TESOH
n. MsCl then OsO4
(74%)
513
2
Me
H
Me
H
f. NaHMDS, TBSCl (94%)
then DMDO
Two-Phase Synthesis of Taxol Yuzuru Kanda , Hugh Nakamura, Shigenobu Umemiya, Ravi Kumar Puthukanoori, Venkata Ramana Murthy Appala, Gopi Krishna
Gaddamanugu, Bheema Rao Paraselli, and Phil S. Baran* Department of Chemistry, Scripps Research, Chemveda Life Sciences. This work
J. Am. Chem. Soc. 2020, 142, 10526. JOC Perspective
10.1021/acs.joc.0c01287
–C2 Stereochemistry and KIE Effect
C2 C2 ketone / Product α-H major : ND β-H major : trace β-D 10 : 20%
–C10 Stereochemistry Effect–C4 Substituent Effect
• sterically too hindered for directing group chemistry • chemo-, regio-, stereoselective triple oxidation • substrate directed (C2, C4, C5, C10) • KIE assisted • solvent and concentration driven
–Solvent and Concentration Effect
25 / 10 x9 / 37 29 / 12 34 / 10 49 / 11
in acetone (0.09 M) C2 H instead of D in DCM (0.21 M) in CHCl3 (0.19 M) in CHCl3 (0.30 M)
result [%] (product/C2 ketone)
–C5 Substituent Effect
Me
H
Me Me
Me Me
H OH
OTES AcO
8. Conclusion • efficient oxidase phase for lowly oxidized taxanes • represented a blueprint of a medicinal chemistry exploration • unpredictable chemoselectivity and reactivity for highly
oxygenated taxanes (medium ring, similar FGs, proximity of FGs) • complex oxidation choreography
9. Acknowledgements and References Baran lab, Phil S. Baran, NIH, BMS, LEO pharma, Funai scholarship, Honjo scholarship, Otsu conference
Shigenobu Umemiya Hugh Nakamura
Could a Complex Terpene Represent a Viable Starting Point for a Medicinal Chemistry Campaign without Semisynthesis?
1. Hypothesis
Me
H
[3 syntheses] [6 syntheses] [1 synthesis]
Me ORO
oxidations: C5, 13/10, 9, 7, 2, 1/4/20
Oxidation Level
α-oxidation, C2 C2, C9
Me
H
13
2
α-OH, α-OPG, =O olefin, β-OH α-OH, α-OPG 2H, α-OPG, =O 2H, β-OPG, =O 2H, α-OPG, =O olefin, 3H
C# oxidation pattern 2 4 5 9
10 13 20 PG = TES, TBS, MOM, Ac
Examined Variables TFDO, DMDO, time,
temperature, co-solvent substrates (left)
2
20
2. Step a • early stage C13 oxidation • essential oxidation for bioactivity • maximum analog diversity • Cr(V)-mediated • synergistic effect (TMSOH/HFIP)
O O CrV O
Kharasch type (Cr, Se, Cu, Mn,
Pd, Fe, Rh, Bi, Ru)
6. Step i –Stereoselective C2 Reduction Examined Substrates and Conditions
– The Key C4 Motif
C# oxidation pattern 1
(4/20)
10
Rdiol = carbonate, CMe2, Si(i-Pr)2 R10 = H, TES, R20 = H, Boc, TBS, MOM
• stereoselective C2 reduction (staggered conformation) • could be elaborated to oxetane
Me
H
solvent C2 α:β PhMe
Me MeMe
19
16
20
HX
4
3. Step b • regioselective (C5 over C1, 3, 10, 14, 18) • oxidation placeholder • Δ5,6-olefin precursor (oxidation relay to C7)
Previous substrates necessitated C5 PG
4. Early Stage Oxidations • C13, 5, 10 choreography gave the best yield • allylic oxidations analogous to previous syntheses:
en route to
7. Step j, k
• unreactive Δ9,10-olefin • undesired C10 and C7 stereochemistry • no suitable PG for C7
(DIBAL, LiAlD4, DMDO, Na)
– Unsuccessful C7 Oxidation Attempts
Step j • highly FG tolerant • chemo-, stereoselective • orthogonally reactive and
volatile reagents
– Oxidation Relay Step k • highly FG tolerant • novel silane additive
• C9 directed C7 oxidation (poor reactivity of C9 FGs, steric hindrance at C7) • Direct C7 allylic oxidation (steric hindrance atC7)
BF3 quencher BSA
ca. 35 67
Yield [%]