Stereoselective synthesis of enantiopure oxetanes, a carbohydrate mimic, an ε-lactone, and cyclitols from biocatalytically derived β-hydroxy esters as chiral precursors

FULL PAPER

DOI: 10.1002/ejoc.201402521

Stereoselective Synthesis of Enantiopure Oxetanes, a Carbohydrate Mimic, an

ε-Lactone, and Cyclitols from Biocatalytically Derived β-Hydroxy Esters as

Chiral Precursors

Debabrata Das,^[a]Joydev Halder,^[a]Rajib Bhuniya,^[a]and Samik Nanda*^[a]

Keywords: Synthesis design / Asymmetric synthesis / Carbocycles / Enzyme catalysis / Kinetic resolution / Biological

activity

Biocatalytically derived enantiopure α-substituted β-hydroxy

esters serve as excellent chirons for the synthesis of a diverse

set of structures such as oxetanes, a carbohydrate mimic, an

ε-lactone, and carbocyclic and aromatic cyclitols. The start-

ing materials can be easily accessed in enantiopure form

from α-substituted β-keto esters by biocatalytic reduction

with Klebsiella pneumoniae (NBRC 3319). Ring-closing

metathesis (RCM) is one of the key transformations used to

create the carbocyclic/heterocyclic frameworks reported in

this article. The synthesized cyclitols were screened for their

inhibitory effect on α- and β-glucosidases.

selectively to give only a single stereoisomer out of a pos-

sible four, in one step. There has been phenomenal growth

in the use of asymmetric bioreduction processes for the syn-

thesis of enantiopure secondary alcohols using various mi-

crobial and plant ketoreductases in the last two decades.^[5]

α-Substituted β-keto esters act as very good substrates for

several ketoreductase enzymes, and numerous literature re-

ports demonstrate the successful application of this class of

enzymes to yield β-hydroxy esters in a stereocontrolled

way.^[2]Enantiopure β-hydroxy esters are useful intermedi-

ates for the synthesis of the corresponding hydroxy acids,

aldehydes, and other useful small organic molecules.^[6]We

have earlier demonstrated that fermenting cells of Klebsiella

pneumoniae (NBRC 3319) can selectively reduce several 2-

substituted ethyl 3-oxobutyrates to give the corresponding

syn-β-hydroxy esters with remarkable stereocontrol (de Ͼ

99%, ee Ͼ 99%). The resulting α-substituted β-hydroxy

esters can then be synthetically manipulated to give cyclo-

pentane- or cyclohexane-based carbocyclic compounds.^[7]

Introduction

The enantio- and diastereoselective reduction of α-sub-

stituted β-keto esters by dynamic kinetic resolution (DKR)

can be achieved using yeast and other microorganisms, and

a few examples of this have been reported in the scientific

literature.^[1]α-Substituted β-keto esters are unique sub-

strates for the ketoreductase class of enzymes.^[2]Due to the

high kinetic acidity of the protons on the α-carbon, these

compounds are very prone to epimerization. For the biore-

duction of α-substituted β-keto esters, starting with the

enantiopure substrate is not a prerequisite for obtaining en-

antio- and diastereomerically pure products. Racemic sub-

strates can serve the purpose very well. The enzyme takes

up the reactive enantiomer into its active site, and transfers

the “hydride” in a Prelog or anti-Prelog manner, depending

on the number and kind of keto-reductases involved.^[3]The

slow-reacting enantiomer is easily epimerized (due to the

high kinetic acidity of the proton at the 2-position) to re-

form the racemic mixture, and the cycle goes on. The

requirements for a successful reduction by this DKR pro-

cess are first, that the racemization of the β-keto ester

should be faster than the bioreduction, and second, that the

product hydroxy ester is not racemized under the reaction

conditions.^[4]Thus, the bioreduction of α-substituted β-keto

esters follows a DKR pathway as shown in (Figure 1), and

the reduction proceeds enantioselectively and diastereo-

[a] Department of Chemistry, Indian Institute of Technology,

Kharagpur 721302, India

E-mail: snanda@chem.iitkgp.ernet.in

http://ww w .chemistr y .iitkgp.ac.in/~snanda/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402521.

Figure 1. Enantioselective and diastereoselective bioreduction of α-

substituted β-keto esters (dynamic kinetic resolution).

Eur. J. Org. Chem. 2014, 5229–5246

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D. Das, J. Halder, R. Bhuniya, S. Nanda

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presented in Figure 2 has three principal reaction sites: R¹

(OH group; useful for intramolecular cyclization reactions

such as lactonization and S_N2 displacement), R²(stereo-

chemically pure allyl/propargyl appendage; useful for ene–

ene/ene–yne metathesis, carbophilic activation by soft tran-

sition metals and other related reactions), and R³(–CO₂Et

group; can act as a masked –CHO or –CH₂OH group). The

three reaction sites can be synthetically manipulated at the

same time or in a mutually exclusive permutation–combina-

tion manner (i.e., with two reaction sites being manipulated

at the same time while the other site remains untouched) to

generate a diverse set of new chemical entities by adopting

a purely transformation-based strategy. Following the strat-

egy shown in Figure 2, in this article, we present the synthe-

sis of enantiopure oxetanes (R¹–R³combination), an oxe-

pane (R¹–R²combination), and new polyhydroxylated car-

bocyclic scaffolds and an ε-lactone (R²–R³combination),

starting from biocatalytically derived enantiopure α-substi-

tuted β-hydroxy esters (Scheme 2).

Results and Discussion

We have also shown that ethyl 2-acetylpent-4-enoate (1)

acts as one of the best substrates for the ketoreductase from

Klebsiella pneumoniae, as it yields the corresponding hy-

droxy ester (2) in excellent yield (yield 60 g/L; Scheme 1).

The yield has been substantially improved (1.5-fold) com-

pared to our earlier report. A subtle change in the medium

composition (CaCO₃was used at 10 g/L instead of 40 g/L

as earlier) might be responsible for the yield enhancement.

The presence of a large amount of CaCO₃in the growing

media makes the overall isolation process tedious and diffi-

cult. We assume that the product hydroxy esters become

trapped in the insoluble CaCO₃matrix, so repeated extrac-

tion with organic solvent (EtOAc) is required to isolate the

product. But a modified medium composition with a new

isolation procedure by centrifugation (to remove the cell de-

bris and insoluble inorganic salts; see Experimental Sec-

tion) enables us to obtain a better overall yield of the β-

hydroxy ester product.

Synthesis of Enantiopure Oxetanes (R¹–R²Reaction Sites)

Enantiopure oxetanes are useful building blocks, and

they are also found as essential structural components in

some biologically active natural products.^[8]We decided to

carry out the asymmetric synthesis of several oxetanes,

starting from biocatalytically derived syn-β-hydroxy esters.

For that purpose, enantiopure β-hydroxy esters 3–8 were

reduced with DIBAL-H (diisobutylaluminium hydride) to

Scheme 1. Bioreduction of ethyl 2-acetylpent-4-enoate with K.

pneumoniae.

We envisioned that the enantiopure β-hydroxy esters ob- give the corresponding 2-substituted 1,3-propane diols (i.e.,

tained from the bioreduction of several α-substituted β-keto 9–14) in excellent yields. Treatment with tosyl chloride (4-

esters with Klebsiella pneumoniae could serve as excellent toluenesulfonyl chloride) and Et₃N resulted in a regioselec-

chiral synthons for the synthesis of various carbocyclic and tive reaction of the primary hydroxy groups to give tos-

heterocyclic scaffolds, as shown in Scheme 2. The precursor ylates 15–20. The tosylates were then treated with base

Scheme 2. Klebsiella pneumoniae (NBRC 3319) mediated synthesis of various 2-substitited β-hydroxy esters and further proposed synthetic

manipulation.

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Stereoselective Synthesis of Enantiopure Oxetanes

Figure 2. Enantiopure α-substituted β-hydroxy esters as potential precursors for generating molecular diversity through a transformation-

based approach.

Scheme 3. Synthesis of enantiopure oxetanes.

(NaH in refluxing THF) to give the corresponding oxetanes Synthesis of an Enantiopure Carbohydrate Mimic (R¹–R³

(i.e., 21–26) stereospecifically (Scheme 3). The oxetanes are Reaction Sites)

fairly unstable at room temperature, so attempted purifica-

tion by silica gel chromatography resulted in decomposi-

tion. Hence, the crude oxetanes were not purified prior to ring carbohydrate mimic chose to start from enantiopure β-

characterization (¹H and ¹³C NMR spectroscopy).

hydroxy ester 2 (ee Ͼ 99%). The secondary hydroxy group

For the stereoselective synthesis of a seven-membered-

Scheme 4. Synthesis of an oxepane as a carbohydrate mimic; CSA = camphorsulfonic acid.

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in compound 2 was protected as its O-allyl ether by treat- refluxing CH₂Cl₂gave seven-membered-ring lactone 37 in

ment with allyl imidate^[9]to give compound 27 in 80% 82% yield. Finally, deprotection of the TBDPS group with

yield. Compound 27 when subjected to a ring-closing me- HF/pyridine^[14]gave enantiopure ε-lactone 38 in 78% yield

tathesis (RCM) reaction with Grubbs I catalyst^[10]at room (Scheme 5).

temperature to give the corresponding cycloheptene deriva-

tive (i.e., 28) in 65% yield. Asymmetric dihydroxylation un-

der Sharpless conditions^[11]gave compound 29 in good

yield (Scheme 4). Oxepane derivative 29, upon reduction

with DIBAL-H in CH₂Cl₂gave the corresponding hydrox-

ylated oxepane (i.e., 30) in 78% yield. This type of chiral

hydroxylated cycloheptane-based scaffold (i.e., 30) is new in

the scientific literature. So by applying a simple four-step

synthetic manipulation starting from a biocatalytically de-

rived enantiopure β-hydroxy ester, new hydroxylated scaf-

folds can be synthesized in good yield with retention of en-

antiopurity in the final product.

Synthesis of Cyclopentane/Cyclohexane Based Cyclitols

(R²–R³Reaction Sites)

A strategy combining the R²and R³reaction sites (Fig-

ure 2) was devised for the synthesis of cyclitols based on

cyclopentane and cyclohexane frameworks. Initially, alde-

hyde 32 was treated with CH₂=CHMgBr at –78 °C to give

compound 39 as the sole product. The reaction of aldehyde

2 with CH₂=CHCH₂MgBr under similar conditions was

sluggish. But aldehyde

2

reacted nicely with

CH₂=CHCH₂ZnBr to give compound 40 in 86% yield. The

stereochemical outcome of both of these reactions can be

predicted satisfactorily through a Felkin type (non-chelat-

ing conditions)^[15]model, as shown in Scheme 6. The rela-

tive stereochemistry (1,3-syn) of compounds 39 and 40 was

Synthesis of an Enantiopure ε-Lactone (R²–R³Reaction

Sites)

The synthesis started from known enantiopure β-hydroxy confirmed by the Rychnovsky method, as described above

ester 2. The free hydroxy group in compound 2 was pro- (Scheme 6). Compounds 39 and 40 were then subjected to

tected as its TBDPS (tert-butyldiphenylsilyl) ether by treat- RCM reactions with Grubbs II catalyst to give ring-closed

ment with imidazole and TBDPS-Cl to give compound 31 products 43 and 44 in 90 and 84% yields, respectively. Sub-

in 90% yield. Reduction of the ester functionality with DI- strate-directed dihydroxylation reactions with OsO₄gave

BAL-H at –78 °C gave the corresponding aldehyde (i.e., 32) stereochemically pure diols 45 and 46 as major dia-

in 82% yield. Addition of MeMgI at –78 °C to aldehyde 32 stereomers, along with 47 and 48 as minor diastereomers,

gave compound 33 as a single diastereomer. The configura- in 80–82% combined yield (Scheme 6; 45/47 = 10:1; 46/48

tion of the newly generated stereocentre was confirmed by = 12:1). The high diastereoselectivity in the dihydroxylation

the Rychnovsky method.^[12]Deprotection of the TBDPS reaction of 43 and 44 can be explained by assuming enve-

group in compound 33 gave known symmetrical diol 34 in lope and half-chair-like conformations for the compounds

88% yield.^[13]The diol functionality was then protected as in their respective ground states; the bulky OTBDPS group

its acetonide by treatment with 2,2-DMP (2,2-dimeth- effectively shields the bottom face, so dihydroxylation oc-

oxypropane) to give compound 35. Analysis by ¹³C NMR curs from the top face (Scheme 6). Removal of the TBDPS

spectroscopy revealed that the relative stereochemistry of protecting group with TBAF (tetrabutylammonium fluor-

the two hydroxy groups was syn, as shown in Scheme 5. ide) gave the corresponding cyclopentane- and cyclohexane-

Condensation of 33 with acrolyl chloride in the presence of based cyclitols (i.e., 49–52; Scheme 6) in 88% yield. Tetrols

DIPEA (diisopropylethylamine) and DMAP (4-dimethyl- 49–52 were subsequently converted to their corresponding

aminopyridine) gave acrylate 36 in 88% yield. RCM reac- tetraacetates by treatment with Et₃N and Ac₂O in order to

1

tion of compound 36 with Grubbs II catalyst (5 mol-%) in get well-resolved H NMR spectra.

Scheme 5. Synthesis of an enantiopure ε-lactone; reagents and conditions: a) imidazole, TBDPS-Cl, room temp., 8 h, 90%; b) DIBAL-

H, CH₂Cl₂, –78 °C, 2 h, 82%; c) MeMgI, –78 °C to room temp., 6 h, 90%; d) TBAF, THF, room temp., 92%; e) 2,2-DMP, CSA, room

temp., 8 h, 88%; f) CH₂=CHCOCl, DIPEA, DMAP, 88%; g) Grubbs II (5 mol-%), CH₂Cl₂, 8 h, 82%; h) HF/pyridine, 0 °C, 6 h, 78%.

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Stereoselective Synthesis of Enantiopure Oxetanes

Scheme 6. Synthesis of cyclitols based on cyclopentane/cyclohexane frameworks; reagents and conditions: a) (i) TBAF, THF, room temp.,

6 h; (ii) 2,2-DMP, PPTS (pyridine p-toluenesulfonate), room temp., 8 h; b) Grubbs I (5 mol-%), room temp., 12 h, 84–90%; c) OsO₄,

NMO (N-methylmorpholine N-oxide), THF/H₂O (3:1), 80–82%; d) TBAF, THF, room temp., 2 h, 88–90%.

Synthesis of Aromatic Cyclitols (R²–R³Reaction Sites)

extra aromatic ring, could have interesting properties such

as stacking properties and enhanced lipophilicity.^[17]We en-

Aryl cyclitols are structural analogues of conduritols Ϫ visioned that our biocatalytically derived enantiopure β-

which can be regarded as locked cyclitols Ϫ in which the hydroxy ester might act as an excellent precursor for such

ring double bond is replaced by an aromatic ring. The quest aromatic cyclitols, as shown in Scheme 7.

for new analogues of conduritols has mainly been focussed

We started our synthesis from ethyl acetoacetate, which

on ring modification and side-chain variation (Scheme 7). was alkylated with 1-(bromomethyl)-2-vinylbenzene in the

Aryl cyclitols are such analogues generated by ring modifi- presence of KOtBu to give substituted β-keto ester 53 in

cation.^[16]Many unnatural synthetic analogues with the ba- 80% yield. Bioreduction of this β-keto ester with growing

sic core structural units of conduritols have been synthe- cells of K. pneumoniae gave the corresponding β-hydroxy

sized. Aryl cyclitols, bicyclic mimics of conduritols with an ester (i.e., 54) as the sole product in 76% yield (ee Ͼ 99%,

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D. Das, J. Halder, R. Bhuniya, S. Nanda

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Scheme 7. Retrosynthetic analysis of an enantiopure aromatic cyclitol to start from a β-keto ester.

and de Ͼ 99%). The secondary hydroxy group was pro- Ph₃P=CH₂gave olefinic compound 57 in 70% yield. Ring-

tected as its TBDPS ether by treatment with imidazole and closing metathesis was then attempted on compound 57

TBDPS-Cl to give compound 55 in 88% yield. The ester using Grubbs II catalyst^[18]and CH₂Cl₂as a solvent. This

functionality in compound 55 was then partially reduced went smoothly, and after 12 h at room temperature the cor-

with DIBAL-H at –78 °C to give the corresponding responding ring-closed product (i.e., 58) was formed in 78%

aldehyde (i.e., 56) in 82% yield. Wittig olefination with yield. Substrate-directed dihydroxylation^[19]with OsO₄gave

Scheme 8. Synthesis of an aromatic cyclitol; reagents and conditions: a) KOtBu, THF, reflux, 12 h, 80%; b) K. pneumoniae, 5 d incubation,

76%; c) imidazole, TBDPS-Cl, 6 h, 88%; d) DIBAL-H, –78 °C, 82%; e) PH₃P⁺MeI^–, LHMDS (lithium hexamethyldisilazide), –78 °C,

70%; f) Grubbs II (5 mol-%), CH₂Cl₂, room temp., 12 h, 78%; g) OsO₄, NMO, THF/water (3:1), 24 h, 70%; h) TBAF, THF, room temp.,

6 h, 90%.

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Stereoselective Synthesis of Enantiopure Oxetanes

diol 59 as the major diastereomer in 70% yield. Subsequent started from the biocatalytically derived known aldehyde

removal of the TBDPS group with TBAF in THF gave 32. Addition of the Grignard reagent generated from 2-

enantiopure aromatic cyclitol 60 in 90% yield (Scheme 8). vinyl-1-bromobenzene to aldehyde 32 at –78 °C gave the

Triol 60 was subsequently converted into its triacetate by stereotriad 61/62 with excellent diastereoselectivity (15:1;

treatment with Et₃N and Ac₂O to obtain a well-resolved Scheme 9). The stereochemistry in 61/62 was confirmed by

¹H NMR spectrum. The structure of triol 60 was confirmed the Rychnovsky protocol by preparing the corresponding

by X-ray crystal analysis of the corresponding triacetate de- acetonide (i.e., 68/70). A ring-closing metathesis reaction

rivative. The ORTEP presentation of the triacetate deriva- was then attempted with the major diastereomer (i.e., 61),

tive of 60 is shown in Scheme 8.

but this did not give any ring-closed product after repeated

attempts with Grubbs I and Grubbs II catalysts. However,

ring-closing metathesis with the Hoveyda–Grubbs II cata-

lyst^[20](10 mol-%) was successful, and gave cycloheptane

scaffold 63 in 82% yield. Subsequent deprotection of the

Synthesis of Aromatic Cyclitols with a Cycloheptane Ring

(R²–R³Reaction Sites)

We went on to synthesize an enantiopure aromatic cycli- TBDPS group with TBAF gave enantiopure diol 64 in 89%

tol containing a cycloheptane ring. The synthesis was yield. Dihydroxylation of compound 63 with OsO₄/NMO

Scheme 9. Synthesis of cycloheptane-ring-containing aromatic cyclitol; reagents and conditions: a) Et₂O, –78 °C to room temp., 6 h, 80%;

b) Hoveyda–Grubbs II (10 mol-%), CH₂Cl₂, reflux, 8 h, 88%; c) TBAF, THF, room temp., 6 h, 89%; d) (i) OsO₄, NMO, THF/water (3:1),

24 h, 70%; (ii) TBAF, THF, room temp., 8 h, 82%; e) same as (c), 86%; f) 2,2-DMP, PPTS, room temp., 12 h, 90%.

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D. Das, J. Halder, R. Bhuniya, S. Nanda

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gave triol 65 in 70% yield, which, after TBDPS-group de- steres, five-membered iminocyclitols have also been found

protection gave tetrol 66 (57% yield over two steps; to inhibit glycosidases.^[23]This has prompted a huge invest-

Scheme 9). The high diastereoselectivity in the dihydrox- ment of research into the synthesis and screening of cyclitol

ylation reaction of 63 can be explained as shown in libraries.

Scheme 9, by assuming a chair–boat-like conformation for

We carried out glycosidase (α-glucosidase and β-glucos-

the cycloheptene core. Tetrol 66 was subsequently converted idase) inhibition studies for all the cyclitols whose synthesis

to its tetraacetate by treatment with Et₃N and Ac₂O to ob- is reported in this article (i.e., 49–52, 60 and 66), using the

1

tain a well-resolved H NMR spectrum.

corresponding para-nitrophenyl glucosides as substrates.

The results are summarized in Table 1. Cyclitol 52, based

on a cyclohexane framework, seems to show the best inhibi-

tion of both α- and β-glucosidases. The inhibition rates

found were 53.0Ϯ2% (for α) and 59.0Ϯ1.6% (for β) for a

10 μm concentration of compound 52. Cyclopentane-based

cyclitol 51 showed moderate inhibition of both α- and β-

glucosidases (the respective inhibition rates were

36.0Ϯ2.5% and 30.0Ϯ1.8% for a 10 μm concentration of

the inhibitor). Compounds 49 and 50 (with similar stereo-

chemical substitution patterns) showed low inhibitory ac-

tivities against both α- and β-glucosidases at a 10 μm inhibi-

tor concentration. Although the synthesized cyclitols show

good inhibitory activities against glucosidases, their activi-

ties are substantially lower than clinically used anti-diabetic

Glycosidase Inhibition Study

Glycosidase inhibition is an important pharmaceutical

goal, as proved by current treatments for influenza

(Tamiflu) and non-insulin-dependent diabetes (Miglitol/

Glyset).^[21]Iminocyclitols and other designed analogues

(also often called azasugars or iminosugars) are particularly

well-studied glycosidase inhibitors that have shown tremen-

dous potential for the treatment of cancer, glycosphingoli-

pid storage disorders, and viral diseases such as HIV and

hepatitis B and C.^[22]Their efficacy has mainly been attrib-

uted to their structural mimicry of the glycosidase “oxo-

carbenium-ion-like” transition state and the special electro-

static binding interactions at the glycosidase active site.

Interestingly, as well as the six-membered pyranoside iso-

drugs like miglitol (IC₅₀= 1.3 μm), voglibose (IC₅₀

=

0.11 μm), and acarbose (IC₅₀= 0.35 μm),^[24]all of which are

potent α-glucosidase inhibitors. The inhibitory activity of

the synthesized cyclitols can be attributed to their mimick-

ing of the structure of a “strained activated complex”^[25]

(transition-state analogue) involved in glycoside hydrolysis.

Table 1. Inhibition of glycosidases by cyclitols 49–52, 60, and 66.

Conclusion

In conclusion, we can claim that biocatalytically derived

enantiopure α-substituted β-hydroxy esters act as excellent

precursors for the synthesis of stereochemically pure

carbocycles and heterocycles. In the majority of cases, we

have shown that RCM reactions can be successfully used

for the construction of core carbocyclic frameworks from

linear precursors using a distinctive transformation-based

strategy. Once the cyclic scaffold is created, new function-

ality can be introduced by several stereoselective reactions,

such as the substrate-directed dihydroxylation reaction de-

scribed in this paper. The creation of further molecular di-

versity from biocatalytically synthesized enantiopure α-sub-

stituted β-hydroxy esters is currently in progress, and the

results will be reported in due course. The synthesized cycli-

tols were tested for their inhibitory activity against glycosid-

ases, and moderate to good inhibition was found.

It is also noteworthy that fermenting cells of Klebsiella

pneumoniae (NBRC 3319) accept α-substituted acetoacet-

ates (bearing a terminal Me group) as their main substrate,

and that they produce the corresponding hydroxy esters.

Our initial screening of other substrates (without the ter-

minal Me group) was not very encouraging. But we need

to screen various α-substituted β-keto esters (without a ter-

minal Me group) to have a better understanding of the sub-

strate spectrum of the ketoreductase from Klebsiella

pneumoniae.

[a] α-glucosidase from yeast; The inhibitor concentration was

10 μm. [b] β-glucosidase from sweet almonds; The inhibitor concen-

tration was 10 μm. [c] Concentration required for 50% inhibition of

enzyme activity under the assay conditions. [d] Experiments were

performed at four different concentrations for each compound.

Each experiment was performed in triplicate. [e] n.i.: no inhibition

(the compound was added in the concentration range of 10–

100 μm). [f] For compound 66, the inhibitor concentration was

50 μm. n.d.: not determined.

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Stereoselective Synthesis of Enantiopure Oxetanes

(2S,3S)-2-Isobutylbutane-1,3-diol (11): R_f= 0.25 (EtOAc/hexane,

Experimental Section

1

1:1). [α]²_D⁹= –23.7 (c = 1.1, MeOH). H NMR (200 MHz, CDCl₃):

General Information: Unless otherwise stated, materials were ob-

tained from commercial suppliers and used without further purifi-

cation. THF and diethyl ether were distilled from sodium benzo-

phenone ketyl. Dimethylformamide (DMF) and dimethyl sulfoxide

(DMSO) were distilled from CaH₂. Klebsiella pneumoniae (NBRC

3319; microbial ketoreductase strain form) was obtained from

NBRC, Japan. The microorganism is safely handled in a biosafety

level 2 enviornment (BSL-2). Bioreductions were carried out in an

incubator shaker at 35 °C. Reactions were monitored by thin-layer

chromatography (TLC) on 0.25 mm silica gel plates (Merck), which

were visualized with UV light, and using ethanolic anisaldehyde

and phosphomolybdic acid/heat as developing agents. Silica gel

100–200 mesh was used for column chromatography, yields refer to

chromatographically and spectroscopically homogeneous materials,

unless otherwise stated. Proton nuclear magnetic resonance (¹H

NMR) and carbon nuclear magnetic resonance (¹³C NMR) spectra

were acquired in CDCl₃, unless otherwise stated. Chemical shifts

are reported in parts per million (ppm, δ), downfield from tetra-

methylsilane (δ = 0.00 ppm), and are referenced to residual solvent

[CDCl₃, δ = 7.26 ppm (¹H) and 77.16 ppm (¹³C)]. Coupling con-

stants (J) are reported in Hertz (Hz). Optical rotations were mea-

sured with a JASCO P1020 digital polarimeter. HPLC analysis was

performed with a CHIRALPAK AD-H (Daicel) column using a

UV/Vis detector and a Shimadzu prominence system. Mass spec-

trometric analysis was performed at the CRF, IIT-Kharagpur (TOF

analyser). CCDC-988087 contains the supplementary crystallo-

graphic data for this paper. These data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

δ = 4.09–4.03 (m, 1 H), 3.79–3.64 (m, 2 H), 3.38 (br., 2 H, OH),

1.82–1.78 (m, 1 H), 1.16 (d, J = 6.4 Hz, 3 H), 1.10–0.98 (m, 2 H),

0.89 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 70.9, 64.2, 42.3, 35.1, 25.4, 23.1, 22.0,

18.3 ppm. HRMS (ESI): calcd. for C₈H₁₈O₂Na [M + Na]⁺

169.1204; found 169.1208.

(2S,3S)-2-(4-Methoxybenzyl)butane-1,3-diol (12): R_f

=

0.15

(EtOAc/hexane, 1:1). [α]²_D⁹= +15.4 (c = 1.1, MeOH). ¹H NMR

(200 MHz, CDCl₃): δ = 7.04 (d, J = 8.4 Hz, 2 H), 6.77 (d, J =

8.4 Hz, 2 H), 4.12–3.86 (m, 1 H), 3.71 (s, 3 H), 3.64–3.44 (m, 2 H),

2.64–2.37 (m, 2 H), 1.89–1.79 (m, 1 H), 1.19 (d, J = 6.2 Hz, 3 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 157.8, 132.4, 129.9, 113.8,

70.1, 63.3, 55.2, 47.3, 31.3, 19.1 ppm. HRMS (ESI): calcd. for

C₁₂H₁₈O₃Na [M + Na]⁺233.1154; found 233.1151.

(2S,3S)-2-(But-3-enyl)butane-1,3-diol (13): R_f= 0.15 (EtOAc/hex-

ane, 1:1). [α]²_D⁹= –17.1 (c = 1.1, MeOH). ¹H NMR (200 MHz,

CDCl₃): δ = 5.90–5.69 (m, 1 H), 5.08–4.95 (m, 2 H), 4.14–4.03 (m,

1 H), 3.85–3.68 (m, 2 H), 2.81 (br., 2 H, OH), 2.18–2.01 (m, 2 H),

1.77–1.69 (m, 1 H), 1.42–1.31 (m, 2 H), 1.21 (d, J = 6.4 Hz, 3 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 138.4, 114.9, 71.1, 64.2,

44.3, 31.7, 25.0, 18.9 ppm. HRMS (ESI): calcd. for C₈H₁₆O₂Na [M

+ Na]⁺167.1048; found 167.1051.

(2S,3S)-2-(Pent-4-enyl)butane-1,3-diol (14): R_f= 0.15 (EtOAc/hex-

ane, 1:1). [α]²_D⁹= –7.2 (c = 1.1, MeOH). ¹H NMR (200 MHz,

CDCl₃): δ = 5.88–5.68 (m, 1 H), 5.02–4.91 (m, 2 H), 4.12–4.03 (m,

1 H), 3.92–3.67 (m, 2 H), 3.31 (br., 2 H, OH), 2.06–1.98 (m, 2 H),

1.76–1.68 (m, 1 H), 1.58–1.24 (m, 4 H), 1.18 (d, J = 6.4 Hz, 3 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 138.6, 114.7, 71.0, 64.2,

44.9, 33.9, 26.9, 25.5, 18.7 ppm. HRMS (ESI): calcd. for

C₉H₁₈O₂Na [M + Na]⁺181.1204; found 181.1209.

General Procedure for Bioreduction: NBRC-3319 mediated biored-

uction of several α-substituted β-keto esters for the synthesis of

compounds 3–8 is reported in our earlier article.^[7]

Typical Procedure for the Selective Tosylation of the Primary

Hydroxy Group, Synthesis of 15: Compound 9 (56 mg, 0.384 mmol)

was dissolved in anhydrous CH₂Cl₂(3 mL). Triethylamine

(0.045 mL, 0.384 mmol) was added at 0 °C, and the reaction mix-

ture was then stirred for 15 min at the same temperature. After that

time, p-toluenesulfonyl chloride (74 mg, 0.384 mmol) was added,

and the reaction mixture was stirred for a further 1 h at room tem-

perature. After TLC indicated that the reaction was complete, water

was added, and the organic layer was washed with excess water and

brine. The organic layer was dried (MgSO₄), and the solvents were

evaporated to dryness. The residue was then purified by flash

chromatography (EtOAc/hexane, 1:5) to give compound 15

(101 mg, 88%) as a colourless liquid.

Typical Procedure for the Reduction of Esters to Alcohols Using

DIBAL-H, Synthesis of 9: Compound 3 (80 mg, 0.426 mmol) was

dissolved in dry THF (3 mL), and the solution was cooled to

–78 °C. A solution of DIBAL-H (1 m in cyclohexane; 1 mL,

1 mmol) was added over 15 min. The reaction mixture was stirred

for a further 2 h at the same temperature, and then it was warmed

to room temperature. After that, the reaction mixture was

quenched with dry methanol, and stirred for a further 1.5 h. Then

the mixture was filtered through a pad of Celite to remove the solid

residues. The filtrate was concentrated, and the resulting residue

was dissolved in EtOAc. The organic phase was then washed with

brine, and dried with MgSO₄. The organic phase was evaporated,

and the residue was purified by flash chromatography (EtOAc/hex-

ane, 1:3) to give compound 9 (60 mg, 96%) as a colourless liquid.

(S)-2-[(S)-1-Hydroxyethyl]hexyl 4-Methylbenzenesulfonate (15): R_f

= 0.5 (EtOAc/hexane, 1:3). [α]²_D⁹= –7.5 (c = 1.5, MeOH). ¹H NMR

(200 MHz, CDCl₃): δ = 7.75 (d, J = 8.4 Hz, 2 H), 7.31 (d, J =

8.0 Hz, 2 H), 4.09–3.94 (m, 2 H), 3.91–3.83 (m, 1 H), 2.41 (s, 3 H),

1.64–1.59 (m, 1 H), 1.34–1.07 (m, 12 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 144.9, 132.8, 129.9, 127.9, 70.6, 67.2, 44.4, 29.5, 25.3,

22.8, 21.6, 20.1, 13.9 ppm. HRMS (ESI): calcd. for C₁₅H₂₄O₄SNa

[M + Na]⁺323.1293; found 323.1297.

(2S,3S)-2-Butylbutane-1,3-diol (9): R_f= 0.2 (EtOAc/hexane, 1:1).

[α]²_D⁹= –13.2 (c = 1.1, MeOH). H NMR (200 MHz, CDCl₃): δ =

1

4.08–4.00 (m, 1 H), 3.82–3.65 (m, 2 H), 3.00 (br., 2 H, OH), 1.79–

1.65 (m, 1 H), 1.31–1.17 (m, 12 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 71.3, 64.4, 45.1, 30.1, 26.0, 23.1, 18.8, 14.2 ppm.

HRMS (ESI): calcd. for C₈H₁₈O₂Na [M + Na]⁺169.1204; found

169.1208.

(S)-2-[(S)-1-Hydroxyethyl]octyl 4-Methylbenzenesulfonate (16): R_f

(2S,3S)-2-Hexylbutane-1,3-diol (10): R_f= 0.2 (EtOAc/hexane, 1:1). = 0.5 (EtOAc/hexane, 1:3). [α]²_D⁹= –4.6 (c = 1.1, MeOH). ¹H NMR

[α]²_D⁹= –6.8 (c = 1.1, MeOH). ¹H NMR (200 MHz, CDCl₃): δ =

(200 MHz, CDCl₃): δ = 7.79 (d, J = 7.6 Hz, 2 H), 7.35 (d, J =

4.09–4.05 (m, 1 H), 3.84–3.67 (m, 2 H), 2.89 (br., 2 H, OH), 1.73–

7.8 Hz, 2 H), 4.13–3.98 (m, 2 H), 3.95–3.87 (m, 1 H), 2.45 (s, 3 H),

1.54 (m, 3 H), 1.38–1.18 (m, 14 H) ppm. ¹³C NMR (50 MHz, 1.67–1.61 (m, 2 H), 1.25–1.11 (m, 15 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 71.5, 64.6, 45.3, 32.0, 29.94, 27.94, 26.38, 22.89, 18.97,

14.33 ppm. HRMS (ESI): calcd. for C₁₀H₂₂O₂Na [M + Na]⁺

197.1517; found 197.1515.

CDCl₃): δ = 144.8, 132.9, 129.9, 127.9, 70.6, 67.3, 44.4, 31.7, 29.4,

27.3, 25.7, 22.6, 21.6, 20.1, 14.0 ppm. HRMS (ESI): calcd. for

C₁₇H₂₈O₄SNa [M + Na]⁺351.1606; found 351.1606.

Eur. J. Org. Chem. 2014, 5229–5246

www.eurjoc.org

5237

D. Das, J. Halder, R. Bhuniya, S. Nanda

FULL PAPER

(S)-2-[(S)-1-Hydroxyethyl]-4-methylpentyl 4-Methylbenzenesulfon-

(dd, J = 7.7, 1.5 Hz, 1 H), 4.24 (t, J = 6.2 Hz, 1 H), 3.02–2.93 (m,

1 H), 1.60–1.14 (m, 11 H + grease) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 81.6, 75.3, 37.6, 31.9, 27.1, 22.7, 22.5, 14.1 ppm.

ate (17): R_f= 0.4 (EtOAc/hexane, 1:3). [α]²_D⁹= –16.5 (c = 1.4,

1

MeOH). H NMR (200 MHz, CDCl₃): δ = 7.75 (d, J = 8.4 Hz, 2

H), 7.31 (d, J = 8.0 Hz, 2 H), 4.09–3.86 (m, 3 H), 2.46 (s, 3 H),

1.81–1.65 (m, 2 H), 1.49–1.29 (m, 1 H), 1.08 (d, J = 6.4 Hz, 3 H),

0.80 (d, J = 6.6 Hz, 3 H), 0.77 (d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 144.9, 132.9, 129.9, 127.9, 70.7, 67.1, 41.9,

34.5, 15.6, 23.3, 21.9, 21.6, 19.9 ppm. HRMS (ESI): calcd. for

C₁₅H₂₄O₄SNa [M + Na]⁺323.1293; found 323.1297.

(2S,3S)-3-(4-Methoxybenzyl)-2-methyloxetane (24): R_f

=

0.4

(EtOAc/hexane, 1:15). ¹H NMR (200 MHz, CDCl₃): δ = 6.99 (d, J

= 8.4 Hz, 2 H), 6.77 (d, J = 8.4 Hz, 2 H), 5.13–5.0 (m, 1 H), 4.64

(dd, J = 7.4, 1.2 Hz, 1 H), 4.25 (t, J = 6.3 Hz, 1 H), 3.72 (s, 3 H),

2.84 (d, J = 8.2 Hz, 2 H), 1.33 (d, J = 6.4 Hz, 3 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 158.0, 131.5, 129.2, 113.9, 81.1, 74.1, 55.1,

38.6, 33.5, 17.8 ppm.

(S)-2-[(S)-1-Hydroxyethyl]-2-(4-methoxybenzyl)

4-Methylbenz-

enesulfonate (18): R_f= 0.35 (EtOAc/hexane, 1:3). [α]²_D⁹= +9.5 (c =

0.9, MeOH). ¹H NMR (200 MHz, CDCl₃): δ = 7.68 (d, J = 8.4 Hz,

2 H), 7.29 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 6.69 (d,

J = 8.4 Hz, 2 H), 4.16–3.79 (m, 3 H), 3.71 (s, 3 H), 2.81–2.50 (m,

2 H), 2.46 (s, 3 H), 1.89–1.79 (m, 1 H), 1.15 (d, J = 6.2 Hz, 3 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 158.0, 144.9, 132.7, 131.3,

129.9, 127.9, 113.9, 69.7, 66.8, 55.2, 46.9, 31.2, 21.7, 20.5 ppm.

HRMS (ESI): calcd. for C₁₉H₂₄O₅SNa [M + Na]⁺387.1242; found

387.1238.

(2S,3S)-3-(But-3-enyl)-2-methyloxetane (25): R_f= 0.72 (EtOAc/hex-

ane, 1:15). H NMR (200 MHz, CDCl₃): δ = 5.88–5.67 (m, 1 H),

5.11–4.94 (m, 3 H), 4.72 (dd, J = 7.6, 1.8 Hz, 1 H), 4.24 (t, J =

5.2 Hz, 1 H), 3.02–2.84 (m, 1 H), 2.01–1.91 (m, 2 H), 1.67–1.24 (m,

5 H + grease) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 138.2, 115.2,

81.4, 74.9, 37.3, 32.1, 22.9, 14.3 ppm.

1

(2S,3S)-2-Methyl-3-(pent-4-enyl)oxetane (26): R_f= 0.75 (EtOAc/

hexane, 1:15). ¹H NMR (200 MHz, CDCl₃): δ = 5.85–5.68 (m, 1

H), 5.10–4.93 (m, 3 H), 4.72 (dd, J = 7.6, 1.8 Hz, 1 H), 4.21 (t, J

= 6.0 Hz, 1 H), 2.94–2.83 (m, 1 H), 2.09–1.99 (m, 2 H), 1.67–1.56

(m, 5 H), 1.32–1.25 (m, 2 H + grease) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 138.4, 114.7, 81.3, 74.7, 37.5, 33.7, 26.6, 22.7,

17.6 ppm.

(S)-2-[(S)-1-Hydroxyethyl]hex-5-enyl

4-Methylbenzenesulfonate

(19): R_f= 0.4 (EtOAc/hexane, 1:3). [α]²_D⁹= –12.4 (c = 1.0, MeOH).

¹H NMR (200 MHz, CDCl₃): δ = 7.79 (d, J = 8.0 Hz, 2 H), 7.35

(d, J = 8.0 Hz, 2 H), 5.80–5.60 (m, 1 H), 4.99–4.91 (m, 2 H), 4.14–

3.91 (m, 3 H), 2.45 (s, 3 H), 2.1–1.94 (m, 2 H), 1.68–1.55 (m, 3 H),

1.13 (d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

144.9, 137.9, 132.9, 129.9, 127.9, 115.2, 70.3, 67.2, 43.6, 31.4, 24.8,

21.6, 20.2 ppm. HRMS (ESI): calcd. for C₁₅H₂₂O₄SNa [M + Na]⁺

321.1136; found 321.1141.

(R)-Ethyl 2-[(S)-1-(Allyloxy)ethyl]pent-4-enoate (27): A solution of

allyl alcohol (0.34 mL, 5 mmol) in anhydrous diethyl ether (10 mL)

was added dropwise to a suspension of NaH (60% in oil; 12 mg,

0.5 mmol) in diethyl ether (10 mL) at room temperature under a

nitrogen atmosphere. The resulting mixture was stirred at room

temperature for 20 min, and then cooled to 0 °C. Trichloroaceto-

nitrile (TCA, 0.67 mL, 5 mmol) was added dropwise over 5 min,

and the reaction mixture was warmed slowly to room temperature

over 1 h. The solution was evaporated to give an orange syrup, to

which anhydrous hexane (10 mL) containing a few drops of MeOH

was then added. The resulting suspension was then shaken vigor-

ously and filtered through Celite, and the filtrate was concentrated

to give the crude imidate.

(S)-2-[(S)-1-Hydroxyethyl]hept-6-enyl

4-Methylbenzenesulfonate

(20): R_f= 0.4 (EtOAc/hexane, 1:3). [α]²_D⁹= –7.1 (c = 0.8, MeOH).

¹H NMR (200 MHz, CDCl₃): δ = 7.77 (d, J = 8.0 Hz, 2 H), 7.33

(d, J = 8.0 Hz, 2 H), 5.81–5.61 (m, 1 H), 4.98–4.89 (m, 2 H), 4.23–

3.74 (m, 3 H), 2.43 (s, 3 H), 2.02–1.93 (m, 3 H), 1.65–1.53 (m, 2

H), 1.48–1.41 (m, 2 H), 1.03 (d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 144.0, 138.3, 132.8, 129.9, 127.9, 114.8, 70.5,

67.2, 44.3, 33.8, 26.6, 25.2, 21.7, 20.1 ppm. HRMS (ESI): calcd. for

C₁₆H₂₄O₄SNa [M + Na]⁺335.1293; found 335.1298.

Typical Procedure for Oxetane Synthesis, Synthesis of 21: Sodium

hydride (60% suspension in mineral oil; 12 mg, 0.266 mmol) was

dissolved in anhydrous THF (1 mL), then tosylate compound 15

(80 mg, 0.266 mmol) was added at room temperature. The resulting

reaction mixture was then heated at reflux for 1 h. After that time,

water was added at 0 °C and the reaction mixture was extracted

with Et₂O. The organic layer was successively washed with

NaHCO₃solution and brine, and then dried (MgSO₄). The organic

extract was evaporated in vacuo to give crude oxetane compound

21 as a colourless liquid. The oxetane compounds were then char-

acterized without further purification as they tend to decompose

during flash chromatography.

The crude imidate was dissolved in cyclohexane (14 mL), and a

solution of alcohol 2 (435 mg, 2.53 mmol) in CH₂Cl₂(7 mL) was

added. The resulting solution was cooled to 0 °C, and CSA (58 mg,

0.25 mmol) was added. The reaction mixture was stirred for 3 d at

room temperature, and a white precipitate of trichloroacetamide

developed slowly. The precipitate was removed by filtration, and

washed with CH₂Cl₂. The filtrate was washed with NaHCO₃solu-

tion, water, and brine. The organic phase was evaporated in vacuo,

and the residue was purified by flash chromatography (EtOAc/hex-

ane, 1:100) to give compound 27 (428 mg, 80%) as a colourless

liquid. R_f= 0.5 (EtOAc/hexane, 1:40). [α]²_D⁵= +7.25 (c = 1.2,

MeOH). ¹H NMR (200 MHz, CDCl₃): δ = 5.96–5.65 (m, 2 H),

5.30–4.92 (m, 4 H), 4.19–3.84 (m, 4 H), 3.74–3.57 (m, 1 H), 2.63–

2.25 (m, 3 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.17 (d, J = 6.2 Hz, 3 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 135.5, 134.9, 116.7,

116.4, 75.1, 69.9, 60.2, 51.6, 33.1, 17.5, 14.2 ppm. HRMS (ESI):

calcd. for C₁₂H₂₀O₃Na [M + Na]⁺235.1342; found 235.1338.

(2S,3S)-3-Butyl-2-methyloxetane (21): R_f= 0.7 (EtOAc/hexane,

1

1:15). H NMR (200 MHz, CDCl₃): δ = 5.11–4.98 (m, 1 H), 4.73

(dd, J = 7.6, 1.8 Hz, 1 H), 4.19 (t, J = 6.0 Hz, 1 H), 2.97–2.83 (m,

1 H), 1.66–1.24 (m, 12 H + grease) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 81.4, 74.8, 37.0, 31.9, 30.2, 27.0, 22.6, 14.0 ppm.

(2S,3S)-3-Hexyl-2-methyloxetane (22): R_f= 0.7 (EtOAc/hexane,

1:15). H NMR (400 MHz, CDCl₃): δ = 5.05–5.02 (m, 1 H), 4.72

(dd, J = 7.6, 1.6 Hz, 1 H), 4.18 (t, J = 6.0 Hz, 1 H), 2.90–2.85 (m,

1 H), 1.85–1.56 (m, 4 H), 1.32–1.21 (m, 12 H + grease) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 81.3, 74.8, 37.6, 31.7, 29.3, 28.5,

27.2, 22.5, 17.6, 14.0 ppm.

Ethyl (Z,2S,3R)-2,3,4,7-Tetrahydro-2-methyloxepine-3-carboxylate

(28): Compound 27 (350 mg, 1.651 mmol) was dissolved in anhy-

drous degassed CH₂Cl₂(200 mL). Grubbs first generation metathe-

sis catalyst (Grubbs I; 132 mg, 0.165 mmol) was then added, and

the solution was stirred at room temperature for 3 h. The solvent

was then evaporated, and the contents of the flask were loaded

directly onto a silica gel column. The residue was purified by flash

1

(2S,3S)-3-Isobutyl-2-methyloxetane (23): R_f= 0.6 (EtOAc/hexane,

1:15). ¹H NMR (200 MHz, CDCl₃): δ = 5.08–5.0 (m, 1 H), 4.74 chromatography (EtOAc/hexane, 1:30) to give compound 28

5238

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5229–5246

Stereoselective Synthesis of Enantiopure Oxetanes

(197 mg, 65%) as a colourless liquid. R_f= 0.4 (EtOAc/hexane,

1:40). [α]²_D⁹= +36.82 (c = 0.8, MeOH). ¹H NMR (200 MHz,

9.302 mmol) in dry CH₂Cl₂(40 mL) at 0 °C. The mixture was

stirred at room temperature for 6 h. After the reaction was com-

CDCl₃): δ = 5.77–5.53 (m, 2 H), 4.27–3.99 (m, 5 H), 2.66–2.21 (m, plete, water was added, and the mixture was extracted with CH₂Cl₂

3 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.12 (d, J = 6.4 Hz, 3 H) ppm. ¹³C (2ϫ). The combined organic extracts were dried with anhydrous

NMR (50 MHz, CDCl₃): δ = 172.7, 129.7, 129.5, 75.2, 67.2, 60.6,

MgSO₄, and evaporated in vacuo. The crude product was then

49.2, 25.1, 17.3, 14.4 ppm. HRMS (ESI): calcd. for C₁₀H₁₆O₃Na purified by flash chromatography (EtOAc/hexane, 1:20) to give

[M + Na]⁺207.0972; found 207.0988.

compound 31 (3.432 g, 90%) as a viscous liquid. R_f= 0.6 (EtOAc/

hexane, 1:10). [α]²_D⁵= –9.04 (c = 1.2, CHCl₃). ¹H NMR (200 MHz,

CDCl₃): δ = 7.76–7.69 (m, 4 H), 7.49–7.35 (m, 6 H), 5.78–5.61 (m,

1 H), 5.08–4.94 (m, 2 H), 4.19–4.04 (m, 3 H), 2.66–2.55 (m, 1 H),

2.37 (t, J = 6.6 Hz, 2 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.08 (12 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 173.7, 136.1, 136.0, 134.6,

133.9, 129.9, 129.8, 127.8, 127.7, 116.5, 70.6, 60.3, 53.4, 33.0, 27.1,

20.8, 19.5, 14.4 ppm. HRMS (ESI): calcd. for C₂₅H₃₂O₃SiNa [M +

Na]⁺433.2175; found 433.2199.

Ethyl (2S,3R,5S,6R)-5,6-Dihydroxy-2-methyloxepane-3-carboxylate

(29): tBuOH (0.2 mL), H₂O (0.2 mL), and AD-mix-β (87 mg) were

mixed, and the mixture was stirred for 15 min. MeSO₂NH₂(20 mg)

was then added, and stirring was continued for a further 15 min.

Compound 28 (120 mg, 0.652 mmol) was then added in one por-

tion. The slurry was then stirred vigorously at 20 °C for 24 h. After

that time, sodium sulfite (25 mg) was added, and stirring was con-

tinued for a further 1 h. The reaction mixture was then extracted

with EtOAc. The organic layer was dried (MgSO₄), and the sol-

vents were evaporated in vacuo. The crude diol was purified by

flash chromatography (EtOAc/hexane, 1:5) to give streochemically

pure diol 29 (102 mg, 72%) as a colourless liquid. R_f= 0.3 (EtOAc/

hexane, 1:3). [α]²_D⁹= +21.73 (c = 1.2, MeOH). ¹H NMR (200 MHz,

CDCl₃): δ = 4.30–4.09 (m, 2 H), 3.98–3.79 (m, 4 H), 3.65–3.54 (m,

1 H), 2.62–2.21 (m, 3 H), 1.25 (t, J = 7.4 Hz, 3 H), 1.11 (d, J =

6.8 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 172.4, 77.0,

72.2, 70.1, 68.8, 61.2, 48.9, 24.8.17.6, 14.3 ppm.

(R)-2-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]pent-4-enal

(32):

TBDPS-protected β-hydroxy ester 31 (3.737 g, 9.116 mmol) was

dissolved in dry CH₂Cl₂(37 mL), and DIBAL-H solution (1 m in

toluene; 9.11 mL, 9.11 mmol) was added at –10 °C. The mixture

was stirred for 4 h at –10 °C. After that time, the reaction was

quenched by the addition of a saturated solution of sodium potas-

sium tartrate. The mixture was then filtered through a pad of Celite,

and the filtrate was extracted several times with CH₂Cl₂. The com-

bined CH₂Cl₂extracts were then evaporated under vacuum, and

the crude aldehyde was purified by flash chromatography (EtOAc/

hexane, 1:10) to give pure 32 (2.736 g, 82%) as a colourless liquid.

(3R,4S,6S,7S)-6-(Hydroxymethyl)-7-methyloxepane-3,4-diol (30):

Oxepane ester 29 (102 mg, 0.47 mmol) was dissolved in dry CH₂Cl₂

(37 mL) and DIBAL-H solution (1 m in toluene; 1.0 mL, 1.0 mmol)

was added at –10 °C. The reaction mixture was stirred for 4 h at

0 °C. After that time, the reaction was quenched by the addition

of a saturated solution of sodium potassium tartrate. The mixture

was then filtered through a pad of Celite, and then extracted several

times with CH₂Cl₂. The combined CH₂Cl₂extracts were then evap-

orated under vacuum, and the crude alcohol was purified by flash

chromatography (EtOAc/hexane, 1:10) to give pure 30 (64 mg,

R_f= 0.5 (EtOAc/hexane, 1:10). [α]²_D⁵= –0.58 (c = 0.5, CHCl₃). H

1

NMR (200 MHz, CDCl₃): δ = 9.95 (d, J = 1.2 Hz, 1 H), 7.75–7.68

(m, 4 H), 7.50–7.38 (m, 6 H), 5.62–5.53 (m, 1 H), 5.04–4.94 (m, 2

H), 4.26–4.21 (m, 1 H), 2.56–2.40 (m, 2 H), 2.15–2.10 (m, 1 H),

1.12 (12 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 205.0, 136.1,

135.8, 134.2, 133.6, 130.1, 130.0, 128.0, 127.8, 116.7, 69.5, 58.1,

29.2, 27.2, 20.4, 19.5 ppm. HRMS (ESI): calcd. for C₂₃H₃₀O₂SiNa

[M + Na]⁺389.1913; found 389.1936.

78%) as a colourless liquid. R_f= 0.2 (EtOAc/hexane, 1:1). [α]²_D⁹

=

(2R,3S)-3-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]hex-5-en-2-ol (33):

Aldehyde 32 (300 mg, 0.82 mmol) was dissolved in dry diethyl

ether, and then a freshly prepared MeMgI solution (1.23 mmol in

Et₂O) was added at –78 °C. The reaction mixture was then allowed

to reach room temperature. After 6 h, the reaction was quenched

by the addition of saturated NH₄Cl solution, and then the mixture

was extracted with diethyl ether (3ϫ). The combined organic ex-

tracts were then dried with anhydrous MgSO₄, and evaporated in

vacuo. The residue was purified by flash chromatography (EtOAc/

hexane, 1:15) to give compound 33 (282 mg, 90%) as a colourless

+32.0 (c = 1.0, MeOH). ¹H NMR (200 MHz, CDCl₃): δ = 4.37–

4.06 (m, 5 H), 3.76–3.55 (m, 2 H), 2.14–1.96 (m, 1 H), 1.86–1.72

(m, 1 H), 1.63–1.55 (m, 1 H), 1.11 (d, J = 6.6 Hz, 3 H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 75.0, 72.4, 70.2, 68.6, 61.3, 38.9, 25.0,

17.5 ppm.

Ethyl (R)-2-[(S)-1-Hydroxyethyl]pent-4-enoate (2): The following

procedure was modified a little compared to our earlier reported

procedure.^[7]Klebsiella pneumoniae cells were grown in YM (yeast

malt) glucose medium in a 500 mL conical flask for 24 h. Com-

pound 1 (2 g, 11.67 mmol) was directly added to the growing cell

culture. The reaction was monitored periodically by TLC analysis.

It usually took 4 d for quantitative conversion. After the reaction

was complete, the mixture was centrifuged (10000 rpm) for 30 min,

then the supernatent was collected, and the product alcohol was

extracted with EtOAc (3ϫ). The combined organic extracts were

washed with brine, and dried with MgSO₄. The crude alcohol was

then purified by flash chromatography (EtOAc/hexane, 1:10) to

give alcohol 2 (1.77 g, 88%) as a colourless liquid. R_f= 0.3 (EtOAc/

hexane, 1:5). [α]²_D⁵= +15.3 (c = 1, CHCl₃). ¹H NMR (200 MHz,

CDCl₃): δ = 5.88–5.68 (m, 1 H), 5.12–4.98 (m, 2 H), 4.17 (q, J =

7.2 Hz, 2 H), 4.10–3.94 (m, 1 H), 2.56–2.37 (m, 3 H), 1.29–1.19 (m,

6 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 174.8, 135.5, 116.7,

67.9, 60.6, 52.0, 31.9, 20.3, 14.2 ppm. HRMS (ESI): calcd. for

C₉H₁₆O₃Na [M + Na]⁺195.0887; found 195.0988.

liquid, as the sole product. R_f= 0.4 (EtOAc/hexane, 1:10). [α]²_D⁵

=

+8.18 (c = 1.2, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 7.72–

7.69 (m, 4 H), 7.49–7.36 (m, 6 H), 5.83–5.63 (m, 1 H), 5.05 (d, J

= 17.0 Hz, 1 H), 4.9 (d, J = 10.2 Hz, 1 H), 4.18–4.02 (m, 2 H),

2.43–2.11 (m, 3 H), 1.22 (d, J = 6.6 Hz, 3 H), 1.05 (12 H) ppm.

¹³C NMR (50 MHz, CDCl₃): δ = 139.2, 136.1, 136.0, 134.7, 133.8,

130.0, 129.8, 127.9, 127.7, 115.5, 72.5, 69.5, 51.0, 29.7, 27.2, 22.5,

20.8, 19.4 ppm. HRMS (ESI): calcd. for C₂₄H₃₄O₂SiNa [M +

Na]⁺405.2226; found 405.2211.

(2R,3r,4S)-3-Allylpentane-2,4-diol (34): Alcohol 33 was dissolved in

dry THF (80 mg, 0.21 mmol), and TBAF solution (1 m in THF;

0.42 mL, 0.42 mmol) was added at room temperature. After 4 h,

the solvent was evaporated using a rotary evaporator. The residue

was purified by flash chromatography (EtOAc/hexane, 1:3) to give

diol 34 (27 mg, 92%) as a colourless liquid. R_f= 0.3 (EtOAc/hex-

(R)-Ethyl

2-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]pent-4-enoate ane, 1:2). ¹H NMR (200 MHz, CDCl₃): δ = 6.03–5.82 (m, 1 H),

(31): Imidazole (1.898 g, 27.907 mmol) and TBDPS-Cl (5 mL,

18.605 mmol) were added to a solution of alcohol 2 (1.6 g,

5.08 (d, J = 17.0 Hz, 1 H), 4.93 (d, J = 10.2 Hz, 1 H), 4.17–4.06

(m, 2 H), 3.62 (br., 2 H, OH), 2.33–2.27 (m, 2 H), 1.43–1.38 (m, 1

Eur. J. Org. Chem. 2014, 5229–5246

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5239

D. Das, J. Halder, R. Bhuniya, S. Nanda

H), 1.23 (d, J = 6.4 Hz, 6 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ was continued for 72 h. Then the reaction mixture was quenched

FULL PAPER

= 140.1, 115.3, 72.4, 49.3, 26.8, 21.8 ppm. HRMS (ESI): calcd. for

with a saturated solution of NaHCO₃, and the mixture was ex-

tracted with EtOAc (2ϫ 20 mL). The combined organic extracts

were dried with MgSO₄, and concentrated in a rotary evaporator.

The crude residue was then purified by flash chromatography on

silica (EtOAc/hexane, 1:10) to give ε-lactone 38 (23 mg, 78%) as a

colourless liquid. R_f= 0.5 (EtOAc/hexane, 1:5). [α]²_D⁵= +15.21 (c

= 1.0, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 5.88 (d, J =

11.2 Hz, 1 H), 4.63–4.47 (m, 1 H), 3.86 (q, J = 5.6 Hz, 1 H), 2.6–

2.36 (m, 2 H), 1.89–1.83 (m, 1 H), 1.23 (d, J = 6.4 Hz, 3 H), 1.1–

1.05 (12 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 170.2, 127.8,

127.6, 122.0, 68.8, 53.1, 25.4, 22.6, 18.9 ppm. HRMS (ESI): calcd.

for C₂₅H₃₂O₃SiNa [M + Na]⁺193.0841; found 193.0822.

C₈H₁₆O₂Na [M + Na]⁺167.1048; found 167.1102.

(4S,5r,6R)-5-Allyl-2,2,4,6-tetramethyl-1,3-dioxane (35): Diol 34

(27 mg, 0.18 mmol) was dissolved in dry CH₂Cl₂(1 mL). 2,2-DMP

(0.07 mL, 0.54 mmol) was added to the solution, followed by a

catalytic amount of PPTS. The reaction mixture was then stirred

for 12 h at room temperature. After that time, the solvent was evap-

orated under vacuum, and the residue was purified by flash

chromatography (EtOAc/hexane, 1:7) to give pure product 35

(26 mg, 90%) as a colourless liquid. R_f= 0.6 (EtOAc/hexane, 1:5).

¹H NMR (200 MHz, CDCl₃): δ = 5.99–5.78 (m, 1 H), 5.3 (d, J =

17.2 Hz, 1 H), 4.92 (d, J = 10.0 Hz, 1 H), 4.1 (dq, J = 6.4, 2.0 Hz,

2 H), 2.28–2.22 (m, 2 H), 1.5 (m, 1 H), 1.43 (s, 3 H), 1.38 (s, 3 H),

(3R,4S)-4-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]hepta-1,6-dien-3-

1.15 (d, J = 6.4 Hz, 6 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = ol (39): Aldehyde 32 (400 mg, 1.093 mmol) was dissolved in dry

140.4, 114.5, 99.1, 69.8, 43.1, 30.2, 25.6, 19.8, 19.5 ppm.

THF (5 mL), and then vinylmagnesium bromide (1 m in THF;

1.64 mL, 1.64 mmol) was added at –78 °C. The reaction mixture

was then allowed to reach room temperature. After 3 h, the reac-

tion was quenched by the addition of saturated aqueous NH₄Cl,

then the THF was evaporated under vacuum, and the mixture was

extracted with diethyl ether (3ϫ). The combined organic extracts

were then dried with anhydrous MgSO₄, and evaporated in vacuo.

The residue was purified by flash chromatography (EtOAc/hexane,

1:15) to give compound 39 (345 mg, 80%) as a colourless liquid,

as the sole product. R_f= 0.5 (EtOAc/hexane, 1:10). [α]²_D⁵= +28.0

(2R,3S)-3-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]hex-5-en-2-yl Ac-

rylate (36): Freshly distilled acryloyl chloride (0.128 mL,

1.579 mmol), DIPEA (0.27 mL, 1.579 mmol), and a catalytic

amount of DMAP were added to a solution of alcohol 33 (200 mg,

0.526 mmol) in dry CH₂Cl₂at 0 °C. The mixture was left at room

temperature for 6 h. The reaction was then quenched by the ad-

dition water, and the mixture was extracted with CH₂Cl₂(2ϫ

25 mL). The combined organic extracts were then dried with anhy-

drous MgSO₄and evaporated in vacuo, and the residue was puri-

fied by flash chromatography (EtOAc/hexane, 1:20) to give pure

compound 36 (201 mg, 88%) as a colourless liquid. R_f= 0.5

(EtOAc/hexane, 1:10). [α]²_D⁵= –0.87 (c = 1.1, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 7.73–7.68 (m, 4 H), 7.43–7.40 (m, 6 H),

6.39 (dd, J = 17.2, 1.6 Hz, 1 H), 6.18–6.04 (m, 1 H), 5.80 (dd, J =

10.2, 1.4 Hz, 1 H), 5.63–5.37 (m, 2 H), 4.97–4.85 (m, 2 H), 4.01–

3.93 (m, 1 H), 2.32–2.01 (m, 2 H), 1.71–1.61 (m, 1 H), 1.29 (d, J

= 6.4 Hz, 3 H), 1.10–1.02 (m, 12 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 165.7, 137.7, 136.1, 134.7, 134.1, 130.3, 129.9, 129.7,

129.4, 127.8, 127.6, 115.8, 70.4, 69.5, 49.8, 31.1, 27.2, 19.5, 19.4,

1

(c = 0.5, CHCl₃). H NMR (200 MHz, CDCl₃): δ = 7.71–7.67 (m,

4 H), 7.42–7.30 (m, 6 H), 5.92–5.83 (m, 1 H), 5.51–5.75 (m, 1 H),

5.29–4.86 (m, 4 H), 4.55–4.53 (m, 1 H), 4.08 (dd, J = 6.4, 3.4 Hz,

1 H), 2.25–2.09 (m, 2 H), 1.70–1.62 (m, 1 H), 1.09–1.06 (s, 12 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.9, 138.5, 136.1, 134.6,

133.9, 130.0, 129.8, 127.9, 127.7, 115.8, 114.6, 73.7, 72.0, 49.7, 29.8,

27.3, 20.5, 19.4 ppm. HRMS (ESI): calcd. for C₂₅H₃₄O₂SiNa [M +

Na]⁺417.2226; found 417.2252.

(4S,5R,6R)-5-Allyl-2,2,4-trimethyl-6-vinyl-1,3-dioxane (41): The

TBDPS group was removed from compound 39 with TBAF, as

19.2 ppm. HRMS (ESI): calcd. for C₂₇H₃₆O₃SiNa [M + Na]⁺described above for the synthesis of compound 34, to give

459.2331; found 459.2348.

(2S,3R,4R)-3-allylhex-5-ene-2,4-diol. R_f= 0.4 (EtOAc/hexane, 1:3).

1

[α]²_D⁵= +23.2 (c = 0.5, CHCl₃). H NMR (200 MHz, CDCl₃): δ =

(6S,7R,Z)-6-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]-7-methyl-6,7-

dihydrooxepin-2(5H)-one (37): Ester 36 (100 mg, 0.23 mmol) was

dissolved in CH₂Cl₂(200 mL), which had previously been was de-

gassed by purging a positive pressure of argon. Grubbs 2^ndgenera-

tion catalyst (Grubbs II; 0.0115 mol, 10 mg) was added, and the

reaction mixture was heated at reflux under an argon atmosphere

for 8 h. After TLC indicated that the reaction was complete, air was

bubbled into the reaction mixture to quench any catalyst present in

the solution. The solvent was then evaporated, and the residue was

purified by flash chromatography (EtOAc/hexane, 1:20) to give

6.0–5.77 (m, 2 H), 5.30–4.92 (m, 4 H), 4.41 (d, J = 1.4 Hz, 1 H),

4.18–4.09 (m, 1 H), 2.27–2.21 (m, 2 H), 1.58 (dd, J = 5.6, 2.6 Hz,

1 H), 1.22 (d, J = 6.4 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃):

δ = 139.9, 139.5, 115.6, 115.0, 76.4, 71.3, 48.7, 27.4, 21.7 ppm.

HRMS (ESI): calcd. for C₉H₁₆O₂Na [M + Na]⁺179.1048; found

179.1093.

The diol obtained in the previous step (40 mg, 0.256 mmol) was

dissolved in dry CH₂Cl₂(1 mL). 2,2-DMP (0.157 mL, 1.282 mmol)

was added to the solution, followed by a catalytic amount of PPTS.

pure RCM product 37 (77 mg, 83%) as a colourless liquid. R_f= The reaction mixture was then stirred for 12 h at room temperature.

0.4 (EtOAc/hexane, 1:10). [α]²_D⁵= +30.51 (c = 1.5, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 7.67–7.64 (m, 4 H), 7.43–7.27 (m, 6

After that time, the solvent was evaporated under vacuum, and the

residue was purified by flash chromatography (EtOAc/hexane, 1:7)

H), 6.68–6.59 (m, 1 H), 5.97 (d, J = 11.0 Hz, 1 H), 4.64–4.50 (m, to give pure product 41 (45 mg, 90%) as a viscous liquid. R_f= 0.5

1 H), 3.89 (q, J = 5.8 Hz, 1 H), 2.74–2.35 (m, 2 H), 1.93–1.85 (m, (EtOAc/hexane, 1:20). [α]²_D⁵= +15.4 (c = 0.5, CHCl₃). ¹H NMR

1 H), 1.24 (d, J = 6.4 Hz, 3 H), 1.07–1.04 (12 H) ppm. ¹³C NMR

(200 MHz, CDCl₃): δ = 5.90–5.74 (m, 2 H), 5.31–4.87 (m, 4 H),

(50 MHz, CDCl₃): δ = 170.1, 144.1, 136.1, 136.0, 134.3, 133.2, 4.51–4.40 (m, 1 H), 4.17–4.11 (m, 1 H), 2.33–2.10 (m, 2 H), 1.72–

130.2, 129.9, 128.0, 127.7, 122.5, 69.4, 52.7, 27.2, 25.7, 22.4, 19.5, 1.59 (m, 1 H), 1.44 (d, J = 6.4 Hz, 6 H), 1.18 (d, J = 6.4 Hz, 3 H)

19.1 ppm. HRMS (ESI): calcd. for C₂₅H₃₂O₃SiNa [M + Na]⁺ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.2, 137.6, 115.4, 114.6,

431.2018; found 431.2047.

99.3, 74.5, 69.5, 42.7, 30.1, 26.2, 19.8, 19.6 ppm. HRMS (ESI):

calcd. for C₁₂H₂₀O₂Na [M + Na]⁺219.1361; found 219.1356.

(6R,7R,Z)-6-[(S)-1-Hydroxyethyl]-7-methyl-6,7-dihydrooxepin-

2(5H)-one (38): TBDPS-protected ε-lactone 37 (70 mg,

0.172 mmol) was dissolved in dry THF (1 mL), and HF/pyridine

(7:3; 250 μL) was added dropwise to the solution at 0 °C. The reac-

tion mixture was then warmed to room temperature, and stirring

(1R,5S)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]cyclopent-2-enol

(43): Compound 39 (260 mg, 0.66 mmol) was dissolved in anhy-

drous CH₂Cl₂(degassed by argon purging; 300 mL), and Grubbs

1^stgeneration catalyst (Grubbs I; 0.033 mol, 27.0 mg) was added.

5240

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Eur. J. Org. Chem. 2014, 5229–5246

Stereoselective Synthesis of Enantiopure Oxetanes

The reaction solution was stirred under an argon atmosphere for

8 h. After that time, air was bubbled into the reaction solution to

quench any remaining catalyst present in the solution. The organic

solvent was then evaporated, and the residue was purified by flash

chromatography (EtOAc/hexane, 1:20) to give pure product 43

(217 mg, 90%) as a colourless liquid. R_f= 0.3 (EtOAc/hexane, 1:5).

(m, 1 H), 1.16 (d, J = 6.0 Hz, 3 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 171.0, 170.3, 76.2, 75.5, 70.9, 68.1, 40.0, 28.7, 21.5,

21.0, 20.9, 20.8, 18.4 ppm. HRMS (ESI): calcd. for C₁₅H₂₂O₈Na

[M + Na]⁺353.1212; found 353.1224.

(1R,2R,3S,4R)-4-[(S)-1-Acetoxyethyl]cyclopentane-1,2,3-triyl Tri-

acetate (Tetraacetate of 51): [α]²_D⁵= –8.12 (c = 0.5, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 5.45–5.27 (m, 2 H), 5.14–5.10 (m, 1

H), 4.94–4.88 (m, 1 H), 2.62–2.55 (m, 1 H), 2.23–2.13 (m, 1 H),

2.07–1.97 (m, 12 H), 1.97–1.89 (m, 1 H), 1.16 (d, J = 6.4 Hz, 3 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 171.0, 170.3, 170.1, 76.1,

75.6, 72.8, 70.5, 40.1, 28.6, 21.5, 21.1, 21.0, 20.9, 18.3 ppm. HRMS

(ESI): calcd. for C₁₅H₂₂O₈Na [M + Na]⁺353.1212; found 353.1224.

1

[α]²_D⁵= –20.53 (c = 0.5, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

7.72–7.70 (m, 4 H), 7.44–7.36 (m, 6 H), 6.01 (t, J = 2.8 Hz, 1 H),

5.88 (dd, J = 5.6, 2.0 Hz, 1 H), 4.67 (s, 1 H), 4.27–4.24 (m, 1 H),

2.431 (d, J = 7.6 Hz, 2 H), 2.27–2.23 (m, 1 H), 1.14 (d, J = 6.0 Hz,

3 H), 1.03 (s, 9 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 135.9,

135.8, 135.0, 134.6, 133.9, 139.6, 129.5, 127.6, 127.4, 77.4, 70.8,

48.8, 33.6, 27.0, 22.8, 19.3 ppm. HRMS (ESI): calcd. for C₂₃H₃₀O₂-

SiNa [M + Na]⁺389.1913; found 389.1923.

(4R,5S)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]octa-1,7-dien-4-ol

(40): Aldehyde 32 (477 mg, 1.3033 mmol) was dissolved in THF,

and then Zn dust (170 mg) and allyl bromide (0.26 mL,

2.6066 mmol) were added at 10 °C. Then, saturated aqueous

NH₄Cl solution (0.1 mL) was added portionwise to the reaction

mixture over 0.5 h. The reaction mixture was then allowed to reach

room temperature, and stirred vigorously for 6 h. The mixture was

extracted with diethyl ether (3ϫ). The combined organic extracts

were then dried with anhydrous MgSO₄and evaporated in vacuo.

The residue was purified by flash chromatography (EtOAc/hexane,

1:20) to give compound 40 (372 mg, 70%) as a colourless liquid.

(1S,2S,3S,4S)-4-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]cyclopent-

ane-1,2,3-triol (45) and (1R,2R,3S,4S)-4-[(S)-1-(tert-Butyldiphenyl-

silyloxy)ethyl]cyclopentane-1,2,3-triol (47): Compound 43 (90 mg,

0.246 mmol) was dissolved in a THF/water mixture (3:1; 4 mL),

and the solution was cooled to 0 °C. OsO₄(0.05 m solution in tolu-

ene; 0.492 mL, 0.0246 mmol) and NMO (57.6 mg, 0.492 mmol)

were added successively to the reaction mixture at 0 °C, and the

reaction mixture was allowed to reach room temperature. The mix-

ture was then stirred at room temperature for 12 h. When the reac-

tion was complete, a saturated Na₂SO₃solution was added at 0 °C

to quench the reaction. Then the mixture was extracted with EtOAc

(3ϫ), and the combined organic extracts were dried with MgSO₄,

and evaporated under vacuum. The product was purified by flash

chromatography (EtOAc/hexane, 1:10) to give a mixture of triols

45 (72.8 mg) and 47 (7.2 mg) in a 10:1 ratio (80%) as a viscous

liquid. R_f= 0.3 (EtOAc/hexane, 1:1).

Data for 45: [α]²_D⁵= +16.78 (c = 0.5, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.74–7.69 (m, 4 H), 7.45–7.39 (m, 6 H), 4.36–4.33 (m,

2 H), 4.20 (d, J = 4.4 Hz, 1 H), 2.41–2.39 (m, 1 H), 2.24–2.20 (m,

1 H), 1.82–1.76 (m, 1 H), 1.02 (s, 9 H), 0.96 (d, J = 6.0 Hz, 3 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 136.0, 135.9, 134.5, 133.2,

130.2, 129.9, 128.1, 127.8, 79.8, 79.4, 71.5, 71.0, 44.9, 30.8, 27.2,

22.5, 19.4 ppm. HRMS (ESI): calcd. for C₂₃H₃₂O₄SiNa [M +

Na]⁺423.1967; found 423.2000.

R_f= 0.5 (EtOAc/hexane, 1:10). [α]²_D⁵= +9.95 (c = 0.5, CHCl₃). H

1

NMR (200 MHz, CDCl₃): δ = 7.71–7.66 (m, 4 H), 7.44–7.34 (m, 6

H), 5.78–5.59 (m, 2 H), 5.12–4.86 (m, 4 H), 4.07–4.02 (m, 2 H),

2.33–2.10 (m, 4 H), 1.57–1.49 (m, 1 H), 1.06–1.04 (12 H) ppm. ¹³

C

NMR (50 MHz, CDCl₃): δ = 138.9, 136.1, 136.0, 135.7, 134.7,

133.9, 129.9, 129.7, 127.8, 127.6, 117.9, 115.5, 72.0, 71.6, 48.9, 40.8,

29.5, 27.2, 20.5, 19.4 ppm. HRMS (ESI): calcd. for C₂₆H₃₆O₂SiNa

[M + Na]⁺431.2382; found 431.2381.

(4R,5R,6S)-4,5-Diallyl-2,2,6-trimethyl-1,3-dioxane (42): The

TBDPS group was removed from compound 40 with TBAF as de-

scribed above for the synthesis of compound 34, to give

(2S,3R,4R)-3-allylhept-6-ene-2,4-diol. R_f= 0.4 (EtOAc/hexane,

1:3). [α]²_D⁵= +5.71 (c = 0.5, CHCl₃). ¹H NMR (200 MHz, CDCl₃):

δ = 6.0–5.66 (m, 2 H), 5.15–4.94 (m, 4 H), 4.14–4.03 (m, 1 H),

3.95–3.87 (m, 1 H), 2.32–2.25 (m, 4 H), 1.51–1.46 (m, 1 H), 1.21

(d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 139.8,

Data for 47: [α]²_D⁵= +20.52 (c = 0.5, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.74–7.70 (m, 4 H), 7.45–7.38 (m, 6 H), 4.39–4.33 (m, 135.1, 118.3, 115.4, 75.5, 72.5, 47.3, 40.2, 26.7, 21 ppm. HRMS

2 H), 4.21 (d, J = 4.2 Hz, 1 H), 2.41–2.39 (m, 1 H), 2.26–2.20 (m,

1 H), 1.82–1.76 (m, 1 H), 1.02 (s, 9 H), 0.96 (d, J = 6.2 Hz, 3 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 136.0, 135.9, 134.5, 133.8,

130.1, 130.0, 128.0, 127.7, 81.6, 79.5, 72.9, 72.0, 45.0, 30.8, 27.1,

22.5, 19.5 ppm.

(ESI): calcd. for C₁₀H₁₈O₂Na [M + Na]⁺193.1205; found 193.1212.

The acetonide protection of the diol was done by the same pro-

cedure described above for the synthesis of compound 35, to give

42. R_f= 0.5 (EtOAc/hexane, 1:20). [α]²_D⁵= +10.04 (c = 0.5, CHCl₃).

¹H NMR (200 MHz, CDCl₃): δ = 5.90–5.65 (m, 2 H), 5.14–4.90

(1S,2S,3S,4R)-4-[(S)-1-Acetoxyethyl]cyclopentane-1,2,3-triyl Tri- (m, 4 H), 4.10–4.06 (m, 1 H), 3.94–3.87 (m, 1 H), 2.31–2.21 (m, 4

acetate (Tetraacetate of 49): A solution of triol 45 in dry THF

(70 mg, 0.175 mmol) was treated with TBAF (1 m in THF;

0.35 mL, 0.35 mmol) at room temperature. After 6 h, the solvent

was evaporated, and the residue was purified by flash chromatog-

raphy (EtOAc/hexane, 1:5) to give tetrol 49 (27 mg, 0.167 mmol) as

a viscous liquid.

H), 1.42–1.39 (m, 6 H), 1.36–1.25 (m, 1 H), 1.17 (d, J = 6.4 Hz, 3

H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.1, 134.8, 117.2,

114.7, 99.3, 74.1, 67.0, 41.2, 37.6, 30.2, 25.9, 19.8, 19.6 ppm.

HRMS (ESI): calcd. for C₁₃H₂₂O₂Na [M + Na]⁺233.1517; found

233.1521.

(1R,6S)-6-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]cyclohex-3-enol

Tetrol 49 (25 mg, 0.154 mmol) was dissolved in distilled Et₃N (44): Compound 40 (250 mg, 0.613 mmol) was dissolved in anhy-

(1 mL), and Ac₂O (0.122 mL, 0.875 mmol) was added along with drous CH₂Cl₂(degassed by argon purging; 300 mL), and Grubbs

a catalytic amount of DMAP at room temperature. The reaction

mixture was stirred at room temperature for 3 d, then the Et₃N was

evaporated under vacuum, and the residue was purified by column

chromatography (EtOAc/hexane, 1:10) to give the pure tetraacetate

(35.6 mg, 70%) as a gummy solid. R_f= 0.4 (EtOAc/hexane, 1:5).

[α]²_D⁵= +63.13 (c = 0.5, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ =

5.35–5.27 (m, 2 H), 5.13–5.10 (m, 1 H), 4.94–4.88 (m, 1 H), 2.61–

2.55 (m, 1 H), 2.23–2.13 (m, 1 H), 2.07–1.98 (m, 12 H), 1.97–1.89

1^stgeneration catalyst (Grubbs I; 0.03 mmol, 25.0 mg) was added.

The reaction solution was stirred under an argon atmosphere for

10 h. After that time, air was bubbled into the reaction solution to

quench the catalyst, the solvent was evaporated, and the residue

was purified by flash chromatography (EtOAc/hexane, 1:20) to give

pure product 44 (196 mg, 84%) as a colourless liquid. R_f= 0.3

(EtOAc/hexane, 1:5). [α]²_D⁵= +76.43 (c = 0.5, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 7.77–7.72 (m, 4 H), 7.47–7.37 (m, 6 H),

Eur. J. Org. Chem. 2014, 5229–5246

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5241

D. Das, J. Halder, R. Bhuniya, S. Nanda

FULL PAPER

5.86–5.81 (m, 1 H), 5.62–5.59 (m, 1 H), 4.25–4.19 (m, 2 H), 2.42–

2-vinylbenzene (6 g, 31.98 mmol) in dry THF was added dropwise.

2.14 (m, 4 H), 1.64–1.60 (m, 1 H), 1.04 (s, 9 H), 0.95 (d, J = 6.4 Hz, The reaction mixture was then stirred at reflux. After 12 h, the

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 136.1, 136.0, 134.7,

133.4, 130.1, 129.8, 128.0, 127.7, 126.7, 123.5, 74.8, 68.7, 44.1, 34.3,

mixture was cooled to room temperature, and then ice-cooled water

was added to quench the reaction. The THF was evaporated under

27.2, 21.6, 20.8, 19.5 ppm. HRMS (ESI): calcd. for C₂₄H₃₂O₂SiNa vacuum, and diethyl ether was added. The product was extracted

[M + Na]⁺403.2069; found 403.2108.

with diethyl ether (3ϫ), and the combined organic extracts were

dried with MgSO₄, and concentrated. The residue was purified by

flash chromatography (EtOAc/hexane, 1:25) to give pure com-

pound 53 (6.293 g, 80%) as a colourless liquid. R_f= 0.6 (EtOAc/

hexane, 1:10). ¹H NMR (200 MHz, CDCl₃): δ = 7.50–7.45 (m, 1

H), 7.27–7.10 (m, 3 H), 7.06–6.92 (dd, J = 17.0, 11.0 Hz, 1 H), 5.65

(d, J = 17.0 Hz, 1 H), 5.35 (d, J = 11.0 Hz, 1 H), 4.19–4.08 (m, 2

H), 3.80–3.73 (m, 1 H), 3.29–3.22 (m, 2 H), 2.16 (s, 3 H), 1.20 (t,

J = 7.2 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 202.7,

169.3, 137.0, 135.5, 134.3, 130.3, 128.0, 127.3, 126.3, 116.7, 61.6,

60.3, 31.4, 29.9, 14.1 ppm. HRMS (ESI): calcd. for C₁₅H₁₈O₃Na

[M + Na]⁺269.1154; found 269.1169.

(1S,2R,4R,5S)-5-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]cyclohex-

ane-1,2,4-triol (46) and (1R,2S,4R,5S)-5-[(S)-1-(tert-Butyldiphenyl-

silyloxy)ethyl]cyclohexane-1,2,4-triol (48): Compound 44 (105 mg,

0.276 mmol) was dissolved in a THF/water mixture (3:1; 4 mL),

and the solution was cooled to 0 °C. OsO₄(0.05 m solution in tolu-

ene; 0.553 mL, 0.0276 mmol) and NMO (64.7 mg, 0.552 mmol)

were added at 0 °C, and the mixture was allowed to reach room

temperature. The mixture was then stirred at room temperature for

12 h. When the reaction was complete, a saturated Na₂SO₃solution

was added at 0 °C to quench the reaction. The product was ex-

tracted with EtOAc (3ϫ), and the combined organic extracts were

dried with MgSO₄, and evaporated under vacuum. The residue was

purified by flash chromatography (EtOAc/hexane, 1:10) to give a

mixture of two diastereomeric triols, 46 (86.8 mg) and 48 (7.2 mg),

in a 12:1 ratio (82%) as a viscous liquid. R_f= 0.3 (EtOAc/hexane,

1:1).

(2R,3S)-Ethyl-3-hydroxy-2-(2-vinylbenzyl)butanoate (54): Bioreduc-

tion of compound 53 with K. pneumoniae (NBRC 3319) was carried

out as described above for the synthesis of compound 2, to give 54

(76%) as a colourless liquid. R_f= 0.5 (EtOAc/hexane, 1:5). [α]²_D⁵

=

+29.1 (c = 1.0, MeOH). ¹H NMR (200 MHz, CDCl₃): δ = 7.49–

7.45 (m, 1 H), 7.26–7.08 (m, 3 H), 7.05–6.91 (dd, J = 17.2, 11.0 Hz,

1 H), 5.65 (d, J = 17.4 Hz, 1 H), 5.31 (d, J = 11.0 Hz, 1 H), 4.06–

3.93 (m, 3 H), 3.19–2.93 (m, 2 H), 2.75–2.65 (m, 1 H), 1.26 (d, J

= 6.2 Hz, 3 H), 1.05 (t, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 174.7, 136.9, 136.6, 134.4, 130.2, 127.8, 127.0, 126.0,

116.1, 68.3, 60.7, 53.7, 31.0, 20.5, 14.1 ppm. HRMS (ESI): calcd.

for C₁₅H₂₀O₃Na [M + Na]⁺271.1310; found 271.1357.

Data for 46: [α]²_D⁵= +27.47 (c = 0.5, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.76–7.70 (m, 4 H), 7.46–7.38 (m, 6 H), 4.32–4.15 (m,

4 H), 2.12–2.06 (m, 1 H), 1.96–1.93 (m, 2 H), 1.77–1.71 (m, 2 H),

1.01 (s, 9 H), 0.92 (d, J = 6.4 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 136.0, 135.9, 134.4, 133.1, 130.2, 129.9, 128.1, 127.7,

74.8, 71.8, 69.3, 68.6, 39.9, 35.4, 27.1, 24.5, 22.0, 19.4 ppm. HRMS

(ESI): calcd. for C₂₄H₃₄O₄SiNa [M + Na]⁺437.2124; found

437.2151.

(2R,3S)-Ethyl 3-(tert-Butyldiphenylsilyloxy)-2-(2-vinylbenzyl)but-

anoate (55): Imidazole (197.6 mg, 2.903 mmol) and TBDPS-Cl

(0.44 mL, 1.742 mmol) were added to a solution of alcohol 54

(360 mg, 1.452 mmol) in dry CH₂Cl₂(6 mL) at 0 °C. The mixture

was stirred at room temperature for 6 h. After the reaction was

complete, water was added, and the mixture was extracted with

CH₂Cl₂(2ϫ). The combined organic extracts were then dried with

anhydrous MgSO₄. The organic solvent was evaporated in vacuo,

and the residue was purified by flash chromatography (EtOAc/hex-

ane, 1:20) to give pure 55 (622.3 mg, 88%) as a viscous liquid. R_f

= 0.7 (EtOAc/hexane, 1:10). [α]²_D⁵= +34.22 (c = 1.4, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 7.81–7.79 (m, 4 H), 7.49–7.46 (m, 7

H), 7.30–6.97 (m, 4 H), 5.71 (d, J = 17.4 Hz, 1 H), 5.35 (d, J =

11.0 Hz, 1 H), 4.27–4.17 (m, 1 H), 4.04 (q, J = 7.2 Hz, 2 H), 3.28–

3.18 (m, 1 H), 3.07–2.91 (m, 2 H), 1.36 (3 H), 1.21–1.09 (12 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 173.6, 137.1, 136.9, 136.1,

134.7, 133.8, 130.2, 129.9, 129.8, 127.9, 127.7, 126.8, 126.0, 115.9,

71.1, 61.3, 55.3, 32.5, 29.9, 27.2, 21.1, 19.6, 14.2 ppm. HRMS

(ESI): calcd. for C₃₁H₃₈O₃SiNa [M + Na]⁺509.2488; found

509.2495.

Data for 48: [α]²_D⁵= +13.4 (c = 0.5, CHCl₃). H NMR (400 MHz,

1

CDCl₃): δ = 7.75–7.71 (m, 4 H), 7.46–7.39 (m, 6 H), 4.28–4.26 (m,

1 H), 4.05 (s, 1 H), 3.96 (s, 1 H), 3.56 (s, 1 H), 2.35–2.30 (m, 1 H),

2.0–1.94 (m, 2 H), 1.57–1.50 (m, 1 H), 1.41–1.33 (m, 1 H), 1.02 (s,

9 H), 0.96 (d, J = 6.0 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 136.0, 135.9, 134.2, 133.0, 130.2, 129.9, 128.1, 127.8, 74.4, 71.8,

71.0, 70.5, 46.4, 35.7, 27.1, 23.8, 21.7, 19.5 ppm.

(1S,2R,4R,5R)-5-[(S)-1-Acetoxyethyl]cyclohexane-1,2,4-triyl Tri-

acetate (Tetraacetate of 50): The tetraacetate of compound 50 was

prepared as described above for the synthesis of the tetraacetate of

49. R_f= 0.4 (EtOAc/hexane, 1:5). [α]²_D⁵= +11.53 (c = 0.5, CHCl₃).

¹H NMR (200 MHz, CDCl₃): δ = 5.40 (s, 1 H), 5.28 (s, 1 H), 5.04–

4.99 (m, 1 H), 4.77–4.74 (m, 1 H), 2.11–1.91 (m, 16 H), 1.816–

1.746 (m, 1 H), 1.2 (d, J = 6.0 Hz, 3 H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 170.3, 170.2, 70.9, 69.3, 68.1, 38.9, 30.2, 27.2, 21.2,

21.1, 20.9, 18.1 ppm. HRMS (ESI): calcd. for C₁₆H₂₄O₈SiNa [M +

Na]⁺367.1369; found 367.1385.

(1R,2S,4R,5R)-5-[(S)-1-Acetoxyethyl]cyclohexane-1,2,4-triyl Tri-

acetate (Tetraacetate of 52): The tetraacetate of compound 52 was

prepared as described above for the synthesis of the tetraacetate of

49. R_f= 0.4 (EtOAc/hexane, 1:5). [α]²_D⁵= –8.72 (c = 0.5, CHCl₃).

¹H NMR (200 MHz, CDCl₃): δ = 5.27–5.27 (m, 1 H), 5.01–5.0 (m,

1 H), 4.90–4.81 (m, 2 H), 2.06–1.98 (m, 15 H), 1.794–1.686 (m, 2

H), 1.18 (d, J = 6.0 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 170.4, 170.2, 170.1, 170.0, 70.9, 70.7, 67.2, 66.9, 42.8, 31.9, 23.9,

21.2, 21.1, 21.0, 20.9, 17.9 ppm.

(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(2-vinylbenzyl)butanal (56):

TBDPS-protected hydroxy ester 55 (600 mg, 1.232 mmol) was dis-

solved in dry CH₂Cl₂(15 mL) and DIBAL-H (1 m solution in tolu-

ene; 1.23 mL, 1.23 mmol) was added at –10 °C. The mixture was

stirred for 4 h at –10 °C. After that time, the reaction was quenched

by the addition of a saturated solution of sodium potassium tar-

trate. Then the mixture was filtered through a pad of Celite, and

extracted several times with CH₂Cl₂. The combined CH₂Cl₂ex-

tracts were then evaporated under vacuum. The residue was then

purified by silica gel flash chromatography (EtOAc/hexane, 1:10) to

give pure 56 (446 mg, 82%) as a colourless liquid. R_f= 0.6 (EtOAc/

hexane, 1:10). [α]²_D⁵= +17.88 (c = 1.0, CHCl₃). ¹H NMR (200 MHz,

CDCl₃): δ = 9.93 (d, J = 1.2 Hz, 1 H), 7.67–7.59 (m, 4 H), 7.44–

Ethyl 3-Oxo-2-(2-vinylbenzyl)butanoate (53): KOtBu (3.588 g,

31.98 mmol) and tBuOH (0.27 mL, 089 mmol) were added to a

solution of ethylacetoacetate (4 mL, 31.98 mmol) in dry THF at

0 °C under an argon atmosphere. The reaction mixture was then

stirred at 0 °C for 20 min, and then a solution of 1-(bromomethyl)-

5242

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Eur. J. Org. Chem. 2014, 5229–5246

Stereoselective Synthesis of Enantiopure Oxetanes

7.35 (m, 7 H), 7.22–7.08 (m, 2 H), 7.02–6.98 (m, 1 H), 6.85 (dd, J

= 17.4, 11.0 Hz, 1 H), 5.58 (dd, J = 17.4, 1.4 Hz, 1 H), 5.26 (dd, J

= 11.0, 1.4 Hz, 1 H), 4.24–4.13 (m, 1 H), 3.21–3.10 (m, 1 H), 2.88–

give pure diol 59 (159.6 mg, 70%) as a colourless liquid. R_f= 0.3

(EtOAc/hexane, 1:5). [α]²_D⁵= +64.68 (c = 1.0, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 7.78–7.67 (m, 4 H), 7.50–7.39 (m, 6 H),

2.79 (m, 1 H), 2.74–2.64 (m, 1 H), 1.13 (d, J = 6.4 Hz, 6 H), 1.11 7.26–7.20 (m, 3 H), 7.09–7.05 (m, 1 H), 4.76 (d, J = 3.8 Hz, 1 H),

(9 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 204.8, 137.0, 136.8, 4.18–4.05 (m, 3 H), 2.68–2.49 (m, 3 H), 1.24 (d, J = 7.2 Hz, 3 H),

136.0, 134.6, 134.2, 133.4, 130.3, 130.1, 129.9, 127.9, 127.8, 126.9,

126.4, 116.3, 69.7, 59.6, 28.3, 27.2, 20.5, 19.5 ppm. HRMS (ESI):

calcd. for C₂₉H₃₄O₂SiNa [M + Na]⁺465.2226; found 465.2239.

1.09 (9 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 136.1, 135.7,

135.3, 132.9, 131.1, 130.3, 130.1, 128.7, 128.6, 128.1, 127.9, 127.8,

126.6, 72.1, 71.8, 70.3, 39.6, 30.5, 27.2, 19.4, 18.3 ppm. HRMS

(ESI): calcd. for C₂₈H₃₄O₃SiNa [M + Na]⁺469.2175; found

469.2041.

tert-Butyldiphenyl[(2S,3S)-3-(2-vinylbenzyl)pent-4-en-2-yloxy]silane

(57): Ph₃P⁺CH₃I^–(694 mg, 1.761 mmol) was dissolved in dry THF

(5 mL), and the solution was cooled to –78 °C. LHMDS (1 m in

THF; 1.76 mL, 1.76 mmol) was added at –78 °C. After 15–20 min,

aldehyde 56 (390 mg, 0.88 mmol), dissolved in dry THF (4 mL),

was added at –78 °C, and then the reaction mixture was warmed

to room temperature. The reaction mixture was stirred for 3 h at

room temperature, and then ice-cold water was added at 0 °C to

quench the reaction. After that, the THF was evaporated under

vacuum, the residue was extracted with diethyl ether (2ϫ), and the

combined organic extracts were dried with anhydrous MgSO₄and

evaporated under vacuum. The residue was purified by flash

chromatography (EtOAc/hexane, 1:40) to give pure olefinic com-

pound 57 (544 mg, 70%) as a colourless liquid. R_f= 0.8 (EtOAc/

hexane, 1:10). [α]²_D⁵= +33.45 (c = 0.8, CHCl₃). ¹H NMR (200 MHz,

CDCl₃): δ = 7.73–7.67 (m, 4 H), 7.51–7.34 (m, 7 H), 7.21–7.13 (m,

2 H), 7.10–6.90 (m, 2 H), 5.85–5.71 (m, 1 H), 5.6 (d, J = 17.0 Hz,

1 H), 5.30 (d, J = 11.0 Hz, 1 H), 5.0 (d, J = 10.4 Hz, 1 H), 4.83 (d,

J = 17.0 Hz, 1 H), 3.92–3.87 (m 1 H), 3.08–3.04 (m 1 H), 3.60–3.45

(m 2 H), 1.09–1.05 (m, 12 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 138.3, 136.9, 136.1, 135.1, 134.2, 130.9, 129.7, 129.6, 127.7, 127.6,

127.4, 126.3, 125.8, 116.8, 115.4, 72.0, 52.8, 34.3, 27.3, 20.4,

19.6 ppm. HRMS (ESI): calcd. for C₃₀H₃₆OSiNa [M + Na]⁺

463.2433; found 463.2434.

(R)-3-[(S)-1-acetoxyethyl]-1,2,3,4-tetrahydronaphthalene-1,2-diyl

Diacetate (Triacetate of 60): A solution of diol 59 in dry THF

(86 mg, 0.192 mmol) was treated with TBAF (1 m in THF; 0.4 mL,

0.4 mmol) at room temperature. After 6 h, the solvent was evapo-

rated. The residue was purified by flash chromatography (EtOAc/

hexane, 1:5) to give triol 60 (36 mg, 0.173 mmol) as a viscous liquid.

Triol 60 (36 mg, 0.173 mmol) was dissolved in distilled Et₃N

(0.7 mL), and Ac₂O (0.073 mL, 0.78 mmol) was added along with

a catalytic amount of DMAP at room temperature. The reaction

mixture was stirred at room temperature for 2 d, then the Et₃N

was evaporated under vacuum. The residue was purified by flash

chromatography (EtOAc/hexane, 1:10) to give the pure triacetate

(40 mg, 70%) as a colourless crystalline solid. R_f= 0.5 (EtOAc/

hexane, 1:5). [α]²_D⁵= +44.28 (c = 1.0, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.32–7.26 (m, 2 H), 7.22–7.19 (m, 2 H), 6.21 (d, J =

3.2 Hz, 1 H), 5.36–5.33 (m, 1 H), 5.16 (dd, J = 11.6, 3.2 Hz, 1 H),

3.15–2.95 (m, 2 H), 2.51 (dd, J = 16.6, 11.4 Hz, 1 H), 2.08–1.98 (9

H), 1.32 (d, J = 6.0 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 170.7, 170.6, 170.5, 136.0, 132.4, 130.8, 129.5, 129.1, 126.8, 70.2,

69.9, 67.2, 37.4, 27.8, 21.4, 21.3, 21.0, 17.4 ppm. HRMS (ESI):

calcd. for C₁₈H₂₂O₆Na [M + Na]⁺357.1314; found 357.1278.

(1S,2S)-2-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]-1-(2-vinylphenyl)-

pent-4-en-1-ol (61) and (1R,2S)-2-[(S)-1-(tert-Butyldiphenylsilyl-

oxy)ethyl]-1-(2-vinylphenyl)pent-4-en-1-ol (62): Aldehyde 32

(588 mg, 1.606 mmol) was dissolved in dry diethyl ether, and then

the freshly generated Grignard reagent from 2-vinyl-1-bromobenz-

ene (2 mmol) was added at –78 °C. The reaction mixture was al-

lowed to reach room temperature. The reaction mixture was then

stirred at room temperature for 6 h. After the reaction was com-

plete, it was quenched by the addition of a saturated solution of

NH₄Cl. The crude product was extracted with diethyl ether (3ϫ),

and the combined organic extracts were dried with MgSO₄. The

organic extract was evaporated using a rotary evaporator to give

the crude alcohol as a diastereomeric mixtures. The diastereomeric

ratio of the two products was 15:1, which was unchanged after

purification by flash chromatography. The mixture of dia-

stereomers (total yield 80 %) containing isomer 61 (566 mg,

1.205 mmol) and isomer 62 (38 mg, 0.0803 mmol) was obtained as

a colourless liquid. R_f= 0.4 (EtOAc/hexane, 1:10).

Data for 61: [α]²_D⁵= –3.47 (c = 0.6, CHCl₃). ¹H NMR (data for 61;

200 MHz, CDCl₃): δ = 7.75–7.59 (m, 4 H), 7.56–7.49 (m, 1 H),

7.47–7.46 (m, 6 H), 7.42–7.21 (m, 3 H), 7.03 (dd, J = 17.0 Hz,

11.0 Hz, 1 H), 5.66–5.37 (m, 3 H), 5.14–5.08 (m, 1 H), 4.87–4.71

(m, 2 H), 4.26–4.20 (m, 1 H), 2.34–2.06 (m, 2 H), 1.89–1.88 (m, 1

H), 1.10–1.04 (12 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.9,

138.7, 136.2, 136.0, 135.1, 135.0, 134.7, 134.3, 133.9, 129.9, 129.8,

127.8, 127.7, 127.2, 126.6, 125.9, 116.0, 115.3, 72.9, 71.5, 49.8, 27.7,

27.3, 20.9, 19.5 ppm. HRMS (ESI): calcd. for C₃₁H₃₈O₂SiNa [M +

Na]⁺493.2539; found 493.2562.

tert-Butyl{(S)-1-[(S)-1,2-dihydronaphthalen-2-yl]ethoxy}diphenyl-

silane (58): Compound 57 (250 mg, 0.566 mmol) was dissolved in

anhydrous degassed CH₂Cl₂(250 mL), and then Grubbs 2^ndgener-

ation catalyst (Grubbs II; 0.028 mol, 24.0 mg) was added. The solu-

tion was then stirred at room temperature under an argon atmo-

sphere for 12 h. After that, air was bubbled into the reaction mix-

ture to quench the catalyst, and then the solvent was evaporated.

The residue was purified by flash chromatography (EtOAc/hexane,

1:25) to give RCM product 58 (183 mg, 78%) as a colourless liquid.

R_f= 0.7 (EtOAc/hexane, 1:10). [α]²_D⁵= +12.33 (c = 1.4, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 7.70–7.65 (m 4 H), 7.43–7.30 (m, 6

H), 7.14–6.99 (m 4 H), 6.49 (dd, J = 9.8, 2 Hz, 1 H), 6.01 (dd, J =

9.8, 3 Hz, 1 H), 3.95–3.83 (m, 1 H), 2.94–2.74 (m, 2 H), 2.70–2.60

(m, 1 H), 1.05 (12 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 136.1,

135.1, 134.9, 134.3, 134.2, 130.7, 129.8, 129.7, 128.5, 128.1, 127.7,

127.6, 127.1, 126.5, 126.1, 71.6, 42.3, 29.8, 27.3, 20.9, 19.6 ppm.

HRMS (ESI): calcd. for C₂₈H₃₂OSiNa [M + Na]⁺435.2120; found

435.2122.

(S)-3-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]-1,2,3,4-tetrahydro-

naphthalene-1,2-diol (59): Compound 58 (210 mg, 0.51 mmol) was

dissolved in a THF/water mixture (3:1; 4 mL), and the solution was

cooled to 0 °C. OsO₄(0.05 m solution in toluene; 1.02 mL,

0.051 mmol) and NMO (119.5 mg, 1.02 mmol) were added at 0 °C,

and the reaction mixture was then allowed to reach room tempera-

ture. The reaction solution was stirred at room temperature for

24 h, and after the reaction was complete, saturated Na₂SO₃solu-

tion was added at 0 °C to quench the reaction. The product was

extracted with EtOAc (3 ϫ), and the combined organic extracts

were dried with MgSO₄and evaporated under vacuum. The prod-

uct was purified by flash chromatography (EtOAc/hexane, 1:6) to

Data for 62: R_f= 0.45 (EtOAc/hexane, 1:10). [α]²_D⁵= –3.77 (c = 0.8,

CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 7.73–7.65 (m, 4 H),

7.47–7.39 (m, 6 H), 7.34–7.30 (m, 1 H), 7.23–7.19 (m, 3 H), 6.87

Eur. J. Org. Chem. 2014, 5229–5246

www.eurjoc.org

5243

D. Das, J. Halder, R. Bhuniya, S. Nanda

FULL PAPER

(dd, J = 17.2, 10.8 Hz, 1 H), 5.76 (s, 1 H), 5.55 (d, J = 17.6 Hz, 1

300 mL), and Hoveyda–Grubbs 2^ndgeneration catalyst (HG-II,

H), 5.32–5.24 (m, 1 H), 5.21 (d, J = 10.8 Hz, 1 H), 4.76–4.67 (m, 0.041 mol, 25.6 mg) was added. The reaction solution was heated

2 H), 4.13–4.10 (m, 1 H), 2.43–2.35 (m, 2 H), 2.09–2.06 (m, 1 H), at reflux under an argon atmosphere for 8 h. After that time, air

1.29–1.26 (m, 3 H), 1.11–1.0 (9 H) ppm. ¹³C NMR (50 MHz, was bubbled into the reaction solution to quench any catalyst pres-

CDCl₃): δ = 141.0, 137.9, 136.0, 135.7, 135.2, 135.1, 134.4, 134.1,

133.7, 130.1, 129.8, 127.6, 127.5, 127.3, 126.5, 125.7, 116.1, 115.1,

73.1, 71.5, 50.1, 27.5, 27.1, 20.8, 19.5 ppm.

ent in the solution. The solvent was then evaporated, and the resi-

due was purified by flash chromatography (EtOAc/hexane, 1:20) to

give pure product 63 (290 mg, 88%) as a colourless liquid. R_f= 0.6

(EtOAc/hexane, 1:5). [α]²_D⁵= –82.74 (c = 1.4, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 7.85–7.73 (m, 4 H), 7.57–7.35 (m, 11 H),

6.51 (d, J = 12.2 Hz, 1 H), 6.04–5.95 (m, 1 H), 4.14–4.09 (m, 1 H),

2.81–2.64 (m, 2 H), 1.26 (d, J = 6.4 Hz, 3 H), 1.19 (9 H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 142.1, 136.1, 136.0, 134.8, 134.6,

134.0, 132.4, 131.3, 129.9, 129.4, 128.8, 128.0, 127.8, 127.7, 127.1,

78.9, 73.0, 46.9, 28.3, 27.2, 19.8, 19.5 ppm. HRMS (ESI): calcd. for

C₂₉H₃₄O₂SiNa [M + Na]⁺465.2226; found 465.2232.

(1S,2R,3S)-2-Allyl-1-(2-vinylphenyl)butane-1,3-diol (67): The

TBDPS group was removed from compound 61 with TBAF as de-

scribed above for the synthesis of compound 34, to give diol 67. R_f

= 0.4 (EtOAc/hexane, 1:3). [α]²_D⁵= –7.03 (c = 2.6, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 7.60–7.47 (m, 1 H), 7.44–7.43 (m, 1 H),

7.35–7.29 (m, 2 H), 6.94 (dd, J = 17.2, 11 Hz, 1 H), 5.61–5.44 (m,

2 H), 5.34–5.29 (m, 2 H), 4.89–4.75 (m, 2 H), 4.22–4.12 (m, 1 H),

2.59 (br., 2 H, OH), 2.30–2.23 (m, 2 H), 1.80–1.75 (m, 1 H), 1.26

(d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.3,

139.5, 135.4, 134.3, 128.0, 127.5, 126.3, 126.1, 116.7, 115.0, 74.2,

72.0, 48.9, 26.6, 21.9 ppm. HRMS (ESI): calcd. for C₁₅H₂₀O₂Na

[M + Na]⁺255.1361; found 255.1416.

(5S,6R,Z)-6-[(S)-1-Hydroxyethyl]-6,7-dihydro-5H-benzo[7]annulen-

5-ol (64): A solution of alcohol 63 (50 mg, 0.113 mmol) in dry THF

(0.5 mL) was treated with TBAF (1 m solution in THF; 0.23 mL,

0.23 mmol) at room temperature. After 4 h, the solvent was evapo-

rated, and the residue was purified by flash chromatography

(EtOAc/hexane, 1:5) to give diol 64 (20.4 mg, 80%) as a colourless

liquid. R_f= 0.2 (EtOAc/hexane, 1:5). [α]²_D⁵= –66.2 (c = 1.0, CHCl₃).

¹H NMR (200 MHz, CDCl₃): δ = 7.17–7.09 (m, 4 H), 6.30 (d, J =

12.4 Hz, 1 H), 5.92–5.82 (m, 1 H), 4.84 (s, 1 H), 4.04–4.01 (m, 1

H), 2.65–2.40 (m, 1 H), 2.38–2.28 (m, 1 H), 1.98–1.85 (m, 1 H),

1.12 (d, J = 6.4 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

140.7, 134.9, 132.1, 131.6, 129.8, 128.6, 128.3, 127.0, 79.4, 72.6,

45.9, 24.9, 20.8 ppm. HRMS (ESI): calcd. for C₁₃H₁₆O₂Na [M +

Na]⁺227.1048; found 227.1053.

(1R,2R,3S)-2-Allyl-1-(2-vinylphenyl)butane-1,3-diol (69): The

TBDPS group 62 was removed from compound with TBAF as de-

scribed above for the synthesis of compound 34, to give diol 69. R_f

= 0.4 (EtOAc/hexane, 1:3). [α]²_D⁵= +2.91 (c = 0.8, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 7.61 (d, J = 7.2 Hz, 1 H), 7.44 (d,

J = 7.8 Hz, 1 H), 7.37–7.22 (m, 2 H), 6.86 (dd, J = 17.0, 11.0 Hz,

1 H), 5.65–5.46 (m, 3 H), 5.30 (d, J = 11.0 Hz, 1 H), 5.02–4.88 (m,

2 H), 4.21–4.08 (m, 1 H), 2.52 (br., 2 H, OH), 2.40–2.23 (m, 2 H),

2.05–1.99 (m, 1 H), 1.47 (d, J = 6.4 Hz, 3 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 140.0, 137.8, 134.9, 134.2, 127.8, 127.3,

126.6, 126.4, 116.5, 69.2, 68.9, 47.3, 28.9, 21.9 ppm.

(8S,9S)-8-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]-6,7,8,9-tetra-

hydro-5H-benzo[7]annulene-5,6,9-triol (65): Compound 63 (335 mg,

0.758 mmol) was dissolved in a THF/water mixture (3:1; 4 mL),

and the solution was cooled to 0 °C. OsO₄(0.05 m solution in tolu-

ene; 1.516 mL, 0.076 mmol) and NMO (177.6 mg, 1.516 mmol)

were added to the reaction mixture at 0 °C, and the mixture was

allowed to reach room temperature. The reaction solution was then

stirred at room temperature for 24 h. After the reaction was com-

plete, saturated Na₂SO₃solution was added at 0 °C to quench the

reaction. The product was extracted with EtOAc (3ϫ), and the

combined organic extracts were dried with MgSO₄, and evaporated

under vacuum. The residue was purified by flash chromatography

(EtOAc/hexane, 1:3) to give pure triol 65 (252.5 mg, 70%) as a

viscous liquid. R_f= 0.3 (EtOAc/hexane, 1:1). [α]²_D⁵= – 27.92 (c =

2.4, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 7.70 (d, J = 6.4 Hz,

4 H), 7.64 (d, J = 8 Hz, 1 H), 7.46–7.30 (m, 7 H), 7.23–7.16 (m, 2

H), 5.61 (s, 1 H), 5.08 (s, 1 H), 4.24 (s, 1 H), 4.04 (s, 1 H), 2.44–

2.41 (m, 1 H), 1.88–1.72 (m, 2 H), 1.08 (9 H), 1.04 (d, J = 5.6 Hz,

3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 139.7, 138.8, 136.0,

135.9, 134.4, 133.6, 130.0, 129.9, 128.4, 128.2, 127.9, 127.7, 127.4,

127.1, 78.0, 75.1, 73.7, 41.7, 29.3, 27.2, 20.6, 19.4 ppm. HRMS

(ESI): calcd. for C₂₉H₃₆O₄SiNa [M + Na]⁺499.2281; found

499.2273.

(4S,5R,6S)-5-Allyl-2,2,4-trimethyl-6-(2-vinylphenyl)-1,3-dioxane

(68): Compound 67 (25 mg, 0.11 mmol) was dissolved in dry

CH₂Cl₂(0.5 mL). 2,2-DMP (0.07 mL, 0.54 mmol) was added to

the reaction mixture, followed by a catalytic amount of PPTS. The

reaction solution was then stirred for 12 h at room temperature.

After that time, the solvent was evaporated under vacuum. The

residue was purified by flash chromatography (EtOAc/hexane, 1:7)

to give pure product 68 (26 mg, 90%) as a colourless liquid. R_f=

0.5 (EtOAc/hexane, 1:20). [α]²_D⁵= –40.3 (c = 2.3, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 7.60–7.56 (m, 1 H), 7.46–7.42 (m, 1 H),

7.35–7.24 (m, 2 H), 6.92 (dd, J = 17.2, 11.0 Hz, 1 H), 5.63 (dd, J

= 17.2, 1.2 Hz, 1 H), 5.37–5.25 (m, 3 H), 4.67–4.64 (m, 1 H), 4.58

(s, 1 H), 4.37–4.33 (m, 1 H), 2.14–2.01 (m, 2 H), 1.69–1.63 (m, 1

H), 1.59–1.55 (m, 6 H), 1.23 (d, J = 6.4 Hz, 3 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 139.4, 137.8, 135.0, 134.3, 127.8, 127.3,

126.6, 126.1, 116.4, 114.1, 99.5, 72.3, 69.5, 42.4, 30.3, 25.8,

19.7 ppm. HRMS (ESI): calcd. for C₁₈H₂₄O₂Na [M + Na]⁺

295.1674; found 295.1732.

(4S,5R,6R)-5-Allyl-2,2,4-trimethyl-6-(2-vinylphenyl)-1,3-dioxane

(70): Diol 69 was protected as its acetonide as described above for

the synthesis of compound 35, to give compound 70 (13 mg, 90%).

1

R_f= 0.5 (EtOAc/hexane, 1:20). [α]²_D⁵= +76.0 (c = 2.2, CHCl₃). H

(8R,9S)-8-[(S)-1-Acetoxyethyl]-6,7,8,9-tetrahydro-5H-benzo[7]annul-

ene-5,6,9-triyl Triacetate (Tetraacetate of 66): A solution of triol

65 in dry THF (110 mg, 0.23 mmol) was treated with TBAF (1 m

solution in THF; 0.46 mL, 0.46 mmol) at room temperature. After

6 h, the solvent was evaporated, and the residue was purified by

column chromatography (EtOAc/hexane, 1:5) to give tetrol 66

(50 mg, 0.21 mmol) as a colourless liquid.

NMR (200 MHz, CDCl₃): δ = 7.57–7.52 (m, 1 H), 7.46–7.42 (m, 1

H), 7.34–7.20 (m, 2 H), 6.62 (dd, J = 17.0, 11.0 Hz, 1 H), 5.63 (dd,

J = 17.0, 1.2 Hz, 1 H), 5.40–5.26 (m, 3 H), 4.82–4.75 (m, 2 H),

3.71–3.65 (m, 1 H), 1.97–1.66 (m, 3 H), 1.56–1.42 (m, 6 H), 1.29

(d, J = 6.2 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 137.4,

137.2, 135.1, 134.3, 127.8, 127.1, 126.8, 125.7, 116.4, 115.8, 101.1,

69.5, 68.0, 47.3, 33.4, 25.5, 24.3, 21.8 ppm.

(5S,6S,Z)-6-[(S)-1-(tert-Butyldiphenylsilyloxy)ethyl]-6,7-dihydro-

5H-benzo[7]annulen-5-ol (63): Compound 61 (385 mg, 0.82 mmol)

was dissolved in anhydrous CH₂Cl₂(degassed by argon purging;

Tetrol 66 (50 mg, 0.21 mmol) was dissolved in distilled Et₃N

(0.8 mL), and Ac₂O (0.175 mL, 1.26 mmol) was added along with

a catalytic amount of DMAP at room temperature. The reaction

5244

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Eur. J. Org. Chem. 2014, 5229–5246

Stereoselective Synthesis of Enantiopure Oxetanes

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mixture was stirred at room temperature for 2 d, then the Et₃N was

evaporated under vacuum, and the crude product was purified by

flash chromatography (EtOAc/hexane, 1:10) to give the pure tetra-

acetate (60 mg, 70%) as a gummy solid. R_f= 0.4 (EtOAc/hexane,

1:5). [α]²_D⁵= –44.1 (c = 2.5, CHCl₃). H NMR (200 MHz, CDCl₃):

1

δ = 7.43–7.23 (m, 4 H), 6.318 (s, 2 H), 5.44–5.39 (m, 1 H), 4.90

(dd, J = 6.2, 5.0 Hz, 1 H), 2.15–2.09 (m, 10 H), 1.95 (s, 3 H), 1.79 (s,

3 H), 1.21 (d, J = 8.0 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 170.3, 170.2, 170.0, 169.8, 136.6, 133.8, 128.5, 128.3, 71.3, 69.7,

54.0, 31.8, 29.8, 29.4, 28.3, 21.3, 21.2, 21.1, 18.0 ppm. HRMS

(ESI): calcd. for C₂₁H₂₈O₈Na [M + Na]⁺429.1525; found 429.1550.

General Method for Glycosidase Inhibition Study: The inhibitory

activities of cyclitols 49–52, 60, and 66 were determined using a

spectrophotometric glycosidase assay with p-nitrophenyl glucosides

(α or β) as substrates. The residual hydrolytic activities of the

glycosidases were measured spectrophotometrically (Shimadzu

UV/Vis spectrophotometer). A typical enzymatic assay (final vol-

ume 3 mL) contained 0.03–0.06 unitsmL^–1of the enzyme (1 unit =

1 enzyme unit liberating 1 μmol of p-nitrophenol per minute from

the p-nitrophenyl glycoside). Each assay was performed with the p-

nitrophenyl glucoside derivatives as substrate in a potassium phos-

phate buffer (67 mm, pH 6.8). The assays were performed with four

different concentrations of the substrates (1, 2, 3, and 4 mm in the

aq. buffer solution). Enzyme and inhibitors (buffered solutions of

the cyclitols; for compounds 60 and 66, a very small amount of

DMSO was added to tackle the solubility issue) were preincubated

for 1–2 min at 37 °C, depending on the enzyme, and the reaction

was started by addition of the substrate. The p-nitrophenolate

formed was measured by UV spectroscopy at 400 nm at 30 s inter-

vals. A suitable control assay was performed in each case without

adding the inhibitors.

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Financial support from Board of Research in Nuclear Science

(BRNS), India [grant number 37(2)/14/09/2014-BRNS] is gratefully

acknowledged. The authors are grateful to the Department of Sci-

ence and Technology (DST), India (IRPHA) for an NMR instru-

ment. R. B., D. D., and J. H. are grateful to the Council of Scien-

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Grants Commitee (UGC), India for research fellowships. Special

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Received: May 1, 2014

Published Online: July 15, 2014

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Article Doi

Stereoselective synthesis of enantiopure oxetanes, a carbohydrate mimic, an ε-lactone, and cyclitols from biocatalytically derived β-hydroxy esters as chiral precursors

DOI: 10.1002/ejoc.201402521

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