114
P. D. Bailey et al. / Tetrahedron Letters 42 (2001) 113–115
Acknowledgements
We thank Dr. Alan Boyd and Dr. Rod Ferguson for
NMR and mass spectra, Waseem Ashraf for work
relating to note 12, and Zeneca Agrochemicals for
funding.
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Figure 1.
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7. For example, see: (a) Bailey, P. D.; Mclay, N. R. J.
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Morgan, K. M.; Smith, D. I.; Vernon, J. M. J. Chem.
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Morgan, K. M.; Rodair, G. M.; Thomas, R. Ll. Tetra-
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8. (a) Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.;
Everett, J. H.; Reynolds, C. D.; Wood, S. D.; Giordano,
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gler reactions,10 so that much longer and less efficient
procedures have been used by ourselves8 and
others5,11,12 to introduce the dimethylallyl unit into
fumitremorgins and related alkaloids. However, using
our kinetically controlled Pictet–Spengler reaction,13
we can obtain 2a in 38% yield with 6:1 cis selectivity
(0.033 M imine in CHCl3, 10 equiv. TFA, −40°C, 10
h), although for the synthesis of 4b we chose conditions
that provided 2a in 58% yield with a 3:1 cis selectivity
(0.2 M imine in CHCl3, 20 equiv. TFA, −40°C, 4 h).
The diastereochemistry was confirmed by single crystal
X-ray structure determination of 2b (Fig. 1),14 the
minor trans epimer of 2a. Its optical integrity was
confirmed by formation of the R- and S-Mosher’s
amide derivatives, and analysis of the diastereomeric
1
derivatives by H NMR.15
Step 2. We encountered some problems identifying
an activated/protected proline derivative that would
generate the required peptide bond with high efficiency
without leading to simultaneous racemisation. Ulti-
mately, the (fluorenylmethyl)oxycarbonyl (Fmoc) acid
chloride16 met our needs; the intermediate dipeptide
was not fully characterised, due to the complex ro-
tamers present, but the crude product was taken
straight on to the next step.
9. (a) Cui, C.-B.; Kakeya, H.; Okada, G.; Onose, R.; Osada,
H. J. Antibiot. 1996, 49, 527; (b) Cui, C.-B.; Kakeya, H.;
Osada, H. J. Antibiot. 1996, 49, 534.
10. Harrison, D. M.; Sharma, R. B. Tetrahedron Lett. 1993,
34, 3165 (Pictet–Spengler reaction failed with a,b-unsatu-
rated aldehydes).
11. (a) Plate, R.; Hermkens, P. H. H.; Behm, H.; Ottenheijm,
H. C. J. J. Org. Chem. 1987, 52, 560; (b) Hino, T.;
Kawate, T.; Nakagawa, M. Tetrahedron 1989, 45, 1941;
(c) Boyd, S. A.; Thompson, W. J. J. Org. Chem. 1987, 52,
1790; (d) Wang, H.; Ganesan, A. Tetrahedron Lett. 1997,
38, 4327 (c/d use acyl-Pictet–Spengler reactions with very
poor stereo-control).
Step 3. Removal of the Fmoc protection using pipe-
ridine led directly to the diketopiperazine target 4b in
53% isolated yield from 2a. The overall yield of 4b from
L
-Trp-OMe was thus 21%. Its purification was rela-
12. We substantially improved the stereo-selectivity of Dan-
ishefsky’s synthesis (Ref. 5) by carrying out the Pictet–
Spengler reaction with 4Me-C6H4-S-C(Me)2CH2CHO
under our conditions of kinetic control (Ref. 13), giving
the adduct in 64% yield with 3:1 cis:trans selectivity [in
Ref. 5, the phenylthio derivative was used which requires
the use of thiophenol (stench); the 4-tolyl analogue is
much less malodorous].
tively straightforward, as virtually all by-products had
much lower Rfs by silica gel chromatography due to the
presence of free basic NH group(s). It was identical to
the natural product9 in all respects.
We have therefore shown that enantiopure demethoxy-
fumitremorgin C can be prepared quickly and effi-
ciently using a diastereoselective three-step route, and
this methodology should be applicable to the synthesis
of fumitremorgin analogues in the search for effective
anti-MDR drugs.
13. (a) Bailey, P. D.; Hollinshead, S. P.; Mclay, N. R.;
Morgan, K. M.; Palmer, S. J.; Prince, S. N.; Reynolds, C.
D.; Wood, S. D. J. Chem. Soc., Perkin Trans. 1 1993,