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DOI: 10.1055/s-2004-835653
Stereoselective Synthesis of the C1-C12 Fragment of the Cytotoxic Macrolide FD-891
Publication History
Publication Date:
08 November 2004 (online)
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Abstract
A stereoselective synthesis of the C1-C12 fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. The initial chirality was created via an asymmetric Evans aldol reaction. Two other asymmetric reactions, a Sharpless epoxidation and an aldehyde Brown allylation were further key steps of the synthesis.
Key words
antitumor agents - aldol reactions - chiral auxiliaries - stereoselective synthesis - asymmetric allylations
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1a
Eguchi T.Kobayashi K.Uekusa H.Ohashi Y.Mizoue K.Matsushima Y.Kakinuma K. Org. Lett. 2002, 4: 3383 -
1b Detailed spectral data of FD-891 are given in:
Seki-Asano M.Tsuchida Y.Hanada K.Mizoue K. J. Antibiot. 1994, 47: 1234 - 2
Murga J.García-Fortanet J.Carda M.Marco JA. Tetrahedron Lett. 2004, 45: 7499 - 3
Eguchi T.Yamamoto K.Mizoue K.Kakinuma K. J. Antibiot. 2004, 57: 156 - 4
Bartra M.Urpí F.Vilarrasa J. In Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products Vol. 2:Lukacs G. Springer Verlag; Berlin: 1993. p.1-65 - 5
Blakemore PR. J. Chem. Soc., Perkin Trans. 1 2002, 2563 - 6 The synthesis of a compound structurally related to fragment A has recently been reported:
Chng S.-S.Xu J.Loh T.-P. Tetrahedron Lett. 2003, 44: 4997 - 7
Trost BM.Chisholm JD.Wrobleski ST.Jung M. J. Am. Chem. Soc. 2002, 124: 12420 - 8 This Z → E isomerization during the oxidation with PCC has been reported to occur with the corresponding benzyl derivative:
Danishefsky SJ.Berman EM.Ciufolini M.Etheredge SJ.Segmuller BE. J. Am. Chem. Soc. 1985, 107: 3891 -
9a
Evans DA. Aldrichimica Acta 1982, 15: 23-32 -
9b
Kim BM.Williams SF.Masamune S. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I.Winterfeldt E. Pergamon Press; Oxford: 1993. p.239-276 -
9c See also:
Cowden CJ.Paterson I. Org. React. 1997, 51: 1 - 10
Sibi MP. Org. Prep. Proced. Int. 1993, 25: 15 - 11 This olefination gave a better yield in 1,2-dichloroethane at 60 °C than in toluene at 110 °C, in contrast to that observed in a structurally similar situation:
Marshall JA.Adams ND. J. Org. Chem. 2002, 67: 733 - 12
Horita K.Yoshioka T.Tanaka T.Oikawa Y.Yonemitsu O. Tetrahedron 1986, 42: 3021 - 13
Katsuki T.Martín VS. Org. React. 1996, 48: 1 -
14a
Brown HC.Ramachandran PV. J. Organomet. Chem. 1995, 500: 1 -
14b
Ramachandran PV. Aldrichimica Acta 2002, 35: 23
References
Compound A: 1H NMR (500 MHz, CDCl3): δ = 7.10 (br s, 1 H), 5.83 (m, 1 H), 5.55 (d, J = 10.0 Hz, 1 H), 5.10-5.00 (m, 2 H), 4.20 (q, J = 7.0 Hz, 2 H), 3.61 (dd, J = 5.0, 4.0 Hz, 1 H), 3.48 (dt, J = 5.5, 6.5 Hz, 1 H), 2.96 (dd, J = 5.5, 2.2 Hz, 1 H), 2.88 (dd, J = 4.0, 2.2 Hz, 1 H), 2.68 (ddq, J = 10.0, 5.0, 6.8 Hz, 1 H), 2.28 (t, J = 6.5 Hz, 2 H), 2.00 (d, J = 1.3 Hz, 3 H), 1.85 (d, J = 1.0 Hz, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 169.1, 142.7, 138.1, 134.5, 131.9, 125.9, 117.3, 73.6, 73.0, 60.6, 58.5, 57.2, 39.5, 37.7, 25.9 (× 3), 25.8 (× 3), 18.3, 18.2, 16.6, 15.7, 14.3, 14.0, -4.2, -4.4, -4.8, -4.9.
16None of the intermediates in the way towards A nor compound A itself was crystalline. Therefore, X-ray analyses aimed at configurational confirmation could not be performed. However, the key asymmetric transformations used here (Evans aldolization, Sharpless epoxidation and Brown allylboration) are well-known processes with safely predictable stereochemical outcomes. We are thus confident that the structure of synthetic intermediate A is that depicted in Scheme [3] . Furthermore, a comparison of 1H/13C NMR chemical shift and coupling constants values within the relevant fragment of FD-891 with those of compound A (see Table [1] below, atom numbering is shown in Figure [1] , coupling constant values are given in parenthesis) gives support to our structural assignment (the observed differences can be accounted for with the fact that the cyclic FD-891 is much more rigid than A from the conformational point of view; moreover, A bears two bulky TBSO groups instead of the free hydroxyls).
17Preliminary experiments have shown that oxidative cleavage of the terminal double bond in A can be performed via sequential osmylation and NaIO4 oxidation to yield an unstable aldehyde.
Table 1 Comparison of Spectroscopic Data of Compounds A and FD-891 |
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Atom | FD-891 | A | Atom | FD-891 | A | ||||||||||||||
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H-3 | 7.30, t (1.3) | 7.10, br s | C-1 | 168.9 | 169.1 | ||||||||||||||
H-5 | 5.53, d (10.3) | 5.55, d (10.0) | C-2 | 124.3 | 125.9 | ||||||||||||||
H-6 | 3.12, ddq (10.3, 4.1, 6.9) | 2.68, ddq (10.0, 5.0, 6.8) | C-3 | 144.0 | 138.1 | ||||||||||||||
H-7 | 4.17, dd (6.0, 4.1) | 3.61, dd (5.0, 4.0) | C-4 | 135.7 | 131.9 | ||||||||||||||
H-8 | 3.25, dd (6.0, 2.5) | 2.88, dd (4.0, 2.2) | C-5 | 141.6 | 134.5 | ||||||||||||||
H-9 | 3.15, dd (2.5, 0.8) | 2.96, dd (5.5, 2.2) | C-6 | 35.9 | 37.7 | ||||||||||||||
H-10 | 3.55, m | 3.48, dt (5.5, 6.5) | C-7 | 70.8 | 73.0 | ||||||||||||||
H-11 | 2.55, m, 2 H | 2.28, t, 2 H (6.5) | C-8 | 55.1 | 57.2 | ||||||||||||||
MeC2 | 2.10, d (1.2) | 2.00, d (1.3) | C-9 | 56.0 | 58.5 | ||||||||||||||
MeC4 | 2.03, d (1.2) | 1.85, d (1.0) | C-10 | 71.1 | 73.6 | ||||||||||||||
MeC6 | 1.15, d (6.9) | 1.06 d (6.8) | C-11 | 37.9 | 39.5 | ||||||||||||||
MeC2 | 13.6 | 14.0 | |||||||||||||||||
MeC4 | 15.5 | 15.7 | |||||||||||||||||
MeC6 | 16.5 | 16.6 | |||||||||||||||||
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