Total synthesis of arylomycin A2, a signal peptidase I (SPase I) inhibitor

Article abstract of DOI:10.1055/s-2008-1078209

A concise total synthesis of arylomycin A₂ has been accomplished featuring a key intramolecular Suzuki-Miyaura reaction for the formation of the 14-membered meta,meta-cyclophane and direct coupling of a fully elaborated peptide side chain with

Full text of DOI:10.1055/s-2008-1078209

LETTER
2355
Total Synthesis of Arylomycin A2, a Signal Peptidase I (SPase I) Inhibitor
Total
Syn
e
A
r
rylomyci 2
e
n A my Dufour, Luc Neuville,* Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: neuville@icsn.cnrs-gif.fr; E-mail: zhu@icsn.cnrs-gif.fr
Received 23 May 2008
HO
HO
Abstract: A concise total synthesis of arylomycin A2 has been ac-
complished featuring a key intramolecular Suzuki–Miyaura reac-
tion for the formation of the 14-membered meta,meta-cyclophane
and direct coupling of a fully elaborated peptide side chain with the
COOH
HN
OH
O
O
Me
O
macrocyclic core.
H
H
N
N
N
N
Key words: total synthesis, cross-coupling, palladium, macrocy-
cles, antibiotics
O
H
N
O
Me
O
MeO
OMe
Me
Me
1 arylomycin A2
8
Arylomycins are secondary metabolites recently isolated
from Streptomyces Strain Tü 6075 by Friedler, Jung, and
co-workers.1 In 2004, several related lipohexapeptides
and glycopeptides have been added to this family of natu-
ral products.2 They display moderate activity against a se-
ries of Gram-positive and Gram-negative bacteria. Most
importantly, it has been established that these cyclopep-
tides acted as potent inhibitors of bacterial signal pepti-
dase I (SPase I), an enzyme essential for bacterial
viabilitity and growth3 and blocked bacterial protein se-
cretion in vivo leading to bacterial death. This unique
mechanism of action is different from any of the previous-
ly known antibiotics. Consequently, they represent ideal
candidates for the development of new antibiotics to com-
bat bacterial resistance, a field that gained momentum
ever since the emergence of the vancomycin-resistant en-
terococci.4 Structurally, arylomycins are hexapeptides (D-
MeSer-D-Ala-Gly-L-MeHpg-L-Ala-L-Tyr) having a fatty
acid residue attached to the N-terminal amino acid. The
aromatic rings of L-MeHpg and L-Tyr are cross-linked by
an aryl–aryl bond forming a 14-membered meta,meta-cy-
clophane.5 Due to the ring strain associated with this mac-
rocycle, arylomycins can exist as a mixture of two
atropisomers. Interestingly, X-ray crystal structure of an
Escherichia coli SPase-arylomycin A2 complex indicated
that only the P-configured stereomer of the natural prod-
uct was bound to the SPase.6
OH
O
Me
O
H
COOMe
HN
N
H
N
N
H
OH
MeHN
N
O
O
Me
2
3
O
Me
OMe
8
O
I
O
BocMeN
O
B
H
N
O
N
H
COOMe
O
Me
4 R = H 5 R = Me
RO
Scheme 1 Retrosynthetic analysis of arylomycin A2
ing the course of this study, Romesberg et al. reported the
first total synthesis of 1 following a similar strategy.8
Our synthesis began with the preparation of N-methyl D-
4-hydroxy-3-iodophenylglycine (Scheme 2). In order to
minimize racemization of this highly base-sensitive ami-
no acid, we decided to leave the phenol group unprotected
during the synthesis. We reasoned that the formation of
phenoxide could render the a-CH of Hpg less prone to
deprotonation avoiding consequently the racemization.
The N-methyl group was introduced through an oxazoli-
dinone formation–reduction strategy.9 D-Hydroxyphenyl-
glycine (6) was first protected as tert-butoxycarbamate
and subsequently converted into oxazolidinone 8. Iodina-
tion of 8 by the in situ generated trifluoroacetyl hypoiodite
(I2, CF3CO2Ag)10 furnished the desired amino acid 9 in
47% yield, that is readily separated from the bisiodinated
side product. Reduction of the oxazolidinone (Et3SiH,
TFA) followed by reinstallation of the N-Boc function af-
forded the N-Boc-N-MeHpg 1011 in 90% yield.
We have been interested in this type of macrocyclic natu-
ral products and have recently accomplished the total syn-
theses of biphenomycin and RP-66453.7 As a continuation
of this reseach program, we report herein a total synthesis
of arylomycin A2 (1) based on a convergent synthetic
scheme involving an intramolecular Suzuki–Miyaura re-
action and the coupling of the resulting macrocycle with
the fully elaborated peptidic side chain (Scheme 1). Dur-
Synthesis of linear tripeptides 4 and 5 is shown in
Scheme 3. L-N-Boc-3-iodo-4-methoxyphenyl alanate 11
was prepared from L-tyrosine in three steps according to
Joullié.12 Coupling of 11 with L-Boc-alanine proceeded
smoothly to afford 12 in 94% yield (EDC, HOBt, DMF),13
which underwent the palladium-catalyzed cross-coupling
with bis(pinacolato)diboron following Miyaura’s proce-
SYNLETT 2008, No. 15, pp 2355–2359
1
5
.0
9
.2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078209; Art ID: G18308ST
© Georg Thieme Verlag Stuttgart · New York

2356
J. Dufour et al.
LETTER
(CH2O)n, p-
TsOH, toluene,
Dean–Stark
OH
1. Et3SiH, TFA, r.t.
2. 0.5 M NaOH–THF BnO
(1:1), Boc2O, r.t.
OH
OH
BnO
BnO
0.5 N NaOH in
dioxane (1:1)
Boc2O, r.t.
(CH2O)n, p-TsOH
toluene, reflux
O
90%
90%
HO2C
NHBoc
16
HO2C
18
NBoc
Me
NBoc
Dean–Stark, 80%
quantitative
O
17
O
Me
O
BocN
EDC, HOBt, NMM, D-Ala-
Gly-OMe, DMF, 0 °C to r.t.
H
N
H2N
CO2H
BocHN
CO2H
CO2Me
N
O
OH
6
OH
7
8
N
Boc
H
94%
I
O
I
I2, CF3CO2Ag
CHCl3, r.t.
1. Et3SiH, TFA, r.t.
2. 0.5 N NaOH in
19
OBn
Me
1. TFA–CH2Cl2 (1:4)
2. isolauric acid, oxalyl
chloride, Et3N, CH2Cl2,
r.t.
O
H
N
CO2R
N
47%
dioxane (1:1), Boc2O, r.t.
90%
N
8
H
O
Boc
BocN
O
O
N
CO2H
91%
OBn
O
9
10
Me
Me3SnOH, (CH2)2Cl2, 70 °C
20 R = Me
21 R = H
quantitative
Scheme 2 Synthesis of N-methyl-Hpg 10
RO
OR
3, DEPBT, THF, 0 °C to r.t.
83%
OMe
OMe
X
I
1. TFA in CH2Cl2 (1:4)
2. EDC, HOBt, L-Boc-Ala
COOR
HN
OR'
O
Me
O
H
H
N
N
Me
N
N
H
O
DMF, 0 °C to r.t, 94%
CO2Me
H
N
N
O
Me
O
Me
BocHN
Me
8
22 R = Me, R' = Bn 1 M AlBr3 in CH2Br2, EtSH,
r.t. 65%
O
CO2Me
NHBoc
11
O
bis(pinacolato)diboron, KOAc,
PdCl2(dppf), DMSO, 90 °C, 96%
12 X = I
13 X = Bpin
1 R = R' = H
OMe
1. TFA, CH2Cl2
2. EDC, HOBt, 10,
DMF, 0 °C to r.t.
Scheme 4 Synthesis of arylomycin A2
O
B
BocMeN
O
H
91%
I
N
O
significant improvement in terms of product yield (entries
8, 9 vs. 5).
N
COOMe
H
O
Me
RO
4 R = H
5 R = Me
TMSCHN2, MeOH–CH2Cl2
(3:1), r.t., 90%
Cyclization of compound 5 was next investigated. Con-
trary to the results obtained in the cyclization of 4, DMSO
(entry 12) was found to be not as good as a mixture of sol-
vent (toluene–H2O, 30:1). When compound 5 was placed
under the best conditions found for phenol 4, [toluene–
H2O (30:1), PdCl2(SPhos)2], two cyclized products were
isolated. The major compound was identical to a sample
prepared through methylation of the phenol-derived mac-
rocycle 14. We therefore asumed that the major product
was the desired macrocycle 15, while the minor one was
an epimer of 15, most probably resulting from the epimer-
ization of N-methyl Hpg unit. Fortunately, when the reac-
tion was conducted in the presence of a weaker base
(NaHCO3, entry 14), the extent of epimerization was re-
duced significantly leading to 15 in 54% yield under this
optimized condition [PdCl2(S-Phos)2, c 0.02 M in tolu-
ene–H2O (30:1), 90 °C, NaHCO3]. Performing the cy-
clization under high-dilution conditions did not improve
the yield of 15 significantly, indicating that 5 may be con-
formationally preorganized for the intramolecular reac-
tion.19
Scheme 3 Synthesis of linear tripeptides 4 and 5
dure to provide the corresponding aryl boronate 13.14 N-
Deprotection followed by peptide coupling with 10 (EDC,
HOBt, DMF) furnished the tripeptide 4 in 96% isolated
yield. Finally, methylation of phenol 4 with TMSCHN2
afforded compound 5 in 90% yield.15
With the properly functionalized tripeptide in hand, we set
out to examine the desired macrocyclization by the way of
an intramolecular Suzuki–Miyaura reaction.7,16 We were
concerned with a potential racemization problem associ-
ated with the inherent need of a base in such cross-cou-
pling reaction. Therefore, the study was conducted on
both tripeptide 4 and 5 (Table 1). It was assumed that the
presence of free phenol could, in certain extent, minimize
the epimerization of 4. In the event, treatment of a DMSO
solution of 4 (c 0.02 M, 90 °C) in the presence of
PdCl2(dppf) (0.05 equiv) and K2CO3 (7 equiv) afforded 14
in an encouraging 29% yield (entry 1). Both the solvent
and the palladium source influenced the reaction outcome.
Acetonitrile turned out to be an ineffective solvent for this
reaction, while DMSO or toluene–H2O (30:1) afforded 14
in comparable yield in the presence of PdCl2(SPhos)2 as a
catalyst (entries 5, 6). Addition of (n-Bu)4NBr was detri-
mental to the cyclization (entry 7). Microwave
irradiation17,18 shortened the reaction time, but showed no
The synthesis of the side chain is depicted in Scheme 4.
According to the strategy adopted for methylation of
arylglycine 10, the N-Boc Ser(OBn) 16 was converted
into oxazolidinone 17, then into the N-methylated deriva-
tive 18 in excellent overall yield. Coupling of 18 with
dipeptide D-Ala-Gly-OMe afforded the tripeptide 19 in
94% yield. Removal of N-Boc function (TFA, CH2Cl2)
furnished the amine, which was acylated by isolauric acyl
chloride,20 generated in situ to provide 20 in 91% yield.
Synlett 2008, No. 15, 2355–2359 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Arylomycin A2
2357
Table 1 Palladium-Catalyzed Intramolecular Cyclization of 4 and 5: Survey of Reaction Conditions
MeO
OR
Pd catalyst (5 mol%)
K2CO3 (7 equiv)
c = 0.02 M
COOMe
HN
4 or 5
H
N
BocMeN
14 R = H
O
15 R = Me
O
Me
Entry
1
Reagent
Solvent
Catalyst
Temp, time
90 °C, 2 h
Yield (%)a
4
DMSO
MeCN
PdCl2(dppf)
29
2
PdCl2(dppf)
80 °C, 2 h
9
3
toluene–H2O (30:1)
toluene–H2O (30:1)
toluene–H2O (30:1)
DMSO
PdCl2(dppf)
90 °C, 2 h
23
4
Pd(dba)2 + (R)-MOP
PdCl2(SPhos)2
PdCl2(SPhos)2
PdCl2(SPhos)2
PdCl2(SPhos)2
PdCl2(SPhos)2
PdCl2(SPhos)2
PdCl2(SPhos)2
PdCl2(dppf)
90 °C, 2 h
13
5
90 °C, 2 h
35
6
90 °C, 2 h
37
7b
8
toluene–H2O (30:1)
toluene–H2O (30:1)
toluene–H2O (30:1)
toluene–H2O (30:1)
toluene–H2O (30:1)
DMSO
90 °C, 2 h
0
MW 90 °C, 1 h
MW 110 °C, 0.5 h
MW 90 °C, 1 h
90 °C, 2 h
39
9
38
10
11
12
13
14c
5
40 + 20
39 + 17
12
90 °C, 2 h
EtCN
PdCl2(SPhos)2
PdCl2(SPhos)2
90 °C, 18 h
90 °C, 2 h
28+9
54+9
toluene–H2O (30:1)
a Isolated yield.
b In the presence of 1 equiv of (n-Bu)4NBr.
c Sodium bicarbonate (7 equiv) was used instead of K2CO3.
Hydrolysis of methyl ester 20 was performed in the pres- are: a) formation of 14-membered meta,meta-cyclophane
ence of Me3SnOH21 furnishing quantitatively acid 21.
by an intramolecular Suzuki–Miyaura reaction; b) incor-
poration of N-MeHpg in the cyclization precursor thus
avoiding the difficult and low-yielding N-methylation of
macrocycle; and c) direct coupling of a fully elaborated
peptide side chain to the macrocycle making the synthesis
more convergent. Work is currently in progress towards
the synthesis of members of this family of natural prod-
ucts as well as their analogues.
Coupling of a sterically encumbered secondary amine to a
peptide could be problematic. One solution is the stepwise
elongation of the secondary amine22 and this was indeed a
strategy employed in Romesberg’s synthesis. However,
we found that using DEPBT23 as a coupling reagent, the
reaction of secondary amine 3, obtained quantitatively by
N-deprotection of 15 (TFA in CH2Cl2) with 21 afforded
22 in 83% yield. Finally, global deprotection of 22 under
push–pull conditions (1 M AlBr3 in CH2Br2, excess of Et-
SH) afforded arylomycin A2 (1) in 65% yield. The spec-
troscopic data (1H NMR, 13C NMR, HRMS) of synthetic
material were identical to those reported for the natural
product. As found for natural product, synthetic arylomy-
cin A2 (1) existed as a mixture of atropoisomers/rotamers
in its 1H NMR spectrum.
Acknowledgment
Financial supports from CNRS and this institute are gratefully ac-
knowledged. J.D. thanks this institute for a doctoral fellowship.
References and Notes
(1) (a) Höltzel, A.; Schmid, D. G.; Nicholson, G. J.; Stevanovic,
S.; Schimana, J.; Gebhardt, K.; Friedler, H. P.; Jung, G. J.
J. Antibiot. 2002, 55, 571. (b) Schimana, J.; Gebhardt, K.;
Höltzel, A.; Schmid, D. G.; Süssmuth, R.; Müller, J.; Pukall,
R.; Friedler, H. P. J. Antibiot. 2002, 55, 565.
In summary, we have accomplished a concise total syn-
thesis of arylomycin A2 (1) in a longest linear sequence of
twelve steps from commercially available L-3 iodoty-
rosine in 20% overall yield. Key features of our approach
Synlett 2008, No. 15, 2355–2359 © Thieme Stuttgart · New York

2358
J. Dufour et al.
LETTER
of rotamers): d = 9.06–9.01 (m, 1 H), 8.37 and 8.31 (d,
J = 8.3 Hz, 1 H), 7.24–7.11 (m, 2 H), 7.10–7.05 (m, 1 H),
7.00 (d, J = 8.5 Hz, 1 H), 6.70–6.60 (m, 2 H), 5.92 and 5.74
(s, 1 H), 4.91–4.79 (m, 1 H,), 4.78–4.65 (m, 1 H), 3.78 (s, 3
H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.33–3.27 (m, 1 H,
(2) Kulanthaivel, P.; Kreuzman, A. J.; Strege, M. A.; Belvo,
M. D.; Smitka, T. A.; Clemens, M.; Swartling, J. R.; Minton,
K. L.; Zheng, F.; Angleton, E. L.; Mullen, D.; Jungheim,
L. N.; Klimkowski, V. J.; Nicas, T. I.; Thompson, R. C.;
Peng, S.-B. J. Biol. Chem. 2004, 279, 36250.
(3) Paetzel, M.; Karla, A.; Strynadka, N. C.; Dalbey, R. E.
overlapped with solvent), 3.07–2.96 (m, 1 H), 2.53 (s, 3 H,
overlapped with solvent), 1.44 and 1.41 (s, 9 H), 1.18 (d,
J = 6.8 Hz, 3 H) ppm. HRMS (ES+): m/z calcd for
Chem. Rev. 2002, 102, 4549.
(4) (a) Brown, E. D.; Wright, G. D. Chem. Rev. 2005, 105, 759.
(b) Zhu, J. Expert Opin. Ther. Pat. 1999, 9, 1005.
(c) Nicolaou, K. C.; Boddy, C. N. C.; Bräse, S.; Winssinger,
N. Angew. Chem. Int. Ed. 1999, 38, 2096. (d) Williams, D.;
Bardsley, B. Angew. Chem. Int. Ed. 1999, 38, 1172.
(e) Kahne, D.; Leimkuhler, C.; Lu, W.; Walsh, C. T. Chem.
Rev. 2005, 105, 425.
(5) For reviews on aryl-bridged natural products, see: (a) Feliu,
L.; Planas, M. Int. J. Pept. Res. Ther. 2005, 11, 53. (b) Zhu,
J.; Islas-Gonzalez, G.; Bois-Choussy, M. Org. Prep. Proced.
Int. 2000, 32, 505.
C29H37N3O8Na [M + Na]+: 578.2478; found: 578.2490.
Arylomycin A2 (1): [a]D24 +29 (c 0.3, MeOH). 1H NMR (500
MHz, MeOD, 1:6.4 mixture of isomers): d = 8.91 (d, J = 8.0
Hz, 1 H), 8.61 (d, J = 8.1 Hz, 1 H), 8.17–8.05 (m, 2 H), 7.23
and 7.13 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 7.03
(br s, 1 H), 7.00 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.87 (d,
J = 8.4 Hz, 1 H), 6.35 and 5.87 (s, 1 H), 4.99–4.94 (m, 1 H),
4.57–4.51 (m, 2 H, overlapped with solvent), 4.56–4.46 (m,
1 H), 4.25 (d, J = 17.1 Hz, 1 H), 4.08–4.00 (m, 2 H), 3.95–
3.85 (m, 1 H), 3.46–3.36 (m, 1 H), 3.16–3.07 (m, 1 H), 3.11
and 2.89 (s, 3 H), 2.80 and 2.76 (s, 3 H), 2.57–2.42 (m, 2 H),
1.67–1.58 (m, 2 H), 1.52 (sept, J = 6.6 Hz, 1 H), 1.41 (d,
J = 7.0 Hz, 3 H), 1.35 (d, J = 6.6 Hz, 3 H), 1.42–1.26 (m, 10
H), 1.21–1.15 (m, 2 H), 0.88 (d, J = 6.6 Hz, 6 H) ppm. 1H
NMR (500 MHz, DMSO-d6, 1:3.1 mixture of isomers): d =
12.81 (br s, 1 H), 9.69 (br s, 2 H), 9.07–8.95 and 8.35–8.27
(m, 1 H), 8.62–8.54 (m, 1 H), 8.03–7.87 (m, 2 H), 7.14 and
7.10 (d, J = 7.8 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.95 and
6.93 (br s, 1 H), 6.91–6.80 (m, 3 H), 6.29 and 5.85 (s, 1 H),
5.03–4.98 and 4.91–4.84 (m, 1 H), 4.97 and 3.44 (dd,
J = 8.2, 5.8 Hz, 1 H), 4.83–4.73 (m, 1 H), 4.69–4.61 (m, 1
H), 4.41–4.30 (m, 1 H), 4.20 and 4.02 (d, J = 17.3 Hz, 1 H),
3.96 (dd, J = 17.3, 4.4 Hz, 1 H), 4.85–4.74 (m, 1 H), 3.71–
3.62 (m, 1 H), 3.28–3.20 (m, 1 H), 3.16–3.07 (dd, J = 16.7,
12.1 Hz, 1 H), 2.93 and 2.76 (s, 3 H), 2.69 and 2.63 (s, 3 H),
2.39–2.27 (m, 2 H), 1.56–1.45 (m, 3 H), 1.25 (d, J = 7.3 Hz,
3 H), 1.32–1.20 (m, 10 H), 1.18 (d, J = 6.7 Hz, 3 H), 1.18–
1.11 (m, 2 H), 0.85 (d, J = 6.6 Hz, 6 H). HRMS (ES–): m/z
calcd for C42H59N6O11 [M – H]– 823.4242; found: 823.4269.
(12) Chiarello, J.; Joullié, M. M. Synth. Commun. 1988, 18, 2211.
(13) Abbreviations: DEPBT = 3-(diethyloxyphosphoryloxy)-
1,2,3-benzotriazin-4 (3H)-one; EDC = 1-[3-(eimethyl-
amino)propyl]-3-ethylcarbodiimide; HOBt = N-hydroxy-
benzotriazole, SPhos = 2-dicyclohexylphosphino-2¢,6¢-di-
methoxybiphenyl; MOP = (diphenylphosphino)-2¢-meth-
oxy-1,1¢-binaphtyl; NMP = N-methylpyrolidinone.
(6) Paetzel, M.; Goodall, J. J.; Kania, M.; Dalbey, R. E.; Paghe,
M. G. J. Biol. Chem. 2004, 279, 30781.
(7) For biaryl-containing macrocycles, see: (a) Carbonnelle,
A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477. (b) Boisnard, S.;
Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2001, 3, 2061. (c)Jia,
X.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2007, 9, 2401.
(d) Lépine, R.; Zhu, J. Org. Lett. 2005, 7, 2981. (e) Bois-
Choussy, M.; Cristau, P.; Zhu, J. Angew. Chem. Int. Ed.
2003, 42, 4238. (f) Jia, X.; Bois-Choussy, M.; Zhu, J.
Angew. Chem. Int. Ed. 2008, 47, 4167.
(8) Roberts, T. C.; Smith, P. A.; Cirz, R. T.; Romesberg, F. E.
J. Am. Chem. Soc. 2007, 129, 15830.
(9) (a) Freidinger, R. M.; Hinkle, J. S.; Perlow, D. S.; Arison,
B. H. J. Org. Chem. 1983, 48, 77. (b) Aurelio, L.; Browlee,
R. T. C.; Hughes, A. B.; Sleebs, B. E. Aust. J. Chem. 2000,
53, 425. (c) Aurelio, L.; Browlee, R. T. C.; Hughes, A. B.
Chem. Rev. 2005, 104, 5823.
(10) Barnett, R.; Andrews, L. J.; Keefer, R. M. J. Am. Chem. Soc.
1972, 94, 6129.
(11) Selected Physical and Spectroscopic Data
Compound 10: [a]D25 +86 (c 0.9, MeOH). 1H NMR (300
MHz, MeOD): d = 7.61 (d, J = 2.0 Hz, 1 H), 7.12 (dd,
J = 8.3, 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 5.47 (s, 1 H),
2.66 (s, 3 H), 1.48 (s, 9 H) ppm. HRMS (ES+): m/z calcd for
C14H18NO5NaI [M + Na]+: 430.0127; found: 430.0128.
Compound 5: [a]D25 +16 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3, 1:1 mixture of rotamers): d = 7.72 and 7.71 (d,
J = 2.2 Hz, 1 H), 7.42 and 7.30 (d, J = 2.3 Hz, 1 H), 7.29–
7.24 (m, 0.5 H, overlapped with solvent), 7.22 (dd, J = 8.5,
2.2 Hz, 0.5 H), 7.22 (dd, J = 8.5, 2.2 Hz, 0.5 H), 7.10 (dd,
J = 8.5, 2.2 Hz, 0.5 H), 6.78 (d, J = 8.5 Hz, 1 H), 6.71 (d,
J = 8.5 Hz, 1 H), 6.58–6.32 (m, 1 H), 6.54 and 6.37 (d,
J = 7.3 Hz, 1 H), 5.67–6.57 (m, 1 H), 4.81–4.70 (m, 1 H),
4.59–4.46 (m, 1 H), 3.88 and 3.87 (s, 3 H), 3.79 and 3.77 (s,
3 H,), 3.72 and 3.71 (s, 3 H), 3.11–2.96 (m, 2 H), 2.71 and
2.69 (s, 3 H), 1.48 and 1.47 (s, 9 H), 1.41–1.24 (m, 15 H)
ppm. MS (ES+): m/z = 832 [M + Na]+. Anal. Calcd for
C35H49N3O10IB: C, 51.93; H, 6.10; N, 5.19. Found: C, 51.83;
H, 6.30; N, 5.10.
(14) Ishiyama, T.; Murata, M.; Miyaura, M. J. Org. Chem. 1995,
60, 7508.
(15) For a related methylation of boron-containing peptide, see:
Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 9032.
(16) (a) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443.
(b) Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527.
(c) Lobrégat, V.; Alcaraz, G.; Bienaymé, H.; Vaultier, M.
Chem. Commun. 2001, 817. (d) Kaiser, M.; Siciliano, C.;
Assfalg-Machleidt, I.; Groll, M.; Milbradt, A. G.; Moroder,
L. Org. Lett. 2003, 5, 3435. (e) Shinohara, T.; Deng, H.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 7334.
Compound 15: [a]D26 +44 (c 1.1, CHCl3). 1H NMR (500
MHz, CDCl3, 1:1.9 mixture of rotamers): d = 7.20–7.25 (m,
1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.94 and 6.93 (d, J = 8.5 Hz,
1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.78 and 6.73 (s, 1 H), 6.75
and 6.68 (s, 1 H), 6.34–6.27 (m, 1 H), 6.26 and 6.21 (d,
J = 8.5 Hz, 1 H), 5.93 and 5.61 (s, 1 H), 4.95–4.87 (m, 1 H),
4.77–4.67 (m, 1 H), 3.83 (s, 3 H), 3.82 and 3.81 (s, 6 H),
3.58–3.47 (m, 1 H), 3.05 and 3.04 (dd, J = 15.9, 6.9 Hz, 1 H),
2.71 and 2.70 (s, 3 H), 1.51 and 1.49 (br s, 9 H), 1.42–1.37
(m, 3 H) ppm. 1H NMR (500 MHz, DMSO-d6, 1:1 mixture
(17) Microwave experiments were conducted using a Discover
microwave reactor from CEM. All experiments were
performed in sealed tubes (capacity 10 mL) under argon
atmosphere. Microwave irradiation of 300 W was used, the
temperature being ramped from r.t. to 90 °C or 110 °C in 1
min. Once this temperature was reached, the reaction
mixture was held at 90 °C or 110 °C for the indicated time.
(18) For recent reviews, see: (a) Kappe, C. O. Angew. Chem. Int.
Ed. 2004, 43, 6250. (b) de la Hoz, A.; Diaz-Ortiz, A.;
Moreno, A. Chem. Soc. Rev. 2005, 34, 164.
Synlett 2008, No. 15, 2355–2359 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Arylomycin A2
2359
(19) For a review on conformation-directed macrocyclization,
see: Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949.
(20) We synthesized isolauric acid following a Cu-catalyzed
coupling of a Grignard reagent with an alkylbromide
according to: Cahiez, G.; Chaboche, C.; Jézéquel, M.
Tetrahedron 2000, 56, 2733.
(21) (a) Furlan, R. L. E.; Mata, E. G.; Mascaretti, A. O. J. Chem.
Soc., Perkin Trans. 1 1998, 355. (b) Nicolaou, K. C.;
Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew.
Chem. Int. Ed. 2005, 44, 1378.
(22) Bigot, A.; Tran Huu Dau, M. E.; Zhu, J. J. Org. Chem. 1999,
64, 6283.
(23) Li, H.; Jiang, X.; Fan, C.; Romoff, T.; Goodman, M. Org.
Lett. 1999, 1, 91.
Synlett 2008, No. 15, 2355–2359 © Thieme Stuttgart · New York

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