J. Am. Chem. SOC.1990, 112, 7416-7418
7416
Table 1. Representative Urethane-Protected N-Carboxy Anhydrides amino acid urethane mp, OC CY]*^^, deg L-Ala Fmoc 106-107 +28.7 D-Ala Fmoc 109-1 13 dec -28.7 +29.1 Fmoc 134-137 L-Asn(trity1) +22.4 Fmoc 65-70 dec L-Asp(P-tert-buty1) +19.4 Fmoc 123-126 L-Gln(trity1) +29.3 Fmoc 120-123 L-Glu(y-tert-butyl) Fmoc 156-1 57 dec 00.0 GlY Fmoc 117-118 +25.9 L-He L-Leu Fmoc 118-120 +38.0 L- Lys(t- BOC) Fmoc 81-85 +25.3 L-Met Fmoc 74-75 +69.3 L-Phe Fmoc 59-61 +101.9 L-Ser(0-tert-butyl) Fmoc 54-57 +27.5 L-Thr(O:tert-butyl) Fmoc 124-127 +31.2 L-Trp(P-formy1) Fmoc 108 dec 87.9 + I 10.6 L-Tyr(O-rert-butyl) Fmoc 122-124 L-Val Fmoc 83.5-87 +14.8 I 03- 104.5 +21.6 L-Ala Boc L-Ser(0-benzyl) Boc 98-99.5 +47.2 D-Ala Z 103-104.5 -52.1 L-Phe Z 105-106 127.6
+
reagents will greatly facilitate and enhance the scope of peptide synthesis. Acknowledgment. We are pleased to acknowledge Mr. Adam D. Mann, Mr. David T. Jones, and Dr. Sherrell S. Early for their technical support and Dr. Raj. K. Chadha for X-ray crystallography. Supplementary Material Available: Analytical data (mp, IR,
'HNMR, CHN analysis, optical rotation) for all compounds listed in Table I, FAB mass spectrum of crude acyl carrier peptide (65-74), and crystallographic structure determination summary, experimental procedures, data collection, data reduction, structure solution and refinement, tables of general temperature factor expressions and torsional angles, and drawings and unit cell packing diagram of Fmoc-0-tert-butylthreonine-NCA (27 pages); listing of observed and calculated structure factors of Fmoc-0tert-butylthreonine-NCA (7 pages). Ordering information is given on any current masthead page.
Synthesis of Dynemicin A Models K. C. Nicolaou,* C.-K. Hwang, A. L. Smith,+ and S. V . Wendebornt
Department of Chemistry Research Institute of Scripps Clinic 10666 North Torrey Pines Road La Jolla. California 92037 Department of Chemistry University of California, San Diego La Jolla, California 92093 Received May 18, 1990 Dynemicin A (1, Scheme I) is a potent antibacterial and anticancer agent recently isolated from Micromonospora chersina.' Its striking molecular structure combines characteristics of both the enediyne2J and the anthracycline4 classes of antibiotics and ~
~~
'Recipient of a NATO (SERC, U.K.) Postdoctoral Fellowship, 1990-1992. *Recipient of a Verband Der Chemischen Industrie Doctoral Fellowship, 1989-1 990. (1) (a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, J. J . Am. Chem. Soc. 1990, 112, 3715-3716. (b) Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D.; Clardy, J. J . Antibiot. 1989, 42, 1449-1452. (c) Sugiura, Y.; Shiraki, T.; Konishi, M.; Oki, T. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 3831-3835.
0002-7863/90/1512-7416$02.50/0
Scheme I. Structure of Dynemicin A (1) and Retrosynthetic Disconnection of Model Systems 2 and 3
OH
a
0
OH
1
Functlonalise
'A
t
.--
2:R=OH 3:R=H
Functlonalise
presents a considerable challenge to organic synthesis as well as a unique opportunity for the development of new synthetic technology and therapeutic agents. In this communication we report the synthesis, crystal structures, and Bergman-type cyclizations of two novel dynemicin A models (2 and 3, Scheme I) containing the nitrogen, epoxide, and enediyne functionalities of the natural product. The retrosynthetic analysis that led to the present synthetic strategy is outlined in Scheme I (2, 3 4). Scheme IIs summarizes the construction of 2 and 3 starting from quinoline derivative 4. Thus treatment of 46 with mCPBA in dichloromethane gave the corresponding ilr-oxide, which underwent regiospecific rearrangement' upon heating in acetic anhydride to give the acetoxy derivative 5 (62% overall yield). This was converted to the corresponding silyl ether 7 in 92% overall yield by standard methods via hydroxy compound 6. Addition of phenyl chloroformate* to a mixture of compound 7 and ethynylmagnesium bromide at -78 OC led to the formation of compound 8 in 92% yield.9 Treatment of 8 with mCPBA led to epoxide 9 (85%),1° which was converted to ketone 11 via alcohol 10 by desilylation followed by oxidation (79% overall). Coupling 11 with vinyl
-
(2) Calicheamicins: (a) Lee,M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. 0.; Borders, D. B. J . Am. Chem. Soc. 1987, 109, 3464-3466. (b) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. 0.;McGahren, W. J.; Borders, D. B.J . Am. Chem. SOC.1987, 109, 3466-3468. (3) Esperamicins: (a) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Doyle, T. W. J . Am. Chem. Soc. 1987,109, 3461-3462. (b) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohjuma, H.; Doyle, T. W. J . Am. Chem. Soc. 1987, 109, 3462-3464. (4) (a) Anthracycline Antibiotics; El Khadem, H. S.,Ed.; Academic Press: New York 1982. (b) Recent Aspects in Anthracyclinone Chemistry; Tetrahedron Symposia-in-Print No. 17, Kelly, T. R., Ed.; Tefrahedron1984,40, 4537-4794. (5) All new compounds exhibited satisfactory spectral and analytical and/or exact mass data. Yields refer to chromatographically and spectroscopically homogeneous materials. (6) (a) Masamune, T.; Takasugi, M.; Suginome, H.; Yokogama, M. J . Org. Chem. 1964,29,681-685. (b) Curran, D. P.;Kuo, S.-C. J . Org. Chem. 1984, 49, 2063-2065. (c) Hollingsworth, B. L.; Petrow, V. J . Org. Chem. 1948. 13, 1537-1541. (7) Boekelheide, N.; Linn, W. J. J. Am. Chem. Soc. 1954,76,1286-1291. (8) Comins, D. L.; Myoung, Y. C. J . Or . Chem. 1990, 55, 292-298. (9) Compounds 8-10 exhibited two sets of 7H and I3C NMR signals (ca. 3:l ratio), due to the presence of two isomers. This phenomenon disappeared, as expected, upon arrival at intermediate 11 as evidenced by NMR spectroscopy. (10) The stereochemistry of the epoxide functionalityin this compound was tentatively assigned as shown and was confirmed by its subsequent conversion into 2.
Q 1990 American Chemical Society
J . Am. Chem. Soc., Vol. 1 1 2, No. 20, 1990 741 7
Communications to the Editor
&)
Scheme 11. Synthesis and Chemistry of Dynemicin A Model 3'
a,b
OR
~
4 cc r
Kl
5: R = AC 6:R.H 7: R ISi'BuMe,
c3
a
9: R = Si'BuMe, h
r
Figure 1. ORTEP drawing of the dynemicin A model 3. Hydrogen atoms are omitted for clarity. Distance cd (CI9-Cl4) = 3.59 A. Angles: C17-CIg-CI9 = 170.2'; C9-CIp-C1g = 162.0°; C14-CIs-C16 = 170.1'; C13-C14-CIs = 163.7'.
's
11
13 : R = SiMe, 14: R = H
L
16 : X=OH [cd = 3.21 A] 16a : X=CI [cd = 3.19 A]
t r
I
'"
r
2: X = OH [cd = 3.63A; X-Ray and MMX]
3: X = H [cd = 3.59A; X-Ray and MMX]
phoi& HO'"
0 L
1 7 : X=OH 178 : X = U
l a : X=OH 1aa: X=CI
"Reagents and conditions: (a) 1.0 equiv of mCPBA, CH2CI2, 25 OC, I h, 80%; (b) Ac,O, reflux, 20 h, 77%; (c) K2C03 (catalytic), MeOH, 25 OC, 1 h, 100%; (d) 1.2 equiv of 'BuMe2SiOTf, 1.4 equiv of 2,6-lutidine, CH2CI2, 0 OC, 0.5 h, 92%; (e) 3.0 equiv of ethynyl25 "C, 1 h, magnesium bromide, 3.0 equiv of PhOCOCI, THF, -78 92%; (0 2.0 equiv of mCPBA, CH2CI2,25 OC, 3 h, 85%; (8) 1.2 equiv of TBAF, THF, 42 OC, 3 h, 95%; (h) 3.0 equiv of PCC, CH2C12,4-A molecular sieves, 25 OC, I h, 81%; (i) 1.4 equiv of 12, 1.5 equiv of n-BuNH2, 0.25 equiv of PPh3, 0.05 equiv of Pd(OAc),, 0.2 equiv of CUI, PhH, 25 OC, 4 h, 88%; (j)4.0 equiv of AgN03, 7.0 equiv of KCN, H 2 0 , EtOH, THF, 25 OC, IO min, 90%; (k) 1.1 equiv of LDA, toluene, -78 OC, I h, 80% based on 25% recovery of 14; (I) 3 equiv of thiocarbonyldiimidazole,0.5 equiv of DMAP, CH2CI2, 25 OC, 48 h, 91%; (m) 2 equiv of n-Bu,SnH, AlBN (catalytic), toluene, 75 OC, 2 h, 75%; (n) (i) 0.05 M in benzene-1,4-cyclohexadiene (4:1), 1.2 equiv of TsOH.H,O, 24 h, 25 OC, 86% (X = OH); or (ii) HCl(g), 40 equiv of 1 ,4-cyclohexadiene, CH2C12, 1 min, 25 "C, 82% (X = CI).
-
chloride 12 via Pd(O)
