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New Technology for the Synthesis of Vancomycin-Type Biaryl Ring Systems.

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COMMUNICATIONS
New Technology for the Synthesis of
Vancomycin-Type Biaryl Ring Systems**
K. C. Nicolaou,* Xin-Jie Chu, Joshi M. Ramanjulu,
Swaminathan Natarajan, Stefan Brase, Frank Riibsam,
and Christopher N. C. Boddy
+
OMe
Dedicated to Prqfessor Samuel J. Danishefsky
on the occasion of' his 60th birthday
2
a
Due to their effective action against drug-resistant bacterial
strains, the vancomycin antibiotics"] are currently receiving unprecedented attention from chemists,['] biologists, and clinic i a n ~ . [As
~ ] a target molecule, vancomy~in[~I
(1, Figure 1) pre-
4
3
(90%)
0
0
0
b
(57%)
OMe
5
4
P
Scheme 1. Synthesis of vancomycin model system 5 a) 1.5 equiv of EDC, 1.5 equiv
ofHOBT, D M E O ' C . 10 h: b) 1.8 equivof(Ph,P),NiCI,. l.XequivofZn, 3.6equiv
of Ph,P. D M F ( 0 . 0 0 2 ~ ) , 55'C, 16 h. EDC = 1-(3-dirnethylamino-propyl)-3ethylcarbodiimide hydrochloride; HOBT = 1-hydroxybenzotriazole; Boc = ferfbutoxycarbonyl, D M F = N,N-dimethylformamide.
CI
H
Me
Figure 1. Molecular structure of vancomycin (1)
sents several synthetic challenges, amongst which the construction of the 12-membered biaryl ring system stands, perhaps, as
the most formidable. It is, therefore, not surprising that to date
only one report[2a1exists for its construction. In this communication, we describe a new method for the construction of the
biaryl ring system of vancomycin, which is direct and involves
mild conditions. The application of the present Nio-mediated
C-C coupling strategy to the synthesis of model systems 5 and
12- 14 demonstrates its generality and scope and holds promise
for a solution to the vancomycin problem itself.
Scheme 1 summarizes the chemistry for the construction of
the vancomycin model system 5, which contains the 12-membered peptide ring. Coupling of fragments 2r61and 3r61with
EDC as the coupling reagent in the presence of HOBT provided
the targeted precursor 4 in 90% yield. The crucial cyclization
reaction was carried out at 50 "C with tetrakis(tripheny1phos[*] Prof. Dr. K c'. Nicolaou. Dr. X.-J Chu, Dr. J M. Ramanjulu,
Dr S. Natarajan, Dr. S . Brase, Dr F. Riibsam, C N. C. Boddy
Department of Chemistry and The Skaggs Institute for Chemical Biology
The Scrippb Research Institute
10550 North Torrey Pines Road, La Jolla. CA 92037 (USA)
F a x . Int code +(619)784-2469
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive. La Jolla, CA 92093 (USA)
[**I This work n'as financially supported by The Skaggs Institute for Chemical
Biology and the U. S. National Institutes of Health (NIH). J. M. R. acknowledges the NIH. S. B. the NATO/DAAD. F. R. the Alexander-von-HumboldtStiftung for a post-doctoral fellowship. We thank Dr. Gary Siuzdak and Dr.
Dee H. Huang for assistance with mass spectrometry and NMR spectroscopy,
respective11
A n p i $ . C'heni h i . Ed. Engl.
1997,36,No. 13/14
phane)nickel [(Ph,P),Ni] generated in situ in D M F (16 h) to
afford the vancomycin model system 5 as a mixture of atropisomers (57 o/' total yield). In thin-layer chromatography (TLC),
compound 5 behaved as a single compound, but in the 'H NMR
spectrum (CDCl,, 500 MHz, 25 "C) it exhibited splitting and
broadness of signals characteristic of siow interconversion of its
two atropisomers. On heating to 50 "C, the spectrum sharpened
considerably, as expected (Table 1).
Encouraged by this result we then attempted the construction
of the more advanced systems 12-14, which are closely related to vancomycin (Scheme 2). The required precursors 9-11
Table 1. Selected physical properties of compounds 5, 14a.and 14b
5 (mixture of atropisomers): R, = 0.50 [silica gel, 50% EtOAc in hexanes]; [ r ] i 5
- 3 1 (L. = 0.13 in CH,CI,); IR (film): i,,, = 3289. 2924, 2851. 1726. 1689, 1647,
1527.1454. 1371,1298, 1240, I l l O c m - ; 1HNMR(500MHz.CDCI,)6=1.42(s,
9 H , I B u ) . 3 . 7 9 ( ~ , 3 H , O M e ) . 4 . 2 4 ~ 4 . 4 1 ( m , 3 H . H , . H , ) . 5 . 0 75.18(m,2H,H,).
5.43 (bs. 1 H. BocNH), 6.91 (d. J = 4.5 Hz. 1 H, Ar,H,). 7.21 (hs, 1 H, H,), 7.357.43(m.6H,Ar,H,.,,Ar,);13CNMR(125
MHz,CDCI,):d =171.8, 171.2.168.9,
1684. 168.1. 167.8. 156.3, 156.2. 155.7, 155.5. 140.7, 140.4, 132.8, 132.7. 131.6,
131.5. 130.7, 130.5. 1299. 128.6, 128.51. 128.4. 127.9. 127.6. 127.4, 127.3. 127.1,
123.7.1104,107.4,80.3,67.0,65.9,56.7,55.6,55.5,52.2,42.7.42.3,29.6.29.5.28.2,
28.1, 28.0; HRMS (FAB) calcd for C,,H,,N,O,Cs
( M + C s . ) 559.0845: found
559.0828.
14a:R, = 0.20 [silica. 2.5% MeOH in CHCI,]; [XI:' -45.7 (c
0.37 in CH,CI,);
IR (film): i.,,, 3320, 2924, 1673, 1611, 1585, 1501, 1366, 1324. 1256, 1157. 1110,
1063 cm", ' H N M R (600 MHz, CDCI,): 6 =1.34(s, 9H, rBu). 3.28-3.30(m, 1 H,
H,), 3.63 (s,6H,OMe), 3.64-3.66(m.lH,H4),3.72 (s, 3H.OMe). 3.74-3.76(m,
l H , HA),3.X4-3.86(m3 I H , H,),4.81 (br s, l H , H,), 6.56 (d. .I = 2.2Hz, l H , H
Ar,H,). 6.58 (d, J = 2.2 Hz, l H , Ar,H,), 6.85 (br s, 1H. BocNH). 6.95 (d,
J = 8.3 Hz. I H, Ar,H,), 7.08 (br s, 1 H, Ar,H,), 7.30 (dd, J := 8 3, 2.1 Hz. 1H,
ArAH,).7.40(brs, l H , N 6 H ) , 7 . 8 2 ( t , J = 6.6Hz, l H , N , H ) ; ',C:NMR(150MHz,
[D6IDMSO)6=172.l, 170.4, 167.5, 159.5, 158.1, 1567. 137.4. 1329, 129.9, 127.7,
124.1, 120.8. 110.8, 107.9.97.9, 78.3, 59.7,55.7. 55.5, 55.3.43 7.43.3. 28.l;HRMS
(FAB) calcd for C,,H,,N,O,Na ( M + N a + ) 508.2060: found: 508.2067, 14b
R,=0.25 [silica, 2.5% MeOH in CHCI,];
-18.1 ( c = 0 6 3 in CH,CI,), IR
(film): i.,,, 3314, 2924, 2853, 1677. 1581. 1504, 1459. 1366. 1320, 1262, 1160,
lllOcm~l'
; H N M R ( ~ O ~ M H ~ . [ D , ] D M S O ) . ~iBu),3.67(s,3H,
=~.~~(S.~H.
OMe).3.68~3.70(m.lH,H,),3.74(s.3H,OMe),3.82-3.X6~in,lH.H,).3.81(s,
2
3H,OMe),4.13-4.24(m.2H,H,).5.12-5.13(m,1H.H1).680(s.2H,Ar,H,,),
6.98(d,J=8.6Hz,1H.Ar,H,).7.18(s,lH.Ar,H,),7.36-73X(m,~H.BocNH.
Ar,HJ. 8.29 (br s, 1 H. N,H). 8 57 (br s. 1 H. N,H); "C NMR (150 MHz,
[DJDMSO) b =171.1, 168.9, 160.8, 158.4, 156.4, 155.3. 142 3. 130.2, 130.1, 129 8,
128.2. 127.8, 111.0, 105.4, 97.4, 78.7, 57.6, 56.5, 55 5, 55.1.47 X. 42.4, 28.1; HRMS
(FAB) calcd for C,,H,,N,O,Na ( M + N a + ) 508.2060: found 208.2069.
VCH Verlagsgesvllschafi mbH, 0-69451 Weinheim. 1997
0570-0833i97:33613-t53YS 1 7 . j O f S0:O
1539
COMMUNICATIONS
9
o y N H 2
I
x’l
+
Me0aOMe
OMe
6 :X=O;R=H
7 :X=O;R=CH3
8 :X=NH;R=H
3
14a
J8
OMe
OMe
Me0
1
;
11 (92%)
Me0
X=O;R=H
X = 0; R = CH3
X = NH; R = H
12 (35%)
Scheme 2. Synthesis of vancomycin model systems 12-14: a) 1.2equiv of 3,
1.3equiv of EDC, 2.2equiv of Et,N, DMF. O‘C, 12 h; b) 1.8equiv of
(Ph,P),NiCI,, 1.8 equiv of Zn, 3.6 equiv of Ph,P, DMF (0.002~).55’C. 16 h.
were synthesized in high yield (90-95 %) by peptide coupling of
the appropiate amino fragment (6-8)[61with carboxylic acid 3.
Exposure of depsipeptides 9 and 10 with Nio under the conditions of Scheme 1 gave the cyclized systems 12 and 13 in
35% and 26% yield, respectively, along with the reduced
products 15 (43%) and 16 (29%) (Figure 2). Apparently, a
0
0
:
,...NHBoc
I
Me0
H
OMe
OMe
1 5 : X = O ; R = H /43%/
16 : X = 0;
R = CH3 29%
17:X=NH;R=H 27%
MeO
OMe
18 (20%)
Figure 2 Reduced products from the Nio-mediated cyclizations of 9-11.
higher degree of substitution on one of the aromatic rings slows
down the intramolecular reaction, allowing the formation of
reduced products. Finally, peptide 11, upon treatment with Ni’,
resulted in the formation of biaryl system 14 in 26% yield as a
mixture of two atropisomers. The two isomers (14a and 14b)
were separated by preparative layer chromatography [silica gel,
2.5% MeOH in CHCI,, R, = 0.20 (14a) and 0.25 (14b)l.
NOESY experiments enabled assignment of the major atropisomer (14a) as indicated in Figure 3. It is noteworthy that the
unnatural atropisomer 14a prevailed as the major product in
this cyclization reaction. However, removal of the methyl
groups from the trimethoxybiaryl moieties of 14a and 14b is
expected to facilitate their interconversion, as previously observed for a similar system.f2a1
The formation of dimers was also observed in all cases described above (MS, ‘HNMR). Further dilution of the reaction
mixture disfavored dimerization, but increased the amount of
1540
14b
Figure 3. Structural assignment of atropisomers 14a and 14b based on NOESY
experiments.
VCH Verlrrg.~~Rrsellschafr
mhH, 0-69451 Weinheim. 1997
reduced by-products. Work is currently in progress for further
optimization of these reactions and for the invention of new
ones for the purposes of efficiently constructing this challenging
biaryl system.
In conclusion, a mild method for the construction of the rigid
12-membered biaryl ring system of the vancomycin antibiotics
has been developed. Its application to the total synthesis of
natural and designed members of this class of conipounds for
biological studies may prove fruitful.
Received: December 23, 1996 [Z9929IE]
German version: Angew. Chem. 1997, 109, 1551- 1552
Keywords: asymmetric synthesis
tides * vancomycin
*
biaryls
*
cyclizations
- pep-
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2135-2167 and references therein; b) Clycopeptide Antibiotics (Ed.: R. NagaraJan), Dekker, New York, 1994; c) K. Burgess, D. Lim, C. 1. Martinez, Angew
Chem. 1996,108,1162-1163; Angew. Chem. Int. Ed. Engl. 1996,35,1077-1078.
[2] a) D. A. Evans, C. J. Dinsmore, D. A. Evrard, K. M De Vries, J Am. Chem.
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1993, 34. 6029-6032; c) A. J Pearson, G. Bignan, ihid 1996, 37, 735-738;
d) A. J. Pearson, G. Bignan, P. Zhang, M. Celliah, J Org. Chem. 1996, 61,
3940-3941; e) D. L. Boger, R. M. Borzilleri, S. Nukui. Bioorg. Med. Chem.
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Zhu, ihid. 1994, 59, 583555542; h) J. P. Zhu, J.-P. Bouillon, G. P. Singh, I.
Chastanet, R. Beugelmans, TerrahedronL e f t . 1995,36,7081-7084; i) R. Beugelmans, M. Bois-Choussy, C. Vergne, J.-P. Bouillon, J. P Zhu, J Chem. SOC.
Chem. Commun. 1996, 1029-1030; j) T. Inoue, T. Sasaki, H. Takayanagi, Y
Harigaya, 0. Hoshino, H. Hara, T. Inaba, J Org. Chem. 1996,61, 3936-3937;
k) D. H. Williams, J. R. Kalman, J Am. Chem. Soc. 1977, 99, 2768-2774;
1) A. G. Brown. M. J. Crimmin. P. D. Edwards, J Chem. Soc. Perkin Trans 1
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Soc. 1989, 111, 8912-8914; n) A. V. R. Rao, T. K Chakraborty, S. P. Josh],
Tetrahedron Lett. 1992, 33, 4045-4048; 0 ) A. V. R. Rao. K. L. Reddy, M. M.
Reddy, ;hid. 1994, 35, 5039-5042; p) J. P. Zhu, R. Beugelmans, A. Bigot, G. P.
Singh, M. Bois-Choussy, ihirl. 1993, 34, 7401 -7404; q) D. A. Evans, P. S. Watson, rhid. 1996. 37, 3251-3254; r) H. Konishi, T. Okuno, S. Nishiyama, S.
Yamamura, K. Koyasu, Y Terada, rhid. 1996.37, 8791 -8794.
[3] a) G . M. Sheldrick, P. G. Jones. 0. Kennard, D. H. Williams, G. A. Smith.
Nuture 1978,271.223-225; b) C. T. Walsh, Science 1993,261,308-309; c) P. J.
Loll, A E. Bevivino, B. D. Korty, P. H. Axelson, J Am. Chem. SOC.1997, 119.
1516-1522.
[4] a ) M. H. McCormick, W. M. Stark, R. C. Pittenger, G. M. McGuire, Anfihiot.
Annu. 1955-1956.606-611; b) R. S. Griffith, J Antimicroh. Chemofher.1984,
14 iSuppl. 0).
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61 1-616; b) M. F. Semmelhack, P. Helquist, L. D. Jones, L. Keller, L. Mendelson, L. S. Ryono. J. G Smith, R. D. Stauffer, J An?. Chem. SOC.1981. 103,
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[6] The fragments 2, 3, and 6-8 used in this study were constructed by standard
methods from readily available aromatic systems Details will be published in a
full account of this work. AII new compounds exhibited satisfactory spectral and
exact mass data.
0570-0833/97/3613-1540$l7.50+ .SO10
Angen’. Chem. Int. Ed. EngI. 1997, 36, No. 13/14
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