Synthesis of ent-Ketorfanol via a C-H Alkenylation/Torquoselective 6- Electrocyclization Cascade

J. A. Ellman and K. N. Hauk et al., Angew. Chem. Int. Ed. 2015, 54, 12044.

HO Daniel Meyer O

University of Bern N H 19.11.2015, Journal Club Content

> Autors

> Opioids

> Retrosynthetic Analysis

> Forward Synthesis

> Conclusion

2 Autors

> Jonathan A. Ellman (Yale University) — tert-butanesulfinamide chemistry — catalytic conversion of C-H to C-C bonds — structures that interact with biological systems

> Kendall N. Houk (University of California) — theoretical and computational methods and programs — experimental research to test theoretical predictions

3 Opioids

> Oxycodone and related semisynthetic opioids — Effective for the management of pain — Dependency, tolerance → higher dose → side effects

> Design of new opioid ligands with reduced drawbacks

> Ketorfanol — by multistep degradation of morphine and naltrexone

4 Retrosynthetic Analysis

Me Me H O Me O O Me HO speculative redox- reductive O O Friedel-Crafts cyclization N neutral process N amination O N N H R

Ar OH OH

6 electro- cyclization

Me Me Me O Me Me Me Sharpless asym. O OR imin O syn C-H bond O OR dihydroxylation formation O addition O O O alkyne H N N R R benzylation Ar Ar Ar

5 Forward Synthesis

. . .

a) (COCl) ,DMSO AD-mix- 2 OH Et3N MeSO NH OEt 2 2 (S) OEt OH (S) b) LDA, O 81% OH O O O (95% ee) P EtO OEt OEt

60% 2,2-dimethoxypropane, pTsOH 94%

Me Me Me Me PdCl2(CH3CN)2 O O XPhos, Cs CO 2 3 O OEt O OEt Cl O O Cl Ar

OTBS 73%

6 Forward Synthesis

.

Me Me Me Me H N O Me Me 2 O O a) DIBAL O H O OR b) Dess-Martin O H 3Å MS N O O 65%

Ar Ar Cl

TBSO

Me2N PEt2

[RhCl(coe)2]2

Me Me Me Me Me Me O O O O O O NaHB(OAc)3 N N N 69% TBSO over two steps TBSO TBSO

Cl Cl Cl

> 20:1 d.r. 7 Electrocyclization

> Woodward-Hoffmann rules: suprafacial for (4n + 2)  systems under thermal conditions

8 Calculations conformers and transition structures

9 Forward Synthesis

10 Forward synthesis

11 Conclusion

> Synthesis of ent-Ketorfanol: 9% yield over 11 steps

> Key steps — intramolecular C-H alkenylation/torquoselective 6 electrocyclization cascade

— Redox-neutral rearrangement of a vicinal diol → ketone then intramolecular Friedel-Crafts alkylation

12 Horner-Wadsworth-Emmons

.

13 Sharpless asymmetric dihydroxylation

.

14 Palladium-Catalyzed Heck alkynylation of

benzyl chlorides .

. 15 CH-functionalization/6 electrocyclization cascade .

via

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