Novel dipeptide macrocycles from 4-oxo, -thio, and -amino-substituted proline derivatives.

Article abstract of DOI:10.1021/jo011160b

Dipeptide macrocycles of type A have been constructed in a versatile manner from the corresponding 4-heteroatom-substituted proline derivatives using an intramolecular Mitsunobu strategy.

Full text of DOI:10.1021/jo011160b

J . Org. Chem. 2002, 67, 3923-3926
3923
tuted proline derivative are rare.5 Herein we describe the
synthesis of these macrocyclic molecules starting from
commercially available trans- or cis-4-hydroxyproline
derivatives. The key step in our synthesis was macrocy-
clization via an intramolecular Mitsunobu protocol.6
Novel Dip ep tid e Ma cr ocycles fr om 4-Oxo,
-Th io, a n d -Am in o-Su bstitu ted P r olin e
Der iva tives
Ashok Arasappan,* Kevin X. Chen, F. George Njoroge,
Tejal N. Parekh,† and Viyyoor Girijavallabhan
Schering Plough Research Institute, 2015 Galloping Hill
Road, Kenilworth, New J ersey 07033
ashok.arasappan@spcorp.com
Received December 19, 2001
Abstr a ct: Dipeptide macrocycles of type A have been
constructed in a versatile manner from the corresponding
4-heteroatom-substituted proline derivatives using an in-
tramolecular Mitsunobu strategy.
While peptides are used extensively to probe the
binding pocket of enzymes or receptors, their use as drug
candidate is severely limited. This is due to the fact that
peptides are prone to rapid degradation by proteolytic
enzymes and, therefore, lack acceptable pharmaceutical
properties.1 An effective solution to this problem involves
cyclization of the linear peptides resulting in macrocyclic
molecules.2 The aforementioned strategy leads to con-
formationally constrained structures devoid of peptide-
like properties. In general, macrocycles are resistant
toward proteolytic enzymes and often exhibit improved
binding affinity and acceptable pharmacokinetic profile.2
Several groups have successfully demonstrated this
approach in the design and synthesis of biologically
important molecules.3
A common structural motif that emerges in the mac-
rocyclization strategy is the aryl-O-alkyl linkage, which
has been well exploited in the HIV protease inhibitor
field.4 During the course of our studies leading to novel
peptidomimetics, we designed macrocyclic structures of
type A that incorporated the aryl-alkyl ether linkage.
Furthermore, introduction of the 4-heteroatom substitu-
tion on the core proline moiety was required to provide
macrocycles of suitable size and conformation. These
types of macrocycles arising from 4-heteroatom-substi-
Our efforts started with the construction of the 16-
membered macrocycle with a 4-ether linkage as depicted
in Scheme 1. Commercially available trans-4-hydroxy-
proline derivative 1 was alkylated with 3-benzyloxy-1-
bromopropane to install the “top” three-carbon linker.
Esterification of the crude residue with trimethylsilyl-
diazomethane afforded compound 2 in 44% isolated yield
for two steps. Attempted alkylation of the methyl ester
of 1 (structure not shown) using cesium carbonate or
sodium hydride resulted in no reaction or low yields of 2
with concomitant loss of stereochemical integrity at the
R-center next to the ester functionality. Deprotection of
the N-Boc residue of 2 (4 M HCl in dioxane) and
subsequent coupling with N-Boc-L-cyclohexylglycine us-
ing EDCI and HOOBt under cold (-20 to -10 °C)
conditions provided the dipeptide 3. The “bottom” amide
linker was introduced via a similar protocol involving
deprotection followed by coupling with commercially
available 3-hydroxyphenylacetic acid to afford compound
4. Cleavage of the benzyl-protecting group under catalytic
hydrogenation unraveled the free alcohol 5, setting the
stage for the key macrocyclization step. The final cycliza-
tion was carried out by intramolecular Mitsunobu strat-
egy. The reaction was performed in dichloromethane
using triphenylphosphine and 1,1′-(azodicarbonyl)dipip-
† Current address: Argonaut Technologies, Foster City, CA 94404.
(1) (a) Hirschmann, R.; Smith, A. B., III; Sprengeler, P. A. In New
Perspectives in Drug Design; Dean, M., J olles, G., Newton, C. G., Eds.;
Academic Press Inc.: New York, 1995; p 1. (b) West, M. L.; Fairlie, D.
P. Trends Pharm. Sci. 1995, 16, 67.
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Bioorg. Med. Chem. Lett. 2001, 11, 219. (b) Tyndall, J . D. A.; Reid, R.
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P. F.; Birch, C. J .; Martin, J . L.; Fairlie, D. P. J . Med. Chem. 2000, 43,
3495. (c) Martin, J . L.; Begun, J .; Schindeler, A.; Wickramasinghe, W.
A.; Alewood, D.; Alewood, P. F.; Bergman, D. A.; Brinkworth, R. I.;
Abbenante, G.; March, D. R.; Reid, R. C.; Fairlie, D. P. Biochemistry
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Wickramasinghe, W.; Begun, J .; Martin, J . L.; Fairlie, D. P. J . Am.
Chem. Soc. 1996, 118, 3375. (f) Abbenante, G.; March, D. R.; Bergman,
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D. P. J . Am. Chem. Soc. 1995, 117, 10220. (g) Chen, J . J .; Coles, P. J .;
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Cody, W. L.; He, J . X.; Humblet, C.; Lu, G. H.; Lunney, E.; Major, T.
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10.1021/jo011160b CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/26/2002

3924 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) BsCl, Et3N, DMAP (97%); (b)
3-mercaptopropanol, NaH (78%); (c) (i) 4M HCl/Dioxane; (ii) N-Boc-
Chg-OH, EDCl, HOOBt, NMM (80%); (d) (i) 4 M HCl/Dioxane; (ii)
3-hydroxyphenylacetic acid, EDCl, HOOBt, NMM (40%); (e) PPh3,
ADDP (22%).
a
Reagents and conditions: (a) (i) 3-benzyloxy-1-bromopropane,
NaH, NaI; (ii) TMSCHN2 (44%); (b) (i) 4 M HCl/dioxane; (ii) N-Boc-
Chg-OH, EDCl, HOOBt, NMM (84%); (c) (i) 4 M HCl/dioxane; (ii)
3-hydroxyphenylacetic acid, EDCl, HOOBt, NMM (90%); (d) H2,
10% Pd/C (87%); (e) PPh3, ADDP (35%).
HOOBt, NMM) resulted in the dipeptide 14. In this case,
attachment of the “top” three-carbon linker followed an
intermolecular Mitsunobu protocol under neutral condi-
tions with 3-benzyloxypropanol to afford compound 15.
Subsequent steps for the building of 16, i.e., installation
of the “bottom” amide linker, release of the alcohol, and
final cyclization proceeded as described previously in
Scheme 1. After purification, the N-linked proline-derived
macrocycle 16 was isolated in 20% yield over two steps.
No attempts were made to optimize the yields of the final
cyclization step in the above schemes.
In summary, we have developed a versatile synthetic
route for the construction of novel conformationally
restrained 16 membered macrocyclic structures contain-
ing 4-oxo-, 4-thio-, and 4-aminoproline moiety via intra-
molecular Mitsunobu protocol. These macrocycles are cur-
rently being evaluated as appropriate peptidomimetics.
eridine (ADDP) to provide the constrained dipeptide
macrocycle 6 in 35% isolated yield. It was found neces-
sary to bubble argon gas into the reaction mixture before
addition of triphenylphosphine to obtain reasonable
yields of the cyclized product.
Preparation of the 4-thioether-linked macrocycle was
initiated with commercially available 4-cis-hydroxypro-
line derivative 7 (Scheme 2). The hydroxyl group was
activated as the brosylate (Bs) via treatment with brosyl
chloride and triethylamine in the presence of catalytic
amounts of DMAP. Displacement of the brosylate 8 with
the monosodium salt of mercaptopropanol resulted in the
incorporation of the 4-thioether moiety along with the
“top” linker in high yields (78%) to provide compound 9.
It should be noted that use of the corresponding 4-me-
sylate (structure not shown) derived from 7 did not afford
the required product 9. Processing of compound 9 as
outlined above (from 2 to 3) gave the dipeptide 10. The
amide-linked macrocycle precursor (step d, Scheme 2)
was obtained by deprotection of the N-Boc functionality
of 10 and coupling with 3-hydroxyphenylacetic acid. The
intramolecular Mitsunobu cyclization for the construction
of macrocycle 11 took place in dichloromethane with
triphenylphosphine and ADDP in 22% isolated yield.
Synthetic studies on the 4-nitrogen-linked macrocycle
(Scheme 3) started with the 4-aminoproline derivative
12 that was obtained from 1 using previously reported
chemistry.7 Treatment of 12 with benzenesulfonyl chlo-
ride furnished the phenylsulfonamido derivative 13.
Deprotection followed by peptide coupling with N-Boc-
L-cyclohexylglycine using standard conditions (EDCI,
Exp er im en ta l Section
All reagents/solvents were purchased from commercial sources
and used without further purification. When required, reactions
were performed under N2 or Ar atmosphere. Flash chromatog-
raphy was carried out using Selecto silica gel (230-400 mesh).
NMR spectra (300 or 400 MHz for 1H and 75 or 100 MHz for
13C) were obtained in CDCl3 unless otherwise specified.
4(R)-[3-(P h en ylm eth oxy)p r op oxy]-1,2(S)-p yr r olid in ed i-
ca r boxylic Acid , 1-(1,1-Dim eth yleth yl) 2-Meth yl Ester (2).
To a solution of N-Boc-Hyp-OH 1 (7.0 g, 30.3 mmol) and benzyl
3-bromopropyl ether (7.8 g, 34.0 mmol) in anhydrous DMF (400
mL) at room temperature were added sodium hydride (3.5 g,
60% dispersion in mineral oil, 87.5 mmol) and sodium iodide
(0.5 g, 3.34 mmol). The resulting suspension was vigorously
stirred at room temperature overnight (18 h). The reaction
mixture was cooled to 0 °C and was quenched carefully with
slow addition of water (50 mL) followed by 6 N HCl solution (20
mL). After addition of ethyl acetate (800 mL), brine (150 mL),
and more water (150 mL), the two layers were separated, and
the organic solution was washed with 5% H3PO4 (3 × 200 mL),
dried (MgSO4), filtered, and concentrated in vacuo to afford an
(7) (a) Bhagwat, S. S.; Fink, C. A.; Gude, C.; Chan, K.; Qiao, Y.;
Sakane, Y.; Berry, C.; Ghai, R. D. Bioorg. Med. Chem. Lett. 1994, 4,
2673. (b) Anderson, N. G.; Lust, D. A.; Colapret, K. A.; Simpson, J . H.;
Malley, M. F.; Gougoutas, J . Z. J . Org. Chem. 1996, 61, 7955.

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3925
Sch em e 3a
room temperature. The progress of the reaction was monitored
by TLC. After 4 h, the solution was concentrated in vacuo and
the residue was kept under vacuum overnight to give a white
solid that was used in the next coupling reaction without further
purification: 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.27 (m, 5
H), 4.43 (s, 2 H), 4.35-4.31 (m, 1H), 3.88 (d, J ) 11.7 Hz, 1 H),
3.62 (s, 3 H), 3.62-3.57 (m, 2 H), 3.53-3.41 (m, 3 H), 2.32-2.27
(m, 1 H), 1.97-1.91 (m, 1 H), 1.79-1.60 (m, 8 H), 1.17-1.07 (m,
5 H); 13C NMR (100 MHz, DMSO-d6) δ 171.5, 167.4, 138.6, 133.3,
129.1, 128.8, 128.2, 127.4, 77.1, 71.9, 66.5, 65.3, 57.8, 54.9, 52.4,
52.0, 34.0, 29.6, 27.7, 27.0, 25.6, 25.5, 25.48; HRMS m/z 433.2702
(calcd for C24H36N2O5, 433.2702). To the amine‚HCl from above
in anhydrous DMF (250 mL) and CH2Cl2 (100 mL) at -20 °C
were added 3-hydroxyphenylacetic acid (1.90 g, 12.5 mmol),
HOOBt (2.10 g, 12.9 mmol), EDCI (2.85 g, 14.9 mmol), and NMM
(4.20 mL, 38.2 mmol). After 30 min at this temperature, the
reaction mixture was kept in a freezer overnight (18 h). It was
then allowed to warm to room temperature over 1 h. EtOAc (500
mL), brine (100 mL), and 5% H3PO4 (100 mL) were added. The
separated organic solution was washed with 5% H3PO4 (100 mL),
saturated aqueous sodium bicarbonate solution (2 × 150 mL),
water (150 mL), and brine (150 mL), dried with magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatog-
raphy (10-20% EtOAc-CH2Cl2) afforded 4 (6.30 g, 11.1 mmol,
90% (two steps)) as a white solid: 1H NMR (400 MHz, DMSO-
d6) δ 9.26 (s, 1 H), 8.19 (d, J ) 8.5 Hz, 1 H), 7.36-7.25 (m, 5 H),
7.05-7.01 (m, 1 H), 6.66-6.64 (m, 1 H), 6.60-6.57 (m, 1 H),
4.46-4.39 (m, 2 H), 4.34 (t, J ) 8.3 Hz, 1 H), 4.29-4.25 (m, 1
H), 4.09-4.08 (m, 1 H), 3.91 (d, J ) 11.0 Hz, 1 H), 3.66-3.58
(m, 1 H), 3.61 (s, 3 H), 3.50-3.39 (m, 5 H), 3.30 (d, J ) 13.7 Hz,
1 H), 2.24-2.18 (m, 1 H), 1.95-1.89 (m, 1 H), 1.74-1.57 (m, 8
H), 1.18-0.89 (m, 5 H); 13C NMR (100 MHz, DMSO-d6) δ 172.0,
170.3, 170.0, 157.1, 138.6, 137.6, 128.9, 128.2, 127.4, 127.3, 119.6,
116.1, 113.2, 76.9, 71.8, 66.6, 65.2, 57.4, 54.7, 51.9, 51.8, 41.8,
34.4, 29.6, 28.5, 28.0, 25.5, 25.5; HRMS m/z 567.3073 (calcd for
C32H42N2O7, 567.3070).
a
Reagents and conditions: (a) PhSO2Cl, Et3N, DMAP (59%);
(b) (i) 4 M HCl/dioxane; (ii) N-Boc-Chg-OH, EDCl, HOOBt, NMM
(60%); (c) 3-benzyloxypropanol, PPh3, ADDP (34%); (d) (i) 4 M HCl/
Dioxane; (ii) 3-hydroxyphenylacetic acid, EDCl, HOOBt, NMM
(99%); (e) H2, 10% Pd/C; (f) PPh3, ADDP (20%).
oil. To this oil in benzene (25 mL) and methanol (28 mL) at
ambient temperature was added a solution of trimethylsilyldia-
zomethane (27 mL, 2.0 M in hexane) with caution. After being
stirred at room temperature for 1 h, the mixture was concen-
trated and the product purified by flash chromatography (8-
20% EtOAc-CH2Cl2) to afford 2 (5.15 g, 44%) as an oil: HRMS
m/z 394.2228 (calcd for C21H32NO6, 394.2230).
Meth yl 1-[(2S)-2-Cycloh exyl-2-[[(3-h ydr oxyph en yl)acetyl]-
a m in o]-1-oxoet h yl]-4(R)-(3-h yd r oxyp r op oxy)-2(S)-p yr r o-
lid in eca r boxyla te (5). To a solution of 4 (6.23 g, 11.0 mmol)
in ethanol (200 mL) under nitrogen at room temperature was
added 10% Pd-C (1.5 g) cautiously. The resulting suspension
was vigorously stirred at room temperature under hydrogen
atmosphere for 23 h. After filtration through Celite, the solution
was concentrated in vacuo. Flash chromatography (2-5% MeOH-
CH2Cl2) afforded 5 (4.54 g, 9.52 mmol, 87%) as a solid: mp 49-
Meth yl 1-[2(S)-Cycloh exyl-2-[[(1,1-d im eth yleth oxy)ca r -
b on yl]a m in o]-1-oxoet h yl]-4(R)-[3-(p h en ylm et h oxy)p r o-
p oxy]-2(S)-p yr r olid in eca r boxyla te (3). Compound 2 (5.83 g,
14.8 mmol) was dissolved in 4 M HCl/dioxane (80 mL, 320
mmol), and the resulting solution was stirred at ambient
temperature. The progress of the reaction was monitored by
TLC. After 5 h, the solution was concentrated in vacuo, and the
residue was kept under vacuum overnight to yield a white solid.
To this solid in anhydrous DMF (150 mL) and CH2Cl2 (150 mL)
at -20 °C were added N-Boc-cyclohexylglycine (4.10 g, 14.9
mmol), HOOBt (2.60 g, 15.9 mmol), EDCI (3.41 g, 17.8 mmol),
and NMM (6.50 mL, 59.1 mmol). After this temperature was
maintained for 30 min, the reaction mixture was kept in a
freezer overnight (18 h). It was then allowed to warm to room
temperature over 1 h. EtOAc (450 mL), brine (100 mL), and 5%
H3PO4 (100 mL) were added. After the two layers were sepa-
rated, the organic solution was washed with 5% H3PO4 (100 mL),
saturated aqueous sodium bicarbonate solution (2 × 150 mL),
water (150 mL), and brine (150 mL), dried (MgSO4), filtered,
and concentrated in vacuo. Flash chromatography (10 to 20%
EtOAc-CH2Cl2) afforded 3 (6.60 g, 84% two steps) as a white
solid: 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.25 (m, 5 H), 6.87
(d, J ) 8.9 Hz, 1 H), 4.46-4.40 (m, 2 H), 4.25 (t, J ) 8.3 Hz, 1
H), 4.11 (s, 1 H), 4.05-4.04 (m, 1 H), 4.03-3.94 (m, 1 H), 3.60
(s, 3 H), 3.50-3.41 (m, 4 H), 2.25-2.20 (m, 1 H), 1.95-1.88 (m,
1 H), 1.77-1.55 (m, 9 H), 1.35 (s, 9 H), 1.19-0.90 (m, 4 H); 13C
NMR (100 MHz, DMSO-d6) δ 172.0, 170.7, 155.6, 138.8, 128.2,
127.4, 127.3, 78.0, 77.1, 71.9, 66.6, 65.1, 57.4, 56.3, 51.8, 34.5,
29.6, 28.6, 28.2, 25.9, 25.6, 25.5; HRMS m/z 533.3232 (calcd for
C29H45N2O7, 533.3227).
1
51 °C; H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1 H), 8.22 (d, J
) 8.6 Hz, 1 H), 7.06-7.02 (m, 1 H), 6.66-6.58 (m, 3 H), 4.42-
4.40 (m, 1 H), 4.35-4.31 (s, 1 H), 4.27 (t, J ) 8.3 Hz, 1 H), 4.10-
4.09 (m, 1 H), 3.92 (d, J ) 11.2 Hz, 1 H), 3.64 (dd, J ) 11.2, 4.3
Hz, 1 H), 3.61 (s, 3 H), 3.59-3.43 (m, 5 H), 3.40-3.38 (m, 1 H),
2.26-2.21 (m, 1 H), 1.97-1.90 (m, 1 H), 1.74-1.55 (m, 8 H),
1.18-0.89 (m, 5 H); 13C NMR (100 MHz, DMSO-d6) δ 172.0,
170.3, 170.1, 157.1, 137.6, 129.0, 119.6, 116.0, 113.3, 76.9, 65.2,
57.6, 57.4, 54.8, 51.9, 51.8, 41.7, 34.4, 32.6, 28.5, 28.0, 25.9, 25.52,
25.49; HRMS m/z 477.2606 (calcd for C25H36N2O7, 477.2601).
Meth yl (7R,9S)-12(S)-Cycloh exyl-11,14-d ioxo-2,6-d ioxa -
10,13-diazatr icyclo[14.3.1.17,10]h en eicosa-1(20),16,18-tr ien e-
9-ca r boxyla te (6). Argon gas was bubbled into a solution of 5
(4.50 g, 9.43 mmol) and ADDP (6.60 g, 26.2 mmol) in anhydrous
CH2Cl2 for 20 min while the reaction mixture was cooled to 0
°C. To this solution was added triphenylphosphine (4.10 g, 16.3
mmol). After the solution was stirred at 0 °C for 20 min, a second
portion of triphenylphosphine (3.40 g, 13.5 mmol) was added.
The solution was then warmed to room temperature and stirred
overnight (24 h) under nitrogen atmosphere until TLC indicated
complete consumption of the starting material. After removal
of solvent in vacuo, the residue was purified by flash chroma-
tography (1-2% MeOH in CH2Cl2) to afford the macrocycle 6
(1.51 g, 35%) as an off-white solid: mp 77-79 °C; [R]20
)
D
-54.85° (c 0.5, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 8.47
(d, J ) 9.7 Hz, 1 H), 7.17-7.13 (m, 1 H), 6.79 (s, 1 H), 6.73 (d,
J ) 1.8 Hz, 1 H), 6.71 (d, J ) 1.8 Hz, 1 H), 4.50-4.45 (m, 1 H),
4.24 (dd, J ) 10.3, 7.6 Hz, 1 H), 4.17-4.06 (m, 4 H), 3.68 (d, J
) 15.1 Hz, 1 H), 3.63 (s, 3 H), 3.60-3.51 (m, 2 H), 3.37 (d, J )
15.1 Hz, 1 H), 3.35-3.27 (m, 1 H), 2.51-2.43 (m, 1 H), 1.85-
1.47 (m, 9 H), 1.22-1.12 (m, 3 H), 0.97-0.88 (m, 2 H); 13C NMR
(100 MHz, DMSO-d6) δ 172.0, 170.0, 169.8, 158.4, 138.1, 129.1,
Meth yl 1-[(2S)-2-cycloh exyl-2-[[(3-h yd r oxyp h en yl)a cety-
l]a m in o]-1-oxoet h yl]-4(R)-[3-(p h en ylm et h oxy)p r op oxy]-
2(S)-p yr r olid in eca r boxyla te (4). The N-Boc-amino methyl
ester 3 (6.53 g, 12.3 mmol) was dissolved in 4 M HCl/dioxane
(60 mL, 240 mmol), and the resulting solution was stirred at

3926 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
121.8, 115.4, 112.2, 77.0, 64.9, 63.6, 57.0, 54.3, 53.4, 51.8, 41.3,
33.2, 28.9, 28.5, 28.2, 26.0, 25.2; HRMS m/z 459.2495 (calcd for
C25H34N2O6, 459.2495).
7.93 (m, 2H); HRMS (FAB) calcd for C25H38N3O7S 524.2430 (M
+ H)+, found 524.2425.
Met h yl 1-[(2S)-2-Cycloh exyl-2-[[(1,1-d im et h ylet h oxy)-
ca r b on yl]a m in o]-1-oxoet h yl]-4(R)-[[3-(p h en ylm et h oxy)-
p r op yl](p h en ylsu lfon yl)a m in o]-2(S)-p yr r olid in eca r boxy-
la te (15). Argon gas was bubbled into a cold (0 °C) solution of
14 (1.72 g, 3.28 mmol) in dichloromethane (40 mL) for 20-30
min. ADDP (2.5 g, 9.84 mmol) was added followed by triph-
enylphosphine (2.6 g, 9.84 mmol) and 3-benzyloxypropanol (0.57
mL, 3.61 mmol). The reaction was warmed to ambient temper-
ature and allowed to stand for 2 days. The reaction mixture was
concentrated, and Et2O (50 mL) was added to the residue. The
precipitated solid material was filtered off. This operation was
repeated twice to remove most of the side products. The filtrate
was concentrated and purified by flash chromatography using
90/10 to 85/15 dichloromethane/EtOAc to provide 330 mg of 15.
The recovered starting material, along with some triphenylphos-
phine oxide, was resubjected to the above conditions to provide
additional 420 mg of 15: combined yield ) 34%; 1H NMR
(CDCl3) δ 0.85-1.25 (m), 1.39 (s, 9H), 1.50-1.84 (m), 1.90-2.06
(m, 3H), 2.12-2.24 (m, 1H), 3.02-3.35 (m, 3H), 3.44-3.57 (m,
3H), 3.72 (s, 3H), 3.99 (dd, 1H), 4.44-4.66 (m, 4H), 5.09 (br. d,
1H), 7.27-7.35 (m, 5H), 7.53-7.64 (m, 3H), 7.79-7.85 (m, 2H);
13C NMR (CDCl3) δ 25.90, 26.23, 27.82, 28.30, 29.54, 31.32,
31.96, 40.83, 41.78, 47.05, 52.48, 55.40, 56.21, 56.39, 66.92, 67.02,
73.00, 79.53, 127.05, 127.68, 127.74, 128.43, 129.34, 132.99,
138.12, 139.72, 155.62, 171.15, 171.44; HRMS (FAB) calcd for
4(R)-[(3-H yd r oxyp r op yl)t h io]-1,2(S)-p yr r olid in ed ica r -
boxylic Acid , 1-(1,1-Dim eth yleth yl) 2-Meth yl Ester (9). To
a suspension of sodium hydride (60% dispersion in mineral oil,
187 mg, 4.68 mmol) in DMF at 0 °C was added 3-mercaptopro-
panol (0.42 mL, 4.85 mmol) under argon atmosphere. The
mixture was stirred for 30 min while the temperature was
maintained. A solution of brosylate 8 (1.5 g, 3.23 mmol) in DMF
(total volume ) 10 mL) was added slowly, and the mixture was
warmed to ambient temperature over 2 h. The reaction was
quenched by pouring into cold 10% citric acid solution. The
aqueous layer was extracted with ethyl acetate, and the organic
layer was dried (Na2SO4) and concentrated. The crude material
was purified by flash column chromatography using 85/15
dichloromethane/ethyl acetate to provide 800 mg (78% yield) of
the sulfide 9 as an oil: 1H NMR (mixture of rotamers, CDCl3) δ
1.41 and 1.47 (2s, 9H), 1.83-1.89 (m, 2H), 2.13-2.34 (m, 2H),
2.69 (t, 2H), 3.23-3.49 (m, 2H), 3.73-3.78 (m, 5H), 3.86-3.95
(m, 1H), 4.33-4.37 and 4.42-4.46 (2dd, 1H); 13C NMR (mixture
of rotamers, CDCl3) δ 28.21, 28.30, 32.15, 32.23, 36.65, 37.27,
40.45, 40.89, 52.16, 52.35, 52.50, 52.84, 58.32, 58.55, 61.22, 61.41,
80.35, 153.49, 153.99, 173.05, 173.23; HRMS (FAB) calcd for
C14H26NO5S 320.1532 (M + H)+, found 320.1528.
Met h yl 1-[(2S)-2-Cycloh exyl-2-[[(1,1-d im et h ylet h oxy)-
car bon yl]am in o]-1-oxoeth yl]-4(R)-[(3-h ydr oxypr opyl)th io]-
2(S)-p yr r olid in eca r boxyla te (10). The desired compound was
prepared by the protocol described for compound 3. Reaction
conditions: Boc deprotection, 0 °C, 1 h; coupling reaction, -8
°C, 2 days. After workup, the product 10 was sufficiently pure
by TLC and was obtained in 80% yield: HRMS (FAB) calcd for
C22H39N2O6S 459.2529 (M + H)+, found 459.2523.
C
35H50N3O8S 672.3319 (M + H)+, found 672.3330.
Meth yl (7R,9S)-12(S)-Cycloh exyl-11,14-d ioxo-6-(p h en yl-
su lfon yl)-2-oxa -6,10,13-tr ia za tr icyclo[14.3.1.17,10]h en eicosa -
1(20),16,18-tr ien e-9-ca r boxyla te (16). Deprotection of the Boc
functionality of 15 and subsequent coupling with 3-hydroxyphe-
nylacetic acid was carried out as described for 4. Purification
by flash chromatography with 60/40 to 50/50 dichloromethane/
EtOAc provided the coupled product in almost quantitative (99%)
yield: 1H NMR (CDCl3) δ 0.80-0.96 (m, 2H), 1.00-1.26 (m, 3H),
1.55-1.74 (m, 6H), 1.90-2.04 (m, 3H), 2.10-2.18 (m, 1H), 3.10-
3.18 (m, 1H), 3.24-3.53 (m, 7H), 3.68 (s, 3H), 4.25 (app. t, 1H),
4.43-4.50 (m, 3H), 4.54-4.64 (m, 1H), 6.39 (d, 1H), 6.62 (app.
t, 1H), 6.69-6.71 (m, 2H), 7.11 (app. t, 1H), 7.25-7.34 (m, 6H),
7.48-7.53 (m, 2H), 7.57-7.61 (m, 1H), 7.79-7.81 (m, 2H); 13C
NMR (CDCl3) δ 25.76, 25.95, 26.08, 28.14, 29.38, 31.19, 31.43,
31.86, 36.48, 40.41, 41.73, 43.31, 47.13, 52.46, 55.12, 55.28,
56.50, 67.07, 72.95, 114.49, 116.17, 120.78, 127.02, 127.68,
127.79, 128.41, 129.34, 129.96, 133.02, 136.00, 138.05, 139.90,
157.00, 162.54, 171.10, 171.25, 171.32; HRMS (FAB) calcd for
C38H48N3O8S 706.3162 (M + H)+, found 706.3157. Removal of
the benzyl-protecting group was carried out in MeOH as
described for 5. The final macrocyclization reaction was per-
formed as described for 6. After completion of reaction, the
solvent was evaporated. Et2O (50 mL) was added, and the solids
were filtered off. The filtrate was concentrated and Et2O/EtOAc
(50 mL/50 mL) was added. The precipitated solids were filtered
off, and the filtrate was concentrated. The residue was purified
by flash chromatography using 85/15 to 80/20 dichloromethane/
EtOAc to afford 16 in 20% yield (for two steps) as a white solid:
mp 98-100 °C; 1H NMR (CDCl3) δ 0.91-1.10 (m, 1H), 1.16-
1.30 (m, 3H), 1.62-1.84 (m, 9H), 1.98-2.09 (m, 1H), 2.18-2.32
(m, 1H), 2.90-3.08 (m, 2H), 3.20-3.30 (m, 1H), 3.33 (app. d,
1H), 3.57 (app. d, 1H), 3.67 (s, 3H), 3.79 (dd, 1H), 4.20-4.34 (m,
3H), 4.45 (t, 1H), 4.55 (t, 1H), 5.82 (d, 1H), 6.74-6.80 (m, 2H),
6.89 (s, 1H), 7.19 (app. t, 1H), 7.52-7.65 (m, 3H), 7.77-7.80 (m,
2H); 13C NMR (CDCl3) δ 25.59, 26.26, 28.44, 29.61, 30.74, 30.87,
39.35, 40.75, 44.16, 48.64, 52.54, 55.02, 55.41, 56.68, 65.28,
111.91, 116.80, 121.76, 126.89, 129.44, 130.37, 133.05, 137.09,
139.35, 157.91, 170.54, 171.17, 214.91; HRMS (FAB) calcd for
C31H40N3O7S 598.2587 (M + H)+, found 598.2581.
Met h yl (7R,9S)-12(S)-Cycloh exyl-11,14-d ioxo-2-oxa -6-
th ia -10,13-d ia za tr icyclo[14.3.1.17,10]h en eicosa -1(20),16,18-
tr ien e-9-ca r boxyla te (11). Deprotection of the Boc function-
ality and subsequent coupling with 3-hydroxyphenylacetic acid
was carried out as described for 4. The crude product was
purified by flash column chromatography using 98/2 of dichlo-
romethane/methanol to provide the macrocyclization precursor
in 40% yield as a white solid: 1H NMR (mixture of rotamers,
CDCl3) δ 0.90-1.26 (m), 1.66-1.88 (m), 2.22-2.31 (m, 2H), 2.73
(t, 2H), 3.47 (s), 3.5-3.55 (m), 3.65-3.75 (m), 3.88-3.94 (dd, 1H),
4.07-4.12 (dd, 1H), 4.53 (t, 1H), 4.62 (t, 1H), 6.73-6.80 (m, 4H),
7.17 (t, 1H); 13C NMR (mixture of rotamers, CDCl3) δ 25.80,
25.89, 26.14, 27.71, 28.55, 29.22, 31.88, 35.46, 40.58, 42.44, 43.16,
52.32, 52.90, 55.49, 58.46, 60.30, 114.59, 116.27, 121.01, 130.02,
135.90, 156.73, 171.25, 171.87, 171.96; HRMS (FAB) calcd for
C25H37N2O6S 493.2372 (M + H)+, found 493.2364. This material
was subjected to macrocyclization conditions as described for 6.
After completion of the reaction, the crude product was sus-
pended in 80/20 ethyl acetate/hexane and the solid material was
filtered off. The filtrate was concentrated and purified by flash
column chromatography using 80/20 hexane/acetone to yield 22%
of 11 as a solid: mp 123-125 °C; [R]20 ) -33.07° (c 1, CHCl3);
D
1H NMR (CDCl3) δ 0.98-1.30 (m), 1.64-1.90 (m), 2.06-2.14 (m,
1H), 2.16-2.21 (dd, 2H), 2.62-2.70 (m, 2H), 3.38-3.46 (m, 2H),
3.60-3.66 (m, 3H), 3.71 (s, 3H), 3.88-3.94 (dd, 1H), 4.07-4.15
(m, 1H), 4.22-4.29 (m, 1H), 4.48 (t, 1H), 4.60 (t, 1H), 5.97 (br t,
1H), 6.76-6.81 (m, 2H), 6.99 (br s, 1H), 7.20 (dd, 1H); 13C NMR
(DMSO-d6) δ 25.31, 25.36, 26.00, 26.47, 28.12, 28.65, 29.22,
34.71, 38.87, 41.47, 42.22, 51.89, 53.11, 54.63, 57.94, 66.86,
114.91, 115.25, 122.26, 129.20, 137.80, 157.88, 169.31, 170.32,
171.55; HRMS (FAB) calcd for C25H35N2O5S 475.2267 (M + H)+,
found 475.2260.
Met h yl 1-[(2S)-2-Cycloh exyl-2- [[(1,1-d im et h ylet h oxy)-
car bon yl]am in o]-1-oxoeth yl]-4(R)-[(ph en ylsu lfon yl)am in o]-
2(S)-p yr r olid in eca r boxyla te (14). The expected product was
obtained by the method described for preparation of 3. Purifica-
tion of the residue by column chromatography using 99/1
dichloromethane/MeOH provided a 60% yield of 14: mp 75-77
°C; 1H NMR (CDCl3) δ 0.85-1.02 (m, 2H), 1.10-1.25 (m, 3H),
1.46 (s, 9H), 1.61-2.00 (m, 7H), 2.45-2.55 (m, 1H), 3.45-3.55
(m, 1H), 3.72 (s, 3H), 3.80-3.95 (m, 2H), 4.04 (app. d, 1H), 4.64
(app. t, 1H), 5.04 (d, 1H), 6.10 (d, 1H), 7.50-7.64 (m, 3H), 7.86-
Su p p or tin g In for m a tion Ava ila ble: 1H spectra for com-
pounds 9, 13, and 14; 1H and 13C spectra for compounds 3, 4,
6, 11, 15, and 16. Experimental conditions for the preparation
of compounds 8 and 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O011160B