Microwave-assisted intramolecular Suzuki-Miyaura reaction to macrocycle, a concise asymmetric total synthesis of biphenomycin B

Article abstract of DOI:10.1021/ol050949w

(Chemical Equation Presented) A concise and efficient total synthesis of biphenomycin B has been accomplished featuring a key microwave-assisted intramolecular Suzuki-Miyaura reaction for formation of the 15-membered meta,meta-cyclophane 20.

Full text of DOI:10.1021/ol050949w

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2981-2984
Microwave-Assisted Intramolecular
Suzuki Miyaura Reaction to Macrocycle,
−
a Concise Asymmetric Total Synthesis
of Biphenomycin B
Renaud Le´pine and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received April 28, 2005 (Revised Manuscript Received May 18, 2005)
ABSTRACT
A concise and efficient total synthesis of biphenomycin B has been accomplished featuring a key microwave-assisted intramolecular Suzuki
Miyaura reaction for formation of the 15-membered meta,meta-cyclophane 20.
−
Biphenomycin A (1) and B (2, Figure 1) are cyclic tripeptides
isolated from the culture broths of Streptomyces filipinensis
and S. griseorubuginosus.1 The absolute configuration of
these 15-membered meta,meta-cyclophanes have been de-
termined from detailed NMR studies.2 Both compounds
displayed potent activities against Gram-positive, â-lactam-
resistant bacteria, such as Streptococcus aureus, Enterococ-
cus faecalis or Streptococcus, although a detailed mode of
action remained to be elucidated. Structurally, they belong
to a growing family of macrocyclic natural products with
an endo aryl-aryl bond(s) that included TMC-95 A (3,
antitumor agent),3,4 RP-66453 (antagonist of neurotensine
receptor),5,6 and vancomycin-type glycopeptide antibiotics.7
Figure 1. Structure of biphenomycins and TMC-95A.
(1) (a) Ezaki, M.; Iwami, M.; Yamashita, M.; Hashimoto, S.; Komori,
T.; Umehara, K.; Mine, Y.; Kohsaka, M.; Aoiki, H.; Imanaka, H. J. Antibiot.
The combination of structural novelty and potent antibiotic
activity of biphenomycins provided motivation to contem-
1985, 38, 1453-1461. (b) Uchida, I.; Shigematsu, N.; Ezaki, M.; Hashimoto,
M.; Hatsuo, A.; Hiroshi, I. J. Antibiot. 1985, 38, 1462-1468. (c) Uchida,
I.; Ezaki, M.; Shigematsu, N.; Hashimoto, M. J. Org. Chem. 1985, 50,
1341-1342. (d) Chang, C. C.; Morton, G. O.; James, J. C.; Siegel, M. M.;
Kuck, N. A.; Testa, R. T.; Borders, D. B. J. Antibiot. 1991, 44, 674-677.
(2) (a) Kannan, R.; Williams, D. H. J. Org. Chem. 1987, 52, 5435-
5437. (b) Hempel, J. C.; Brown, F. K.; J. Am. Chem. Soc. 1989, 111, 7323-
7327. (c) Brown, F. K.; Hempel, J. C.; Dixon, J. S.; Amato, S.; Mueller,
L.; Jeffs, P. W. J. Am. Chem. Soc. 1989, 111, 7328-7333.
(3) Total synthesis, see: (a) Lin, S.; Danishefsky, S. J. Angew. Chem.
Int. Ed. 2002, 41, 512-515. (b) Inoue, M.; Sakazaki, H.; Furuyama, H.;
Hirama, M. Angew. Chem., Int. Ed. 2003, 42, 2654-2657. (c) Albrecht, B.
K.; Williams, R. M. Proc. Nat. Acad. Sci. U. S. A. 2004, 101, 11949-
11954.
10.1021/ol050949w CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

plate a total synthesis of these compounds, and indeed, a
number of groups have been involved in such exercises.8
However, only two total syntheses are known to date: The
first one was reported by Schmidt in 1991,9 and the second
one was patented by scientists at Bayer in 2004.10 Both
groups employed macrolactamization technology for the key
ring-closure step. We report herein a concise total synthesis
of biphenomycin B (2) based on a novel strategy that is
retrosynthetically depicted in Scheme 1. In a forward sense,
Scheme 2. Enantioselective Synthesis of Amino Acids
5 and 6
Scheme 1. Retrosynthetic Analysis of Biphenomycin B (2)
formation of the aryl-aryl bond with the concomitant ring
closure to the 15-membered macrocycle by an intramolecular
Suzuki-Miyaura reaction11 of the linear tripeptide 4 was
expected to provide the fully protected natural product. The
tripeptide 4 in turn could be prepared from three non-
proteinogenic amino acids, 5, 6, and 7, by standard peptide
chemistry.
The total synthesis began with the preparation of two
substituted phenylalanine derivatives 5 and 6 (Scheme 2).
Following Corey’s procedure,12 enantioselective alkylation
of N-(diphenylmethylene)-glycine tert-butyl ester (8) with
2-isopropyloxy-5-iodo benzylbromide in the presence of a
catalytic amount of O-(9)-allyl-N-(9′-anthracenylmethyl)-
cinchonidinium bromide 10 (0.1 equiv) afforded the amino
ester 11 in 87% yield.13 A three-step sequence involving
N-deprotection, transesterification, and N-tert-butyloxycar-
bonylation converted 11 into 12. The synthesis diverged at
this point. Hydrolysis of 12 provided the acid 5, while
palladium catalyzed cross-coupling between 12 and bis-
(pinacolato)diboron following Miyaura’s protocol afforded
aryl boronate 13 in 90% yield.14 Removal of the N-Boc
function under carefully controlled conditions (0.07 equiv
of TFA in CH2Cl2) provided the amino ester 6 in quantitative
yield. The enantiomeric purity of amino ester 12 was
determined to be higher than 95% by its transformation into
the diastereomeric mandelate derivatives 14 and 15.
(4) (a) Ma, D.; Wu, Q. Tetrahedron Lett. 2000, 41, 9089-9093. (b)
Albrecht, B. K.; Williams, R. M. Tetrahedron Lett. 2001, 42, 2755-2757.
(c) Kaiser, M.; Groll, M.; Renner, C.; Huber, R.; Moroder, L. Angew. Chem.,
Int. Ed. 2002, 41, 780-783. (d) Berthelot, A.; Piguel, S.; Le Dour, G.;
Vidal, J. J. Org. Chem. 2003, 68, 9835-9838.
(5) Bois-Choussy, M.; Cristau, P.; Zhu, J. Angew. Chem., Int. Ed. 2003,
42, 4238-4341.
(6) For earlier synthetic studies, see: (a) Boisnard, S.; Carbonnelle, A.-
C.; Zhu, J. Org. Lett. 2001, 3, 2061-2064. (b) Boisnard, S.; Zhu, J.
Tetrahedron Lett. 2002, 43, 2577-2580. (c) Krenitsky, P. J.; Boger, D. L.
Tetrahedron Lett. 2002, 43, 407-410. (d) Krenitsky, P. J.; Boger, D. L.
Tetrahedron Lett. 2003, 44, 4019-4022. (e) Hitotsuyanagi, Y.; Ishikawa,
H.; Naito, S.; Takeya, K. Tetrahedron Lett. 2003, 44, 5901-5903.
(7) (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1172-1193. (b) Zhu, J. Expert Opin. Ther. Pat. 1999, 9, 1005-1019. (c)
Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem.,
Int. Ed. 1999, 38, 2096-2152.
(8) Synthesis of analogues, see: (a) Schmidt, U.; Meyer, R.; Leitenberger,
V.; Lieberknecht, A. Angew. Chem., Int. Ed. Engl. 1989, 28, 929-930. (b)
Carlstro¨m, A. S.; Frejd, T. J. Chem. Soc., Chem. Commun. 1991, 1216-
1217. (c) Schmidt, U.; Meyer, R.; Leitenberger, V.; Griesser, H.; Lie-
berknecht, A. Synthesis 1992, 1025-1030. (d) Brown, A. G.; Edwards, P.
D. Tetrahedron Lett. 1990, 31, 6581-6584. (e) Brown, A. G.; Crimmin,
M. J.; Edwards, P. D. J. Chem. Soc., Perkin Trans. 1 1992, 123-130. (f)
Paintner, F. F.; Go¨rler, K.; Voelter, W. Synlett 2003, 522-526.
(9) Schmidt, U.; Meyer, R.; Leitenberger, V.; Lieberknecht, A.; Griesser,
H. J. Chem. Soc., Chem. Commun. 1991, 275-277.
A number of synthetic routes have been developed for the
preparation of (2S,4R)-4-hydroxyornithine (7),15 including
(12) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414-12415.
(10) Lampe, T.; Adelt, I.; Beyer, D.; Brunner, N.; Endermann, R.; Ehler,
K.; Kroll, H.-P.; von Nussbaum, F.; Raddatz, S.; Rudolph, J.; Schiffer, G.;
Schumacher, A. WO Patent 2004 012816, 2004; Chem. Abstr. 2004, 140,
164239.
(13) For recent reviews, see: (a) O’Donnell, M. J. Acc. Chem. Res. 2004,
37, 506-517. (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518-
525. (c) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526-533.
(14) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
(11) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
2982
Org. Lett., Vol. 7, No. 14, 2005

the optimized conditions consist of performing the alkylation
of lithiated bislactim ether with bromide 17b in THF at -78
°C in the presence of N,N-dimethylpropylurea (DMPU).20
Under these conditions, compound 18 was obtained in 42%
yield with an excellent diastereoselectivty (de > 95%).
Hydrolysis of 18 under mild acidic conditions (0.1 N HCl,
dioxane, room temperature) provided the desired amino ester
7 ready for peptide coupling.
Scheme 3. Asymmetric Synthesis of
(2S,4R)-4-Hydroxyornithine (7) and Construction of
Tripeptide 4
The construction of the linear tripeptide proceeded without
event (Scheme 3). Coupling of (S)-N-Boc-(2-isopropyloxy-
5-iodo) phenylalanine (5) with (2S,4R)-4-hydroxyornithine
methyl ester (7) (EDC, HOBt, CH2Cl2) provided dipeptide
19 in 91% yield. Subsequent hydrolysis of the methyl ester
(2N LiOH, dioxane-H2O, V/V ) 1/1) followed by amidation
with amino acid 6 (EDC, HOBt, CH2Cl2) afforded the
tripeptide 4 in 78% overall yield.
With the properly functionalized tripeptide 4 in hand, we
set out to examine the desired macrocyclization by way of
an intramolecular Suzuki-Miyaura reaction.21-23 No cy-
clization took place when 4 was submitted to the conditions
that we developed previously [Pd(dppf)Cl2, toluene/H2O )
30/1, 90 °C, 0.001 M] for the synthesis of RP-66453.5 Since
very few examples existed in the literature dealing with this
type of cyclization, a detailed survey of reaction conditions
varying the solvents (toluene, DMSO, DME, water), the
ligands (Figure 2), the bases (K2CO3, Cs2CO3, K3PO4), and
Figure 2. Structure of ligands for Suzuki-Miyaura reaction.
the temperatures (90 °C, 110 °C) was carried out. However,
even after extensive optimization of reaction parameters, the
yield of the desired macrocycle 20 was limited to 20% [Pd-
(dba)2 (0.06 equiv), ligand 21 (0.06 equiv), or catalyst 24
(0.06 equiv), toluene-water ) 30/1, M ) 0.001 M, 90 °C,
one from this laboratory.16 In the course of this study, an
alternative and highly diastereoselective synthesis was
developed on the basis of Scho¨llkopf’s bislactim ether
technology (Scheme 3).17 Initial experiments on the alkyla-
tion of metalated bislactim ether 16 with (5S)-N-benzyloxy-
carbonyl-5-iodomethyl oxazolidine (17a) under standard
Scho¨llkopf’s conditions failed to provide the homologated
product (Table 1, entries 3 vs 4). After survey of different
reaction parameters varying the nature of electrophiles
(X ) Br, I, OTs),18 nucleophiles (lithium salt, potassium salt,
and cuprates),19,20 the reaction temperature and the additives,
(18) Leaving group effect on the alkylation of Scho¨llkopf’s bislactim
ether, see: Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J.
M. J. Org. Chem. 2001, 66, 4525-4542.
(19) (a) Baldwin, J. E.; Adlington, R. M.; Mitchell, M. B. J. Chem. Soc.,
Chem. Commun. 1993, 1332-1335. (b) Beugelmans, R.; Bigot, A.; Bois-
Choussy, M.; Zhu, J. J. Org. Chem. 1996, 61, 771-774.
(20) Kremminger, P.; Umdheim, K. Tetrahedron: Asymmetry 1998, 9,
1183-1189.
(21) Aryl-aryl bond formation via intramolecular Suzuki-Miyaura
coupling, see: (a) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443-
1446. (b) Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527-6530. (c)
Lobre´gat, V.; Alcaraz, G.; Bienayme´, H.; Vaultier, M. Chem. Commun.
2001, 817-818. (d) Kaiser, M.; Siciliano, C.; Assfalg-Machleidt, I.; Groll,
M.; Milbradt, A. G.; Moroder, L. Org. Lett. 2003, 5, 3435-3437.
(22) Aryl-aryl bond formation from bis-arylhalide by a palladium-
catalyzed, diboron-mediated cyclization, see: Carbonnelle, A.-C.; Zhu, J.
Org. Lett. 2000, 2, 3477-3480.
(15) (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Sta¨bler, F.; Lie-
berknecht, A. Synthesis 1991, 409-413. (b) Ha¨usler, J. Liebigs Ann. Chem.
1992, 1231-1237. (c) Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes,
M. J. J. Chem. Soc., Perkin Trans 1 1994, 1719-1726. (d) Rudolph, J.;
Hannig, F.; Theis, H.; Wischnat, R. Org. Lett. 2001, 3, 3153-3155. (e)
Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Klemann, P. Org. Lett.
2005, 7. 1423-1426.
(16) Le´pine, R.; Carbonelle, A.-C.; Zhu, J. Synlett 2003, 1455-1458.
(17) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798-799.
(23) Aryl-aryl bond formation via intramolecular Stille reaction, see:
Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2003, 125, 9032-9034.
Org. Lett., Vol. 7, No. 14, 2005
2983

15 h ], which is of course synthetically nonsignificant. The
presence of water was found to be essential, which might
promote the hydrolysis of arylboronate ester to the aryl-
boronic acid, facilitating the transmetalation and therefore
the Suzuki-Miyaura cross-coupling reaction.
The controlled microwave heating technique was next
applied to the tripeptide 4 with the hope to increase the
cyclization efficiency (Table 1).24 Since it is well-known that
Unmasking all the functional groups from 20 is the last
step of the planned total synthesis of biphenomycin B (2).
There are a number of different protective groups in
compound 20 that included: N-Boc and N-Cbz functions,
an oxazolidine, two isopropyl ethers, and a methyl ester.
Much to our delight, the global deprotection can be realized
in one operation. Thus, treatment of a CH2Cl2 solution of
20 with BCl3 (1 M solution in CH2Cl2) followed by workup
with dry methanol and saponification of the crude product
(2N LiOH, dioxane-H2O, V/V ) 1/1) provided the biphe-
nomycin B (2) in higher than 95% yield after purification
by reverse-phase preparative high-performance liquid chro-
matography (HPLC) (Scheme 4). The spectroscopic data (1H
NMR, 13C NMR, HRMS) of the synthetic material were
identical to those of the natural product.
Table 1. Microwave-Assisted Intramolecular Suzuki-Miyaura
Reaction of Tripeptide 4a
entry
ligand
solvent
additive T (°C) yield (%)b
1
2
3
4
5
6
7
8
21
tol-H2Oc
tol-H2Oc
tol-H2Oc
tol-H2Od
tol-H2Of
MeCN
90
110
110
110
110
80
27
29
40
50
50
32
0
21
24
24
24
24
24
TBABe
TBABg
Scheme 4. Deprotection of 20 to Biphenomycin B (2)
DMSO
110
110
Pd(OAc)2 tol-H2O
33
a General reaction conditions: concentration 0.001 M, Pd(dba)2
(0.06 equiv) as palladium source, potassium carbonate as base. Reaction
time: 30 min with a Discover microwave reactor from CEM. Irradiation
power: 20 W. Ramp time: 2 min. b Yield referred to isolated yield; c V/V
) 30/1. d V/V ) 5/1. e 0.1 equiv. f V/V ) 1/5. g 1 equiv.
the reaction medium needs to have a high dielectric constant
in order to take advantage of the microwave heating effect
and that toluene is almost transparent to the microwave
irradiation, we focused on the solvent effect in this study by
taking advantage of the best ligand-base combination
defined under thermal conditions [K2CO3 - 21/Pd(dba)2 or
24]. As observed, the toluene-H2O system remained to be
the solvent of choice and gave better yield of the cyclization
product than MeCN and DMSO under otherwise identical
conditions (Table 1, entries 1, 6, 7). On the other hand,
increasing the proportion of water increased the product yield
(entries 3 vs 4). Under optimized conditions (catalyst 24,
toluene/H2O ) 5/1, 0.1 equiv of tetrabutylammonium
bromide), the intramolecular Suzuki-Miyaura reaction of 4
afforded macrocycle 20 in 50% yield. The particularly high
efficiency of 2-(2′,6′-dimethoxybiphenyl)dicyclohexyl-
phosphine as the ligand in the Suzuki-Miyaura coupling
reaction has been demonstrated recently by Buchwald.25 It
was postulated that 24, after being in situ reduced to Pd(0)-
L2, would first dissociate to Pd(0)L. Being highly reactive,
this monoligated complex is capable of catalyzing the
difficult coupling reactions by facilitating the oxidative
addition as well as the transmetalation steps. It is nevertheless
interesting to note that, with microwave irradiation, palladium
acetate [Pd(OAc)2] under “ligandless” conditions was able
to promote the cyclization affording 20 in 33% yield.
In conclusion, a concise and efficient total synthesis of
biphenomycin B (2) has been accomplished. Formation of
an aryl-aryl bond with the concomitant formation of the
15-membered meta,meta-cyclophane and minimum protec-
tive group manipulation are the characteristic features of the
present synthesis. We also documented the first example of
microwave-assisted intramolecular Suzuki-Miyaura cross-
coupling reaction26 for the formation of the macrocycle. We
expect that this reaction would find applications in the
synthesis of other natural products and in the diversity-
oriented synthesis of biaryl-containing macrocycles.27
Acknowledgment. We thank CNRS for financial support.
R.L. thanks the Ministe`re de l’Enseignement Supe´rieur et
de la Recherche for a doctoral fellowship. We thank Dr. G.
Mignani of Rhodia, Lyon for the generous gift of ligands
22-24.
Supporting Information Available: 1H and 13C NMR
spectra of compounds 5, 6, 7, 19, 4, 20, 2. Synthesis and
physical data of 20, 2. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL050949W
(26) Microwave-assisted intermolecular Suzuki-Miyaura reaction, see:
(a) Largead, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584. For
more recent examples: (b) Han, J. W.; Castro, J.; Burgess, K. Tetrahedron
Lett. 2003, 44, 9359-9362. (c) Wu, T. Y. H.; Schultz, P. G.; Deng, S.
Org. Lett. 2003, 5, 3587-3590. (d) Arvela, R. K.; Leadbeater, N. E.; Sangi,
M. S.; Williams, V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005,
70, 161-168 and references therein.
(27) Recent examples: (a) Spring, D. R.; Krishnan, S.; Blackwell, H.
E.; Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 1354-1363. (b) Kramer,
B.; Averhoff, A.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2002, 41, 2981-
2982. (c) Surry, D. S.; Su, X.; Fox, D. J.; Franckevicius, V.; Macdonald,
S. J. F.; Spring, D. R. Angew. Chem., Int. Ed. 2005, 44, 1870-1873.
(24) For a recent review, see: (a) Larhed, M.; Moberg, C.; Hallberg, A.
Acc. Chem. Res. 2002, 35, 717-727. (b) Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250-6284. For a monograph, see: (c) MicrowaVe in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002.
(25) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871-1876. (b) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685-4696.
2984
Org. Lett., Vol. 7, No. 14, 2005