In 1894 Emil Fischer proposed the “lock and key” principle for interaction between a drug and its mo — Organic Chemistry Chemistry Question
Cyclobutanes
In 1894 Emil Fischer proposed the “lock and key” principle for interaction between a drug and its molecular target. The interaction is efficient only in case of substances having specific complementary geometry that fit exactly to the molecular target. According to this model, a potential drug should accept a definite conformation with the appropriately located functional groups. One of ways to achieve this goal is restriction of conformational mobility of molecules. Recently Ukrainian chemists reported synthesis of conformationally rigid diamines I and J according to the scheme below.
[VISUAL]
The starting compound A was synthesized for the first time in 1958 by J.D. Roberts and F.F. Caserio (authors of the classical textbook on organic chemistry), according to the scheme:
[VISUAL]
Another method for A synthesis is given below:
[VISUAL]
Decipher the schemes. Write down the structural formulae of compounds A-P accounting for the following:
a) C and D are isomers; J has two planes of symmetry;
b) hydrocarbon K has a single type of hydrogen atoms; wH = 10.0 %;
c) N and O are isomers; wH = 3.8 %; wC = 22.9 %.
[VISUAL]
Model Answer
A: 3-oxocyclobutanecarboxylic acid
B: tert-butyl (3-oxocyclobutyl)carbamate
C: cis-tert-butyl (3-hydroxycyclobutyl)carbamate
D: trans-tert-butyl (3-hydroxycyclobutyl)carbamate
E: cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate
F: trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate
G: trans-tert-butyl (3-azidocyclobutyl)carbamate
H: cis-tert-butyl (3-azidocyclobutyl)carbamate
I: trans-1,3-diaminocyclobutane
J: cis-1,3-diaminocyclobutane
K: allene (propadiene, H2C=C=CH2)
L: 3-methylenecyclobutanecarbonitrile
M: 3-methylenecyclobutanecarboxylic acid
N: 1,1-dibromo-2,2-dimethoxypropane (1,1-dibromoacetone dimethyl ketal)
O: 1,3-dibromo-2,2-dimethoxypropane (1,3-dibromoacetone dimethyl ketal)
P: dimethyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate
Explanation of K: Hydrocarbon K consists of 90% C and 10% H, giving a simplest formula of (C3H4)n. Since it has only a single type of H atoms, it is allene, H2C=C=CH2.
Explanation of L and M: Allene undergoes a [2+2] cycloaddition with acrylonitrile to give 1-cyano-3-methylenecyclobutane (L). Hydrolysis of L gives 3-methylenecyclobutanecarboxylic acid (M), which is oxidized by OsO4/NaIO4 to produce A.
Explanation of N, O, P, A: Acetone is doubly brominated and ketalized with methanol, giving 1,1- and 1,3-dibromoacetone dimethyl ketals (N and O). The 1,3-isomer (O) reacts with dimethyl malonate to form cyclobutane derivative P. Hydrolysis of P with 20% HCl and subsequent decarboxylation produces 3-oxocyclobutanecarboxylic acid (A).
Explanation of B to J: Reaction of A with SOCl2, NaN3, and t-BuOH (Curtius rearrangement) yields Boc-protected 3-aminocyclobutanone B. NaBH4 reduction of B gives cis- and trans-isomers C and D. Mesylation of C and D gives E and F. NaN3 displacement of E and F (with configuration inversion via SN2) gives G and H. Catalytic hydrogenation, deprotection, and neutralization yields trans-diaminocyclobutane I and cis-diaminocyclobutane J (which has two planes of symmetry).
Starting from P, a very interesting compound W was synthesized:
[VISUAL]
Write down the structural formulae of Q – W.
Model Answer
Q: (3,3-dimethoxycyclobutane-1,1-diyl)dimethanol
R: (3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (ditosylate R)
S: dimethyl 6,6-dimethoxyspiro[3.3]heptane-2,2-dicarboxylate
T: 6-oxospiro[3.3]heptane-2-carboxylic acid
U: tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate
V: tert-butyl (6-(hydroxyimino)spiro[3.3]heptan-2-yl)carbamate
W: spiro[3.3]heptane-2,6-diamine
Explanation:
- Reduction of ester P with LiAlH4 yields diol Q.
- Pyridine-assisted tosylation of Q yields ditosylate R.
- Reaction of R with dimethyl malonate yields spirocyclic compound S.
- Hydrolysis of S with 20% HCl under heating causes deketalization and decarboxylation of the malonate group, yielding ketoacid T.
- Curtius rearrangement of T (SOCl2, NaN3, t-BuOH) gives Boc-protected amine U.
- Condensation of U with NH2OH gives oxime V.
- Reduction of V (H2, Pd/C), deprotection (CF3CO2H), and neutralization (NaHCO3) yields spiro[3.3]heptane-2,6-diamine W.
Can W be resolved into enantiomers?
Model Answer
Yes, W can be resolved into enantiomers. Spiro[3.3]heptane-2,6-diamine W has no plane or center of symmetry. It is chiral due to axial chirality (similar to 1,3-disubstituted allenes), which allows it to exist as two enantiomers that can be resolved.