Renaud Group Exercise Set

Transcription

1 Renaud Group Exercise Set Prepared by ick Tappin 08/07/16 Spectroscopy 1. Deduce the structures for compounds A, B, and C C A IR: 1745 and 1720 cm C-MR: δ 208, 172, 51, 37, 32, and 27 ab 4 Br 2, a 2 C B IR: 1770 cm C-MR: δ 178, 89, 43, 29, and 18 C C IR: v. br cm C-MR: δ 175, and 31 Mechanism 2. Propose a structure for the missing intermediates and rationalize the outcomes by use of mechanism. int: draw the structures in 3-D. Cl, pyr.? hν 38% 39% Cl, pyr.? hν 85% (20 g scale)

2 Synthesis 3. Suggest how to effect the transformation from the methyl cyclopentenone to the epoxide. 4. Propose missing compound 8. Can you suggest a why one diastereoisomer is major? 5. Suggest how to effect the transformation from 8 to the allylic acetate, rationalizing E/Z control. reagents? steps? Diastereocontrol? TBS BF 3. Et 2 DCM 8 19:1 d.r. reagents? steps? Diastereocontrol? TBS Ac Mechanism 6. Propose a mechanism from the allylic acetate to the β-vinyl carboxylic acid. ame this reaction. Rationalize the stereochemical outcome. 7. Give the mechanism (and conditions) of the Swern xidation. Ac i) LDA, TBSCl; Δ, Ph Swern x. TBS ii) LiAl 4 TBS TBS 8. Suggest a mechanism for the SmI 2 -mediated coupling. Attempt to justify the diastereoselectivity with use of a 3-D samarium-chelate TS. What could another TS look like and why does the reaction not proceed through that one? TES SmI 2 TS TES 9. The synthesis of a tertiary alcohol is not always evident. utline the hydroxlation reaction with s 4 briefly justifying chemeoselectivity. 10. Explain, with mechanisms, the final sequence to furnish the natural product (±)-jiadifenolide. i) TMSTf, Et 3 ii) cat. s 4, M TES final sequence i) cat. s 4, M, pyr ii) cat. TPAP, M iii) F.pyr (±)-jiadifenolide.

3 Spectroscopy Purpose: to remind/ practise some spectroscopy, particularly the utility of IR. methyl 4-oxopentanoate C 2 Me C A IR: 1745 and 1720 cm C-MR: δ 208, 172, 51, 37, 32, and 27 ab 4 Br 2, a IR and 13 C indicates clearly two carbonyls, 2 one a ketone and the other an ester (fits elemental, i.e. 3 ). There are no upfield methylene shifts suggesting that all C2 units experience EW effect of carbonyls. Shift at 51 indicates ajacency to e-neg heteroatom. solutions 5-methyldihydrofuran-2(3)-one lost Me from ester condensation. retained all else. C IR indicates strained B lactone IR: 1770 cm C-MR: δ 178, 89, 43, 29, and 18 C C IR: v. br cm C-MR: δ 175, and Barton itrile Ester Reaction Purpose: To see another radical cascade reaction coming form the Barton lab. To practise drawing 6-membered rings in 3-D Prepared by ick Tappin 08/07/16 succinic acid IR indicates loss of ester and ketone carbonyls and presence of a carboxylic acid. 13C indicates a large gain in symmetry. ne shift is a carbonyl of an ester or acid, other an α-carbonyl C2 adapted from pp 246, Spectroscopic methods in organic chemistry, 6th Ed., D. Williams, I. Fleming, McGraw-ill, 2008 Cl, pyr. hν [1,5]--atom abstraction conformational restriction means that no other -atom abstraction is possible. ± + ± +

4 39% 38% ratio of 1:1 since the reaction is fast and reversible and there is no particular stabilization of one radical or another. Collect. Czech. Chem. Commun. 1988, 53, Cl, pyr.? hν 85% (20 g scale) This is the same idea as above: -atom abstraction from alkoxy radical to an axially orientated methyl group on a chloresterol-like skeleton. J. rg. Chem., 1997, 62 (4), pp DI: /jo Synthesis Paterson ACIE 2014, 53, Suggest how to effect the transformation from the methyl cyclopentenone to the epoxide. 4. Propose missing compound 8. Can you suggest a why one diastereoisomer is major? 5. Suggest how to effect the transformation from 8 to the allylic acetate, rationalizing E/Z control. reagents? steps? Diastereocontrol? TBS BF 3. Et 2 DCM 8 19:1 d.r. reagents? steps? Diastereocontrol? TBS Ac Purpose: To think about some simple synthesis from very common SM, particularly how to control the outcomes (diastereoselective and regioselective). 4. Regiocontrol: Luche ab4 diatereocontrol: allylic alchol directed m-cpba regiocontrol: no Payne rearrangement possible TBSCl, Im CeCl3 m-cpba Ar -bonded TS TBS

5 5. BF 3.Et 2 BF 3 TBS TBS stereo selective rearrangment: see JC 1997, 62, 4991 TBS The ydride migration comes from below the epoxide, thus setting the would be stereospecific, stereochem at the methyl group but have a d.r. 19:1 which means a second pathway is in operation (see below) In order to exaplin the formation of the minor stereoisomer, or indeed to provide an alternative (possibly more likely) mechanism (this is my theory and not supported in litereature)... BF 3 BF 3 TBS too-high energy pathway via most unstable 2 carbocation TBS + planar 3 carbocation looses stereochem info. TBS BF 3 deprotonate most acidic proton + + BF 3 TBS BF 3 TBS deprotonate least acidic protons TBS BF 3 major minor TBS TBS gives back correct diastereoisomer gives back incorrect diastereoisomer cannot know ratio between these two paths if the suggested pathway is in operation. TBS only TBS substiutent psuedo equatorial TBS in total 1:19 TBS TBS both substiutents psuedo equatorial

6 6. WE see any textbook for an explaination of E-selectivity C 2 Et LiAl 4 ; Ac 2, pyr Ac TBS (Me) 2 ()P a C 2 Et TBS bulky TBS opposite/ away from ester TBS TBS Ac LDA, TBSCl TBS TBS TBS TBS Ireland-Claisen Δ, Ph [3,3]-σtropic rearrangment C 2 TBS TBS TBS

7 7. Swern xidation. Purpose: To think more deeply about this common (and easy?) mechanism: to point out all details and how they make sense with the reaction conditions. To illustrate the pummerer rearrangment. A good textbook will provide a complete mechanism. Control slow addition: 3 eq of gas (including Cl) Control Temp: Pumerer rearrangment above 60 C

8 8. Purpose: to revist (again) the SmI2 reduction mechanism and see hpw it may be used on some exciting cyclization chemistry with an unsaturated lactone. To think about diastereomeric TSs. TES SmI 2 Sm III TES TES Sm II TES Sm III + TES alternatively... TES R TES Sm III TES Sm III Sm III non-chelate TS bulky R group forced equatorial apparently higher energy/ doesn't proceed

9 9. Purpose: to remind about hemiketals and their instability to give back ketones. To think about chemoselective dihydroxylation reactions. TMS TMS ii) cat. s 4, M i) TMSTf, Et approach convex face TMS relatively electron poor terminal alkyl olefin (c.f. silyl enol ether) not touched by e-defeicient s4 catalyst Purpose: to encourage thoughts about an astute and highly intelligent first disconnection that unviels two annulations by encompasing a ketalization under oxidative conditions. To see the use of an alkene as a latent diol/ reactive glyoxal. TES cat. s 4, M TES cat. TPAP, M TES F.Pyr TES further oxidation TES