
15.3 Hz), 4.65 (dd, 1H, Jˆ5.4, 9.3 Hz), 4.54 (d, 1H, Jˆ
19.2 Hz), 3.69 (s, 3H), 3.09 (dd, 1H, Jˆ3.6, 12.3 Hz),
2.87 (dd, 1H, Jˆ6.0, 9.9 Hz), 1.93±1.66 (m, 7H), 1.42 (s,
9H), 1.45±1.40 (m, 4H); 13C NMR (CDCl3, 75 MHz) d
171.9, 171.1, 156.3, 155.4, 132.5, 128.9, 122.5, 113.9,
112.8, 80.4, 55.1, 52.3, 51.9, 45.3, 40.9, 29.6, 28.3, 27.2,
Scheme 3. Reagents andconidtions : (a) (i) BH3´THF, THF, rt, 12 h,
98% (ii) Py´SO3, DMSO, Et3N, CH2Cl2, rt, 6 h, 77% (iii) NaH,
(C2H5O)2P(O)CH2COOC2H5, THF, rt 12 h, 70% (b) (i) H2/Pd/C, EtOAc,
93% (ii) LiOH´H2O, CH3OH/H2O, 5 h, 96% (c) CpRu(CH3CN)3PF6,
ClCH2CH2Cl, re¯ux, 2 h, 59% (d) 9, EDCI, HOBt, DMF, rt, 24 h, 75%;
(e) (i) 5.0 equiv. Cs2CO3, DMF;(f) CH 3CN, hn; lˆ350 nm, 48 h.
26.1, 25.9;MS (FAB)
m/z, relative intensity: 469
([M1Na]1, 30), 447 ([M11]1, 45), 391 (58), 347 (100),
208 (85);HRMS m/z calcd for C24H35N2O6 (M11)1:
447.2491, found: 447.2505.
1. Experimental
1.1.3. (S,S)-Cyclohexylglycine-7-hydroxy-1,2,3-tetrahydro-
isoquinoline-3-carboxylic acid methyl ester hydro-
chloride (9). A solution of 8 (3.8 g, 8.5 mmol) in HCl
(60 mL, 4 M in dioxane) at rt was stirred for 3 h and concen-
trated in vacuo to yield 9 as a colorless solid. The residue
was used as it is in further steps without further puri®cation:
1H NMR (CD3OD, 300 MHz) d 7.03 (d, 1H, Jˆ7.8 Hz),
6.72±6.69 (d, 2H), 5.16 (t, 1H, Jˆ6.3 Hz), 4.82, 4.61
(AB, 2H), 3.64 (s, 3H), 3.14±3.11 (m, 2H), 2.11±1.80 (m,
6H), 1.31±1.16 (m, 6H); 13C NMR (CD3OD, 75 MHz) d
172.2, 169.5, 157.4, 134.3, 129.7, 124.2, 115.5, 113.5,
56.2, 54.7, 52.6, 46.6, 40.6, 30.4, 29.5, 28.1, 26.6;MS
(FAB) HRMS m/z calcd for C19H27N2O4 (M2Cl)1:
347.1971, found: 347.1964.
1.1. General methods
All glassware were dried in an oven at 1508C prior to use.
Dry solvents were purchased from Aldrich or Acros and
used without further puri®cation. Other solvents or reagents
were used as acquired except when otherwise noted. Ana-
lytical thin layer chromatography (TLC) was performed on
pre-coated silica gel plates available from Analtech.
Column chromatography was performed using Merck silica
gel 60 (particle size 0.040±0.055 mm, 230±400 mesh).
Visualization was accomplished with UV light or by
staining with basic KMnO4 solution, methanolic H2SO4 or
Vaughn's reagent. NMR spectra were recorded in CDCl3
unless otherwise noted in either 300 or 400 MHz (1H
NMR), or 75 or 100 MHz (13C NMR).
1.1.4. (S,S)-[h6-3-(4-Chlorophenyl)-1-propionic acid-
cyclohexylglycine-7-hydroxy-1,2,3-tetrahydroisoquino-
line-3-carboxylic acid methyl ester](h5-cyclopenta-
dienyl)ruthenium hexa¯uorophosphate (10). A solution
of CpRu(h6-4-chlorophenylpropionic acid 7, (4.14 g,
8.36 mmol) in dry DMF (20 mL) was treated with HOBt
(1.69 g 12.54 mmol) and HuÈnig's base (6.47 g, 9.20 mL,
50.16 mmol). The reaction mixture was cooled to 08C and
1.1.1. h6-3-(4-Chlorophenyl)-1-propionic acid](h5-cyclo-
pentadienyl)ruthenium hexa¯uorophosphate (7).
solution of 4-chlorophenylpropionic acid (2.0 g, 10.8
mmol) 5 in dichloroethane (200 mL) was treated with
CpRu(CH3CN)3PF6 (4.7 g, 10.8 mmol, 1.0 equiv.)9a and
A

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S. Venkatraman et al. / Tetrahedron 58 (2002) 5453±5458
treated with EDCI (2.39 g, 12.54 mmol). The reaction
mixture was stirred at 08C for 30 min and the ammonium
salt 9 (2.90 g, 7.6 mmol) was added. The reaction mixture
was stirred at rt for 12 h and the DMF was distilled out in
vacuo. The residue was diluted with aq. HCl (1 M, 100 mL)
and extracted with CH2Cl2 (3£100 mL). The combined
organic layers were extracted with aq. NaHCO3
(1£100 mL), brine (100 mL), dried (Na2SO4), ®ltered,
concentrated in vacuo to obtain 5.2 g (83%) of 10 as a
brown solid which was used for cyclization without further
puri®cation. MS (ES) m/z, relative intensity: 647 [(M2
CH3OH±PF6)1, 100];HRMS calcd for C 32H34ClN2O4Ru
[(M2CH3OH±PF6)]1: 647.1256, found: 647.1241.
organic layers were extracted with HCl (2 M, 3£100 mL),
brine (1£100 mL) concentrated in vacuo and puri®ed by
chromatography (SiO2, EtOAc/hex 1:7) to yield 3-(4-chloro-
phenyl)-1-propanal14 which solidi®ed to a waxy solid on
standing (7.1 g, 77%). Anal. calcd for C9H9ClO: C, 64.11;
H, 5.38, found: C, 64.08;H, 5.30.
A solution of triethylphosphonoacetate (6.72 g, 30 mmol) in
dry THF (100 mL) was treated with NaH (60% 1.5 g,
35 mmol) at 08C. The reaction mixture was stirred at 258C
for 1 h until the H2 evolution ceases. A solution of 3-(4-
chlorophenyl)-propanal (4.2 g, 25.0 mmol) in dry THF
(5.0 mL) was added and the reaction mixture was stirred
for 36 h. The reaction mixture was diluted with H2O
(100 mL) and extracted with Et2O (3£70 mL). The com-
bined organic layer was dried (MgSO4), ®ltered concen-
trated in vacuo and chromatographed to yield alkene 12
(4.2 g, 70%) which was used for reduction without further
puri®cation.
1.1.5. Cyclic-(S,S)-[h6-3-phenyl-1-propionic acid-cyclo-
hexylglycine-7-hydroxy-1,2,3-tetrahydroisoquinoline-3-
carboxylic acid methyl ester](h5-cyclopentadienyl)-
ruthenium hexa¯uorophosphate (1). A solution of the
ruthenium complex 10 (5.0 g, 6.01 mmol) in dry DMF
(300 mL) was degassed with dry N2 and treated with
Cs2CO3 (10.0 g, 30 mmol). The reaction mixture was stirred
at rt for 24 h. and concentrated in vacuo. The residue was
diluted with water (100 mL) and extracted with CH2Cl2
(3£100 mL) and propionitrile (3£100 mL). The combined
organic layers were extracted with brine (100 mL), dried
(Na2SO4) ®ltered, concentrated in vacuo, and dried in
vacuum overnight to yield 5.1 g of 11 as a brown solid. It
was used for photolytic removal of Ru without any further
puri®cation. MS (ES) m/z, relative intensity: 643 [(M2
PF6)1, 100], HRMS calcd for C33H37N2O5102Ru (M2
PF6)1: 643.1755, found: 643.1746.
1.1.7. 5-(4-Chlorophenyl)pentanoic acid (13). A solution
of a,b-unsaturated ester 12 (4.2 g, 8.0 mmol) in EtOAc
(50 mL) was treated with Pd/C (10% w/w, 500 mg) and
hydrogenated at 50 psi. The reaction mixture was ®ltered
through a plug of celite and concentrated in vacuo to yield
the reduced ester (3.9 g, 93%) used for hydrolysis.
A solution of the reduced ester (3.9 g, 16.2 mmol) in
CH3OH/THF/H2O (1:1:0.1, 110 mL) was treated with
LiOH´H2O (1.2 g, 30 mmol) and stirred at rt for 5 h. The
reaction mixture was concentrated in vacuo and the residue
was diluted with H2O (100 mL) and extracted into Et2O
(3£50 mL). The aqueous layer was acidi®ed to pH t1
with concentrated HCl and the turbid aqueous layer was
extracted with Et2O (3£100 mL). The combined organic
layers were dried (MgSO4) ®ltered concentrated in vacuo
to yield acid 13 (3.1 g, 96%) as a colorless solid. Anal. calcd
for C11H13ClO2: C, 62.12, H, 6.16, found: C, 62.27, H, 6.23.
Crude 11 was dissolved in CH3CN (50 mL) and ®ltered into
a quartz tube. The solution was degassed and photolysed in
a Rayonet (lˆ350 nm) for 48 h. The reaction mixture was
concentrated in vacuo and the residue was puri®ed by
chromatography (SiO2, EtOAc/hexanes 3:2) to yield a tan
colored solid 1 (289 mg, 20%); Rf: 0.73 (acetone/hexanes
3:7); 1H NMR (CDCl3, 300 MHz) d 7.19 (d, 2H, Jˆ6.1 Hz),
7.20±7.11 (m, 2H), 6.92 (d, 2H, Jˆ8.1 Hz), 6.85 (dd, 1H,
Jˆ2.1, 7.2 Hz), 6.76 (s, 1H), 5.41 (d, 1H, Jˆ17.7 Hz), 4.24±
4.18 (m, 2H), 4.00 (bs, 1H), 3.68 (s, 3H), 3.42 (dd, 1H,
Jˆ12.0, 3.3 Hz), 3.01±2.86 (m, 1H) 2.94 (t, 2H, Jˆ
7.8 Hz), 2.63 (t, 2H, Jˆ8.1 Hz), 2.18±2.10 (m, 1H), 1.84±
1.62 (m, 5H), 1.34±1.03 (m, 5H); 13C NMR (CDCl3,
100 MHz) d 173.2, 167.0, 163.8, 156.5, 155.1, 135.7,
132.7, 130.2, 129.6, 126.2, 119.1, 117.5, 115.7, 60.2, 55.5,
51.6, 44.2, 41.9, 35.7, 33.6, 30.1, 29.3, 26.4, 26.2, 25.7,
25.6;MS (ES) m/z, relative intensity: 477 [(M11)1, 100],
315 (20);HRMS calcd for C 28H33N2O5 (M11)1: 477.2389,
found: 477.2375;Anal. calcd for C 28H32N2O5´0.5H2O: C,
69.26;H, 6.85;N, 5.77, found: C, 69.62;H, 6.59;N, 5.77.
1.1.8. h6-[5-(4-Chlorophenyl)pentanoic acid]-h5-(cyclo-
pentadienyl)ruthenium hexa¯uoro phosphate (14). A
solution of 5-(4-chlorophenyl) pentanoic acid 13 (3.0 g,
14.15 mmol) in dry dichloroethane (150 mL) was treated
with CpRu(CH3CN)3PF6 (6.75 g, 15.10 mmol) and heated
at re¯ux for 2.5 h. The reaction mixture was cooled to 08C
and ®ltered. The ®ltrate was concentrated in vacuo and
dissolved in CH3CN (20 mL) and treated with a large excess
of Et2O. Ether and acetonitrile were decanted and the
residual gum was dissolved in CH2Cl2/CH3OH (1:1,
100 mL) and concentrated in vacuo to obtain 14 as brown
gum which solidi®es on standing (4.36 g, 59%). MS (ES)
m/z, relative intensity: 379 [(M2PF6)1, 100] HRMS calcd
for C16H18O2Cl102Ru (M2PF6)1: 379.0039, found:
379.0035.
1.1.6. Ethyl-5-(4-chlorophenyl)-2-pentenoate (12).
A
solution of 3-[4-chlorophenyl]propan-1-ol (9.2 g, 54.1
mmol) in dry CH2Cl2 (200 mL) was treated with DMSO
(35 mL) and Et3N (16.4 g, 16.3 mmol, 23.4 mL). It was
cooled to 08C and treated with Py´SO3 (12.9 g, 81.2 mmol,
1.50 equiv.) dissolved in DMSO (30 mL). The reaction
mixture was stirred at 08C for 0.5 h and rt for 6 h. It was
concentrated in vacuo and diluted with Et2O (100 mL) and
H2O (200 mL). The layers were separated and the aqueous
layer was extracted with Et2O (3£100 mL). The combined
1.1.9. (S,S)-[h6-3-(4-Chlorophenyl)-1-pentanoic acid-
cyclohexylglycine-7-hydroxy-1,2,3-tetrahydroisoquino-
line-3-carboxylic acid methyl ester](h5-cyclopenta-
dienyl)ruthenium hexa¯uorophosphate (15). A solution
of [CpRu(h6-4-chlorophenylpentanoic acid)]PF6 14 (2.2 g,
4.0 mmol) in dry DMF (10 mL) was treated with HOBt
(810 mg 5.99 mmol) and HuÈnig's base (2.58 g, 3.6 mL,
19.9 mmol) The reaction mixture was cooled to 08C and

S. Venkatraman et al. / Tetrahedron 58 (2002) 5453±5458
5457
C.;Mitchell, H. J.;Jain, N. F.;Winssinger, N.;Hughes, R.;
treated with EDCI (1.14 g, 6.0 mmol) The reaction mixture
was stirred at 08C for 30 min. and the ammonium salt 9
(1.60 g, 4.0 mmol) was added. The reaction mixture was
stirred at rt for 12 h and concentrated in vacuo. The residue
was diluted with aq. HCl (1 M, 100 mL) and extracted with
CH2Cl2 (3£100 mL). The combined organic layers were
extracted with aq. NaHCO3 (40 mL), brine (100 mL),
dried (Na2SO4), ®ltered, concentrated in vacuo to yield 15
as a brown solid (2.41 g, 75%) which was used for cycli-
zation as it is. HRMS calcd for C35H42N2O5Cl102Ru
(M2PF6)1: 707.1826, found: 707.1825.
Bando, T. Angew. Chem., Int. Ed. Engl. 1999, 38, 240.
(g) 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 and references cited therein.
2. (a) Boger, D.;Zhou, J. J. Am. Chem. Soc. 1993, 115, 11426.
(b) Shigeru, N.;Kazuhiko, N.;Yoshikazu, S.;Shosuke, Y.
Tetrahedron Lett. 1986, 27, 4481. (c) Boger, D. L.;Daniel,
Y. J. Org. Chem. 1990, 55, 6000. (d) Boger, D. L.;Daniel, Y.
Tetrahedron Lett. 1989, 30, 5061. (e) Evans, D. A.;Ellmann,
J. A. J. Am. Chem. Soc. 1989, 111, 1063. (f) Schmidt, U.;
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3227. (g) Shigeru, N.;Yoshikazu, S.;Shosuke, Y.
Tetrahedron Lett 1988, 29, 559.
1.1.10. Cyclic-(S,S)-[h6-3-phenyl-1-pentanoic acid-cyclo-
hexylglycine-7-hydroxy-1,2,3-tetrahydroisoquinoline-3-
carboxylic acid methyl ester](h5-cyclopentadienyl)-
ruthenium hexa¯uorophosphate (2). A solution of
complex 15 (2.40 g, 2.8 mmol) in dry DMF (250 mL) was
degassed and treated with Cs2CO3 (4.6 g, 14.0 mmol). The
reaction was stirred at rt for 24 h and concentrated in vacuo.
The residue was diluted with water (100 mL) and extracted
with CH2Cl2 (3£100 mL). The combined organic layers
were extracted, with aq. HCl (1 M, 100 mL), NaHCO3
(100 mL), brine (100 mL), dried (Na2SO4), ®ltered, concen-
trated in vacuo, and dried in vacuum to yield 16 as a brown
solid (1.9 g, 79%). It was used for photolytic removal of Ru
without further puri®cation;MS (ES) m/z, relative intensity:
671 [(M2PF6)1, 40];HRMS calcd for C 35H41N2O5Ru
(M2PF6)1: 671.2059, found: 671.2045.
3. (a) Janetka, J. W.;Raman, P.;Satyshur, K.;Flentke, G. R.;
Rich, D. H. J. Am. Chem. Soc. 1997, 119, 441. (b) Janetka,
J. W.;Rich, D. H. J. Am. Chem. Soc. 1995, 117, 10585.
(c) Decicco, C. P.;Song, Y.;Evans, D. A. Org. Lett. 2001,
3, 1029. (d) Marchetti, A.;Ontoria, J. M.;Matassa, V. G.
Synlett 1999, 1000. (e) West, C. W.;Rich, D. H. Org. Lett.
1999, 1, 1819. (f) Elder, A. M.;Rich, D. H. Org. Lett. 1999, 1,
1433.
4. McGeary, R. P.;Fairlie, D. P. Curr. Opin. Drug Discovery
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The cyclized compound 16 was dissolved in CH3CN
(60 mL) and ®ltered into a quartz tube. The solution was
degassed and photolysed in a Rayonet (lˆ350 nm) for 48 h.
The reaction mixture was concentrated in vacuo and the
residue was puri®ed by chromatography (SiO2, acetone/
hex 3:7) to yield 2 as a tan colored solid (140 mg, 13%).
Rf: 0.73 (acetone/hexanes 3:7); 1H NMR (CDCl3, 300 MHz)
d 7.30±7.12 (m, 5H), 6.92±8.83 (m, 2H), 6.74 (d, 1H,
Jˆ2.4 Hz), 5.43 (dd, 1H, Jˆ13.7, 3.3 Hz), 4.22±4.11 (m,
2H), 4.00 (bs, 1H), 3.66 (s, 3H), 3.44±3.39 (m, 1H), 3.02±
2.91 (m, 1H), 2.66±2.57 (m, 3H), 2.36±2.13 (bt, 1H), 2.10±
2.06 (bt, 1H), 1.83±1.64 (m, 8H), 1.36±1.23 (m, 5H). 13C
NMR (CDCl3, 75 MHz) d 167.2, 167.1, 163.9, 156.7, 154.6,
149.4, 140.3, 132.6, 130.1, 129.9, 129.6, 129.3, 128.4,
120.4, 119.3, 119.1, 117.3, 115.6, 60.2, 60.1, 55.4, 55.2,
51.5, 44.1, 42.0, 34.8, 34.0, 33.8, 33.7, 33.6, 30.9, 30.6,
3087. (m) Pearson, A. J.;Zhang, P.;Bignan, G.
Chem. 1997, 62, 4536.
J. Org.
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29.9, 26.5;MS (FAB)
m/z, relative intensity 505
[(M11)1, 80], 232 (40), HRMS calcd for C30H37N2O5
(M11)1: 505.2702, found: 505.2698.
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