Chapter 14, Problem 40P

15-44 Consider the structure of the immunosuppressant FK-506, a molecule shown to disrupt calcineurin- mediated signal transduction in T-lymphocytes.

1. What is the molecular formula of this immunosuppressant?
2. How manj' stereocenters are present in FK-506? Determine the maximum number of stereoisomers possible.

Identify and label the various functional groups present.

Consider the two stereocenters in this structure labeled with asterisks (*). Determine the absolute configuration of each stereocenter.

FK-506 has been shown to exhibit moderate solubility in various organic solvents. Is this immunosuppressant expected to be soluble in ethanol (CH₃CH₂OH)?

Consider the carbon atom labeled “1." Describe the geometry and approximate bond angles about this carbon atom.

Draw the alternative chair conformations of the cyclohexane ring at the lower right of FK-506 and label the more stable conformation.

Are there any aromatic components present in FK-506?

Patients taking FK-506 have reported several side effects from this medication, including headaches, nausea or diarrhea, and slight shaking. Would you expect the enantiomer of this drug to result in the same side effects?

Interpretation Introduction

(a)

Interpretation:

The molecular formula of FK-506 molecule should be determined.

Concept Introduction:

A molecular formula represents the exact number of atoms present for each element in the compound.

Answer to Problem 40P

The molecular formula of FK-506 is C₄₄ H₆₉ NO_12..

Explanation of Solution

The total number of C, H, n and O in the given structure is:

The total number of carbon = 44.

The total number of hydrogen = 69.

The total number of oxygen = 12.

The total number of nitrogen = 1.

Hence, the molecular formula is C₄₄ H₆₉ NO_12..

Interpretation Introduction

(b)

Interpretation:

The number of stereocenters and the maximum number of stereoisomers possible for FK-506 molecule should be determined.

Concept Introduction:

FK-506 molecule contains various functional groups and also has stereocenters which are the carbon atoms bonded with four different atoms or group of atom. The number of stereoisomers can be calculated with the help of 2ⁿ formula. Here ‘n’ indicates the number of stereocenters in the molecule.

Answer to Problem 40P

The stereocenters are shown by “*”:

There are 14 stereocenters hence 2¹⁴ = 16384 stereoisomers will be there.

Explanation of Solution

A stereocenter atom is that atom in a molecule which is connected to four different group of atoms or atom(s).

There are 14 stereocenters in FK-506 molecule as shown by “*”:

The formula for total stereoisomers is 2ⁿ hence there will be total 2¹⁴ = 16384 stereoisomers in the molecule.

Interpretation Introduction

(c)

Interpretation:

Various functional groups in FK-506 molecule should be identified and labeled.

Concept Introduction:

An atom or group of atoms due to which a compound shows the characteristic properties is said to be the functional group.

Answer to Problem 40P

The molecule of FK-506 contains:

• Alkene group
• Carbonyl group (ketone)
• Alcohol group (hydroxyl)
• Ester group
• Methoxy group (ether)
• Amide group

Explanation of Solution

The molecule of FK-506 contains alkene group, carbonyl group (ketone), alcohol group (hydroxyl), ester group, methoxy group (ether) and amide group.

Interpretation Introduction

(d)

Interpretation:

The absolute configuration of the two stereocenters labeled with asterisks (*) in FK-506 molecule should be determined.

Concept Introduction:

FK-506 molecule contains various functional groups and also have stereocenters which are the carbon atoms bonded with four different atoms or group of atom. The number of stereoisomers can be calculate with the help of 2ⁿ formula. Here ‘n’ indicates the number of stereocenters in the molecule.

Answer to Problem 40P

The marked stereocenters are r and s respectively.

Explanation of Solution

To assign the absolute configuration to C* we need to check the bonded group to this carbon atom. Then give numbers according to their atomic masses. If the movement from number 1 to 3 is clockwise; it will be r and if it will be anticlockwise, it will be s configuration.

Interpretation Introduction

(e)

Interpretation:

Whether FK-506 molecule is soluble in ethanol or not should be determined.

Concept Introduction:

FK-506 molecule contains various functional groups and also have stereocenters which are the carbon atoms bonded with four different atoms or group of atom. The number of stereoisomers can be calculate with the help of 2ⁿ formula. Here ‘n’ indicates the number of stereocenters in the molecule.

Answer to Problem 40P

FK-506 is insoluble in water whereas moderatelysoluble in ethanol and other organic solvents because it is bulky structure.

Explanation of Solution

The organic compounds which cannot form hydrogen-bond with water are insoluble in water. Usually organic compounds are soluble in organic solvents like ethanol. Here FK-506 has bulky structure therefore it is unable to form hydrogen bonds with water and water insoluble but soluble in organic solvents like ethanol.

Interpretation Introduction

(f)

Interpretation:

The geometry of carbon atom labeled “1” in FK-506 molecule should be determined.

Concept Introduction:

FK-506 molecule contains various functional groups and also have stereocenters which are the carbon atoms bonded with four different atoms or group of atom. The number of stereoisomers can be calculate with the help of 2ⁿ formula. Here ‘n’ indicates the number of stereocenters in the molecule.

Answer to Problem 40P

Here H and CH₃ are in opposite directions therefore it has E-configuration. Here the C-1 carbon atom has double bond therefore it must have sp² hybridization.

Explanation of Solution

The double bonded carbon atom is always sp² hybridized hence here C-1 will be sp² hybridized. If the groups of same priority are on same side; it will be Z-configuration whereas the groups of same priority on opposite side will be E-configuration. Here H and CH₃ have low priority are on opposite sides hence it is E-configuration.

Interpretation Introduction

(g)

Interpretation:

The alternative chair conformations of the cyclohexane ring at the lower right of FK-506 should be drawn and more stable conformation should be labeled.

Concept Introduction:

FK-506 molecule contains various functional groups and also have stereocenters which are the carbon atoms bonded with four different atoms or group of atom. The number of stereoisomers can be calculate with the help of 2ⁿ formula. Here ‘n’ indicates the number of stereocenters in the molecule.

Answer to Problem 40P

Here this will be most stable conformation as least repulsion between all bonded groups is there.

Explanation of Solution

Here in the given structure of FK-506; there is one cyclohexane ring with OCH3, OH and other C chain at 1, 3 and 4 position. Hence this will be most stable conformation as least repulsion between all bonded groups is there.

Interpretation Introduction

(h)

Interpretation:

Whether there is any aromatic component present in FK-506 molecule or not should be determined.

Concept Introduction:

The ring structures of the compound having uncommon stability due to delocalized pi electron density shared in between all the carbon atoms of the ring is said to be an aromatic compound.

Answer to Problem 40P

There is no aromatic component in the molecule.

Explanation of Solution

There is no conjugated pi system or benzene ring is present; hence there is no aromatic component in the molecule.

Interpretation Introduction

(i)

Interpretation:

Whether the enantiomer of FK-506 has same side effects as that of FK-506 should be determined.

Concept Introduction:

FK-506 molecule contains various functional groups and also have stereocenters which are the carbon atoms bonded with four different atoms or group of atom. The number of stereoisomers can be calculate with the help of 2ⁿ formula. Here ‘n’ indicates the number of stereocenters in the molecule.

Answer to Problem 40P

Yes. enantiomers of FK-506 also report same side effects as enantiomers exhibit same physical and chemical properties; only differ in their optical properties.

Explanation of Solution

Enantiomers are optical isomers with same chemical and physical properties hence enantiomers of FK-506 also show same side effects.