Synthesis of the (S,S,S)-diastereomer of the 15-membered biaryl ring system of RP 66453

Article abstract of DOI:10.1016/S0040-4039(03)00856-6

The synthesis of the 15-membered biaryl ring system constituting an appropriately functionalized AB ring system of RP 66453 is detailed.

Full text of DOI:10.1016/S0040-4039(03)00856-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4019–4022
Synthesis of the (S,S,S)-diastereomer of the 15-membered biaryl
ring system of RP 66453
Paul J. Krenitsky and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, San Diego, CA 92037, USA
Received 9 March 2003; accepted 3 April 2003
Abstract—The synthesis of the 15-membered biaryl ring system constituting an appropriately functionalized AB ring system of RP
66453 is detailed. © 2003 Elsevier Science Ltd. All rights reserved.
RP 66453 (1) is a secondary metabolite isolated from a
Streptomyces strain while screening for compounds that
bind to the neurotensin receptor. Although its connec-
tivity structure was determined through spectroscopic
methods, its relative and absolute stereochemistry have
not been established. RP 66453 was found to possess a
unique and highly strained bicyclic ring system consist-
ing of a 15-membered ring containing an endo arylꢀaryl
bond and a 14-membered ring containing a diaryl
ether.1 The latter constitutes a cycloisodityrosine sub-
unit possessing an amide orientation reversed relative to
that found in preceding natural products,2 and its 14-
membered ring size makes it even more challenging to
form than the 16-membered diaryl ether ring system of
vancomycin3 and related structures. We recently dis-
closed the first synthesis of the S,S-diastereomer of this
reversed cycloisodityrosine BC subunit of 1 in efforts
directed at its stereochemical assignment and total
synthesis.4
spectroscopic and synthetic studies.6 Consequently, in
the absence of a stereochemical assignment for 1 and
with this related precedent, we pursued the preparation
of (S,S,S)-2.
Herein we report studies exploring the preparation of
the 15-membered biaryl AB ring system of 1 conducted
some time ago now, culminating in the synthesis of
(S,S,S)-2. These studies complement an earlier disclo-
sure of Zhu,5 and define an optimal macrocyclization
site and strategy, while exploring the atropisomer issues
associated with this unique ring system.
The structure of the 15-membered ring of RP 66453 is
similar to the ring system found in the biphenomycins,
a series of antibiotics also isolated from Streptomyces.
The a-carbons of the three biphenomycin amino acids
were found to possess the S configuration through
It was envisioned that the 15-membered ring of 2 could
be constructed through a sequence of Suzuki coupling
of two appropriately functionalized tyrosines to form
the biaryl linkage, followed by introduction of
isoleucine and macrolactamization at one of the two
amide bonds.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00856-6

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P. J. Krenitsky, D. L. Boger / Tetrahedron Letters 44 (2003) 4019–4022
Construction of substituted tyrosine A began with 3-
iodo- -tyrosine (Scheme 1). The amine and phenol
Scheme 2. Reagents and conditions: (a) NBS, CH3CN, 25°C,
18 h, 99%; (b) K2CO3, MeI, DMF, 25°C, 5 h, 94%; (c)
CF3CO3H, CH2Cl2, reflux, 2 days, 61%; (d) HCl, dioxane,
25°C, 2 h, 97%; (e) TBDMSOTf, lutidine, THF, 25°C, 4 h,
81%; (f) 3, (o-tolyl)3P, Pd2(dba)3, 1 M Na2CO3, toluene/
MeOH, 85°C, 15 min, 95%.
L
groups were first protected as the t-butyl carbamate
and methyl ether, respectively. Conversion of the iodide
to the boronic acid was unsuccessful when attempted
with the unprotected carboxylic acid, so the acid was
reduced and masked as the methoxymethyl ether.
Deprotonation of the carbamate with isopropyl magne-
sium bromide, lithium–halogen exchange, and treat-
ment of the resulting aryllithium with trimethyl borate
afforded 3, the boronic acid component for the Suzuki
coupling.
superb yield, following a protocol we first used for
formation of the vancomycin biaryl ring system.9 Nota-
bly, this protocol provides excellent conversions even
with highly hindered, electron-rich partners that fail to
couple with alternative phosphine ligands, less active Pd
catalysts, and at higher temperature or in alternative
solvent systems.
Construction of tyrosine B started with bromination of
47 with N-bromosuccinimide and protection of the
phenol as the methyl ether (Scheme 2). Baeyer–Villiger
oxidation with trifluoroperacetic acid, cleavage of the
acetate, and protection of the resulting phenol as the
TBDMS ether gave the second functionalized tyrosine.
Suzuki coupling of the two tyrosine subunits was cata-
lyzed by Pd2(dba)3 to give biaryl compound 58 in
Treatment of 5 with HCl cleaved both the MOM ether
and the Boc groups, and the Boc group was reintro-
duced using di-t-butyl dicarbonate (Scheme 3). The
unmasked alcohol was oxidized to the carboxylic acid
with catalytic chromium trioxide in the presence of
periodic acid,10 and the carboxylic acid was coupled
with isoleucine benzyl ester giving tripeptide 7.
Hydrogenolysis of the Cbz and benzyl protecting
groups provided 8, the first macrolactamization precur-
sor. Without a serious effort at optimization, several
peptide coupling agents were examined under high dilu-
tion reaction conditions (1 mM), with EDCI in the
presence of HOAt and NaHCO3 providing the best
yield of 911 (Table 1).
Alternatively, the Cbz group of 5 was removed by
hydrogenolysis, and the resulting amine was coupled to
Cbz-protected isoleucine. Treatment with HCl cleaved
both the MOM ether and the Boc groups, necessitating
replacement of the Boc group using di-t-butyl dicar-
bonate. Jones oxidation of the alcohol and deprotection
of the isoleucine amine provided the alternative macro-
lactamization precursor 13. Table 1 summarizes the
results of cyclization of this second substrate (site A)
with a range of peptide coupling reagents under condi-
Scheme 1. Reagents and conditions: (a) Boc2O, NaHCO3,
dioxane/H2O, 25°C, 18 h, 99%; (b) NaH, MeI, 5% DMF–
THF, 25°C, 3 days, 78%; (c) EtOCOCl, NaBH4, THF/
MeOH, 0°C, 20 min, 82%; (d) MOMCl, i-Pr2NEt, CH2Cl2,
25°C, 8 h, 92%; (e) i-PrMgCl, t-BuLi, (MeO)3B, THF, −78 to
25°C, 1 h, 99%.

P. J. Krenitsky, D. L. Boger / Tetrahedron Letters 44 (2003) 4019–4022
4021
Scheme 3. Reagents and conditions: (a) 3 M HCl/EtOAc, −10°C, 30 min, then Boc2O, NaHCO3, THF/H2O, 69%; (b) cat. CrO3,
H5IO6, CH3CN/H2O, 0°C, 1 h, 61%; (c) Ile-OBn tosylate, EDCI, HOAt, NaHCO3, DMF, 25°C, 90%; (d) 1 atm H2, Pd/C, MeOH,
25°C, 15 h, 99%; (e) coupling reagent (see table), DMF, 1 mM; (f) Cbz-Ile, EDCI, HOAt, DMF, 93%; (g) Jones reagent, acetone,
10 mM, 0°C, 1 h, 55%.
tions analogous to those employed for 8. Although
most reagents examined for this closure were not as
effective as the B site closure, FDPP was effective and
significantly better than the comparable closure at the B
site. Typically, this closure might have been expected to
be the preferred site of macrolactamization by virtue of
use of a less racemization prone activated carboxylate
bearing an a-N-carbamate versus a-N-acyl group.
The proton NMR spectrum of the macrocycle 9 con-
tains two complete sets of peaks for a pair of isomers
that interconvert slowly relative to the NMR time scale.
Consistent with the chromatographic detection of a
single species for 9 (TLC, HPLC), the isomers were
demonstrated to be interconverting, rather than stable
or separable conformational isomers or atropisomers,
by the presence of chemical exchange peaks in the
1H–1H ROESY NMR spectrum. Chemical exchange
peaks have a sign opposite of NOE crosspeaks in the
ROESY spectrum and clearly indicate one proton
appearing at two different chemical shifts, diagnostic of
Table 1. Reaction conditions for macrolactamization
slowly interconverting conformational isomers.12
Coupling reagent
% yield of 9
While methoxy groups ortho to a biphenyl link do not
usually hinder rotation about the biphenyl axis, the
TBDMS group in 9 can create a buttressing effect,
increasing the energy barrier to free rotation. Global
deprotection of 9 with AlBr3 in EtSH13 provided 214 in
which the two aryl methyl ethers, the methyl ester, as
well as the N-Boc and TBDMS protecting groups were
effectively cleaved. Unlike the proton NMR spectrum
of 9, the NMR spectrum of 2 exhibits a single set of
proton signals.
Site A
Site B
EDCI, HOAt, NaHCO3
HATU
DEPBT
PyBOP, NaHCO3
DPPA
FDPP
26
29
0
–
0
53
30
14
19
–
64
18
Conditions: 1 mM in DMF, 5 equiv. coupling reagent, 25°C, 3 days.

4022
P. J. Krenitsky, D. L. Boger / Tetrahedron Letters 44 (2003) 4019–4022
Thus, an appropriately functionalized derivative of the
(S,S,S)-diastereomer of the 15-membered ring system
of RP 66453 has been prepared by an unusually effec-
tive Suzuki coupling to form the arylꢀaryl bond fol-
lowed by macrolactamization. In route to the
preparation of 2, an optimal site of macrolactamization
was identified, and the conformational and atropiso-
mers issues associated with this unusual ring system
were established. Extensions of these studies to 1 itself
are in progress and will be disclosed in due course.
172.1, 155.9, 155.6, 155.5, 148.8, 148.6, 136.4, 133.3,
132.4, 130.6, 129.7, 129.6, 128.7, 128.3, 127.6, 125.3,
121.4, 111.2, 97.0, 68.2, 67.1, 60.3, 55.8, 55.6, 54.9, 52.4,
51.8, 37.7, 37.0, 28.5, 25.9, 18.5, −4.4; IR (film) wmax 3341,
2931, 1716, 1506, 1364, 1252, 1174, 1111, 1028, 841, 754
cm−1; MALDIFTMS (DHB) m/z 819.3827 (M++Na,
C42H60N2O11Si requires 819.3858).
9. (a) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.;
Loiseleur, O.; Castle, S. L. J. Am. Chem. Soc. 1999, 121,
3226–3227; (b) 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.
10. Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D.
M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett.
1998, 39, 5323–5326.
Acknowledgements
1
11. For 9: [h]2D5 −4.8 (c 3.0, CHCl3); H NMR (CDCl3, 600
We gratefully acknowledge the financial support of the
National Institute of Health (CA41101) and The
Skaggs Institute for Chemical Biology. P.J.K. is a
Skaggs Fellow.
MHz) l 7.02 (d, 1H, J=6.5 Hz), 6.89 (s, 1H), 6.76 (s,
1H), 6.65 (s, 1H), 6.62 (s, 1H), 4.59 (s, 1H), 4.54 (d, 1H,
J=11.0 Hz), 4.48 (d, 1H, J=9.1 Hz), 3.78 (s, 3H), 3.72
(s, 3H), 3.41 (s, 3H), 2.80 (m, 2H), 2.61 (m, 2H), 1.76 (m,
1H), 1.56 (m, 1H), 1.48 (s, 9H), 1.16 (m, 1H), 1.01 (s,
9H), 0.93 (d, 3H, J=6.7 Hz), 0.87 (m, 3H), 0.22 (s, 3H),
0.17 (s, 3H); and 7.17 (d, 1H, J=6.5 Hz), 6.87 (s, 1H),
6.76 (s, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 4.89 (m, 1H), 4.41
(d, 1H, J=9.5 Hz), 4.06 (d, 1H, J=12.1 Hz), 3.75 (s,
3H), 3.69 (s, 3H), 3.51 (s, 3H), 3.32 (m, 1H), 3.23 (m,
1H), 3.05 (m, 1H), 3.01 (s, 1H), 1.71 (m, 1H), 1.46 (m,
1H), 1.45 (s, 9H), 1.12 (m, 1H), 1.01 (s, 9H), 0.95 (d, 3H,
J=6.7 Hz), 0.86 (m, H), 0.21 (s, 3H), 0.18 (s, 3H); 13C
NMR (CDCl3, 150 MHz) l 173.5, 173.2, 172.1, 157.3,
149.6, 149.4, 149.3, 149.0, 135.6, 135.3, 135.1, 134.1,
133.5, 132.4, 131.2, 130.9, 130.4, 130.2, 129.6, 129.2,
125.8, 123.9, 122.4, 122.1, 112.1, 111.7, 80.8, 80.7, 60.8,
60.6, 59.2, 58.7, 58.6, 56.1, 55.4, 55.3, 53.1. 53.0, 52.2,
39.9, 39.4, 38.4, 38.1, 38.0, 34.8, 30.9, 28.9, 28.7, 26.5,
26.4, 26.3, 25.9, 19.4, 16.0, 15.6, 11.5, 11.3, −4.0, −4.1,
−4.4; IR (film) wmax 3293, 2960, 2412, 1747, 1713, 1644,
1427, 1252, 1177, 1029, 844, 756 cm−1; MALDIFTMS
(DHB) m/z 750.3727 (M++Na, C38H57N3O9Si requires
750.3756).
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14. For 2: [h]2D5 −12 (c 0.63, 20% CH3CN–H2O); 1H NMR
(CD3OD, 500 MHz) l 7.03 (dd, 1H, J=1.9, 8.0 Hz), 6.90
(d, 1H, J=1.8 Hz), 6.84 (d, 1H, J=8.1 Hz), 6.65 (d, 1H,
J=1.5 Hz), 6.61 (s, 1H), 4.58 (d, 1H, J=9.1 Hz), 4.49 (d,
1H, J=9.5 Hz), 4.25 (t, 1H, J=3.7 Hz), 3.34 (dd, 1H,
J=2.6, 15.0 Hz), 2.93 (dd, 1H, J=4.4, 15.0 Hz), 2.84 (d,
1H, J=14.0 Hz), 2.57 (m, 1H), 1.81 (m, 1H), 1.61 (m,
1H), 1.18 (m, 1H), 0.99 (d, 1H, J=6.6 Hz), 0.90 (t, 1H,
J=7.4 Hz); 13C NMR (CDCl3, 125 MHz) l 177.3, 172.9,
169.1, 154.3, 146.7, 141.5, 135.0, 133.5, 131.6, 128.7,
128.0, 126.1, 122.8, 117.6, 116.9, 59.6, 57.2, 55.0, 39.3,
36.7, 30.9, 26.5, 16.2, 11.4; IR (film) wmax 3250 (broad),
1643, 1496, 1391, 1253, 1007, 664 cm−1; MALDIFTMS
(DHB) m/z 472.2074 (M++Na, C24H29N3O7 requires
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8. For 5: [h]2D5 +20 (c 8.3, CHCl3); 1H NMR (CDCl3, 500
MHz) l 7.32 (s, 5H), 7.16 (d, 1H, J=7.4 Hz), 7.03 (s,
1H), 6.86 (d, 1H, J=8.4 Hz), 6.61 (d, 1H, J=1.9 Hz),
6.57 (s, 1H), 5.31 (bs, 1H), 5.10 (s, 2H), 4.83 (bs, 1H),
4.64–4.58 (m, 3H), 3.91 (bs, 1H), 3.72 (s, 3H), 3.68 (s,
3H), 3.50 (s, 3H), 3.46 (d, 2H, J=9.2 Hz), 3.33 (s, 3H),
3.05–2.98 (m, 2H), 2.85–2.76 (m, 2H), 1.41 (s, 9H), 1.00
(s, 9H), 0.19 (s, 6H); 13C NMR (CDCl3, 150 MHz) l