Synthesis of macrolide analogues of sanglifehrin by RCM: Unique reactivity of a Ruthenium carbene complex bearing an Imidazol-2-ylidene ligand

Full text of DOI:10.1021/jo001296u

J . Org. Chem. 2000, 65, 9255-9260
9255
recently, this methodology was shown to be extendable
to the synthesis of other natural products, namely
asteriscanolide and griseoviridin.6,7 Even though catalyst
1 exhibits a remarkably wide scope and excellent com-
patibility with a range of functional groups, it is very
sensitive toward the substitution pattern on the alkene.
Tri- and tetrasubstituted alkenes cannot be formed by
using catalyst 1. This gap promises to be filled by a new
generation of ruthenium catalysts bearing one bulky
imidazol-2-ylidene ligand. Among these new catalysts,
complex 2 has been most widely used.8 This reagent
allows the formation of tri- and tetrasubstituted cycloalk-
enes while retaining excellent stability toward heat and
moisture.9 These very interesting properties combined
with its user-friendly character prompted us to test 2 on
our system.
Syn th esis of Ma cr olid e An a logu es of
Sa n glifeh r in by RCM: Un iqu e Rea ctivity of
a Ru th en iu m Ca r ben e Com p lex Bea r in g a n
Im id a zol-2-ylid en e Liga n d
J u¨rgen Wagner,*,† Luisa M. Martin Cabrejas,†
Catharine E. Grossmith,† Charles Papageorgiou,†
Francesco Senia,† Dieter Wagner,† J ulien France,† and
Steven P. Nolan*,‡
Novartis Pharma AG, S-350.207, CH-4002 Basel,
Switzerland and Department of Chemistry, University of
New Orleans, New Orleans, Louisiana 70148
juergen.wagner@pharma.novartis.com.
Received August 28, 2000
In tr od u ction
Sanglifehrin A (SFA) was isolated from Streptomyces
flaveolus in 1995 by scientists at Novartis.1 The com-
pound is a potent immunosuppressant and has a remark-
ably high affinity for an intracellular binding protein
called cyclophilin (IC50 ) 2-4 nM). Degradation studies
on sanglifehrin and X-ray analysis of the cyclophilin-
sanglifehrin complex showed that the binding was es-
sentially mediated through the 22-membered macrolide.2
To clarify the importance of the various functionalities
attached to the macrocyclic core, we embarked on the
synthesis of a series of simplified analogues containing
the tripeptide fragment as well as an alkene or a
conjugated 1,3-diene (Figure 1).
Herein, a detailed account of the synthesis of unsatur-
ated sanglifehrin macrolide analogues by RCM in high
yields is described. The methodology provides an efficient
and convergent route toward macrolides containing
either an alkene or a conjugated 1,3-diene. Additionally,
an unexpected difference in reactivity between catalysts
1 and 2 with regard to conjugated dienes was observed.
A retrosynthetic analysis shows that the macrocyclic
core can be approached via different routes including
macrolactonization, macrolactamization, or Stille cou-
pling. The latter has been used successfully in the total
synthesis of sanglifehrin A.3 Early on, we considered the
ring-closing metathesis (RCM) reaction as a convergent
and flexible route to construct these unsaturated mac-
rocyclic structures.4 The approach was successful using
Grubbs’s ruthenium catalyst 1, and we demonstrated for
the first time that macrolides containing a conjugated
1,3-diene system can be obtained directly by RCM.5 More
Resu lts a n d Discu ssion
The synthesis of the precursors for the RCM reaction
is shown in Scheme 1. Two separate series of structures
are described, each containing one unnatural amino
acid: hexahydropyridazine-3-carboxylic acid (piperazic
acid, Piz) or piperidine-3-carboxylic acid (nipecotic acid,
Nip). The fully protected piperazic acid derivative 3 was
obtained in an optically pure form and on a multigram
scale according to the procedure published by Hale et al.10
On the other hand, resolution of racemic nipecotic acid
ethyl ester was achieved by recrystallization with tartaric
acid.11 With the protected unnatural amino acids 3 and
4 in our hands, the tripeptides 6a ,b were assembled by
using carbodiimide-based coupling procedures. In the
case of 5b, preactivation of the carboxylic acid by the
* To whom correspondence should be addressed. Tel:
+41.61.324.26.83. Fax: +41.61.324.45.13.
† Novartis Pharma AG.
‡ University of New Orleans.
(1) (a) Sanglier, J .-J .; Quesniaux, V.; Fehr, T.; Hofmann, H.;
Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.;
Maurer, C.; Schilling, W. J . Antibiot. 1999, 52, 466. (b) Fehr, T.; Kallen,
J .; Oberer, L.; Sanglier, J .-J .; Schilling, W. J . Antibiot. 1999, 52, 474.
(2) Fehr, T.; Oberer, L.; Quesniaux Ryffel, V.; Sanglier, J .-J .; Schuler,
W.; Sedrani, R. (Sandoz Ltd); WO 9702285 A1, 1997.
(3) (a) Nicolaou, K. C.; Murphy, F.; Barluenga, S.; Ohshima, T.; Wei,
H.; Xu, J .; Gray, D. L. F.; Baudoin, O. J . Am. Chem. Soc. 2000, 122,
3830. (b) Nicolaou, K. C.; Xu, J .; Murphy, F.; Barluenga, S.; Baudoin,
O.; Wei, H.; Gray, D. L. F.; Ohshima, T. Angew. Chem., Int. Ed. 1999,
38, 2447. (c) Hall, P.; Brun, J .; Denni, D.; Metternich, R. Synlett 2000,
3, 315.
(6) Paquette, L. A.; Tae, J .; Arrington, M. P.; Sadoun, A. H. J . Am.
Chem. Soc. 2000, 122, 2742.
(7) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J .; Pryde, D. C.; Lawson,
J . P.; Amos, R. A.; Meyers, A. I. Angew. Chem., Int. Ed. 2000, 39, 1664.
(8) (a) Huang, J .; Stevens, E. D.; Nolan, S. P.; Petersen, J . L. J . Am.
Chem. Soc. 1999, 121, 2674. (b) Scholl, M.; Trnka, T. M.; Morgan, J .
P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247.
(9) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J .;
Nolan, S. P. J . Org. Chem. 2000, 65, 2204. (b) Ackermann, L.; Tom, D.
E.; Fu¨rstner, A. Tetrahedron 2000, 56, 2195. (c) Bourgeois, D.;
Mahuteau, J .; Pancrazi, A.; Nolan, S. P.; Prunet, J . Synthesis 2000,
869.
(10) Hale, K. J .; Cai, J .; Delisser, V.; Manaviazar, S.; Peak, S. A.;
Bhatia, G. S.; Collins, T. C.; J ogiya, N. Tetrahedron 1996, 52, 1047.
(11) (a) Zheng, X.; Day, C.; Gollamudi, R. Chirality 1995, 7, 90. (b)
Akkerman, A. M.; De J ongh, D. K.; Veldstra, H. Rec. Trav. Chim. Pays-
Bas 1951, 70, 899.
(4) For recent reviews see: (a) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036. (b) Armstrong, S. K. J . Chem.
Soc., Perkin Trans.
1 1998, 371. (c) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (d) Pandit, U. K.; Overkleeft, H. S.; Borer,
B. C.; Biera¨ugel, H. Eur. J . Org. Chem. 1999, 959. (e) Roy, R.; Das, S.
K. Chem. Commun. 2000, 519.
(5) Preliminary communication: Martin Cabrejas, L. M.; Rohrbach,
S.; Wagner, D.; Kallen, J .; Zenke, G.; Wagner, J . Angew. Chem., Int.
Ed. 1999, 38, 2443.
10.1021/jo001296u CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/07/2000

9256 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
F igu r e 1.
Sch em e 1a
a
(a) TFA, CH2Cl2; (b) EDC, HOBT, NMM, RCO2H (Boc-L-XX-OH, Cbz-L-XX-OH, 6-heptenoic acid or 4,6-heptadienoic acid), CH2Cl2; (c)
NMM, isobutyl chloroformate, Cbz-L-Phe-OH, THF; (d) Pd/C, H2, EtOH; (e) LiOH, THF/H2O; (f) Ph3P, DEAD, hexen-5-ol-1 or hexadien-
3,5-ol-1, THF.
mixed

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9257
Sch em e 2a
a
(a) Catalyst 1 (0.15 equiv), CH2Cl2, concentration: 6 mM, reflux; (b) catalyst 1 (0.15 equiv), CH2Cl2, concentration: 40 mM, reflux;
(c) air.
anhydride method was required for coupling the less
reactive nipecotic acid derivative 4 in good yield.
The results of the RCM leading to macrolides contain-
ing an isolated double bond are summarized in Scheme
2. Under dilute conditions (<5 mM), the macrocycles
11a ,b were obtained using Grubbs’s ruthenium catalyst
1 in refluxing CH2Cl2 in excellent yields after HPLC
purification. Other solvents, e.g., benzene and toluene,
gave lower yields. The configuration of the newly formed
double bond was predominantly trans as assessed by IR
In the next step, the N-terminus of the tripeptide was
coupled to 6-heptenoic acid or 4,6-heptadienoic acid to
afford 7a -c.12 Modification of the N-terminus had to be
performed first, because partial isomerization of the diene
moiety in 9a ,b occurred under the acidic Boc-cleavage
conditions. Finally, saponification of the methyl ester of
7a -c provided the corresponding acids, which were
esterified with 5-hexenol or 3,5-hexadien-1-ol under
Mitsunobu conditions.13 Similar yields of the esterifica-
tion could be obtained using DCC and DMAP, but in this
case a careful removal of the urea side-product was
important to avoid deactivation of the ruthenium catalyst
in the following step. The metathesis precursors 8a , 8b,
9a , 9b, and 10 for the RCM reaction were thus obtained
in good overall yield (11-33%) and allowed the study of
the formation of 22-membered macrolides containing an
alkene, a conjugated diene, or a triene unit.
1
(absorption band at 971 cm-1) and H NMR in benzene-
d6 (J 13-14 ) 15.5 Hz). In both cases, approximately 5% of
the cis isomer could be detected by 1H NMR and/or
HPLC. To our surprise, the unprotected R nitrogen in
the piperazic acid ring 8a did not affect the rate of the
RCM, even though the ruthenium catalysts are known
to be highly sensitive to free nitrogen groups. The
nitrogen atom is either sterically hindered or involved
in a strong intramolecular hydrogen bond, which pre-
vents interaction with the catalyst. This explanation is
supported by the fact that attempts to use a monopro-
tected piperazic acid ester in a cross-metathesis reaction
failed, whereas the reaction with the corresponding
diprotected substrate succeeded. Compound 11a is un-
stable and is slowly oxidized to 12 in the presence of
oxygen even at low temperatures (-18 °C). This stands
in sharp contrast to the stability of the parent molecule,
(12) 4,6-Heptadienoic acid was prepared according to: Hudlicky, T.;
Koszyk, F. J .; Kutchan, T. M.; Sheth, J . P. J . Org. Chem. 1980, 45,
5020.
(13) 3,5-Hexadien-1-ol was prepared according to: (a) Stevens, R.
V.; Cherpeck, R. E.; Harrison, B. L.; Lai, J .; Lapalme, R. J . Am. Chem.
Soc. 1976, 98, 6317. (b) Hoye, T. R.; Magee, A. S.; Trumper, W. S.
Synth. Commun. 1982, 12, 183.

9258 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
Sch em e 3a
mentally useful protocol for the synthesis of conjugated
trienes.
Con clu sion
Simplified macrolide analogues of sanglifehrin could
be prepared in excellent yields via a convergent and
flexible route. The crucial step was the RCM reaction,
which lead selectively to 22-membered macrocycles con-
taining either E-alkenes (11a ,b) or conjugated E,E-dienes
(15a ,b). The attempt to form E,E,E-trienes was not
successful. In the case of the diene formation, the
reactivity of the two ruthenium catalysts 1 and 2 was
compared. Surprisingly, the catalysts had opposite se-
lectivity with respect to the double bond of the initial
diene undergoing metathesis. Catalyst 1 reacted selec-
tively with the less sterically hindered terminal double
bond, whereas catalyst 2, bearing an imidazol-2-ylidene
ligand, predominantly reacted with the more substituted,
electron-rich internal double. One explanation could be
that the higher reactivity of catalyst 2 counterbalances
the steric effect, resulting in a preferential attack of the
electron-richer internal double bond of the diene.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were monitored by TLC
carried out on glass plates precoated (0.25 mm) with silica gel
60 F254. Materials were detected by visualization under a UV
lamp (254 nm) and/or using molybdenum solution followed by
heat as developing agent. Flash column chromatography (FCC)
was performed with Merck silica gel 60 (230-400 mesh). All
mixed solvent systems are reported as v/v solutions. The purity
of the compounds was analyzed by reverse-phase HPLC using
the following conditions: C18 column; 10 min linear gradient
followed by 5 min isocratic; elution 30-100% (H2O/CH3CN (1:
9) in H2O/CH3CN (9:1)); flow rate 1.5 mL/min. The retention
time (rt) is indicated in min. All reagents were purchased at
highest commercial quality and used without further purifica-
tion.
a
(a) Catalyst 1 (0.15 equiv), CH2Cl2, reflux; (b) catalyst 2 (0.15
equiv), CH2Cl2, reflux.
sanglifehrin A, under the same conditions. Performing
the RCM at higher concentrations (>40 mM) yielded two
dimeric products, 13 and 14, in low yield without cis/
1
trans selectivity as revealed by H NMR.
Scheme 3 shows the results of the RCM leading to
macrolides containing a conjugated 1,3-diene system.
Surprisingly, catalysts 1 and 2 displayed a very different
reactivity toward the diene. Using Grubbs’s ruthenium
catalyst 1, the desired E,E-dienes 15a ,b were formed in
excellent yields of 57% and 62%, respectively. Best results
were obtained under conditions (dilution, solvent, tem-
perature) similar to those described for 11a ,b. The E,Z
isomer was present as a minor component (<5%), but we
could not detect any product resulting from metathesis
of the internal diene double bond. On the other hand,
the new ruthenium catalyst 2 showed the opposite
selectivity, reacting preferentially with the internal diene
double bond of 9a ,b to give 16a ,b as the major products
in 45% and 40% yield, respectively. In this case, the
dienes 15a ,b represented ∼10% of the crude mixture as
determined by HPLC analysis. Again, in both cases the
trans alkene was formed predominantly as determined
by IR (absorption band at 970 cm-1) and 1H NMR in
pyridine-d5 (J 13-14 ) 15.4 Hz). The product distribution
was not affected by running the reaction at a higher
temperature (reflux in 1,2-dichloroethane).
Gen er a l P r oced u r es for Dep r otection /Cou p lin g Rea c-
tion s
Meth od A: (ter t-Bu toxycar bon yl)-L-ph en ylalan in e-h exa-
h yd r op yr id a zin e-3S-ca r boxylic Acid Meth yl Ester (5a ).
N,N′-Bis(tert-butoxycarbonyl)-hexahydro-pyridazine-3S-carbox-
ylic acid methyl ester 3 (41.7 g, 0.12 mol) was dissolved in CH2-
Cl2 (500 mL) and cooled to 0 °C. Trifluoroacetic acid (70 mL)
was added dropwise, and the mixture was stirred for 2 h at room
temperature. All volatile materials were evaporated under high
vacuum, and the residue was redissolved in CH2Cl2 (500 mL).
To this solution were added N-methylmorpholine (61.2 g, 0.6
mol), EDC (25.0 g, 0.13 mol), HOBT (24.5 g, 0.18 mol), and Boc-
L-Phe-OH (35.3 g, 0.13 mol). The mixture was stirred overnight.
The reaction was diluted with CH2Cl2 (500 mL) and washed with
1.0 M aqueous tartaric acid (2 × 200 mL), 1.0 M aqueous
NaHCO3 (2 × 200 mL), and brine (100 mL). The organic phase
was dried over Na2SO4 and evaporated. The residue was purified
by FCC (AcOEt/hexane 1:1) to afford 5a (36.0 g, 76%) as a white
solid. [R]20 ) +2.8 (c ) 1.0, CHCl3); rt ) 4.96 min; 1H NMR
D
(CDCl3) δ 1.41 (s, 9H), 1.40-1.49 (m, 2H), 1.73-1.76 (m, 2H),
2.32-2.41 (m, 1H), 2.69-2.78 (m, 1H), 2.86-3.00 (m, 2H), 3.54
(m, 1H), 3.71 (s, 3H), 4.29 (m, 1H), 5.26 (d, J ) 8.5 Hz, 1H),
5.54 (m, 1H), 7.15-7.31 (m, 5H); 13C NMR (CDCl3) δ 23.0, 28.6,
28.7, 40.6, 42.1, 50.9, 52.5, 58.3, 79.7, 127.1, 128.7, 130.1, 137.4,
155.4, 171.9, 173.4; IR (KBr) νmax 3292, 1740, 1705, 1655, 705;
ESI-MS 392 (M + H)+. Anal. Calcd for C20H29N3O5 (391.47): C
61.36, H 7.47, N 10.73. Found: C 61.29, H 7.51, N 10.73.
Meth od B: (Ben zyloxyca r bon yl)-L-va lin e-L-p h en yla la -
n in e-p ip er id in e-3R-ca r boxylic Acid Eth yl Ester (6b). Com-
pound 5b (21.0 g, 48.0 mmol) was dissolved in EtOH (500 mL),
and 10% Pd/C (1.2 g, 1.13 mmol) was added. The mixture was
hydrogenated overnight and filtered through Celite. The solvent
was evaporated to afford the crude amine (13.2 g). To a solution
Finally, the possibility of forming a conjugated triene
system directly was tested by submitting precursor 10
to the same RCM conditions in the presence of catalyst
1. The sluggish reaction resulted in a complex mixture
of products. HPLC-MS confirmed that the desired triene
(MW ) 536.68) had been formed in small amounts along
with several peaks (MW ) 510.64) corresponding to
various isomeric dienes. Further experimentation would
be needed to transform the latter results into an experi-

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9259
of the amine in THF (200 mL) at 0 °C were added Cbz-L-Val-
OH (13.4 g, 53.4 mmol), EDC (10.2 g, 53.4 mmol), and HOBT
(7.2 g, 53.4 mmol). The mixture was stirred overnight at room
temperature, and the solvent was evaporated. The residue was
taken up in AcOEt (500 mL) and washed with H2O (2 × 100
mL). The organic phase was dried over Na2SO4 and evaporated.
The residue was purified by FCC (AcOEt/Hexane 1:1) to afford
6b (21.0 g, 82%) as a colorless oil: [R]20D ) -31.1 (c ) 2.0, EtOH);
13C NMR (CDCl3, 125.6 MHz) δ 18.0, 19.2, 22.7, 25.0, 25.2, 27.9,
28.4, 28.5, 31.5, 33.2, 33.4, 36.6, 39.5, 41.8, 49.9, 57.9, 58.0, 64.9,
114.6, 115.0, 126.8, 128.4, 129.7, 136.6, 138.1, 138.4, 170.5, 171.1,
172.1, 172.7; IR (KBr) νmax 3288, 2933, 1742, 1635, 911, 697;
HRMS: Calcd for C32H48N4O5 [M + Na]+ 591.3522, found
591.3523.
Meth od B: Hep t-6-en -1-oyl-L-va lin e-L-p h en yla la n in e-
h exa h yd r op yr id a zin e-3S-ca r boxylic Acid Hexa -3,5-d ien yl
Ester (9a ). To a solution of 7a (700 mg, 1.4 mmol) in THF (30
mL) at 0 °C was added 1.0 M aqueous LiOH (3.5 mL). The
reaction was stirred at room temperature for 2 h, neutralized
with 1.0 M aqueous HCl, and evaporated. The residue was
redissolved in AcOEt (50 mL) and washed with 1.0 M aqueous
HCl (10 mL). The organic phase was dried over Na2SO4 and
evaporated to afford the crude acid. To a solution of the crude
acid in THF (20 mL) were added 3,5-hexadien-1-ol (358 mg, 3.64
mmol), triphenylphosphine (460 mg, 1.75 mmol), and DEAD (275
µL, 1.75 mmol). The reaction was stirred overnight at room
temperature and concentrated. The residue was taken up in
AcOEt (50 mL) and washed with 1.0 M aqueous NaHCO3 (10
mL). The organic phase was dried over Na2SO4 and evaporated.
The residue was purified by FCC (AcOEt/Hexane 4:1) to afford
1
rt ) 5.86 min; H NMR (DMSO, 120 °C, 400 MHz) δ 0.82 (d, J
) 6.6 Hz, 6H), 1.18 (t, J ) 6.6 Hz, 3H), 1.25-1.38 (m, 1H), 1.50-
1.65 (m, 2H), 1.81-1.90 (m, 1H), 1.96 (dsept, J ) 6.8, 6.6 Hz,
1H), 2.03-2.18 (m, 1H), 2.85 (dd, J ) 12.6, 6.3 Hz, 1H), 2.80-
2.90 (m, 1H), 2.96 (dd, J ) 12.6, 6.6 Hz, 1H), 2.91-3.02 (m, 1H),
3.75-3.85 (m, 1H), 3.89 (dd, J ) 9.0, 6.2 Hz, 1H), 3.97-4.05 (m,
1H), 4.07 (q, J ) 6.6 Hz, 2H), 5.01 (m, 1H), 5.03 (s, 2H), 6.68 (d,
J ) 7.8 Hz, 1H), 7.12-7.38 (m, 10H), 7.74 (d, J ) 6.2 Hz, 1H);
13C NMR (CDCl3, 125.6 MHz, 1:1 mixture of two conformers) δ
14.1, 14.2, 17.5, 19.2, 23.7, 25.0, 26.9, 27.2, 31.2, 31.4, 39.7, 40.3,
40.6, 41.1, 42.4, 43.9, 45.7, 47.3, 49.9, 60.1, 60.2, 60.7, 66.9, 67.0,
127.0, 127.1, 128.0, 128.1, 128.4, 128.5, 128.6, 129.4, 129.7, 135.9,
136.1, 136.3, 156.3, 169.3, 169.5, 170.4, 170.5, 172.3, 172.9; IR
(KBr) νmax 3298, 2961, 1730, 1630, 699; HRMS: Calcd for
C30H39N3O6 [M + Na]+ 560.2736, found 560.2745.
9a (507 mg, 64%) as a white foam: [R]20 ) -26.0 (c ) 1.0,
D
Meth od C: (Ben zyloxyca r bon yl)-L-p h en yla la n in e-p ip er -
id in e-3R-ca r boxylic Acid Eth yl Ester (5b). To a solution of
Cbz-L-Phe-OH (19.3 g, 64.5 mmol) and N-methylmorpholine (7.2
g, 71.0 mmol) in dry THF (200 mL) cooled to -15 °C was added
isobutyl chloroformate (9.7 g, 71.0 mmol) dissolved in THF (50
mL). A white precipitate fell out immediately, and the suspen-
sion was stirred for 30 min at -15 °C. The tartaric acid salt of
piperidine-3R-carboxylic acid ethyl ester 4 (19.8 g, 64.5 mmol)
was dissolved in CH2Cl2 (100 mL) containing diisopropylethyl-
amine (9.2 g, 71.0 mmol). The solution was added to the
chloroformate, and the reaction was stirred overnight at room
temperature. The solvent was evaporated, and the residue was
redissolved in AcOEt (500 mL). The organic phase was washed
with H2O (2 × 150 mL), dried over Na2SO4, and evaporated. The
residue was purified by FCC (AcOEt) to afford 5b (21.7 g, 77%)
as a colorless oil: [R]20D ) -24.7 (c ) 2.0, EtOH); rt ) 5.76 min;
1H NMR (DMSO, 120 °C, 400 MHz) δ 1.21 (t, J ) 7.5 Hz, 3H),
1.27-1.39 (m, 1H), 1.54-1.65 (m, 2H), 1.85-1.93 (m, 1H), 2.12-
2.25 (m, 1H), 2.86 (dd, J ) 13.2, 6.9 Hz, 1H), 2.94 (dd, J ) 13.2,
6.6 Hz, 1H), 2.90-3.04 (m, 2H), 3.78-3.86 (m, 1H), 4.03-4.14
(m, 1H), 4.10 (q, J ) 7.5 Hz, 2H), 4.74 (dd, J ) 6.9, 6.6 Hz, 1H),
4.98 (d, J ) 13.7 Hz, 1H), 5.03 (d, J ) 13.7 Hz, 1H), 6.85 (br,
1H), 7.18-7.38 (m, 10H); 13C NMR (CDCl3, 100.6 MHz, mixture
of two conformers) δ 14.6, 24.1, 25.4, 27.3, 27.6, 40.5, 41.1, 41.2,
41.5, 42.8, 44.3, 46.1, 47.7, 51.8, 52.1, 60.9, 61.0, 67.2, 127.4,
127.5, 128.4, 128.5, 128.9, 129.0, 129.9, 130.1, 136.4, 136.6, 136.8,
136.9, 155.9, 156.0, 170.1, 170.2, 172.7, 173.4; IR (film) νmax 3291,
2942, 1728, 1642, 700; HRMS: Calcd for C25H30N2O5 [M + Na]+
461.2052, found 461.2052.
CHCl3); rt ) 7.54 min; 1H NMR (DMSO, 400 MHz) δ 0.78, 0.80
(2d, J ) 6.5 Hz, 6H), 1.28-1.58 (m, 6H), 1.62-1.80 (m, 2H), 1.95
(m, 1H), 2.01 (m, 2H), 2.07-2.23 (m, 2H), 2.41 (m, 2H), 2.75 (dd,
J ) 13.3, 7.5 Hz, 1H), 2.87 (dd, J ) 13.3, 6.0 Hz, 1H), 2.92 (br,
2H), 3.92 (br, 1H), 4.14 (m, 3H), 4.90-5.10 (m, 3H), 5.14 (m,
2H), 5.48 (m, 1H), 5.66-5.85 (m, 2H), 6.14 (dd, J ) 15.3, 10.5
Hz, 1H), 6.32 (dt, J ) 17.0, 10.5 Hz, 1H), 7.12-7.27 (m, 5H),
7.64 (d, J ) 8.0 Hz, 1H), 7.76 (d, J ) 9.0 Hz, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ 18.4, 19.6, 23.0, 25.6, 28.7, 28.9, 31.9, 32.2,
33.8, 37.0, 39.9, 42.2, 50.2, 58.2, 58.4, 64.4, 115.1, 116.8, 127.3,
128.8, 129.5, 130.1, 134.2, 136.9, 137.0, 138.9, 170.8, 171.4, 172.5,
173.1; IR (KBr) νmax 3288, 2930, 1743, 1635, 1550, 909, 698; ESI-
MS 589 (M + Na)+, 567 (M + H)+. Anal. Calcd for C32H46N4O5
(566.75): C 67.82, H 8.18, N 9.89. Found: C 67.48, H 8.16, N
9.71.
Gen er a l P r oced u r e for t h e R in g-Closin g Met a t h esis
Rea ction
(E)-(3S,6S,21S)-3-Ben zyl-6-isop r op yl-19-oxa -1,4,7,25-tet-
raaza-bicyclo[19.3.1]-pentacos-13-ene-2,5,8,20-tetraone (tra ns-
11a ). To a solution of 8a (700 mg, 1.23 mmol) in CH2Cl2 (250
mL) was added ruthenium catalyst 1 (150 mg, 0.18 mmol). The
reaction was stirred under reflux overnight, and the solvent was
evaporated. The residue was purified by reverse-phase prepara-
tive HPLC [C18 column, 25 min linear gradient followed by 10
min isocratic; elution 30-100% (H2O/CH3CN (1:9) in H2O/CH3-
CN (9:1)); flow rate 20 mL/min] to afford trans-11a (405 mg,
60%) as a white foam and containing ∼5% cis-11a as determined
1
by H NMR; [R]20 ) +83.2 (c ) 1.65, CHCl3); rt ) 4.74 min; 1H
D
NMR (DMSO, 400 MHz) δ 0.81, 0.87 (2d, J ) 6.6 Hz, 6H), 1.06-
1.18 (m, 1H), 1.23-1.46 (m, 5H), 1.47-1.62 (m, 4H), 1.64-1.79
(m, 3H), 1.80-2.00 (m, 5H), 2.18-2.28 (m, 1H), 2.79 (dd, J )
13.8, 8.0 Hz, 1H), 2.85 (dd, J ) 13.8, 5.6 Hz, 1H), 2.85-3.02 (m,
2H), 3.88-4.18 (m, 4H), 5.06 (d, J ) 10.4 Hz, 1H), 5.19-5.34
(m, 2H), 5.50 (m, 1H), 7.11-7.25 (m, 5H), 7.60 (d, J ) 9.0 Hz,
1H), 7.93 (d, J ) 7.5 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
18.6, 19.7, 23.3, 26.2, 26.6, 28.2, 28.6, 28.9, 31.3, 32.5, 32.8, 37.3,
38.9, 42.0, 50.0, 58.3, 59.9, 65.5, 127.4, 129.0, 129.9, 130.2, 130.4,
136.6, 170.7, 171.3, 172.6, 173.8; IR (KBr) νmax 3318, 2927, 1736,
1644, 970, 700; HRMS: Calcd for C30H44N4O5 [M + Na]+
563.3209, found 563.3219.
Gen er a l P r oced u r es for Sa p on ifica tion /Ester ifica tion
Met h od A: Hep t -6-en -1-oyl-L-va lin e-L-p h en yla la n in e-
h exa h yd r op yr id a zin e-3S-ca r boxylic Acid Hex-5-en yl Ester
(8a ). To a solution of 7a (61 mg, 0.12 mmol) in THF (5 mL) was
added 1.0 M aqueous LiOH (0.3 mL). The mixture was stirred
for 4 h at room temperature, neutralized with 1.0 M aqueous
HCl, and concentrated. The residue was taken up in AcOEt (30
mL) and washed with 2.0 M aqueous HCl (5 mL), H2O (5 mL),
and brine (2 mL). The aqueous phases were reextracted with
AcOEt (2 × 10 mL). The combined organic phases were dried
over Na2SO4 and evaporated to afford the crude acid. To a
solution of the acid in CH2Cl2 (15 mL) were added 5-hexen-1-ol
(12.3 mg, 0.12 mmol), DCC (26.5 mg, 0.13 mmol), and DMAP
(12.6 mg, 0.12 mmol). The mixture was stirred overnight at room
temperature, diluted with CH2Cl2 (15 mL), and filtered over
Celite. The organic phase was washed with 1.0 M aqueous
tartaric acid (5 mL) and brine (2 mL). The organic phase was
dried over Na2SO4 and evaporated. The residue was purified by
FCC (AcOEt/Hexane 4:1) to afford 8a (40 mg, 58%) as a white
(E)-(3S,6S)-3-Ben zyl-6-isopr opyl-19-oxa-1,4,7,25-tetr aaza-
b icyclo[19.3.1]-p en t a cosa -13,21(25)-d ien e-2,5,8,20-t et r a -
on e (12). 11a is slowly oxidized into the white foam 12 in the
presence of air: [R]20 ) +115.5 (c ) 1.86, CHCl3); rt ) 5.68
D
1
min; H NMR (DMSO, 400 MHz) δ 0.82, 0.90 (2d, J ) 6.6 Hz,
6H), 1.02-1.11 (m, 2H), 1.26-1.46 (m, 3H), 1.47-1.62 (m, 3H),
1.63-1.75 (m, 2H), 1.76-2.00 (m, 6H), 2.17-2.30 (m, 1H), 2.31-
2.42 (m, 2H), 2.87 (d, J ) 6.8 Hz, 2H), 3.41-3.54 (m, 1H), 3.64-
3.75 (m, 1H), 3.91-4.02 (m, 1H), 4.21 (m, 1H), 4.31-4.40 (m,
1H), 5.16-5.33 (m, 2H), 5.57 (m, 1H), 7.09-7.26 (m, 5H), 7.64
(d, J ) 9.0 Hz, 1H), 8.27 (d, J ) 7.4 Hz, 1H); 13C NMR (CDCl3,
100.6 MHz) δ 16.7, 18.7, 19.7, 21.9, 26.3, 27.1, 28.5, 29.2, 31.3,
32.3, 33.0, 37.3, 38.9, 39.6, 51.3, 58.6, 65.8, 127.4, 128.9, 129.7,
130.1, 136.3, 141.0, 164.6, 171.2, 172.8, 173.9; IR (KBr) νmax 3312,
foam: [R]20 ) -24.0 (c ) 1.11, CHCl3); rt ) 8.51 min; 1H NMR
D
(DMSO, 400 MHz) δ 0.78, 0.80 (2d, J ) 6.7 Hz, 6H), 1.28-1.81
(m, 12H), 1.88-2.23 (m, 7H), 2.75 (dd, J ) 13.1, 7.4 Hz, 1H),
2.81-3.01 (m, 3H), 3.89-4.20 (m, 4H), 4.91-5.07 (m, 4H), 5.14
(d, J ) 10.4 Hz, 1H), 5.46 (m, 1H), 5.72-5.87 (m, 2H), 7.12-
7.26 (m, 5H), 7.66 (d, J ) 7.8 Hz, 1H), 7.75 (d, J ) 9.0 Hz, 1H);

9260 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
2933, 1694, 1645, 969, 700; HRMS: Calcd for C30H42N4O5 [M +
Su p p or tin g In for m a tion Ava ila ble: Analytical data of
compounds 6a , 7a -c, 8b, 9b, 10, 11b, 13-16. Copies of 1H
NMR spectra of compounds 5-16. This material is available
free of charge via the Internet at http://pubs.acs.org.
Na]+ 561.3053, found 561.3063.
Ack n ow led gm en t. We thank I. Lewis and M. Men-
gus for the HPLC-MS analyses and K. Hinterding for
reading the manuscript.
J O001296U