Lipase-catalyzed kinetic resolution approach toward enantiomerically enriched 1-(β-hydroxypropyl)indoles

DOI: 10.1016/j.tetasy.2017.10.010

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Tetrahedron Asymmetry p. 1717 - 1732 (2017)

Update date:2022-08-03

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Borowiecki, Pawe?

Justyniak, Iwona

Ochal, Zbigniew

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Article abstract of DOI:10.1016/j.tetasy.2017.10.010

In a route towards enantiomerically enriched 1-(β-hydroxypropyl)indoles, which are potentially useful building blocks for high value-added chemicals synthesis, a kinetic resolution approach by means of lipase-catalyzed enantioselective acylation as well as hydrolysis/methanolysis has been elaborated for the first time. The enzymatic resolution of chiral N-substituted indole-based sec-alcohols was successfully accomplished, yielding both enantiomeric forms of the employed derivatives with up to >99% enantiomeric purity via an enantioselective transesterification under mild reaction conditions. The most selective resolutions were obtained using fungal (CAL-B and TLL) and bacterial (PFL and BCL) lipases and vinyl acetate as the acyl group donor. The synthetic protocol described herein is very simple, user-friendly and efficient, thus paving the way for future access towards more complex compounds of this type. The absolute configurations of novel enantiomeric derivatives, and thus stereoselectivity of the described enzymatic reactions were confirmed by application of CDA-based NMR methodology and single-crystal X-ray diffraction analysis.

Full text of DOI:10.1016/j.tetasy.2017.10.010

Tetrahedron: Asymmetry 28 (2017) 1717–1732

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry

journal homepage: w ww.elsevier.com/locate/tetasy

Lipase-catalyzed kinetic resolution approach toward

enantiomerically enriched 1-(b-hydroxypropyl)indoles

Paweł Borowiecki ^a,, Iwona Justyniak , Zbigniew Ochal

⇑

^aWarsaw University of Technology, Faculty of Chemistry, Department of Drugs Technology and Biotechnology, Koszykowa St. 3, 00-664 Warsaw, Poland

^bInstitute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka St. 44/52, 01-224 Warsaw, Poland

a r t i c l e i n f o

a b s t r a c t

Article history:

In a route towards enantiomerically enriched 1-(b-hydroxypropyl)indoles, which are potentially useful

building blocks for high value-added chemicals synthesis, a kinetic resolution approach by means of

lipase-catalyzed enantioselective acylation as well as hydrolysis/methanolysis has been elaborated for

the ﬁrst time. The enzymatic resolution of chiral N-substituted indole-based sec-alcohols was success-

fully accomplished, yielding both enantiomeric forms of the employed derivatives with up to >99% enan-

tiomeric purity via an enantioselective transesteriﬁcation under mild reaction conditions. The most

selective resolutions were obtained using fungal (CAL-B and TLL) and bacterial (PFL and BCL) lipases

and vinyl acetate as the acyl group donor. The synthetic protocol described herein is very simple, user-

friendly and efﬁcient, thus paving the way for future access towards more complex compounds of this

type. The absolute conﬁgurations of novel enantiomeric derivatives, and thus stereoselectivity of the

described enzymatic reactions were conﬁrmed by application of CDA-based NMR methodology and sin-

gle-crystal X-ray diffraction analysis.

Received 17 August 2017

Revised 25 August 2017

Accepted 18 October 2017

Available online 22 November 2017

1. Introduction

and biochemical processes of living organisms, they have attracted

considerable attention for their application in the pharmaceutical

Indole chemistry has been used for over 100 years since 1883 in

the pioneering useful protocol of so-called ‘Fischer indole synthe-

sis’.¹A tremendous amount of effort has been directed toward

adaptation of the classical Fischer methodology, as well as the

development of more efﬁcient and versatile synthetic attempts to

obtain indoles.²Furthermore, since the indole backbones are par-

ticularly desirable in modern organic synthesis, many innovative

protocols to prepare³and transform⁴them into highly functional-

ized molecules have been published. The indole motif is present in

a large family of natural compounds with a wide range of struc-

tural diversity and biological activity. In this regard, over the past

few decades a plethora of synthetic campaigns, encompassing sig-

niﬁcant knowledge of how to obtain a variety of structurally com-

plex and challenging alkaloids of plant,⁵marine,⁶fungal,⁷and

bacterial⁸origin, as well as natural and semi-synthetic triptans⁹

has been widely elaborated. Moreover, since many of the indole-

ring-containing derivatives play an important role in physiological

industry. In this context, the indole scaffold as the privileged

structure is present in over 200 of clinically approved drugs.¹⁰

Indole-based molecules are also common building blocks in other

countless applications, including catalysis,¹¹manufacturing of dyes

and pigments,¹²dietary supplements and nutraceuticals,¹³as well

as the production of fungicides,¹⁴veterinary drugs,¹⁵and fragrance

ingredients.¹⁶

As already mentioned, the indole core has become one of the

most utilized structures especially in medicinal chemistry. There-

fore, miscellaneous attempts toward novel derivatives with

enhanced bioactive properties have been performed and are con-

tinuously under evolution each year.¹⁷In the last two years it

has been shown that the indole ring system is a pharmacophore

in many pharmacologically relevant compounds across a wide

range of therapeutic areas (Fig. 1).

The most common among them are compounds possessing

anti-cancer,¹⁸anti-microbial,¹⁹anti-viral [including anti-HIV,²⁰

anti-HCV,²¹anti-Chikungunya virus (anti-CHIKV),²²anti-varicella

zoster virus (anti-VZV),²³anti-Coxsackie B4 virus²⁴etc.], anti-

diabetic,²⁵anti-parasitic [including anti-leishmanial²⁶and anti-

trypanosomiasis²⁷], and anti-inﬂammatory²⁸activity. The design

strategies employed for the synthesis of novel indole-containing

⇑

Corresponding authors. Tel.: +48 22 660 53 42; fax: +48 22 628 27 41 (P.B.);

tel.: +48 22 234 73 27; fax: +48 22 628 27 41 (Z.O.).

E-mail addresses: pawel_borowiecki@onet.eu, pborowiecki@ch.pw.edu.pl

(P. Borowiecki), zbigniew.ochal.ztibsl@gmail.com, ochal@ch.pw.edu.pl (Z. Ochal).

https://doi.org/10.1016/j.tetasy.2017.10.010

1718

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

Anti-cancer agents:

Anti-Alzheimer agents:

F₃C

CF₃

Anti-HIV agents:

Anti-parasitic agents:

NH₂

Anti-microbial agents:

Cardiovascular agents:

NH₂⁺Cl^-

NH₂

Figure 1. Selected chemical structures of indole-containing compounds currently under clinical investigation.

cardiovascular therapeutics with improved anti-hypertension,²⁹

anti-platelet,³⁰and -adrenergic³¹activities seem to be very

2. Results and discussion

promising options. Besides the above-mentioned bioactive com-

pounds bearing indole moieties, novel derivatives of this kind

can be also found in the group of potential therapeutics dedicated

to treatment of aging-diseases, such as chronic neurodegenerative

Alzheimer’s disease,³²wet age-related macular degeneration³³or

benign prostatic hyperplasia.³⁴The results of different studies

report that the indole ring is a privileged core structure in many

synthetic compounds exhibiting a broad range of other interesting

biological activities, such as analgesic,³⁵anti-lipidemic,³⁶anti-psy-

chotic,³⁷and anti-oxidant.³⁸Finally, indole scaffold is becoming an

important structural component of potential therapeutic agents

useful in the treatment of obesity³⁹and opioid dependence.⁴⁰

On the other hand, although there are many literature reports

on the use of lipases as biocatalysts for the resolution of various

heterocyclic secondary alcohols, surprisingly, the role of hydrolytic

enzymes regarding chiral indoles of this type is still undeveloped.

The described lipase-mediated racemate resolutions have been

limited to derivatives structurally closely related to indoles, such

as indolines (2,3-dihydroindoles),⁴¹isoindoles,⁴²and carbazoles;⁴³

however, all of them involve reactions with the amino group

instead of the hydroxyl moiety. Herein, we describe the challenge

of designing simple enzymatic methodology based on highly

stereoselective transformations, mild reaction conditions and low

environmental impact for the efﬁcient synthesis of non-racemic

sec-alcohols with an indole skeleton.

Herein, we continue our efforts toward exploring synergism

between chemistry and biochemistry by expanding on novel sub-

strates for biotechnological processes of high scientiﬁc importance.

Our ultimate goal was to provide a simple and robust approach for

utilizing lipase-based biocatalysis for the preparation of three new

enantiomerically enriched 1-(b-hydroxypropyl)indoles (S)-(+)- and

(R)-(ꢀ)-3a–c, which are potentially valuable synthons for manu-

facturing pharmaceuticals. Scheme 1 outlines the synthetic path-

way of chemoenzymatic preparation of non-racemic indole

derivatives 3a–c consisting of classical enzymatic kinetic resolu-

tion (Ekinetic resolution, EKR) methodology as a key-step.

2.1. Synthesis of racemic 1-(b-hydroxypropyl)indoles 3a–c

Our initial research focused on preparing the racemic alcohols

rac-3a–c required for enzymatic transformations. In this context,

readily available 5-nitro-substituted 1a, 3-methyl-substituted 1b

and 2,3-dimethyl-substituted indoles 1c were used as starting

materials in the regioselective propylene oxide 2 ring-opening

reaction promoted by NaH used in slight excess in dry DMF. After

24 h of stirring at room temperature, the alcohols were ﬁnally iso-

lated in moderate (43% for rac-3a, 56% for rac-3b) to good (70% for

rac-3c) yields in a straightforward manner. In turn, the racemic

indole esters rac-4a–c and rac-5a–c requested as the substrates

and as analytical standards for enzymatic reaction’s progress

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

R²

1719

R²

R³

iia-b)

iv)

R¹

43-70%

R⁴

1a c

rac-3a-c

(S)-(+)-4a-b: R⁴= CH₃

a: R¹= H, R²= H, R³= NO₂;

b: R¹= H, R²= CH₃, R³= H;

c: R¹= CH₃, R²= CH₃, R³= H.

rac-4a-c: R⁴= CH₃(78-85%)

rac-5a-c: R⁴= C₃H₇(62-73%)

(R)-(-)-

(S)-(+)- : R⁴= C₃H₇

iii)

R²

R³

R¹

(R)-(-)-4a-c

(S)-(+)-3a-c

Scheme 1. Lipase-catalyzed kinetic resolution of racemic 1-(b-hydroxypropyl)indoles rac-3a–c and their esters rac-4a–c and rac-5a–c. Reagents and conditions: (i) 2 (1.1

equiv), NaH (1.1 equiv), dry DMF, 20 min at 0–5 °C, then 24 h at RT; (iia) Ac₂O (1.1 equiv), DMAP (cat.), dry CH₂Cl₂, 24 h at RT; (iib) C₃H₇COCl (1.0 equiv), Et₃N (1.0 equiv),

DMAP (cat.), dry PhCH₃, 24 h at RT; (iii) vinyl acetate (10 equiv) or isopropenyl acetate (10 equiv), lipase (10% w/w), organic solvent, 30 °C, 300 rpm (laboratory shaker); (iv)

satd aq TBME or MeOH (10 equiv), lipase (10% w/w), organic solvent, 30 °C, 300 rpm (laboratory shaker).

monitoring and enantiomeric excess (% ee) measurements, were

obtained in very good yields (78–85%) for acetates rac-4a–c and

in good yields (62–73%) for butyrates rac-5a–c, respectively. The

esteriﬁcation reactions were carried out by using 1.1 equiv of

acetic anhydride or a stoichiometric amount of butyryl chloride

in the presence of 4-dimethylaminopyridine (DMAP) as the acyl

transfer catalyst at room temperature for 24 h. In the case of race-

mic acetates rac-4a–c, the reactions were performed in dry

dichloromethane, and in turn, butyrates rac-5a–c were prepared

in dry toluene solution, into which an equimolar amount of tri-

ethylamine as an organic base was added.

that would be impossible to carry out; (ii) the increase of the

enzymes’ activity and selectivity in action; and (iii) the incense-

ment of enzymes’ thermo-stability and resistance toward prote-

olytic degradation caused by the simultaneously presence of

traces of proteases in technical grade commercial preparations.

Moreover, in nearly anhydrous organic solvents: (iv) the scope

of potential substrates for enzymes is signiﬁcantly widened as

substrate solubility is improved (this also allows higher substrate

loadings); (v) product recovery from organic solvents is relatively

simple as compared to water; (vi) the insolubility of enzymes in

organic media permits their easy recovery and further reuse; as

well as (vii) the catalytic performance is not much inﬂuenced

by the pH, and ﬁnally (viii) space/time yield and volumetric pro-

ductivity are mostly enhanced. Therefore, to develop a general

procedure for the efﬁcient enzymatic kinetic resolution of various

indole alcohols rac-3a–c and their esters rac-4a–c and rac-5a–c,

and thus to produce both enantiomeric forms of this compounds

with high enantiomeric purity, our aim herein was to study the

differences in the stereochemical outcome between lipase-cat-

alyzed selective hydrolysis/alcoholysis and lipase-mediated enan-

tioselective O-acylation methodology. Moreover, since in purely

aqueous media the non-enzymatic hydrolysis often occur in com-

petition with the enzymatic reaction, therefore, we decided to

examine all the hydrolytic attempts (hydrolysis and alcoholysis)

in organic solvents using a small amount of water or methanol

as the nucleophile, respectively. These biphasic hydrolytic condi-

tions were also applied due to the fact that lipases often show

lower catalytic activity in homogeneous aqueous solutions than

in the presence of interfaces. Moreover, to avoid the expense

and the work, the appropriate optimization of the operating

parameters is sufﬁcient to yield a faster and more enantioselec-

tive enzymatic reactions. It is however noteworthy that studies

on the variation of temperature and mixing speed were ignored

by us, and considered to be kept at the same values for each bio-

catalytic approach, that is 30 °C and 300 rpm, respectively. The

reason is two-fold: on the one hand a higher temperature leads

to lower enantioselectivity due to the lower difference between

energy barriers for two substrate enantiomers occurs, and, on

the other hand, although the external mass transfer can be facil-

itated by increasing the stirring speed, it does not limit the over-

all reaction rate.

2.2. Enzymatic reactions

In order to investigate the activity of the employed enzymes

and enantioselectivity (E) of the lipase-catalyzed kinetic resolu-

tions, at the outset of enzymatic studies the chromatographic

separation conditions for all racemates, including indole alcohols

rac-3a–c and their respective esters rac-4a–c and rac-5a–c, were

ﬁrst established (see Supporting Information). The base-line reso-

lution of the enantiomers of all racemic mixtures was successfully

accomplished by using only one HPLC chiral column [Chiralcel

OD-H (Daicel)]. Moreover, the selected chiral-stationary-phase

HPLC conditions led to the separation of both pairs of respective

alcohol and ester enantiomers in a single run, which gave us

the opportunity to follow the results of kinetic resolution reactions

directly from the crude mixtures.

It is well-known that lipase-catalyzed reactions can be imple-

mented in two synthetic variants depending on the reaction

medium.⁴⁴They can be carried out in: (i) the aqueous solutions,

and/or in (ii) nearly anhydrous organic solvents. The ﬁrst syn-

thetic option closely mimics the physiological biotransformation

pathways of naturally occurring compounds (i.e. triglycerides),

however such an attempt often leads to unpredictable side-reac-

tions yielding undesired by-products, due to in situ racemization

of chiral compounds and limits overall the reaction progress due

to low-solubility of the organic substrates. In turn, although the

implementation of non-aqueous conditions to a biocatalysis pro-

vides an artiﬁcial environment for enzymes, such a tactic hope-

fully offers an extraordinary advantages, amongst which the

most important are: (i) the enzymes’ ability to catalyze reactions

1720

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

2.2.1. Analytical-scale biotransformations

them chromatographically by GC and chiral HPLC. Screening at

slightly elevated temperature (30 °C) revealed that all of the

employed CAL-B preparations displayed high E-values. In turn,

the experiments clearly indicated that the most active lipase from

the studied group of biocatalysts is Lipozyme 435, which afforded

desired 50% conversion after 3 days. Moreover, the rates of enzy-

matic methanolysis reactions were signiﬁcantly higher than those

for enantioselective hydrolysis. The differences in enzyme activity

concerning those experiments is especially distinguishable for the

kinetic resolution of butyric ester rac-5a. Novozyme 435 and Chi-

razyme L-2, C-2 both catalyzed the reactions of ester methanolysis

faster in ca. 14 days when compared to hydrolytic attempts using

water as the nucleophile. In parallel experiments conducted with

Lipozyme 435 as the catalyst, the differences between the reaction

rates for both biotransformation attempts toward rac-5a were also

signiﬁcant as the resolution lasted for 14 days less when compared

with the kinetic resolution of rac-4a. It is noteworthy that hydroly-

tic reactions were much faster for racemic acetate rac-4a than for

butyrate rac-5a when catalyzed by Novozym 435, and Chirazyme

L-2, C-2, but with the exception of Lipozyme 435, which the oppo-

site results were found in the kinetically-controlled esters’

methanolysis. In that case, differences in the reaction times

required to reach nearly 50% conversions were even more notice-

able in favor of kinetic resolutions carried out for butyrate rac-5a

than those proceeded for acetate rac-4a. In this context, the kinetic

resolutions catalyzed by Novozym 435 were 11 days faster (Table 1,

entry 2 vs entry 4), while the attempts catalyzed by Chirazyme L-2,

C-2 lasted approximately 10 days less (Table 1, entry 6 vs entry 8).

Moreover, when comparing both of the hydrolytic processes for

both examined racemic esters, we observed that all three CAL-B

lipase preparations displayed higher enantioselectivities when

2.2.1.1. Lipase-catalyzed kinetic resolution of rac-3a and its

esters. At ﬁrst, we decided to utilize a lipase-catalyzed hydrolytic

methodology. In this regard, 1-(5-nitro-1H-indol-1-yl)propan-2-yl

acetate rac-4a and 1-(5-nitro-1H-indol-1-yl)propan-2-yl butyrate

rac-5a were employed as the model substrates, and tested under

various reaction conditions including enantioselective hydrolysis

and alcoholysis (Table 1). In the ﬁrst set of experiments, several

types of common commercial enzyme preparations [5% (w/w) in

accordance to substrate], including the typically employed solid-

supported lipase B from Candida antarctica (CAL-B) available in

chemically immobilized form (Novozym 435, Chirazyme L-2, C-2,

Lipozyme 435), immobilized lipase from Thermomyces lanuginosus

(Lipozyme TL-IM, TLL) as well as two the powder native lipases

from Pseudomonas ﬂuorescens (Amano AK, PFL) and Burkholderia

cepacia (Amano PS, BCL) were assessed for their catalytic ability.

In addition, since tert-butyl methyl ether (TBME) has been gener-

ally established as one of the most suitable media used in lipase-

catalyzed biotransformations of secondary alcohols and their

esters, at this step of investigations we decided to carry out all

enzymatic reactions only in this solvent. An initial screening of

lipases revealed that both native enzymes (Amano AK and Amano

PS) were catalytically inactive toward esters rac-4a and rac-5a,

while all CAL-B preparations exhibited promising activity. To

investigate more deeply the stereoselectivity of the (CAL-B)-cat-

alyzed processes, we set the reaction systems at 50 mg scale of

the employed substrates rac-4a and rac-5a, in TBME saturated with

H₂O (for enantioselective hydrolysis) or in TBME with the addition

of MeOH as an acyl-group acceptor used in 10-fold molar excess

(for enantioselective methanolysis). The reaction progress was

traced systematically by taking samples every day and analyzing

Table 1

Enantioselective hydrolysis and methanolysis of rac-4a and rac-5a under kinetic resolution conditions

TBME (3 mL), MeOH (10 equiv)

O₂N

sat. aq. TBME (3 mL),

Lipase (10% w/w),

30 ^oC, 300 rpm

R⁴

rac-4a: R⁴= CH₃

rac-5a: R⁴= C₃H₇

(50 mg)

(S)-(+)-4a: R⁴= CH₃

(S)-(+)-5a: R⁴= C₃H₇

(R)-(-)-

Entry

Lipase

Compound

Nucleophile

t [d]

Conv.^e[%]

ee_s[%]

ee_p[%]

E^g

Novozym 435

rac-4a

H₂O^a

170

MeOH^b

H₂O^c

rac-5a

MeOH^d

>200

Chirazyme L-2, C-2

Lipozyme 435

rac-4a

rac-5a

H₂O^a

>200

MeOH^b

H₂O^c

MeOH^d

rac-4a

rac-5a

H₂O^a

>99

172

>200

MeOH^b

H₂O^c

MeOH^d

>99

Conditions: rac-4a 50 mg, lipase 5 mg, satd aq TBME 3 mL, 30 °C, 300 rpm (laboratory shaker).

Conditions: rac-4a 50 mg, lipase 5 mg, TBME 3 mL, MeOH 77 L (10 equiv), 30 °C, 300 rpm (laboratory shaker).

Conditions: rac-5a 50 mg, lipase 5 mg, satd aq TBME 3 mL, 30 °C, 300 rpm (laboratory shaker).

Conditions: rac-5a 50 mg, lipase 5 mg, TBME 3 mL, MeOH 70

lL (10 equiv), 30 °C, 300 rpm (laboratory shaker).

Based on GC, for conﬁrmation the % conversion was calculated from the enantiomeric excess of the unreacted ester (ee_s) and the product (ee_p) according to the formula

conv. = ee_s/(ee_s+ ee_p).

Determined by chiral HPLC analysis by using a Chiralcel OD-H column.

Calculated according to Chen et al.,⁴⁵using the equation: E = {ln[(1 ꢀ conv.)(1 ꢀ ee_s)]}/{ln[(1 ꢀ conv.)(1 + ee_s)]}.

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

1721

butyrate rac-5a was employed as the substrate. Moreover, the best

results in terms of enantiomeric excess of optically active acetate

(S)-(+)-4a (>99% ee) and butyrate (S)-(+)-5a (>99% ee) were

obtained in (Lipozyme 435)-mediated methanolysis of the respec-

tive racemic esters. In turn, the highest enantioenrichment for (R)-

(ꢀ)-3a (99% ee) was achieved when enantioselective hydrolytic

kinetic resolution of rac-5a was catalyzed by Chirazyme L-2, C-2,

and stopped at 47% conversion.

match to lipase stability requirements, and in which rac-3a easily

forms homogenous solutions. The conversions, enantiomeric

excesses of the resulting resolution products as well as the enan-

tioselectivities of the reactions were determined by GC and chiral

HPLC analysis, respectively.

The resolution process of rac-3a was ﬁrst attempted with the

previously used commercial lipase preparations. We found that

Amano PS and Amano AK, which both were completely inactive

under the hydrolytic conditions applied before, this time furnished

the most enantioselective resolutions with the highest possible

theoretical values for the E-factor (Table 2, entries 8 and 10). The

results obtained with those lipases were very promising, since

highly selective transformations catalyzed by them yielded both

resolution products (S)-(+)-3a and (R)-(ꢀ)-4a with excellent enan-

tiomeric purity (>99% ee). When comparing the reaction courses

for these preparations, the best compromise between conversion

and selectivity for the O-acetylation of rac-3a was achieved with

Amano AK suspended in TBME as the co-solvent. In this regard,

Amano AK required only 48 h to accomplish the successful resolu-

tion of rac-3a, whereas under the same conditions, the reactions

catalyzed by Amano PS proceeded sluggishly, yielding desired

homochiral products after only as much as 15 days. On the other

hand, although the rest of the investigated lipases catalyzed the

kinetic resolutions at similar rates as Amano AK, they displayed

lower enantioselectivities, providing the slower reacting enan-

tiomer (S)-(+)-3a with an excellent enantiomeric excess (99% ee),

and its acetylated counterpart (R)-(ꢀ)-4a in enantioenriched form

(89% ee). Experimental data for the acetylation of rac-3a with vinyl

acetate in organic solvent revealed that the reaction velocity was

the highest when lipases were suspended in DIPE. However, the

enantioselectivity was improved when the kinetic resolutions were

performed in TBME.

Taking into account the above facts concerning the low activity

of the studied enzyme preparations under hydrolytic conditions, it

is apparent that these reactions are far from being preparative.

Therefore, it was worthwhile investigating the reverse process,

i.e., the lipase-catalyzed synthesis of the ester; the results are

shown in Tables 2 and 3. The evaluation of an alternative protocol

based on the kinetic resolution of 1-(5-nitro-1H-indol-1-yl)pro-

pan-2-ol rac-3a using a 10-fold molar excess of enol esters as

acyl-transfer-reagents was made deliberately since these reagents

can signiﬁcantly accelerate the rate of lipase-mediated reactions.

This is mostly due to the fact that such activated esters efﬁciently

shift the equilibrium towards the synthesis of esters by generating

side-products, which rapidly tautomerize in situ to give stable car-

bonyl compounds (acetaldehyde in the case of vinyl esters or ace-

tone in the case of isopropenyl esters). Moreover, the great beneﬁt

of this strategy is that the laborious work-up is not required, which

stems from the fact that the solid biocatalyst can be removed by

simple ﬁltration, and the permeate, after being concentrated, can

be directly subjected on column chromatography. This thus

reduces operational complexity, time, and the overall cost of the

process.

Moreover, due to the well-recognized fact that the nature of the

reaction medium is a critical factor for biocatalysis, since it exerts a

strong inﬂuence on the catalytic performance of the enzymes, an

optimization of the lipase activity and enantioselectivity by solvent

variation is mandatory for the development of an efﬁcient resolu-

tion of stereoisomers. Therefore, we employed three different non-

polar, water-immiscible solvents [toluene (PhCH₃), diisopropyl

ether (DIPE), and tert-butyl methyl ether (TBME)], which usually

Next, we examined isopropenyl acetate as an acyl group donor

in the enantioselective O-acetylation of rac-3a (Table 3). This was

made intentionally since lipases are particularly prone to being

hampered by the side-product released in the reactions carried

out with vinyl acetate. This is an acetaldehyde which can form a

Table 2

Enantioselective O-acetylation of rac-3a with vinyl acetate under kinetic resolution conditions

Lipase

O₂N

(5 mg; 10%, w/w)

Organic solvent (3 mL),

30 ^oC, 300 rpm.

rac-

266 mg, 287 µL

(10 equiv)

(S)-(+)-3a

(R)-(-)-4a

50 mg

Lipase^a

Novozym 435

Solvent

t [h]

Conv.^b[%]

ee_s[%]

ee_p[%]

E^d

Entry

PhCH₃

DIPE

TBME

Chirazyme L-2, C-2

PhCH₃

DIPE

TBME

Lipozyme TL-IM

Amano PS

TBME

360

>99

ꢁ200

Amano AK

PhCH₃

TBME

>99

ꢁ200

Conditions: rac-3a 50 mg, lipase 5 mg, organic solvent 3 mL, vinyl acetate 287

Based on GC, for conﬁrmation the% conversion was calculated from the enantiomeric excess of the unreacted alcohol (ee_s) and the product (ee_p) according to the formula

L (10 equiv), 30 °C, 300 rpm (laboratory shaker).

conv. = ee_s/(ee_s+ ee_p).

Determined by chiral HPLC analysis by using a Chiralcel OD-H column.

Calculated according to Chen et al.,⁴⁵using the equation: E = {ln[(1 ꢀ conv.)(1 ꢀ ee_s)]}/{ln[(1 ꢀ conv.)(1 + ee_s)]}.

1722

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

Table 3

Enantioselective O-acetylation of rac-3a with isopropenyl acetate in TBME under kinetic resolution conditions

Lipase

O₂N

(5 mg; 10%, w/w)

TBME (3 mL),

30 ^oC, 300 rpm.

(R)

(S)

rac-3a

50 mg

309 mg, 340 µL

(10 equiv)

(R)-(-)-

(S)-(+)-

Entry

Lipase^a

Novozym 435

Chirazyme L-2, C-2

Lipozyme TL-IM

Amano PS

t [h]

Conv.^b[%]

ee_s[%]

ee_p[%]

E^d

192

>99

ꢁ200

Amano AK

ꢁ200

Conditions: rac-3a 50 mg, lipase 5 mg, organic solvent 3 mL, isopropenyl acetate 340

See footnote of the Table 2.

lL (10 equiv), 30 °C, 300 rpm (laboratory shaker).

See footnote of the Table 2.

Schiff base with the amine moiety of the protein amino acid resi-

dues (especially lysine residues),⁴⁶and/or simultaneously being

oxidized to acetic acid, thus poisoning the catalyst by changing

the enzyme ionization state. To avoid such disadvantageous alter-

ations in the micro-environments surrounding the catalytic

domain, the less harmful isopropenyl acetate producing inoffen-

sive for the enzyme acetone, seems to be the optimal acyl-trans-

fer-reagent. Of course, it is obvious that disruptions in ionization

state affecting enzyme activity can be simply overcome by increas-

ing the catalyst loading, however, we sought to identify optimal

conditions for the desired enzymatic systems by using only 10%

wt/wt of lipase in respect to substrate rac-3a, and thus chose

innocuous to ester-hydrolyzing enzymes isopropenyl acetate acyl

donor reagent.

Taking into consideration the results of earlier performed

experiments devoted to solvent selection, we chose TBME as the

reaction medium. Again, to afford comparable results, the reactions

were stopped as close to 50% substrate conversion as possible

according to GC indications, and after subsequent chromatographic

isolation, the ee-values were determined by chiral HPLC. Compar-

ing the data from Table 3, it is possible to infer that the lipase-cat-

alyzed kinetic resolution carried out with vinyl acetate was

superior to that performed with isopropenyl acetate. From these

results, it was also possible to observe that the enzymatic kinetic

resolution showed very similar to the aforementioned approach

moderate enantioselectivity upon rac-3a for immobilized CAL-B

preparations. In the case of native lipase preparations (Amano AK

and Amano PS), the reactions were less selective as the ee-values

for the isolated alcohol (S)-(+)-3a decreased to 93–96% (Table 3,

entries 4 and 5). Nevertheless, the enantioenrichment was remark-

ably high for the formed acetate (R)-(ꢀ)-4a, which was obtained

with excellent enantiomeric excess (99–100% ee). The other posi-

tive aspect of the kinetic resolution conducted with isopropenyl

acetate was that the rate of the acylated product formation in

the case of Amano PS was almost two times faster which is some-

how intriguing since vinyl esters usually give better reaction rates

than isopropenyl esters due to steric reasons. In addition, a similar

situation was observed for Novozym 435, which takes 24 h less to

convert the substrate when isopropenyl acetate was used as the

acyl donor.

1-(3-methyl-1H-indol-1-yl)propan-2-yl acetate rac-4b. For this

purpose, the enzymatic kinetic resolution was examined with

three different CAL-B preparations previously established as the

most potent in water-immiscible (biphasic aqueousꢀorganic) sol-

vent system composed of TBME saturated with water. All of the

experimental data regarding hydrolytic approach are summarized

in Table 4. As a result, Chirazyme L-2, C-2 was found to hydrolyze

rac-4b with the highest enantioselectivity to furnish optically

active alcohol (R)-(ꢀ)-3a with 96% ee, and the remaining acetate

(S)-(+)-4b with 86% ee (Table 4, entry 2). Unfortunately, when ana-

lyzing the ee-values and the reaction times it turned out that all

lipases have presented worse results upon rac-4b if compared to

the kinetic resolution of rac-4a. The most active enzyme prepara-

tion (Novozym 435) led to low reaction rates affording the desired

conversions after as much as 5 days and enantioenriched resolu-

tion products with moderate 81–85% ee (Table 4, entry 1). More-

over, for the rest of the studied enzymes, the time required to

reach ca. 50% conversion exceeded 23 days (Table 4, entries 2

and 3). In this instance, enantioselective hydrolysis of rac-4b under

kinetically controlled conditions was excluded as being prepara-

tive, and thus not studied further.

Again, since the results of lipase-catalyzed hydrolysis of the

acetate rac-4b were not satisfactory, we opted to use the reverse

process, i.e., the O-acetylation procedure of the resolution of

rac-3b (Table 5). Initially the reaction system with vinyl acetate

(10 equiv) as the source of an acyl group in the presence of 10%

wt/wt loading of the appropriate lipase preparation with respect

to the substrate rac-3b at 30 °C was investigated. In general, all

experiments of the kinetic resolution of rac-3b were conducted

under the same reaction conditions as described above for the

enantioselective O-acetylation of rac-3a. In this regard, the respec-

tive immobilized preparations (Novozym 435, Chirazyme L-2, C-2,

Lipozyme 435), and one native lipase (Amano AK) were suspended

in three different co-solvents (PhCH₃, DIPE, TBME) each. At

ﬁrst glance, a detailed survey on the selection of the optimal lipase

catalyst and the solvent upon the acylative kinetic resolution of

rac-3b gave the best results when Amano AK was employed. The

most effective resolution mediated by PFL preparation was fur-

nished in DIPE, thus yielding the unreacted alcohol (S)-(+)-3b with

87% ee and the formed acetate (R)-(ꢀ)-4b with 98% ee (Table 5,

entry 11). For (Amano AK)-catalyzed reactions carried out in TBME,

the resolution of rac-3b was obtained with similar conversions as

those achieved under the screening conditions of rac-3a, but with

a signiﬁcantly lower rates, and enantiomeric excesses of both

2.2.1.2. Lipase-catalyzed kinetic resolution of rac-3b and its

acetate.

The next stage of studies was designed to ﬁnd the

most suitable reaction conditions for the resolution of racemic

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

1723

Table 4

Enantioselective hydrolysis of rac-4b under kinetic resolution conditions

sat. aq. TBME (3 mL),

Lipase (5 mg, 10% w/w),

30 ^oC, 300 rpm

(S)

(R)

CH₃

(R)-(-)-

rac-4b

(50 mg)

(S)-(+)-

Lipase^a

t [d]

Conv.^b[%]

ee_s[%]

ee_p[%]

E^d

Entry

Novozym 435

Chirazyme L-2, C-2

Lipozyme 435

137

Conditions: rac-4b 50 mg, lipase 5 mg, satd aq TBME 3 mL, 30 °C, 300 rpm (laboratory shaker).

See footnote of the Table 2, but ee_scorresponds to acetate and ee_pto alcohol.

Table 5

Enantioselective O-acetylation of rac-3b with vinyl acetate under kinetic resolution conditions

Lipase

(5 mg; 10%, w/w)

Organic solvent (3 mL),

30 ^oC, 300 rpm.

(R)

(S)

rac-

228 mg, 246 µL

(10 equiv)

(S)-(+)-3b

(R)-(-)-4b

Conv.^b[%]

50 mg

Lipase^a

Solvent

ee_s[%]

ee_p[%]

E^d

Entry

Novozym 435

Chirazyme L-2, C-2

Lipozyme 435

Amano AK

PhCH₃

DIPE

TBME

6 h

4 h

5 h

PhCH₃

DIPE

TBME

3 h

2 h

3 h

PhCH₃

DIPE

TBME

4 h

2 h

PhCH₃

DIPE

TBME

9 d

4 d

195

>200

114

Conditions: rac-3b 50 mg, lipase 5 mg, organic solvent 3 mL, vinyl acetate 246

See footnote of the Table 2.

lL (10 equiv), 30 °C, 300 rpm (laboratory shaker).

See footnote of the Table 2.

kinetic resolution products being obtained in range of 88–95%. In

turn, all immobilized CAL-B preparations catalyzed the reactions

very efﬁciently with conversions over 36% achieved after relatively

short reaction times (2–6 h) (Table 5, entries 1–9). Under these

conditions, optically active acetate (R)-(ꢀ)-4b was obtained with

high enantiomeric purity (86–96% ee). In turn, since the reactions

catalyzed by CAL-B did not exceed 50% conversion, the enan-

tiomeric excesses for the remaining alcohol (S)-(+)-3b were mod-

erate (50–87% ee). Lipozyme 435 also appeared to be a quite

efﬁcient catalyst reaching 36–43% conversion in a short reaction

time (2–4 h), thus affording (S)-(+)-3b with moderate enan-

tiomeric excess (50–70%) and the acetate (R)-(ꢀ)-4b with high

89–94% ee, respectively. In general, when taking into account the

effect of the solvent on the stereochemical outcome, it was clear

that the most efﬁcient kinetic resolutions were available in TBME.

However, as stated above, the kinetic resolution of rac-3b in the

presence of Amano AK lipase was more efﬁcient when using DIPE.

On the other hand, when the reaction was carried out in a less

polar solvent (PhCH₃, logP 2.52), it was slower.

It should be noted that the collected data from the performed

experiments gave us detailed insight into the role of the selected

lipases under speciﬁed conditions, and showed us how the activity

of particular enzyme can be controlled to provide the most selec-

tive transformations after relatively short reaction times. Never-

theless, the results presented in Table 5 are not sufﬁcient for

successful preparative kinetic resolution, and further optimization

of the acetylation of rac-3b was attempted using isopropenyl acet-

ate instead of vinyl acetate. Experimental data for the acylation of

rac-3b with isopropenyl acetate in three different co-solvent

systems is shown in Table 6. Based on the results achieved with

1724

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

Table 6

Enantioselective O-acetylation of rac-3b with isopropenyl acetate under kinetic resolution conditions

Lipase

(5 mg; 10%, w/w)

Organic solvent (3 mL),

30 ^oC, 300 rpm.

(R)

(S)

rac-

265 mg, 287 µL

(10 equiv)

(R)-(-)-

(S)-(+)-3b

50 mg

Entry

Lipase^a

Solvent

Conv.^b[%]

ee_s[%]

ee_p[%]

E^d

113

Novozym 435

Chirazyme L-2, C-2

Lipozyme 435

Amano AK

PhCH₃

DIPE

TBME

7 h

5 h

4 h

PhCH₃

DIPE

TBME

6 h

5 h

3 h

103

PhCH₃

DIPE

TBME

5 h

3 h

N.D.^e

174

195

PhCH₃

DIPE

TBME

21 d

12 d

3 d

<15

N.D.^e

Conditions: rac-3b 50 mg, lipase 5 mg, organic solvent 3 mL, isopropenyl acetate 287

Based on GC, for conﬁrmation the% conversion was calculated from the enantiomeric excess of the unreacted alcohol (ee_s) and the product (ee_p) according to the formula

L (10 equiv), 30 °C, 300 rpm (laboratory shaker).

conv. = ee_s/(ee_s+ ee_p).

Determined by chiral HPLC analysis by using a Chiralcel OD-H column.

Calculated according to Chen et al.,⁴⁵using the equation: E = {ln[(1 ꢀ conv.)(1 ꢀ ee_s)]}/{ln[(1 ꢀ conv.)(1 + ee_s)]}.

Not determined.

isopropenyl acetate it was obvious that the most effective resolu-

tion occurred in the presence of Amano AK. Both the ether solvents

promoted lipase-mediated acetylative kinetic resolution of rac-3b

with comparatively high E-values, albeit slightly better conditions

in terms of enantiomeric excess of the resolved enantiomers were

obtained in TBME. In this solvent, Amano AK catalyzed the kinetic

resolution process faster by four orders-of-magnitude when com-

pared with DIPE, furnishing optically active alcohol (S)-(+)-3b

(65% ee) and ester (R)-(ꢀ)-4b (98% ee) with 40% conversion. In gen-

eral, the enantioselective O-acetylation of rac-3b with isopropenyl

acetate under kinetic resolution conditions mostly lead to a negli-

gible decrease in the catalytic activity and selectivity of the studied

enzymes. Similarly as in the kinetic resolution of rac-3b with vinyl

acetate, all CAL-B preparations acted with a high reaction rate, but

moderate enantioselectivity. Notwithstanding, two exceptions are

worth mentioning. The kinetic resolution of rac-3b in the presence

of Novozym 435 in DIPE was more efﬁcient when using iso-

propenyl acetate, thus obtaining (S)-(+)-3b with 76% ee and the

formed acetate (R)-(ꢀ)-4b with 96% ee (Table 6, entry 2).

dure toward racemic 1-(2,3-dimethyl-1H-indol-1-yl)propan-2-ol

rac-3c. At ﬁrst, the lipase-catalyzed transesteriﬁcation of rac-3c

was carried out in the presence of commercial CAL-B (Novozym

435, Chirazyme L-2, C-2, Lipozyme 435), TLL (Lipozyme TL-IM)

and PFL (Amano AK, the results were omitted for clarity) lipase

preparations by using a 10-fold molar excess of vinyl acetate as

an acylating agent at 30 °C (Table 7). The experiments gave us

valuable information regarding the activity and stereoselectivity

of the employed enzymes. It was noticed that in the studied biocat-

alytic reaction systems, the above-mentioned parameters vary sig-

niﬁcantly depending on the source of the biocatalyst and the type

of solvent. However, among the tested enzymes, the reaction with

Novozym 435 undoubtedly displayed the highest enantiomeric

ratio (Table 7, entries 1–3). Moreover, the experimental results

obtained with Novozym 435 showed that the best chirality induce-

ment occurred when this enzyme was suspended in TBME and the

kinetic resolution was continued until the desired 50% conversion

was achieved. Under these conditions, the slower-reacting enan-

tiomer (S)-(+)-3c was isolated in enantiomerically pure form

(>99% ee), whereas the acetate (R)-(ꢀ)-4c was afforded with very

high 98% ee (Table 7, entry 3). It is worth noting that rac-3c was

less reactive than the previously studied 5-nitro-substituted rac-

3a and 3-methyl-substituted (rac-3b) derivatives since the trans-

formations lasted 6–24 days. The most active lipases turned out

to be Lipozyme 435, which after 6–7 days gave 49% conversion of

rac-3c, thus furnishing the unreacted optically active alcohol (S)-

(+)-3c with 88% ee when suspended in DIPE and 92% ee in TBME,

whereas the acetate (R)-(ꢀ)-4c was isolated with 91% ee when

the reaction was conducted in DIPE, and with 95% ee if carried

out in TBME (Table 7, entries 8–9). Although Amano AK lipase usu-

ally gave high activity and enantioselectivity toward previously

studied racemic alcohols rac-3a-b, in a transesteriﬁcation manner,

this time, it was preparatively useless. The collected data also indi-

cate that an additional electron-donating methyl group in the pyr-

In addition, a slightly improved enantioselectivity toward rac-

3b was also observed when the reaction was carried out in the

presence of Chirazyme L-2, C-2 in TBME, attaining 42% conversion

after 3 h, and yielding (S)-(+)-3b with 70% ee and (R)-(ꢀ)-4b with

96% ee (Table 6, entry 6). When comparing both approaches with

vinyl acetate and isopropenyl acetate as acyl donors, it was clear

that the best enzymatic system for the selective and fast resolution

of rac-3b enantiomers consisted of Amano AK suspended in a mix-

ture of vinyl acetate/DIPE.

2.2.1.3. Lipase-catalyzed kinetic resolution of rac-3c.

Our

next aim was to set up a simple and practical method for the

preparation of enantiomerically pure 2,3-dimethyl-substituted

indole derivatives (S)-(+)-3c and (R)-(ꢀ)-4c. For that reason, we

decided to extend the described acylative kinetic resolution proce-

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

1725

Table 7

Enantioselective O-acetylation of rac-3c with vinyl acetate under kinetic resolution conditions

Lipase

(5 mg; 10%, w/w)

Organic solvent (3 mL),

30 ^oC, 300 rpm.

(R)

(S)

rac-3c

50 mg

212 mg, 229 µL

(10 equiv)

(S)-(+)-

(R)-(-)-

Lipase^a

Solvent

t [d]

Conv.^b[%]

ee_s[%]

ee_p[%]

E^d

Entry

Novozym 435

Chirazyme L-2, C-2

Lipozyme 435

PhCH₃

DIPE

TBME

>99

113

109

ꢁ200

PhCH₃

DIPE

TBME

PhCH₃

DIPE

TBME

129

Lipozyme TL-IM

PhCH₃

DIPE

TBME

N.D.^e

149

Conditions: rac-3c 50 mg, lipase 5 mg, organic solvent 3 mL, vinyl acetate 229

Based on GC, for conﬁrmation the% conversion was calculated from the enantiomeric excess of the unreacted alcohol (ee_s) and the product (ee_p) according to the formula

L (10 equiv), 30 °C, 300 rpm (laboratory shaker).

conv. = ee_s/(ee_s+ ee_p).

Determined by chiral HPLC analysis by using a Chiralcel OD-H column.

Calculated according to Chen et al.,⁴⁵using the equation: E = {ln[(1 ꢀ conv.)(1 ꢀ ee_s)]}/{ln[(1 ꢀ conv.)(1 + ee_s)]}.

Not determined.

role ring efﬁciently enhances the substrate activation in reactions

catalyzed by Lipozyme TL-IM. It should be note that in the

above-mentioned transesteriﬁcation approaches this enzyme was

ineffective, while in the kinetic resolution of rac-3c preformed in

TBME it gave an excellent 98% ee for the recovered optically active

alcohol (S)-(+)-3c and very high 94% ee for the formed acetate (R)-

(ꢀ)-4c (Table 7, entry 12). The lowest enantioselectivity was

observed for the kinetic resolution reactions catalyzed by Chi-

razyme L-2, C-2, which yielded the unreacted enantioenriched

alcohol (S)-(+)-3c with ee-values in range of 59–89%, while opti-

cally active acetate (R)-(ꢀ)-4c was isolated with 57–92% ee

(Table 7, entries 4–6).

In turn, the data of lipase-catalyzed enantioselective transester-

iﬁcation of rac-3c using isopropenyl acetate as the source of an

acetate group are collected in Table 8. The experiments clearly

indicated that the best enantiomeric recognition was observed

with Novozym 435 suspended in TBME, leading to excellent results

in terms of the enantiomeric excess of both kinetic resolution

products, yielding (S)-(+)-3c and (R)-(ꢀ)-4c in almost homochiral

forms (up to >99% ee) (Table 8, entry 3). Unexpectedly, substan-

tially better results in comparison to those obtained with vinyl

acetate were noticed in the reactions carried out with Chirazyme

L-2, C-2 in TBME (Table 8, entry 6). Although still not satisfactory,

the rate of this reaction was signiﬁcantly enhanced affording enan-

tiomerically enriched alcohol (S)-(+)-3c with 83% ee, and ester (R)-

(ꢀ)-4c with 96% ee (Table 8, entry 6). However, in general there are

some disadvantages in the use of isopropenyl acetate as in most

cases it slowed down the reactions. We found that the tested

enzymes exhibited a notably lower activity towards the acetylation

of the target racemic substrate rac-3c especially when suspended

in DIPE. For example, the reaction rates of acetate (R)-(ꢀ)-4c for-

mation conducted with Novozym 435, Chirazyme L-2, C-2 and

Lipozyme 435 were approximately 9, 8, and 13 days longer than

in the case of homologous catalytic systems performed with vinyl

acetate as the acyl donor.

2.3. Assignment of the lipases’ enantiopreference

In order to verify the stereochemistry of the performed

enzymatic reactions, the absolute conﬁguration of the respective

resolution products is pivotal. This task is challenging and time-

consuming especially if novel compounds with chiral properties

are synthesized, and also if they exist in an oil or amorphous state,

from which the crystallization of proper crystals is not feasible, and

thus X-ray diffraction analysis cannot be performed. To overcome

this drawback, various alternative analytical approaches were

applied, including NMR spectroscopic investigations carried out

mostly by means of chiral derivatization agents (CDAs),⁴⁷chiral

solvating agents (CSAs),⁴⁸and lanthanide shift reagents (LSRs),⁴⁹

respectively. Moreover, metal complexes and liquid crystals are

also employed in NMR spectral investigations, although their

application in assignment of absolute stereochemistry is less com-

mon.⁵⁰Another well-established technique for absolute conﬁgura-

tion determination of optically active compounds is vibrational

circular dichroism (VCD),⁵¹exciton-coupled circular dichroism

(ECCD),⁵²and vibrational optical activity (VOA).⁵³In addition, very

practical approach toward absolute conﬁguration assignment of

enantioenriched stereogenic centers seems to be so-called

Competing Enantioselective Conversion (CEC) method utilizing

thin-layer chromatography (TLC).⁵⁴

Of course, it is also reasonable to follow tactics concerning cor-

relation by asymmetric synthesis. For example, These syntheses

would require the use of commercially available enantiomerically

pure propylene oxide of a deﬁned stereochemistry to obtain ana-

lytical standards for the comparison of speciﬁc rotation signs

and/or pick elution order of chiral gas chromatography (C-GC) or

chiral high-performance liquid chromatography (C-HPLC) analysis,

respectively.

Herein, we applied a modiﬁed Mosher’s methodology described

by Riguera et al.^47abased on NMR spectra of mandelic acid esters of

investigated alcohols. The advanced Mosher method is very simple,

1726

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

Table 8

Enantioselective O-acetylation of rac-3c with isopropenyl acetate under kinetic resolution conditions

Lipase

(5 mg; 10%, w/w)

Organic solvent (3 mL),

30 ^oC, 300 rpm.

(R)

(S)

rac-3c

50 mg

246 mg, 267 µL

(10 equiv)

(S)-(+)-3c

(R)-(-)-

Conv.^b[%]

Entry

Lipase^a

Solvent

t [d]

ee_s[%]

ee_p[%]

E^d

Novozym 435

Chirazyme L-2, C-2

Lipozyme 435

PhCH₃

DIPE

TBME

>99

103

ꢁ200

128

PhCH₃

DIPE

TBME

PhCH₃

DIPE

TBME

Lipozyme TL-IM

TBME

113

Conditions: rac-3c 50 mg, lipase 5 mg, organic solvent 3 mL, isopropenyl acetate 267

Based on GC, for conﬁrmation the% conversion was calculated from the enantiomeric excess of the unreacted alcohol (ee_s) and the product (ee_p) according to the formula

L (10 equiv), 30 °C, 300 rpm (laboratory shaker).

conv. = ee_s/(ee_s+ ee_p).

Determined by chiral HPLC analysis by using a Chiralcel OD-H column.

Calculated according to Chen et al.,⁴⁵using the equation: E = {ln[(1 ꢀ conv.)(1 ꢀ ee_s)]}/{ln[(1 ꢀ conv.)(1 + ee_s)]}.

practical, rapid, precise, accurate and reliable for the stereochem-

istry determination of chiral secondary alcohols.⁵⁵In addition,

we have already proven the applicability of this methodology

towards wide range of chiral sec-alcohols with heteroaromatic

substituent, including imidazole,⁵⁶1,2,4-triazole,⁵⁷1,3-benzothia-

zole,⁵⁸and phenothiazine ring.⁵⁹

In order to determine the absolute conﬁguration of unknown

compounds with an indole moiety bearing the secondary carbinol

stereogenic centre, one of the investigated alcohol enantiomer (+)-

3c was independently transformed into two diastereomeric esters

6 and 7 with use of an appropriate chiral auxiliary reagent

(Scheme 2). Herein, a double derivatization procedure of (+)-3c

was performed in dry dichloromethane solution with a stoichio-

Figure 2. Description of the substituents for assignment of the absolute conﬁgu-

ration of (+)-3c and

d^RSvalues obtained for the MPA-esters 6 and 7.

metric amount of (R)-(ꢀ)- and (S)-(+)-

a-methoxyphenylacetic acid

(MPA) as the CDA reagent using Steglich esteriﬁcation reaction

with dicyclohexylcarbodiimide (DCC) as a coupling reagent and

4-dimethylaminopyridine as a catalyst. After 3 h of stirring at room

temperature the two diastereoisomers 6 and 7 were obtained in

85% and 82% yields, respectively.

the information on the relative position of L₁/L₂substituents with

respect to the anisotropic effect generated by the phenyl group of

the MPA unit, which is responsible for an upﬁeld chemical shift

(lower frequency) in the NMR spectrum for the spatially proximal

Next, high-resolution 500 MHz ¹H NMR spectra of the resulting

protons. The positive

the L₁protons (

^RSL₁>0), and the negative value for the protons

belonging to L₂substituent (

^RSL₂<0) indicate an (S)-conﬁgura-

^RSvalue, which corresponds to the signal of

MPA-esters 6 and

recorded and compared. The differences in chemical shifts (

of the corresponding protons attached to carbon atoms directly

bonded to the stereogenic centre were measured (Fig. 2). The

d^RS

in deuterated chloroform (CDCl₃) were

d^RS

)

tion for the investigated alcohol (+)-3c (Fig. 2).

values are crucial for the absolute conﬁguration determination

since the sign of the calculated delta parameter (+ or ꢀ) carries

It is worth mentioning that the utility of MPA Mosher’s reagent

in sec-alcohols stereochemistry determination mainly stems from

OMe

COOH

(R)-MPA

(S)-MPA

(R)-MPA-Ester

(S)-MPA-Ester

(

or )

DCC, DMAP,

CH₂Cl₂

DCC, DMAP,

CH₂Cl₂

(85%)

(82%)

(R or S)-(+)- , >99% ee

Scheme 2. Transformation of enantiopure alcohol (+)-3c using Mosher’s reagents [(R)- and (S)-MPA)] as CDA. Reagents and conditions: (R)-(ꢀ)-MPA or (S)-(+)-MPA (1.0

equiv), DCC (1.0 equiv), DMAP (cat.), dry CH₂Cl₂, 3 h at RT.

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

1727

the great preference toward the adoption of syn-periplanar (sp)

conformation in the respective rotamer of the formed ester deriva-

tive (this phenomenon was empirically conﬁrmed by Latypov

et al.⁶⁰using dynamic NMR studies). In this context, the carbinol

proton of the methine group of the substrate (+)-3 part of the ester

theoretical chemical relationship (correlation) must always be

applied with caution.

Therefore, we decided to carry out a thorough study to unequiv-

ocally determine the absolute conﬁguration of the (ꢀ)-4a pure

enantiomer obtained from the (Lipozyme 435)-catalyzed enantios-

elective methanolysis of rac-5a (Table 1, entry 12). This was per-

formed arbitrarily since only (ꢀ)-4a gave single crystals of

sufﬁcient quality for a XRD structure analysis. With single crystals

in hand, we solved the X-ray diffraction structure of (ꢀ)-4a to be

(R)-(ꢀ)-4a (Fig. 4). For details concerning the procedure of

(R)-(ꢀ)-4a, single crystal growth conditions and XRD measure-

ments see the Section 4.

derivative 6 and 7 as well as the respective C

a carbon, and both the

carbonyl and the methoxy group of the MPA unit are all situated in

the same plane, whereas the benzene ring is coplanar with the C H

bond and perpendicular to the C@O bond. This indicates that in the

dominant conformer of the MPA-esters both the methoxy and the

carbonyl group are in an sp disposition (see Newman projections of

the appropriate (1R,2S)- and (1S,2S)-conformations in diastere-

omeric esters 6 and 7 depicted in Fig. 3). As can be seen in the

Figure 3, the phenyl ring causes shielding of the methyl group

protons H(1⁰) of L2 substituent in (R)-MPA-ester 6 and the methy-

lene group protons H(2⁰) residing within group L1 in the ester with

(S)-MPA 7. This result indicates that the absolute conﬁguration of

(+)-3c at the secondary carbinol stereogenic centre is (S)-(+)-3c.

Analyzing the ¹H NMR spectra of the MPA-esters we also observed

a unique phenomenon, whereby the inverted inﬂuence of anisotro-

pic effect derived from heteroaromatic substituent of the alcoholic

(+)-3 part was responsible for up-ﬁelding the d-values of both sin-

glets of protons belonging to methoxy and methine group of the

MPA moiety. Due to the shielding by the indole ring signiﬁcant

chemical shift differences between those two diastereomers can

After all of the above-mentioned stereochemistry investigations

toward indoles with an asymmetric atom of the secondary carbinol

be found (i.e.

Dd Dd

^RS= 0.20 ppm for OCH₃and ^RS= 0.21 ppm for

protons C H adjacent to the corresponding methine centers).

The absolute conﬁgurations of the remaining compounds 3a–b

were determined by comparison of the speciﬁc rotation values

exclusively predicated on the assumption that they belong to the

homologous series. As it was ﬁrmly established by Tschúgaeff,⁶¹

the determination of the absolute conﬁguration on the basis of

the speciﬁc rotation signs is sufﬁciently reliable within the scope

of similar compounds possessing a single stereogenic center,

however, the history of chemistry showed that the validity of such

Figure 4. An ORTEP plot of optically pure (R)-(ꢀ)-1-(5-nitro-1H-indol-1-yl)propan-

2-yl acetate (R)-(ꢀ)-4a. Thermal ellipsoids were drawn at 50% probability and

hydrogen atoms omitted for clarity (C black, H gray, N blue, O red). The following

crystal structure has been deposited at the Cambridge Crystallographic Data Centre

and allocated the deposition number CCDC-1500811.

Figure 3. The ¹H NMR (CDCl₃, 500 MHz) spectra of the (R)-MPA (6, blue colored line) and (S)-MPA (7, red colored line) derivatives of chiral alcohol (+)-3c. Additionally, with

red color are marked protons shielded by the phenyl ring of chiral auxiliary, blue labels stand for unaffected protons. Green arrows indicate the anisotropic shielding effect

caused by the aromatic system. The ester carbonyl group is not shown in both the extended Newman projections for the sake of clarity.

1728

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

type [(S)-(+)-3c and (R)-(ꢀ)-4a], it was clear that the stereochem-

ical course of the performed enzymatic reactions is in agreement

with Kazlauskas’ empirical rule⁶²regarding lipases’ enantioprefer-

ence towards chiral sec-alcohols. In this context, the examined

lipases favored faster transformation of (R)-alcohols over their

antipodes. The same situation refers toward reversed reaction, in

which the (R)-enantiomer of an ester was hydrolyzed at a faster

rate than its (S)-counterpart.

All commercial formulations of enzymes studied herein were used

without any pretreatment.

4.2. Analytical methods

Melting points, uncorrected, were determined with a commer-

cial apparatus on samples contained in rotating glass capillary

tubes open on one side (1.35 mm inner diam. and 80 mm length).

Analytical thin-layer chromatography was carried on TLC alu-

minum plates (Merck) covered with silica gel of 0.2 mm thickness

ﬁlm containing a ﬂuorescence indicator green 254 nm (F₂₅₄), and

using UV light as a visualizing agent. Preparative separations were

carried out by: (i) column chromatography using thick-walled

glass columns and silica gel (230–400 mesh) with grain size 40–

3. Conclusion

Herein, an exploration of commercially available lipase prepara-

tions for enantioselective resolution of indole-based secondary

alcohols and their respective esters has been reported for the ﬁrst

time. The enzymatic kinetic resolution methodology served as a

model process, during which the reaction conditions were opti-

mized with respect to enzyme screening, the organic solvent selec-

tion, and type of acyl group donor or acceptor, respectively. In this

regard, three different approaches were compared: (i) lipase-cat-

alyzed transesteriﬁcation of racemic alcohols by means of enol

esters (vinyl acetate and isopropenyl acetate), (ii) enzymatic

hydrolysis, and (iii) enzymatic methanolysis of the target esters.

By employing enzymatic kinetic resolution strategy both enan-

tiomers of the studied racemates were accessible in enantiomeri-

cally pure form (>99% ee) or at least highly enantiomerically

enriched. The most selective enzyme was lipase Amano AK from

Pseudomonas ﬂuorescens (up to E ꢁ 400). All of the enantiomeric

compounds are potentially useful chiral intermediates for the syn-

thesis of biologically active agents. To support the assignment of

the absolute conﬁgurations of novel compounds a detailed ¹H

NMR studies of Mosher esters as well as single-crystal XRD analy-

sis were carried out appropriately.

lm or (ii) PLC PSC-Fertigplatten Kieselgel 60 F₂₅₄(20 ꢂ 20 cm

with 2 mm thickness layer) glass plates purchased from Merck,

Germany. The chromatographic analyses (GC) were performed

with a Agilent Technologies 6850 instrument equipped with a

ﬂame ionization detector (FID) and ﬁtted with HP-50+ (30 m)

semipolar column (50% phenyl–50% methylpolysiloxane); helium

(2 mL/min) was used as carrier gas; retention times (t_R) are given

in minutes under these conditions. The enantiomeric excesses (%

ee) of kinetic resolution products were determined by HPLC anal-

ysis performed on Shimadzu CTO-10ASV chromatograph equipped

with STD-20A UV detector and Chiralcel OD-H chiral column (4.6

mm ꢂ 250 mm, from Daicel Chemical Ind., Ltd.) equipped with a

pre-column (4 mm ꢂ 10 mm, 5 m) using mixtures of n-hexane/2-

PrOH as mobile phase in the appropriate ratios given in experi-

mental section [both the mobile phase composition as well as

the ﬂow rate were ﬁne tuned for each analysis (see Table S1 in

Supplementary data)]; the wavelength of UV detection was set at

254 nm; the HPLC analyses were executed in an isocratic and

isothermal (30 °C) manner. Optical rotations ([a]) were measured

with a PolAAr 32 polarimeter in a 2 dm long cuvette using the

sodium D line (k = 589 nm); the units of the speciﬁc rotation

are: (deg ꢂ mL)/(g ꢂ dm). ¹H NMR (500 MHz) and ¹³C NMR

(126 MHz) spectra were recorded on a Varian NMR System

500 MHz spectrometer; ¹H and ¹³C chemical shifts (d) are reported

in parts per million (ppm) relative to the solvent signals [CDCl₃, d_H

(residual CHCl₃) 7.26 ppm, d_C77.16 ppm]. Chemical shifts are

quoted as s (singlet), d (doublet), dd (doublet of doublets), t (tri-

plet), q (quartet), m (multiplet), and br s (broad singlet); coupling

constants (J) are reported in Hertz. Mass spectrometry was

recorded on Micro-mass ESI Q-TOF spectrometer [ESI, ESI-HRMS:

additives of mixtures of MeCN/MeOH/H₂O (50:25:25, v/v) + 0.5%

formic acid and MSI concept 1H (EI, 70eV ionization)].

4. Experimental section

4.1. Materials

Reagents and solvents were purchased from various commer-

cial sources (Sigma Aldrich, Alfa Aesar, POCH) and were used with-

out further puriﬁcation. High-performance liquid chromatography

(HPLC)-grade solvents were purchased from POCH (Poland).

Methylene chloride and N,N-dimethylformamide were dried by

allowing them to stand over activated (oven-roasted in high-vac-

uum) 3 Å molecular sieves [20% mass/volume (m/v) loading of

the desiccant] at least for 48 h before use,⁶³‘super-dry’ (absolute)

toluene was prepared by simple passage thereof over a column

of silica gel. All reactions, which needed anhydrous conditions

(non-aqueous reactions), were carried out under an atmosphere

of dry argon using ﬂame-dried glasswares. Evaporation of the sol-

vent residues was performed at reduced pressure by means of

Büchi rotary evaporator. Lipase from Candida antarctica B (CAL-B)

{Novozym 435—immobilized on the macroporous acrylic resin

[poly (methyl methacrylate-co-butyl methacrylate)], speciﬁed

activity: >10,000 U/g or 10 PLU/mg, water content 1.4%, and Lipo-

zyme 435—immobilized on Lewatit VP OC 1600, both purchased

from Novozymes A/S (Bagsvaerd, Denmark); and Chirazyme L-2,

c.-f., C2, Lyo. —carrier-ﬁxed on (carrier 2), speciﬁed activity: 150

kU, purchased from Roche}, lipase from Thermomyces lanuginosus

(Lipozyme TL-IM-immobilized on silica gel (a silica granulated),

speciﬁed activity: 170 IUN/g, purchased from Novozymes (Bags-

vaerd, Denmark), lipase from Burkholderia (formerly Pseudomonas)

cepacia [Amano PS—native lipase, speciﬁed activity: >23,000 U/g,

purchased from Amano Pharmaceutical Co., Ltd], lipase from

Pseudomonas ﬂuorescens [Amano AK—native lipase, speciﬁed activ-

ity: >20,000 U/g, purchased from Amano Pharmaceutical Co., Ltd.],

4.3. Preparation of the racemic indole derivatives rac-3a–c

To a suspension of NaH (1.1 equiv, 60% mineral oil dispersion)

in dry DMF (40 mL) the respective indole derivative 1a–c (3 g)

was added portionwise at 0–5 °C. Next, propylene oxide 2 (1.1

equiv) was added dropwise in a sufﬁcient tempo not to increase

the temperature over 0 °C. After the addition, stirring of the resul-

tant suspension was continued for 24 h at room temperature. The

content of the ﬂask was poured over H₂O (80 mL), and the sepa-

rated aqueous solution was extracted with EtOAc (3 ꢂ 15 mL).

The combined organic layer was dried over anhydrous MgSO₄,

then the drying agent was ﬁltered off, and the volatiles were

removed under reduced pressure. The resultant crude mixture

was further high-vacuum-dried in order to remove the residual

DMF, and subsequently puriﬁed by column chromatography on

SiO₂using mixture of n-hexane/EtOAc in various volume ratios

depending on the reaction, thus yielding the corresponding race-

mic alcohols rac-3a–c.

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

1729

4.3.1. 1-(5-Nitro-1H-indol-1-yl)propan-2-ol rac-3a

4.4.2. 1-(3-Methyl-1H-indol-1-yl)propan-2-yl acetate rac-4b

Puriﬁed using 50% EtOAc/n-hexane as an eluent; yield 43%

(1.75 g); yellow solid; mp 101–103 °C (n-hexane/EtOAc); ¹H NMR

(500 MHz, CDCl₃): d 1.28 (d, J = 6.4 Hz, 3H), 1.80 (br s, 1H), 4.01–

4.13 (m, 1H), 4.14–4.28 (m, 2H), 6.55–6.74 (m, 1H), 7.28–7.32

(m, 1H), 7.33–7.44 (m, 1H), 7.97–8.13 (m, 1H), 8.45–8.58 (m,

1H); ¹³C NMR (126 MHz, CDCl₃): d 20.8, 53.9, 67.3, 104.2, 109.5,

117.3, 118.2, 127.7, 131.9, 139.3, 141.5; HRMS (ESI-TOF) m/z:

[M+H]⁺Calcd for C₁₁H₁₃N₂O⁺₃221.0926, Found 221.0833; GC

[150–260 (10 °C/min)]: t_R= 12.12 min or [100–260 (2 °C/min)]:

t_R= 60.49 min; HPLC [5% 2-PrOH/n-hexane; f = 0.8 mL/min;

k = 254 nm]: t_R= 46.03 (S-isomer) and 53.32 min (R-isomer).

Puriﬁed using 29% EtOAc/n-hexane as an eluent; yield 85%

(1.04 g); yellowish oil; ¹H NMR (500 MHz, CDCl₃): d ppm 1.23 (d,

J = 6.4 Hz, 3H), 1.98 (s, 3H), 2.32 (d, J = 1.0 Hz, 3H), 4.08 (dd, J =

14.7, 5.4 Hz, 1H), 4.22 (dd, J = 14.7, 6.4 Hz, 1H), 5.18–5.27 (m,

1H), 6.83–6.88 (m, 1H), 7.08–7.14 (m, 1H), 7.19–7.24 (m, 1H),

7.33–7.38 (d, J = 8.3 Hz, 1H), 7.53–7.59 (m, 1H); ¹³C NMR (126

MHz, CDCl₃): d 9.6, 17.7, 21.2, 50.1, 69.8, 109.3, 110.9, 118.8,

119.0, 121.6, 125.8, 128.7, 136.8, 170.3; HRMS (ESI-TOF) m/z:

[M+H]⁺Calcd for C₁₄H₁₈NO⁺₂232.1338, Found 232.1242; GC

[150–260 (10 °C/min)]: t_R= 7.15 min; HPLC [5% 2-PrOH/n-hexane;

f = 0.7 mL/min; k = 254 nm]: t_R= 13.61 (S-isomer) and 14.96 min

(R-isomer).

4.3.2. 1-(3-Methyl-1H-indol-1-yl)propan-2-ol rac-3b

Puriﬁed using 29% EtOAc/n-hexane as an eluent; yield 56%

(2.43 g); green oil; ¹H NMR (500 MHz, CDCl₃): d 1.26 (d, J = 6.4,

3H), 1.70 (br s, 1H), 2.33 (d, J = 1.0, 3H), 3.93–4.01 (m, 1H), 4.07–

4.14 (m, 1H), 4.14–4.23 (m, 1H), 6.87–6.96 (m, 1H), 7.09–7.16

(m, 1H), 7.19–7.25 (m, 1H), 7.30–7.36 (m, 1H), 7.55–7.62 (m,

1H); ¹³C NMR (126 MHz, CDCl₃): d 9.5, 20.4, 53.6, 67.4, 109.3,

110.0, 110.8, 118.8, 119.1, 121.6, 126.0, 136.6; HRMS (ESI-TOF)

m/z: [M+H]⁺Calcd for C₁₂H₁₆NO⁺190.1232, Found 190.1231; GC

[150–260 (10 °C/min)]: t_R= 6.53 min; HPLC [5% 2-PrOH/n-hexane;

f = 0.7 mL/min; k = 254 nm]: t_R= 18.69 (S-isomer) and 21.31 min

(R-isomer).

4.4.3. 1-(2,3-Dimethyl-1H-indol-1-yl)propan-2-yl acetate rac-4c

Puriﬁed using 60% EtOAc/n-hexane as an eluent; yield 78% (941

mg); yellowish oil; ¹H NMR (500 MHz, CDCl₃): d ppm 1.28 (d, J =

6.4 Hz, 3H), 1.95 (s, 3H), 2.27 (s, 3H), 2.40 (s, 3H), 4.06 (dd, J = 14.9,

5.6 Hz, 1H), 4.24 (dd, J = 14.9, 7.1 Hz, 1H), 5.24 (dd, J = 12.7, 6.4 Hz,

1H), 7.07–7.13 (m, 1H), 7.14–7.20 (m, 1H), 7.30–7.36 (m, 1H),

7.47–7.52 (m, 1H); ¹³C NMR (126 MHz, CDCl₃): d 8.9, 10.3, 17.9,

21.1, 47.3, 69.7, 107.1, 109.0, 117.9, 118.9, 120.7, 128.6, 132.2,

136.4, 170.2; HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₅H₂₀NO⁺₂

246.1494, Found 246.1419; GC [150–260 (10 °C/min)]: t_R= 7.81

min; HPLC [4% 2-PrOH/n-hexane; f = 0.4 mL/min; k = 254 nm]:

t_R= 12.38 (S-isomer) and 13.43 min (R-isomer).

4.3.3. 1-(2,3-Dimethyl-1H-indol-1-yl)propan-2-ol rac-3c

Puriﬁed using 60% EtOAc/n-hexane as an eluent; yield 70%

(2.95 g); yellowish oil; ¹H NMR (500 MHz, CDCl₃): d ppm 1.29 (d,

J = 6.4 Hz, 3H), 1.65 (br s, 1H), 2.26 (s, 3H), 2.38 (s, 3H), 3.95–

4.10 (m, 2H), 4.13–4.26 (m, 1H), 7.02–7.19 (m, 2H), 7.22–7.35

(m, 1H), 7.44–7.56 (m, 1H); ¹³C NMR (126 MHz, CDCl₃): d 8.8,

10.5, 20.5, 50.8, 67.4, 107.0, 108.9, 110.0, 118.0, 118.9, 120.7,

128.7, 136.2; HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₃H₁₈NO⁺

204.1388, Found 204.1365; GC [150–260 (10 °C/min)]: t_R= 7.32

min; HPLC [4% 2-PrOH/n-hexane; f = 0.4 mL/min; k = 254 nm]:

t_R= 26.59 (S-isomer) and 29.35 min (R-isomer).

4.5. Preparation of the racemic indole butyrates rac-5a–c

To a solution of the appropriate racemic alcohol rac-3a–c (600

mg) in dry PhCH₃(10 mL), Et₃N (1 equiv) and catalytic amount of

DMAP (15 mg) were added. Next, butyryl chloride (1 mmol) was

dissolved in dry PhCH₃(2 mL), and subsequently added to the reac-

tion mixture in a dropwise manner at 0–5 °C. The content of the

ﬂask was warmed to room temperature, and stirred at room tem-

perature for 24 h. After this time, the crude mixture was quenched

with H₂O (20 mL), the water phase was extracted with EtOAc

(3 ꢂ 10 mL), and the combined organic layer was washed with sat-

urated aqueous solution of NaHCO₃(50 mL), brine (50 mL), and

dried over anhydrous MgSO₄. After evaporation of the residuals

of solvent, the crude product was puriﬁed by column chromatogra-

phy on silica gel using mixture of n-hexane/EtOAc in various vol-

ume ratios depending on the reaction, thus obtaining desire

butyrate rac-4a–c, respectively.

4.4. Preparation of the racemic indole acetates rac-4a–c

To the solution of the appropriate racemic alcohol rac-3a–c

(1 g) in dry CH₂Cl₂(20 mL), acetic anhydride (1.1 equiv) and a

catalytic amount of DMAP (15 mg) were added in one portion.

The resulting reaction mixture was stirred at room temperature

for 24 h, and then quenched with saturated NaHCO₃solution

(3 ꢂ 20 mL), and H₂O (20 mL). The water phase was extracted with

CH₂Cl₂(3 ꢂ 50 mL), the combined organic layers were washed

with aqueous NaHCO₃(100 mL), and then dried over anhydrous

MgSO₄. After solvent removal under reduced pressure, the crude

product was passed through short column chromatography on sil-

ica gel using a mixture of n-hexane/EtOAc in various volume ratios

depending on the reaction, thus yielding the corresponding race-

mic acetate rac-4a–c, respectively.

4.5.1. 1-(5-Nitro-1H-indol-1-yl)propan-2-yl butyrate rac-5a

Puriﬁed using 50% EtOAc/n-hexane as an eluent; yield 73% (580

mg); brownish solid; mp 78–83 °C (n-hexane/EtOAc); ¹H NMR

(500 MHz, CDCl₃): d 0.81 (t, J = 7.3 Hz, 3H), 1.28 (d, J = 6.4 Hz,

3H), 1.51 (sxt, J = 7.4 Hz, 2H), 2.05–2.27 (m, 2H), 4.16–4.25 (m,

1H), 4.26–4.36 (m, 1H), 5.13–5.41 (m, 1H), 6.62–6.75 (m, 1H),

7.21–7.25 (m, 1H), 7.37–7.49 (m, 1H), 8.07–8.18 (m, 1H), 8.52–

8.61 (m, 1H); ¹³C NMR (126 MHz, CDCl₃): d 13.4, 17.7, 18.2, 36.1,

50.9, 69.0, 104.5, 109.5, 117.4, 118.2, 127.7, 131.4, 139.3, 141.7,

172.7; HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₅H₁₉N₂O⁺₄

291.1345, Found 291.1163; GC [150–260 (10 °C/min)]: t_R= 13.99

min; HPLC [5% 2-PrOH/n-hexane; f = 0.8 mL/min; k = 254 nm]:

t_R= 24.25 (S-isomer) and 26.48 min (R-isomer).

4.4.1. 1-(5-Nitro-1H-indol-1-yl)propan-2-yl acetate rac-4a

Puriﬁed using 50% EtOAc/n-hexane as an eluent; yield 85%

(1.01 g); yellow solid; mp 58.5–59 °C (n-hexane/EtOAc); ¹H NMR

(500 MHz, CDCl₃): d 1.27 (d, J = 6.4 Hz, 3H), 1.93 (s, 3H), 4.18–

4.25 (m, 1H), 4.27–4.35 (m, 1H), 5.16–5.33 (m, 1H), 6.65–6.73

(m, 1H), 7.21–7.25 (m, 1H), 7.36–7.48 (m, 1H), 8.04–8.17 (m,

1H), 8.49–8.63 (m, 1H); ¹³C NMR (126 MHz, CDCl₃): d 17.7, 21.0,

50.9, 69.3, 104.5, 109.5, 117.4, 118.2, 127.7, 131.4, 139.3, 141.7,

170.1; HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₃H₁₅N₂O⁺₄

263.1032, Found 263.1089; GC [100–260 (2 °C/min)]: t_R= 61.34

min; HPLC [5% 2-PrOH/n-hexane; f = 0.8 mL/min; k = 254 nm]: t_R

= 34.83 (S-isomer) and 36.74 min (R-isomer).

4.5.2. 1-(3-Methyl-1H-indol-1-yl)propan-2-yl butyrate rac-5b

Puriﬁed using 60% EtOAc/n-hexane as an eluent; yield 65% (535

mg); yellowish oil; ¹H NMR (500 MHz, CDCl₃): d 0.89 (t, J = 7.3 Hz,

3H) 1.25 (d, J = 6.4 Hz, 3H), 1.52–1.70 (m, 2H), 2.15–2.29 (m, 2H),

2.34 (s, 3H), 4.09 (dd, J = 14.7, 5.4 Hz, 1H), 4.24 (dd, J = 14.9, 6.6

Hz, 1H), 5.25 (dq, J = 12.3, 6.2 Hz, 1H), 6.87 (s, 1H), 7.05–7.18 (m,

1H), 7.19–7.29 (m, 1H), 7.32–7.44 (m, 1H), 7.51–7.65 (m, 1H);

1730

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

¹³C NMR (126 MHz, CDCl₃): d 9.6, 13.5, 17.8, 18.3, 36.3, 50.1, 69.5,

109.3, 110.9, 118.8, 119.0, 121.6, 125.9, 128.7, 136.8, 173.0; HRMS

(ESI-TOF) m/z: [M+H]⁺Calcd for C₁₆H₂₂NO⁺₂260.1651, Found

260.1143; GC [150–260 (10 °C/min)]: t_R= 8.06 min.

>90% (referred to the corresponding conversion value), and fully

characterized in terms of spectroscopic and optical properties.

The detailed experimental conditions, and the results of enzymatic

kinetic resolution reactions (including enantiomeric excess data

for the resolved products and values of enantioselectivity factor)

are collected in Tables: 2, 3, and 6–8. The speciﬁc rotations for

the enantiomerically enriched esters (R)-(ꢀ)-4a–c and alcohols

4.5.3. 1-(2,3-Dimethyl-1H-indol-1-yl)propan-2-yl butyrate rac-

Puriﬁed using 60% EtOAc/n-hexane as an eluent; yield 62% (502

mg); brown oil; ¹H NMR (500 MHz, CDCl₃): d 0.83 (t, J = 7.6 Hz, 3H),

1.25 (d, J = 6.4 Hz, 3H), 1.52 (dqd, J = 14.8, 7.5, 7.5, 7.5, 2.0 Hz, 2H),

2.08–2.22 (m, 2H), 2.24 (s, 3H), 2.38 (s, 3H), 4.01–4.09 (m, 1H), 4.23

(dd, J = 15.2, 7.3 Hz, 1H), 5.24 (dq, J = 13.1, 6.4 Hz, 1H), 7.03–7.19

(m, 2H), 7.29–7.37 (m, 1H), 7.44–7.50 (m, 1H); ¹³C NMR (126

MHz, CDCl₃): d 8.8, 10.3, 13.5, 17.9, 18.2, 36.2, 47.3, 69.4, 107.1,

109.0, 117.9, 118.8, 120.7, 128.6, 132.1, 136.4, 172.9; HRMS (ESI-

TOF) m/z: [M+H]⁺Calcd for C₁₇H₂₄NO⁺₂274.1807, Found

274.1528; GC [150–260 (10 °C/min)]: t_R= 9.12 min.

(S)-(+)-3a–c are as follows: (S)-(+)-3a: [a]

²⁵= +12.3 (c 0.54, CH₂Cl₂,

>99% ee); (R)-(ꢀ)-4a: [

]

²⁵= ꢀ8.6 (c 0.46, CH₂Cl₂, >99% ee); (S)-(+)-

3b: [

²⁵= +14.5 (c 1.0, CH₂Cl₂, 87% ee); (R)-(ꢀ)-4b: [

]

²⁵= ꢀ10.0 (c

1.0, CH₂Cl₂, 98% ee); (S)-(+)-3c: [

]

²⁵= +10.3 (c 0.82, CH₂Cl₂, >99%

ee); (R)-(ꢀ)-4c: [

²⁵= ꢀ6.8 (c 1.02, CH₂Cl₂, 99% ee).

4.7. Determination of the absolute conﬁguration of (S)-(+)-3c

4.7.1. Esteriﬁcation of (S)-(+)-1-(2,3-dimethyl-1H-indol-1-yl)

propan-2-ol (S)-(+)-3c with (R)- or (S)-a-methoxy-a-

phenylacetic acid

4.6. Enzymatic kinetic resolution studies

A solution of enantiopure indole-like alcohol (S)-(+)-3c (13.3

mg, 0.07 mmol, >99% ee), (R)- or (S)- -methoxy- -phenylacetic

4.6.1. General procedure for lipase-catalyzed enantioselective

hydrolysis/methanolysis of rac-4a–b and rac-5a under

kinetically-controlled conditions

acid (10.9 mg, 0.07 mmol) as appropriate, DCC (16.2 mg, 0.07

mmol) and DMAP (15 mg) in anhydrous CH₂Cl₂(4 mL) was stirred

for 3 h at room temperature. Next, the precipitated dicyclohexy-

lurea (DCU) was removed by ﬁltration, and the urea cake was

rinsed with CH₂Cl₂(10 mL). The combined CH₂Cl₂solutions were

washed with saturated NaHCO₃(3 ꢂ 10 mL) and H₂O (10 mL),

dried over anhydrous MgSO₄, and after ﬁltration of the drying

agent evaporated in vacuum. The crude product was puriﬁed by

preparative layer chromatography using a mixture of 50% EtOAc/

n-hexane as an eluent to afford the corresponding products 6 or

7 as yellowish oils.

To a solution of rac-4a or rac-4b or rac-5a (50 mg) in water-sat-

urated TBME (3 mL) or a mixture of organic solvent (3 mL) and

methanol (10 equiv), the respective lipase preparation [5 mg, 10%

w/w (catalyst/substrate)] was added, and the reaction mixture

was shaken (300 rpm) with incubation at 30 °C by using a labora-

tory rotatory shaker. After the necessary time to achieve good

kinetic resolution (see Tables 1 and 4), the biotransformation pro-

cess was terminated by enzyme removal and subsequent washing

with the appropriate solvent (1.5 mL). For hydrolytic attempts, the

permeate was additionally dried over Na₂SO₄, ﬁltered off, and

evaporated to dryness under reduced pressure, and only then puri-

ﬁed by column chromatography. For enzymatic methanolysis, after

enzyme removal the concentrated crude residue was directly sub-

jected to column chromatography on silica gel using mixture of

50% EtOAc/n-hexane as the eluent yielding optically active prod-

ucts [acetates (S)-(+)-4a–b or butyrate (S)-(+)-5a, and alcohol (R)-

(ꢀ)-3a] in yields >90% (referred to the corresponding conversion

value). For the most enantiomerically pure resolution products,

4.7.1.1. (R)-MPA ester 6.

Yield = 85%; ¹H NMR (500 MHz,

CDCl₃) d: 1.16 (d, J = 6.4 Hz, 3H), 2.23 (s, 3H), 2.36 (s, 3H), 3.11 (s,

3H), 4.06 (dd, J = 14.9, 5.1 Hz, 1H), 4.22 (dd, J = 15.2, 8.2 Hz, 1H),

4.46 (s, 1H), 5.17–5.37 (m, 1H), 7.02–7.51 (m, 9H).

4.7.1.2. (S)-MPA ester 7.

Yield = 82%; ¹H NMR (500 MHz,

CDCl₃) d: 1.26 (d, J = 6.4 Hz, 3H), 2.18 (s, 3H), 2.23 (s, 3H), 3.31 (s,

3H), 3.95 (dd, J = 15.2, 5.9 Hz, 1H), 4.14 (dd, J = 15.2, 7.3 Hz, 1H),

4.67 (s, 1H), 5.20–5.30 (m, 1H), 7.04–7.17 (m, 2H), 7.22–7.48 (m,

7H).

the speciﬁc rotations were measured, and are as follows: (S)-(+)-

4a: [

]

²⁵= +8.3 (c 0.30, CH₂Cl₂, >99% ee); (R)-(ꢀ)-3a: [

ꢀ20.7 (c 0.29, CH₂Cl₂, 99% ee).

4.8. X-ray structure determination

4.6.2. General procedure for lipase-catalyzed enantioselective

transesteriﬁcation of rac-3a–c under kinetically-controlled

conditions

In order to produce single crystals suitable for X-ray diffraction

analysis, enantiomerically pure (R)-(ꢀ)-4a (20 mg, >99% ee) was

dissolved in n-hexane (1 mL) at reﬂux. Next, EtOAc (0.5 mL) was

carefully added, and the solution was rapidly cooled down to room

temperature to initiate nucleation under stagnant conditions. The

system was stored at room temperature, and crystal growth was

allowed to proceed overnight with slow evaporation of the sol-

vents. The crystals were selected under Paratone-N oil, mounted

on the nylon loops and positioned in the cold stream on the diffrac-

tometer. The X-ray data for (R)-(ꢀ)-4a was collected at 100(2) K on

To a solution of the appropriate racemic indole-like alcohol rac-

3a–c (50 mg) in the respective organic solvent (3 mL), lipase prepa-

ration [5 mg, 10% w/w (catalyst/substrate)] and vinyl acetate (10

equiv) or isopropenyl acetate (10 equiv) were added in one por-

tion. Thus composed reaction mixture was shaken (300 rpm) at

30 °C by using a laboratory rotatory shaker, while its aliquots were

regularly analyzed by analytical chromatographic assays (GC and

HPLC). When the appropriate conversion was reached, the reaction

was terminated by ﬁltering off the enzyme on a Schott funnel, and

by subsequent washing it with corresponding organic solvent (2 ꢂ

5 mL). The permeate was concentrated under reduced pressure,

and the crude residue was puriﬁed by column chromatography

on silica gel using a binary solvent system composed of mixture

of 50% EtOAc/n-hexane for kinetic resolution of rac-3a, 60%

EtOAc/n-hexane for kinetic resolution of rac-3b, and 50% EtOAc/

n-hexane for kinetic resolution of rac-3c. The respective resolution

products [(R)-(ꢀ)-3a–c and (S)-(+)-4a–c] were isolated in yields

a SuperNova Agilent diffractometer using CuKa radiation (k =

1.54184 Å). The data were processed with CrysAlisPro.⁶⁴The struc-

ture was solved by direct methods using the SHELXS-97 program

and was reﬁned by full matrix least-squares on F²using the pro-

gram SHELXL-97.⁶⁵All non-hydrogen atoms were reﬁned with ani-

sotropic displacement parameters. Hydrogen atoms were added to

the structure model at geometrically idealized coordinates and

reﬁned as riding atoms. Crystallographic data (excluding structure

factors) for the structure reported in this paper have been depos-

ited with the Cambridge Crystallographic Data Centre as supple-

P. Borowiecki et al. / Tetrahedron: Asymmetry 28 (2017) 1717–1732

1731

Biomol. Chem. 2013 , 11 , 6119–6130; (c) Lancianesi, S.; Palmieri, A.; Petrini, M.

Chem. Rev. 2014 , 114 , 7108–7149.

mentary publication. Copies of the data can be obtained free of

charge on application to CCDC, 12 Union Road, Cambridge CB21EZ,

UK (fax: (+44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).

Crystal data for (R)-(ꢀ)-4a; C₁₃H₁₄N₂O₄: M = 262.26, crystal

dimensions 0.32 ꢂ 0.24 ꢂ 0.12 mm³, triclinic, space group Pꢀ1

(no. 2), a = 4.69080(10) Å, b = 10.7522(3) Å, c = 12.3836(4) Å, b =

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87.214(2), U = 624.58(3) Å³, Z = 2, F(000) = 276, D_c= 1.395 g cm^ꢀ3

T = 100(2) K, (Mo-K

) = 0.877 mm^ꢀ1, SuperNova Agilent diffrac-

tometer, h_max= 69.482°, R1 = 0.0302, wR2 = 0.0782 for all data,

R1 = 0.0299, wR2 = 0.0779 for 2197 reﬂections with I_o> 2 (I_o).

The goodness-of-ﬁt on F²was equal 1.064. A weighting scheme

w = [

²(F²_o+ (0.0418P)²+ 3.1964P]^ꢀ1where P = (F_o²+ 2F²_c)/3 was

used in the ﬁnal stage of reﬁnement. The residual electron den-

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Acknowledgements

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This work was ﬁnancially supported by Warsaw University of

Technology (Faculty of Chemistry) in the frame of ‘Dean’s Funding

Program for Young Investigators’. The authors wish to gratefully

acknowledge Prof. Jan Plenkiewicz for proof-reading and critical

opinions helpful for preparing this manuscript. In addition, we

would like to extend our sincere gratitude and appreciation for

all of the hard work and dedication provided by undergraduate

students: Maryia Sheiherevich, Anna Stolarczyk, and Katarzyna

Banasik.

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A. Supplementary data

Supplementary data associated with this article can be found, in

the online version, at https://doi.org/10.1016/j.tetasy.2017.10.010.

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