CHAPTER The calculations are shown for each molecule using values from Table 1.5 in Chapter 1. K eq = B A = B 1-B

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1 Chapter CPTER. The calculations are shown for each molecule using values from Table.5 in Chapter. 2 C N 2 C 2 N 2 C C-C N 2 C C 2 C C C (a) = CR2 + C = = 2. kcal mol - If + = = NR + G C + G CR2 = = 2. kcal mol - then, = - = = = 0.2 kcal mol - t 50 C, 2.0RT = 2.0(.987)(42)* =.96 kcal mol - K eq = = - K eq (-) = [* T is in Kelvin = C + 27] and = K eq +K eq, via therefore G = 0.2 =.96 log K eq.27(-) = log K eq = = = K eq = = = = (2.27) = = 0.56 Therefore, 56% of and = 44% of. Since has two axial groups and has only one, an initial glance suggests that will be lower in energy and be the greatest contributor to the chair population. Conformation has one axial group (C 2 ) on the top and one axial group (C C) on the bottom so CR2 and C are used from Table.5. In there is only one axial group (N 2 ) so R is used. The two equatorial groups in (C 2 and C C) are on adjacent carbons, so there are two G terms, G C and G CR2. C C C Copyright 20 Elsevier Inc. ll rights reserved.

2 2 rganic Synthesis Solutions Manual (b) = 4 ( C2 R + ) = =.65 kcal mol - If + = = 4 ( R + G C2 R + G ) = 4 ( ) = 2.0 kcal mol - then, = - = = = 0.8 kcal mol - at 25 C, G = 0.8 = -.64 log K eq K eq = = - K eq (-) = log K eq = = and = K eq +K eq K eq = = Therefore, 4.5% of and = 65.5% of = = 0.45 lthough has two axial groups, it is actually lower in energy because the axial chlorine has a lower interaction that the combined G value interactions in. It accounts for only 5% of the population of chair conformers. Conformation has two adjacent and diequatorial groups, so G C2 R and G are used from Table.5. Since has one axial methoxy group, R is used. = R + + G C2 R + G R = =.2 kcal mol - If + = = U R + U R + C2 R + G + G R = = 4. kcal mol - then, = - = = 4..2 = 0.9 kcal mol - at 25 C, G = 0.9 =.64 log K eq K eq = = - K eq (-) = log K eq = = 0.66 and = K eq +K eq K eq = = 0.22 Therefore, 8% of and 00-8 = 82% of = = 0.8 The three axial groups in, along with the two G-interactions make it much more sterically demanding than the two axial groups and the two G-interactions in. Therefore, accounts for the greater percentage of chair conformations. Copyright 20 Elsevier Inc. ll rights reserved.

3 Chapter C C C (e) = no interactions = 0 kcal mol - If + = = aryl + CR = = 9.0 kcal mol - then, = - = = = 9.0 kcal mol - at 25 C, G = 9.0 =.64 log K eq K eq = = - K eq (-) = log K eq = = K eq 8 and = +K eq K eq = = x0-7 Therefore, % of and = % of. x = =x0-7 Since has two large equatorial groups and have two large axial group, the equilibrium is pushed in the direction of, in essentially 00%. 2. The absolute configuration for each chiral center in the following molecules is shown beside the appropriate chiral center. (b) (a) (+)-absinthin see J. m. Chem. Soc., 2005, 27, 8 biepiasterolide see J. rg. Chem., 2004, 69, 900 r c (+)-laurencin see rg. Lett., 2005, 7, 75. Copyright 20 Elsevier Inc. ll rights reserved.

4 4 rganic Synthesis Solutions Manual (a) amphidinolide X see J. m. Chem. Soc., 2004, 26, 5970 (b) N 2 C N (+)-lapidilectine see J. rg. Chem., 2004, 69, 909 mycolactone C see rg. Lett. 2004, 6, fter donor and acceptor sites for disconnect fragments 22 and 2, fragment represents an umpolung reagent (acyl anion equivalent - see Chap. 8, Sec. 8.6.), F. Fragment is simply the alkyl halide, 22 2 a d ND C d a D r S S CuLi 2 E F G E. The other d/a combination is C (which is the equivalent of organocuprate, G) and D (which is the equivalent of acid chloride ). oth are viable processes but we not will choose the reaction of E and F since alkylation of dithiane reagents can be sluggish (see Chap. 8, Sec ii) and because an extra step is required to convert the dithiane back to the carbonyl (see Chap. 7, Sec. 7...ii). cid chloride contains I J the four carbons of the starting material, and it is obviously derived from isobutyric acid (I), available from ldrich ( ), $25.50/L. ssume it must be made from 2-methylpropene, however. ccording to Figure., one route to an acid is by oxidation of an alcohol (see Chap., Sec..2.). The alcohol (J) can be prepared from the alkene by hydroboration (see Chap. 5, Sec. 5.4.). nce acid chloride is available, it is reacted with organocuprate G, derived from bromide E. In this analysis, E is not formally prepared from 2-methylpropene (although a synthesis could be designed if desired), and G is considered to be a reagent in this synthesis (an 'off the Copyright 20 Elsevier Inc. ll rights reserved.

5 Chapter 5 shelf' compound that is reacted with the molecules derived from the retrosynthesis, just like 2 6 or Cr in the sequence shown). If the reagents provided in this synthesis are not familiar, careful reading of the remainder of this book and the literature will explain these choices. 5. There is more than one "correct" answer. ne possible solution is shown for each transformation. The letters (a), (f), etc., beside each reagent refer to the lettered transformations from Figure. in Chapter. (a) Na/ 2 2 (w) (b). NaCN, TF RC 2. hydrolysis (v) C N dilute Na Cr, + r (a) C The first reaction is a poor one since elimination will be a major process. Limiting the choices to those in Figure. is a problem since there are other ways to do this. (d) (e) Pr (d) S r K, Et (f) Mgr (x) (b) see Table. 2. S 2 ; C 2 C 2 (x) & no reactions for conversion to acid derivatives. + (f) CN CN 2 No reagents are provided in Figure S 2 they are part of the conversion to acid derivatives. N 6. There are potentially many examples for each part (but not always; see the last sentence for this answer). This is a literature searching question, and there are no correct or incorrect answers. The appropriate sections and pages from Vol. of the Compendium are indicated for each category. (a) cids from Nitriles. Section 28. Volume : p. 5 (0 examples). (b) ldehydes from Nitriles. Section 58. Volume : p. 0 (0 examples). mines from alides. Section 00. Volume : pp (28 examples). Copyright 20 Elsevier Inc. ll rights reserved.

6 6 rganic Synthesis Solutions Manual (d) mides from Nitriles. Section 88. Volume : p. 257 (5 examples). (e) Ethers from alides. Section 0. Volume : pp (6 examples). (f) alides from mines. Section 42. Volume : p. 69 (0 examples) (g) Ketones from lefins. Section 79. Volume : p. 409 ( examples). (h) lefins from ldehydes. Section 99. Volume : pp (7 examples). The real lesson from this exercise, apart from learning to use this literature resource, is that some functional group exchange reactions are well studied and there are many variations. thers yield only a handful of possibilities. Despite the request for three examples in the question, no examples were found for (a), (b) or (f). In this case, further literature searching in the older literature is a necessity. 7. The bicyclo[2.2.]heptane unit () is very rigid and greatly influences the stereochemistry for the molecule. The appended six-membered ring assumes a conformation that is close to a twist-boat, and it cannot 'ring flip' easily due to the conformationally immobile bicycloheptane unit. This constraint forces the methyl group ( 2 ) into a pseudo-axial position. The other methyl group ( ) is at a bridgehead position of the bicycloheptane and is effectively perpendicular to that ring, as shown. The hydroxyl group is formally in a pseudo-axial position relative to ring For each molecule, a representative model from the indicated perspective using Spartan is shown. 4 c 2 (+)-mycoepoxydiene see J. rg. Chem., 2004, 69, 8789 (plus 'top' [above page] and 'bottom [below page] views) Copyright 20 Elsevier Inc. ll rights reserved.

7 Chapter 7 top view bottom view 2 4 (b) 2 N halochlorine see J. rg. Chem., 2004, 69, 7928 (plus 'top' [above page] and 'bottom [below page] views) top bottom 2 The purpose of this drawing exercise is to cast yourself in the role of a reagent approaching a molecule. Different angles of approach means the reagent "sees" a different set of groups and atoms for each portion of the molecule, which will have an important effect on the reactivity of the incoming reagent. y drawing the molecule Copyright 20 Elsevier Inc. ll rights reserved.

8 8 rganic Synthesis Solutions Manual from several perspectives, the goal is to see how angle of approach and topography may influence reactivity in a given molecule. lso, it emphasizes that the two-dimensional drawings we usually use often have little meaning in terms of the real structure of a molecule and determining its reactivity. 9. The R or S configuration for the chiral axis of each molecule that has a chiral axis rather, as well as that of stereogenic centers chiral center, is shown for (a) - (e). Et C 2 C 2 (a) C (b) (d) (e) N 2 r C 2 C 2 N 2 C C 2 C For (a), is and is 2; r is and C 2 C 2 is 4. For (b), is and C aryl is 2; N 2 is and C aryl is 4. For, is and Et is 2; is and is 4. For (d), C 2 is and Et is 2; C is and C 2 is 4. For (e) the epoxy is and M 2 is 2; is and C 2 is r Et R C P Et Mg Cp Fe R P r Et 2 C P (a) (b) (d) ipr. When the hydroxy-acid cyclizes to form the lactone (see ) the two methyl groups are,-diaxial, with the tertbutyl group equatorial. In the presence of acid, the hydroxyl group can be protonated and eliminate water and form a cation. In the presence of water, the alcohol is re-formed, but both epimers are generated since reaction with water leads to the methyl group being axial or equatorial in the lactone. Under equilibration conditions, the lactone with one axial methyl and one equatorial methyl will be lower in energy due to diminished -strain, and the equilibrium will shift to favor that lactone (net epimerization of the alcohol-bearing carbon in the hydroxy-acid). cid catalyzed opening of the lactone gives, of course, the hydroxy-acid. t-u t-u 2. The diaxial conformation allows hydrogen bonding (see ). Such hydrogen bonding counterbalances the Copyright 20 Elsevier Inc. ll rights reserved.

9 Chapter 9 energy difference of the diaxial (which has U-strain) vs. diequatorial conformations. The net result is that although the diaxial conformation has U-strain, the hydrogen bonding makes it the dominant species. a c si b (a) b (b) a re c b c re a. c b N a N- si 4. The correlation is. Taken from Eur. J. rg. Chem. 2004, r 7 r r ery th ro and syn 2S, R, 5R r 7 r r threo an d an ti 2S, S, 5 S 6. (a) diastereoselective (b) enantiospecific regiospecific and diastereoselective. 7. Cyclodecane has a relatively small internal cavity where transannular interactions are maximized. This transannular interaction disappears in cyclooctadecane where the additional carbons make the internal cavity large enough for the "internal" hydrogens to have little interaction. Compare 82 and 84 on in the text. Inspection of Figure. of the text can answer the second part of this question. Cyclohexadecane is an even-membered ring and, as such, will fit better on the diamond lattice. Since cyclopentadecane has an odd-membered ring, there is a "twist" in the ring when attempting to "lay it on the diamond lattice". This "twist" makes the energy of the ring slightly higher. Copyright 20 Elsevier Inc. ll rights reserved.

10 0 rganic Synthesis Solutions Manual 8. See J. m. Chem. Soc., 994, 6, 006. Copyright 20 Elsevier Inc. ll rights reserved.