The 3o alcohol is a retron for nucleophilic addition to 2-methylcyclohexanone. All the synthetic
plans given below are based on the nucleophilic addition to 2-methylcyclohexanone.
Retrosynthesis (1-5) is based on the use of acetylide as acyl anion equivalent.1, 2 Attack of the
nucleophile on cyclohexanone should be a stereoselective reaction. The nucleophile should
attack from equatorial position to give the desired relative stereochemistry. Hydrolysis of
product will give ketone 4.3, 4 Michael addition of 2 with 3 will give the target molecule.5 This
will require protection of alcohol in 4 prior to addition.5 4 has been prepared by reduction of
beta diketone 7, but was discarded as yield was only 40 %.6
Scheme-1
O
O
(12)
(10)
Protection
O
Selective protection
at both ends
O
S
+
(11)
O
S
O
O
+
O
O
+
O
(9)
Nucleophilic addition
to cyclohexanone,
deprotection
Nucleophilic addition to
cyclohexanone (umpolung)
,deprotection
(4)
Protection of
alcohol
O
O
Me3SiO
O
O
HO
(3)
deprotection
(1)
(2)
Michaels addition to alpha beta
unsaturated aldehyde, deprotection
(8)
O
OH
Reduction of
beta diketone
(7)
CHO
+
Target Molecule
O
(5) Nucleophilic
addition of
cyclohexanone
O
HO
O
O
HO
O
+
(6)
CHO
(3)
Scheme-1
Retrosynthesis (1-10) and (1-12) are shorter routes. Both of these eliminate the Michael addition
step of retrosynthesis (1-5). Retrosynthesis (1-10) was discarded as it had a problematic step of
selective protection at both the ends of 10 to produce 9. Route (1-12) looks good. 11 can be
synthesized by commercially available 12 in one step in good yield.7 Relative stereochemistry
will follow the same arguments given in route (1-5). This route is taken in the direction of
forward synthesis, (Scheme-2) as it is shorter. The attacking nucleophile is bulkier and hence it
should give better stereoselectivity.
Proposed synthesis: Alkyne (11) is a known material, prepared from (12) which is a
commercially available material. Specific example of this kind of protection of carbonyl group is
found and outlined in scheme 3.7 Use of acetylide as acyl anion is a well known reaction.
Hydrolysis of alkyne gives ketone. (Scheme-4).1, 2
O
O
O
HO
ethylene glycol, H
O
4
O
O
heptane, reflux
3
O
1.1. BuLi, THF
2. Hg2 , H3O
O
aq AcOH
HO
O
Scheme-2
O
ethylene glycol, H
O
heptane, reflux
O
Scheme-3
(a) CH CLi
(b) H3O+ , Hg2+ 85%
OR
O
R1
O
R1
R2
O
NaC CH
R2
in liq. NH3
Scheme-4
R2
OH
C CH
R3
Considering the issue of stereoselectivity, attack of the bulkier nucleophile on cyclohexanone
should be a stereoselective reaction. The nucleophile should attack from equatorial position; it
should give the desired relative stereochemistry.
O
OH
R
R
Scheme-5
The closet precedents found from the literature are outlined below.4
OH
O
MgBr
THF, OoC
References:
1. Milas, N. A.; MacDonald, N. S.; Black, D. M. J. Am. Chem. Soc. 1948, 70, 1829.
2. Linden, E.; Palomo, C.; González, A.; García, M. J.; Landa,C.; Oiarbide, M.; Rodríguez,
S. Angew Chem. Int. Ed. 1998, 37, 180.
3. Tarr, C. J.; Johnson, S. J. Org. Lett., 2009, 11, 3870.
4. Cl e´ment, R.; Grise´, C. M.; Barriault, L. Chem. Commun. 2008, 3004.
5. Clayton H. Tetrahedron Lett. 1986, 27, 6169.
6. Kariv, E.; Wenker, E.; Chem. Commun. 1965, 22, 570.
7. Wuts, G. M.; et. al. Org. Process Res. Dev. 2009, 13, 331.
total score 22 / 25
Criteria:
1) (5 pts.) Does the student have an appreciation for the molecular complexity of the
structure and does the solution effective solve these problems.
5/5: You did well in this criterion.
2) (10 pts.) Are the precedents given to support the synthetic proposal well-documented?
Are the precedents close.
9/10 You did well here too.
3) (5 pts.) Are the commercial sources cited? Does the student tell me where they are going
to get the starting materials?
3/5 You chased your bits and pieces down to commercial sources but you did not state
where you found the molecules. Quoting a price and source was expected. I am going to be
lenient for the first assignment.
4) (5 pts.) Are at least two COMPETITIVE retrosynthetic schemes offered and a logical
argument given about why one of these designs is better?
5/5 You did very well here. The retrosynthetic analyses that you chose to develop into a
forward synthesis had documentation problems. I think if you look you probably would have
found precedent for the regiochemistry of hydration of the triple bond. .
You will get better at this with a little practice. In general you did a great job.