Reagent directing group controlled organic synthesis: Total synthesis of (R,R,R,)-α-tocopherol

DOI: 10.1002/anie.200703268

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Angewandte Chemie - International Edition p. 8670 - 8673 (2007)

Update date:2022-08-04

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Authors:

Rein, Christian

Demel, Peter

Outten, Robert A.

Netscher, Thomas

Breit, Bernhard

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Article abstract of DOI:10.1002/anie.200703268

(Chemical Equation Presented) The direct approach: The efficient use of substrate control has served as the basis for the enantioselective total synthesis of (R,R,R)-α-tocopherol. A single reagent directing group (ortho-diphenylphosphanyl benzoate, o-DPPB) served to control the stereoselectivity of a rhodium-catalyzed hydroformylation reaction and the directed allylic substitution as the fragment-coupling step (see picture).

Full text of DOI:10.1002/anie.200703268

Communications

DOI: 10.1002/anie.200703268

Total Synthesis

Reagent Directing Group Controlled Organic Synthesis: Total

Synthesis of (R,R,R)-a-Tocopherol**

Christian Rein, Peter Demel, Robert A. Outten, Thomas Netscher, and Bernhard Breit*

Selectivity control during the course of a total synthesis can be

achieved either by the reagents employed (reagent control)

or, generally less frequently used, by the substrate (substrate

control). However, the latter approach could be particularly

efficient if attractive substrate–reagent interactions are

involved which allow for the optimal transfer of a substrateꢀs

structural information into the associated selectivity-deter-

mining transition state of a subsequent transformation.^[1]One

way to enforce such attractive substrate–reagent interactions

is to employ substrate-bound reagent-directing groups

(RDGs, Figure 1).^[2]In an ideal scenario, such an RDG

report herein on the first realization of the concept of an

RDG-controlled organic synthesis by an enantioselective

total synthesis of (R,R,R)-a-tocopherol (1).

(R,R,R)-a-Tocopherol (1) is the most prominent and

biologically most active naturally occurring member of the

compounds covered by the term vitamin E, which is an

essential food ingredient and the most important fat-soluble

antioxidant.^[3]As a consequence, tocopherol (1) has been the

target of many synthetic endeavors which have been,

however, directed almost exclusively at the stereoselective

preparation of either chroman or isoprenoid side-chain

building blocks, which then had to be connected in a

subsequent step.^[4]In contrast, strategies involving, for

example, C C or C O coupling reactions with concomitant

creation of a stereogenic center are rare.^[5,6]

Our synthetic plan is outlined in Scheme 1. As a final

fragment-coupling step we envisioned using our recently

developed o-DPPB-directed copper-mediated allylic syn-

substitution reaction^[7]between the tocopherol nucleus I

functionalized as an organometallic nucleophile and the

allylic electrophile II. The latter could stem from the aldehyde

IV, which could be chain-elongated (after reduction and

activation) by way of an sp sp cross-coupling reaction.

Aldehyde IV could be the product of an o-DPPB-directed

stereoselective hydroformylation of the homomethallylic

precursor VI.^[8]A temporary protecting group ꢀ for the

allylic alkene function might need to be incorporated to shield

the double bond from an undesired hydroformylation reac-

tion. A catalytic asymmetric allylation could deliver the

alcohol precursor of VI.

Figure 1. Concept of reagent directing group (RDG) controlled organic

synthesis.

would not only control the selectivity of a single trans-

formation but also a sequence of reactions that introduce

structural elaborations (with reagents a,b,c) until it is finally

removed from the product. Ideally, the removal step

(reagent d) would be incorporated during the course of a

further skeleton-expanding operation, which at best would be

a fragment-coupling step at a late stage of the synthesis. We

The heterocyclic organometallic nucleophile I could be

envisaged to stem from alcohol building block III, which itself

could be the product of a Brønsted acid catalyzed cyclization

of ketal-protected diol V. A Heck-type coupling between the

aromatic system VII and a C₁-chain-elongated terminal

alkene derived from the known alcohol 2 could be used for

installation of the isoprenoid side chain into the cyclized

precursor.^[9]

Construction of the chroman system began with alcohol 2,

which was obtained from an efficient enzymatic ester

hydrolysis.^[9]Oxidation and Wittig olefination furnished

alkene 3 (Scheme 2). A subsequent Mizoroki–Heck coupling

reaction^[10]with aryl iodide 4 proceeded smoothly under the

conditions developed by Jeffrey^[11]to furnish the hexasubsti-

tuted arene system 5 in 75% yield. After hydrogenation of the

alkene to give 6, a one-pot Brønsted acid catalyzed depro-

tection and cyclization gave the fully functionalized chroman

system 7^[12,13]in excellent yield and with complete retention of

configuration^[14,15](99.5% ee). After protection of the phe-

nolic hydroxy group as a benzyl ether, the required two-

[*] Dipl.-Chem. C. Rein, Dr. P. Demel, Prof. Dr. B. Breit

Institut für Organische Chemie und Biochemie

Albert-Ludwigs-Universität Freiburg i. Brsg.

Albertstrasse 21, 79104 Freiburg i. Brsg. (Germany)

Fax: (+49)761-203-8715

E-mail: bernhard.breit@chemie.uni-freiburg.de

Dr. R. A. Outten, Dr. T. Netscher

Research and Development

DSM NutritionalProducts

(former Roche Vitamins and F. Hoffmann—La Roche)

P.O. Box 3255, 4002 Basel(Switzeral nd)

[**] This work was supported by the Fonds der Chemischen Industrie,

the International Research Training group “Catalysts and Catalytic

Reactions for Organic Synthesis” (GRK 1038). We thank Rhodia for

the generous gifts of chemicals.

Supporting information for this article is available on the WWW

under http://www.angewandte.org or from the author.

8670

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8670 –8673

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Angewandte

Chemie

carbon-atom chain elongation was achieved

by employing a sequence consisting of

alcohol oxidation (Swern) followed by a

Horner–Wadsworth–Emmons olefination.

A two-step protocol was chosen to effect a

chemoselective reduction of the a,b-unsatu-

rated ester to the fully saturated alcohol.

Thus, in a first step the ethyl ester was

reduced with DIBAL-H to give the corre-

sponding allylic alcohol, which could be

hydrogenated cleanly under an atmosphere

of hydrogen in the presence of Adamꢀs

catalyst. A redox condensation^[16]with pre-

formed iodotriphenylphosphonium iodide

under the conditions developed by

Mukaiyama led to iodide 9, the precursor

for the final fragment-coupling step.

To implement our RDG-controlled syn-

thesis strategy for construction of the iso-

prenoid side chain,

hydroformylation of

position-selective

homomethallylic

alkene function in the presence of an allylic

alkenic function was needed. However, test

experiments revealed that for the parent

diene system VI (ꢀ = H) the required posi-

tion selectivity could not be achieved, as

Scheme 1. Synthesis plan. o-DPPB=ortho-diphenylphosphanyl benzoate).

both alkene functions reacted with similar

rates. To solve this problem we decided to

install a temporary silicon substituent at the

allylic alkene function. It is well-known that hydroformyla-

tion of trisubstituted alkenes proceeds in general significantly

slower than hydroformylation of disubstituted alkenes.^[17]

diphenylmethylsilyl substituent was eventually found to serve

this purpose. Thus, synthesis of the C₁₆isoprenoid side chain

of tocopherol began by trapping lithiopropyne (generated

from 1-bromopropene with 2 equiv nBuLi)^[18]with chlorodi-

phenylmethylsilane to give alkyne 10 (Scheme 3). Regiose-

lective hydroalumination with DIBAL-H followed by activa-

tion as the corresponding ate complex through reaction with

methyllithium allowed for a C₁chain elongation with

paraformaldehyde. Oxidation with Dess–Martin reagent

furnished aldehyde 11.^[19]To install the first stereogenic

center in an efficient manner, we decided to explore the

asymmetric catalytic methallylation of aldehyde 11. Unfortu-

nately, all attempts to achieve this transformation using the

protocol developed by Keck et al. failed,^[20]presumably as a

consequence of significant steric hinderance. Finally, a silver/

binap catalyst developed by Yamamoto turned out to be

effective.^[21]Under optimized conditions, the homomethal-

lylic alcohol 12 was obtained on a gram scale in 85% yield and

with greater than 97% ee. Next, the reagent-directing o-

DPPB group was installed by employing a standard Steglich

protocol^[22]to furnish the substrate for an o-DPPB-directed

rhodium-catalyzed hydroformylation.^[23]Thus, at a synthesis

gas pressure of 40 bar and 408C, the corresponding anti-

aldehyde 14 was obtained in 81% yield and a diastereoselec-

tivity of 91:9. Reduction of the aldehyde function with sodium

borohydride led to alcohol 15, and allowed the minor syn

diastereomer to be separated. Transformation of the primary

Scheme 2. Synthesis of the chroman system. Reagents and conditions:

a) Swern; b) Wittig; c) Pd(OAc)₂(5 mol%), DMF, NaHCO₃, 1108C,

Bu₄NBr; 75%; d) Pd/C, H₂(1 atm), NaOAc, MeOH; 93%; e) HCl,

EtOH; 86%; f) K₂CO₃, BnCl, DMF, RT; 98%; g) (COCl)₂, DMSO,

CH₂Cl₂À508C, then NEt₃; 98%; h) (EtO)₂P(O)CH₂CO₂Et, nBuLi, DME,

08C to RT; 97%; i) DIBAL-H, CH₂Cl₂, À788C; 98%; j) H₂(1 atm), PtO₂

(8 mol%), TBME, RT; 95%; k) Ph₃PI₂, CH₂Cl₂, 08C to RT; 92%.

Bn=benzyl, DME=1,2-dimethoxyethane, DIBAL-H=diisobutylalumi-

num hydride, TBME=tert-butylmethylether.

Angew. Chem. Int. Ed. 2007, 46, 8670 –8673

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

8671

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Communications

Scheme 3. Synthesis of 17. Reagents and conditions: a) nBuLi, THF,

À788C, then Ph₂MeSiCl, À788C to RT; 98%; b) DIBAL-H, Et₂O, 08C to

RT; then MeLi, À58C to RT; then (CH₂O)_n; 68%; c) Dess–Martin

periodinane, CH₂Cl₂; 99%; d) Bu₃SnCH₂CMe CH₂; AgOTf (20 mol%),

(S)-binap (20 mol%), THF, À208C; 85%; e) o-DPPBA, DCC, DMAP,

CH₂Cl₂, RT; 86%; f) [Rh(CO)₂(acac)] (2 mol%), P(OPh)₃(8 mol%),

H₂/CO (1:1, 40 bar), toluene, 408C; 81%; g) NaBH₄, MeOH, 08C;

82%; h) Ph₃PI₂, CH₂Cl₂, 08C to RT; i) iBuMgCl, Li₂CuCl₄(10 mol%),

THF, À108C; 72% over two steps; j) KF, KHCO₃, TBAF, DMSO, 358C;

77%. Tf=trifluoromethanesulfonyl, binap=2,2’-bis(diphenylphos-

phanyl)-1,1’-binaphthyl, o-DPPBA=ortho-diphenylphosphanylbenzoic

acid, DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-dimethylamino-

pyridine, acac=acetylacetonate, TBAF=tetra-n-butylammonium fluo-

ride.

Scheme 4. Fragment assembly and completion of the synthesis.

Reagents and conditions: a) 9, tBuLi, Et₂O, À858C; then MgBr₂·Et₂O;

then addition to 17/CuBr·SMe₂, Et₂O, RT; 78%; b) Raney-Ni, H₂

(1 atm), EtOH, RT; 91%; c) dimethylsuflate, KOH, DME, RT; quant.

In conclusion, a new strategy that makes efficient use of

substrate control by employing the concept of an RDG-

controlled synthesis has been realized in the context of an

enantioselective total synthesis of (R,R,R)-a-tocopherol.

Thus, the reagent-directing group (o-DPPB) served to control

the stereoselectivity during the course of a rhodium-catalyzed

hydroformylation reaction for the construction of the C₁₆

isoprenoid side chain. The same o-DPPB group subsequently

acted as a reagent-directing leaving group during the course

of a directed copper-mediated allylic substitution, which

simultaneously served as the fragment-coupling step and led

to the removal of the o-DPPB group, which may be recovered

during the work-up process. To the best of our knowledge, this

is also the first application of a copper-mediated allylic

substitution as a fragment-coupling reaction in a total syn-

thesis, and clearly demonstrates the synthetic potential of o-

DPPB-directed allylic substitution for total synthesis.

alcohol function in 15 into the corresponding iodide allowed

the remaining isobutyl side chain to be installed through a

copper-catalyzed sp sp cross-coupling reaction with isobu-

tylmagnesium chloride.^[24]Desilylation of the vinylsilane to

generate the fragment-coupling precursor 16 was achieved

upon treatment with potassium fluoride and TBAF in the

presence of potassium bicarbonate in DMSO at 358C.

An o-DPPB-directed allylic substitution was chosen as the

final fragment-coupling step. We recently demonstrated that

this reaction proceeds with high levels of chemo-, regio-, and

diastereoselectivity, concomitant with a 1,3-chirality trans-

fer.^[7]Furthermore, stoichiometric amounts of organometallic

reagent are sufficient to achieve complete conversions, which

render this reaction suitable for the coupling of valuable

metal–organic building blocks with allylic o-DPPB esters.

Thus, the Grignard reagent (tBuLi, MgBr₂·OEt₂) of chro-

manyl iodide 9 was generated at À858C in diethyl ether.

Reaction with the allylic electrophile 17 at room temperature

in the presence of 0.5 equivalents of copper(I) bromide

dimethylsulfide initiated a clean and highly selective directed

allylic syn substitution to give the coupling product 18 in 78%

yield (Scheme 4). For completion of the synthesis, cleavage of

the benzyl ether and reduction of the alkene were accom-

plished in one pot with Raney-Ni under an atmosphere of

hydrogen (in EtOH at RT, 91%) to give (R,R,R)-a-toco-

pherol in 13 steps (longest linear sequence) and 30% overall

yield. A combination of HPLC and GC analysis of the

corresponding methyl ether 19 showed the synthetic material

to be identical to the natural material.^[25]

Received: July 21, 2007

Published online: October 12, 2007

Keywords: enantioselectivity · homogeneous catalysis ·

hydroformylation · isoprenoids · vitamin E

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8672 www.angewandte.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8670 –8673

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Chemie

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Information.

Angew. Chem. Int. Ed. 2007, 46, 8670 –8673

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

8673

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Article Doi

Reagent directing group controlled organic synthesis: Total synthesis of (R,R,R,)-α-tocopherol

DOI: 10.1002/anie.200703268

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