only the two exo-transition states TS-A (leading to 4) and
TS-B (leading to 4′) can be adopted. DFT calculations
(B3LYP/6-31G(d)) predicted a better conjugation of the diene
unit and a lower energy difference between HOMO and
LUMO in the reactants of TS-A, making it 2.5 kcal/mol
lower in energy than TS-B. Hence, 4 was expected to be
formed with high selectivity. However, it was an open
question how such a highly unsaturated macrocycle as 5 can
be constructed and if the (Z)-double bonds would survive
the Diels-Alder conditions, to yield the desired cis-fused
hexahydronaphthalene ring.8 Additionally, the behavior of
Z,E,Z-trienol derivatives as diene substrates in Diels-Alder
reactions is unknown and, as already mentioned, exo-
transition states are uncommon in TADA reactions. On this
background, our project promised novel insight into such
transformations,9 all the more so as the Roush group reported
a related TADA example in which a cis-octahydronaphtha-
7a
lene is formed via an endo transition state.
The synthesis of macrolide 5 was started from known
butenolide 6,10 which was protected as the TBDPS-ether
(Scheme 1). Vinyl-1,4-addition was found to proceed
Scheme 1. Synthesis of E,Z-Diene 10
Figure 2. Retrosynthesis and transition state calculations: for TS-
A, C11-C6 ) 243.7 pm and C10-C9 ) 214.5 pm; for TS-B,
C11-C6 ) 251.5 pm and C10-C9 ) 210.8 pm.
Alder cycloaddition (Figure 2). Early studies had shown that
an open-chain Z,E,Z-trienol was unstable under various
IMDA conditions. Therefore, a TADA version under sub-
strate control showed the highest promise to perform this
reaction with optimal stereocontrol. This led us to intermedi-
ate 4 as this compound could be constructed by a TADA
reaction from macrolide 5. To obtain the correct relative
configurations at C6, C9, C10, and C11 the macrolide must
have a 6,7-E-8,9-Z-10,11-E-configuration. The absolute
configuration can be induced by the chiral tether, for which
we chose a lactol ring. On the basis of molecular model
inspections we found that a cis-fused lactol at C3/C12 is
too flexible for a stereocontrolled cyclization. In the trans-
fused system, however, endo-geometries are strained, where
smoothly by using catalytic amounts of CuCl/LiCl at -78
°C. As lactone 7 proved incompatible with the subsequent
reaction conditions, it was reduced immediately with
DIBAL-H and converted to the methyl lactol 8 with Ag2O
(7) (a) Roush, W. R.; Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am.
Chem. Soc. 1996, 118, 7502. (b) Coe, J. W.; Roush, W. R. J. Org. Chem.
1989, 54, 915. (c) Roush, W. R.; Coe J. W. Tetrahedron Lett. 1987, 28,
931. (d) Go¨ssinger, E.; Schwartz, A.; Sereinig, N. Tetrahedron 2001, 57,
3045 and references therein.
(8) For a review on cis-decalins see: Singh, V.; Iyer, S. R.; Pal, S.
Tetrahedron 2005, 61, 9197 and references therein.
(9) For Diels-Alder reactions of decatrienones, see: (a) Dineen, T. A.;
Roush, W. R. Org. Lett. 2005, 7, 1355. (b) Kim, K.; Maharoof, U. S. M.;
Raushel, J.; Sulikowski, G. A. Org. Lett. 2003, 5, 2777. (c) Miyaoka, H.;
Shida, H.; Yamada, N.; Mitome, H.; Yamada, Y. Tetrahedron Lett. 2002,
43, 2227. (d) Taber, D. F.; Nakajima, K.; Xu, M.; Rheingold, A. L. J. Org.
Chem. 2002, 67, 4501. (e) Melekhov, A.; Forgione, P.; Legoupy, S.; Fallis,
A. G. Org. Lett. 2000, 2, 2793. (f) Roush, W. R.; Champoux, J. A.; Peterson,
B. C. Tetrahedron Lett. 1996, 37, 8989.
(5) (a) For a review see: Kallmerten, J. Studies in Natural Products
Chemistry; Elsevier: Amsterdam, The Netherlands, 1995; Vol. 17, pp 283-
310 and cited literature. (b) Nargenicin: Celmer, W. D.; Chmurny, C. N.;
Moppett, C. E.; Ware, R. S.; Watts, P. C.; Whipple, E. B. J. Am. Chem.
Soc. 1980, 102, 4203. (c) See also: Tone, J.; Shibakawa, R.; Maeda, H.;
Yamauchi, Y.; Niki, K.; Saito, M.; Tsukuda, K.; Whipple, E. B.; Watts, P.
C.; Moppett, C. E.; Jefferson, M. T.; Huang, L. H.; Cullen, W. P.; Celmer,
W. D. 20th Interscience Conference on Antimicrobial Agents and Chemo-
therapeutics; New Orleans, LA, 1980, pp 22-24. (d) Nodusmycin: Whaley,
H. A.; Chidester, C. G.; Mizak, S. A.; Wnuk, R. J. Tetrahedron Lett. 1980,
21, 3659. (e) See further: Whaley, H. A.; Coates, J. H. 21st Interscience
Conference on Antimicrobial Agents and Chemotherapeutics, Chicago, IL,
1981, Abstract 187.
(6) Total synthesis of 2c: (a) Plata, D. J.; Kallmerten, J. J. Am. Chem.
Soc. 1988, 110, 4041. (b) Kallmerten, J.; Plata, D. J. Heterocycles 1987,
25, 145. (c) Rossano, L. T.; Plata, D. J.; Kallmerten, J. J. Org. Chem. 1988,
53, 5189.
(10) (a) Andrews, G. C.; Crawford, T. C.; Bacon, B. E. J. Org. Chem.
1981, 46, 2976. (b) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara,
K. Synthesis 1986, 403.
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