Asymmetric chemoenzymatic synthesis of 1,3-diols and 2,4-disubstituted aryloxetanes by using whole cell biocatalysts

Article abstract of DOI:10.1039/c6ob02320g

Regio- and stereo-selective reduction of substituted 1,3-aryldiketones, investigated in the presence of different whole cell microorganisms, was found to afford β-hydroxyketones or 1,3-diols in very good yields (up to 95%) and enantiomeric excesses (up to 96%). The enantiomerically enriched aldols, obtained with the opposite stereo-preference by baker's yeast and Lactobacillus reuteri DSM 20016 bioreduction, could then be diastereoselectively transformed into optically active syn- or anti-1,3-diols by a careful choice of the chemical reducing agent (diastereomeric ratio up to 98 : 2). The latter, in turn, were stereospecifically cyclized into the corresponding oxetanes in 43-98% yields and in up to 94% ee, thereby giving a diverse selection of stereo-defined 2,4-disubstituted aryloxetanes.

Full text of DOI:10.1039/c6ob02320g

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Perna, G. Agrimi, A. Scilimati, A. Salomone, C. Cardellicchio and V. Capriati, Org. Biomol. Chem., 2016,
DOI: 10.1039/C6OB02320G.
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DOI: 10.1039/C6OB02320G
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ARTICLE
Asymmetric Chemoenzymatic Synthesis of 1,3-Diols and 2,4-
Disubstituted Aryloxetanes by Using Whole Cell Biocatalysts†
Paola Vitale,*a Filippo Maria Perna,a Gennaro Agrimi,b,c Antonio Scilimati,a Antonio Salomone,d
Received 00th January 20xx,
Accepted 00th January 20xx
Cosimo Cardellicchio,e and Vito Capriati*a
DOI: 10.1039/x0xx00000x
Regio- and stereoselective reduction of substituted 1,3-aryldiketones, investigated in the presence of different whole cell
microorganisms, was found to afford β-hydroxyketones or 1,3-diols in very good yields (up to 95%) and enantiomeric
excesses (up to 96%). The enantiomerically enriched aldols, obtained with opposite stereo-preference by baker’s yeast and
Lactobacillus reuteri DSM 20016 bioreduction, could then be diastereoselectively transformed into optically active syn- or
anti-1,3-diols by a careful choice of the chemical reducing agent (diastereomeric ratio up to 98:2). The latter, in turn, were
stereospecifically cyclized into the corresponding oxetanes in 43–98% yields and in up to 94% ee, thereby giving a diverse
selection of stereodefined 2,4-disubstituted aryloxetanes.
www.rsc.org/
a. Ishizaki (2007): Enantioselective reduction of !-halogenoketones
O
Introduction
O
LiBH4
R
X
chiral ligand
R
Oxetanes are an important group of four-membered
heterocyclic compounds found in natural products, and widely
used in synthetic organic chemistry, in the fields of polymer
science and technology, and in materials science.1 The oxetane
motif has become popular within medicinal chemistry and
drug discovery particularly after the pioneering studies by
Carreira and co-workers that demonstrated its effectiveness
for fine-tuning the physicochemical properties of organic
molecules (e.g. improving solubility, lipophilicity, etc.) and as
isosteric replacement of both the carbonyl functional group
and the gem-dimethyl moiety.2 In addition, oxetanes proved to
be versatile templates in organic synthesis for the construction
of valuable heterocyclic compounds and chiral building blocks
by ring expansion, ring opening, rearrangement and
desymmetrization reactions.3 More functionalized derivatives
can also be prepared by exploiting direct organolithium-
mediated functionalization processes, while preserving the
integrity of the oxetanyl skeleton.4
X = halogen 3 examples
up to 89% ee
b. Shibasaki (2009): Ring opening/closing from optically active oxiranes
chiral cat.
chiral cat.
O
H3C
R
H3C
R
O
sulfur ylide
sulfur ylide
O
R
CH3
THF, RT
THF, 45 °C
93–97% ee
99–>99.5% ee
8 examples
c. Bull (2014): Rh-catalyzed O–H insertion and cyclization
O–H
Ph
EtO2C
N2
insertion
Ph
Br
EtO2C
O
+
Br
EtO2C
EtO2C
HO
CO2Et
CO2Et
O
cyclization
Ph
85% ee
d. Smith (2015): Enantioselective NHC-catalyzed redox [2+2] cycloaddition
R1
O
R1
O
O
a) LiBH4
NHC
base
R1
+
R2
R3
b) NaH
TrisCl
R2
R3
O
R2
R3
O
H
OCOAr
91:9–>95:5 dr
5 examples
90–94% ee
e. Osumi (1989): BF3-catalyzed [2+2] cycloadditions from sugars
O
XR2
O
O
O
*
H
BF3 OEt2
*
XR2
+
O
CH2Cl2, –78 °C
X = O,R
R1
R1
O
a. Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “A. Moro”,
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy. E-mail:
paola.vitale@uniba.it, vito.capriati@uniba.it
f. Nelson (2000): Stereospecific conversion of 1,3-diols
into 2,4-disubstituted oxetanes
diastereoselective
reduction
whole cell
O
OH
*
b. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of
Bari, Via Orabona 4, 70125 Bari, Italy
O
O
biocatalytic reduction
Ar
R
Ar
Ar
R
R
c. CIRCC Via Celso Ulpiani 27, I-70126 Bari, Italy
2
1
d. Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del
Salento, Prov.le Lecce-Monteroni, I-73100 Lecce, Italy.
stereospecific
Ar
cyclization
OH
*
OH
*
O
Ar = Phenyl, (hetero)aryl
R = alkyl, cycloalkyl
*
e. CNR ICCOM, Dipartimento di Chimica, Università di Bari “A. Moro”, Via E.
Orabona 4, I-70125 Bari, Italy
*
3
4
R
†Electronic Supplementary Information (ESI) available: material and methods,
experimental details
chromatograms of oxetanes. For ESI see DOI: 10.1039/x0xx00000x.
,
additional spectroscopic data, NMR spectra and
Scheme 1 Current available methods for the preparation of
variously substituted stereodefined oxetanes.
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Several methods have been developed throughout the years collections
ARTICLE
CBS 7336,
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(Saccharomyces
cerevisiae
DOI: 10.1039/C6OB02320G
for the preparation of diversely substituted oxetanes, Kluyveromyces marxianus CBS 6556, Yarrovia Lipolytica Y16,
however, mainly in racemic form.5 Thus, the synthesis of and Trigonopsis variabilis DSM 70714), under the same
stereodefined bespoke skeletons still remains a challenge in experimental conditions (see footnote of Table 1 and
contemporary organic synthesis. The few reported methods Experimental Section). While baker’s yeast-mediated
include: (i) the asymmetric synthesis of 2-aryl-substituted bioreductions were run directly in tap water, the ones with
oxetanes via enantioselective reduction of β-halogenoketones Lactobacillus reuteri DSM 20016 resting cells (RC) were carried
with LiBH4 in the presence of chiral ligands (Scheme 1a);6 (ii) out with diketones (1g/L) suspended in phosphate-buffered
ring-opening/closing from optically active oxiranes using saline (PBS) solutions.15 The reaction progress was monitored
sulfoxonium ylides to give 2,2-disubstituted oxetane by TLC and 1H NMR, and the results are reported in Table 1.
derivatives (Scheme 1b);7 (iii) the Rhodium-catalyzed O–H
No reduction of 1a was noticed in the presence of Yarrovia
insertion of optically active β-bromohydrins into diazo Lipolytica Y16, baker’s yeast (RC) and Lactobacillus reuteri DSM
compounds followed by C–C bond-forming cyclization en route 20016 (Table 1, entries 1–3), whereas a complex reaction
to 2,2,4-trisubstituted oxetanes (one example) (Scheme 1c);8 mixture was obtained with Trigonopsis variabilis DSM 70714
(iv) the enantioselective N-heterocyclic carbene (NHC)- (GC) (Table 1, entry 4). Despite diketone 1a is often found to
catalyzed redox [2+2] cycloadditions with perfluoroketones as be unreactive under mild conditions,17 we were delighted to
a means of access to 2,2,3-trisubstituted fluorinated oxetanes find out that Saccharomyces cerevisiae CBS 7336 (GC)
(Scheme 1d).9 To our best knowledge, the only way reported successfully catalyzed its bioreduction, thereby allowing the
for making optically active 2,4-disubstituted oxetanes is that isolation of the corresponding (S)-aldol 2a as the main product
based on a BF3-catalyzed [2+2] cycloaddition route from sugars with 50% yield and 58% enantiomeric excess (ee) after 96 h
(Scheme 1e).10a,b
incubation at 30 °C (Table 1, entry 5). Disappointedly, under
Whole-cell biocatalysis has emerged in the last decades as the same conditions but using Kluyveromyces marxianus CBS
an elegant, competitive and formidable way of producing 6556 (GC) as the biocatalyst, (S)-aldol 2a was formed in 12%
biologically active molecules of pharmaceutical interest.11 yield and with 36% ee only. Interestingly, however, a
Wild-type whole-cell biocatalysts are often preferable to competitive unusual reduction of both carbonyl moieties also
isolated and purified enzymes since they are cheaper, easy to took place18 and anti-diol 3a could be directly isolated in 76%
handle, with efficient internal cofactor regeneration systems, yield as the sole diastereomer [diastereomeric ratio (dr)
and working with high regio- and stereoselectivity under mild >98:2], albeit essentially in racemic form (8% ee) (Table 1,
operational and environmentally friendly conditions.12 In 2000, entry 6). Switching to RC of Kluyveromyces marxianus CBS
Nelson and co-workers reported the stereospecific conversion 6556, did not lead to greater than 27% yield of 2a jointly with a
of (1R*,3S*)- and (1R*,3R*)-3-cycloxexyl-1-phenylpropane-1,3- racemic mixture of 3a in 55% yield (Table 1, entry 7). Hence,
diols 3 into the corresponding 2,4-disubstituted oxetanes 4 the formation of highly enantioenriched aldol 2a and/or diol
(vide infra). The former could be obtained by
a
3a, via stereoselective reduction of β-diketone 1a, proved to
diastereoselective reduction of aldols 2 (Scheme 1f).13 Inspired be a challenging task with all the microorganisms screened.
by this report and building on our recent findings in using Structural features of different 1-aryl-1,3-diones were, then,
whole cell microorganisms (i.e., thermotolerant Kluyveromyces investigated en route to optically active 2,4-disubstituted
marxianus yeast14 and Lactobacillus reuteri strain15) for the aryloxetanes.
highly stereoselective biocatalytic reduction of arylketones to
Reduction of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (1b)
optically active 1-arylethanols, we wondered whether the with both GC and RC of Kluyveromyces marxianus afforded the
synthesis of such challenging scaffolds (4) in an optically active corresponding aldol derivative 2b in 91 and 74% chemical
form could be achieved starting directly from 1,3-aryldiketones yield, respectively, while no appreciable stereoselectivity was
1 via a stereoselective whole-cell based biocatalytic reduction observed after 24 or 48 h incubation at pH 7.4 (Table 1, entries
(Scheme 1f). Previous attempts to achieve this goal from 1,3- 8,9). In the latter case, acetophenone (5) could also be isolated
diphenylpropane-1,3-diol,
via
phosphonium
ether (10% yield), most likely as the result of a base-catalyzed retro-
intermediates, however, failed.16 In this paper, we present the aldol reaction (Table 1).19 The use of GC of Saccaromyces
results of such an investigation aimed at preparing cerevisiae CBS 7336 provided aldol 2b in 20% yield and with an
stereodefined 1,3-diols and the corresponding 2,4- ee value of 40% in favour of the R-enantiomer, whereas the
disubstituted aryloxetanes by cyclization.
exposure of 1b to RC resulted in an increase in yield (60%) but
a decrease in ee (8%) of 2b after 48 h incubation at pH 7.4
(Table 1, entries 10,11). Variable amounts of 5 (10–12%) were
also obtained. The different stereoselectivity observed is
probably due to different ADH expression in different
metabolic conditions of Saccaromyces cerevisiae CBS 7336.20
Diketone 1b was smoothly converted into aldol 2b only after 4
h incubation in tap water at 30 °C in high chemical yield (73%)
and ee (82%) when RC of baker’s yeast were used (Table 1,
entry 12). The apparent, unusual anti-Prelog R-
Results and discussion
Screening of whole-cell biocatalysts
As a bench reaction, we set out to investigate the bioreduction
of 1,3-diphenyl-1,3-propandione (1a). This was incubated in
the presence of growing cells (GC) of some previously
characterized microbial biocatalysts,14,15 from european
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stereopreference observed in entries 10–12 is due to a change in the priority of the groups around the stereogenViciewceAnrtitcelerO.2n1line
DOI: 10.1039/C6OB02320G
Table 1. Screening of different biocatalysts for the stereoselective reduction of diketones 1a–e.a
O
OH
*
OH
*
OH
*
O
O
O
O
EtOH/EtO
EtOH/EtO
biocatalyst
PhCOCH3 + CF3COOEt
+
Ar
R
Ar
R
Ph
CF3
OEt
Ar
R
5
1a–e
2a–e
3a–e
Ar = Ph, R = CF3
a: Ar = R = Ph, b: Ar = Ph, R = CF3; c: Ar = 2-furyl, R = CF3; d: Ar = Ph, R = CH3; e: Ar = 2-naphtyl, R = CF3
Entry Biocatalyst
Ar
R
Compound t (h)
Conversion Product
Product
(%)b
(yield %)c
(ee %, abs. conf.)d
–
1
2
3
4
5
Yarrovia Lipolytica Y16 (GC)
Ph
Ph
Ph
Ph
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
96
96
24
96
96
NRe
NRe
NRe
12
NDf
NDf
NDf
j
–
Baker’s yeast (RC)
Lactobacillus reuteri (RC)g,h
Trigonopsis variabilis (GC)i
–
–
Saccharomyces cerevisiae (GC)k Ph
50
2a (50)
2a (58, S)
2a (12)
2a (36, S)
3a (8)
–
6
Kluyveromyces marxianus (GC)l Ph
Ph 1a
96
90
3a (76)m
7
Kluyveromyces marxianus (RC)l Ph
Kluyveromyces marxianus (GC)l Ph
Kluyveromyces marxianus (RC)l Ph
Saccharomyces cerevisiae (GC)k Ph
Saccharomyces cerevisiae (RC)k Ph
Ph 1a
CF3 1b
CF3 1b
CF3 1b
CF3 1b
CF3 1b
CF3 1b
CF3 1b
CF3 1c
CF3 1c
CF3 1c
CH3 1d
CH3 1d
CH3 1d
CH3 1d
96
24
48
24
48
4
82
2a (27); 3a (55)n
2b (91)
2b (74)
2b (20)
2b (60)
2b (73)
2b (39)
2b (80)
2c (90)
2c (78)
2c (29)
2d (75)
2d (93)
2d (95)
NDf
2b (8, S)
8
95
2b (8, S)o
2b (40, R) o
2b (8, R) o
2b (82, R)
2b (88, R)
2b (84, S)
2c (64, R)
2c (38, S)
2c (28, S)
2d (90, S)
9
84
10
11
12
13
14
15
16
17
18
19
20
21
22
30
72
Baker’s yeast (RC)
Ph
65
Lactobacillus reuteri (RC)g,h
Lactobacillus reuteri (RC)g,h
Baker’s yeast (RC)
Ph
4
43
Ph
24
4
87
Furanyl
90
Kluyveromyces marxianus (GC)l Furanyl
96
24
24
4
98
Lactobacillus reuteri (RC)h
Furanyl
Ph
36
Baker’s yeast (RC)
75
Lactobacillus reuteri (RC)g,h
Lactobacillus reuteri (RC)g,h
Ph
>98
>98
NRe
31
53
2d (96, R)
2d (96, R)
–
Ph
24
24
24
24
Saccharomyces cerevisiae (GC)k Ph
Lactobacillus reuteri (RC)g
Napht-2-yl CF3 1e
Napht-2-yl CF3 1e
2e (26)
2e (40)
2e (32, S)
2e (80, R)
23
Baker’s yeast (RC)
a
Typical reaction conditions: orbital incubator: 200 rpm; temperature: 30 °C; (GC): inoculum after 24 h growth in a sterile medium containing
glucose (1%), peptone (0.5%), yeast extract (0.3%) and malt extract (0.3%) in sterile water; (RC): 0.5 g/L of cell wet mass in 0.1 M KH2PO4 buffer (pH =
7.4) enriched with 1% glucose, diketone (2 mM final concentration). Calculated by 1H NMR based on the diagnostic enolic protons of the unreacted
b
diketone in the crude. c Isolated yield after column chromatography. d Enantiomeric excess (ee) determined by HPLC analysis. Absolute configuration (abs.
conf.) of aldols (2a–e) determined by comparing optical rotation sign and retention time (HPLC analysis) with known data.e No reaction. f ND means not
determined because of trace content. g PBS solution as reaction media (T = 37 °C). h DSM 20016. i DSM 70714. j Complex mixture. k CBS 7336. l CBS 6556.m Only
the anti-3a diol (dr >98:2) was detected and isolated. n Racemic mixture. o Acetophenone (10–12% yield) was also isolated.
Similarly, aldol 2b was recovered with high ee (88%) by using RC of baker’s yeast and GC of Kluyveromyces marxianus,
Lactobacillus reuteri DSM 20016 after 4 h incubation, albeit in although with moderate ee (38–64%) but opposite
lower yield (39%). Chemical yield, however, could be increased stereopreference (Table 1, entries 15,16).On the other hand,
up to 80% by increasing the incubation time up to 24 h with bioreduction of 1c with Lactobacillus reuteri DSM 20016
only a little erosion in ee (84%) (Table 1, entries 13, 14). High provided 2c with even lower chemical (29%) and optical (28%)
conversions (90–98%) were obtained for the bioreduction of yields (Table 1, entry 17). Baker's yeast and Lactobacillus
furanyl-substituted butane-1,3-dione 1c to aldol 2c with both reuteri DSM 20016 whole cells proved to be the best
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biocatalysts for the conversion of 1-phenylbutane-1,3-dione even after 24 h incubation (Table 1, entry 21). Finally, upon
View Article Online
DOI: 10.1039/C6OB02320G
(1d) into the two enantioenriched stereoisomeric aldols 2d. In subjecting 2-naphtyl-substituted 1-butane-1,3-dione 1e to the
the former case, S-enantiomer was produced in a remarkable action of Lactobacillus reuteri DSM 20016 and baker’s yeast,
yield of 75% and ee of 90%, whereas in the latter case R- while S-aldol 2e formed both in low yield (26%) and
enantiomer was isolated in up to 95% yield and 96% ee (Table enantioselectivity (32%), R-aldol 2e could be isolated in 40%
1, entries 18–20). Saccharomyces cerevisiae CBS 7336 was yield and in up to 80% ee (Table 1, entries 22, 23).
ineffective for the reduction of 1d, and aldol 2d did not form
Table 2. Chemical reduction of aldols 2b–e for the preparation of racemic and optically active 1,3-diols 3b–e.
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
(R)
(R)
(S)
(R)
(R)
(R)
(S)
(R)
(R)
(S)
CH3
Ph
CF3 Ph
OH
CF3
CF3
CF3 Ph
reducing
agent
O
OH
*
anti-3b
OH
syn-3b
OH
anti-3c
syn-3c
anti-3d
O
O
Ar
R
OH
OH
OH
(R)
OH
OH
OH
OH
2b–e
(S)
(R)
(R)
(S)
(R)
(S)
(S)
CF3
CF3
(R)
(R)
Ph
CH3 Ph
CH3
Ph
CH3
syn-3e
anti-3e
anti-3d
syn-3d
syn-3d
Entry
Product (yield %)a
Aldol (ee %)
(R)-2b (82)
(R)-2c (64)
Reducing agent
Me4NHB(OAc)3
DIBAL-H
dr anti: synb
91:9d
Stereoisomer (ee %)c
1
2
3b (98)
3c (78)
anti-(1R,3R)-3b (80); syn-(1S,3R)-3b (50)
anti-(1R,3R)-3c (42); syn-(1S,3R)-3c (34)
75:25e
3
4
5
6
7
8
(S)-2d (90)
(R)-2d (98)
(R)-2d (98)
(S)-2d (90)
(R)-2e (80)
(R)-2e (80)
Me4NHB(OAc)3
3d (89)
3d (95)
3d (93)
3d (91)
3e (86)
88:12d
2:98d
51:49d
57:43d
88:12e
6:94e,f
anti-(1R,3S)-3d (86); syn-(1S,3S)-3d (82)
syn-(1R,3R)-3d (98)
Et2BOCH3/NaBH4
NaBH4
anti-(1S,3R)-3d (98);syn-(1R,3R)-3d (96)
anti-(1R,3S)-3d (98); syn-(1S,3S)-3d (96)
anti-(1R,3R)-3e (60); syn-(1S,3R)-3e (56)
syn-(1S,3R)-3e (72)
NaBH4
Me4NHB(OAc)3
Et2BOCH3/NaBH4
3e (88)
a Overall isolated yield in the two diastereomers. b Calculated by H NMR. Ee determined by HPLC analysis; abs. conf. determined by comparing optical
1
c
d
rotation sign and retention time (HPLC analysis) of diols with known data (see Experimental); the chemical formulas refers to the major enantiomer.
Separable mixture of diols by column chromatography. e Unseparable mixture of diols. f Ee determination of anti-(1R,3R)-3e was impractical.
Synthesis of steredefined 1,3-diols
Me4NHB(OAc)3 and sodium borohydride (NaBH4) as reducing
agents, whereas diisobutylaluminum hydride (DIBAL-H) cleanly
provided a mixture of the expected optically active syn- and
anti-diols 3c in good overall yield (78%), moderate
diastereoselectivity (75:25), although eroded of 20–30% in
their ees (Table 2, entry 2). Trifluoromethyl carbinol derivatives
are, indeed, known to easily undergo partial racemization even
under mild acidic conditions.23 Interestingly, reduction of (R)-
2d (98% ee) and (R)-2e (80% ee) with the combination
diethylmethoxyborane (Et2BOMe)/NaBH4, in place of
Me4NHB(OAc)3, stereospecifically afforded syn-(1R,3R)-3d and
syn-(1S,3R)-3e, respectively, in excellent yield (up to 95%) and
diastereoselectivity (up to 98:2), and with no or slight erosion
(8%) of the enantiomeric purity (Table 2, entries 4,8). Notably,
by subjecting both enantiomerically enriched aldols (R)- and
(S)-2d to the action of NaBH4, two separable mixtures of anti-
and syn-diols 3d formed in almost equimolar ratio in high
chemical yield (91–93%) and high optical purity (96–98% ee)
(Table 2, entries 5,6). The relative configuration of all the
Having established the strain specificity and the optimal
conditions for efficient biosynthesis of some representative
classes of optically active aldols, we next focused on their
chemical transformation into the corresponding syn- and/or
anti-diols according to the reported procedures.22 The mild
reducing agent tetramethylammonium triacetoxyborohydride
[Me4NHB(OAc)3] converted aldols (R)-2b, (S)-2d, and (R)-2e
mainly into the corresponding anti-diols (1R,3R)-3b, (1R,3S)-
3d, (1R,3R)-3e with high yield (up to 98%) and high
diastereoselectivity (up to 91:9) (Table 2, entries 1,3,7). The ee
of the starting aldol was mainly preserved in the final diols,
with the exceptions of syn-(1S,3R)-3b, anti-(1R,3R)-3e, and
syn-(1S,3R)-3e for which a slight racemization took place most
probably during the acidic workup procedure (Table 2, entries
1,3,7) (see Experimental Section). As for the sensitive
trifluoromethyl furanyl-substituted aldol (R)-2c, a complex
mixture of diols (including products of hydrolysis and
reduction of the furanyl ring), was recovered using both
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synthesized diasteromeric diols 3a–e (Tables 1 and 2) was Table 3. Synthesis of stereodefined 2,4-VdieiswuAbrtsictleitOuntleinde
aryloxetanes 4a, 4b, 4d, and 4e.a
assigned by 1H NMR analysis, particularly by comparing
chemical shifts and coupling constants with those previously
reported (see Experimental Section). Mohar and co-workers
recently succeeded in the preparation of highly
enantiomerically enriched CF3-substituted anti-1,3-diols from
the corresponding 1,3-diketones by exploiting an ansa-
ruthenium (II)-catalyzed asymmetric transfer hydrogenation
under a dynamic kinetic resolution control.24 Complementary
syn-1,3-diols could also be accessed from stereopure aldols,
however, only by chanching the configuration of the
stereocenters of the chiral catalyst. We have now shown that a
variety of enantioenriched syn- and anti-1,3-diols can be easily
synthesized directly from β-diketones by simply using cheap
and commercially available whole cells and by selecting a
chemical reducing agent.
DOI: 10.1039/C6OB02320G
O
O
O
Ph
Ph
Ph
CF3
Ph
CH3
1) (MeO)3CMe, PPTS
OH
*
OH
*
trans-4a
trans-4b
trans-4d
2) AcBr
Ph
R
3) NaH, MeOH
O
3a,b,d,e
O
CF3
Ph
CH3
cis-4e
cis-4d
Diol 3 (dr anti:syn,b ee %) Oxetane 4 (yield %,c dr trans:cis,b ee %)
anti-3a (>98:2, 8)
trans-4a [75, >98:2, 6]d,e
anti-(1R,3R)-3b (91:9, 78) trans-(2R,4R)-4b [98, >98:2, 60]d
anti-(1R,3S)-3d (88:12, 86) trans-(2R,4S)-4d [51, 90:10, 88]d
syn-(1S,3S)-3d (8:92, 82)
syn-(1S,3R)-3e (6:94, 72)
cis-(2S,4S)-4d [43, 9:91, 94]d
cis-(2S,4R)-4e [73, 10:90, 80 ]f
b
1
a The chemical formulas refers to the major enantiomer. Calculated by H
c
d
NMR. Isolated yield after column chromatography. Ee determined by GC
analysis on a chiral stationary phase (see ESI). e For this cyclization, the anti-
3a diol, straightforwardly obtained by bioreduction of ketone 1a, was used
(see Table 1, entry 6). f Ee determined by HPLC analysis.
Synthesis of stereodefined 2,4-disubstituted aryloxetanes
Sterospecific cyclization of 1,3-diols into the corresponding
2,4-disubstituted oxetanes was then investigated. We followed
the two-step procedure reported by Nelson for racemic
(1R*,2S*)- and (1R*,3R*)-3-cyclohexyl-1-phenylpropane-1,3-
diols, which is based on a preliminary conversion of diols into
orthoesters with acetyl bromide, followed by methanolysis of
the putative bromoacetate intermediates and ring-closure
promoted by NaH/THF. The whole transformation is known to
proceed via two stereospecific inversion reactions, and thus
with overall retention of configuration at the involved
Conclusions
In summary, stereodefined 2,4-disubstituted aryloxetanes
have, for the first time, been synthesized starting from
symmetrical and unsymmetrical 1,3-diones. The key step in
obtaining these challenging, still rarely present in abstracted
literature, building blocks is the regio- and stereoselective
bioreduction of the above diones into the corresponding
aldols, which proved to be successfully catalysed by cheap and
commercially available whole-cell biocatalysts such as baker’s
yeast and Lactobacillus reuteri DSM 20016. Next,
diastereomerically enriched or almost equimolar mixtures of
optically active syn- and anti-1,3-diols can be produced
according to the nature of the reducing agent. Finally, a two-
step stereospecific cyclization allowed the obtainment of the
enantiomerically enriched oxetanes in good yields and with
overall retention of configuration. The final dr and ee proved
to be slightly affected by the relative chemical stability of the
various syn- and anti-diastereomeric diols synthesized under
the acidic conditions of the cyclization process. We expect the
whole asymmetric methodology presented in this paper is
easily and widely expanded to other oxetanyl systems, thereby
enabling the preparation of target architectures for
pharmaceutical exploration. Our current efforts are now
focused on the preparation of stereodefined, more substituted
oxetanes by exploiting lithiation-electrophilic trapping
strategies starting from the valuable chiral, nonracemic
oxetanes described herein.
stereogenic centers.13 According to such
a
strategy,
stereospecific conversion of diastereomeric diols 3a, 3b, 3d,
and 3e into the corresponding stereodefined oxetanes 4a, 4b,
4d, and 4e took place smoothly with only slight reduction of
the starting ee in the case of the trifluoromethyl-substituted
derivative 4b (3b: 78% ee; 4b: 60% ee) (Table 3). Formation of
elimination products was also noted to compete in the
cyclization of diols 3a and 3d. The increasing amount of trans-
oxetane detected in the final mixture, compared to that of the
starting diol, indicates a higher chemical stability of the anti-
diastereomer under the experimental conditions used. On the
other hand, cyclization of furanyl-substituted diol 3c (Table 2)
failed
because
of
furan
hydrolysis.25
Preparation of the corresponding racemic oxetanes, which
is necessary for ee analysis, was performed as well by
subjecting to cyclization mixtures of racemic syn- and anti-diols
(see ESI). The relative stereochemistry of the newly
synthesized oxetanes was determined by a careful analysis of
3
both NMR chemical shifts and vicinal JHH coupling constants,
and was supported for the unknown compounds by NOESY
6
phase-sensitive experiments (see ESI).2 The absolute
stereochemistry was instead assigned based on the
stereospecificity of the cyclization reaction starting from the
3
corresponding diols.1
Experimental
All the synthesized optically active aldols 2a–e and diols 3a–e
obtained by bioreduction showed analytical and spectroscopic
data identical to those previously reported,24,27 or to the
commercially available compounds. Aldols 2a–e and diols 3a–e
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were also prepared as racemic mixtures (for HPLC references) Stereoselective reduction of aldols 2b–e with Me4NHB(OAc)3.
View Article Online
DOI: 10.1039/C6OB02320G
by NaBH4 reduction in EtOH in 89–95% yields, according to the General procedure.
reported procedures,14 excepted when otherwise specified.
Acetic acid (5 mL) was added to a stirred solution of
tetramethylammonium triacetoxyborohydride (2.9 g, mmol) in
dry acetonitrile (5 mL) and the reaction was stirred for 30 min.
The reaction was cooled to –40 °C and a solution of the aldol
Bioreduction of 1a–e by baker’s yeast. General procedure.
Baker’s yeast (10 g) was dispersed to give a smooth paste in
(0.5 mmol) in acetonitrile (3 mL) was added. The reaction was
tap water (50 mL). The substrate (0.1 g) was added and stirred
stirred for 4 h, left overnight at –20 °C, quenched with aq.
at 30 °C in an orbital shaker (250 rpm). The reaction progress
sodium potassium tartrate solution (0.5 M, 40 mL) and finally
was monitored by TLC. After the time indicated in Table 1, the
stirred for additional 30 min. Dichloromethane (100 mL) and
reaction was stopped by centrifugation, decantation and
sat. aq. sodium bicarbonate solution (100 ml) were added, the
extraction by EtOAc. The extract was dried over anhyd Na2SO4,
layers separated, and the aqueous fraction extracted with
and the solvent evaporated under reduced pressure. The
CH2Cl2 (3 × 50 mL). The combined organic fractions were finally
residue was purified by silica gel column chromatography
washed with sat. aq. sodium bicarbonate solution (3 × 50 mL),
using hexane and EtOAc (90:10 or 60:40) as eluents to yield
the desired aldols (2a–e) reported in Table 1.
dried (Na2SO4), filtered and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography, eluting with 1:15 EtOAc–hexane, to give anti-
Bioreduction of 1a–e by Lactobacillus reuteri resting cells. diol.
General procedure.
Lactobacillus reuteri pre-culture was inoculated in MRS29 and Stereoselective
reduction
of
aldols
2d–e
with
incubated for 24 h (37 °C). Cells were collected after Et2BOCH3/NaBH4. General procedure.
centrifugation (4000 rpm, 10 min), and washed twice with Diethylmethoxyborane (1.0 M in THF, 425 μL, 0.386 mmol) was
phosphate buffer saline at pH 7.4 (PBS, Sigma-Aldrich). Finally added to a stirred solution of the selected 3-hydroxy-1-
the cells were suspended in the same buffer and adjusted for arylpropan-1-one (2d,e) (76 mg, 0.35 mmol) in dry THF (16 mL)
cell density. To this cell suspension, 1% glucose and the and MeOH (4 mL). The reaction was stirred for 15 min at –78
desired concentration of diketone were added. To ensure the °C and sodium borohydride (15 mg, 0.386 mmol) was added.
anaerobic conditions, flasks were degassed with a N2 flux for 3 The reaction mixture was stirred for additional 2 h at –78 °C,
min. The reaction mixture was incubated at 37 °C, 200 rpm. quenched with acetic acid (5 mL), and slowly warmed to room
After appropriate conversion, the suspension was centrifuged temperature overnight. The reaction mixture was diluted with
(4000 rpm, 10 min, 4 °C), and the aqueous phase was EtOAc (20 mL) and washed with sat. aq. sodium bicarbonate
extracted with Et2O (3 x 15 ml). The organic phase was dried solution (3 × 20 mL) until the vigorous evolution of CO2 ceased.
over anhyd Na2SO4, filtered, and evaporated under reduced The combined organic extracts were dried over Na2SO4,
pressure. The residue was purified by silica gel column filtered and evaporated under reduced pressure to give the
chromatography using hexane and EtOAc (90:10 or 60:40) as crude product, which was purified by silica gel column
eluents to yield the desired aldols (2a–e) reported in Table 1.
chromatography (EtOAc/hexane 3 : 7), to give syn-diol in the
yield reported in Table 2.
Bioreduction of 1a–c by Kluyveromyces marxianus growing
cells (GC). General procedure.
General procedure for the synthesis of oxetanes 4a–e.13
Cells preserved on agar slants at 4 °C were used to inoculate Trimethyl orthoacetate (132 μl, 0.86 mmol) and pyridinium
250 mL flasks containing 100 mL of the culture medium. The toluene-p-sulfonate (2 mg) were added to a stirred solution of
flasks were incubated aerobically at 30 °C on an orbital shaker diols 3a–e (202 mg, 0.70 mmol) in dry CH2Cl2 (7 mL). The
and stirred at 250 rpm. Flasks (250 mL) containing 100 mL of reaction mixture was stirred for 10 min at room temperature,
the culture medium were then inoculated with 5 mL of the 24- cooled to –78 °C, and acetyl bromide (156 μl, 1.78 mmol) was
h-old suspension and incubated under the same conditions for added. The reaction was stirred for additional 1.5 h, quenched
24 h. Flasks (1 L) containing 400 mL of the culture medium with sat. aq. NaHCO3 solution, extracted with CH2Cl2 (3 × 5 ml),
were then inoculated with 5 mL of the latter suspension and dried (Na2SO4), filtered and evaporated to give a crude
incubated for 24 h. The optical density was checked at 620 nm product. The latter was dissolved in dry THF (10 ml), and
for all cultures before adding aryldiketones 1a–c (100 mg) MeOH (32 μl, 0.95 mmol) and NaH (104 mg, 60% dispersion in
dissolved in 1 mL of EtOH. The progress of the reactions was oil, 2.13 mmol) were sequentially added. The vessel was sealed
monitored by TLC and/or GC and stopped at the times with a glass cap and the reaction stirred for 24 h at 60 °C. After
indicated in Table 1. The content of the flask was then this time, the reaction was quenched with water and extracted
centrifuged and the supernatant extracted with EtOAc. All the with EtOAc (3 × 15 ml). The combined organic extracts were
reactions were repeated at least twice without any noticeable dried (Na2SO4), filtered and evaporated to give a crude product
bias in the results. The residue was purified by silica gel which was purified by flash silica gel column chromatography
column chromatography using hexane and EtOAc (90:10 or (10% Et2O in petroleum ether), to give the oxetanes 4a–e
60:40) as eluents to yield the desired aldols (2a–c) and the diol (Table 3).
3a, as reported in Table 1.
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Characterization data of synthesized oxetanes.
ARTICLE
H), 2.29–2.23 (m, 1 H), 1.47 (d, 3 H, J = 6.1 Hz); 13C NMR (125
View Article Online
trans-2,4-Diphenyloxetane (4a).28 White solid, mp (Et2O) 122– MHz, CDCl3) δ 143.6, 128.4, 127.7, 125.4, 78.0, 74.4, 38.2,
123 °C, 75% yield (57% overall yield; 54 mg starting from 100 24.1; GC MS (70 eV) m/z (%) 148 (7), 107 (60), 106 (11), 105
mg of 1a), dr >98:2. Er (2S,4S):(2R,4R) = 53:47 determined by (100), 104 (87), 103 (27), 79 (9), 78 (40), 77 (51), 51 (25), 43
HPLC, Lux Cellulose-1 column, hexane: 2-propanol = 90:10, 0.8 (9); FT-IR (neat): 2954, 2925, 2853, 1720, 1648, 1455, 1377,
mL/min), tR [major (S,S)-enantiomer] = 14.4 min, tR [minor 1259, 1095, 1022, 872, 799, 699 cm-1. HRMS (ESI-TOF) m/z: [M
DOI: 10.1039/C6OB02320G
1
(R,R)-enantiomer] = 15.8 min. H NMR (600 MHz, CDCl3) δ + Na]+ Calcd for C10H12NaO+ 171.0786; Found 171.0780.
7.52–7.50 (m, 4 H), 7.43–7.39 (m, 4 H), 7.32–7.29 (m, 2 H),
5.82 (t, J = 5.8 Hz, 2 H), 3.00 (t, J = 5.8 Hz, 2 H); 13C NMR (100 (2S,4R)-2-(Naphthalen-2-yl)-4-(trifluoromethyl)oxetane (4e).
MHz, CDCl3) δ 143.5, 128.6, 127.8, 125.3, 79.6, 38.4; GC MS (70 Colourless waxy solid, 73% yield (25% overall yield; 63 mg
eV) m/z (%) 210 (M+, 1), 105 (21), 104 (100), 103 (18), 89 (1), starting from 100 mg of 1e), dr 90:10. Er (2S,4R):(2R,4S) =
79 (2), 78 (18), 77 (19), 63 (2), 51 (8); FT-IR (KBr): 3011, 2920, 90:10 determined by HPLC, Lux Cellulose-1 column, hexane: 2-
1644, 1290, 1155, 1121, 863, 751, 699 cm-1. HRMS (ESI-TOF) propanol = 90:10, 0.8 mL/min), tR [major (S,R)-enantiomer] =
m/z: [M + Na]+ Calcd for C15H14ONa+: 210.1045; Found 7.6 min, tR [minor (R,S)-enantiomer] = 7.0 min, [α]D20 = –22.0 (c
210.1052.
0.35, CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.91–7.86 (m, 4 H),
7.58 (dd, J = 8.5, 1.5 Hz, 1 H), 7.54–7.50 (m, 2 H), 5.99 (t, J = 7.7
Hz, 1 H), 5.14–5.08 (m, 1 H), 3.18 (dt, J = 11.8, 7.5 Hz, 1 H), 2.90
(2R,4R)-2-Phenyl-4-(trifluoromethyl)oxetane (4b).26b
Colourless oil, 98% yield (58% overall yield; 56 mg starting (dt, J = 11.8, 7.8, 1 H); 13C NMR (125 MHz, CDCl3) δ 138.1,
from 100 mg of 1b), dr >98:2. Er (2R,4R):(2S,4S) = 80:20 133.3, 133.1, 128.6, 128.2, 127.7, 126.4, 126.3, 124.7, 122.9,
determined by GC-Chirasil-DEX CB capillary column, (He flow 1 121.9 (q, 1JC-F = 281.0 Hz), 80.0, 72.8 (q, 2JC-F= 36.0 Hz), 30.0; 19
F
3
mL/min, 100 °C), tR [major (R,R)-enantiomer] = 18.5 min, tR NMR (376 MHz, CDCl3) δ –81.8 (d, JF-H = 6.5 Hz); GC MS (70
[minor (S,S)-enantiomer] = 17.5 min, [α]D20 = +8.42 (c 1, CHCl3). eV) m/z (%) 252 (M+, 4), 183 (30), 156 (100), 69 (9); FT-IR (KBr):
1H NMR (400 MHz, CDCl3) δ 7.44–7.31 (m, 5 H), 5.87 (t, J = 7.5 2930, 2852, 1649, 1232, 1150, 1116, 1000, 894, 862, 820, 765
Hz, 1 H), 4.93–4.86 (m, 1 H), 3.12–3.07 (m, 1 H), 2.89–2.82 (m, cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H11F3ONa+:
1 H); 13C NMR (100 MHz, CDCl3) δ 141.5, 128.8, 128.5, 125.2, 275.0660; Found 275.0654.
1
2
124.9 (q, JC-F = 280 Hz), 81.9, 74.1 (q, JC-F = 35 Hz), 29.9; 19F
3
NMR (376 MHz, CDCl3) δ –80.4 (d, JF-H = 6.5 Hz); GC MS (70
eV) m/z (%) 202 (M+, 7), 133 (1), 115 (2), 107 (4), 106 (51), 105
(100), 104 (15), 103 (10), 91 (2), 78 (14), 77 (28); FT-IR (neat):
3064, 3030, 2955, 2926, 2856, 1455, 1364, 1173, 1099, 1060,
1016, 760, 700 cm-1. HRMS (EI): m/z Calcd for C10H9F3O:
202.0605; Found: 202.0599.
Acknowledgements
This work was financially supported by the University of Bari within
the framework of the Project “Sviluppo di nuove metodologie di
sintesi mediante l’impiego di biocatalizzatori e solventi a basso
impatto ambientale” (code: Perna01333214Ricat), and by both
C.I.N.M.P.I.S. and CIRCC consortia. This work was partially
supported also by the "Reti di Laboratori - Produzione Integrata di
Energia da Fonti Rinnovabili nel Sistema Agroindustriale Regionale "
program funded by the Apulia Region Project Code 01’. (Intervento
cofinanziato dall’Accordo di Programma Quadro in materia di
Ricerca Scientifica – II Atto Integrativo – PO FESR 2007–2013, Asse I,
Linea 1.2-PO FSE 2007–2013 Asse IV ‘‘Investiamo nel vostro
futuro’’). The authors are also indebted to Mr Antonio Palermo for
expert technical NMR assistance, and to Dr. Marilena D'Introno,
(2R,4S)-2-Phenyl-4-methyloxetane (4d). Colourless oil, 51%
yield (26% overall yield; 24 mg starting from 100 mg of 1d), dr
90:10. Er (2R,4S):(2S,4R) = 94:6 determined by GC-Chirasil-DEX
CB capillary column, (He flow 2 mL/min, 100 °C), tR [minor
(S,R)-enantiomer] = 12.1 min, tR [major (R,S)-enantiomer] =
12.4 min), [α]D = +31.7 (c 1.0, CHCl3). H NMR (600 MHz,
CDCl3) δ 7.45–7.27 (m, 5 H), 5.70–5.66 (m, 1 H), 5.05–4.97 (m,
1 H), 2.71–2.67 (m, 2 H), 1.56 (d, J = 6.4 Hz, 3 H); 13C NMR (600
MHz, CDCl3) δ 143.9, 128.4, 127.4, 125.1, 78.6, 75.6, 36.9,
23.8; GC MS (70 eV) m/z (%) 148 (8), 107 (60), 106 (10), 105
(100), 104 (88), 103 (27), 79 (11), 78 (38), 77 (53), 51 (24), 43
(11); FT-IR (neat): 2952, 2923, 2852, 1734, 1719, 1646, 1456,
1376, 1260, 1093, 1023, 873, 799, 699 cm-1. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C10H12NaO+ 171.0786; Found
171.0783.
20
1
Dr. Giovanni Clemente, Miss Rosa Giannelli
and Mr Roberto Capobianco for their contribution to the
Experimental Section
, Miss Simona Summa,
.
Notes and references
1
(a) B. Das and K. Damodar, Epoxides and Oxetanes, in
Heterocycles in Natural Product Synthesis, eds. K. C. Majumdar
and S. K. Chattopadhyay, Wiley-VCH, Weinheim, 2011, pp 63–90;
(b) H. C. Hailes and J. M. Behrendt, Oxetanes and Oxetenes:
Monocyclic, in Comprehensive Heterocyclic Chemistry III., ed. A.
R. Katritzky, Pergamon, Oxford, 2008, vol. 2, ch. 2.05, p. 321; (c)
J. V. Crivello, J. Polym. Sci. Part A, 2007, 45, 4331–4340; (d) B.
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(2S,4S)-2-Phenyl-4-methyloxetane (4d). Colourless oil, 43%
yield (37% overall yield; 34 mg starting from 100 mg of 1d) (dr
91:9). Er (2S,4S):(2R,4R) = 97: 3 determined by GC-Chirasil-DEX
CB capillary column, (He flow 2 mL/min, 100 °C), tR [major
(S,S)-enantiomer] = 11.4 min, tR [minor (R,R)-enantiomer] =
11.8 min, [α]D = –2.51 (c 0.9, CHCl3). H NMR (600 MHz,
CDCl3) δ 7.44–7.42 (m, 2 H), 7.38–7.35 (m, 2 H), 7.30–7.27 (m,
1 H), 5.70–5.65 (m, 1 H), 5.05–4.97 (m, 1 H), 3.07–3.01 (m, 1
20
1
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