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.