Attention was then directed to the preparation of ketone
6 (Schemes 4 and 5) which starts with Roche ester (12) and
aldol reaction with 14 and freshly prepared Sn(OTf)2 to yield
the desired product as a single diastereomer.7 The reaction
time varied on the reaction scale, and we realized that
prolonged reaction times favor the undesired aldol condensa-
tion product. Finally, the stereoselective reduction provides
the anti-diol, and simultaneous TES protection of both
hydroxyl groups generates 16.
Scheme 4. Synthesis of Ketone 6
For the construction of the terminal diene moiety, the
primary hydroxy group was liberated and oxidized (Scheme
5) followed by a two-step Peterson olefination8 that installs
the C1-C4 diene 18 in high yields and selectivities (71%,
two steps, only cis isomer). Gratifyingly, the two diastere-
omers resulting from the Sharpless asymmetric dihydroxy-
lation can be separated after reductive cleavage of the
pivaloyl group, and an oxidation-methylation sequence
furnishes ketone 6. With aldehyde 5 and ketone 6 in hand,
we investigated the pivotal aldol coupling.
Careful examination of the directing effects in this aldol
transformation led to the conclusion that the Felkin opposing
effect of the C25 TES-ether would provide the desired
selectivity.2,9
On the other hand, literature precedence using R-oxygen-
ated methyl ketones did not provide a conclusive picture of
the directing effects of the ketone. This prompted us to
investigate this uncommon aldol connection and various
reaction conditions. In particular, the observations by Pater-
son et al. that acetonides would provide the undesired
stereoisomers (LDA 3.5:1; cHex2BCl/NEt3 5:1) indicate that
this particular setup would be one of the key transformations
in the synthesis. Paterson and his group solved this problem
by using a chiral boron enolate that furnished the desired
is transformed to the corresponding alcohol via PMB
protection and DIBAl-H reduction. This alcohol is subse-
quently used in an Appel reaction to generate the bromide
which in turn is displaced with vinylmagnesium cuprate to
yield alkene 13. This double bond serves in a Sharpless
asymmetric dihydroxylation6 with AD-mix R to provide the
respective diol in a diastereomeric ratio of 4:1 favoring the
desired stereoisomer. For selective functional group trans-
formations, the primary alcohol is protected as a pivaloyl
ester and the secondary as a TES ether. At this stage, we
decided to use the Paterson aldol reaction of ketone 145d
and the corrseponding aldehyde to yield 15 and a stereose-
lective 1,3-anti reduction for installing the C14-C18
anti-syn-anti stereopentad.7 Thus, after PMB deprotection,
the alcohol is oxidized to the aldeyhde and subjected to an
(6) (a) Smith, A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547. (b)
Sharpless, K. B.; VanNienwenhze, M. S.; Kolb, H. C. Chem. ReV. 1994,
94, 2483.
(7) (a) Paquette, L. A.; Konetzki, I.; Duan, M. Tetrahedron Lett. 1999,
40, 7441. (b) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.
(c) Vicario, J. L.; Job, A.; Wolberg, M.; Mu¨ller, M.; Enders, D. Org. Lett.
2002, 4, 1023. (d) Paterson, I.; Temal-Laib, T. Org. Lett. 2002, 4, 2473.
(e) Vicario, J. L.; Job, A.; Wolberg, M.; Mu¨ller, M.; Enders, D. Chem.-Eur.
J. 2002, 8, 4272. (f) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.;
Lister, A. A. J. Am. Chem. Soc. 1994, 116, 11287. (g) Paquette, L. A.;
Konetzki, I.; Duan, M.; Kempmann, C. J. Am. Chem. Soc. 2002, 124, 4257.
(8) (a) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; O’Brien,
M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150. (b) Marshall,
J. A.; Lu, Z-H.; Johns, B. A. J. Org. Chem. 1998, 63, 817. (c) Hodgson,
D. M.; Wells, C. Tetrahedron Lett. 1992, 33, 4761. (d) Paterson, I.; Delgado,
O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org. Lett. 2003,
5, 35.
(9) Selected examples of R-oxygenated methyl ketones in aldol reactions:
(a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc.
1996, 118, 4322. (b) Paquette, L. A.; Konetzki, I.; Duan, M.; Kempmann,
C. J. Am. Chem. Soc. 2002, 124, 4257. (c) Paquette, L. A.; Duan, M. Angew.
Chem., Int. Ed. 2001, 40, 3632; Angew. Chem. 2001, 113, 374. (d) Gustin,
D. J.; VanNieuwenhze, M. J.; Roush, W. R. Tetrahedron Lett. 1995, 36,
3443. (e) Evans, D. A.; Gage, J. R. Tetrahedron Lett. 1990, 31, 6129. (f)
Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (g) Jiang, Y.; Hong,
J.; Burke, S. D. Org. Lett. 2004, 6, 1445. (h) Paterson, I.; Goodman, J. M.
Tetrahedron Lett. 1989, 30, 997. (i) Paterson, I.; Florence, G. J.; Gerlach,
K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. (j) Evans,
D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem. Soc. 2001,
123, 10840. (k) Ishikawa, T.; Aikawa, T.; Ohata, E.; Iseki, T.; Maeda, S.;
Matsuo, T.; Fujino, T.; Saito, S. J. Org. Chem. 2007, 72, 435. (l) Fuerstner,
A.; Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006, 128, 9194. (m) White,
J. D.; Bolton, G. L.; Dantanarayana, A. P.; Fox, C. M. J.; Hiner, R. N.;
Jackson, R. W.; Sakuma, K.; Warrier, U. S. J. Am. Chem. Soc. 1995, 117,
1908. (n) Fernandez-Megia, E.; Gourlaouen, N.; Ley, S. V.; Rowlands, G. J.
Scheme 5. Synthesis of Ketone 6
Synlett 1998, 991
.
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