MOS

Solutions Manual for
MODERN ORGANIC SYNTHESIS:

An Introduction

Michael H. Nantz University of Louisville

Hasan Palandoken Western Kentucky University

George S. Zwiefel University of California, Davis

W. H. Freeman and Company New York

ISBN 13: 97807167-7494-5 ISBN 10: 0-7167-7494-1

© 2006 by W. H. Freeman and Company All rights reserved

Printed in the United States of America

First printing

W. H. Freeman and Company 41 Madison Avenue

New York, NY 10010

Houndmills, Basingstoke RG21 GXS, England

www.whfrccman.com

Contents

Preface iv

CHAPTER 1. SYNTHETIC DESIGN 1

CHAPTER 2. STEREOCHEMICAL CONSIDERATIONS IN PLANNING

SYNTHESES 22

CHAPTER 3. THE CONCEPT OF PROTECTING FUNCTIONAL GROUPS 40

CHAPTER 4. FUNCTIONAL GROUP TRANSFORMATIONS:

OXIDATION AND REDUCTION

CHAPTER 5. FUNCTIONAL GROUP TRANSFORMATIONS:

THE CHEMISTRY OF CARBON-CARBON 3t-BONDS

AND RELATED REACTIONS 79

CHAPTER 6. FORMATION OF CARBON-CARBON SINGLE BONDS

VIA ENOLATE ANIONS 107

CHAPTER 7. FORMATION OF CARBON-CARBON BONDS VIA ORGANOMETALLIC REAGENTS

136

CHAPTER 8. FORMATION OF CARBON·CARBON n-BONDS

165

CHAPTER 9. SYNTHESES OF CARBOCYCLIC SYSTEMS

186

55

iii

Preface

How does an organic chemist go about synthesizing a desired molecule? The goal of this Solutions Manual is not only to provide you with the "correct" answers to end-ofchapter problems, but also to give you the opportunity to develop a methodical approach to synthesizing a given target molecule using the tools and concepts covered in Modern Organic Synthesis: An Introduction.

We assume that the student is well acquainted with the basic concepts of organic chemistry taught at the sophomore level. The introductory chapters provide step-by-step solutions to illustrate how a problem is broken down to smaller problems and solved. Later chapters assume the student is well versed in the concepts covered in the previous chapters; however, the key steps involved in the solutions are highlighted. Throughout the manual, literature references are provided for problems that have been inspired by 'real' world examples.

To assimilate synthetic methodologies and to integrate them into a synthetic design requires actual problem solving and not merely looking at the text. Only by writing the answer do we pay attention to details such as proper choice of reagents, reaction conditions, mechanistic implications, and so forth. Thus, it is important that you refer to the Solutions Manual only after you have made a real effort to solve the problem, or simply to verify that your approach is the same as or even better than the one presented in the manual.

We are grateful to the Chemistry 131 students at UC Davis and especially to the teaching assistants of the course for their suggestions and contributions to the development of the problem sets.

Michael Nantz, Hasan Palandoken and George Zweifel June 2006

iv

ABBREVIATIONS

Ac acetyl. acetate

acae acetylacetonate

ATBN 2,2' -azobisisobutyronitrile

anhydr anhydrous

A PA 3-amillopropylamine

aq aqueous

ann atmosphere

9-BBN 9-borabicyclo[3.3.1]nonane

Bn benzyl

Boc tert-blltoxycarbonyl

bp boiling point

BPS rcrr-butyldiphenylsilyl

n-Bll n-butyl

s-Bu sec-butyl

r-Bu tert-butyI

Bz benzoyl

cat. catalytic

CBS 2.5-oxazoborolidine

Cbz benzy loxycarbonyl

CDr carbony ldiirnidazole

Chx cycIohexyl

Cp cyclopentadienyl

CSA 1 O-camphorsu Ifonie acid

DABCO 1,4-diazabicyclo[2. 2.2]octane

DBN .I,5-diazabicyclo[4.3.0]

non-e-erie

DBU .I.8-diazabicyclo[5.4.0]

undec-? -ene

DCC l.3-dicyclohexy1carbodiimide

DDQ 2.3-dichloro-5.6-dicyano-

1.4-benzoquinone

de diastereomeric excess

DEAD diethyl azodicarboxylate

DET diethyl tartrate

DHP 3,4-dihydro-2H-pyran

DrAD diisopropyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DWT diisopropyl tartrate

DMAP .4-dimethy larninopyridine

DMDO dimethyldioxirane

DME l.2-dimethoxyethallc

DMF N,N-dimelhylfonnamide

DMP Dess-Martin periodinane

DMPU .N.N'-dimelhylpropyleneurea

DMS dimethyl sulfide

DMSO dimethyl sulfoxide

DS diastereofacial selectivity

ee enantiomeric excess

cq equivalents

Et : ethyl

EWG electron-withdrawing group

FO functional group

h hour

HMOS hexamethyldisilazanc

HMPA hexarncthylphosphoramide

HQ hydroquinone

hv .Iight

IBX o-iodcxybenzoic acid

imid imidazole

Ipc isopinocampheyl

KAPA potassium

3-ami nopi opylamide KI1MOS ......... potassium hexarnethyldisilazide L-Selectride .... lithium

tri-rec-butylborohydride

LAH lithium aluminum hydride

LOA .lithium diisopropylamide

LHMDS lithium

hexamethyldisilazide

mCPBA m-chloroperoxybenzoic acid

Me methyl

MEM 2-methoxyethoxymethyl

mol mole

MOM methoxymethyl

mp melting point

Ms mesyl (rnethanesulfonyl)

MS molecular sieves

MVK methyl vinyl ketone

NBS N-bromosuccinimide

NCS .N-chlorosllccinimide

NMO .N-methylmorpholille

N-oxide

NMP .N-methyl-pyrrolidinone

PCC pyridiuiurn chlorochromate

PDC pyridinium dichromate

PO protecting group

Ph phenyl

Piv pivaloyl

PMB -l-mcrhoxybenzyl

PPTS pyridinium

p-toluenesul fonate

i-Pr. iso-propyl

n·Pr n-propyl

psi.. pounds per square inch

PT 1-phenyl-lH-tetrazol-5-yl

py pyridine

Ra-Ni Raney-nickel (usually

W-TT type)

RCM ring-closing olefin

metathesis Red-AI... ......... sodium bis (2-methoxyethoxy) aluminum hydride

rt room temperature

SAE Sharpless asymmetric

expoxidation

SE synthetic equivalent

SEM 2-(trimethylsilyl)ethoxy·

methyl

Sia disiamyl

TBAF tetra-u-butylammonium

fluoride

TBS tert-bulyldimethylsilyl

TES triethylsilyl

Tf. trifluoromethanesulfonyl

TFA .trifluoroacctic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

THP tetrahydropyranyl

Thx thexyl (Me2CHMe2C-)

TIPS triisopropylsilyl

TMEDA .N,N.N',N' -tetrarnethylerhy 1-

enediamine

TMS trimethylsilyl

TMSOTf trimethylsilyl

tri l1uoromethanesul f onate

TPAP tetra-a-propylammonium

perrutheuate

'1'1' trityl (triphenylmethyl)

Ts tosyl (p-tolllenesulfonyl)

6. heat

CHAPTER!

Synthetic Design

Overview

Chapter 1 focuses on how to design and execute the synthesis of a variety of target molecules (TM) using the tools and strategies you encountered in Modern Organic Synthesis: An Introduction.

Problem 1 (Functional Group Interconversions) introduces how to recognize precursors of key functional groups present in a target molecule. Problem 2 (Umpolung) highlights the use of carbonyl group polarity reversal, an important synthetic tool. Problem 3 (Retrosynthetic Analysis) stresses approaches to disassembling a target molecule into simpler fragments and ultimately into starting materials. Problem 4 (Synthesis) provides the opportunity to put into practice these concepts by designing protocols for the syntheses of various target molecules.

Key Concepts

..

Retrosynthetic analysis Synthetic equivalent (SE)

Functional group intcrconversion (FGI) Carbonyl group polarity reversal (Umpolung)

..

..

2 • Chapter 1 Synthetic Design

SOLUTIONS TO CHAPTER 1 PROBLEMS

The more challenging problems are identified by an asterisk (*).

1. Functional Group Interconversion. Show how each of the following compounds can be prepared from the given starting material.

a.

Solution:

FGls in this problem:

1. Primary (10) alkyl chloride to ethyl ester

2. 10 alcohol to nitrile

o

o

1. DHP ,cat. TsOH

2a. Mg, Et20

2b. CO2

3. EtOH, cat. H2S04

4. TsCI, py

Step 1 Step 2a

The 10 alcohol is protected with dihydropyran (DHP).

Reaction of an alkyl chloride with magnesium (Mg) provides the corresponding Grignard reagent (conversion of an electrophilic carbon to a nucleophilic carbon).

Reaction of a Grignard reagent with carbon dioxide affords the carboxylic acid.

Fischer esterification (reaction of a carboxylic acid with excess alcohol and a strong acid catalyst).

The 10 alcohol is converted to a good leaving group (tosylate) for the ensuing displacement reaction (Step 5).

SN2 displacement of the tosylate group with cyanide anion provides the TM.

Step 2b

Step 3

Step 4

Step 5

b.

Solution:

FGI in this problem:

Carboxylic acid to 10 amine

Solutions to Chapter I Problems • 3

Step 1

Step 2 Step 3a

Steps 3b+c

c.

Solution:

Carboxylic' acid is converted to an acyl chloride with thionyl chloride (SOCh) or oxalyl chloride [(CO)2Ch].

Reaction of the acyl chloride with ammonia (NH3) affords the amide. Reduction of the amide with lithium aluminum hydride (LiAIH4) provides the TM.

Workup protocol.

o

exOAC

.;==(CHs

H H


1. Alkene to acetate

2. Alkene to a higher carbon homolog (Z)-alkene

(Note: Acetate and propenyl functionalities need to be trans to each other.)

3. Lindlar's cat.,

1. mCPBA ex.OH H2, EtOH, exOAC

O CH2CI2. 0 °C quinoline

I ------.,.. ----'-----l~ •• =--,CH3

2a. CHsC==CMgBr •• ~ 4. CH3C(O)CI / \

THF CHs py H H

2b. aq NaHC03

Step 1 Step 2a

Step 2b Step 3

Step 4

d.

Conversion of the alkene to the epoxide.

Epoxide opening proceeds via SN2 displacement to give the transadduct.

Workup protocol.

Semi-hydrogenation of the triple bond with Lindlar's catalyst gives the (Z)-alkene.

Conversion of the alcohol to the acetate with acetyl chloride (CH3C(O)CI or AcCI) provides the TM.


Solution:

FGI in this problem:

One-carbon homologation of a terminal double bond to a terminally deuterated carbon

Step 1 Step 2 Step 3

*c.

Solution:

1a. BH3'THF

1 b. NaOH, H202

2. PCC, CH2CI2

3. Ph3P=CD2 toluene

~CHO

~D

o

Hydroboration-oxidation yields the 10 alcohol.

Oxidation with pyridinium chlorochromate (PCC) affords the aldehyde. Wittig reaction provides the TM. (Note: The ylide reagent is prepared

by treating Ph3P with CD31 to obtain Ph3P+CD3·r and followed by deprotonation with n-BuLi.)

o

MJ.-HO I OH


1. Carboxylic acid to benzyl ether

2. 10 alcohol to carboxylic acid

1 3

HOjOTHP

3a. KH, THF, a -c

3b. PhCH2Br --~~~----~ TM

4. H+, H20 55%

5. Jones oxidation

Step 1 Step 2a

Step 2b Step 3 Step 4 Step 5

10 alcohol at C(3) is protected as its tetrahydropyranyl (THP) ether. Reduction of the carboxylic acid with lithium aluminum hydride (LiAIH4) affords the alcohol.

Workup protocol.

Williamson ether synthesis provides the C(l) benzyl ether. THP hydrolysis at C(3).

Jones oxidation produces the TM in 55% overall yield.

Reference: McGuirk, P. R.; Collum, D. B. 1. Org. Chern. 1984,49,843.


*f.

THPO/···.~ ~ O~

o

Solution:


1. Tetrahydropyran-2-yloxymethyl (THPOCH2-) to carbonyl (C=O)

2. Carbonyl (C=O) to methylene (-CHr)

1 tr'= 1a.LiAIH4,THF T("=12

THPO/···· -- 1b. NaOH, H20 HO: --

o 4 ------;;;,~ HO 4

o 2. HCI, MeOH OH

H~ o ~

OH

4. Cr03, H2S04 acetone, H20

Jones oxidation

HO~

Lactol (hemiacetal)

Step la

Reduction of the lactone with lithium aluminum hydride LiAlH4 provides the diol.

Workup protocol.

THP hydrolysis affords the triol with C(l), C(2) and C(4) bearing the hydroxyl groups.

Oxidative cleavage of the 1,2-diol [C(1)-C(2)] with sodium periodate (NaI04) gives the aldehyde at C(2).

Acidic media of Jones oxidation allows the in-situ formation of the lactol (a hemiacetal), which is then oxidized to the lactone (TM).

Step lb Step 2

Step 3 Step 4

Reference: For a similar synthesis, see Takano, S.; Tamura, N.; Ogasawar, K . .J Chern, Soc., Chem. Commun. 1981, 1155.

2. Umpolung. Show how each of the following compounds can be prepared from the given starting material using either a formyl or an acyl anion equivalent in the synthetic scheme.

a.


Solution:

1 a. n-BuLi, THF 1 b. I(CH2)sCI

2. n-BuLi, THF -78°C

1,3-dithiane pKa = 31

3. HgO, HgCI2 MeOH, H20

Step 1 b Selective SN2 displacement of the iodide (better leaving group than chloride).

Step 2 Intramolecular displacement of the chloride.

b.

o n-pr~ ~

o

H~

o

Solution:

02N

~ 1. CH3N02, NaOMe ~ 2. TiCI3, H20

MeOH ~ Net-type reaction

TM

nitromethane pKa = 10

o

Note that the deprotonation of the strong acid nitromethane (pKa = 10) IS accomplished using the relatively weak base sodium methoxide (NaOMe).

c.

o II

CICH2(CH2)2 - C = C- (CH2)4CH3 ~ CH3(CH2)gC(CH2hCH = CH(CH2)4CH3

cis

Solution:

CI~

THF

Solutions to Chapter 1 Problems • 7

2. HgCI2, HgO

acetone, H20 0

3. H2, cat. Pd/BaS04 CH3(CH2)g

EtOH, quinoline

cis

Reference: For an analogous synthesis, see Smith, R. G.; Daves, Jr., G. D.; .

Daterman, G. E . .! Org. Chem. 1975,40, 1593.

*d.

ctMe

OMe

Solution:

o 1[ ()<~e 1 6 THF

sf']

HaS

Me

1

2.HgO HgCI2

MeOH H20

6

OMe

2+ H~··O

H-0~' \ Me

4:1

~

"OMe H

methanolysis of the 30 allylic alcohol

(1 ,2-addition prevails in the absence of HMPA)

*e.

o

~H

o :

~ ~C02Me

Solution:

o

~H

1a. TMSCN, Znl2

CH2CI2 OR1

1b.1N HCI ~ 1

-2';;";'. #'--?'---O ...... E-t--1IIo> /~6~H

4a. PPTS, MeOH acetal hydrolysis

[+C02Me ]_4_b_. ~_:_~_C_O-,3111o> ~C02Me

cyanohydrin, unstable to base


Step 3b The resonance-stabilized enolate anion reacts both chemo- and regioselectively: iodide displacement occurs in preference to 1,2-addition; alkylation occurs a to the nitrile moiety.

Reference: For an analogous synthesis, see Kang, S. H.; Lee, H. S. Tetrahedron Lett. 1995,36,6713.

3. Retrosynthetic Analysis - One-Step Disconnections. For each of the following compounds, suggest a one-step disconnection. Use FGIs as needed. Show charge patterns, the synthons, and the corresponding synthetic equivalents.

a.

~~

(±)-multistriatin

Retrosynthetic analysis:

(±)-multistriatin (an acetal)

synthetic equivalent (SE)

Synthesis:

~o

SnCI4 toluene

~]

___.... TM

63%

mixture of diastereomers

Lewis acid-catalyzed (SnCl4) ring opening of the epoxide IS regioselective, placing the nucleophile at the more substituted carbon.

Reference: Pearce, G. T.; Gore, W. E.; Silverstein, R. M. J. Org. Chern. 1976, 41,2797.


b.

Retrosynthetic analysis:'

o

o

A

B

SEs

Synthesis:

o

~

a. LDA

THF, -78°C

b. SE B

A

c.
Me
M~H =>
(±)-terpineol Retrosynthetic analysis:

(±)-terpineol

Me Me

0~r.

M:+OH +A~OH

Me Me I

Me

cyclohexene ~ Diels-Alder transform

The 30 allylic alcohol is not well suited as a dienophile (bulky, acid-sensitive). A better choice is methyl acrylate ( electron-deficient alkene). Addition of MeMgBr to the ester after cycloaddition furnishes the 30 alcohol moiety.


Synthesis:

Me

~

~

1 . Me02C , heat

Diels-Alder reaction

2. MeMgBr (2 eq)

Me

(j (±)-terpineol Me+OH

Me

d.

o OH

HO

OMe

gingerol


o OH Meo~~...l__ C H

I n- 5 11

HO ,9

gingerol

o Meo~_

Jl) ...

HO III

+

III

o Meo~

HO)l) A

o +)l_

H n-C5H11

SEs B

Synthesis:

o Meo~

TMsoN SEA

a. LOA 0 OH

THF,-78°C ~

_b_. S_E:--B ~ ..... MeO I -.::::: n-C5H11

c. H+, H20 HO'o

workup cleaves TMS group gingerol

53%

Reference: Denniff, P.; Macleod, I.; Whiting, D. A. J. Chern. Soc., Perkin Trans. 11981, 82.

e.



o

::>-to

o EtO~ Et02C~\~J

{} SE

Add an electron-withdrawing group to obtain the desired charge pattern

m~

Et02C~)

Ii

conjugate addition

Synthesis:

1. NaH, DME Dieckmann condensation

o Et02C--Co ~-keto ester

2. KOH, EtOH +

3. H ,heat

-C02


Intramolecular condensation of two esters (Dieckmann condensation). Saponification of the ethyl ester provides the ~-keto carboxylic acid. Decarboxylation of the carboxylic acid (Note: This requires a ~-keto group.)

f.


o

~~ UO~\

o

~

1,5-dicarbonyl

III

o~

SE

Generally, the alkylation of active methylene compounds proceeds in good yield. However, in this case, as illustrated below, the alkylation requires displacement of


a sterically hindered halide. Thus, the alkyation approach (shown below) is not recommended.

o 0

)ty~~O ~ ~ '~-O~+~ ==

U U hindered electrophile

4. Synthesis. Outline a retrosynthetic scheme for each of the following target molecules using the indicated starting material. Show (1) the analysis (including FGI, synthons, and synthetic equivalents) and (2) the synthesis of each TM.

a.

~O Y

o

from

CI

~OH

Y

OMe

OMe


CI o~~O. q:o~+~O

~ I~

o 0

OMe OMe

CI ~O;rr~Br

y 8 (SE)

OMe

III

1,3-diketone A (SE)

CI

qOH ~

OMe

D (SE)

+~Br=Br~Br C (SE)

OMe


Synthesis:

o 1b. C

CI

B _2_._N_a_I,_a_ce_t_on_e ... q: O~I FInkelstein

reaction

OMe

Step 1 Step 2

Phenol (pKa = 10) deprotonation and alkylation gives B.

Conversion of the alkyl bromide to the corresponding alkyl iodide (Finkelstein reaction).

Alkylation of the 1 ,3-diketone enol ate A provides the TM.

Step 3

Reference: For a similar synthesis, see Diana, G. D.; Salvador, U. J.; Zalay, E. S.; Carabateas, P. M.; Williams, G. 1.; Collins, J. C. J. Med. Chern. 1977,20, 757.

b.

o

~O

c5 p

O~

o

(- )-pyrenophorin (antifungal compound)

from

~I OH


o

~O

~ P O~

o

(- )-pyrenophorin

~I OH

A (SE)

~+ OH

+

o 2~COOH =>

OH -\. dissonant Umpolung

symmetry

III

¢::

Wittig


Synthesis:

c

1a. LOA, THF 1b.~1

OTHP

(l

S S

~CHO 6THP

2. e, toluene

3a. UOH, MeOH 3b. HCI

(l

S S ~COOH OH

(l

<, ./"-....SXS~/p T "" -....:? \.

c5 P

x, /..... ..... ..f._

O/"'~"SXS <;»: <,

V

6. HgCI2, HgO MeOH, H20

TM

Step la Step Ib

Deprotonation using the non-nucleophilic base LDA avoids 1,2-addition to the aldehyde C.

Note that the -OH group of the alkyl iodide substrate A must be protected prior to alkylation.

Wittig reaction.

Ester saponification and acidification, which also cleaves the acidsensitive THP group.

Head-to-tail esterifications of two hydroxy acid substrates give the bislactone.

Removal of the dithiane provides the TM.

Step 2 Step 3

Step 4

Step 5

Reference: For an analogous synthesis, see Seebach, D.; Seuring, B.; Kalinowski, H.-O.; Lubosh, W.; Renger, B. Angew. Chern. Int. Ed. 1977,16,264.

c.

from

/'-.../Br



+

CH20H == formaldehyde

SE

_ MevMgBr _ ~ _ MeVBr _ FGI Me OH

~ -r ~ ~ ~~..s"~

-JJ

Me 2~- + }-OH

III III

2/~Br SE

FGI

¢: 2 ~MgBr MeC02Me

SE

Synthesis:

o )loMe

1 a. n-PrMgBr (2 eq) Et20

1b. Ht; H20 (workup)

Me OH 2. PBr3 Me Br

~__..~

3a. Mg, Et20 3b.H2C=O

Step 3 The reaction of a tertiary Grignard reagent with a hindered ketone may result in reduction and/or enolization of the ketone. However, in the present example, the use of formaldehyde (an excellent electrophile) circumvents these side reactions.

d.

from

Br~



r\._.. OH r\._.. OH

LJ~~ => LJ+ +-~

TM . III III

0=0 BrMg~ ~ Br~

A (SE)

B (SE)

UFGI
HOJ + -~ ¢: HO~~I
III III
0 BrMg~ ~ Br~
D
SE C (SE) Synthesis:

B

3a. Mg, Et20 3b.A

TM

e.

M~ 0

CI~~ from

Ph Valium (tranquilizer)

f)NHMe -..::::

CI



o

EtO-'\_ ==

NH2

A (SE)

Me

~~o r(y"- )

CI~N Ph

Me

('yNI(NH2

CI~O Ph

FGI

=>

The imine is the nitrogen analog of the C=O group and is formed by the reaction of a 10 amine with an aldehyde or ketone.

ONHMe ONHMe

== I ~ +

CI CI ~-

D (SE)

EAS = electrophilic aromatic substitution

Synthesis:

ONHMe ~

CI

D

1. CH3C(O)CI 2a. C, AICI3

2b. rr-, H20 2c. NaOH, H20

3. A B

heat

TM

+

Me I

r(yN-

CI~O Ph

III

EAS

¢:

Me

I

~NH

CI~"""''f° Ph B (SE)

Reaction of CH3C(O)CI with D affords the amide (weak activator compared to an amine), which should circumvent multiple substitutions in Step 2a.

Electrophilic aromatic substitution occurs ortho to the amide. Workup.

Hydrolysis of the amide provides B.

Reaction of the 2° amine (of the aromatic ring B) with the ethyl ester forms the amide while the reaction of the 1 ° amine (of glycine A) with the carbonyl group forms the imine.

Step 1

Step 2a Step 2b Step 2c Step 3

Reference: For an analogous synthesis, see Gates, M. J. Org. Chem. 1980, 45, 1675.


f.

OH

<, I ,-----. acetal protecting group for ,0 1 ,2-diols; cleaved by W, H20

0~C02Et .

HO

from


symmetry

OH ~2HO~+

III

+

-

c=o

OH 0 OH

HO~~I"~OH

A (SE)

III

<:J

B (SE)

OH FGI OH

HO~OH ¢: HO~Br

Synthesis:

1 a. LiAIH4, Et20

1 b. Na2S04, H20

2. CBr4, Ph3P Et3N, CH2CI2

')-0

O~Br C

73%

HMPA, THF -78°C

4b. C

4a. n-BuLi THF

74%

70%


6. H+, H20

HO

OH

Step 2 Conversion of the 10 alcohol to the 10 alkyl bromide.

Reference: Sharma, A.; Iyer,P.; Gamre, S.; Chattopadhyay, S. Synthesis 2004, 1037.


g.

~CHO o :

~d

Retrosynthetic analysis:'

#"~ =>

OH (CH2)4CH3

homopropargylic

alcohol => epoxide

III

~

(CH2)4CH3

B (SE)

-lJ, FGI

acetylene A (SE)

FGI

HO~~ ¢:: TSO~

OH (CH2)4CH3 OH (CH2)4CH3

C

U FGI (Wittig reaction)

HO~CHO +

OH E

Ph3P=CH(CH2)4CH3 D

Synthesis:

5a, HC=CLi

3, TsCI (1 eq), THF,

py HMPA

C---- .... B TM

4, DBU, THF se. H+, H20 62%

Step 1

The diol E must be protected (acetal, in this example) for the Wittig reaction to proceed. The Wittig reagent is prepared from the phosphonium iodide using sodium dimsylate, NaCH2S(O)CH3.

Mild acid hydrolysis of the acetonide prevents acid-induced isomerization of the (Z)-alkene.

Selective tosylation of the 10 alcohol.

DBU (1 ,8-diazabicyclo[5.4.0]undec-7 -ene), a bulky, non-nucleophilic nitrogen base, is used to form the epoxide.

Under basic conditions, the epoxide ring opening proceeds at the less substituted carbon (compare to Problem 3a).

Workup protocol.

Step 2

Step 3 Step 4

Step 5a

Step 5b

Reference: Corey, E. J.; Kang, J. J. Am. Chern. Soc. 1981,103,4618.


*h.

HO"'l"\_o ,;._r from

HO

eOOH HO+H H+OH eOOH


H0x=~ HO):+ - <:)
,.(=0 => + .,9=0 =
HO HO +
consider the III 8 (SE)
symmetry I OH
HO~ FGI HO~ FGI HOrC02H
=> =>
HO HO HO e02H
I OH
A (SE) ijFGI
e02H
H+OH
HO H
C02H Synthesis:

1. Dimethoxypropane, ~OH

MeOH, p- TsOH XO •.•

2a. LiAIH4, THF 0

2b. EtOAc OH

2c. NaOH, H20

[Li+_<S)]

5a. S

3. TsCI, py

4. Nal, acetone

THF

H

><:~t)

I

H°j)=O HO

5b. n-BuLi


Step 2b+c Workup protocol.

Reference: For an analogous synthesis, see Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J.-J.; Rokach, J. J. Org. Chem. 1995,60, 7548.


*' 1.

from

o

6


l) ~ °0-0H => O~JH => 0"(+

o 0 retro-eldol 0 Umpolung 0

o

+ -ll H

1 ,4-diketone III III
A
0 CH3N02
0 0 ~ (formyl anion
Ph3P~ + 6 ¢: oN\#' equivalent)
Wittig 0 B
D (SE)
C (SE)
Synthesis:
1. 0 0 2.~MgBr
0 (2 eq)
6 (EtO)2P~ 4. NaOH
Cui, Et20 (0.1 eq)
C A TM
KH, EtOH, 5 °C 3. OS04, Nal04 EtOH, rt
t-BuOH, H2O Step 1 (3-keto phosphonates often are used for olefination of ketones (Homer-Wadsworth-Emmons modification of the Wittig reaction).

Steps 2 + 3 The cuprate-mediated 1,4-addition and subsequent Lemieux-Johnson oxidation of a vinyl group are excellent procedures for the introduction of the (3-formyl group.

Step 4 Intramolecular aldol condensation provides the TM.

Reference: For the synthetic sequence applied to a similar TM, see Corey, E. J.; Smith, J. G. J Am. Chern. Soc. 1979,101, 1038.

CHAPTER 2

Stereochemical Considerations in Planning Syntheses

Overview

Chapter 2 focuses on conformational analysis as a tool for assessing the relative reactivity and stereochemistry of cyclic compounds.

Problems 1-3 emphasize the three dimensional representation of various cyclic molecules and evaluation of their energies by the A, G, and U parameters. In Problems 4-6, we apply conformational analysis to predict the reactivity of carbocyclic systems toward various reagents and to gather information regarding the preferred stereochemical course of the corresponding reactions. Further examples of applications of conformational analysis in organic synthesis arc incorporated in Problems 7-9.

Key Concepts

•

Conformational analysis

Corey and Feiner's A, G, and U energy parameters AI,2 strain

•

•

22

Solutions to Chapter 2 Problems 0 23



1. Draw the chair or the half-chair conformations (where applicable) for each of the molecules shown. below and determine the corresponding Eo and ~Eo values. Use the A, G, and U values of Table 2.3 and assume 0.7 kcal/mol for Me/H A 1,2 strain.

Me

Q"'OH

;-Pr

a.

c.

Solution:

a.

Q"'OH

i-Pr

interactions:

H ;-Pr

fSf(

Me H

A

one 1 ,3-diaxial Me / OH one 1,3-diaxial Me / H one 1 ,3-diaxial OH / H two 1 ,3-diaxial i-Pr / H

i-Pr

¢::e

Me

b.

Me

M",CO

e H

f.

Me"Q .. Me Me
((e
Me Me
c. d.
cD OWE'
• OEt
H Me
H Me
g. h. ~OH

Me ~i-Pr

B

one 1 ,2-diequatorial OH / i-Pr

A: Eo = UMe + UOH + 112 (AMe + AOH) + A-Pr = 1.8 + 0.9 + 112 (1.8 + 0.9) + 2.1

:;::: 6.15 kcal/mol

B: Eo :;::: GOH + Gi-Pr = 0.2 + 0.8

:;::: 1.0 kcallmol

~ED;:: 6.15 -1.0 ;:: 5.15 kcal/mol

24 • Chapter 2 Stereochemical Considerations in Planning Syntheses

b.

i-Pr

¢r:e

Me

interactions:

A: ED = AMe + 2/3 (AMe) = 1.8 + 2/3 (1.8) = 3.0 kcal/mol

B: ED = Ai-Pr + GMe + GMe = 2.1+ 0.4 + 0.4

= 2.9 kcal/mol

c.

H

f=Y¥(0

H Me

A

two 1,3-diaxial Me / H 2/3 1,3-diaxial Me / H (cyclohexanone system)

~ED = 3.0 - 2.9 = 0.1 kcallmol

eq'H~?2 __

v'<' ---

Me H Me eq'

A

interactions: two A 1,2 strain Me / H

A: ED = 2 (A1,2 Me/I-I) = 2 (0.7)

= 1.4 kcal/mol

B: ED = UMe + UMc + A 1,2 Me/H = 1.8 + 1.8 + 0.7

= 4.3 kcal/mol

~ED = 4.3 - 1.4 = 2.9 kcal/mol

H~i-pr

Me

Me 0

B

two 1,3-diaxial i-Pr / H

one 1 ,2-diequatorial Me I Me

,q'HMo>"'i ~

Me ax' Me

B

one A 1,2 strain Me / H one 1,3-diaxial Me I Me

Solutions to Chapter 2 Problems e 25

d.

Me

A.,Me

UMe

r!~Me~

Me A-

~_~~:eq,

Me

B

interactions:

one 1 ,3-diaxial Me / Me one 1 ,3-diaxial Me / H

one A 1,2 strain Me/H

one 1 ,2-diequatorial Me / Me

A: ED = UMe + UMe + 112 (AMe) = 1.8 + 1.8 + 0.9

= 4.5 kcallmol

B: ED = 2 (GMe + GMe) + A 1,2 Me/H = 2 (0.4 + 0.4) + 0.7

= 2.3 kcal/mol

liED = 4.5 - 2.3 = 2.2 kcallmol

e.

interactions:

NMe

HO H

A

one 1 ,3-diaxial Me lOMe one 1 ,3-diaxial Me I H one 1 ,3-diaxial OMe I H one 1 ,3-diaxial OH / H

Me HOmOMe

Me H

B

two 1 ,3-diaxial Me / H

one 1,2-diequatorial Me IOH

A: ED = UMe + UOMe + 112 (AMe + AOMe + AOH) = 1.8 + 0.9 + 112 (1.8 + 0.9 +0.9)

= 4.5 kcal/mol

B: ED = AMe + GMe+ GOH = 1.8 + 0.4 + 0.2

= 2.4 kcallmol

liED = 4.5 - 2.4 = 2.1 kcal/mol


f.

13 face:

interactions: one 1 ,3-diaxial C(9)-Me I H

11/2 AMe 1

Me

M.··ro

e 6 H 4

interactions:

6

H

Me

A

a face:

one 1 ,3-diaxial C(5)-CH21 H one 1 ,3-diaxial C(7)-CH2 I H

1 AACH21

A: ED = 112 CAMe) + ARCH2 = 0.9 + 1.8

= 2.7 kcal/mol

B: ED = AMe + UMe + URCH2 + 112 (AMe + ARCH2) = 1.8 + 1.8 + 1.8 + 112 (1.8 + 1.8)

= 7.2 kcal/mol

13 face:

two 1 ,3-diaxial C(9)-Me I H

lAMe I

H

vs

H

B

a face:

one 1,3-diaxial C(6)-Me I C(4)-CH2 one 1,3-diaxial C(6)-Me I H

one 1 ,3-diaxial C(4)-CH21 H

ilED = 7.2 - 2.7 = 4.5 kcal/mol

g.

f3 face:

two 1 ,3-diaxial C(4)-Me / H interactions: one 1,2-diequatorial

C(1 }-OH / C(8)-CH2

lAMe + GOH of GRCH21

~ \td

Me

A

interactions:

a face:

one 1 ,3-diaxial C(5)-CH2 / H one 1 ,3-diaxial C(1 )-CH2 / H

I ARCH2 + 1/2 ARCH2 I

A: ED = AMe + GOH + GRCH2 + ARCH2 + 112 (ARCH2) = 1.8 + 0.2 + 0.4 + 1.8 + 112 (1.8)

= 5.1 kcal/mol

B: ED = AOH + GMe + GRCH2 + ARCH2 + 112 (ARCH2) = 0.9 + 0.4 + 0.4 + 1.8 + 1/2 (1.8)

= 4.4 kcal/mol

i1ED = 5.1 - 4.4 = 0.6 kcal/mol


j3 face:

two 1,3-diaxial C(1 )-OH / H one 1,2-diequatorial C(4)-Me / C(5)-CH2

I AOH + GMe + GRCH21

vs

H

B

a face:

two 1,3-diaxial C(8)-CH2 / H one 1 ,3-diaxial C(4)-CH2 / H

I ARCH2 + 1/2 ARCH2 I


h.

j3 face:

one 1,3-diaxial C(4)-Me ! C(2)-OEt interactions: one 1,3-diaxial C(4)-Me ! H

one 1,3-diaxial C(2)-OEt / H

'I UMe + UOEt + 1/2 AMe + 1/2 AOE! 1

j3 face:

one 1,2-diequatorial C(4)-Me / C(5)-CH2

I GMe + GRCH21

o 8 H PEt

~OEt=;

~

Me

OEt

vs

OEt

A

B

interactions:

a. face:

two 1,3-diaxial C(5)-CH2! H

1 ARCH21

a. face:

one 1,3-diaxial C(2)-OEt / C(8)-CH2 one 1,3-diaxial C(2)-OEt ! H

one 1,3-diaxial C(8)-CH2 ! H

one 1,3-diaxial C(4)-CH2 / H

UOEt + URCH2+ 1/2 AOE! + 1/2 ARCH2+ 1/2 ARCH2

A: ED = UMe + UOE! + 112 (AMe) + 1/2 (AoEt) + ARCH2 = 1.8 + 0.9 + 112 (1.8) + 1/2 (0.9) + 1.8

= 5.85 kcal/mol

B: ED = GMe + GRCH2 + UOEt + URCH2 + 1/2 (AOEt) + 1/2 (ARCH2) + 112 (ARCH2) = 0.4 + 0.4 + 0.9 + 1.8 + 1/2 (0.9) + 1/2 (1.8) + 112 (1.8)

= 4.4 kcal/mol

~ED = 5.85 - 5.75 = 0.10 kcal/mol


2. Draw the most stable conformation for each of the compounds shown below.

You do not need to compute the ED and ~ED values.

o~ 0;Q ctEfXoH c&
>< : 0 >< : 0 .
OH
o OMe o .__ 'flOMe H
H ••• H ...
HO OH HO OH H H
a. b. c. d. Me Me
We
HO'" Me
: H
Me
e. f.
Solution:
a.
Me
0;Q Me~o_H
>< : 0
o OMe - 0 OCH3
H "
HO OH
H
b.
Me
Me~o
0;Q 0
>< : 0
o __ - 'flOMe
H ' H
HO bH
H OH H
A B
B is the more stable conformer. 30 • Chapter 2 Stereochemical Considerations in Planning Syntheses

c.

H

H

trans-anti-trans; each ring is in the chair conformation.

d.

d1f

H

H

cis-synods; each ring is in the chair conformation.

e.

: H Me

f.

Me

A~e

Me(J)

H H

Me

==H

chair-boat-chair-envelope

Mbve Me

Me

I

H


3. For each molecule shown below, calculate the percentage (%) of the more stable conformation at the temperature indicated.

eN

Me 9H
6"Me ¢r0H
OH Me
b. c.
500e 25°e a.

at: 25°e, 1000e

Solution:

a. eN

H i-Pr

Pi?

eN H

A

H Me

NC~"pr

B

interactions:

two 1 ,3-diaxial eN / H two 1 ,3-diaxial i-Pr / H

two 1 ,3-diaxial Me / H

A: ED = ACN + Ai-Pr = 0.2 + 2.1

= 2.3 kcallmol

B: ED =AMe

= 1.8 kcallmol

B has fewer unfavorable interactions (lower ED), therefore, it is the more stable conformer.

The percentage of conformer B at a given temperature can be calculated as shown below:

~ED = 1.8 - 2.3 = - 0.5 kcallmol

Assuming ~ED ~ ~Go = -RT InKeq

At 25°C (298 K): ~Go = - 500 kcal/mol = - (1.987 cal/Kvmol) (298 K) InKeq

InK - 500 = 0.844

eq - 1.987 x 298

conformerS Keq = 2.33 = conformer A

conformer B + conformer A = 1


2.33

%B= (100)=70% at25°C

(2.33 + 1)

At 100°C (373 K): ~Go = - 500 kcal/mol = - (1.987 cal/Konol) (373 K) 1nKeq

InK - 500 = 0.675

eq - 1.987 X 373

conformerB Keq = 1.96 = -c-o-n-fo-rm-e-r-A-

1.96

% B = (100) = 66% at 100°C

(1.96 + 1)

b.

Me

6"Me-

OH

Me~~OH

T~

H H

A

~Me

H OH

B

two 1,3-diaxial Me / H two 1 ,3-diaxial OH / H

interactions: two 1 ,3-diaxial Me I H

A: ED =AMe

= 1.8 kcal/mol

B: ED = AMe + AOH = 1.8 + 0.9

= 2.7 kcallmol

A has fewer unfavorable interactions (lower ED), therefore, it is the more stable conformer.

The percentage of conformer A at 50°C is calculated in the same manner as in Problem 3a:

~ED = 1.8 - 2.7 = - 0.9 kcal/mol

At 50°C (323 K): ~Go = - 900 kcal/mol = - (1.987 cal/Kvmol) (323 K) InKeq

11'V - 900 = 1.40

Ul"eq - 1.987 x 323

conformer B K = 4.06 = -----

eq conformer A

4.06

%A= (100)=80% at500C

(4.06 + 1)


c.

HO HO~Me

OH H

interactions:

A

one 1 ,3-diaxial OH / Me one 1,3-diaxial OH / H one 1 ,3-diaxial Me / H two 1 ,3-diaxial OH / H

B

one 1 ,2-diequatorial OH /OH

A: ED = VOH + VMe + 112 [AoH + AMe] + Am-l = 0.9 + 1.8 + 112 [0.9 + 1.8] + 0.9

= 4.95 kcal/mol

B: ED = GOI-I + GmI = 0.2 + 0.2

= 0.4 kcal/mol

B has a considerably lower ED than A, therefore, it is the more stable conformer.

The percentage of conformer B at 25°C is calculated in the same manner as in Problem 3a-b:

t!.E[) = 0.4 - 4.95 = .- 4.55 kcal/mol

At 25°C (298 K): t!.Go = - 4550 kcallmol = - (1.987 cal/Kvmol) (298 K) InKeq

InK - 4550 = 7.68

eq - 1.987 x 298

conformer B K = 2165 = -----

eq conformer A

2165

% B = (100) = 99.9% at 25°C

(2165 + 1)

4. Show the conformation of each of the following alcohols and arrange them in order of decreasing ease of esterification with p-nitrobenzoyl chloride.

HOm CH3 Hofi)
HaJj:)
H H H
a h c 34 • Chapter 2 Stereochemical Considerations in Planning Syntheses

Solution:

H

a

HO

H

H

c

The order of reactivity for esterification is c > b > a.

5. Given below are the observed a : f3 epoxide ratios from epoxidations of the decalins A and B with m-chloroperbenzoic acid (mCPBA) in CHC13. How do you explain the differences in stereoselectivity?

mCPBA CHCI3

mCPBA CHCI3

B

Solution:

o:::cO + o<£)
H H
95 5
cO + cP
"'0
60 40 p-face

I CH3

H.~~~

H~

: H

a-face

The angular CH3 group shields the ~-face of A. Hence, the a-face is more accessible for epoxidation, resulting in epoxide ratio of 95 : 5 a to ~.

Q)

H B


Although the angular CH3 group also shields the ~-face of B, the a-face of B is less accessible relative to that in A due to the axial a-face HIs resulting in the epoxide ratio of 60 : 40 a to ~.

Reference: Marshall, J.,A.; Hochstetle, A. R. J. Org. Chern. 1966,31, 1020.

6. Reagents. Show the major product formed for each of the following reactions.

a.

KOt-Bu t-BuGH

Solution:

OTs

i-pr--Cfl-H

Me

KOt-Bu t-BuOH

E2 elimination proceeds via anti-periplanar arrangement of the OTs and the adjacent H.

h.

i-Pr

cfx::

H

TsCI (1 eq) py

Solution:

i-Pr

cfx::

H

TsCI (1 eq) py

i-Pr

cfx::s

H

favored conformer

preferential tosylation of the equatorial-OH


c.

Me

~ ••• Br NaSPh (1 eq)

Br"'~ THF,O°C-rt

H

Solution:

Me ~ ••• Br==

Br"'~

H

d.

cO BrOH

H

Solution:

cO

H

e.

Me

.. rtl

D'~

BrMe

Me

Br

NaSPh (1 eq)

THF,

o °C - rt

Me ~ ••• Br

PhS~

H

Br

H

SN2 displacement of the axial-Br is sterically favored.

BrOH )Do

bromonium ion formed at the less hindered face

./?~ ~ ..

Br H

anti-periplanar and anti-parallel opening of bromonium ion

NaOEt EtOH


Solution:

rl~ ~

D Me-

EtO-._)

NaOEt EtOH

Me

m

Me

E2 elimination proceeds via anti-periplanar arrangement of the Br and the adjacent D.

*7. Consider the conformational equilibrium of the ketone below. Explain why conformer A predominates in DMSO (100% A) whereas B is the major conformer in isooctane (22% B: 78% A).

A

Me

~ A{1

o HoA

B

OH

Solution:

Me

p+;J

H----(O

Me

sterically disfavored conformer (axial Me and axial isopropenyl groups), but the intramolecular hydrogenbonding in a non-polar solvent offsets the

unfavorable steric and dipole interactions.

favored conformer; opposing dipole interaction

Reference: Suga, T.; Shishibori, T. Chemistry and Industry 1971, 733.

*8. Suggest a reason why the equilibrium below favors the conformation on the right.

+ H2N~

F

4

96


Solution:

In the compound on the left, the F and NH2R2 + groups are anti to each other, while in the compound on the right these groups are gauche to each other.

+ H2N~

~F

anti

gauche

The key orbital interactions that favor the gauche arrangement are shown below.

In addition, there is weak hydrogen bonding between the F lone pairs and one of the H's on N favoring the conformer on the right.

H <, ~

+N

t."""".: F :

••

*9. Why does the adamantyl compound shown below behave more like a ketone than an amide? (Hint: Draw the corresponding resonance hybrid.)

Solution:

+ 0-

.. M Bredt'. rule violation

A

8


The resonance hybrid B with the double bond at a bridgehead violates Bredt's rule. Therefore, without the delocalization of the nitrogen lone pair of electrons, the carbonyl moiety behaves more like a ketone than an amide.

Reference: For a crystallographic and ab initio investigation of the amide resonance model, see Quifionero, D.; Frontera, A.; Capo, M.; Ballester, P.; Sufier, -G. A.; Garau, C.; Deya, P. M. New J. Chern. 2001,25, 259.

CHAPTER 3

The Concept of Protecting Functional Groups

Overview

Chapter 3 deals with concepts of protecting functional groups. This important tool allows the chemist to manipulate one functional group selectively in the presence of others in a molecule.

Problems 1 and 2 illustrate the formation and cleavage of various protecting groups. Problems 3 and 4 introduce how to design syntheses of molecules that require the use of protecting groups. Problem 5 provides an example of how a protecting group may influence both the regio- and stereochemical outcome of a reaction sequence.

Key Concepts

• Protecting and deprotecting a functional group

• Protection ofNR groups

o N-benzylamines

o Carbamates (Boc, Cbz)

• Protection of OR groups of alcohols

o Alkyl ethers (ROBn, ROBn, ROTr)

o Silyl ethers (ROTMS, ROTBS, ROBPS)

o Acetals (ROTHP)

o Esters

• Protection of diols as acetals

o 1,2-diols (5-membered cyclic acetals)

o 1,3-diols (ri-membered cyclic acetals)

• Protection of carbonyl groups in aldehydes and ketones

o OJ O-acetals

o SJS-acetals • Deoxygenations

40




1. Reagents. Give the structure of the major products (A-G) expected from the following reactions. Assume standard aqueous workup conditions are used for product isolation.

a.

OH

II

HO OH

large excess

1. TBSCI

imid, CH2CI2

A 80%

DMF, -18°C to rt

2. Na104, CH2CI2

Solution:

OH

II

HO OH

1. TBSCI

imid, CH2CI2

o

H~

OTBS

DMF, -18°C to rt

2. Na104, CH2CI2

A 80%

Step 1 To obtain the monosilylation product, a large excess of the starting triol is used.

Step 2 Vicinal diol cleavage.

Reference: Paterson, 1.; Delgado, 0.; Florence, G. 1.; Lyothier, 1.; O'Brien, M.; Scott, J. P.; Sereinig, N. 1. Org. Chem. 2005, 70, 150.

b.

1. TsCI, py

B

Solution:

1. TsCI, py

Step 1 Conversion of the 2° alcohol to the corresponding tosylate (a good leaving group).

Step 2 Displacement of the tosylate with a hydride as the nucleophile.

(Note: Steps 1 + 2 represent a common deoxygenation procedure for alcohols.)

42 • Chapter 3 The Concept of Protecting Functional Groups

c.

1. TrCI (1 eq)

py, cat. DMAP

2. TB80Tf 2,6-lutidine, CH2CI2

Solution:

Me02C-', OH

~OH

°

1. TrCI (1 eq)

py, cat. DMAP

2. TB80Tf 2,6-lutidine, CH2CI2

3. LiBH4' THF

4. Ph3P, 12, imid

1

\.--"'r--(0TB8

(_).._.;OTr

°

C2

89%

C1 82%

3. LiBH4' THF

4. Ph3P, 12, imid

C2 89%

Me02C -"'r--(0TB8 (_).._..-OTr

°

C1

82%

Step 1 Protection of the 10 alcohol in the presence of a 20 alcohol.

Step 2 Protection of the sterically hindered 20 alcohol requires the use of the reactive silylating reagent TBSOTf.

Step 3 The milder reducing agent LiBH4 was used for the reduction of the ester moiety instead of the more powerful LiAIH4' presumably to facilitate the workup in the presence of the acid-labile OTr group.

Step 4 Conversion of the resultant 10 alcohol to the corresponding iodide.

Reference: Gu, Y.; Snider, B. B. Org. Lett. 2003, 5, 4385.

d.

° ° ~OCH3

1. HOCH2CH20H cat. TsOH

2a. CH3MgBr (2 eq), Et20 2b. aq NaHC03

3a. NaH, THF, 0 °C 3b. BnBr, cat. n-Bu4N1

Solution:

° ° ~OCH3


2a. CH3MgBr (2 eq), Et20 2b. aq NaHC03

3a. NaH, THF, 0 °C 3b. BnBr, cat. n-Bu4N1

Step 2b Workup protocol.

D

1\

° ° OBn

~

D


e.

1. n-Bu4NF (xs) THF, 0 °C to rt

2. (MeOhCMe2

BPSO~ cat. TsOH,

TBSO ••• l..1\1 ~OBn , __ ac_e_to_n_e..;_' _rt __ --l..... E1

,. ~ 3. H2, cat Pd(OHb/C 89%

Boc EtOAc, rt

4, PCC, CH2CI2

5. Ph3P=CHClOH21 THF, 0 °C

E2

6. H2, cat. Pd(OH)2/C EtOAc, rt

Solution:

1. n-Bu4NF (xs) THF, 0 °C to rt

2. (MeO)2CMe2

BPSOQ cat. TsOH, \ ""0Q 4. PCC,

acetone, rt --r CH2CI2

TBSO, .• ' N OBn ---_;_----:l.... 0.......... N OH

• 3. H2, cat. Pd(OH)2.1C

I I

Boc EtOAc, rt Boc

E1

89%

-y0~ 91OH21 o <, ····l..N~

I

Boc

5. Ph3P=CHC10H21 THF, 0 °C

6. H2, cat. Pd(OH)z/C EtOAc, rt

t:nN C H

I 12 25

Boc

E2

99%

Step 1 Deprotection of the silyl ethers. Step 2 Acetonide formation.

Step 3 Benzyl ether deprotection.

Step 4 pee oxidation of the 10 alcohol should furnish the aldehyde; however, the

authors (reference below) used the Swern oxidation.

Step 5 Wittig reaction.

Step 6 Alkene hydrogenation.

(Note: Boc, t-butoxycarbonyl, protecting group is stable to the reaction conditions in Steps 1-6.)

Reference: Wang, Q.; Sasaki, N. A. J. Org. Chern. 2004,69,4767.


f.

1. TBSOTf, 2,6-lutidine CH2CI2

F

2. DDQ, pH 7 buffer CH2CI2

3. PCC, CH2CI2

Solution:

1. TBSOTf, 2,6-lutidine CH2CI2

2. DDQ, pH 7 buffer CH2CI2

HO~C02Me OTBS

96%

Step 1 Silylation of the 20 alcohol.

Step 2 Removal of p-methoxybenzyl (PMB) ether with 2,3-dichloro-5,6-dicyanol,4-benzoquinone (DDQ) requires H20 (present in pH 7 buffer).

Step 3 pee oxidation of the 10 alcohol to the corresponding aldehyde.

Reference: Paterson, 1.; Delgado, 0.; Florence, G. 1.; Lyothier, 1.; O'Brien, M.; Scott,1. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150.

g.

1. PCC, CH2CI2, 0 °C

2. [HC=CLi] THF, -78°C

G1

4a. n-Bul,i, THF, -35°C 4b. Etl

G2

TBSO~OH

3. BPSCI, imid, DMF, rt

74% 5. PPTS, MeOH, rt 69% 6.12, Ph3P, imid, CH2CI2

Solution:

TBSO~OH

1. PCC, CH2CI2, 0 °C

2. [HC=CLi] THF, -78°C

OBPS TBSO~ G1

74%

4a. »suu THF, -35°C

4b. Etl

3. BPSCI, imid, DMF, rt

5. PPTS, MeOH, rt

OBPS

HO~

Et

6.12, Ph3P, imid, CH2CI2

OBPS

I~

G2 Et

69%


Step 5 Selective cleavage of the sterically less hindered TBS ether. Step 6 Conversion of the 10 alcohol to the corresponding iodide.

Reference: Nomura, 1.; Mukai, C. J. Org, Chern. 2004,69,1803.

2. Selectivity. Show the product(s) expected for the following transformations.

a.

(MeO)2CMe2 cat. TsOH

DMF

A

Solution:

(MeO)2CMe2 cat. TsOH

DMF

Acetal formation occurs between the cis C(2)- and C(3)-OH groups rather than between the trans C(3)- and C(4)-OH groups.

Reference: Gyergy6i, K.; T6th, A.; Bajza, 1.; Liptak, A. Synlett 1998, 127.

b.

1 a. MeLi (>2 eq) THF, 0 °C

1 b. BPS-CI (1.3 eq) imid,DMF

o

:¢o

H

2. MsCI, Et3N (xs) DMAP

81 90%

82 (alkene) 85%


Solution:

o

~o

H

1 a. MeLi (>2 eq) THF, 0 °C

1 b. BPS-CI (1 .3 eq) imid,DMF

Me Me

~OH

2. MsCI, Et3N (xs) DMAP

H OBPS

Et3~

~H

I MetCH2

~MS

H OBPS

3° mesylate

81 90%

____...~ ~Me

H OBPS

82

85%

Step lc Workup protocol.

Step 2 Elimination of the mesylate group.

Reference: Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J Org. Chern. 2004,69,4626

c.

1.TsOH toluene reflux (-H20)

C1 bridged product

2. TBS-CI (1.2 eq) Et3N, cat. DMAP cat. n-Bu4N I DMF, 0 °C

C2 75%

Solution:

1.TsOH toluene reflux

(-H20)

o 2. TBS-CI ~O

(1.2 eq)

HO OH --Et-3N-.--'I .... TBSO. 0 OH

cat. DMAP

cat. n-Bu4NI OH

DMF. 0 °C

C2 75% overall

OH

C1

Step 1 Lactonization occurs between the carboxylic acid and the -OH that is cis.


Step 2 Selective silylation of the 2°-equatorial-OH group (reaction rate: 2°eq > 2°ax > 3°); the ammonium iodide presumably produces the more reactive TBS-I species.

Reference: Setkow, M.; Kelling, A.; Schilde, U. Eur. J. Org. Chern. 2001,2735.

d.

("'yCHO O~""/

1. HC(OEtb, cat. NH4N03

2. H2NNH2

D1

3. (-BuOK, DMSO

4. H02CC02H THF, H20

02

Solution:

("'yCHO O~""/

1. HC(OEtb, cat. NH4N03

2. H2NNH2 MeOH

CH(OEt) 3. t-BuOK

("'y 2 DMSO

N~""/ 4. H02CC02H

I THF, H20

NH2 01

("'yCHO ~.",/

02

Step 1 Step 2 Step 3 Step 4

Mild conditions for the selective acetalization of the aldehyde. Hydrazone formation.

Wolff-Kischner reduction (Huang-Minlong modification). Acetal hydrolysis.

e.

1. MeNH2 (no solvent)

2. TrCI (1.0 eq), py, DMF

E1 95%

3a. LiAIH4, THF 3b. MeOH, H20

E2 97%

Solution:

1. MeNH2 (no solvent)

2. TrCI (1.0 eq), py, DMF

OH 0

TrO I II ,.Me

'~N

H

3a. LiAIH4' THF 3b. MeOH, H20

E1 95%

OH Tro~N,.Me H

E2 97%


Step 1 Lactone cleavage furnishes the amide.

Step 2 Selective protection of the resultant 10 alcohol. Step 3b Workup protocol.

Reference: Ella-Menye, J.-R.; Sharma, V.; Wang, G. J. Org. Chern. 2005, 70, 463.

f.

1. TBSCI, imid, DMF

2. K2C03, MeOH rt, 30 min.

3. PCC, CH2CI2

F1

4. MeLi (1.2 eq) Et20, -40 °C

5. n-Bu4NF THF, rt

F2

Solution:

AC0-cr0H

1. TBSCI, imid, DMF

2. K2C03, MeOH rt, 30 min.

3. PCC, CH2CI2

°VOTBS F1

58%

4. MeLi (1.2 eq) Et20, -40°C

5. n-Bu4NF THF, rt

~~~OH

F2 37%

Step 4 1,2-Addition of MeLi occurs from the less hindered face of the 5- membered ring.

Reference: Atanu Roy, A.; Schneller, S. W. J. Org. Chern. 2003, 68, 9269.

g.

G1

3. TBSCI, cat. imid, i-Pr2NEt, CH2CI2

G2

0:::0

1a. NaH, THF, O°C 1b. BnBr

2. MeOH, cat. CSA

4. H2, Pd/C, EtOH

5. PCC, CH2CI2

OH


Solution:

0:::0

t a. NaH, THF, 0 °C 1b. BnBr

2. MeOH, cat. CSA

exOMe

• OH

OBn

3. TBSCI, cat. imid, i-Pr2NEt, CH2CI2

(,(OMe Y"'OTBS o

OH t1a+1b

4. H2, Pd/C, EtOH

5. PCC, CH2CI2

0:::0

2

t H ......... Me

H /t:_. H

Bno)""V\: ;(

/0+ H H

anti-parallel opening

OBn

3. Retrosynthetic analysis. Outline a retrosynthetic scheme for the following target molecules. Show (1) the analysis (including FOI, synthons, synthetic equivalents) and (2) the synthesis of each TM. You may only use compounds with five or fewer carbons as starting materials.

a.

OH H3C~CH3 =>


OH H3C~CH3

a hemiacetal

1~

H3C~~OH

o '-lrCH3

symmetrical 0 diketone

=>

+

o II

= HCOEt

B (SE)

Synthesis:

1. HOCH2CH20H TsOH (caL), C6H6

2a. Mg, Et20

2b. HC(O)OEt (0.5 eq)

2c. dil. HCI

TM


Step 1 Step 2a Step 2b

Protection of the keto group.

Formation of the Grignard reagent (SE A).

Utilization of 0.5 equivalent of ethyl formate HC(O)OEt ensures that the SE A and Bare formed in a 2 : 1 ratio, a prerequisite for the formation of the symmetrical diketone.

Dilute HCI deprotects the keto groups and facilitates the formation of the hemiacetal moiety in the TM.

Step 2c

b.

Br~ Ph3P~ ~O


Br+

PhP~ FGI

3 ~O ~

Br~ ~O

FGI

~

0 HO'-""_'+ + 'Co
L.:::.. -
A (SE) ijFGI
0 (l
H~ Sxc
~O -
B (SE) ~O Synthesis:

o

H~ l;0

(l

1. SH SH BF3'Et20, CH2CI2

2a. n-BuLi, THF 2b.A

(l

S S HO~ ~O

3. Ra-Ni EtOH

HO~ ~O

4. TsCI, py

5. LiBr, acetone

Br~ ,..,.,n/ ~O 53%

Ph3P toluene

TM 78%

Step 3 THPO-CH2CFb-Br was used instead of ethylene oxide as a SE of A in the original procedure.


Reference: Magatti, C. V.; Kaminski, J. J.; Rothberg, I. .J Org. Chern. 1991, 56, 3102.

4. Synthesis. Supply the missing reagents required to accomplish each of the following transformations. Be sure to control the relative stereochemistry.

a.

Solution:

1. acetone, cat. TsOH HC(OMeb

2. HO(CH2)20H cat. TsOH, HC(OMeb

4b. TsOH,

THF,

H20 ---~TM

Step 3 Fischer esterification (I-t", MeOH) would cleave the acetal protecting groups.

Step 4b Acetal hydrolysis followed by dehydration of the 30 alcohol fumishes the TM.

b.


Solution:

H ~OH ~NH

1. BOC20 (1 eq) Et3N, CH2CI2

H OH

cXb-)

Boc 82%

H 0 [BrMgb)]

~H _3. ________

~NJ(Ot-BU THF,-78 OCto rt

o

HO

cXb)

Boc

Step 1 N-acylation occurs preferentially over O-acylation. The amine must be protected to avoid N-oxidation in subsequent steps.

Step 4 Dess-Martin oxidation was used in the original procedure.

Reference: Alibs, R.; Ballb, M.; Busqu, F.; de March, P.; Elias, L.; Figueredo, M.; Font, 1. Org. Lett. 2004, 6, 1813.

H

HOH2Cw 1. PhCHO I 2. TBSCI (1 eq),

cat. TsOH Ph~~OH Et3N, cat. DMAP

HO'" '''OCH3 ------I.... 0 ·0

(-H20) HO CH2CI2

HO OH

Methyl a-D-mannopyranoside OCH3

H

Ph--\;~~~,

TBSO~ OCH3

c.

Solution:

3a. NaH, DME

H

\ C 4. n-BU4NF

Ph~~O H3 THF

o .0 ------I .... TM

TBSO 5. HCI, H20

OCH3



Selective formation of a six-membered ring acetal using PhCHO. Selective silylation of the equatorial hydroxyl group.

Hydrolysis of both the benzylidene acetal and the glycoside.

d.

o

~

Solution:

r=:

~

~o

2. HSCH2CH2SH cat. BF3'Et20 CH2CI2

TM

o

~


3. NiCI2, NaBH4 DMF

4. 5% aq HCI, THF

e.

TBSO~ o

Solution:

TBS O...._ »<: /"-i S2.-1 + 7 H2

~ ~ '6 HO ............... •••Ph

n-PrOH 97°C

94%

2. TMSCI, THF

3. BOC20, Et3N

TBSO~N/BOC TMSO ("Ph TMSO

4. NaOCH3 MeOH

5. TsCI, DMAP Et3N, CH2CI2

HO~

. . I NH

O-J"Ph

Reference: For a similar synthesis, see Lanman, B. A.; Myers, A. G. Org. Lett. 2004,6, 1045.


f.

Solution:

NH
H 0 0 II ~o
:eo ::eo 2. CI3CCOBn
1a. BH3, THF TfOH (cat.)
1 b. NaOH, H202 hexane,
CH3 HO CH3 CH2CI2 BnO CH3 Step 2 The acid-catalyzed benzylation procedure prevents translactonization and/or substrate polymerization.

*5. Explain the regio- and stereochemical outcome of the following sequence of reactions by showing the structures of the intermediates obtained after each step.

1. PhCHO, H+

2. LiAIH4'AICI3 (1 :1)

3. PhCH(OMe)2, H+

H HO~yPh

BnOV

H

Solution:

H <, 1&- \
Al- AI-
EIO,CtO 2. AICI3 l'b~ ~ H / H H+
rPh __. to ----- ------
Et02C H 0 LiAIH4 rPh rPh from H2O
~ H 0) ~ H 0+ CI- LiAIH4
product of Step 1 Lewis acid-assisted cleavage diester
of the acetal reduction H HO]:: OH

HO rPh o

H

3. PhCH(OMeb, H+

Step 2 Step 3

Reductive cleavage of the acetal and reduction of the ester groups. Selective trans-acetalization of the 1,3-diol with benzaldehyde dimethyl acetal.

Reference: Cheol, E. L.; Park, M.; Yun, 1. S. J. Am. Chern. Soc. 1995, 117, 8017.

CHAPTER 4

Functional Group Transformations:

Oxidation and Reduction

Overview

Chapter 4 centers on two key transformations in organic synthesis: (l) oxidation of alcohols and of unsaturated hydrocarbons (i.e., alkenes and alkynes) to carbonyl compounds; (2) reduction of various carbonyl compounds to alcohols.

Problem 1 emphasizes reagents for oxidation and reduction. Problems 2- 4, stress the selectivity of oxidations and reductions in reaction sequences. Syntheses of Problem 5 TMs require choosing specific reagents to achieve cherno-, stereo-, or enantioselective oxidations or reductions.

Key Concepts

..

Alcohol oxidations

o Jones, Swem, Dess-Martin

Chemos elective oxidations of allylic or benzylic alcohols Oxidation of terminal alkynes

Allylic oxidation of alkenes

Reduction of carbonyl compounds

o Nucleophilic reducing agents

o Electrophilic reducing agents Diastereoselective reduction of cyclic ketones

o Use of conformational analysis for the prediction of hydride approach (axial vs equatorial)

Diastereoselective reduction of acyclic ketones

o Cram's rule

o Felkin-Anh model

Mitsunobu reaction (inversion of2° alcohol stereochemistry) Hydroxyl-directed reduction of ~-hydroxy ketones Enantioselective reductions

•

..

..

"

"

•

•

55

56 • Chapter 4 Functional Group Transformations: Oxidation and Reduction



1. Reagents. Give the structure 'Of the major products (A-H) expected from the following reactions. Be sure to indicate product stereochemistries. Assume that standard aqueous workup conditions are used fer product isolation.

a.

Solution:

1. DMP, CH2CI2, rt

2. H2N »<; Me NaBH3CN,PPTS MeOH

1 . DMP, CH2CI2, rt

2. H2N ............ Me NaBH3CN,PPTS MeOH

Step 1 Dess-Martin periodinane 'Oxidation. Step 2 Reductive amination,

b.

o EtO~ OH L-ethyllactate

Solution:

o EtO~

OH

L-ethyllactate

1. TBSCI THF, imid

2a. DIBAL-H (1.2 eq) Et20, -78 0 to -40°C 2b. Rochelle's salt workup

1. TBSCI THF, imid

2a. DIBAL-H (1.2 eq) Et20, -78 0 to -40 °C 2b. Rochelle's salt workup

A

~Me

F3C CH3

fenflu ram ine (neuroactive drug)

B 85%

o

H~

OTBS

B 85%


Step 2a Utilization of I eq of diisobutylaluminum hydride (DIBAL-H) ensures reduction of the ester group stops to the corresponding aldehyde.

Step 2b Workup protocol (Na-K tartrate).

Reference: Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J Org. Chern. 2004, 69, 4626.

c.

~o

1. NaBH4 THF, MeOH

3a. DMSO, (COCI)2 CH2CI2, -78°C

b. Et3N

C2 74%

2. BPSCI (1.0 eq) imid, DMF

-20 DC, 10 min.

C1 54%

4. NaCI02, NaH2P04 2-methyl-2-butene acetone, H20, rt

Solution:

~o ~OH 3a. DMSO, (COCI)2
1. NaBH4 CH2CI2, -78°C Ph
THF, MeOH b. Et3N <02H
2. BPSCI (1.0 eq), 4. NaCI02, NaH2P04
imidazole, DMF, OBPS 2-methyl-2-butene OBPS
-20 °C, 10 min. acetone, H20, rt
C1 C2
54% 74% Step 1 Note: Sodium borohydride (NaBH4) can reduce lactones. Step 2 Selective silylation of the least hindered 10 alcohol.

Step 3 Swem oxidation of the 10 alcohol to the aldehyde.

Step 4 Oxidation of the aldehyde to the corresponding carboxylic acid.

(Note: Steps 3 + 4 represent a mild, stepwise oxidation of the 10 alcohol to a carboxylic acid.)

Reference: Yamaguchi, K.; Kazuta, Y; Abe, H.; Matsuda, A.; Shuto, S. J. Org.

Chern. 2003, 68, 9255.

d.

D1 80%

3. PCC, NaOAc CH2CI2

D2 89%

2. Ph3P=CH2 (4 eq) THF, rt

Note: The excess Wittig reagent cleaves the acetate ester.


Solution:

BPSOJ""~OAC HO

2. Ph3P=CH2 (4 eq)

THF

3. PCC, NaOAc CH2CI2

o BPSO.__/""~H H2C

02 89%

Step 1 Dess-Martin oxidation.

BPSOJ""~OH H2C

01 80%

Reference: Jiang, L.; Martinelli, 1. R.; Burke, S. D. J. Org. Chern. 2003, 68, 1150.

e.

o

1. 0 ,cat. TsOH

2a. MeMgl, Et20 2b. H+, H20, heat

Solution:

o

1. 0 ,cat. TsOH

2a. MeMgl, Et20

[Me OMgl ]

~ . 3°-benzylic

~CH20THP

2b. H+, H20 heat (-H20)

E1

3. PCC, CH2CI2


E2

3. PCC, CH2CI2


Step 3 pee oxidation of the 10 alcohol to the aldehyde.

Step 4 Jones oxidation of the aldehyde to the corresponding carboxylic acid. (Note: Steps 3 + 4 represent another two step oxidation of a 10 alcohol to the corresponding carboxylic acid: see Problem 1 c.)

f.

Solution:

TBSO

TBSO~ H«!P

Oi-

1. LiAIH4' Et20

2. Me2C(OMeh cat. CSA

CH2CI2

3. cat. TPAP NMO,.CH3CN

1 a. LiAIH4, Et20

1 b. mild acid workup

3. cat. TPAP, NMO CH3CN


F bicyclic product

TBSO~ «, '.

'OH OH

OH

2. Me2C(OMe)2

cat. CSA, CH2CI2

Step 2 Step 3

Acetonide selectively produces the five-membered ring dioxolane. Oxidation of the 10 alcohol to the corresponding aldehyde.

g.

Solution:

1 . Mn02, CH2CI2

2. rl

HO OH

cat. TsOH, benzene

---------.,.. G

3. KOH, MeOH

4. PCC, CH2CI2

OH

OH

HO OH

78%

CHOO)

gYo

G 78%

Step 1 Step 2

Oxidation of the allylic alcohol to the corresponding aldehyde. Protection of the resultant aldehyde as an acetal.

cat. TsOH, benzene

3. KOH, MeOH

4. PCC, CH2CI2


Reference: Tanis, S. P.; Nakanishi, K. J. Am. Chem. Soc. 1979, 101,4398.

*11.

1. TBSCI, imid, DMF

2. LiAIH(Ot-Bub EtOH, -78°C

H1 89%

3. NaH, BnBr

cat. n-BU4N1, DMF

4. CF3C02H, H20

H2 72%

Solution:

1. TBSCI, imid, DMF

OH TBSO~C14H29 NHBoc

2. LiAIH(Ot-Bub EtOH, -78°C

anti H1 89%

t

chelation control

u

"

Boc-HN'6

H~OTBS H- C14H29

3. NaH, BnBr cat. n-Bu4N I DMF

OBn HO~C14H29 NH2

H2

72%

Step 2 Chelation-controlled reduction of the ketone produces the anti-alcohol diastereoselectively.

Step 3 The ammonium iodide salt presumably converts the BnBr to the more reactive alkylating agent (Bnl).

Step 4 A basic workup is used to obtain the amino-alcohol product.

Reference: So, R C.; Ndonye, R; lzmirian, D. P.; Richardson, S. K.; Guerrara, R L.; Howell, A. R J. Org. Chem. 2004, 69, 3233.


2. Selectivity. Show the product(s) obtained or the appropriate reagent(s) to be used for the following transformations.

a.

HS=o0AC

i-Pr

two steps_

Solution:

H~OAC

i-Pr Me

1 . K2C03, MeOH

2. DMP (2.5 eq) py, CH2CI2

A

one step

o O~

¢DO

i-Pr Me

89% dicarbonyl product

~O

i-Pr Me A 89%

3. 1\

TMSO OTMS

(1 eq)

TM

cat. TMSOTf CH2CI2, -78°C

Reference: Shi, B.; Hawryluk, N. A.; Sluder, B. B. J Org. Chern. 2003, 68, 1030.

h.

1. NaBH4 EtOH,O°C

2. cat. TsOH,

o

o

Solution:

1. NaBH4 EtOH, a °C

2. cat. TsOH,

o

o

3a. LiAIH4' THF 3b. mild acid workup

OTHP ~Br 82

4. CBr 4, PPh3

81

3. LiAIH4' THF

4. CBr4, PPh3

82

81


c.

OH one step

Solution:

OH

AgC03-celite acetone

o

Fetizon's reagent

Alternatively, Mn02 or Ba[Mn04h may be used as selective reagents for the oxidation of allylic or benzylic alcohols.

d.

cb···OH

. "'OH

OH

PCC (1.1 eq) CH2CI2

D

Solution:

Me H

~OH,q

OH OHax

PCC (1.1 eq) CH2CI2

r-h ... OH ~O

OH

D

The 2° axial alcohol is oxidized preferentially.

e.

Cb

: H HO

X:H

two steps l_)_)

TBS6 H 95%


Solution:

1. TEMPO (cat.) Phl(OAc)2 CH2CI2, CH3CN

2. TBSCI imid, DMF

as

TBS6 H 95%

Step 1. Chemos elective oxidation of the primary alcohol; (diacetoxyiodo )benzene (DIB) is the stoichiometric co-oxidant.

Reference: Moman, E.; Nicoletti, D.; Mourifio, A. J. Org. Chern. 2004, 69, 4615.

*f.

o

;¢ 'r«,

o

one step

F1 + F2 cyclic products

one step

~OH

hemiacetal

Solution:

o

;¢ <.

o

1. NaBH4 CeCI3·7H20

MeOH, rt ~90% (3:1, cis: trans)

+~

o 0

4. DIBAL-H (1 eq) CH2CI2, -78°C

~OH

F1 F2

2. UOH, THF t

3. DEAD, PPh3 (Mitsunobu reaction)

95%

~80%

Step! 1,2-reduction of the enone followed by lactonization.

Steps 2 + 3 Intramolecular Mitsunobu reaction.

Step 4 Controlled DIBAL-H reduction (1 eq) to the lactol.

Reference: Kang, S. H.; Lee, H. S. Tetrahedron Lett. 1995,36,6713.


*g.
BnO
¢b 1. H2• Pd(OH)2
EtOH G1
2. BH3'SMe2 67%
THF. a °C
0 K-Selectride

G2 51%

Solution:

BnQ H

(b

o

1. H2. Pd(OH)2 EtOH

HO

¢b

o

2a. BH3'SMe2 THF. a °C 2b. EtOH

G1 67%

a. K-Selectride Et20. -78°C

BnO

¢>

o

G2 51%

b. aq NaHC03 workup

Step 2b Workup protocol where the reaction is quenched with EtOH and the resultant B(OEt)3 is evaporated.

Reference: Lee, H. K.; Chun, 1. S.; Chwang, S. P. J Org. Chem. 2003,68,2471.

3. Stereochemistry. Predict the stereochemistry of the major products formed (A-H) in the following reactions. Explain your choices.

a.

a. LiAIH4• THF

A

b. acidic workup

Solution:

b.

Solution:

2. CICH2C02H, DEAD, Ph3P


Chx -O~Et

-.- ~

Me H H

Felkin-Anh model

M 0 srEt L

Cram's rule

1. DIBAL-H (1.1 eq) hexane, -78°C to rt

A

89%

B

2. CICH2C02H,

DEAD, Ph3P, solvent

3. LiAIH4' THF

concave face access hindered

1. DIBAL-H Me 'Jt, 0

---,(_1._1 _eq_)--; Me ~:-I( __ Me

hexane ~ convex face

: ~ \ more open to

~ H Me attack

H

3a. LiAIH4' THF 3b. NaOH, H20 (workup)

H 9H

. .

>CR-

B

58% for steps 2 + 3

Step 1 1,2-Addition occurs from the least hindered convex face.


Step 2 Several procedures for the Mitsunobu reaction were tried; the best results were achieved using the more acidic CICH2C02H.

Reference: Clive, D. L. 1.; Magnuson, S. R.; Manning, H. W.; Mayhew, D. L. J.

Org. Chern. 1996,61,2095.

c.

LiBH(s-Buh THF

c

Solution:

LiBH(s-Bub THF

o

H

approach

is too hindered

favored conformer

Me H -

Cb"'OH

H

C

The large steric requirement of L-Selectride generally favors reduction of cyc1ohexanones to form axial alcohols. However, in this cis-decal one example, the formation of the axial alcohol is hindered by the adjacent ring.

d.

OMOM

~JSO

NaBH4' CeCI3 MeOH,O °C

D


Solution:

NaBH4' CeCI3 MeOH,O°C

consider the axial (antiparallel) addition of hydride (R = CH20MOM): tl- I Me (ax)

tke

0- --

~ R~

H (ax')

H Me (ax')

o__6 ~e

4 ~ 4R -

--

--

H

favored approach

disfavored approach

Note: Luche reagent (NaBH4, CeCh) favors 1,2-additions.

Reference: Mohr, P. J.; Halcomb, R. L. J. Am. Chern. Soc. 2003,125, 1712.

e.

H3CY"?0 1. LiBH(s-Bub, THF l._) 2. TsCI, py

E1

3. NaCN, DMSO 4a. LiAIH4' THF 4b. NaOH, H20

(workup)

E2

Solution:

1. LiBH(s-Bu)s THF

HOTs H3CU-H

2. TsCI, py

3. NaCN, DMSO

NH2 H3C·"O·...I

E2 (cis)


Step I Equatorial delivery of hydride from L-Selectride.

Step 3 Tosylate displacement occurs with an inversion of stereochemistry. Step 4 The amine (free base) is isolated after a basic workup.


*f.

OH 0 ~C02t-Bu

1a. Et2BOMe THF, -78°C 1b. NaBH4

F1

3. DIBAL-H (1.2 eq) toluene, -78°C

2. TESCI (2.5 eq), imid, DMAP (cat.) DMF, rt

Solution:

OH 0 ~C02t-Bu

ta, Et2BOMe THF, -78°C 1b. NaBH4

HO OH

~C02t-BU

syn 1,3-diol

TESO OTES

~C02t-BU

F1

3a. DIBAL·H (1.2 eq) toluene, -78°C

3b. Rochelle's salt

Step l c Workup protocol.

Step 3b Workup protocol (Na-K tartrate).

stereocontrol feature:

R1 resides equatorial

hydride attack via axial H- (antiparallel) approach

Ht Et

R~o-_-J

R2 "0""'" 'Et

R1 = CH=CH-CH3 R2 = CH2C021-Bu

2. TESCI (2.5 eq), imid, cat. DMAP DMF, rt

TESO OTES

~CHO

F2

92% (>95:5, syn: anti)

Reference: Fettes, A.; Carreira, E. M. J. Org. Chern. 2003, 68,9274.

*g.

[6:: 1

NaBH4 MeOH

G

F2


Solution:

{3-face [HI
favored conformer H-
[6::] . ~H Md ~~CH20H
NaBH4 v-·-N-.........:, _,,_.
Me i-IBn
MeOH _ CH20H
H A 1,2 strain
a-face [HI
t t
/OH /OH
(rsn + CJsn
Me 'Me trans - product

G 93%

92:8 trans: cis

cis - product

Reduction of the iminium ion proceeds via perpendicular hydride attack (antiparallel) via a chair-like TS minimizing Al,2 strain.

Reference: Hofman, S.; De Baecke, G.; Benoit, K.; De Clerq, P. J. Synthesis 1998,479.

*11.
0 ~12SCI
Ci- neat
+ ~ B
12h
H-DIPCI
Solution:
CI
I
0 ~l,BCI O,B'lpc ~
Ci- + ~ if +
a-pinene 70 • Chapter 4 Functional Group Transformations: Oxidation and Reduction

Workup procedure:

a. remove a-pinene (vacuum)

b. add Et20

OH

tI-

c. add (HOCH2CH2)2NH

d. filter precipitate

H

_ 71% (98% ee)

Step a Step c Step d

a-Pinene is the by-product formed in the reduction.

Diethanolamine is added to sequester boron from the boron intermediates. Filtration removes the insoluble dtethanolamlne-boron complex.

The stereochemical outcome may be explained by considering the following transition state:

:j:

~-.........:- 9~ Ipc OH

H3C~~l :r.0B~ workup (j-

H3C H3C ~ a-pinene

\.

gem-dimethyl paints away

from the axlal-Cl-l ,

Reference: Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.

Chern. Soc. 1988,110, 1539.

*-

1_

Propose a method to accomplish the following stereochemical inversion.

c;P'R_~R

o

o

Solution:

1 a. 20% aq NaOH MeOH, rt

1 b. 1 N HCI (workup)

2. DMP, CH2CI2, rt

o

R H02C a-alkoxy ketone: use chelation control

3. L-Selectride (2.0 eq), THF, -78 to O°C

4.PPTS,C6H6 reflux


Step 3 2.0 equivalents of L-Selectride are required since the carboxylic acid is deprotonated on addition of the hydride reagent.

Reference: Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993.

4. Reactivity. Explain the regioselectivity and stereochemistry observed in the transformations below.

a,

H02C~C02H OH (S)-(-)-malic acid

Solution:

<tJ'I o

o :

~o

"\4-

acetone

intramolecular transesterification

1. Me2C(OMeh cat. TsOH

2a. BH3'THF 2b. H+, H20

3. BOMCI, i-Pr2NEt CH2CI2

1. Me2C(OMeh TsOH (cat.~

1:)

o :

OBOM

64%

2a. BH3·THF 2b. H+; H20

1:)

o _

OBOM

75%

Step 1 Acetonide formation occurs selectively to give the five-membered ring dioxolane.

Step 2 Chemoselective reduction of COOH.

J:)

o :

OH

3. BOMCI i-Pr2NEt

CH2CI2

Reference: Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc. 1980,102,2118.


b.

Solution:

NaBH4, CeCI3-7 H20 EtOH, H20

HO ~CHO

CeCI3 promotes the formation of the hydrate; hence, only the keto group is available for reduction.

Reference: Luche, 1. -L.; Gemal, A. L. 1. Am. Chem. Soc. 1979, 101,5848.

*c.
xV OH OH
J X
PhCHO X
",1o~ , ... ~
+
°XO CF3C02H 0 ........... 0 0 ........... 0
toluene
72% Ph Ph
5 Solution:

,(~J w

~....,.. PhCHO

0yO acid-catalyzed

I \ hemiacetal

formation

oxocarbenium ion

The initially formed oxocarbenium ion intermediate may be intercepted by the acetonide oxygens to form oxonium ion species (depicted below). Acetonide rupture with eventual loss of acetone yields benzylidene acetals (e.g., A and B), which equilibrate via C to afford the axial hydroxymethyl product. Altematively, in the presence of the water formed, the acetonide may hydrolyze to provide a more direct route to C.

path a ~O (S~.H

Ph-I .......... ~

~o::T-- ~ +

favored

H

path b 0 ."

-yl*

H o (S),"

+ {ot~~ 'For

favored


OH I

X····~

__...., 0 0

acetone Y Ph

A

OH

" ..... r'Y"~

__...., 0 0

acetone Y Ph B

OH OH
~~ I Ph-'\~
H+ X 0,
~\""~
AorB --- ',: ) ~
-
HO (0+ 0 ........... 0 H ......
0
Ph Ph stabilized by
C major product hydrogen bonding Reference: Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H.; Jun, H.-Y.; Lee, B.

M.; Park, C. M.; Jeong, J. W. Angew. Chem., Int. Ed 2003, 42, 4779.

*d.

OMe

2

o 0

~

DIBAL-H

OPMB

HO~

CH2CI2• hexane -78 ° to -40 "C

92%


Solution:

OMe

2

o 0

~

Ar = p-methoxyphenyl

DIBAL-H CH2CI2• hexane -78 ° to

-40°C

favored

Ar H

I -I o...A...6- AI(i-Bu)2

~

disfavored

oxocarbenium ion intermediate

OPMB

HO~

workup MeOH aq NaOH

~ hydride transfer

H Ar

(i-BuhAI ... ;~

~

92%

Reference: Holloway, G. A.; Hugel, H. M.; Rizzacasa, M. A. J. Org. Chern. 2003,68,2200.

5. Synthesis. Supply the missing reagents required to accomplish each of the following syntheses. Be sure to control the relative stereochemistry.

a.


Solution:

HO"'Q

a

1. Swern [0] 2. 1\

°XO Me a

3. LiAIH4' THF

4. H+, H20

H:~OH

~80% (Steps 1-4)

cat. p-TsOH, CH2CI2, rt

transacetalization

Reference: Su, Z.; Paquette, L. A. J Org. Chern. 1995,60, 764.

b.

a

6--Me

OAc

~ 6-Me

Solution:

1. NaBH4, CeCI3 MeOH

Reference: Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985,107, 1448.

c.

~OH~ CCCHO

V"'OH CHO

Solution:

1. H2, Pd/C EtOH

2. MeS02CI (2.1 eq) Et3N, CH2CI2

4a.DIBAL-H (2.2 eq), hexane,

CCCN -78°C

CN 4b. H+, H20

CCCHO CHO

3. KCN (xs) DMSO, heat

Step 3 Step 4

Mesylate displacement occurs with inversion of stereochemistry.

Acidic workup is required to hydrolize the intermediate imine that is formed on nitrile reduction.

Reference: Mcfrermott, T. S.; Mortlock, A. A.; Heathcock, C. H. .1. Org.

Chem. 1996, 61, 700.


d.

OH

Solution:

OH

1. NaH (1.0 eq), TBS-CI, THF

OC(O)Ph

6

TBSO'" 93%


2. DEAD, Ph3P, PhC02H, THF

4. n-Bu4NF, THF

Step 1 NaH treatment results in mono-alkoxide formation, which is critical to minimize formation of a bis-silyl ether. In the original procedure, a 96% yield is reported for the formation of the mono-silyl ether.

Reference: Clive, D. L. 1.; Magnuson, S. R.; Manning, H. W.; Mayhew, D. L. J.

Org. Chem. 1996,61,2095.

e.

OH

HO ••• j~ ~

HO~"'OCH3 OH

O~./C:H HO~"'OCH3 OH

Solution:

0!5oTr +

o 4. H ,H20

o ~OCH35.MeOH+

~O cat. H

O~,/C:H HO~"'OCH3 OH

Step 2 Step 4

The cis 1,2-diol reacts selectively to form an acetonide.

Both acetals (aceonide and glycoside) are hydrolyzed as well as the trityl group. Step 5 is required to selectively re-form the glycoside.

*f.

o OMe H~OBPS

Solution:

-

1. BH3·SMe2 (xs),

B(OEtb

2. acetone, cat. p- TsOH, CUS04


o-k

PMBO~O

4. cat. TsOH, MeOH

5. BPSCI (1.0 eq), Et3N, cat. DMAP

6. NaH, Mel

3. t-BuOK, PMBCI

cat. n-Bu4NI, DMSO

OMe PMBO~OBPS

43% overall yield

8a. (COCI)2, DMSO 8b. Et3N

a OMe H~OBPS

86%

Reference: Pattenden, G.; Plowright, A. T.; Tomos, J. A.; Ye, T. Tetrahedron Lett. 1998,39,6099.

*g.

a HYOH NHBoc

Solution:

1. (BoebO

(1.2 eq), a

NaOH Y

------~~ Mea OH

2. Mel

K2C03 NHBoc

(1 .1 eq) 1 00%

3. TBSCI, imid, DMF

a HYOH NHBoc

4.DIBAL-H (2.5 eq), toluene, -78°C

5. n-Bu4F, THF

Step 4 A minimum of two equivalents of DIBAL-H is required due to the presence of the active N-H.

Reference: Nicolaou, K. C.; Bunnage, M. E.; Koide, K. 1. Am. Chern. Soc. 1994, 116, 8402.


*h.

Solution:

69%

3. TBSCI, imid, DMF

4a. LiAIH4

Et20, 0 °C to rt 4b. sat'd aq Na2S04 (workup)

84%

Step 1 Step 2

Selective cleavage of the I-Bu ester (analogous to Boc deprotection). Chemos elective reduction of a carboxylic acid in the presence of an ester.

Reference: Dauben, W. G.; Warshawsky, A. M. J Org. Chem. 1990,55,3075.

*.

I.

OH

HoJLYOH

Me N

HO. .r". _.. l.:r "NH2

Me N

Solution:

OH

HO. ~-~OH

l.~J .

Me N

1. acetone cat. TsOH

2. NaCI02 NaH2P04 isobutylene t-BuOH

3. SOCI2

4. NH3

TM

5. LiAIH4' THF

6. H+, H20

Step 1 Preferential formation of the six-membered acetal rather than the sevenmembered acetal.

Step 6 Basic workup after acetal hydrolysis to obtain the amine in its free base form.

CHAPTERS

Functional Group Transformations:

The Chemistry of Carbon-Carbon zr-Bunds and Related Reactions

Overview

Chapter 5 deals with transformations of carbon-carbon z-bonds into a variety of functional groups.

Problem 1 highlights reagents for carbon-carbon rt-systeru transformations. Problems 2-4 and 6 emphasize selectivity in reactions of carbon-carbon nbonds. The syntheses of TMs in Problems 5 and 7 require the selection of specific reagents to achieve chemo-, stereo-, or enantioselectivity.

Key Concepts

• Hydrogenation of alkenes

.. Dissolving metal reductions o Birch reduction

• Hydration of alkenes

o Hydroboration-oxidation of alkenes

o Oxymercuration -demercuration .. Epoxidation of alkenes

• Epoxidation of ally lie alcohols

o Sharpless asymmetric epoxidation .. Dihydroxylation of alkenes

o Sharpless asymmetric dihydroxylation

• Halolactonization

• Cleavage of carbon-carbon double bonds

o Ozonolysis

o Lemieux-Johnson oxidation " Semireduction of alkynes

o Conversion of alkynes to (E)-alkenes

o Conversion of alkyncs to (Z)-alkenes " Hydration of alkynes

79

80 • Chapter 5 Functional Group Transformations: The Chemistry of Carbon-Carbon zr-Bonds



1. Reagents. Give the structures of the major product(s) expected for each of the following reactions. Be sure to indicate product stereochemistry where applicable.

a.

1. Hg(N03)2 CH3CN, H20

2. NaBH4

A 70%

Solution:

Reference: Brown, H. C.; Kurek, J. T. J. Am. Chern. Soc. 1969,91,5647.

b.

a-xylene

1. Na (2.5 eq), NH3 (I) Et20, EtOH

81

3a. BH3, THF 3b. NaOH, H202

82

2. H2, cat. (Ph3P)sRhCI toluene

Solution:

Q:CH3 1. Na (2.5 eq), NH3 (I)

2. H2, (Ph3P)sRhCI toluene

CH3 Et20, EtOH

a-xylene

82

Step 2 Wilkinson's catalyst allows for the selective hydrogenation of the less substituted double bond.


c.

1. mCPBA CH2CI2, 0 °C

2a. LOA (>2 eq) THF, -78°C to rt 2b. aq NH4CI (workup) _

C 45%

Solution:

J5

H3C CH3

85%

2a. LOA (>2 eq) THF, -78°C to rt

2b. aq NH4CI (workup)

1. mCPBA

Step 1 Step 2

Stereoselective epoxidation from the less hindered a-face. Regioselective base-mediated epoxide elimination.

Reference: Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.; Meghani, P.; Kocovsky, P. 1. Org. Chern. 2003,68,4727.

d.

cjjMOM

1. OMOO,CH2CI2, acetone

3. TMSCI (1 eq) Et3N, CH2CI2

2. KOH, H20 OMSO, 120°C

01 58%

4. MOMCI, i-Pr2NH OMAP, CH2CI2

5. TBAF, THF, 0 °C

02 86%

Solution:

1.0MOO, CH2CI2, acetone

cj5MOM

°

2. KOH, H20 OMSO, 120°C

cjjMOM

: OH HO

01 58%

Step 1 Exo (convex) face approach of oxidant gives I)-face epoxide.

82 • Chapter 5 Functional Group Transformations: The Chemistry of Carbon-Carbon z-Bonds

3. TMSCI (1 eq) Et3N, CH2CI2

cjjMOM

TMScS OH

4. MOMCI, i-Pr2NH DMAP, CH2CI2

cjjMOM

H60MOM 02

86%

5. TBAF, THF, 0 °C

Reference: Lepage, 0.; Deslongchamps, P. J. Org. Chern. 2003, 68, 2183.

e.

OMe

A

VMe

1. Li, NH3 (I) Et20, t-BuOH

E1 84%

3. mCPBA, CH2CI2, 0 °C

4. AC20, i-Pr2NEt

cat. DMAP, CH2CI2, rt

E2 79%

2. oxalic acid, rt MeOH, H20 (Hint: mild acid)

Solution:

OMe

A

VMe

1. Li, NH3 (I) Et20, t-BuOH

o

~~

~Me

y

E1 84%

3. mCPBA, CH2CI2, 0 °C

4. AC20, i-Pr2NEt

cat. DMAP, CH2CI2, rt

o

c!Me

OAc E2 79%

2. oxalic acid, rt MeOH, H20 (Hint: mild acid)

Step 2 Mild acid catalyzes the enol ether hydrolysis without subsequent (3, y to a, (3 alkene isomerization.

Step 4 Htmig's base promotes f3-elimination of the epoxide followed by O-acylation.

Reference: Piers, E.; Oballa, R. M. J. Org. Chern. 1996,61, 8439.

f.

1. 12, KI, NaHC03 t-BuOH, H20

2. t-BuOK, THF

3. 0504 (cat.), NMO t-BuOH, H20

4. NaOH, H20

F

~

[~]-~

Solution:

5-ring formation

is preferred (anti-parallel opening of the iodonium ion)

g.

Solution:


1.12' KI, NaHC03 t-BuOH, H20

2. t-BuOK, THF

HO~C02Na

HO"'Y

OH F

o l-

~~OH

3.·0S04 (cat), NMO t-BuOH, H20

4. aq. NaOH

o

2. t? ~ro

OH

cis-diol

1a. Sia2BH, THF 1b. NaOH, H202

G

2. Hg(OAch, THF, H20

3. NaBH4, NaOH, H20

1a. Sia2BH, THF 1 b. NaOH, H202

2. Hg(OAc)2 THF, H20

3. NaBH4 NaOH, H20

~OH

Step 1 Step 2

Hydroboration-oxidation of sterically less hindered terminal alkene. Oxymercuration-demercuration of the internal alkene yields the diol G.

h.

t-Bu ---:::=--CH3

1 a. Na, NH3 (I) 1b. aq NH4CI workup

3a. [U-C = CH] THF

H1

H2

84 • Chapter 5 Functional Group Transformations: The Chemistry of Carbon-Carbon z-Bonds

Solution:

1 a. Na, NH3 (I) 1b. aq NH4CI workup

o

B L'i •• CH3 t- u'~'

H1

3a. [Li-C = CH] THF

H)OH CH3 t-Bu

H

II

H2

i.

1. mCPBA cyclohexane rt, 7 days

2. K2C03 (1.2 eq) MeOH

3. POC, CH2CI2

90%

Solution:

1. mCPBA cyclohexane rt, 7 days

c$H

TBSO H

c$

TBSO H

I 96%

2. K2C03 (1.2 eq) MeOH

94%

Steps 1-2 Baeyer-Villiger oxidation followed by acetate hydrolysis.

Reference: Moman, E.; Nicoletti, D.; Mourifio, A. J. Org. Chern. 2004,69, 4615.

j.

1 a. Na, NH3 (I) Et20

1b. Br~ 1c. aq NH4CI workup

J 91%


Solution:

1 a. Na, NH3 (I), Et20

Me

C\z

J 91%

1b. Br~ tc. aq NH4C1 workup

Reference: Chuang, C.-P.; Hart, D. 1. J. Org. Chern. 1983,48,1782.

*k.

Ph'b~

o OMe

1. "

~MgCI

Me

K 83%

2.DMSO (CF3CObO

3a. DIBAL-H, Et20 3b. 1 N HCI workup

Solution:

3.DIBAL-H Et20

Ph'b0-'\ ~

H~

HOMe

K

83%


Diaxial opening of the epoxide.

Modified Swem oxidation; see J. Org. Chern. 1998,63,8522.

Hydride addition occurs preferentially from the a-face (anti to the axial isopropenyl moiety).

Reference: Chen, L.; Wiemer, D. F. J. Org. Chern. 2002, 67, 7561.

86 • Chapter 5 Functional Group Transformations: The Chemistry of Carbon-Carbon n-Bonds

2. Selectivity. Show the product(s) obtained or the appropriate reagent(s) to be used for the following transformations.

a.

o

1. CH2N2, Et20

. 2. AC20, pyridine

3. cat. OS04 Nal04 (excess)

OH H20, MeOH

OCH3 4. CH2N2, Et20

Solution:

°n·H H02~~OH OCH3

A

1. CH2N2, Et20

2. AC20, pyridine

3. cat. OS04 Nal04 (excess) H20, MeOH

OH
0
Nal04
-HC02H
OAc
OCH3 CH302C CHO

CH'02~OAC OCH3

A

Step 2 Lemieux-Johnson oxidation.

Reference: For an analogous synthesis, see Woodward, R. B.; Bickel, B. H.; Frey, A. 1.; Kierstead, R. W. Tetrahedron 1958, 2, 1.

b.

9H II

Me~

1. SAE, (-)-DIPT

2. MeOH, CSA 50°C

B 56%

3a. 03, MeOH CH2CI2, -70°C 3b. Me2S

Solution:

~H II

Me~

3a. 03, MeOH CH2CI2, -70 °C


1. SAE, H-DIPT

2. MeOH, CSA 50°C

J:N

Me :

OH 84%

~

Me "'0

76%

OH OMe 0 Me~H OH

Me

HOH

MeO OH B (87%) 56% overall

Reference: Roush, W. R.; Brown, R. 1. J. Org. Chem. 1983,48,5093.

c.

Solution:

a. b.

M=.rOH

c.

(one-pot)

58%

a. Sia2BH, THF

b. CH3CH2C02H

c. NaOH, H202

r<~OH

58%

Step b Step c

Protonolysis of the intermediate vinylborane.

Oxidation of the Sia2B- moieties as well as saponification of the acetate.

Note: Steps a-c represent a method to prepare Z-alkenes without the use of H, in the presence of Lindlar's catalyst.

Reference: Corey, E. J.; Herron, D. K. Tetrahedron Lett. 1971, 1641.

d.

H

1. Os04 (cat)

Et20, pyridine (2 : 1) -78°C


Solution:

H

1.0804 (cat)

Et20, pyridine (2 : 1) -78°C

2. Nal04, H20, THF

3. A920, H20,-THF

H

HO,C___r}f><

o 50%


Dihydroxylation of the terminal alkene. Oxidative cleavage of the resultant 1,2-diol.

Oxidation of the resultant aldehyde to the corresponding carboxylic acid.

Reference: Nozoe, S.; Furukawa, 1.; Sankawa, U.; Shibata, S. Tetrahedron Lett. 1976,195.

e.

H

q;;

H

a. BH3, THF

b. NaOH, H202

E1 + E2

major minor

Solution:

H H HOLt>
q;; a. BH3, THF HOJt/ +
b. NaOH, H202
H H H
E1 E2
major minor
+ +
H--fb 6- H
H,S--W
. . • •
H2B-- H--
s: 0 o 0
H H
A B The hydroboration occurs from the less hindered face (i.e., the convex face). Transition state B is destabilized by the electron-withdrawing effect of oxygen.

Reference: Paquette, L. A.; Youssef, A. A.; Wise, M. L. J. Am. Chern. Soc. 1967,89,5246.


*f.

_....OTBS
1a. 3.
1b. au 4.
.2. 5.
-X 6.
major diastereomer _....OTBS

71% (Steps 3-6)

Solution:

1a.9-BBN 1b. NaOH H202

_....OTBS

2. acetone CUS04

3. °3• NaBH4

4. PivCI (1 eq) Et3N CH2CI2

85: 15

(major diastereomer shown)

_....OTBS

5. MsCI

6. LiEt3BH

_....OTBS

~

OH

71 % (Steps 3-6)

Step 3 Step 4

Ozonolysis followed by carbonyl reduction. Selective protection of the 10 alcohol.

Reference: Wovkulich, P. M.; Shankm-an, K.; Kiegiel, J.; Uskokovic, M. R. J.

Org. Chem. 1993, 58, 832.

3. Stereochemistry. Give the structure and predict the stereochemistry of the major product formed for each of the following reactions. Give an explanation for your choice of stereochemistry.

1l.

1. Ti(Oi-Pr)4, (+)-DET, t-BuOOH, CH2CI2

3. (MeO)2CMe2, cat. H+

r<0H

Me Me

A1

A2

2. H2C=CHCH2MgCI, THF

4a. 03. EtOH, -78°C 4b. Me2S, NaBH4


Solution:

"0" transfer mediated by (+)-DET

Me ~ Me H~OH

;=--(OH

Me Me

1. Ti(Oi-Pr)4, (+)-DET, t-BuOOH, CH2CI2

I-~"" Me',l1·,Me

H' "'-OH

2. H2C=CHCH2MgCI THF

3. (MeO)2CMe2, cat. H+

4a. 03, EtOH, -78°C 4b. Me2S, NaBH4

Me~HOMe ==

H OH

I

OH OH

,

Me Me

A1

75%

0+

HO < ... 0

~Me

Me

A2 87%

Step 1 Step 2

Sharpless asymmetric epoxidation.

Anti-periplanar opening of the epoxide at the least substituted carbon.

Reference: Evans, D. A.; Bender, S. L.; Morris, 1. J. Am. Chem. Soc. 1988,110, 2506.

b.

Me

I.BuD

Me

Solution:

Me

I.BuD

Me

a. BH3 THF

Me ~BuD·OH

Me B

a. BH3, THF

B


Step a

The predominant cyclohexene conformer places (i) the z-Bu equatorial and (ii) the allylic-Me pseudoaxial to minimize A 1,3 strain. syn-Addition of the H-B bond at the least, after oxidation, to B.

c.

~OBn

HO OBPS

1. Ti(Oi-Pr)4, (-)-DET, t-Bl.'OOH, CH2CI2, -20°C

c

2. Red-AI, THF, rt

Solution:

~OBn

HO OBPS

1. Ti(Oi-Pr)4, (-)-DET, t-BuOOH,

CH2CI2, -20°C

~OBn

HO 0 OBPS

2. Red-AI (2 eq) THF, rt

('(YOBn

HO OH OH

60%

(9 : 1 mixture of diastereomers)

C 85%

BPS group is cleaved during the Red-AI step.

Reference: Nicolaou, K. C.; Uenishi, D. J.; Li, W. S.; Papahatjis, D. P.; Chakraborty, D. K. 1. Am. Chern. Soc. 1988,110,4672.

rl.

1.12, CH3CN, -15°C 2. BnOK, THF, -20°C

D

Solution:

HJ:>=C •••

I 0

o

trans-adduct

2. BnOK,

~ -.wC t

III

89% (20 : 1 trans: cis)

t

D ;;::84%

allylic 1,3-strain destabilizing


Reference: Collum, D. R; McDonald, III, J. H.; Still, W. C. J. Am. Chern. Soc. 1980,102,2118.

e.

Select the appropriate reducing agent from the list shown below.

your choice. .

o H 9-+'

o

o

.

e

BnO

Explain

reducing reagent

HO H 9-+'

~o

BnO

NaBH4, K-Selectride, or DIBAL-H?

Solution:

/~

0- = \ OBn

~ OMe

H

Note that I ,4-reduction is impeded by the adjacent disubsituted carbon center.

The sterically hindered reducing agent K-Selectride favors 1,2-addition from the face opposite the Req substituent.

Reduction with NaBH4 or DIBAL-H furnished a product mixture in which the equatorial allylic alcohol predominated. However, reduction using K-Selectride produced the axial alcohol as the major product (88% yield, 9.8 : 1 mixture of diastereomers ).

Reference: Martin, S. F.; Zinke, P. W. J. Org. Chern. 1991,56,6600.

4. Reactivity. Explain the regioselectivity and stereochemistry observed in each of the following transformations.

a.

1. Hg(OAch THF

2. NaBH4 aq NaOH


Solution:

1. Hg(OAeh THF .

OH

HOH2~

..j..Hg,

, OAe

HOH2Ci1:r

HgOAe

2. NaBH4 aq NaOH

HOH2C~ -

b.

a. cat. MgBr2 PhCH2CH2MgBr

b. aq NH4CI

I\_;0H V \_;Ph

Solution:

("J<.'t ,MgBr2 [rrt~MgBrl-

~E) ~ ~ Br ~

H + H

H

0<;0

PhCH2CH2MgBr b. aq NH4CI

I\_;0H ~\ __ lh

Lewis acid-mediated epoxide rearrangement followed by 1,2-addition.

c.

~O

H 0+ 3 '"

H

ctJ=0

H


Solution:

~o

H30+ . lactone hydrolysis

~C02H OH

d. Why is the ~-epoxide not formed on mCPBA epoxidation, although the ~epoxide is predicted based on Oll-directed epoxidation? Propose a strategy to synthesize the ~-epoxide.

85%

Solution:

The unfavorable steric interactions of a ~-face peracid-hydroxyl group complex with the angular methyl group and with the 2~- and 6~-hydrogens results in the preferential epoxidation from the a-face.

Since an a-face approach to C(4) is favored, presumably attack of the sulfur ylide to a C(4)-carbonyl would yield the j3-face alkoxide leading to the ~-epoxide after protection of the hydroxyl group.

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