Science_-_2019.08.30

a silane to regenerate the phos-

phane. The authors combined

this with the above-mentioned

catalytic system of Taniguchi

to realize a fully catalytic Mit-

sunobu reaction ( 9 ). However,

these findings were reevaluated

and critically discussed in the

community ( 10 , 11 ). Taniguchi

and co-workers performed a de-

tailed study on the fully catalytic

system and showed that the re-

action proceeds under retention

of configuration and that the

azo reagent does not participate

( 10 ). They concluded that the

fully catalytic Mitsunobu reac-

tion was not realized.

These previous findings un-

derline the tremendous chal-

lenges associated with the

development of a fully catalytic

system based on the original

Mitsunobu protocol. It has

proved difficult to realize a cat-

alytic system by implementing

a selective reducing agent to re-

generate the phosphane in the

presence of an oxidizing agent

to regain the azodicarboxylate.

Instead of trying to find a

perhaps unachievable balance

in reactivity and selectivity, Bed-

doe et al.’s catalyst circumvents

the above-mentioned challenges.

Their system provides an exciting

approach to the long-standing

challenge of the direct bimolecu-

lar substitution of nonactivated

chiral alcohols, delivers a new

platform in organocatalysis, and

offers new possibilities for sus-

tainable organic synthesis. j

SCIENCE sciencemag.org

GRAPHIC: C. BICKEL/

SC

IENCE

Beddoe et al. now achieve

this goal, by means of a re-

dox-neutral organocatalytic

Mitsunobu reaction. Most

notably, their protocol is

based on a single, easily ac-

cessible catalyst; no further

stoichiometric reductants

or oxidants are required.

Furthermore, the only by-

product is water, greatly

increasing the overall atom

economy of the reaction.

The structure of the cata-

lyst seems simple: a tertiary

phosphane oxide bearing

a phenolic group (see the

figure). On second glance,

however, it becomes clear

that the design is brilliant,

because it enables the dehy-

drative coupling of primary

and secondary alcohols with

various pronucleophiles. Ini-

tially, the catalyst reacts with

the pronucleophile to form a

cyclic oxyphosphonium salt

while releasing water. The

alcohol then reacts with the

phosphonium salt, form-

ing a new P–O bond and si-

multaneously liberating the

phenolic side chain of the

catalyst. This represents the

activated substrate, which

eventually reacts with the

nucleophile, forming the

substitution product under

liberation of the catalyst.

The authors show that this

reaction works for a broad

range of primary (R= H)

and secondary (R, R 9 Þ H)

alcohols. They converted

chiral alcohols under ste-

reochemical inversion to

the respective substituted

products with excellent

selectivity. As they dem-

onstrate, the methodology

allows the use of various

pronucleophiles, leading to

the formation of C–O, C–N, and C–S bonds.

Beddoe et al.’s approach differs conceptu-

ally from earlier attempts to realize catalytic

Mitsunobu reactions. Previous strategies

stayed close to the original procedure, in-

troducing additional reagents and catalysts

to regenerate the phosphane or azodicar-

boxylate and thereby realize protocols that

were catalytic in these components.

In 2006, But and Toy reported a variant

of the Mitsunobu reaction that was catalytic

in the azo reagent, using an iodine-based

oxidant to regenerate the azo reagent ( 7 ). In

2013, Taniguchi et al. ( 8 ) described further

developments in this direction, showing

that molecular oxygen from air could serve

as the terminal oxidant in the presence of

an iron catalyst. However, besides the in-

creased complexity of the overall systems,

both procedures still required overstoichio-

metric amounts of the phosphane.

Two years later, Buonomo and Aldrich re-

alized a protocol that was catalytic in phos-

phane by using stoichiometric amounts of

A dream reaction: Direct nucleophilic substitution of alcohols

A classic solution: The Mitsunobu reaction

Catalytic variant of Beddoe et al.

Mechanistic proposal

Reaction pathway

OH

+ Nu–H +

Nu–H

Nu–

R R 9

OH

Nu–H

Ph 3 P (≥1 equiv.)

CO 2 Et

EtO 2 C

(≥1 equiv.)

NN

+ + +

R R 9

OH

R R 9

OH

R R 9

O

R R 9

Nu

H 20

By-product

Reagents By-products

Alcohol Pronucleophile Product

R R 9

OH

+ Nu–H +

R R 9

Nu

H 20

Organocatalyst

R R 9

Ph 3 P+ P Ph 3

Ph 3 P=O

CO 2 Et

EtO 2 C

NN–

CO 2 Et

Ph 3 P=O

EtO 2 C

NN

H

Nu H

R R 9

Nu

R R 9

CO 2 Et

EtO 2 C

NN

H

H

+

+

Nu

H 20

Nu–

R R 9

OHO Nu–H

P

Ph

Ph

O

R R 9

Ph Ph

OH

P+

Ph O

Ph

P+

Nu–

Nu, nucleophile; R and/or R 9 , H, alkyl, aryl, etc.; Et, ethyl; Ph, phenyl.

REFERENCES AND NOTES

1. R. H. Beddoe et al., Science 365 , 910
   (2019).


2. K. C. K. Swamy, N. N. B. Kumar,
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3. O. Mitsunobu, Synthesis 1981 , 1 (1981).


4. M. Oyo, Y. Masaaki, M. Teruaki, Bull.
   Chem. Soc. Jpn. 40 , 935 (1967).


5. B. M. Trost, Science 254 , 1471 (1991).


6. S. Fletcher, Org. Chem. Front. 2 , 739 (2015).


7. T. Y. S. But, P. H. Toy, J. Am. Chem. Soc. 128 , 9636 (2006).


8. D. Hirose, T. Taniguchi, H. Ishibashi, Angew. Chem. Int. Ed.
   52 , 4613 (2013).


9. J. A. Buonomo, C. C. Aldrich, Angew. Chem. Int. Ed. 54 ,
   13041 (2015).


10. D. Hirose, M. Gazvoda, J. Košmrlj, T. Taniguchi, Org. Lett. 18 ,
    4036 (2016).


11. R. H. Beddoe, H. F. Sneddon, R. M. Denton, Org. Biomol.
    Chem. 16 , 7774 (2018).

ACKNOWLEDGMENTS

We are grateful for support from the Leibniz ScienceCampus

Phosphorus Research Rostock (www.sciencecampus-rostock.de).

10.1126/science.aay6635

30 AUGUST 2019 • VOL 365 ISSUE 6456 867

Catalytic substitution of alcohols

Beddoe et al. report a redox-neutral organocatalytic analog of the stoichiometric

Mitsunobu reaction for substituting otherwise inert alcohols.

Published by AAAS