Jones M., Fleming S.A. Organic Chemistry

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12.14 Special Topic: Steroid Biosynthesis 559

12.14 Special Topic: Steroid Biosynthesis

There is an extraordinarily important class of molecules called steroids. The carbon

framework common to all steroids is three cyclohexanes and a cyclopentane fused

together (Fig.12.77).This arrangement is often referred to as “three rooms and a bath.”

Steroids are formed in Nature from isoprene units.We will start our summary of the

biosynthesis with two units of farnesyl pyrophosphate, which can be enzymatically

coupled in a tail-to-tail fashion to give the symmetrical triterpene called squalene

(Fig. 12.78).

FIGURE 12.77 Basic steroid ring

system.

WEB 3D

Farnesyl–OPP Farnesyl–OPP

Squalene

OPP

PPO

coupling

FIGURE 12.78 Coupling of two

molecules of farnesyl pyrophosphate

gives squalene, a triterpene.

Squalene can be epoxidized to give squalene oxide, which is written in a sug-

gestive way in Figure 12.79. Protonation of squalene epoxide leads to a relatively

enzymatic

epoxidation

Squalene

oxide

FIGURE 12.79 Enzymatic

epoxidation of squalene gives

squalene oxide, redrawn in a

suggestive fashion at the bottom.

560 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

stable tertiary carbocation that is attacked by the proximate nucleophilic double

bond to give a new cation. This cation is attacked in turn by another nearby

alkene.The process continues until the molecule is sewn up in a four-ring steroid

skeleton as shown in Figure 12.80. The series of rearrangements summarized in

Tertiary

carbocation

The four-ring steroid skeleton is now constructed

FIGURE 12.80 Acid-catalyzed opening of the epoxide gives a tertiary cation that can

undergo a series of ring closings to give a new, tertiary carbocation in which the four-ring

steroid skeleton has been constructed.

12.14 Special Topic: Steroid Biosynthesis 561

PROBLEM 12.36 Starting at the right-hand end of the top molecule in Figure

12.81, write a stepwise mechanism for the conversion to lanosterol. Take the sev-

eral rearrangements one at a time and draw out each reaction intermediate.

WEB 3D

Lanosterol

FIGURE 12.81 A series of skeletal

rearrangements, followed by removal

of a proton, gives lanosterol.

Steroids are commonly found in Nature and are considered important prima-

rily because of their powerful biological activities. They often function as regula-

tors of human biology. The four rings are designated A, B, C, and D, and the

carbons are numbered as shown in Figure 12.82. As in lanosterol, steroids usually

have axial methyl groups attached to C(10) and C(13), and often carry an oxygen

atom at C(3) and a carbon chain at C(17). The rings are usually, but not always,

fused in trans fashion.

FIGURE 12.82 The steroid ring system.

Steroids were, and still can be, isolated from natural sources. Such important bio-

molecules quickly became the subject of attempts at chemical modification and total

synthesis in the hopes of uncovering routes to new molecules of greater and different

Figure 12.81 ensues and a proton is finally lost to give the compound known as

lanosterol.

562 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

Cholesterol

Testosterone Estrone Cortisone

Progesterone

FIGURE 12.83 Some naturally occurring steroids.

Whole industries have been derived from the laboratory syntheses of steroids.

Consider, for example, the steroids used in our attempts to control human fertility.

“The pill”used by women to avoid pregnancy or to control hormonal imbalance con-

tains synthetic steroids that mimic the action of the body’s natural steroids,the estro-

gens and progesterone, which are involved in regulation of ovulation. The body is

essentially tricked into behaving as if it were pregnant, so ovulation does not take

place. It should be no surprise that it has been difficult to use such powerfully bio-

logically active molecules in a completely specific way. The goal of this work is to

interfere specifically with ovulation without doing anything else. Considering the

activity of the molecules involved and the complexity of the mechanisms we are try-

ing to regulate, it is remarkable that we have been so successful. This control is not

totally without cost, however. In fertility, those costs appear as the side effects of the

pill, which occur in some women. Perhaps the most difficult of human problems is

to find the balance between benefits and risks in cases such as this. Although such

problems have been with us throughout our history, questions of biology are partic-

ularly vexing, it seems. It is easier to judge that the benefits of the automobile out-

weigh the societal costs of the certain accidents than to make a decision regarding

the steroids used in the birth-control pill.This problem is certain to become much

worse as our ability to manipulate complicated molecules continues to grow.

bioactivities. Many naturally occurring steroids have been constructed in the labora-

tory and numerous “unnatural” steroids have been created as well. Figure 12.83 shows

a few important steroids found in Nature.

12.15 Summary 563

12.15 Summary

New Concepts

In this chapter, you learned about the cumulated dienes. These

molecules are characterized by at least one sp hybridized inter-

nal carbon atom.

The central topics of this chapter are the chemical and phys-

ical consequences of the overlap of 2p orbitals (conjugation). In

structural terms, conjugation appears as a short

bond, about which the barrier to rotation is small (Fig. 12.18).

Conjugation leads to the formation of allyl systems in

addition reactions to dienes, and is a requirement for the

Diels–Alder reaction (Fig. 12.84).

C(2)

C(3)

An important fundamental concept in this chapter

involves the difference between thermodynamic and kinetic

control of a reaction. Conjugated dienes will react with HX

or X

to give 1,2-addition products when kinetic conditions

are used. The use of thermodynamic conditions will favor

formation of the most stable product, usually the 1,4-addition

product.

In UV/vis spectroscopy, absorption of light results in

the promotion of an electron from the HOMO to the

LUMO.

An allylic cation

⌬

FIGURE 12.84 Two typical reactions of conjugated dienes: addition to

give an allyl cation and the Diels–Alder reaction.

Key Terms

s-cis (p. 523)

conjugated double bonds (p. 512)

cumulated alkene (cumulene) (p. 512)

Diels–Alder reaction (p. 544)

dienophile (p. 544)

electronic spectroscopy (p. 526)

endo (p. 551)

exo (p. 551)

extinction coefficient (p. 527)

isoprene (p. 555)

isoprene rule (p. 558)

ketene (p. 515)

steroid (p. 559)

terpenes (p. 554)

s-trans (p. 523)

ultraviolet/visible (UV/vis) spectroscopy

(p. 526)

Reactions, Mechanisms, and Tools

The base-catalyzed isomerization of disubstituted to terminal

alkynes takes place through allene intermediates (Fig. 12.13).

Addition reactions of HX or X

to conjugated dienes can

give products of both 1,2- and 1,4-additions (Fig. 12.38).

The Diels–Alder reaction forms cyclohexenes and cyclohexa-

dienes from the thermal reaction of conjugated dienes and

alkenes or alkynes. Stereochemical labeling experiments

show that both new σ bonds are formed simultaneously

(Figs. 12.61 and the figure in Problem 12.28). Many

natural products (terpenes, polyisoprene, steroids) are pro-

duced through the combination of various numbers of

isoprene units.

Syntheses

The most important synthetic methods described in

this chapter are a route to allylic halides through additions

to conjugated dienes and the Diels–Alder synthesis of

cyclohexenes and cyclohexadienes. Be especially careful

about the Diels–Alder reaction, because there are many

structural possibilities for the products depending on the

complexity of the diene and dienophile used as starting

materials. See the following page.

564 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

Common Errors

4. Dienes

3. Cyclohexenes

⌬

Diels–Alder reaction; watch out for structural variation; the

reverse reaction is a synthesis of 1,3-dienes and alkenes

from cyclohexenes

⌬

The reverse Diels–Alder reaction; watch out for structural

variation; this picture gives only the simplest version

Be sure to understand how the structures of allenes and cumu-

lenes can be derived from an analysis of the hybridizations of

the atoms involved. Although the structures all look flat on a

two-dimensional page, they are not all planar by any means.

Although the Diels–Alder reaction mechanism can be

quickly drawn using only three little curved arrows, and

although it is not difficult to see that all cyclohexenes can be

constructed on paper from the reaction of a diene and a

dienophile, very complex structures can be built very quickly

using Diels–Alder reactions. The simplicity can quickly disap-

pear in the wealth of detail! Try to see to the essence of the

problem; locate the cyclohexene, and then take it apart to find

the building-block diene and dienophile.

It is even harder to find a reverse Diels–Alder reaction in a

mechanism problem or a chemical synthesis. Not only can

cyclohexenes be constructed through Diels–Alder reactions, but

they can serve as sources of dienes and dienophiles as well.

It is time to mention again another very common conceptual

error that often traps students. Look, for example, at Figure 12.44.

Protonation of 1,3-butadiene leads to an allyl cation in which two

different carbons share the positive charge. Addition of chloride at

these two positions leads to the two products. It is very easy to

think of the resonance forms of the allyl cation as each having a

separate existence; of chloride adding to one resonance form to

give one product and addition to the other resonance form to give

the other product.This notion is absolutely wrong! The allyl

cation is a single species that has two partially positive carbon

atoms. Chloride adds to the allyl cation, not to one resonance form

or the other. The figure tries to help out by showing a summary

structure, but this is not always done, and you must be careful.

(a)

AcO

(b)

PROBLEM 12.37 Use the rules given in Table 12.2 (p. 530) to

calculate λ

max

for the following steroids:

12.16 Additional Problems

2. Cyclohexadienes

⌬

The dienophile is an alkyne; watch out for

structural variation and the reverse reaction

H X

The 1,2- and 1,4-addition; watch out, these allylic halides

can be transformed further though S

2 reactions

Both 1,2- and 1,4-addition take place

1. Allylic Halides

12.16 Additional Problems 565

–

(a) (b)

–

PROBLEM 12.39 Are any of the following compounds chiral?

Explain with good drawings.

PROBLEM 12.45 Suggest a plausible arrow formalism mecha-

nism to account for the products in the following reaction:

CCC

PROBLEM 12.40 Show the reaction conditions you would

use to make 3-azido-1-butene if your only source of carbon is

1,3-butadiene.

PROBLEM 12.41 What are the possible nonhalogenated prod-

ucts in the reaction between cis-1,2-dibromocyclohexane and

excess strong base? Show the mechanism for the formation of

each product. Which one do you suppose would be the major

product? Explain why.

PROBLEM 12.42 Predict the major product for the hydrohalo-

genation reaction (HBr, cold, short time) with each of the

following dienes:

(a) 1,3-butadiene (b) 1,3-cyclopentadiene

(e) 1-methyl-1,3-cyclohexadiene

PROBLEM 12.43 Predict the major product for the hydrohalo-

genation reaction (HBr, reflux, long time) with each of the

following dienes:

(a) 1,3-butadiene (b) 1,3-cyclopentadiene

(e) 1-methyl-1,3-cyclohexadiene

PROBLEM 12.44 Show the main products of the reactions of

trans,trans-2,4-hexadiene under the following conditions. There

may be more than one product in some cases.

(a) HCl (b) H

/Pd (c) Cl

/CCl

(d) ⌬, H

COOC COOCH

(63%)

(22%)

(10%)

(4%)

Br Br

BrBr

OCH

–15 ⬚C

/CH

PROBLEM 12.46 Predict the products of the reaction of hydro-

gen chloride with isoprene under kinetic and thermodynamic

control.

Isoprene

HCl

PROBLEM 12.47 Solvolysis of 3-chloro-4,4-dimethylcyclohex-

ene proceeds through an intermediate carbocation. Draw that ion.

Does an alkyl shift occur? Why or why not? Hint: Table 12.3.

PROBLEM 12.48 Show the reactions you would use to synthe-

size cis-4,5-dimethylcyclohexene if your only source of carbon is

cis-2-butene.

PROBLEM 12.49 Devise syntheses for the following molecules.

You may use 1-butyne and ethyl iodide as your only sources of

carbon, as well as any inorganic reagents you need.

PROBLEM 12.38 Write resonance forms for the following ions:

566 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

PROBLEM 12.50 Conversion of 2-butyne into 1-butyne is

easy. The reverse reaction is more difficult. Suggest routes for

doing both these conversions. Mechanisms are not required.

CCC

PROBLEM 12.51 You have a bottle of C

. You know it

contains a terminal alkyne. Which alkyne does it need to be

in order to make 2,2-dimethyl-3-octyne most directly?

PROBLEM 12.52 Predict the major product for the Diels–Alder

reaction (toluene, reflux) between 2-methyl-1,3-butadiene and

the following dienophiles:

(a) cyclopentene

(b) diphenylacetylene

(d) (Z)-4-octene

PROBLEM 12.53 Predict the products of the following

Diels–Alder reactions:

(b)

(a)

(c)

(d)

0–25 ⬚C

ether

150 ⬚C

toluene

0 ⬚C

alcohol

dichlorobenzene

⌬

Ph =

COOCH

(f)

benzene

⌬, 9 h

(g)

25 ⬚C

dioxane

COOCH

OCH

(e)

toluene

⌬,10 h

PROBLEM 12.54 Although simple alkyl and aryl nitriles

are poor dienophiles, nitriles substituted with electron-

withdrawing groups are more reactive. Provide mechanisms

for the formations of the two products in the following

reaction:

OOC

COOCH

12.16 Additional Problems 567

PROBLEM 12.55 Although the Diels–Alder reaction is con-

certed, an analysis of a polar, stepwise mechanism can explain

the regiochemical preferences often observed. Use such

an analysis to explain the following data:

PROBLEM 12.58 In each of the following three reactions, two

products are possible. Could

C NMR spectroscopy distinguish

between the isomeric products formed? Explain. Can you

remember or predict which products are actually formed in

these reactions?

PROBLEM 12.56 In Problem 12.53c, the initially formed

adduct can be closed in a photochemical reaction to give a com-

plex cage structure (shown below). Write an arrow formalism

for this process and explain how the observation of this reaction

was helpful in determining the stereochemistry (exo or endo) of

the original Diels–Alder adduct.

CH C N

70% 30%

PROBLEM 12.57 Use a carefully constructed Energy versus

Reaction progress diagram to rationalize the following data. Be

sure to explain why the product at low temperature is mainly

endo and why the product at high temperature is mainly exo.

exo

endo

90 ⬚C

(minor)

(major)

25 ⬚C

(minor)

(major)

Cyclohexene or

vinylcyclobutane

(a)

(b)

(c)

HCN

endo or exo Product

PROBLEM 12.59 Here are two reactions of allyl systems that

are related to the Diels–Alder reaction. Use a HOMO–LUMO

molecular orbital analysis to show why reaction a succeeds

whereas reaction b fails.

PROBLEM 12.60 In principle, one of the following reaction

sequences could give two products, while the other must pro-

duce only one. Explain.

(a)

–

(b)

(a)

(b)

⌬

/Pd

⌬

/Pd

568 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

PROBLEM 12.61 In 1951, the great Kurt Alder himself exam-

ined the reactions of a mixture of dienes 1 and 2 with maleic

anhydride. He discovered that diene 1 reacted at 35 °C to give a

single adduct (A). Diene 2 reacted only at 150 °C to give a

single, different, adduct (B). Write structures for A and B and

explain the difference in the ease of reaction. Why is reaction of

1 so much easier than reaction with 2? Alder never actually

looked at the reaction with diene 3, but if he had, we predict

that no reaction would have occurred at 150 °C. Explain.

PROBLEM 12.62 Propose a synthesis of the powerful vesicant

(blister inducer) cantharidin, the active ingredient in the puta-

tive aphrodisiac “Spanish fly.” You may assume that organic

starting materials containing no more than six carbon atoms are

available, along with any inorganic materials you may need.

Hint: The thermodynamically more stable exo Diels–Alder

adducts of furan are generally isolable.

reaction

150 ⬚C

Cantharidin

PROBLEM 12.63 Write arrow formalism mechanisms for the

following transformations:

(a)

188–214 ⬚C

(b)

200–250 ⬚C

COOCH

COOC COOCH

COOC

(c)

140 ⬚C

PhCOO

OOC

COOCH

(d)

25 ⬚C

COOCH

COOC