OUTLINE 535 SESSION 5 (2007)
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42
Synthesis of Alkenes, Control of Stereochemistry
1. A word about the control of stereochemistry of disubstituted alkenes
1.1. Two choices cis or trans
1.2. Trans is easier to get.
1.2.1. Trans is most stable by approx. 2 kcal/mol.
1.2.2. This translates to usable ratios of
1.2.3. ∆G = -RTlnKeq
1.2.4. -2 kcal/mol = -2 x 10-3 kcal/(moleK)(298 K)ln Keq
1.2.5. 28.6/1 or ~97 % trans
2. Alkenes from Alkynes
2.1. Lindar catalyst-from alkene gives the cis alkene.
2.2. Dissolving metal (Na, Li) and alkyne gives the trans alkene.
3. From ketones and aldehydes
3.1. Non-stabilized Wittig generated with Li+ counter ions give trans
disubstituted olefins.
3.2. Horner-Emmons reagents give trans olefin.
4.
for above see: Roush, W. J. Am. Chem. Soc. 1980, 102, 1390.
Stec Ac. Chem. Res. 1983, 16, 411.
5. Cis selective non-stabilized Wittig olefination.
5.1.1. These reactions have early transition states
5.1.2. Salt free conditions
5.1.2.1. Those below and
5.1.2.2. KHMDS/ 10%HMPA/ THF
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6. Stabilized ylides tend to be trans selective
6.1.1. This reflects the stability of the trans-oxaphosphatane
6.1.2. trans-oxaphosphatane is more stable than cis
6.1.3. Both reactions are under kinetic control
7. (KINETIC versus THERMODYANMIC CONTROL)
7.1. non-equilibrium conditions opens the way to possible kinetic control.
Thermodynamic control of product distribution is always reflective of the
relative free-energies of the products.
Ph
Ph P
O
Ph
H
H
Ph
Ph P
O
H
Ph
H
Steric Problems Occur here between the
ethyl and the phenyl substituents
8. Stabilized ylides possess ÿ-CO2R or ÿ--CO2R or ÿ-CN groups adjacent to the
anion center.
8.1. or any other group that stabilizes negative charge
8.2. Stabilized ylides -> trans alkenes
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8.3. Unstabilized ylides in the absence of oxophilic cations (Mg and Li) -> cis
alkenes
8.4. There are exceptions to the above
9. THE NEXT SECTION OF THIS LECTURE IS DESIGNED TO CONVICE YOU
THAT TRISUBSTITUTED ALKENES ARE CHALLENGING TO SYNTHESIZE.
9.1. A good question at this point might be: why should they be synthetically
complex?
9.2. When there are two equivalent substituents on the same side of the
alkene, cuprate mediated non-polar additions to alkynes is a general solution.
See: Kozlowski, J. A. "Organocuprates in the Conjugate Addition Reaction." In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4; pp 169.
10. 1970's Normant developed the stereospecific addition of organocopper
reagents to alkynes.
R'
R
CuLi
RCuMgXY
Et2O
E+
R
E
R'
R'
-50 to -20
15 min
10.1. The above protocol looks good in theory
10.2. In practice
Ph
Ph
Ph
iPr2CuMgBr
Et2O
iPr
iPr
68%
-50 to -20
15 min
2. aqueous quenching
32%
10.3. Problems
10.3.1. In general the regiochemistry gets worse if the alkyne is di-substituted.
10.3.2. There are a few cases in which groups on the alkyne effectively direct
the regiochemistry of the addition. For these see the citation above.
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OUTLINE 535 SESSION 5 (2007)
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Synthesis of Cecropia-C18 Juvenile Hormone
O
O
H
O
Molecular structure of Cecropia-C18 Juvenile || Cecropia Moth, the silk moths
(Hyalophora cecropia).
In the next three syntheses of the Cecropia-C18 Juvenile Hormone think about
general principles and specific reactions. Do not conceptualize the following
information in terms of your instructor wanting you to memorize or even study
three synthetic approaches to the Cecropia-C18 Juvenile Hormone.
10.4. That the synthesis appears to be convergent is the first thing you should
notice. The solution to the molecular complexity in the form of trisubstituted
alkenes is the second thing you notice in the synthesis below.
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OUTLINE 535 SESSION 5 (2007)
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46
OH
OH
H
H
Trans double bond in
pericyclic transition state
Cis double bond in
pericyclic transition state
Lower energy
10.5. The retro-ene reaction runs with the double bond in an S-cis relationship
to the cyclopropane ring. The pericyclic transition state is tight, C—H—C
proximity at near bond distance needs to be attained. This favors the
developing cis-double bond in the 6 electron transition state. You can
convince yourself with a model.
10.5.1. Read about the ene reaction Snider, B. B. "Ene Reactions with Alkenes
as Enophiles." In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5; pp 1.
10.5.2. Ripoll, J.-L.; Vallee, Y. "Synthetic applications of the retro-ene
reaction." Synthesis 1993, 659-77.
THPO
PPh3
1. nBuLi / THF / 0 °C
2. cooled to -78 °C then A
3. -25 °C then 2 equiv. sec-BuLi
4. p-formaldehyde at 0 °C.
O
THPO
1. MnO2 / Hexane
2. PPh3CH2 / benzene
3. hydrazine/ EtOH /
H2O2 / CuCl2(cat)
OH
A
THPO
11. The end game of cecropia synthesis
11.1. Yield for the removal of the THP group was not reported. I suspect it was
low due to non-orthogonality issues with trisubstituted alkenes. These are acid
sensitive and you need acid to remove the THP group.
11.2. The rest of the synthesis was accomplished by Corey-Ganem oxidation to
the carboethoxy functionality.
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12. The following approach to Cecropia C18 Juvenile hormone is instructive and
provides a more general solution to stereocontrol in trisubstituted olefins than
the synthesis above.
12.1. General is good!
12.1.1. Corey, E.J.; Katzenellenbogen, J.A.; Gilman, N.W.; Roman S.A.;
Erickson,B.W. J. Am. Chem. Soc. 1968, 90, 5618-5620.
13. This synthesis of juvenile hormone centers around the stereoselective
reduction of alkynes by LAH with the hydroxide as the directing group.
13.1. The rest of the synthesis was designed around this idea.
13.1.1. The intermediates have C-M functionality (carbon/metal bonds), this
means it should be able to construct C-X (oxidation) or C-C bonds
(substitution) with electrophiles.
OH
Al
O
CH2OH
CO2Me
OMe
CH2OH
14. The triple bonds were operated on stereospecifically make double bonds.
14.1. Stereocontrol from lineland to flatland.
14.1.1. Alkene to alkyne is usually less complex.
14.1.2. The retrosynthesis simplifies the target (from the standpoint of
molecular complexity) by the following criteria
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48
14.1.2.1. The triple bond has no stereochemical complications
14.1.2.2. sp C-H bond is easily deprotonated for anionic disconnections
OCH3
NH3/Li
OCH3 1 equiv
O3/CH3OH
DMS
CO2CH3
CHO
NaBH4
CO2CH3
OH
THF/tAmyl
alcohol
OH
1. TsCl
C5H5N
1. TsCl
C5H5N
2. LAH
ether
CH2OH
2. propargylTHP ether
(tetrahydropyranyl)
3. HCl/MeOH
1. PBr3
2. 3-lithio-1-trimethyl
silylpropyne
3. AgNO3, KCN
4. BuLi then CH2O
CH2OH
1. LAH, NaOCH3
THF
2. I2
3. Me2CuLi
4. MnO2/hexane
5. MeOH, NaCN
1. LAH, NaOCH3
THF
X
OH
2. I2
3. Et2CuLi
X=I
X=Et
CO2Me
14.2. The enol ether reacts instead of the other double bond during ozonolysis
in the second step.
14.2.1. Why?
14.3. Reduction the aldehyde in the presence of the ester is usually a simple
matter.
14.3.1. Why?
14.4. Birch reduction:
14.4.1. Is tough to predict the products. Normally a mixture of products results.
14.4.2. Regioselective protonation of the birch intermediate.
14.4.3. Birch reduction preserves the conjugated double bond.
14.4.4. LOOK UP the Birch Reduction. Get comfortable with the mechanism
and the kind of molecules you can make with this procedure. Realize that
Birch reduction and the dissolving metal reduction of alkynes are related.
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OUTLINE 535 SESSION 5 (2007)
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14.4.5. Mander, L. N. (1991). Partial Reduction of Aromatic Rings by
Dissolving Metals and by Other Methods. Comprehensive Organic Synthesis.
B. M. Trost and I. Fleming. Oxford, Pergamon Press. 8: 489.
14.4.6. Rabideau, P. W. and Z. Marcinow (1992). “The Birch Reduction of
Aromatic Compounds.” Org. React. (N.Y.) 42: 1-334.
14.4.7. Birch, A. J. and D. H. Williamson (1976). “Homogeneous
Hydrogenation Catalysts in Organic Synthesis.” Org. React. (N.Y.) 24: 1.
14.5. ozone14.5.1. Made by striking an arch across an atmosphere of O2.
14.5.2. Electrophilic 1,3-dipolar cycloaddition.
14.5.3. Mechanism on next page.
14.5.4. Slow addition allows for kinetically differentiate between the two double
bonds in the birch reduced product.
O
O R
O
O
O
O
O
O
O
R
O
O
R'
R'
R'
S
R
O
O
O
R'
R
R R'
S
O
O
R
O
O
O
R'
R
S
DMSO
O
+
R'
O
14.6. Borohydride reduction
14.6.1. Usually done in methanol or ethanol
14.6.2. Takes place from the more reactive boroester at about pH = 10 or so
14.6.2.1. Careful, pH refers strictly to aqueous solution. To facilitate
discussion, this rule is broken all the time.
14.6.3. Very mild reducing agent, by moderating temperature you can
selective reduce aldehydes and ketones in the presence of esters and
enones.
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OUTLINE 535 SESSION 5 (2007)
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14.7. Reductive defunctionalization.
14.7.1. Tosylation is sophomore org chem. It is a method by which alcohols
are activated toward substitution. If necessary, look it up.
14.8. THP protection of -OH functionality.
14.8.1. THP ethers are stable in the presence of base and almost any
reducing agent. Do you know why?
14.8.2. In the presence of acid and excess alcohol THP ethers are
deprotected.
14.8.3. The authors took a beating on the yield here (30%) what else can
happen to the substrate in the presence of H+ and MeOH
14.9. At this point the material is >1:1000 isomerically pure cis!
14.10. LAH reduction of propargyl alcohols
14.10.1. Results in the formation of an alkenylaluminum species.
14.10.2. At this point that this alkenylaluminum is quenched with iodide, the
stereochemistry of alkene is set.
14.10.2.1. Remember, In general, don’t try to control stereochemistry at
anions.
2
3
14.10.2.2. Neither sp nor sp anions are good at trapping electrophiles
stereospecifically.
E
A
C
E+
B
A
A
E+
C
B
B
C
A
E
B
C
14.10.2.3. These reactions are not stereoselective
14.10.3. The cuprate is known to conserve the stereochemistry of addition to
akenylhalides
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51
14.10.3.1. Cuprate reagent reacts with alkenyliodides because it can offer the
alkenyl iodide a d orbital-based mechanism.
Et I
Et
I
Et
R
R
Cu
Et
Li R
Li R
π-complex
Et
Et Cu
Cu
Oxidative
Addition
LiI
Et Cu
Copper III
Reductive
Elimination
Et
Copper I
14.10.3.2. In the oxidative addition step the copper has gone from oxidation I
to oxidation state II
14.11. 3-lithio-1-trimethylsilylpropyne
14.11.1. TMS as a surrogate proton
14.12. Silver + desilylation
14.13. Homologation with formaldehyde
14.14. Corey Ganem oxidation.
O
O
O
Mn
O
Mn
O
H
O
Mn 4+
O
+
H
O
NaCN
H
O
Mn
Mn 2+
OH
OH
CN
H
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15. Final oxidation of the last alkene
15.1. N-bromosuccinamide/dimethoxyethane water mixture
15.1.1. Intermediate bromohydrin
15.1.2. Isopropoxide in isopropyl alcohol
15.1.3. Epoxide final product
16. Testing final product: 0.05 µg of the product injected in 50 µg of chemically
pure olive oil blocked silk worm maturation.
17. The Take Home Lesson and how to study this material
17.1. You need to determine the points in the synthesis of the natural product
that gave rise to stereoselective olefin synthesis and why.
17.2. You need to remember how the carbon-carbon bonds were formed and
be able to apply the method to general problems you will get throughout the
semester.
18. Another synthetic approach to the Cecropia Juvenile hormone:
18.1. Still, W. C.; McDonald, J. H., III; Collum, D. B.; Mitra, A. Tetrahedron Lett.
1979, 20, 593.
18.2. The main focus is the control of the stereochemistry of the
trisubstituted alkene.
18.3. Retrosynthetic analysis:
O
OCH3
O
H
2
1.
HO
HO
O
O
3
*
*
O
HH
O
HH
O
4
O
2,3-sigmatropic
rearrangement
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OUTLINE 535 SESSION 5 (2007)
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18.3.1. In this retrosynthetic analysis the molecule is simplified from two
trisubstituted alkenes to two methylene substructures. The stereochemistry
of the allylic alcohols at the carbinol carbons does not matter. These are
marked with * in structure 4.
18.3.2. The material at this point is a mixture of diastereomers.
6
4
Br
O
O
+
O
5
O
7
O
O
+ Br
O
8
Br
9
18.3.3. Look at 8 and 9.
18.3.3.1. Do you know why the enolate preferentially substitutes the Br on the
sp3 carbon atom instead of the sp2 carbon atom?
18.3.3.2. Do you know why 5 had to be protected at the alcohol oxidation
state with a ketal?
18.3.3.3. Do you know why dianion 6 preferentially reacted with aldehyde 5 at
the carbanion instead of the alkoxide?
18.3.3.4. You should know what is driving the reaction from 12 to 3 forward.
18.3.3.5. You should know how to get from 3 to 1 from our previous
discussions.
+
Br
OLi
O
O
Br
Br
O
aqueous
workup
8
9
O
THF
10
Li
Br
7
Br
OH
1) LAH
2) K2CrO3
O
Br
7
1)t-BuLi
2) 5
O
OH
OH
O
11
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54
1) BuLi
1) KH, / THF
2) Bu3SnCH2I
O
O
O
SnBu3
SnBu3
O
12
3
2) aqueous workup
18.4. The basis of the stereoselectivity of the 2,3-sigmatropic
rearrangement.
R
R
O
H
Me
H
Me
H
Me
H
H
H
R
O
H
H
O
H
H
R
Me
Steric interaction between
these two large pseudoequatorial
substituents
O
H
H
trisubstituted
alkene
18.4.1. This type of interaction is called 1,2-allylic strain.
18.4.2. The production of the E-alkene is more facile than the production of the
Z-alkene.
18.4.3. In the transition state above R and the Me group are on opposite sides
of the bond. They are anti. This anti relationship leads to a trans relationship
between these two groups.
18.4.4. The transition state below is inhibited by interaction between the R and
the Me groups. If this transition occurred preferentially then the syn Me and
the R groups would be cis to one another in the product.
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OUTLINE 535 SESSION 5 (2007)
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R'
R'
H
H
looking down this bond
generates the Newman
projections below
O
O
R
R
R
H
H
H
O
R'
H
H
H
O
H
R'
R'
H
Strain-Minimized t-State
1,3-allylic strain
R
O
H
R
1,3-allylic strain
1,3-tranannular interactio
18.4.5. The diagram above outlines another way to look at the transition that
determines the stereochemistry in Still’s 2,3-sigmatropic shift. Could you see
this better if you made a model?
18.4.6. Read the following review on the 2,3-sigmatropic rearrangement
and its utility as a synthetic tool.
18.4.6.1. Bruckner, R. 2,3-Sigmatropic Rearrangements; Comprehensive
Synthetic Organic Chemistry Trost and Flemming Eds.; Pergamon Press:
Oxford, 1991; Vol. 6, pp 873.
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