Due: Wednesday, Dec.

13

Chem 206

Answer Key
Name:_____________
TF:_______________

Problem Set 10

General Instructions: Neatly, in the space allocated, provide concise answers to the following questions using clear
three-dimensional representations for all relevant structures. Address stereochemical and stereoelectronic issues
where appropriate.
Question 1. Corey's synthesis of ovalicin required the use of the
vinylstannane below as a coupling fragment. This fragment was
synthesized from acetone trisyl hydrazone. Please provide a mechanism
for this sequence of steps.

OH

CH3

CH3
CH3

O
OCH3 Ovalicin

1) BuLi (2.0 equiv), 78 oC

2)
Br

CH3

CH3

CH3
O
N
H3C

NH

90% yield

Li
Li

BuLi

CH3

CH3

SO2Tris
N

H3C
CH3

H3C

CH3

CH3

Tris
O

Bu3Sn

3) TMEDA, BuLi (1.0 equiv),

78 oC 0 oC
4) Bu3SnCl, 78 oC r.t.

NH

CH3

CH3
Br

BuLi

TrisO2S

CH3
Li

CH3

BuLi (3rd equiv)

PRODUCT

CH3

Bu3SnCl
Li

CH3
CH3

CH3

Shapiro Reaction

CH3

N
Li

Total Synthesis of ()-Ovalicin. Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256-257

CH3

Question 2. Kamitori and coworkers have reported the acid catalyzed cyclization illustrated below. Provide a
reasonable mechanism for this transformation.

H3C

O
H3C

CH3

H3C

H CF
3

HOAc

CF3
R

H3C

H3C

H CF
3

H3C

N
N
R

H3C

O
CF3

CF3

H
N

CF3

H
N

N
R

CF3

Acid-Catalyzed Cyclization Reaction of 3-Hydrazono-1,1,1-Trifluoro-2-Alkanones to 6-Trifluoromethyl-3,6-Dihydro-2H[1,3,4]-Oxadiazines. Kamitori, Y.; Tomoko, S. Heterocycles 2005, 65, 2139-2150.

Question 3. The interesting functional group interconversion depicted below was recently published by Matthias
Brewer. Provide a mechanism for this transformation. Note that DMSO and oxalyl chloride are first mixed together
and that hydrazone and triethylamine are added once gas evolution has ceased.

NH2

DMSO (1.1 equiv)

Oxalyl Chloride (1.05 equiv)
Et3N (1.0 equiv)

Cl

CH2Cl2, 78 C r.t.
93% yield

H3C

CH3

Cl
Cl

CH3

Cl

S
H3C

Cl
Cl

H3C

Cl

O
NH2

N
H3C
N
N

N
H

Ph

H3C

H3C

Cl

N
N

S
N

CH3

Ph

CH3

H3C

Ph
Ph

Ph

Et3NHCl
Et3NHCl

Cl
CH3

H3C

Cl
CH3

N
H

H
Ph

Ph

Ph

Cl
NEt3

Cl

H
Ph

Ph

Ph

Ph

Cl
CH3

Cl

Ph

+ CO2 + CO

CH3

Cl
Ph

Ph

Ph

Conversion of Hydrazones to Alkyl Chlorides Under Swern Oxidation Conditions. Brewer, M. Tetrahedron Lett.
2006, 47, 7731-7733.

Question 4. A recent paper by Dolle highlights the rapidity with which one may assemble complex architecture in a
single chemical operation. The transformation in question is illustrated below.
CO2CH3
O

1. BocNHNH2
CO2CH3

NBoc 75% yield, one diastereomer

2. EtOH, reflux

Provide a concise mechanism for the indicated transformation. In that step where the complex stereochemical
relationships are established, a carefully rendered three dimensional illustration is requested.

BocNHNH2

BocHN
N
OCH3

CO2CH3

H2O

OCH3
H

H
H
H

Olefin attack occurs on the

face of the ring opposite the
CH2CO2CH3 substituent.

Boc

N
N

Boc
CO2CH3

[3 +2] Cycloaddition

CO2CH3
N

NBoc

Application of the Intramolecular Azomethine Imine Cycloaddition to the Construction of a Novel, Orthogonally
Protected Spirodiamino Acid Scaffold. Dolle, R. E.; Barden, M. C.; Brennan, P. E.; Ahmed, G.; Tran, V.; Ho, D. M.
Tetrahedron Lett. 1999, 40, 2907-2908.

Question 5. Using clear 3D representations, provide a mechanism for the transformation below.

H3C

H3C
O

BF3OEt2
CF3SO3H

OH

H3C

70 C

CH3

CH3

CH3

HO

CH3
BF3 (or H

CH3

H3C
CH3
H

H
HO

CH3

CHO

H3C

CH3
OH

H3C

CH3

CH3

O
)

CH3
HO

BF3

H3C

CH3

F3B

CH3
BF3

O H3C
H

CHO

H3C
H
CH3
OH

Strategies & Tactics in Org. Syn. 1991, 3, 165-198

CH3
OH

CH3

Question 6. The experiment depicted below was conducted in order to determine whether or not a spirocyclic
intermediate is en route to product in the Pictet-Spengler reaction.
Part A. Provide a mechanism that accounts for the observed labelling pattern of the products. Assume that product
formation is the only irreversible step.
CH3

CH3

N
N

CH3

CH3

CH3
N
CH3

N
H

N
H

HCl

N
B H

+
D

N
H

CH3

D2O, CD3OD
80 C, 3 h

CH3

D
D

N
N

CH2 +

CH3

N
H

N
H

D
D

A:B:C:D ~ 1:1:1:1
CH3

CH3

CH3
N

Cl
CH3

CH2O

CD2O

CH3

H
H

H2O

N
H

H2O

N
H

CH3

D
D
Cl

H3C
N

CH3

CH3

Cl
CH3

N
N

CH3
Cl

CH3

N
H

CH3
N
N
H

CD2O
D
N
H

CH3

+ HCl
H

CH3

H2O

N
H

Cl

CH3

CH3
N

C
D

N
H

CH3

Cl

Cl

H3C

D
N
H

N
H

N
N

Cl
CH3

HD

Part B. Bailey concluded that the above experiment was proof that a spirocycle was involved in the pathway leading
to product formation in the Pictet-Spengler reaction. However, he does note that the experiment does not rule out a
mechanism where product formation occurs via direct attack of the indole 2-position on the iminium ion as shown
below (i.e. the pathway leading from starting material to product does not include a spirocycle)? Explain why this is
in fact the case.
CH3

CH3
N
N
H

CH3

N
H

N
H

CH3

Cl
CH3

CH3

N
H

N
H

Cl

The labelling experiment does not rule out the following scenario: Spirocycle breakdown via iminium ion formation is
faster than product formation via attack of the indole 2-position which in turn is much faster than product formation
via CC migration from the spirocycle intermediate (i.e. the latter is so slow it is not observed).
H3C

N
N
H
N
H

CH3

CH3

Cl Very Fast
CH3

CH3

Very Fast

Cl
CH3

N
N

Cl
N

Moderate
CH3

N
H

Cl

CH3

D
D

N
H

Very Slow

Very Slow

Moderate

Product

Product

CH3

CH3

N
H

HD

Direct Proof of the Involvement of a Spiro Intermediate in the Pictet-Spengler Reaction. Bailey, P. D.
J. Chem. Res. 1987, 202-203.

Question 7. Fitjer and co-workers have reported a very interesting approach to the [3,3,3]propellane 1. This tricyclic
ketone may be produced in quantitative yield through acid-catalyzed rearrangement of ketones 2 or 3.
O

(eq 1)

100%
2

(eq 2)

100%
3

Please provide a plausible mechanism for the rearrangement 21 (eq 1). Use 3-dimensional representations where
appropriate to illustrate your answer.
O

H
OH

O
OH

OH

Towards A Synthesis of ()Modhephene Via Cascade Rearrangement: Synthesis and Rearrangement of

Dispiro[3.0.3.2]Undecane to [3.3.3]Propellanes. Fitjer, L.; Majewski, M.; Kanschik, A.Tetrahedron Lett.
1988, 29, 1263-1264.

Question 8. Barriault recently published the following Lewis-acid mediated reaction cascade as a strategy to rapidly
assemble highly functionalized bicycloalkanones. Using clear 3D representations, please provide a mechanism that
includes a rationalization for the relative stereochemistry observed in the product.
OTBS

H
O

+
O

O
Me

SnCl4 (1.0 equiv)

TMSOTf (0.25 equiv)

CH2Cl2, 78 C

OTBS

96% yield

H
O
Me

Me

Me

LA

O
H

Dienophile

Pinacol Rearrangement
(bond which is correctly
aligned migrates)

O
O
LA

O-LA

LA

LAO
H

R
O

Me

Endo Diels-Alder
(on convex face,
regiochemistry as
dictated by product)

Me

O
Me

Me

Prins

LA
O

Me

LA

Me

acetonide
cleavage

LA
O

H
O

Me

Me

Me
Me

Synthesis of Highly Functionalized Bicyclo[m.n.1]alkanones via a Cationic Reaction Cascade. Lavigen, R. M. A.;
Riou, M.; Girardin, M.; Morency, L.; Barriault, L. Org. Lett. 2005, 7, 5921-5923

Question 9. Using clear 3D representations, provide a mechanism for the transformation below.

H3CO

OTES

SnCl4, CH2Cl2, 0oC

H
H

88%

H3CO

OTES

Cl4Sn
O

CHO
H

OTES

OTES

H3C

Prins

SnCl4

H
H

CHO
O

TES

OCH3

Pinacol

O
TES

Stereocontrolled Construction of Either Stereoisomer of 12-Oxatricyclo[6.3.1.02,7]dodecanes Using Prins-Pinacol

Reactions. Overman, L. E.; Velthulsen, E. J. Org. Lett. 2004, 6, 3853-3856.