152
LETTERS
SYNLETT
References and Notes
(Molecular Simulations Inc., INSIGHT/DISCOVER). A representative,
partially-refined, structure which illustrates several interesting features
is shown in Figure 2.
1.
2.
3.
Hale, K.J.; Cai, J., J. Chem. Soc. Chem. Comm., 1997, in press.
L. A. Carpino, J. Am. Chem. Soc., 1993, 115, 4397.
Castro, B.; Dormoy, J.R.; Evin, G.; Selve, C., Tetrahedron Lett., 1975,
1219.
4.
5.
Hale, K.J.; Cai, J.; Delisser, V.M., Tetrahedron Lett., 1996, 37, 9345.
Hale, K.J.; Delisser, V.M.; Yeh, L.-K.; Peak, S.A.; Manaviazar, S.;
Bhatia, G.S., Tetrahedron Lett., 1994, 35, 7685.
6.
(a) Hale, K.J.; Cai, J.; Delisser, V.; Manaviazar, S.; Peak, S.A.; Bhatia,
G.S.; Collins, T.C.; (in part) Jogiya, N., Tetrahedron, 1996, 52, 1047;
(b) Hale, K.J.; Delisser, V.M.; Manaviazar, S., Tetrahedron Lett., 1992,
33, 7613.
7.
Durette, P.L.; Baker, F.; Barker, P.L.; Boger, J.; Bondy, S.S.;
Hammond, M.L.; Lanza, T.J.; Pessolano, A.A.; Caldwell, C.G.,
Tetrahedron Lett., 1990, 31, 1237.
8.
9.
Stelakatos G.C.; Paganou, A.; Zervas, L., J. Chem. Soc., C, 1966, 1191.
Boissonnas R. A.; Guttmann St.; Jaquenoud, P. -A., Helv. Chim. Acta.,
1960, 43, 1349.
Figure 2
10. Tung, R.D.; Dhaon, M.K.; Rich, D.H., J. Org. Chem., 1986, 51, 3350.
11. Carpino, L.A.; Han, G.Y., J. Org. Chem., 1972, 37, 3404.
The presence of a strong NOE between H(4) and H(9) indicates that the
C(8)-carbonyl group is cis to the piperazic acid A-ring NH in 8. This
contrasts markedly with A83586C itself, where the C(8)-carbonyl is
trans to this NH. The remaining amide bonds in 8 all have the same
configuration as A83586C. NOEs from the N(OH) to H(4) and H(13)
point to the N-hydroxyl being endocyclic in 8. The orientation of the
ester linkage is not well-defined in our structure, due to the lack of
proton restraints. Analysis of vicinal coupling constant and NOE data
shows that both piperazine α-protons, H(4) and H(13), are essentially
equatorial in 8. The D-threonine and L-hydroxyleucine side-chains are
restricted to the rotamers shown by the small couplings between H(19)
12. All new compounds gave satisfactory 400 MHz 1H and 100 MHz 13C
NMR and IR spectral data as well as HRMS data. (8) is an an
amorphous solid: [α]D +43.6 o (c 0.5 CH2Cl2); 500 MHz 1H NMR (24
oC, CDCl3, chemical shifts reported relative to residual CHCl3 peak at
δ 7.24) δ 9.16 (d, J = 8.1 Hz, ThrNH), 6.56 (br, ThrOH), 1.75 (br,
PipNH-Ring A), 8.89 (s, NOH), 6.13 (d, J = 12.4 Hz, PipNH-Ring B),
9.30 (d, J = 10.3 Hz, HLeuNH), 4.47 (dd, J = 1.6, 8.1 Hz, H2), 4.40 (dd,
J = <2.0, 5.7 Hz, H4), 2.02 (m, H5a), 1.78 (m, H5b), 1.89 (m, H6a),
1.70 (m, H6b), 3.11 (m, H7a), 2.75 (m, H7b), 5.47 (q, J = 6.6 Hz, H9),
5.39 (q, J = 6.6 Hz, H11), 5.70 (dd, J = < 4.0, < 4.0 Hz, H13), 1.88 (m,
H14a), 1.79 (m, H14b), 1.55 (m, H15a), 1.29 (m, H15b), 3.09 (m,
H16a), 2.75 (m, H16b), 4.80 (dd, J = 10.3, 10.3 Hz, H18), 4.92 (dd, J =
1.5, 10.4 Hz, H19), 4.69 (m, H20), 1.30 (d, J = 6.7 Hz, H21-Me), 1.28
(d, J = 6.8 Hz, H22-Me), 1.32 (d, J = 6.6 Hz, H23-Me), 1.79 (m, H24),
0.58 (d, J = 6.9 Hz, H25-Me), 0.76 (d, J = 6.7 Hz, H26-Me), 2.97 (s,
H27-NMe), 2.87 (s, H29-OH), 6.31 (s, H30-OH), 1.69 (m, H31a), 1.59
(m, H32a), 1.41 (m, H33), 3.97 (d, J = 10.2 Hz, H34), 5.69 (d, J = 9.0
Hz, H36), 4.08 (dq, J = 7.1, 8.9 Hz, H37), 6.71 (q, J = 6.8 Hz, H40),
1.80 (d, J = 6.8 Hz, H41-Me), 1.99 (m, H42a), 1.58 (m, H42b), 0.86 (t,
J = 7.4 Hz, H43-Me), 0.68 (d, J = 6.5 Hz, H44-Me), 1.55 (s, H45-Me),
1.09 (d, J = 7.0 Hz, H46-Me), 1.71 (s, H47-Me), H31b and H32b
resonate between 1.50 and 1.70 ppm but are not assigned due to
resonance overlap; 100 MHz 13C NMR (CDCl3) δ 203.1, 174.9, 173.4,
172.9, 169.0, 168.0, 167.6, 165.5, 137.3, 136.7, 132.8, 129.0, 99.5,
82.6, 80.2, 79.0, 66.8, 58.4, 56.4, 56.3, 51.1, 50.3, 48.0, 47.3, 45.3,
38.2, 32.6, 30.2, 28.5, 27.2, 27.13, 27.08, 25.8, 24.0, 21.2, 20.4, 20.0,
19.7, 19.5, 17.7, 15.2, 14.9, 14.1, 14.0, 11.6, 11.4, 8.5; HRMS Calcd for
C47H76O14N8Na [M+Na]+. m/z 999.5379, Found: m/z 999.5350.
and H(24) (J
= 1.5 Hz) and between H(2) and H(20) (J
= 1.6
H19,24
H2,20
Hz), with rotational-averaging being minimal. In the pyran ring, the
axial position of H(34) is apparent from its large coupling with H(33).
The weak NOE between H(34) and the C(30)-hydroxyl also confirms
that the latter is axial. The unsaturated side chain in 8 is restrained by
weak NOEs between H(36) and the hydroxyleucine methyls, as well as
strong NOEs between H(37) and H(40), and H(36) with H(34). Work is
continuing on refining this structure further, and the results of these
efforts will be the subject of a future full publication.
To conclude, our total synthesis of 4-epi-A83586C has provided a
further demonstration of the generality and power of the biomimetic
14
BtO ester coupling strategy for constructing molecules of the
A83586C genre. Our work has also shown that macrolactamisation of
the A83586C hexapeptide precursor
2 is accompanied by an
epimerisation in the L-piperazic acid moiety when it is mediated by
excess BOP and DMAP at high dilution. Finally, our 2D NMR and
molecular modelling studies on 8 have allowed a preliminary, partially-
refined, solution structure to be proposed, in which the C(8)-carbonyl
group is oriented cis to the NH of the piperazine A-ring. Further studies
in each of these areas will be reported shortly.
13. Stott, K.; Keeler, J.; Van, Q.N.; Shaka, A.J., J. Mag. Res., 1997, 125,
302.
14. (a) A83586C: Smitka, T.A.; Deeter, J.B.; Hunt, A.H.; Mertz, F.P.; Ellis,
R.M.; Boeck, L.D.; Yao, R.C., J. Antibiotics, 1988, 41, 726; (b)
Azinothricin: Maehr, H.; Liu, C.M.; Palleroni, N.J.; Smallheer, J.;
Todaro, L.; Blount, J.F., J. Antibiotics, 1986, 39, 17; (c) Citropeptin:
Nakagawa, M.; Hayakawa, Y.; Furihata, K.; Seto, H., J. Antibiotics,
1990, 43, 477; (d) Verucopeptin Nishiyama, Y; Sugawara, K.; Tomita,
Acknowledgements. KJH and JC are pleased to acknowledge EPSRC
support of this work through project grant GR/J92590. KJH and JC also
thank Zeneca, Pfizer, and Rhone-Poulenc Rorer for additional financial
assistance. We are also grateful to the ULIRS NMR Service at King's
College London for 2D NMR measurements and to the ULIRS MS
Service at London School of Pharmacy for HRMS data. We thank Dr
B.K. Handa (Roche) for helpful discussions.
K.; Yamamoto, H.; Kamei, H.; Oki, T., J. Antibiotics,
1993, 46, 921;
Suguwara, K.; Toda, S.; Moriyama, T.; Konishi, M.; Oki, T., J.
Antibiotics, 1993, 46, 928; (e) GE3 Sakai, Y.; Yoshida, T.; Tsujita, T.;
Ochiai, K.; Agatsuma, T.; Saitoh, Y.; Tanaka, F.; Akiyama, T.;
Akinaga, S.; Mizukami, T., J. Antibiotics, 1997, 50, 659; Agatsuma, T.;
Sakai, Y.; Mizukami, T.; Saitoh, Y., J. Antibiotics, 1997, 50, 704.