A novel synthesis of biaryl-containing macrocycles by a domino Miyaura arylboronate formation: intramolecular Suzuki reaction.

Article abstract of DOI:10.1021/ol006520g

[reaction: see text] A novel macrocyclization procedure is developed on the basis of a domino process. Thus, treatment of linear diiodide 11 under defined conditions gave the 15-membered m,m-cyclophane 12 via aryl-aryl bond formation. Two distinct cross-c

Full text of DOI:10.1021/ol006520g

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3477-3480
A Novel Synthesis of Biaryl-Containing
Macrocycles by a Domino Miyaura
Arylboronate Formation: Intramolecular
Suzuki Reaction
Anny-Claude Carbonnelle and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France
zhu@icsn.cnrs-gif.fr
Received August 30, 2000
ABSTRACT
A novel macrocyclization procedure is developed on the basis of a domino process. Thus, treatment of linear diiodide 11 under defined
conditions gave the 15-membered m,m-cyclophane 12 via aryl−aryl bond formation. Two distinct cross-coupling manifolds, Miyaura’s arylboronic
ester synthesis and intramolecular Suzuki reaction, proceed in an ordered fashion. Concentration is an important factor for the success of
this process.
Macrocyclic compounds, by virtue of their outstanding
pharmaceutical activity, have played a key role in drug
development enterprise.1 A unique family of macrocycles
are those containing an endo aryl-aryl bond such as
biphenomycin (1),2,3 acerogenin K (2)4 (Figure 1), and
be hindered in certain macrocycles even in the absence of
the ortho substituents. Consequently, the synthesis of such
molecules becomes even more challenging as one has to not
only find the right way to perform the cyclization but also
to control the atropisomerism.6
In planning a synthesis of biaryl bridged macrocycles, ring
closure via formation of an aryl-aryl bond is particularly
(1) (a) Shu, Y. Z. J. Nat. Prod. 1998, 61, 1053-1071. (b) Newman, D.
J.; Gragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000, 17, 215-234.
(2) (a) Ezaki, M.; Iwami, M.; Yamashita, M.; Kohsaka, M.; Aoiki, H.;
Imanaka, H. J. Antibiot. 1985, 38, 1453-1461. (b) Uchida, I.; Shigematsu,
N.; Ezaki, M.; Hashimoto, M. J. Antibiot. 1985, 38, 1462-1468. (c) Uchida,
I.; Ezaki, M.; Shigematsu, N.; Hashimoto, M. J. Org. Chem. 1985, 50,
1341-1342.
(3) (a) Kannan, J. C.; 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.
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1996, 44, 1086-1089.
Figure 1.
(5) (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1173-1193. (b) Zhu, J. Exp. Opin. Ther. Patents 1999, 9, 1005-1019.
(6) (a) Sainsbury, M. Tetrahedron 1980, 36, 3327-3359. (b) Bringmann,
G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977-
991.
structurally complex vancomycin-type glycopeptide antibiot-
ics.5 Due to ring strain, rotation of the aryl-aryl bond may
10.1021/ol006520g CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/12/2000

attractive by virtue of its inherent convergence. Not surpris-
ingly, synthetic activities in such a field are numerous and,
at the same time, rewarding. Thus, nickel(0)-promoted
intramolecular Ullmann-type reductive coupling of aryl
halide,7 biogenetically relevant intramolecular oxidative
coupling of electron rich arenes,8 and redox-neutral photo-
chemical cyclization9 have been developed and applied in
the natural product syntheses to form aryl-aryl bonds.
Diastereoselective ring formation with control of axial
chirality has recently been developed.10
Realizing that the above-mentioned cyclizations were
generally low yielding with few important exceptions, we
were interested in the development of a new cyclization
protocol in connection with our ongoing project on the total
synthesis of macrocyclic natural products.11 The underlying
principle that we sought to pursue was shown in Scheme 1.
constraints of such a strategy are as follows: (a) conditions
might be worked out for realizing the two distinct cross-
coupling reactions, one inter- and one intramolecular, in a
one-pot fashion; (b) the observed rate of macrocyclization
(4 to 6) must be faster than a second intermolecular event
leading to 5 and the dimerization or oligomerization of 4
leading to linear biaryl compounds; (c) concentration
dilemmasthe desired macrocycle 6 will only be produced
by initial bimolecular and subsequent unimolecular events.
Clearly, the concentration of 3 will have an important impact
on the overall process and has to be carefully balanced such
that it will promote the formation of 4 with reasonable
kinetics and at the same time discourage any intermolecular
process of intermediate 4. The powerful palladium-catalyzed
Stille coupling12 and Suzuki reaction13 among other variants14
seems particularly suitable to our purpose. Even more
relevant is that aryltrialkyltin and arylboronic ester, one of
the two reaction partners in the Stille and Suzuki reaction,
respectively, can be prepared by palladium-catalyzed reaction
of hexaalkylditin15 and alkoxydiboron16 with aryl halide.
Scheme 1
We report herein development of a domino sequence
involving Miyura arylboronic ester formation-intramolecular
Suzuki reaction17,18 and a synthesis of biphenomycin model
12. Compound 12 was selected as a target since its precursor
11 is easily accessible and it contains two ortho-substituents,
thus representing a more stringent test than the synthesis of
biphenomycin itself.19
The synthesis of cyclization precursor was summarized
in Scheme 2. Coupling of L-Tyr(OMe) methyl ester (7)20
with L-N-Boc Leu (8) (EDC, HOBt) gave the dipeptide 9.
Removal of N-Boc of 9 followed by its reaction with L-N-
Boc-Tyr(OMe) (10) gave then linear tripeptide 11 in excel-
lent overall yield.
Cyclization of 11 was performed using Pd(dppf)2Cl2 as a
catalyst in the presence of the pinacol ester of diboronic acid
13. Some representative experimental results are listed in
Table 1. The best conditions found consist of heating a
(12) Stille, J. F. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(13) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(14) Stanforth, S. P. Tetrahedron 1998, 51, 263-303.
(15) (a) Kosugi, M.; Shimizu, K.; Ohtani, A.; Migita, T. Chem. Lett.
1981, 829-830. (b) Kashin, A. N.; Bumagina, I. G.; Bumagin, N. A.;
Bakunin, V. N.; Beletskaya, I. P. Zh. Org. Khim. 1981, 17, 905-911. (c)
Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet. Chem. 1981, 215, 49-
58.
(16) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510. (b) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997,
62, 6458-6459. (c) Nakamura, H.; Fujiwara, M.; Yamamoto, Y. J. Org.
Chem. 1998, 63, 7529-7530. (d) Malan, C.; Morin, C. J. Org. Chem. 1998,
63, 8019-8020.
Starting from a linear diaryl halide, transition metal catalyzed
halogen-metal exchange followed by in situ intramolecular
cross-coupling would give the desired macrocycle. The
(7) (a) Semmelhack, M. F.; Ryono, L. S. J. Am. Chem. Soc. 1975, 97,
3873-3875. (b) Semmelhack, M. F.; Helquist, P.; Jones, L. D.; Keller, L.;
Mendelson, L.; Ryono, L. S.; Smith, J. G.; Stauffer, R. D. J. Am. Chem.
Soc. 1981, 103, 6460-6471. (c) Whiting, D. A.; Wood, A. F. J. Chem.
Soc., Perkin Trans. 1 1980, 623-628.
(17) Reagent combination: Pd(0)-Me3SnSnMe3 has been used to
promote the formation of six-membered rings, see: Kelly, T. R.; Li, Q.;
Bhushan, V. Tetrahedron Lett. 1990, 31, 161-164. For earlier examples
of ditin-mediated intermolecular cross-coupling, see: Yokoyama, Y.; Ito,
S.; Takahashi, Y.; Murakami, Y. Tetrahedron Lett. 1985, 26, 6457-6460.
(18) Intramolecular Suzuki coupling, see: Elder, A. M.; Rich, D. H. Org.
Lett. 1999, 1, 1443-1446.
(8) Barton, D. H. R.; Bracho, R. D.; Potter, C. J.; Widdowson, D. A. J.
Chem. Soc., Perkin Trans. 1 1974, 2278-2283 and references therein.
(9) Ito, K.; Tanaka, H. Chem. Pharm. Bull. 1974, 22, 2108-2112.
(10) Recent examples: (a) Miyano, S.; Handa, S.; Shimizu, K. Tagami,
K.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1984, 57, 1943-1947. (b) Dai,
D.; Martin, O. R. J. Org. Chem. 1998, 63, 7628-7633. (c) Lipshutz, B.
H.; Kayser, F.; Liu, Z. P. Angew. Chem., Int. Ed. Engl. 1994, 33, 1842-
1844. (d) Spring, D. R.; Krishnan, S.; Schreiber, S. L.. J. Am. Chem. Soc.
2000, 122, 5656-5657.
(19) (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Lieberknecht, A.;
Griesser, H. J. Chem. Soc., Chem. Commun. 1991, 275-277. Carlstro¨m,
A. S.; Frejd, T. J. Chem. Soc., Chem. Commun. 1991, 1216-1217. (c)
Schmidt, U.; Meyer, R.; Leitenberger, V. Griesser, H.; Lieberknecht, 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.
(11) Zhu, J. Synlett 1997, 133-134.
(20) Chiarello, J.; Joullie´, M. M. Synth. Commun. 1988, 18, 2211-2223.
3478
Org. Lett., Vol. 2, No. 22, 2000

(entries 1 and 2), or further diluting/concentrating the reaction
mixture (entries 3, 5) all led to the failure of the cyclization.21
In their pioneer studies, Miyaura and co-workers16a observed
that potassium carbonate was not a suitable base for the
preparation of arylboronate since it promoted the in situ
Suzuki coupling leading to the homodimer of aryl halidesa
highly desired process for our projected domino sequence.
It is thus interesting to observe that potassium as well as
sodium carbonate was completely ineffective (entries 7 and
8).22 Furthermore, potassium carbonate seems to be harmful
to the overall process since a base combination K2CO3-
KOAc failed to promote the cyclization (entry 9). The unique
role of KOAc may be explained by the formation of an
acetoxypalladium(II) intermediate which is known to undergo
facile transmetalation with organoboron compound.16a In an
attempt to isolate the arylboronate intermediate 4 [M )
B(OR)2], aliquots of the reaction mixture were examined at
different time intervals. However, in none of the experiments
(concentration: 0.05 and 0.005 M in DMSO) was the
intermediate 4 detected.
Scheme 2
A control experiment demonstrated that the presence of
diboron ester 13 was obligatory for the success of this
cyclization, since Pd(dppf)2Cl2 or Pd(PPh3)4 alone did not
promote the intramolecular coupling of compound 11.23
The structure of 12 was determined by NMR spectroscopy
and ESI-MS which clearly indicate that it is a cyclic
monomer and not the cyclodimer. Interestingly, the room
1
temperature H NMR spectrum of compound 12 contains
two sets of peaks with a ratio of 3/1 in both chloroform-d3
and DMSO-d6 solution. Two peaks coalesced when the
spectrum was recorded at 343 K in the latter solvent. The
presence of atropisomerism of compound 12 can explain this
phenomenon and the observed atroposelectivity (3/1) indi-
cated that the asymmetry could in principle be transmitted
from chiral center of the tether into the chiral axis by the
present methodology.
degassed DMSO solution of diiodide 11 (0.02 M) in the
presence of palladium catalyst, diboron 13, and KOAc as a
base at 80-85 °C. Under these conditions, macrocycle 12
was obtained in a 45% isolated yield (entry 4). Switching
the solvent to DME (entry 6), lowering the temperature
To evaluate the relative efficiency of this process, nickel-
(0)-promoted cyclization of 11 was studied.7 Under a
different set of conditions varying the source and the
stoichiometry of Ni(0),24 the solvent (DME and N,N-
dimethylacetamide), and the temperature, only a trace of the
cyclic compound at best was detected by mass spectrom-
etry.25 On the other hand, Edwards et al. have previously
reported that attempted intramolecular oxidative coupling of
Table 1. Pd(dppf)2Cl2 (0.05 equiv) Catalyzed Cyclization of
11 in the Presence of Diboron Ester 13 (1.1 equiv)
entry
base
solvent concn, M temp, °C 12 (%)a
(21) We were unable to isolate dimer or oligomers of 11 under all these
conditions. Longer reaction time (24 h) under our optimized conditions failed
to improve the yield of cyclic compound.
1
2
3
4
5
6
7
8
9
KOAc
DMSO
DMSO
DMSO
DMSO
DME
0.005
0.02
0.005
0.02
0.2
40-45
40-45
80-85
80-85
80-85
80-85
80-85
80-85
80-85
traceb
traceb
10%c
45%c
0%b
KOAc
KOAc
KOAc
KOAc
KOAc
Na2CO3
K2CO3
(22) Dimerization under conditions [PdCl2(dppf)2/Na2CO3/EtOH], see:
Marcuccio, M.; Rodopoulos, H. Weihold, H. Abstracts of the 10th
International Conference on Boron Chemistry, Duram, July; 1999, PB-36.
(23) For recent work on the palladium-catalyzed Ullmann-type reductive
coupling of aryl halides, see: (a) Hassan, J.; Penalva, V.; Lavenot, L.; Gozzi,
C.; Lemaire, M. Tetrahedron 1998, 54, 13793-13804. (b) Hennings, D. D.;
Iwama, T.; Rawal, V. H. Org. Lett. 1999, 1, 1205-1208. (c) Venkatraman,
S.; Li, C. J. Tetrahedron Lett. 2000, 41, 4831-4834 and references therein.
(24) (a) Kende, A. S.; Liebeskind, L. S.; Braitsh, D. M. Tetrahedron
Lett. 1975, 3375-3378. (b) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.;
Osa, M. Bull. Chem. Soc. Jpn. 1990, 63, 80-87.
DME
DME
DMSO
0.02
0.02
0.02
0.02
0%b
0%b
traceb
traceb
KOAc-K2CO3 DMSO
a Mono- and bisdeiodination products are the major isolable side products.
However, the overall mass balance was generally poor. b Detected by MS.
c Isolated yield.
(25) Moreau-Archier, N. DEA Dissertation, Universite´ Paris-Sud, June
1999. These reactions have been performed in the absence of diboron ester
13.
Org. Lett., Vol. 2, No. 22, 2000
3479

suitably functionalized tripeptide failed to give the cyclic
compound.19d
spectrum of compound 15 recorded at room temperature.
Whether this is the result of a free rotation around the aryl
axis due to the decreased steric hindrance (OMe to OH) or
of a highly atropselective cyclization remains to be clarified.
In summary, we have developed a novel palladium
catalyzed-diboron ester mediated cyclization reaction of a
linear diaryl halide. Two distinct cross-coupling reactions,
each involving an oxidative addition-transmetalation-
reductive elimination manifold, were channeled into an
efficient domino process under defined conditions. The
chemistry described in Scheme 2 represents the most
convergent approach to the biphenomycin skeleton. Further
optimization and application of this cyclization technology
in natural product syntheses are in progress.
We next examined the cyclization of diiodide 14 (Scheme
3) containing a free phenol function since the presence of
Scheme 3
Acknowledgment. We thank CNRS for financial support.
This paper is dedicated with deep respect to Professor P.
Potier.
OL006520G
(27) General procedure: To a flask containing melted KOAc (10 equiv),
Pd(dppf)2Cl2 (0.05 equiv), diboron 13 (1.1 equiv), and diiodide was added
degassed DMSO (final concentration: 0.02 M). After being heated under
argon at 80 °C for 12 h, the reaction mixture was worked up as usual.
Compound 12: [R]D ) +11 (c 0.30, CHCl3); IR (CHCl3) ν 2956, 1740,
1
1705, 1651, 1557, 1505 cm-1; H NMR (DMSO-d6, 343 K, 400 MHz) δ
0.78 (m, 1H), 0.88 (d, J ) 6.6 Hz, 3H), 0.90 (d, J ) 6.6 Hz, 3H), 1.45 (s,
9H), 1.40-1.50 (m, 1H), 1.63 (m, 1H), 2.70-3.20 (m, 4H), 3.69 (s, 3H),
3.70 (s, 6H), 4.35-4.45 (m, 2H), 4.65 (m, 1H), 6.67 (s, 1H), 6.80-7.04
(m, 4H), 7.13 (dd, J ) 2.0, 8.2 Hz, 1H); 8.20 (d, J ) 7.5 Hz, 1H, NH),
8.69 (d, J ) 8.0 Hz, 2H, NH); ESI-MS m/z 620 (M + 23)+. Compound 15:
[R]D ) +14 (c 0.24, CHCl3); IR (CHCl3) ν 3291, 2927, 1745, 1708, 1649,
1560, 1499 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.85 (m, 1H), 0.89 (d, J
) 6.0 Hz, 3H), 0.91 (d, J ) 6.0 Hz, 3H), 1.46 (s, 9H), 1.50-1.60 (m, 2H),
2.70 (dd, J ) 8.6, 13.0 Hz, 1H), 2.82 (dd, J ) 1.8, 13.5 Hz, 1H), 3.08 (br
d, J ) 13.0 Hz, 1H), 3.28 (dd, J ) 7.7, 13.5 Hz, 1H), 3.80 (s, 3H), 3.84 (s,
3H), 4.40 (m, 1H), 4.65-4.78 (m, 2H), 5.45 (d, J ) 8.1 Hz, 1H, NH), 6.47
(s, 1H, OH), 6.63 (d, J ) 8.8 Hz, 1H, NH), 6.80-6.90 (m, 3H), 6.97 (m,
4H); 13C NMR (CDCl3, 75 MHz) δ 171.8, 171.6, 170.9, 155.3, 154.0, 152.8,
133.2, 132.2, 131.2, 130.8, 129.6, 128.4, 127.5, 126.4, 117.2, 111.4, 79.5,
56.4, 54.9, 53.6, 52.6, 52.0, 42.3, 37.2, 36.8, 28.4, 24.5, 22.7, 22.3; ESI-
MS m/z 606 (M + Na)+.
suitable anchoring groups are known to accelerate both
palladium-catalyzed transmetalation and cross-coupling reac-
tions.26 However, the presence of free phenol appeared to
have a slightly negative effect on the cyclization as the yield
of cyclic compound 15 decreased.27 It is interesting to note
1
that only one set of peaks was observed in the H NMR
(26) Crisp, G. T.; Gebauer, M. G. Tetrahedron Lett. 1995, 36, 3389-
3392.
3480
Org. Lett., Vol. 2, No. 22, 2000