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Organocatalysis

Atroposelective Silylation of 1,1’-Biaryl-2,6-diols by a Chiral

Counteranion Directed Desymmetrization Enhanced by a Subsequent

Kinetic Resolution

Min Zhu+, Hua-Jie Jiang+, Illia Sharanov, Elisabeth Irran, and Martin Oestreich*

Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 90th birthday

Abstract: A desymmetrizing silylation of aromatic diols

is reported. The previously unknown asymmetric silyl

ether formation of phenol derivatives is achieved by

applying List’s counteranion directed silylation techni-

que. A silylium-ion-like silicon electrophile generated

from an allylic silane paired with an imidodiphosphor-

imidate (IDPi) enables enantioselective discrimination

of achiral 1,1’-biaryl-2,6-diols. The enantioselectivity of

that desymmetrization is further improved by a down-

stream kinetic resolution, converting the monosilylated

minor enantiomer into the corresponding, again achiral

bissilylated diol.

Protecting-group strategies hold a vital position in organic

synthesis.[1] The silylation of alcohols is an effective means

of their protection, and the formed silyl ethers are

undoubtedly one of the most common hydroxy protecting

groups.[2] Established procedures can be rendered enantiose-

lective when merged with a kinetic resolution or desymmet-

rization (Scheme 1, top).[3] This research field has continued

to flourish since an isolated report by Ishikawa and co-

workers more than two decades ago.[4] Their approach of

using chlorosilanes in combination with chiral Lewis base

catalysts was turned into highly stereoselective silylation

reactions of different diol motifs[5] and 2°alcohols[6] by the

laboratories of Hoveyda and Snapper as well as Wiskur.

Based on CuH-promoted dehydrogenative SiO coupling

reactions of alcohols and hydrosilanes, we introduced

reagent- and catalyst-controlled protocols for the (dynamic)

kinetic resolution of various 2°and 3°alcohols.[7] Another

less broadly appreciated but still relevant method is the

activation of hexamethyldisilazane by a chiral Brønsted acid

followed by enantioselective alcohol silylation as described

by Song[8] and List.[9]

All of the aforementioned advances involve aliphatic

alcohols, and enantioselective silylation reactions of phenol

derivatives are not known to date. With our expertise in

silylium-ion chemistry,[10] we became aware of a report by

Morita and co-workers on a Brønsted acid-catalyzed

silylation of alcohols and phenols employing allylic silanes as

silylating reagents.[11] Driving this silylation reaction enantio-

selectively could be achieved by the use of a chiral

counteranion[12] by initiation with a chiral Brønsted acid.[13]

The validity of this working hypothesis was further sup-

ported by very recent work of List and co-workers where

confined imidodiphosphorimidate (IDPi) catalysts[14] al-

lowed for enantioselective capture of silylium-ion-like inter-

mediates with phenol nucleophiles.[15] Starting from this

[*] Dr. M. Zhu,+Dr. H.-J. Jiang,+I. Sharanov, Dr. E. Irran,

Prof. Dr. M. Oestreich

Institut für Chemie, Technische Universität Berlin

Strasse des 17. Juni 115, 10623 Berlin (Germany)

E-mail: [email protected]

Homepage: http://www.tu.berlin/en/organometallics

[+] These authors contributed equally to this work.

published by Wiley-VCH GmbH. This is an open access article under

the terms of the Creative Commons Attribution License, which

permits use, distribution and reproduction in any medium, provided

the original work is properly cited.

Scheme 1. Approaches to asymmetric alcohol silylation. Si=triorgano-

silyl.

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How to cite: Angew. Chem. Int. Ed. 2023,62, e202304475

doi.org/10.1002/anie.202304475

literature precedent, we targeted the desymmetrization of

1,1’-biaryl-2,6-diols (Scheme 1, middle). It must be noted

that Rong and Zhao[16] as well as Cheong and Smith[17] had

developed acylation techniques for the atroposelective

protection[18] of this class of molecules, either for accessing

chiral ligand motifs[16] or the core structure of natural

products[19] (Scheme 1, bottom).

Our studies began with a systematic screening of List-

type IDPis[14] as strong Brønsted acid catalysts BA with

biaryl phenol 1a as the model substrate and allylic silane 2a

as the silylating reagent. A set of 18 catalysts decorated with

different aryl groups and perfluoroalkyl/aryl-substituted

sulfonyl units was tested, and the results for five IDPis

bearing triflate moieties are collected in Table 1 (entries 1–

5; see Table S1 in the Supporting Information for the

complete set of catalysts). IDPi BA4 emerged as the best

catalyst in CH2Cl2at room temperature, affording the

monosilylated product 3a with e.r.=89:11 along with

achiral bissilylated 4a (entry 4). Assuming that the success

of the desymmetrization (1a!3a) is further enhanced by a

downstream kinetic resolution (3a!4a), we increased the

amount of the silylating reagent 2a from 1.1 to 1.5 equiv-

alents (entry 6). This measure indeed improved the enantio-

meric ratio of 3a to 97.5:2.5 yet at the same time inverting

the ratio of 3a and 4 a from 63:37 to 30:70; as a logical

consequence, the yield of 3a decreased from 58% to 29%.

The situation was similar in other solvents, that is slightly

better ratios in favor of monosilylated 3a at the cost of

enantioselectivity (entries 7–10). Lowering the reaction tem-

perature had a significant effect as the enantioinduction in

the desymmetrization 1a!3a was higher while the second

silylation step 3a!4a was slowed down (entries 11 and 12).

At 30°C, the desired product 3a was obtained with e.r.=

96:5:3.5 and in 64% yield as a 71:29 mixture with

byproduct 4a (entry 12). Catalyst BA4 was also employed in

a screening of allylic silanes 2b–dwith different substitution

patterns at the silicon atom (not shown; see Table S3 in the

Supporting Information); smaller silyl groups such as

trimethylsilyl (TMS; 2b) and dimethyl(phenyl)silyl (2c) led

to low levels of enantioselection, and no reaction was seen

with the bulky tert-butyldiphenylsilyl group (TBDPS; 2d).

With these optimized reaction conditions in hand, we

next investigated the substrate scope with regard to the

substitution pattern on the naphth-1’-yl group (Scheme 2).

The model reaction of 1a was repeated on a 1 mmol scale,

furnishing the silyl ether 3a in 57% yield and with an

enantiomeric ratio of 96.5:3.5. The absolute configuration of

3a was determined to be (S) by X-ray diffraction analysis;[20]

the molecular structure of (S)-3a is depicted. Biaryl phenols

1b–fbearing different substituents such as a phenyl group, a

Table 1: Optimization of the atroposelective phenol silylation.[a]

Entry Brønsted acid Solvent T[°C] Ratio[b]

3a:4a

Yield [%][b] e.r.[c]

1BA1 CH2Cl2RT 53:47 45 67.5:32.5

2BA2 CH2Cl2RT 64:36 50 81.5:18.5

3BA3 CH2Cl2RT 67:33 53 80:20

4BA4 CH2Cl2RT 63:37 58 89:11

5BA5 CH2Cl2RT 43:57 41 50:50

6[d] BA4 CH2Cl2RT 30:70 29 97.5:2.5

7[d] BA4 1,2-C2H4Cl2RT 29:71 27 96.5:3.5

8[d] BA4 CDCl3RT 40:60 38 92:8

9[d] BA4 1,2-C6H4Cl2RT 42:58 39 91.5:8.5

10[d] BA4 toluene RT 38:62 37 90.5:9.5

11[d,e] BA4 CH2Cl20 43:57 41 97:3

12[d,f] BA4 CH2Cl230 71:29 64[g] 96.5:3.5

[a] All reactions were performed on a 0.1 mmol scale at a 0.2 M concentration in the indicated solvent for 24 h. [b] Ratios and yields were

determined by 1H NMR spectroscopic analysis of the crude reaction mixtures with CH2Br2as an internal standard. [c] Enantiomeric ratios were

determined by HPLC analysis using a chiral stationary phase. [d] 1.5 equiv of 2a was used. [e] Reaction time was 48 h. [f] Reaction time was 72 h.

[g] 60% isolated yield (ratio was 70:30 and e.r. was 96.5:3.5) on a 0.2 mmol scale after purification on silica gel. TBS=tert-butyldimethylsilyl.

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halogen atom or an alkyl residue at C4’of the naphthalene

ring were tolerated to give the corresponding products 3b–f

with high enantiomeric ratios, e.g. e.r.=98:2 for 3d with

R=Br. While the yields were good throughout for those

reactions, both a cyano group (as in 1g) and a sulfonamide

(as in 1h) were detrimental to the yield but not the

desymmetrization itself. We attribute the poor yield in these

cases to the ability of these functional groups to form

relatively stable Lewis pairs with silylium ions. As for other

positions on naphthalene ring, the products 3i and 3j with

bromination at C5’and C8’, respectively, were obtained in

moderate yields and with good (e.r.=94:6 for 3i) and low

(e.r.=77.5:22.5 for 3j) enantioinduction. For comparison,

the influence of a methyl group at C8’was less pronounced

with product 3k being formed in good yield and with a

moderate enantiomeric ratio of 82.5:17.5. The methodology

was also applied to the desymmetrization of the tetra-ortho-

substituted biaryl diol 1l, and moderate atroposelectivity

was obtained with catalyst BA3, giving 3l in 46% yield and

with e.r.=72.5:27.5 (gray box; 35% yield and e.r.=

67.5:32.5 with BA4). In turn, we found that excellent

enantiocontrol was maintained with substrates having other

polycyclic arenes such as an anthracene (1m!3m) and

fluoranthene (1n!3n) instead of the naphthalene ring.

To further probe the enantiodiscriminating ability of

these IDPi catalysts, we tested a series of biphenyl-based

substrates (Scheme 3). We found that BA3 was a suitable

catalyst for 2’-phenyl-substituted diol 1o, and product 3o

was obtained in 52% yield and with e.r.=84:16 (see

Table S4 in the Supporting Information for a reassessment

of the catalysts). Variation of that ortho substituent was

then evaluated by incorporating an additional methyl (1p),

phenyl (1q), or tert-butyl group (1r) in its para-position,

yielding the monosilylated products 3p–rwith moderate to

high enantiomeric ratios. To verify whether the IDPi catalyst

induces the same sense of asymmetric induction for this

subset of biaryl diols, we correlated silyl ether 3q with an

acylated congener of known absolute configuration;[17] the

crystallographically assigned configuration for (S)-3a was

confirmed for (S)-3q (see the Supporting Information for

details). Interestingly, substrates 1s and 1t either containing

a 2’-chloro or 2’-bromo substituent were well tolerated,

Scheme 2. Scope I: Variation of the substituents on the naphthyl ring.

All reactions were performed on a 0.2 mmol scale at a 0.2 M

concentration in CH2Cl2for 72 to 96 h at 30°C. Yields refer to isolated

products after flash chromatography on silica gel. Enantiomeric ratios

were determined by HPLC analysis using chiral stationary phases.

[a] 1 mmol scale. [b] Catalyst BA3 was used. Ts=4-toluenesulfonyl.

Scheme 3. Scope II: Variation of the substituents on the phenyl ring. All

reactions were performed on a 0.2 mmol scale at a 0.2 M concentration

in CH2Cl2for 96 h at 30°C. Yields refer to isolated products after flash

chromatography on silica gel. Enantiomeric ratios were determined by

HPLC analysis using chiral stationary phases. [a] Catalyst BA5 was

used.

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giving the desired products 3s and 3t in acceptable yields

and with decent enantiomeric ratios. Moreover, the more

challenging substrates 1u (R=Me) and 1v (R=Et) bearing

small primary alkyl groups were subjected to this protocol.

To secure good efficiency in the formation of the corre-

sponding products 3u and 3v, Brønsted acid BA5 had to be

used (see Table S5 in the Supporting Information for

another reassessment of the catalysts).

To distinguish between the desymmetrization in the first

silylation step (1!3) and the assumed kinetic resolution in

the second silylation step (3!4), we performed two control

experiments (Scheme 4, top). The reaction of model diol 1a

was run with an equimolar amount of allylic silane 2a to

minimize the bissilylation. The monosilylated product 3 a

was obtained in 75% yield along with trace amounts of

bissilylated 4a, and the enantiomeric ratio was lower than

with higher loadings of 2a: e.r.=85:15 versus 96.5:3.5 with

1.5 equiv of 2a. Next, the kinetic resolution was independ-

ently investigated. A racemic mixture of monosilylated 3a

was subjected to the same reaction setup using 0.60 equiv of

2a. At 26% conversion (isolated yield of bissilylated 4a),

enantioenriched (S)-3a was formed with e.r.=61.5:38.5,

corresponding to a selectivity factor of 6.0. The absolute

configuration of (S)-3a is consistent with preferential

silylation of (R)-3a. Based on the above results, we conclude

that the outcome of the moderately enantioselective desym-

metrization is further enhanced by a subsequent kinetic

resolution, so that the overall transformation proceeds with

good levels of enantioinduction (Scheme 4, bottom).

In summary, we have developed an efficient approach to

the asymmetric synthesis of axially chiral biaryls through an

atroposelective desymmetrizing electrophilic silylation of

biaryl diols. A downstream kinetic resolution of the chiral

monosilylated product has been shown to be in operation,

thereby further increasing the overall enantioinduction by

preferentially converting the minor enantiomer into the

bissilylated diol. This enantioselective phenol silylation is

another example of the power of chiral counteranion

directed catalysis involving silylium-ion-like intermediates.

Acknowledgements

M.Z. gratefully acknowledges the Alexander von Humboldt

Foundation for a postdoctoral fellowship (2022–2024). I.S.

thanks TU Berlin for financial support. M.O. is indebted to

the Einstein Foundation Berlin for an endowed professor-

ship. Open Access funding enabled and organized by

Projekt DEAL.

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available

from the corresponding author upon reasonable request.

Keywords: Atropisomerism ·Desymmetrization ·Kinetic

Resolution ·Organocatalysis ·Silylium Ions

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Manuscript received: March 28, 2023

Accepted manuscript online: May 2, 2023

Version of record online: May 22, 2023

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