Sie sind auf Seite 1von 4

Alcohol Inversion: Beyond the

Mitsunobu
Claire M. Filloux
Department of Chemistry, Colorado State University, Fort Collins, CO 80523
cfilloux@gmail.com
ABSTRACT

OH
R1

OH
X OH

R2

O
H2O

R1

R1

R2

X
R2

H2O

Despite overt simplicity, alcohol inversion remains a significant synthetic challenge. Classical solutions such as the
Mitsunobu reaction rely on the use of stoichiometric reagents that complicate purification and engender
stoichiometric wastes. Efforts to improve efficiency of inversion within and outside the Mitsunobu manifold have
been advanced. This review examines the contributions and limitations of these strategies, and it identifies progress
that
has
been
made
toward
the
development
of
a
catalytic
inversion
protocol.

The ability to invert the stereochemistry of an alcohol


represents a powerful tool for the synthetic chemist. Not
only does the opportunity for late stage inversion allow
flexibility in the design of a total synthesis,1a but quick
configurational manipulation of complex intermediates
can confirm or debunk established stereochemical
assignments.1b For a relatively subtle transformation,
however, alcohol inversion remains a formidable
synthetic challenge. Difficulties associated with this SN2
reaction reside in fundamentals of undergraduate organic
chemistry. At the core, esterification of alcohols involves
exchange of one C-O bond for another, a degenerate
process. Not only does thermodynamics provide slim
incentive for inversion, but kinetics impose a significant
barrier for the neutral process. Alcohols are modest
nucleophiles, and alkoxides notoriously poor leaving
groups. Activation of these participants to facilitate
nucleophilic substitution can instead promote undesired
reaction pathways.
Chief of methods to invert stereochemistry of
secondary alcohols is the Mitsunobu Reaction.2

Variations of this robust transformation have


commanded the focus of dozens of reviews and have
enabled myriad syntheses since the reactions
discovery.3 In most manifestations, the Mitsunobu
converts an alcohol 1 to its inverted ester 5 with
participation of three stoichiometric components: an
acidic pronucleophile (typically a carboxylic acid) 2, a
diazodicarboxylate (DAD) 3 and a phosphine (typically
triphenylphosphine) 4 (Scheme 1a). The Mitsunobu
reaction works by creating kinetic and thermodynamic
incentive for inversion.4 Interception of betaine
intermediate 6 by alcohol 1 lowers kinetic barriers to
nucleophilic displacement by carboxyalte through
formation of the good leaving group in 8 (Scheme 1b).
Concomitant loss of stable triphenylphosphine oxide 10
gives inversion product 5 and drives the reaction
forward. The true mechanism of the Mitsunobu reaction
is complicated and not fully understood; care must be
taken in choice of reaction conditions and
pronculeophile to promote the desired inversion
pathway. If pronucleophile 2 is too basic, for example,
competitive
formation
of
acyloxyphosphonium

(1) (a) Overman, L. E.; Paone, D. V. J. Am. Chem. Soc. 2001, 123,
9465. (b) Heintzelman, G. R.; Fang, W.; Keen, S. P.; Wallace, G. A.;
Weinreb, S. M. J. Am. Chem. Soc. 2002, 124, 3939.
(2) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380. (b) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
935.

(3) For a comprehensive review, see: Swamy, K. C. K.; Kumar, N.


N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem Rev. 2009, 109, 2551
and references therein.
(4) For mechanistic studies, see: (a) Ahn, C.; Correia, R.; DeShong,
P. J. Org. Chem. Soc. 2002, 67, 1751. (b) Ahn, C.; Correia, R.;
DeShong, P. J. Org. Chem. Soc. 2003, 68, 1176.

intermediate 7 can spur formation of undesired retention


product 9 (Scheme 1b).
Unfortunately for the synthetic chemist, the features
that make the Mitsunobu so effective at inversion also
make it monumentally inefficient. This excess is perhaps
most obvious in the form of raw materials: a
transformation that should generate water as a sole
byproduct produces stoichiometric hydrazine 11 and
phosphine oxide 10 wastes. In addition to resources, the
Mitsunobu makes significant time and labor demands.
DADs 3 can be explosive, and their hydrazine
byproducts toxic; reaction execution obliges care in
reagent handling and disposal. Moreover, product
purification is complicated by the presence of
stoichiometric wastes, especially triphenylphoshine
oxide (TPPO).

Scheme 1. (a) The Mitsunobu Reaction and (b) Mechanism


EtO2C 3
N N
CO2Et
PPh3 4

OH
R1 1 R2

O
R3

2
OH

(a)
O
R3

5 R
1

R2

(b)

3+4
2
R3

O
O

Ph3P

H
N N
EtO2C 6 CO2Et

OH
1
R1 R2

Ph3P

O
R3 7 O

PPh3

R1 1 R2

R3
9 R
1

O
R2

Retention Product

Scheme 2. Toys Organocatalytic Mitsunobu Reaction

R1 8 R2
O
O
2 R3

OH

or filtration step.7 Alternatively, poly-fluorinated


phosphine and DAD reagents allow facile removal of the
corresponding phosphine oxide and hydrazine
byproducts on fluorous silica.8 Nevertheless, these
conveniences mask other expenditures. Certain
substrates do not tolerate acidic work-up conditions.
Polymer-supported phosphines can be expensive and of
capricious quality,9 and fluorous reagents require many
steps to make.8 Finally, engineered phosphine and DAD
reagents often react with less efficiency than their
traditional counterparts; contamination of product with
unreacted starting material can supplant contamination
with hydrazine and phosphine oxide wastes.7
While modified reagents target problematic
purification associated with the Mitsunobu, introduction
of an oxidant eliminates reliance on stoichiometric
azodicarboxylate. In a protocol described by Toy and
coworkers, catalytic DAD 3 is regenerated from
hydrazine 11 in situ with stoichiometric iodosobenzene
diacetate (IBD) 12 (Scheme 2).10 While this protocol
reduces the amount of hazardous starting material
consumed in and toxic byproduct generated from the
reaction, Toys Organocatalytic Mitsunobu nearly
doubles the molar amount of reagents used and waste
products produced. To correct for background oxidation
of triphenylphosphine by IBD, two equivalents of
oxidant and phosphine are required. Moreover, the two
equivalents of acetic acid generated in the reaction can
compete as pronucleophiles. Acetate side products can
form as significant impurities if the chosen
pronucleophile is not sufficiently acidic.10b

O PPh3
10
H
H
N N
EtO2C 11 CO2Et

EtO2C
CO2Et
N N
H 11 H

O
R3
5 R
1

O
R2

Inversion Product

Creative modifications to the Mitsunobu have been


advanced to address these shortcomings.5 A quest for
chromatography-free purification has motivated the
development of specialized phosphine and DAD
reagents. For example, di-tert-butyl azodicarboxylate
(DBAD) 12 and its hydrazine byproduct decompose to
volatile components upon acidic workup.6 Partnership of
DBAD with acid-labile or polymer-supported
phosphines can reduce purification to a simple extraction

(5) For a review, see: Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
(6) Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J. P.
Teterahedron Lett. 1999, 40, 4497.

OH
R1 1 R2

3
N N
CO2Et
EtO2C
(10 mol %)
PPh3 4
(2 equiv)

2
OH
THF, 23 C
R3

PhI(OAc)2 12
(2 equiv)

PhI + AcOH
(2 equiv)
O
R3
5 R
1

O
R2

Most Mitsunobu alternatives to ether- or esterification


of alcohols with inversion of stereochemistry also rely
on stoichiometric alcohol activation. In a powerful
procedure developed by Mukaiyama and coworkers,
quinone 15 behaves as an oxidant towards a
pregenerated alkoxyphopshine 14 to give activated
(7) Pelletier, J. C.; Kincaid, S. Tetrahedron Lett. 1999, 41, 797.
(8) (a) Dandapani, S; Curran, D. P. Tetrahedron 2002, 58, 3855. (b)
Dandapani, S; Curran, D. P. J. Org. Chem. 2004, 69, 8751.
(9) Valeur, E.; Roche, D. Tetradedron Lett. 2008, 49, 4182.
(10) (a) Tracy, Y. S. B.; Toy, P. H. J. Am. Chem. Soc. 2006, 128,
9636. (b) Tracy, Y. S. B.; Lu, J. Toy, P. H. Synlett. 2010, 7, 1115.

alcohol 16 (Scheme 3).11 Recalling Mitsunobu


intermediate 8 (Scheme 1b), alkoxyphosphonium 16 is
intercepted by an oxygen pronucleophile to yield
inverted ether or ester 18 and phosphine oxide byproduct
17. The reaction proceeds in two steps and requires only
the removal of solvent between.

Scheme 3. Mukaiyamas Protocol For Alcohol Inversion


O

R = Acyl, Aryl, Alkyl


13 = 1, 2, 3

OH
R1
13

R3
R2

Me

i) n-BuLi
PPh2
ii) Ph2PCl
O
THF
iii) solvent R
R3
1
R
removal
14 2

Me
15

Scheme 4. Sulfonate Inversion with Carboxylate Complexes


R4

O
ROH
CH2Cl2

OSO2R3

Me
H

OH
R1

Me

R3
R2

18 O

R
inversion
product

Me

Me

+
O
P
Ph2

17

R1

16
O

convenient solution to elimination through the


introduction of amine-carboxylate complex 20. Prepared
in situ from an amine (triethylamine or DBU) and a
carboxylic acid (acetic acid or benzoic acid), complex 20
behaves as an SN2-selective nucleophile towards a
variety of secondary sulfonates 19 to afford inverted
esters 21 in moderate to excellent yields (Scheme 4).12
The identity and stoichiometry of amine and acid
components can be tuned to optimize yield and
selectivity for each substrate.

RO

R1

O
PPh2

R3
R2

This protocol offers a number of advantages.


Procedurally, replacement of DAD with a quinone
oxidant combines two byproducts into one and alleviates
hazards of DAD use. Synthetically, the method widens
substrate scope. Whereas pronucleophile pKa is
constrained to a narrow range in the Mitsunobu reaction,
acids, phenols and alcohols all participate in the
Mukaiyama protocol, provding access to aryl and alkyl
ethers in addition to esters.11d Alcohol substrate tolerance
is also robust. Hindered secondary alcohols such as (l)menthol that are inverted with reluctance by the
Mitsunobu reaction are converted to esters or ethers in
high yields.11a Tertiary alcohols also invert cleanly under
the developed conditions, an impressive feat given their
intransigence to other inversion methods.11c
In a very different strategy, Shi and coworkers
promote alchohol esterification through the SN2
displacement of sulfonates.12 Simple in concept but not
in practice, nucleophilic displacement of sulfonates is
often hampered by the competitive formation of
elimination products when carboxyalte salts of alkali
metals are used as nucleophiles. Soft ammonium13a and
cesium13b counterions can attenuate elimination, but their
salts require preparation. Shi and coworkers provide a
(11) (a) Shintou, T.; Kikuchi, W.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 2003, 76, 1645. (b) Shintou, T.; Mukaiyama, T. Chem. Lett. 2003,
32, 1100. (c) Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem.
Soc. 2003, 125, 10538. (d) Shintou, T.; Mukaiyama, T. J. Am. Chem.
Soc. 2004, 126, 7359.
(12) Shi, X.; Shen, C.; Yao, J.; Nie, L.; Quan, N. Tetrahedron:
Asymmetry 2010, 21, 277.
(13) (a) Floyd, D. M.; Crosby, G. A. Weinshenker, N. M.
Tetrahedron Lett. 1972, 13, 3265. (b) Shimizu, T.; Hiranuma, S.
Nakata, T. Tetrahedron Lett. 1996, 37, 6145.

R2

19

O
!+
R3N H O 20
!PhMe, 50-110 C

O
R4

O 21
R1

R2

R1, R2 = alkyl, alkenyl; R3 = OTs, OMs


R4 = CH3, Ph; NR3 = NEt3, DBU

Aside from required sulfonate preparation, this simple


operation represents an otherwise practical entry to
inverted esters. Not only do functionalized substrates
such as esters, acetals and allylic sulfonates tolerate the
mild reaction conditions, but bulky sulfonates as well as
bis-sulfonates invert efficiently and regioselectively
under the developed conditions. An especially attractive
feature of this methodology is its convenient work-up.
Excess amines and acids are easily removed from the
organic product in an aqueous wash. Given its accessible
starting materials and straightforward execution, this
protocol scales well, unlike the more cumbersome
Mukaiyama and Mitsunobu procedures.
Although the methods developed by Curran, Toy,
Mukaiyama and Shi individually combat inefficiencies
associated with reagent handling, substrate reactivity or
purification, none overcome a lingering limitation: the
generation of stoichiometric waste. An ideal alcohol
inversion procedure would proceed, if not by direct
combination of reactants, then by catalytic substrate
activation.
In organic chemistry and elsewhere, solutions to
difficult problems can occasionally be found through
study of simpler systems. Nucleophilic halogenation of
alcohols is more facile than esterification reactions since
the nucleophilicity of halides lowers kinetic barriers to
the process. Often, too, halogen sources participate as
both pronucleophiles and activating agents in the
reactions, lowering the number of reagents involved.
Although no catalytic alcohol inversion reaction has
been described, two recent chlorination protocols lay
conceptual groundwork for such a process.
A very creative procedure developed by Lambert and
coworkers exploits the unusual reactivity of
dichlorocyclopropenes to promote the nucleophilic
chlorination of a variety of primary, secondary and

tertiary alcohols without reliance on redox processes.14


Dichlorocyclopropanes 22 exist in equilibrium with their
aromatic cyclopropenium salts 23 (Scheme 5). In the
transformation devised by Lambert, cyclopropenium salt
23 is intercepted by alcohol 24 to give oxocyclopropene
25. This intermediate undergoes facile loss of chloride to
cyclopropenium 26. Nucleophilic substitution of 26 by
chloride ion displaces dichlorocyclopropenone 28 in a
final step to provide inverted chloride 27. Although this
reaction proceeds stoichiometrically in cyclopropene, its
compelling mode of activation is instructive;
cyclopropenone byproduct 28 is generated in the same
oxidation state as dichlorodiphenylcyclopropene 22, and
simple functional group manipulation relays byproduct
28 to starting material in good yield on gram scale. Such
divergence from traditional, redox-driven modes of
substrate activation will be necessary in the development
of catalytic alcohol inversion processes.

typical Appel pathway affords inverted chloride 31 and


regenerates TPPO 10. Although no chiral alcohols are
examined in the communication, the reaction is
presumed to proceed in an SN2 fashion. While this
method offers practical improvements to halogenation,
its contribution is perhaps most significantly a
conceptual one: established reactivity of stoichiometric
inversion methods can be accessed catalytically through
thoughtful reaction design.

Scheme 6. Appel Chlorination Reaction


Cl
Cl
P
Ph
Ph
30 Ph
(1 equiv)

OH
29
1
R
R2

Cl
R1

O
10 + HCl
31 +
P
Ph
Ph
R2
Ph

Scheme 5. Cyclopropenium Activation of Alcohols

Ph

Cl

Ph

Cl
Cl

24
R1

OH

-HCl

R2

CH2Cl2 or
CH3CN

Cl
Ph 22
Ph 23
79% recovery
SOCl2
Ph

R1

27

Ph

R1

(COCl)2 32 (1 equiv)
(O)PPH3 10 (10 mol %)

OH

Cl

R1

29
R2

Cl
R2
R1
O

Scheme 7. (a) Dentons Catalytic Appel Reaction and (b)


Mechanism

Ph 25

Ph

Cl
O +

Ph 28

R2

31
R1

CHCl3

Cl
R2

Ph 26

Even more recently, a partially catalytic chlorination


reaction has been described by Denton and coworkers.15
The strategy derives from the Appel reaction, which
converts alcohols 29 to their inverted halides 31 with
stoichiometric halophosphonium salts 30 (Scheme 6).16
Like the Mitsunobu, the Appel procedure harnesses the
stability of the phosphorus-oxygen bond of
triphenylphosphine oxide 10 to drive the reaction.
Although phosphorus is not formally oxidized under
these
reaction
conditions,
regeneration
of
halophosphonium 30 by conventional methods requires
reduction of phosphine oxide to phosphine, a harsh
process.
The strength Dentons protocol is that the
phosphonium salt 30 used stoichiometrically in the
Appel reaction is accessed catalytically from
triphenylphosphine oxide 10 (Scheme 7a). Activation of
TPPO by oxalyl chloride 32 gives acylphosphonium
intermediate 33 (Scheme 7b). This is converted to
halophosphonium salt 30 with loss of CO and CO2 as the
reactions sole stoichiometric byproducts. From here, a
(14) Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131,
13930.
(15) Denton, R. M.; An, J.; Adeniran, B. Chem. Comm. 2010, 46,
3025.
(16) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801.

O
10
P
Ph
Ph
Ph

Ph
Ph
P
Ph
O HCl
34
R1 R2 Cl

29
R1

Cl
R1

OH
R2

Cl
30 Cl P
Ph
Ph
Ph

31
R2

O
Cl
32 O

Cl

O 33
O
Cl P
O
Ph
Ph
Ph

Cl

C=O
O C O

After decades of work, a truly streamlined alcohol


inversion
protocol
remains
evasive.
Partial
improvements targeting purification, reaction hazards or
substrate reactivity have been advanced, but all proceed
through stoichiometric alcohol activation. A complete
solution to inversion will require a move to catalysis.
Novel modes of alcohol activation developed in the
context
of
halogenation
chemistry
provide
encouragement that such a catalytic process is
acheivable. So while waste-free esterification remains
elusive, hope does not. Indeed, if the legacy of alcohol
inversion has taught us one thing, it is that the required
creativity is out there.

Das könnte Ihnen auch gefallen