Team Aggarwal
Steven Bennett, Adam Elmehriki, Durga Hari, Rory Mykura,
Adam Noble, Jack Rogers, Jasper Tyler, and Jingjing Wu
1
Splitting The Difference:
Convergence or Bust
2
Retrosynthesis
3
Retrosynthesis
J. Mulzer et al., Eur. J. Org. Chem., 2012, 2041–2053.; J.-M. Beau et al., Chem. Eur. J., 2014, 20, 12133–12143.
B. G. Davis et al., Nat. Chem., 2009, 1, 377–383.4
Fragment A
• Ring-opening of (R)-glycidol with propargylic Grignard reagents is known
5D. Enders et al., Org. Synth., 2002, 78, 177–188.
J. C. Carretero et al., Chem. Eur. J., 2001, 7, 2435–2448.
• HWE is known on a-oxy aldehydes • The Pauson-Khand has been performed
on the racemic substrate
Fragment A
6J. C. Carretero et al., Chem. Eur. J., 2001, 7, 2435–2448.
H. Waldmann et al., Angew. Chem., Int. Ed., 2013, 52, 9576–9581.
• [3+2] cycloaddition
Fragment A
7M. J. Krische et al., Org. Lett., 2009, 11, 1849–1851.
• The allene is expected to approach from the convex face of the bicycle (rings A and B)
Fragment A
8A. G. Myers et al., J. Am. Chem. Soc., 2004, 126, 5436–5445.
• Mild Wolff-Kishner conditions have been used for similarly hindered substrates
Fragment A
• MeLi addition to pentanones in the presence of unsaturated esters has been reported
9
Re-Face Attack
Favoured
M. Vandewalle et al., Bull. Soc. Chim. Belg., 1983, 92, 1019–1027.
DFT: Molecular geometry optimised at the B3LYP/6-311G** level of theory
Fragment A
10
• This substrate has been utilised in a similar lithiation-borylation protocol
R. A. Fernandes et al., RSC Adv., 2015, 5, 42131–42134.
V. K. Aggarwal et al., J. Am. Chem. Soc., 2013, 135, 16054–16057.
Fragment B
11
• Cross metathesis employing allylic boronic esters has been reported
• Allylboration of α-ketoesters using boronic esters has been developed
N. Miyaura et al., Synlett, 2002, 1, 128–130.
V. K. Aggarwal et al., Angew. Chem., Int. Ed., 2014, 53, 10992–10996.
Fragment B
12
• Allylic oxidation
M. P. Doyle et al., J. Am. Chem. Soc., 2004, 126, 13622–13623.
T. Ling et al., Eur. J. Med. Chem., 2016, 110, 126–132.
Fragment B
13
• Cyclopropanation
A. Mendoza et al., Angew. Chem., Int. Ed., 2019, 58, 5930–5935.
Fragment B
14
• Cyclopropanation
Favoured Approach
DFT: Molecular geometry optimised at the B3LYP/6-311G** level of theory
Fragment B
15
Fragment Coupling
• Giese-type reaction
P. S. Baran et al., Angew. Chem., Int. Ed., 2017, 56, 260–265.
16
• Radical addition expected to occur on the convex face of the B/C bicycle
DFT: Molecular geometries optimised at the B3LYP/6-311G** level of theory
Favoured Approach
Fragment Coupling
17
End Game
• The E-vinyl triflate was the only identified product
P. Deslongchamps et al., Org. Lett. 2013, 15, 6270–6273.
18
• C-H activation has been used for the preparation of similarly sterically crowded
cyclopropanes
N. Cramer et al., Angew. Chem., Int. Ed., 2015, 54, 11826–11829.
End Game
19
• Selective C-H activation results from the formation of a six-membered palladacycle
O. Baudoin et al., Chem. Eur. J., 2014, 20, 11084–11099.
End Game
20
• Hydrogenolysis of tertiary benzyl ethers is possible under mild conditions
K. Toshima et al., J. Am. Chem. Soc., 2013, 135, 15909–15912.
End Game
21
• Hydrogenation is expected to occur on the convex face of the C/D bicycle
DFT: Molecular geometry optimised at the B3LYP/6-311G** level of theory
Favoured Approach
End Game
22
Summary
• Highly convergent strategy
• Longest linear sequence of 17 steps
• 8.3% expected overall yield
23
Thank you for your
kind attention
24
• Mechanistic hypothesis for the observed endo-selectivity
Fragment A
D. Enders et al., Org. Synth., 2002, 78, 177–188.
J. C. Carretero et al., Chem. Eur. J., 2001, 7, 2435–2448.
25
• These Wolff-Kishner conditions are known on sensitive substrates
Fragment A
A. G. Myers et al., J. Am. Chem. Soc. 2004, 126, 5436–5445.
26
Fragment A
T. Hudlicky et al., J. Am. Chem. Soc., 1989, 111, 6691–6707.
27
• RCM employing α-amido allylic
boronic esters has been reported
• Allylboration proceeds through a closed
transition state
Fragment B
B. Carboni et al., Tetrahedron Lett., 2004, 45, 8749–8751.
V. K. Aggarwal et al., Angew. Chem., Int. Ed., 2014, 53, 10992–10996.
28
• Highly enantiospecific and diastereoselective allylboration of α-keto esters is established
• Stereoselective allylboration methodology has also been applied to cyclic systems
Fragment B
V. K. Aggarwal et. al., Angew. Chem., Int. Ed. 2014, 53, 10992–10996.
N. Miyaura et al., Synlett, 2002, 1, 128–130.
29
• A CBS reduction may be empoyed if the
DIBAL-H reduction is poorly selective
Fragment B
T. Ling et al., E. J. Med. Chem. 2016, 110, 126-132.; E. A. Theodorakis et al., Chem. Eur. J. 2013, 19, 6398–6408.
H. Waldmann et al., J. Org. Chem. 2011, 76, 6694-6702.; J. R. Hwu et al., J. Org. Chem., 1992, 57, 922–928.
30
• Cyclopropyl radicals are conformationally unstable
Fragment Coupling
G. Boche et.al., Tetrahedron Lett., 1978, 26, 2327–2330.
31
Fragment Coupling
• Cyclopropyl radicals are conformationally unstable
• Products can be formed with a high degree of stereocontrol
P. S. Baran et al., Angew. Chem., Int. Ed., 2017, 56, 260–265.
32
• The phthalimide ester may be converted to the boronic ester to provide alternative
methods of fragment unification
Fragment Coupling
V. K. Aggarwal et al., Science, 2017 , 357, 283–386.
33
• Cyclopropyl boronic acids and esters are known to participate in conjugate additions
Fragment Coupling
T. Nishimura et al., Chem. Commun., 2015, 51, 8528–8531.
34
• The cyclopropyl bromide may be accessed through decarboxylative bromination or
Simmons–Smith cyclopropanation with bromoform
• The bromide can be used to access a cyclopropyl organocuprate species for use in
the conjugate addition
Fragment Coupling
J. P. Marino et al., J. Org. Chem., 1976, 22, 3629–3632.
35
• Ester to aldehyde reduction may performed in two steps in the event of facile over reduction
End Game
36
• Alkylidene carbenes are readily available through base-induced elimination of vinyl triflates
or vinyl halides
End Game
S. Ohira et al., Tetrahedron Lett., 1995, 36, 8843–8844.
R. S. Grainger et al., Org. Lett., 2004, 6, 2961–2964.
37
• Similarly distal alcohols are able to stereoselectivity reduced hindered olefins
• Tertiary alcohols can engage Crabtree's catalyst for directed hydrogenations
End Game
B. M. Stoltz et al., Agnew. Chem Int. Ed., 2012, 51, 9674–9678
W. Francke et al., Beilstein J. Org. Chem., 2012, 8, 1246–1255.
38
End Game
M. T. Wuesthoff, J. Org. Chem., 1968, 33, 1311–1312. S.; Nishida, J. Chem. Soc., Chem. Commun., 1973, 525 – 526.
A. J. von Wangelin, Green Chem., 2015, 17, 1408–1413.; H. Hiemstra, J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713.