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. 2013;45(6):719-728.
doi: 10.1055/s-0032-1316786.

Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rh-Catalyzed [2+2+2] Cycloaddition

Stéphane Perreault  1 , Tomislav Rovis  1
Affiliations

Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rh-Catalyzed [2+2+2] Cycloaddition

Stéphane Perreault et al. Synthesis (Stuttg). 2013.

Abstract

An efficient approach to the tricyclic framework of FR901483 is described. The sequence features a [3, 3]-sigmatropic rearrangement of a cyanate into an isocyanate, followed by its subsequent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a terminal alkyne for the synthesis of the indolizidine core. The aza-tricyclic core is completed using an intramolecular benzoin reaction to close the last ring of the natural product. Through a model study of the key cycloaddition, we evaluated the impact of different substituents on the tether of the alkenyl isocyanate.

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Figures

Figure 1
Figure 1
Structure and conformation of (−)-FR901483.
Scheme 1
Scheme 1
Scope of the Rh-catalyzed enantioselective [2+2+2] cycloadditions of alkenyl isocyanates and exogenous alkynes.
Scheme 2
Scheme 2
General approach to FR901483.
Scheme 3
Scheme 3
Retrosynthesis of dienyl isocyanates 15a–b.
Scheme 4
Scheme 4
a) i. n-BuLi, TMEDA, Et2O, −78 °C; ii. 18a or 18b, −78 to 23 °C. b) MsCl, Et3N, CH2Cl2, 0 °C. c) LiBr, THF, 0 to 23 °C. d) i. ethyl benzoylacetate, K2CO3, cat. NaI, neat, 50 °C; ii. K2CO3, (CH2O)n, THF, 65 °C. e) MeLi, CeCl3, Et2O, 0 °C. f) i. trichloroacetyl isocyanate, CH2Cl2, 0 °C; ii. K2CO3, MeOH, H2O, −78 to 23 °C. g) TFAA, Me2NEt, CH2Cl2, 0 °C.
Scheme 5
Scheme 5
a) 2 mol% [Rh(C2H4)2Cl]2, 4 mol% L3, PhMe (0.08 M), 110 °C, 36–48 hours.
Scheme 6
Scheme 6
a) NCS, CH2Cl2, −78 °C. b) Red-Al, THF, −78 °C. c) NaBH4, MeOH, CH2Cl2, −78 to 23 °C (77%, 3 steps).
Scheme 7
Scheme 7
Rationale for the stereochemistry of 32.
Scheme 8
Scheme 8
a) NCS, CH2Cl2, −78 °C. b) Red-Al, THF, −78 °C (85%, 2 steps). c) 1% HCl in MeOH, 0 °C (90%). d) i. (COCl)2, DMSO, CH2Cl2, −78 °C; ii. Et3N, −78 to 23 °C (87%). e) i. 39 (50 mol%), KHMDS (45 mol%), PhMe; ii. high vacuum; iii. 36, PhMe (0.05 M), 70 °C (41%).
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References

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