Organic Letters
Letter
M.; Per
293.
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ez, M.; Molins, E.; Bosch, J. Tetrahedron: Asymmetry 2003, 14,
AUTHOR INFORMATION
Corresponding Author
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(14) The energy difference between the two diastereomers of 13 by
DFT calculation (B3LYP/lacvp**) is 0.7 kcal/mol favoring the
desired trans isomer 13a.
(15) Lazar, L.; Fulop, F. Eur. J. Org. Chem. 2003, 3025 and the
references cited therein.
Notes
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The authors declare no competing financial interest.
(16) The cis isomer 16b is more stable by 1.0 kcal/mol by DFT
calculation (B3LYP/lacvp**).
ACKNOWLEDGMENTS
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(17) C-5 esters have shown promising potency in enzyme and
antiviral assays, demonstrating an ability to chelate metals: Kawasuji,
T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama,
R.; Fuji, M.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara,
T. J. Med. Chem. 2012, 55, 8735.
The authors thank Doug Mans and Steve Goodman of
GlaxoSmithKline for helpful suggestions as well as Connie Ye
and Sarah Chen of GlaxoSmithKline for analytical support.
REFERENCES
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(1) For reviews on HIV integrase inhibitors, see: (a) Pommier, Y.;
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2006, WO 2006116764 A1. (b) Johns, B. A.; Kawasuji, T.;
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Jeffrey, J.; Foster, S. A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato,
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(4) Although analogous reactions involving 4-alkoxy or 4-
dialkylamino-3-butene-2-ones and acid chlorides are known, there
are only limited literature examples for reactions between acid
chlorides and the doubly activated substrates: McCombie, S. W.; Metz,
W. A.; Nazareno, D.; Shankar, B. B.; Tagat, J. J. Org. Chem. 1991, 56,
4963.
(5) The product decomposed when the reaction mixture was heated.
Sensitivity toward chromatography has also been noted with
pyranone-3-carboxylates: See reference 4.
(6) Sumino, Y.; Okamoto, K.; Masui, M.; Yamada, D.; Ikarashi, F.
PCT Int. Appl. 2012, WO 2012018065.
(7) Kiyama, R.; Fuji, M.; Hara, M.; Fujimoto, M.; Kawabata, T.;
Nakamura, M.; Fujishita, T. Chem. Pharm. Bull. 1995, 43, 450.
(8) Although LiOH, NaOH, and KOH all led to somewhat selective
cleavage of the C-5 ester, the selectivity was higher when LiOH was
used (∼10:1 vs 3:1 in the case of NaOH or KOH).
(9) (a) Reference 1a. (b) Espeseth, A. S.; Felock, P.; Wolfe, A.;
Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J. Y.;
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(10) On kilogram scale the demethylation is better accomplished
with LiBr, which is lower in cost and gives an easily stirrable slurry.
However, the reaction is much slower (overnight in reflux THF) than
that with MgBr2, presumably due to the weaker chelation of Li+ to 13.
(11) Involvement of other divalent metals as the metal cofactor in
integrase inhibition has also been speculated: (a) Chiu, T. K.; Davies,
D. R. Curr. Top. Med. Chem. 2004, 4, 965. (b) Bacchi, A.; Carcelli, M.;
Compari, C.; Fisicaro, E.; Pala, N.; Rispoli, G.; Rogolino, D.; Sanchez,
T. W.; Sechi, M.; Sinisi, V.; Neamati, N. J. Med. Chem. 2011, 54, 8407.
(12) The ring opening and dr erosion only occurred with strong
acids (HCl or CH3SO3H). No dr erosion was observed with TFA or
weaker acids.
(13) The equilibrium dr of 6:1 can be compared to a similar system,
where a trans:cis = 86:14 mixture was obtained from acid-catalyzed
equilibration: (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto, M.; Perez,
́ ́
M.; Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org.
Chem. 2000, 65, 3074. (b) Amat, M.; Llor, N.; Escolano, C.; Huguet,
D
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