Stereoselective Synthesis of the C1-C12 Fragment of the Cytotoxic Macrolide FD-891

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

References

• 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 
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• 14b Ramachandran PV. Aldrichimica Acta  2002,  35:  23 

15

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.

16

None 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).

17

Preliminary 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

Atom	FD-891	A	Atom	FD-891	A
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