Synthesis of tetrahydrofuran-based natural products and their carba analogs via stereoselective enzyme mediated Baeyer–Villiger oxidation

Article abstract of DOI:10.1016/j.tet.2015.11.048

In this work we present efficient formal syntheses of several biologically interesting natural products (showdomycin, goniofufurone, trans-kumausyne) and their novel carba analogs by applying different Baeyer–Villiger monooxygenases. This strategy provides access to tetrahydrofuran-based natural products, C-nucleosides and both antipodes of the corresponding carba analogs in high optical purities (up to >95% ee) starting from simple achiral and commercially available building blocks (tetrabromoacetone, furan and cyclopentadiene). The striking key features of this chemo-enzymatic approach are the introduction of four stereogenic centers in as few as three reaction steps within a desymmetrization approach and the short-cut of several reaction sequences by the implementation of a biocatalytic step.

Full text of DOI:10.1016/j.tet.2015.11.048

Accepted Manuscript
Synthesis of tetrahydrofuran-based natural products and their carba analogs via
stereoselective enzyme mediated Baeyer-Villiger oxidation
Florian Rudroff, Dario A. Bianchi, Roberto Moran-Ramallal, Naseem Iqbal, Dominik
Dreier, Marko D. Mihovilovic
PII:
S0040-4020(15)30232-5
10.1016/j.tet.2015.11.048
TET 27305
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 October 2015
Revised Date: 19 November 2015
Accepted Date: 20 November 2015
Please cite this article as: Rudroff F, Bianchi DA, Moran-Ramallal R, Iqbal N, Dreier D, Mihovilovic MD,
Synthesis of tetrahydrofuran-based natural products and their carba analogs via stereoselective enzyme
mediated Baeyer-Villiger oxidation, Tetrahedron (2015), doi: 10.1016/j.tet.2015.11.048.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
A Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis of tetrahydrofuran-based natural
products and their carba analogs via
stereoselective enzyme mediated Baeyer-
Villiger oxidation
Leave this area blank for abstract info.
Florian Rudroffa , Dario A. Bianchia, b , Roberto Moran-Ramallala , Naseem Iqbala , Dominik Dreiera and Marko
D. Mihovilovic a,

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of tetrahydrofuran-based natural products and their carba analogs via
stereoselective enzyme mediated Baeyer-Villiger oxidation
Florian Rudroffa , Dario A. Bianchia, b , Roberto Moran-Ramallala , Naseem Iqbala , Dominik Dreiera and
Marko D. Mihovilovic a,
aInstitute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, A-1060 Vienna, Austria
bInstituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha
531, S2002LRK Rosario, República Argentina
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this work we present efficient formal syntheses of several biologically interesting natural
products (showdomycin, goniofufurone, trans-kumausyne) and their novel carba analogues by
applying different Baeyer-Villiger monooxygenases. This strategy provides access to
tetrahydrofuran-based natural products, C-nucleosides and both antipodes of the corresponding
carba analogues in high optical purities (up to >95% ee) starting from simple achiral and
commercially available building blocks (tetrabromoacetone, furan and cyclopentadiene). The
striking key features of this chemo-enzymatic approach are the introduction of four stereogenic
centers in as few as three reaction steps within a desymmetrization approach and the short-cut of
several reaction sequences by the implementation of a biocatalytic step.
Available online
Keywords:
showdomycin
goniofufurone
biotransformation
asymmetric synthesis
chemo-enzymatic
C-nucleosides
2009 Elsevier Ltd. All rights reserved
.
carba-C-nucleosides
Scheme 1. Schematic overview of the syntethic strategy towards natural products containing a tetrahydrofuran motif employed within this work.
———
Corresponding author. Tel.: +43-1-58801-15420; fax: +(43)-1-588-01-163-99; e-mail: marko.mihovilovic@tuwien.ac.at

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Within this contribution we present a conclusive methodology
for the (formal) synthesis of above mentioned bio-active
substances and present additional examples to previously reported
preliminary results of our research effort in this area.34,35
Tetrahydrofuran- and cyclopentane-based compounds were
successfully accessed starting from the very simple achiral starting
materials furan and cyclopentadiene, respectively. Subsequent
enzyme-mediated Baeyer-Villiger oxidation is used to successfully
introduce chirality by exploiting the above mentioned enzymes.
Furthermore, the Baeyer-Villiger biooxidation of the cyclopentane
based starting material afforded both antipodes selectively when
using enzymes CPMOComa and CHMOXantho, respectively. This
behavior is in line with our recently identified correlation of
sequence clustering and stereopreference of BVMOs.36
Consequently, all compounds emerging from these Baeyer-
Villiger products were accessed in an enantiocomplementary form.
Up to four stereogenic centers were established in only three
chemo-enzymatic steps with high optical purity. The precursors
presented in this work may serve as efficient shortcuts for the
synthesis of the mentioned tetrahydrofuran-based natural products
as well as their carba analogs in comparison to current total
syntheses. To our knowledge, carba analogs of these compounds
have not been described in the literature, so far, and are therefore
potentially interesting in means of studying their biological
behavior.
Tetrahydrofuran is a common motif in several important classes
of biologically active compounds such as showdomycin,
goniofufurone and trans-kumausyne (Scheme 1). Showdomycin
displayed antitumor1 and antibiotic2 activity, whereas
goniofufurone has been described as cytotoxic to human tumor
cells.3 The structural characteristics of trans-kumausyne have
attracted remarkable interest by synthetic chemists and a number
of total syntheses have recently been published.4-8
C-nucleosides represent another structural class, which attracts
notable attention in the scientific community, with the above
mentioned showdomycin being one example. C-nucleosides are
compounds containing a C-C bond between the carbohydrate and
the base rather than a C-N bond (N-nucleosides). This structural
feature provides increased stability as the glycosidic C-C bond
cannot be cleaved hydrolytically (increased in vivo stability). An
additional characteristic is the increased enzymatic stability.
Therefore, C-nucleosides exhibit several special biological
features such as antibiotic, anticancer and/or antiviral activity in
combination with an interesting pharmacological behavior.9-13
While common nucleosides are usually derived from pentoses,
their carba analogs (the tetrahydrofuran ring is substituted by a
cyclopentane ring) may not be accessed in this way and often
require a more complex synthetic strategy. Hence, carba-C-
nucleosides are a class of potential bio-active compounds
combining common features of classical C-nucleosides and a non-
carbohydrate core structure that are underrepresented in the
literature so far. In the same way carba analogs of tetrahydrofuran
containing natural products may offer interesting biological
behavior.
2. Results and Discussion
X
X
O
Br
O
X
[4+3] cycloaddition
(i)
debromination
(ii)
+
Br
Br
O
Br Br
3
Br
1, X = O
2, X = CH2
4, X = O
5, X = CH2
X = O, CH2
Scheme 2. Preparation of bicyclic ketones 4 and 5 via Cu/Zn-couple mediated
Since the first publication by Adolf Baeyer and Victor Villiger
in 189914, the Baeyer-Villiger oxidation has become an important
method in synthesis of esters and lactones from acyclic and cyclic
ketones, respectively.15-18 In recent years several methods for the
stereoselective Baeyer-Villiger oxidation became available.19-21
Due to the fact that the chemical Baeyer-Villiger oxidation
requires a peracid as an oxidant in combination with often harsh
reaction conditions, several problems arise, in particular safety
issues imposed by the explosive character of reactants and low
functional group tolerance. The development of a biocatalytic
variant of this transformation by applying Baeyer-Villiger
monooxygenases (BVMOs) enabled synthetic chemists to
circumvent some of these disadvantages and, moreover, achieve
significantly higher regio-, chemo- and stereoselectivity for the
oxygen insertion products. Therefore, BVMO mediated reactions
evolved as an attractive alternative and an important tool for the
preparation of chiral esters and lactones in synthetic chemistry.22-27
[3+4] cycloaddition (i) followed by reductive debromination (ii)..
We envisioned the [4+3] cycloaddition as a powerful tool for the
construction of the desired seven-membered bicyclic ketones 437
and 5, which act as precursors for a subsequent Baeyer-Villiger
oxidation. This cyclization involves a perbromo ketone (1,1,3,3-
tetrabromoacetone 3 was synthesized according to the literature38
)
as dienophile, which generates the reactive oxyallyl species in the
course of the reaction. The cyclization reaction was conducted
with freshly prepared Cu/Zn-couple39 and an excess of the reagent
was used for the subsequent debromination. In line with previous
reports on facilitating such heterogeneous cycloaddition reactions
by ultrasound irradiation 40,41, the synthesis of bicyclic ketones 4
and 5 was carried out according to a sonochemical protocol
developed in our group.42
Furan 1, tetrabromoacetone 3, Cu/Zn-couple and catalytic
amount of dibromoethane were reacted under sonication and at
30°C. After filtration the crude solution of 2,4-dibromo-8-
oxabicyclo[3.2.1]oct-6-en-3-one was used without further
purification for the debromination step. After reduction with
Cu/Zn-couple in the presence of NH4Cl at -78°C and subsequent
extractive work-up oxo-ketone 4 was obtained as beige crystals in
good yield and purity (72%; m.p. 36-38 °C). Reaction of
cyclopentadiene 2 with tetrabromoacetone 3, activated Zn and
catalytic amount of I2 gave crude 2,4-dibromobicyclo[3.2.1]oct-6-
en-3-one via an analogous protocol. Debromination with activated
Zn and work-up provided carba-ketone 5 in adequate yield and
purity (58%).
A large number of BVMOs are known by now and were
successfully applied for the synthesis of chiral building blocks
aiming at the preparation of bioactive compounds. In order to
assist the selection process to identify the most suitable enzyme
for a given substrate, we recently published some decision
guidance for quantitative and comparative evaluation of chiral
catalysts28. Consequently, enzymes of choice for this preparative
work turned out to be cyclopentanone monooxygenase (CPMO;
CE 1.14.13.16)29,30
_ from Comamonas sp. NCIMB 9872 (EC;
CPMOComa) and cyclohexanone monooxygenase (CHMO) from
Xanthobacter sp. ZL5 (CHMOXantho).31 Both enzymes were
overexpressed in Escherichia coli in order to circumvent elaborate
cofactor recycling strategies and troublesome isolation of
NADPH-dependent instable BVMOs, and successful recombinant
whole-cell biotransformations were applied.32,33
2.1. Microbial Baeyer-Villiger oxidation of bicyclic ketones
Having the symmetric ketones 4 and 5 in hands several different
BVMOs from our enzyme collection were tested for their ability to
convert the bicyclic ketones 4 and 5 into the desired lactones (+)-6

3
and (+)- and (-)-7. All tested BVMOs were overexpressed in
Escherichia coli and conversion was monitored by GC. Screening
results are shown in Table 1.
(+)-6 and (+)- and (-)-7 were then used as a platform for
comprehensive chemical transformations.
ACCEPTED MANUSCRIPT
Table 1. Results of screening different BVMOs on their ability to convert the
ketones of interest.
Bicyclic oxo ketone 4
Bicyclic carba ketone 5
Strain
conversiona
eeb
conversiona
eeb
CDMO
-
-
-
+
-
CHMOAcineto
CHMOArthro1
CHMOBrachy
CHMOBrevi1
CHMOBrevi2
CPMOComa
CHMORhodo1
CHMORhodo2
CHMOXantho
CPDMO
-
-
91 (-)
96 (-)
98 (-)
-
-
-
+
-
-
+
-
-
-
+++
93 (+)
++
++
+
59 (+)
89 (+)
97 (-)
98 (-)
99 (-)
-
+++
95 (+)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+
Scheme 3. Enzyme-mediated Baeyer-Villiger oxidations: 95% ee and 70%
yield for (+)-6, 89% ee and 63% yield for (+)-7 and >99% ee and 61% yield for
(-)-7.
++
-
BVMOPaer
BVMOMtub5
HAPMOPfl
2.2. Synthesis of goniofufurone analogs
X
X
aConversion: -: no conversion, +: <50% conversion, ++: 50% - 90%
conversion, +++:.>90% conversion.
b sign of optical rotation in parentheses
methanolysis
(ii)
X
epoxidation
(i)
O
HO
O
O
O
O
O
O
O
(+)-8, X = O
(±)-9, X = CH2
(+)-6, X = O
(±)-7, X = CH2
(-)-10, X = O
(±)-11, X = CH2
CPMOComa and CHMOBrevi2 transformed ketones 4 and 5 to the
corresponding lactones (+)-6 and (+)-7. CPMOComa was preferred
over CHMOBrevi2 based on higher stereoselectivity. CHMOXantho
was also identified to convert both bicyclic ketones 4 and 5. In the
case of substrate 5 the corresponding lactone (-)-7 was formed but
when substrate 4 was supplied, the corresponding epoxide was
formed exclusively while the ketone did not react at all.43 By using
these two different BVMOs we achieved facile access to the
antipodal carba-lactones (+)-7 and (-)-7. Hence, we were able to
prepare all subsequent carba-products in an enantiocomplementary
X
HO
(iii)
O
X
O
HO
RO
O
O
(-)-12, X = O
(±)-13, X = CH2
HO
Scheme 4. Preparation of goniofufurone analogs: (i) m-CPBA, CH2Cl2, reflux
for synthesis of (+)-8, rt for synthesis of (±)-9, 8: yield: 98%, (+)-9: yield:
69%, (-)-9: yield: 75%; (ii) MeOH/H2O, K2CO3, rt, (-)-10: yield: 98%, (+)-11:
yield: 67%, (-)-11: yield: 74%; (iii) SnCl4, CH2Cl2, -78 °C for synthesis of (-)-
12, rt for synthesis of (±)-13, (-)-12: yield: 98%, (+)-13: yield: 85%, (-)-13:
yield: 79%.
manner.
Biotransformations
proceeded
with
perfect
chemoselectivity, very good enantioselectivity in the case of (+)-6
and (-)-7 and reasonable optical purity for (+)-7. According to
screening results, the biotransformation in large scale was carried
out with Escherichia coli DH5α expressing CPMOComa and BL21
(DE3) cells expressing CHMOXantho either under controlled
conditions in a bioreactor or in shake flask experiments.
After one chemoenzymatic step we were able to synthesize the
key building blocks (+)-6 and (+)- and (-)-7 to get access to
goniofufurone and their carba analogs. In Scheme 4 all synthetic
steps including reaction conditions for formal syntheses of
goniofufurone analogs starting from lactones (+)-6 and (+/-)-7 are
displayed. In the first step, a diastereoselective epoxidation was
carried out using m-chloroperbenzoic acid (m-CPBA) as oxidant
reagent. This procedure47,48 afforded selectively exo-epoxide (+)-8
in excellent yield (98%) as well as the carba-epoxides (+)-9 (69%
yield) and (-)-9 (75% yield). Interestingly the shielding effect from
the bridging CH2 group or the oxygen atom in addition to the
geometry of the bicyclic ring characteristics resulted in a perfectly
stereochemically controlled epoxidation. Subsequent methanolysis
was succcessfully applied to obtain compound (-)-10 in 98% yield,
compound (+)-11 was isolated in 67% yield and compound (-)-11
in 74% yield. Intramolecular ring opening of the epoxide via
Lewis acid activation resulted in formation of bicyclic lactone (-)-
12 again in excellent yield (98%). Transformation of (+)-11 gave
access to both antipodes (+)-13 (85% yield) and (-)-13 (79%
yield). Preparation of these key intermediates enables access to
various goniofufurone analogs as interesting natural products
The fermentation of oxo-ketone 4 to the corresponding lactone
(+)-6 was optimized by exploiting the in situ substrate feeding /
product removal concept (SFPR).44 This approach enables higher
compound concentrations which otherwise would be toxic for
cells.44-46 After sequential extraction of the resin and the
fermentation broth and subsequent purification by column
chromatography the desired lactone (+)-6 was isolated in good
yield (70%) and very good optical purity (95% ee; [α]D20: +85.2 (c
= 0.2, CHCl3)). In contrast carba-ketone 5 was transformed into
the corresponding lactone (+)-7 catalyzed by CPMOComa applying
shake flask experiments. The desired product was obtained in
21
reasonable yield (63%) and good optical purity (89% ee; [α]D
=
+80.2 (c = 0.52, CHCl3)). Transforming the same ketone 5 using
CHMOXantho as the catalyst, the enantiocomplementary lactone (-)-
7 was obtained in again good yield (71%) and excellent optical
21
purity (>99% ee; [α]D = −83.3 (c = 0.51, CHCl3)). Compounds

4
Tetrahedron
ACCEPTED MANUSCRIPT
containing
a fused tetrahydrofuran or cyclopentane ring
respectively according to previous references.49,50
2.3. Synthesis of trans-kumausyne analogs
Scheme 5. Preparation of trans-kumausyne analogs: (i) 1) KOH, MeCN/H2O
2) I2/KI, 40°C for synthesis of (-)-14, rt for synthesis of (±)-15, (-)-14: yield:
75%, (+)-15: yield: 92%, (-)-15: yield: 100%; (ii) NaN3, DMSO, 75°C, yield:
100%; (iii) HSn(Bu)3, toluene, 60°C, (-)-17: yield: 99%, (+)-18: yield: 85%, (-
)-18: yield: 81%; (iv) tert-butylchlorodiphenylsilane, imidazole, DMF, rt, (-)-
19: yield: 92%, (+)-20: yield: 95%, (-)-20: yield: 89%.
Furthermore we exploited the geometry of the biotransformation
products (+)-6 as well as (+)- and (-)-7 and introduced two new
stereogenic centers by applying an iodolactonization reaction. This
approach provides goniofufurone analog precursors from the
previous section additionally bearing an iodine atom in position of
the previous hydroxyl as a good leaving group. Following this
route we aimed for the accessibility of another interesting natural
compound, namely trans-kumausyne. Scheme 5 shows the
synthetic strategy carried out for the formal preparation of trans-
kumausyne analogs starting from chiral bicyclic lactones (+)-6 and
(+)- and (-)-7. Lactones were hydrolyzed in situ using KOH in
MeCN/H2O. Subsequent iodolactonization adding I2/KI enabled a
one pot reaction to give iodolactone (-)-14 in good yield (75%).
Applying the same protocol carba analogs (+)- and (-)-15 were
obtained in excellent yields ((+)-15 92% yield; (-)-15 100% yield).
Again, two new stereogenic centers were incorporated with perfect
selectivity. Additionally, these iodide intermediates enable further
chemical transformations. As an example we synthesized the
corresponding azide (+)-16 starting from (+)-15 in the presence of
sodium azide. Azidolactone (+)-16 was obtained quantitatively
with complete inversion of the stereogenic center in position 6.
Next, the iodolactones were dehalogenated using tributyltin
hydride as the reducing agent and gave lactone (-)-17 after
purification as colorless oil with identical spectral properties as
described in the literature51 in perfect yield (99%). Transformation
of the carba analogs gave antipodal products 18 in very good
yields ((+)-18 85%; (-)-18 81%). Discrepancies in published data
about the absolute configuration based on the specific optical
rotation of alcohol (-)-17 prompted us to extend our synthetic
investigations towards the protected alcohol compounds (-)-
19/(+)- and (-)-20. Finally the alcohol functionality was masked by
using tert-butylchlorodiphenylsilane and all three compounds were
obtained in very good yields ((-)-19: 92%; (+)-20: 95%, (-)-20:
89%).
Scheme 6. Preparation of C-nucleosides: (i) NMO/OsO4, DCM/t-BuOH, rt, 21:
yield: 55%, (+)-22: yield: 56%, (-)-22: yield: 50%; (ii) 2-methoxypropene or
2,2-dimethoxypropane, p-toluenesulfonic acid, acetone, rt, (+)-23:
yield: 76%, (+)-24: yield: 60%, (-)-24: yield: 80%; (iii) NMO/OsO4, DCM/t-
BuOH, rt, then AlCl3, acetone, rt, (+)-23: yield: 47%; (iv) aminoguanidine
bicarbonate, pyridine, reflux, (-)-25: yield: 78%, (+)-26: yield: 43%, (-)-26:
yield: 50%, (-)-27: yield: 67%, (+)-26: yield: 71%, (-)-26: yield: 71%, (+)-30:
yield: 69%, (-)-30: yield: 67%; (v) H2, Pd/C, EtOAc, rt, (+)-29: yield: 83%, (-)-
29: yield: 79%.
Special interest was given to the very broad field of C-
nucleosides with showdomycin being one prominent example.
Synthesis of compounds (+)-23 and (+)- and (-)-24 provide
suitable precursors for the formal total synthesis of showdomycin
and its carba analogs They may also act as precursors for the
synthesis of other C-nucleosides like pseudouridines. In Scheme 6
all transformations including the preparation of other C-
nucleosides are summarized. Conversion of the bio-oxidation
products (+)-6 and (+)- and (-)-7 to the key intermediates (+)-23
and (+)- and (-)-24 for modified nucleosides turned out to be
challenging due to the high water solubility of the intermediate
diols 21 and (+)- and (-)-22. Among several protecting groups for
the diol structural motif, the acetonide turned out to be most
suitable for subsequent transformations. Several methods were
investigated in order to obtain an acceptable yield for the target
compounds. First a stepwise synthesis was applied. Olefin 6 was
dihydroxylated using catalytic amount of OsO4 and N-
methylmorpholine oxide (NMO) as the re-oxidant achieving two
new stereogenic centers selectively. Using only little amounts of
an aqueous solution of Na2SO3 for quenching and intensive re-
extraction, diol 21 was obtained with a reasonable yield of 55%
after purification. The diol 21 was then reacted further with 2,2-
dimethoxypropane and para-toluenesulfonic acid (p-TsOH) as a
catalyst to yield acetonide (+)-23 as colorless crystals in good
yield (76%). The most suitable strategy turned out to avoid work-
up of the reaction after the dihydroxylation but rather use the crude
product directly for the protection step. Crude diol 21 was
dissolved in dry acetone and freshly sublimed AlCl3 was added.
After full conversion and purification the acetonide (+)-23 was
obtained in 47% yield over two steps, which was only a slight
improvement. Upon comparison of physical data52 for (+)-23 the
absolute configuration of bio-oxidation product (+)-6 could be
confirmed to be (1S,6S). Similar conditions were applied to
By comparing the specific rotation of (-)-19 with published
data51 we were able to conclude that chiral information was
conserved completely. This is probably true for the carba analogs
but to our knowledge no reference data is available yet. With the
synthesis of these key intermediates, the formal synthesis of trans-
kumausyne and its carba analogs were formally completed.
2.4. Synthesis of C-nucleosides

5
convert the carba analogs (+)- and (-)-7. When synthesizing the
diols (+)- and (-)-22, aqueous conditions were avoided during
work-up by adsorbing the reaction solution directly on silica gel.
After purification by column chromatography comparable yields
of 56% for (+)-22 and 50% for (-)-22 were achieved. Protection of
the diol moiety was performed as described before and
acetonide(+)-24 was obtained in 60% and (-)-24 in 80% yield
respectively. These compounds have been established as key
intermediates for analogs of the natural C-nucleoside
showdomycin. Finally the lactone moiety was addressed to
synthesize other C-nucleosides. As an example 5-amino-4H-1,2,4-
triazol was installed as a base using available oxo- and carba
lactones (Scheme 6). This represents a formal access to novel non-
natural C-nucleosides via the bio-oxidative approach in this work.
Within the general procedure for the preparation of C-nucleosides
the corresponding lactone was refluxed with aminoguanidine
bicarbonate in pyridine under argon atmosphere till conversion
was proved to be complete by TLC analysis. Purification by
column chromatography provided products (-)-25, (+)- and (-)-26,
(-)-27, (+)- and (-)-28 and (+)- and (-)-30. For the elaboration of
saturated lactones (+)- and (-)-29, olefins (+)- and (-)-7 were
hydrogenated using a balloon filled with hydrogen and Pd/C (10%
w/w) as catalyst to provide 83% of (+)-29 and 79% of (-)-29.
standard. Combustion analysis was carried out in the
ACCEPTED MANUSCRIPT
Microanalytic Laboratory, University of Vienna. General
conversion control and examination of purified products were
performed with GC Top 8000 / MS Voyager (quadropol, EI+)
using a standard capillary column BGB5 (30mx0.32mm ID).
Enantiomeric excess was determined via GC using a BGB 175
column (30mx0.25mm ID, 0.25µm film) and a BGB 173 column
(30mx0.25mm ID, 0.25µm film) on a ThermoQuest Trace GC
2000 and a Thermo Focus GC. Specific rotation [α]D was
20
determined using a Perkin Elmer Polarimeter 241 by the following
equation: [α]D20 = 100*α / [c]*l; c[g/100mL], l[dm]
4.1. Biocatalyst performance screening on analytical scale
A baffled Erlenmeyer flask was charged with LB medium with
appropriate antibiotics supplement (10 mL), inoculated with a
bacterial single colony from an Agar plate and incubated at 37 °C
in an orbital shaker o/n. The biotransformation medium,
supplemented with ampicillin (200 mg/L), was then inoculated
with 2% v/v of the preculture and incubated for approx. 1–2 h
under the same conditions until an optical density of 0.2–0.6 was
reached. Inducing agent and β-cyclodextrin (1 equiv.) were added,
the mixture was thouroughly mixed and split in 1.0 mL aliquots
into 24-well plates. Substrates were added as 0.8 M solutions in
1,4-dioxane to a final concentration of 4 mM. The plates were
sealed with adhesive film and incubated at the appropriate
temperature in an orbital shaker for up to 24 h. Analytical samples
were prepared by extraction of 0.5 mL of biotransformation
culture with 1.0 mL dichloromethane (supplemented with 1 mM
methyl benzoate as internal standard) after centrifugal separation
of the cell mass (approx. 15 kRCF, 1 min, rt) and measured by
chiral GC..
3. Conclusions
In summary, we were able to provide facile access to several
biological
interesting
natural
products
(showdomycin,
goniofufurone, trans-kumausyne) as well as C-nucleosides.
Furthermore, enantiocomplementary carba analogs of all presented
compounds were successfully synthesized. An enzyme-mediated
Baeyer-Villiger oxidation was applied to introduce chirality
efficiently. The obtained optically active lactones were used as a
convenient platform for several stereoselective transformations.
Not only can the presented compounds serve as versatile
precursors for the synthesis of above mentioned natural products
(formal synthesis) but the corresponding enantiocomplementary
carba precursors may also be transformed further to carba analogs
of the described compounds which have not been described in the
literature yet. It would be interesting to study their biological
behavior in contrast to the original tetrahydrofuran based
compounds.
4.2. 8-Oxabicyclo-[3.2.1]oct-6-en-3-one (4)
Cu/Zn couple (20.6 g, 0.31 mol), furan 1 (100 mL, 1.39 mol)
and catalytic amount of dibromoethane were suspended in dry
MeCN (80 mL). The reaction mixture was cooled to 10 °C under
nitrogen atmosphere and was sonicated for 30 min under
subsequent addition of tetrabromoacetone 3 (38.2 g, 1.02 mol)
dissolved in dry MeCN. The temperature was maintained below
25 °C. The conversion of the reaction was monitored by GC-MS.
After complete conversion the reaction mixture was filtered
through a pad of Celite®. The crude solution of 1,5-dibromo-8-
oxabicyclo-[3.2.1]oct-6-en-3-one was used without further
purification for the next reaction step. Cu/Zn couple (47.3 g, 0.72
mol) and NH4Cl (26.0 g, 0.49 mol) were suspended in dry EtOH
and cooled to -78 °C. Maintaining a reaction temperature below -
50 °C, 80% of crude 1,5-dibromo-8-oxabicyclo-[3.2.1]oct-6-en-3-
one in MeCN was added slowly. After 15 min the remaining 20%
of the solution were added and the reaction mixture was warmed
to room temperature. Reaction monitoring was performed by GC-
MS. After conversion had reached completion, Cu/Zn couple was
removed by filtration and the solid residue was washed with
dichloromethane. The combined organic phases were vacuum
evaporated. The crude product was cooled with an ice bath upon
neutralization with saturated bicarbonate. The obtained suspension
was filtered again and solids were washed intensively with
dichloromethane. Layers were separated and the organic phase
was dried over Na2SO4 and concentrated (bath temperature below
30 °C!). The purity of the crude product was checked by NMR and
GC/MS. After evaporation of all volatiles and drying in vacuo
compound 4 was obtained as beige crystals; yield 72%; m.p. 36-38
4. Experimental Section
Unless otherwise noted, chemicals and microbial growth media
were purchased from commercial suppliers and used without
further purification. All solvents were distilled prior to use. Flash
column chromatography was performed on silica gel 60 from
Merck (40-63µm). Abbreviations are used as the following: LP =
light petroleum, o/n = over night, rt = room temperature. Basic
silica gel was obtained by mixing NEt3 (5%), the desired solvent
mixture and silica gel. This suspension was stirred for 5 minutes
and was used for column chromatography. Medium pressure
column chromatography was performed on a regular silica gel
column with a Büchi 681 Chromatography Pump with Automatic
Fraction Collector. Melting points were determined using a
Kofler-type Leica Galen III micro hot stage microscope and are
uncorrected. Biotransformations were carried out in a New
Brunswick Bioflow 110 fermenter equipped with pH probe,
oxygen probe, flow controller and temperature control. Monitoring
of all fermentation parameters was performed using the
BiocommandPlus 3.30 software by New Brunswick. Glucose
concentrations were determined with Roche AccuChek-go. NMR-
spectra were recorded from CDCl3, CD3OD or DMSO-d6
solutions on a Bruker AC 200 (200 MHz) spectrometer and
chemical shifts are reported in ppm using TMS as internal
°C (lit.53 37 – 39 °C). H NMR (200 MHz, CDCl3): δ = 2.30 (d, J
1
= 16 Hz, 2 H), 2.80 (dd, J = 16 Hz & 5 Hz, 2 H), 5.05 (d, J = 5 Hz,
2 H), 6.20 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 46.6,
77.1, 133.3, 205.2 ppm.

6
Tetrahedron
4.3. Bicyclo-[3.2.1]oct-6-en-3-one (5)
NMR (50 MHz, CDCl3): δ = 46.7, 71.0, 76.3, 81.6, 129.0, 133.4,
ACCEPTED MANUSCRIPT
172.0 ppm.
Cyclopentadiene was obtained by distillation of
2
4.5. 3-Oxabicyclo[4.2.1]non-7-en-4-one ((+)- and (-)-7)
dicyclopentadiene (Tdist = 38-40 ºC). Tetrabromoacetone 3 was
prepared by reaction of acetone and bromine under acidic
conditions. Cu/Zn couple (20.2 g, 0.309 mol) and catalytic amount
of I2 were suspended in dry MeCN (100 mL) under nitrogen
atmosphere and with sonication (approx. 10 min). The reaction
mixture was cooled to 0 ºC with subsequent dropwise addition of
cyclopentadiene (9.17 g, 0.139 mol) and tetrabromoacetone (37.1
g, 0.099 mol) while sonicated and the temperature was maintained
below room temperature throughout the experiment. The reaction
was monitored by TLC until complete conversion was observed
(approx. 3-7 h). Activated Zn (20.0 g, 0.306 mol), NH4Cl (20.0 g,
0.374 mol) and dry MeOH (100 mL) were added under nitrogen
atmosphere at 0 ºC and with sonication. The reaction was followed
by TLC until complete conversion. Remaining Zn was removed by
filtration through a pad of Celite® and the solid residue was
washed with diethylether. The suspension was cooled with an ice
bath and neutralized with sodium bicarbonate. The obtained
suspension was filtered again, washed with diethylether and
concentrated in vacuo. The crude was extracted with pentane (3
times), trying to achieve a selective extraction of the desired
product taking advantage of its high carbon nature. The combined
organic layers were dried over Na2SO4 and concentrated (bath
temperature below 30 °C!) in vacuo. The purity of the crude
product was checked by NMR, where we can see small amounts of
impurities but the purity of the crude is sufficient for its use in the
next step. After evaporation of all volatiles and drying in vacuo
compound 5 was obtained; yield 58%; To increase the purity of
the product sublimation can be applied to obtain beige crystals;
m.p. 98-100 °C. 1H NMR (200 MHz, CDCl3): δ = 1.75 (d, J = 10.9
Hz, 1 H), 2.03-2.16 (m, 1 H), 2.31 (dd, J = 17.2 Hz & 2.4 Hz, 2
H), 2.44 (dd, J = 17.2 Hz & 3.3 Hz, 2 H), 2.90 (br. s, 2 H), 6.00 (s,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 38.2, 41.7, 46.3, 135.4,
210.4 ppm.
A 1 L Erlenmeyer flask containing 200 mL of sterile TB
medium supplemented with 0.2 mg/mL of ampicillin and a drop of
antifoam was inoculated with 2 mL (1% vol) overnight culture
BL21(DE3)/p11X5.1 grown on LB medium (0.2 mg/mL
ampicillin). The culture was growing at 30 ºC and 120 rpm until
the optical density at 590 nm reached a value between 10-18
(approx. 8-11 h). Then the temperature was decreased to 24 ºC and
IPTG was added to a final concentration of 0.1 mM. After one
hour, β-cyclodextrin (930 mg; 0.820 mmol), compound 5 (100 mg,
0.82 mmol) and 1,4-dioxan (1 mL) were added. The reaction was
followed using GC-MS until 80-90% of conversion (approx. 14-20
h). The cells were separated from the broth by centrifugation
(9600 rpm, 15 min), and the broth was continuously extracted
using dichloromethane (8-10 h). The organic layer was dried over
Na2SO4 and concentrated in vacuo. Purification by column
chromatography (LP/EtOAc = 3/1) gave the desired compounds
(+)- and (-)-7 as a colorless solid; yield 71% (ee > 99%)
(CHMOXantho); yield 63% (ee = 89%) (CPMOComa); m.p. 50-52 °C;
[α]D21 = −83.3 (c = 0.51, CHCl3) (CHMOXantho); [α]D21 = +80.2 (c =
1
0.52, CHCl3) (CPMOComa). H NMR (200 MHz, CDCl3): δ = 1.64
(d, J = 11.5 Hz, 1 H), 2.20 - 2.45 (m, 1 H), 2.65 - 2.87 (m, 2 H),
2.89 - 3.07 (m, 1 H), 4.00 - 4.24 (m, 2 H), 5.83 (dd, J = 5.7 Hz &
2.9 Hz, 1 H), 6.10 (dd, J = 5.7 Hz & 2.9 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 36.7, 42.6, 44.4, 44.7, 70.7, 131.1, 137.0,
174.1 ppm. C8H10O2 (138.16): calcd. C 69.55, H 7.30; found C
69.29, H 7.25.
4.6. (1R,6S,7S,9R)-3,8,10-Trioxatricyclo[4.3.1.07,9]decan-4-one
((+)-8)
m-CPBA (3891 mg, 22.7 mmol) was added to a solution of
compound (+)-6 (390 mg, 2.27 mmol) in dichloromethane (100
mL) at room temperature. The reaction mixture was refluxed for 2
days until no starting material could be detected by TLC. After
that, the residue was purified by column chromatography on silica
gel (Hexane/EtOAc) gave compound (+)-8 as colorless crystals;
4.4. (1S,6S)-3,9-Dioxabicyclo[4.2.1]non-7-en-4-one ((+)-6)
A New Brunswick Bioflow 110 fermenter containing 1 L of
sterile TB medium supplemented with 200 mg/L ampicillin was
inoculated with 20 mL (2 vol%) overnight culture of
DH5α/CPMO grown on LB medium (50 mg/L ampicillin). The
temperature was maintained at 37 °C and the pH was kept constant
at 7.00 ± 0.05 by adding 3N NaOH or 3N H3PO4 automatically.
The 1 L culture was grown with an air flow of 5 L/min and stirring
rates at 500 rpm. The growth was continued until the culture
density reached 3.01 - 3.44 g/L dcw and the temperature was
decreased to 25 °C. IPTG was added to a final concentration of
0.25mM and after an additional hour the fermentation culture was
supplemented with 4 g/L glucose (20% sterile solution). Two
hours after induction 20 mL of cell culture were taken and activity
tests were performed. After passing the activity tests the pre-
loaded resin and any additives were added. The glucose level was
measured periodically as the bioconversion progressed. Compound
4 (5 g, 40 mmol) was dissolved in ethanol (10 mL) and was
subsequently added to the resin (50 g wet resin, load Xeq = 0.2)
and 100 mL of LBAmp. β-cyclodextrin (10 mol%) and the
substrate-resin mixture were added to the fermentation broth. After
36 h and purification via column chromatography (LP/EtOAc =
2/1; 200 g SiO2) the desired lactone (+)-6 was isolated; yield 70%
22
1
yield 98%; m.p. 78-80 °C; [α]D = +94.9 (c = 0.79, CHCl3). H
NMR (200 MHz, CDCl3): δ = 2.92 (dd, J = 16.5 Hz & 3.8, 2 H),
3.05 (dd, J = 16.5 Hz & 2.5 Hz, 1 H), 3.76 (s, 2H), 4.19 (dd, J =
3.6 Hz & 2.7 Hz, 1 H), 4.20 - 4.50 (m, 2 H) ppm. 13C NMR (50
MHz, CDCl3): δ = 41.9, 52.6, 54.2, 69.3, 71.3, 74.2, 171.5 ppm.
C7H8O4 (156.14): calcd. C 53.35, H 5.16; found C 53.55, H 5.12.
4.7. 3,8-Dioxatricyclo[4.3.1.07,9]decan-4-one ((+)- and (-)-9)
m-CPBA (190 mg (purity 70%), 0.77 mmol) was added to a
solution of compound (+)- or (-)-7 (71 mg, 0.51 mmol) in dry
dichloromethane (5 mL) under nitrogen atmosphere. The reaction
was carried out at room temperature and after 17 h no starting
material could be detected by TLC. The reaction mixture was
cooled to -20 ºC, filtered and washed with cold dichloromethane.
The filtrate was neutralized with saturated sodium bicarbonate and
extracted with dichloromethane (x 3). The combined organic
layers were dried over Na2SO4 and concentrated. Purification by
column chromatography (LP/EtOAc = 1/1) gave compounds (+)-
24
and (-)-9; yield 75% (CHMOXantho); yield 69% (CPMOComa); [α]D
24
= −95.5 (c = 1.0, CHCl3) (CHMOXantho); [α]D = +82.8 (c = 1.2,
CHCl3) (CPMOComa). H NMR (200 MHz, CDCl3): δ = 1.29 (d, J
1
1
(95% ee); m.p.: 98-100°C; [α]D20: +85.2 (c = 0.2, CHCl3). H
= 12.5 Hz, 1 H), 1.88 (dt, J = 12.5 Hz & = 6.4 Hz, 1 H), 2.45 (t, J
= 6.4 Hz, 1 H), 2.60 (m, 2 H), 2.93 (ddd, J = 16.0 Hz & = 6.5 Hz
& = 2.0 Hz, 1 H), 3.48 (s, 2 H), 4.18 (d, J = 12.8 Hz, 1 H), 4.41
(ddd, J = 12.8 Hz & = 5.5 Hz & = 1.7 Hz, 1 H) ppm. 13C NMR (50
NMR (200 MHz, CDCl3): δ = 2.90 (dd, J = 16 Hz & 5 Hz, 1 H),
3.20 (dd, J = 16 Hz & 3 Hz, 1 H), 4.05 (dd, J =12 Hz & 3 Hz, 1
H), 4.40 (d, J = 12 Hz, 1 H), 4.70 (d, J = 3 Hz, 1 H), 4.85 (d, J = 3
Hz, 1 H), 6.10 (d, J = 6 Hz, 1 H), 6.35 (d, J =6 Hz, 1 H) ppm. 13C

7
MHz, CDCl3): δ = 31.2, 33.9, 36.8, 39.5, 54.1, 55.7, 71.6, 173.5
ppm.
CD3OD): δ = 1.30 (d, J = 11.1 Hz, 1 H), 1.89 - 2.32 (m, 3 H),
ACCEPTED MANUSCRIPT
2.77 (dd, J = 17.9 Hz & 9.7 Hz, 1 H), 2.93 (qd, J = 8.0 Hz & 2.6
Hz, 1 H), 3.54 (dd, J = 11.0 Hz & 6.2 Hz, 1 H), 3.70 (dd, J = 11.0
Hz & 4.4 Hz, 1 H), 3.87 (dd, J = 8.8 Hz & 3.6 Hz, 1 H), 4.68 (dd,
J = 8.0 Hz & 3.5 Hz, 1 H) ppm. 13C NMR (50 MHz, CD3OD): δ =
32.8, 34.7, 35.3, 49.4, 63.7, 78.4, 92.0, 178.4 ppm.
4.8. (1S,2S,4R,5R)-Methyl-2(-4-(hydroxymethyl)-3,6-
dioxabicyclo[3.1.0]hexan-2-yl)-acetate ((-)-10)
K2CO3 (20 mg, 0.14 mmol) was added to the stirred solution of
compound (+)-8 (47 mg, 0.25 mmol) in MeOH/H2O (1 mL, 8:2) at
room temperature. The reaction mixture was stirred until the
starting material had reacted completely (checked by TLC,
reaction time < 10 seconds). The mixture was quenched with
saturated aqueous solution of ammonium chloride and extracted
with EtOAc (5 x 15). The organic layer was dried over Na2SO4
and evaporated. Purification by column chromatography on silica
gel (Hexane/EtOAc) gave compound (-)-10 as a colorless oil; yield
4.12. (3aS,5R,6R,6aR)-5-(Hydroxymethyl)-6-
iodotetrahydrofuro[3,2-b]furan-2(3H)-one ((-)-14)
To a stirred solution of compound (+)-6 (0.55 g, 3.92 mmol) in
MeCN/H2O (8.6 mL, 2.3:1) was added KOH (230 mg, 4.11
mmol). The reaction mixture was stirred at room temperature for 4
h until TLC showed full consumption of the starting material.
Afterwards, a mixture of I2 (1.09 g, 4.30 mmol) and KI (2.15 g,
12.93 mmol) was added. The resulting mixture was stirred in the
dark for 5 days at 40°C. The reaction was quenched with a 10%
solution of Na2S2O3 until decoloration of the mixture was observed
and then extracted with EtOAc (5 x 15). The organic layer was
washed with brine, dried over Na2SO4 and evaporated. Purification
by column chromatography on silica gel (Hexane/EtOAc) gave
compound (-)-14 as a beige oil which solidified upon standing in
22
1
98%; [α]D = -32.09 (c = 6.19, CHCl3). H NMR (200 MHz,
CDCl3): δ = 2.43 (br s, 1 H), 2.57 (d, J = 7.5 Hz, 2 H), 3.67 (s, 3
H), 3.50 - 3.75 (m, 4 H), 4.11 (t, J = 4.3 Hz, 1 H), 4.43 (t, J = 7.5
Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 35.2, 51.9, 57.9,
62.6, 73.7, 78.9, 171.5 ppm.
4.9. Methyl 2(-4-(hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-yl)-
acetate ((+)- and (-)-11)
22
the refrigerator; yield 75%; m.p. 84-86 °C; [α]D = -70.2 (c =
1.28, CHCl3). H NMR (200 MHz, CDCl3): δ = 1.90 (br s, 1 H),
1
K2CO3 (20 mg, 0.14 mmol) was added to the stirred solution of
compound (+)- or (-)-9 (40 mg, 0.29 mmol) in MeOH/H2O (2.6
mL, 8:2) at room temperature. The reaction mixture was stirred
until the starting material had reacted completely. The reaction
mixture was directly adsorbed on silica gel and after purification
by column chromatography compounds (+)- or (-)-11,
respectively, were obtained as a colorless oil; yield 67%
2.80 (d, J = 3.3 Hz, 2 H), 3.70 (dd, J = 12.4 Hz & 4.6 Hz, 1 H),
3.86 (dd, J = 12.4 Hz & 3.0, 1 H), 4.22 (dd, J = 7.5 Hz & 2.1 Hz, 1
H), 4.33 (ddd, J = 7.5 Hz & 4.6 Hz & = 3.0 Hz, 1 H), 4.85 – 4.90
(m, 1 H), 5.22 (dd, J = 4.5 Hz & 2.1 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 20.0, 36.2, 61.2, 78.2, 90.7, 92.8, 173.8 ppm.
C7H9IO4 (284.05): calcd. C 29.60, H 3.19; found C 30.00, H 3.18.
30
(CHMOXantho); yield 74% (CPMOComa); [α]D = +13.5 (c = 1.0,
4.13. 5-(Hydroxymethyl)-6-iodohexyhydro-2H-
cyclopenta[b]furan-2-one ((+)- and (-)-15)
30
CHCl3) (CHMOXantho); [α]D
= -11.3 (c = 0.4, CHCl3)
1
(CPMOComa). H NMR (200 MHz, CDCl3): δ = 1.22 (d, J = 14.3
Hz, 1 H), 1.92 (dt, J = 14.3 Hz & 8.9 Hz, 1 H), 2.26 - 2.51 (m, 3
H), 2.55 – 2.70 (m, 1 H), 3.13 (bs, 1 H), 3.39 (d, J = 2.3 Hz, 1 H),
3.52 (d, J = 2.3 Hz, 1 H), 3.55 – 3.61 (m, 2 H), 3.67 (s, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 29.7, 35.2, 36.9, 42.0, 51.7, 60.0,
61.0, 63.9, 172.7 ppm.
To a stirred solution of compound (+)- or (-)-7 (100 mg, 0.73
mmol) in MeCN/H2O (2 mL, 2.3:1) was added KOH (43 mg, 0.76
mmol). The reaction mixture was stirred at room temperature for 5
h until TLC showed full consumption of the starting material.
Afterwards, a mixture of I2 (202 mg, 0.80 mmol) and KI (397 mg,
2.39 mmol) was added. The resulting mixture was stirred in the
dark for 39 h at room temperature. The reaction was quenched
with a 10% solution of Na2S2O3 until decoloration of the mixture
was observed and the reaction was neutralized with saturated
NH4Cl. Then the reaction was extracted with EtOAc (3x). The
organic layer was dried over Na2SO4 and evaporated. Purification
by column chromatography (LP/EtOAc = 1/2) gave compounds
(+)- and (-)-15 as a colorless oil; yield 92% (CHMOXantho); yield
4.10. (3aS,5R,6R,6aR)-6-Hydroxy-5-
(hydroxymethyl)tetrahydrofuro[3,2-b]furan-2(5H)-one ((-)-12)
A SnCl4 solution in dichloromethane (1 mL, 100 ꢀL/mL) was
added at -78°C to a solution of compound (-)-10 (0.081 g, 0.430
mmol) in dry dichloromethane (3.0 mL). The reaction mixture was
stirred for 1 h until the starting material had reacted completely
(checked by TLC). Then the residue was purified by column
chromatography (Hexane/EtOAc) to yield compound (-)-12 as an
24
100% (CPMO); [α]D = +62.5 (c = 1.2, CHCl3) (CHMOXantho);
24
1
25
amorphic, semi-crystalline form;54 yield 98%; [α]D = -30.1 (c =
[α]D = -59.4 (c = 0.3, CHCl3) (CPMO). H NMR (200 MHz,
CDCl3): δ = 1.50 (dt, J = 13.2 Hz & 9.0 Hz, 1 H), 2.10 – 2.25 (m,
2 H), 2.40 – 2.48 (m, 2 H), 2.81 (dd, J = 18.0 Hz & 9.5 Hz, 1 H),
3.02 (qd, J = 9.5 Hz & 3.1 Hz, 1 H), 3.68 (dd, J = 10.8 Hz & 4.9
Hz, 1 H), 3.77 (dd, J = 10.8 Hz & 4.5 Hz, 1 H), 4.09 (dd, J = 9.4
Hz & 4.4 Hz, 1 H), 5.17 (dd, J = 7.8 Hz & 4.4 Hz, 1 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 26.8, 33.5, 35.3, 37.1, 52.4, 61.5,
93.9, 176.2 ppm. C8H11IO3 (282.08): calcd. C 34.06, H 3.93; found
C 35.37, H 3.70.
0.86, MeOH). 1H NMR (200 MHz, CD3OD): δ = 2.50 (d, J = 18.4
Hz, 1 H), 2.72 (dd, J = 18.8 Hz & 4.9 Hz, 1 H), 3.21 (br s, 2 H),
3.48 (dd, J = 11.9 Hz & 5.9 Hz, 1 H), 3.68 (dd, J = 11.9 Hz & 3.7
Hz, 1 H), 3.74 (dt, J = 5.9 Hz & 3.7 Hz, 1 H), 4.06 (d, J = 5.5 Hz,
1 H), 4.76 - 4.80 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
37.1, 62.8, 77.2, 79.0, 88.3, 92.2, 177.8 ppm.
4.11. 6-Hydroxy-5-(hydroxymethyl)hexahydro-2H-
cyclopenta[b]furan-2-one ((+)- and (-)-13)
4.14. 6-Azido-5-(hydroxymethyl)hexahydro-2H-
To a solution of compound (+)- or (-)-11 (30 mg, 0.16 mmol) in
dry dichloromethane (2 mL), was added SnCl4 (38 ꢀL, 0.32 mmol)
dropwise under nitrogen atmosphere at −78 ºC. After 2 h all the
starting material was consumed (checked by TLC). The reaction
mixture was directly adsorbed on silica gel and after purification
by column chromatography (EtOAc) compounds (+)- and (-)-13
were obtained as a colorless oil; yield 85% (CHMOXantho); yield
79% (CPMOComa); [α]D21 = +35.1 (c = 0.87, MeOH) (CHMOXantho);
[α]D21 = -32.2 (c = 0.12, MeOH) (CPMOComa). 1H NMR (200 MHz,
cyclopenta[b]furan-2-one ((+)-16)
Compound (+)-15 (27 mg, 0.10 mmol), DMSO (1 mL) and 4Ǻ
molecular sieve were warmed to 75°C. Sodium azide (62 mg, 010
mmol) was added and the solution was stirred at 75°C for 40h. The
reaction was quenched with H2O and extracted with
dichloromethane (3x). The organic layer was dried over Na2SO4
and concentrated in vacuo. Crude mass was purified by column
chromatography (LP/EtOAc = 1/2 to 1/4) to yield compound (+)-

8
Tetrahedron
30
16 as a colorless oil; yield 100%; [α]D = +198.0 (c = 1.0,
Imidazole (53 mg, 0.78 mmol) was added to a solution of
compound (+)- or (-)-18 (22 mg, 0.14 mmol) in dry DMF (1.3 mL)
followed by tert-butylchlorodiphenylsilane (75 µL, 0.29 mmol)
under nitrogen atmosphere. The mixture was stirred for 1 h at
room temperature until the starting material had reacted
completely (checked by TLC). The reaction mixture was extracted
with dichloromethane (3x), the organic layer was dried over
Na2SO4 and concentrated in vacuo. Crude mass was purified by
column chromatography (LP – LP/EtOAc = 20/1) to yield
compounds (+)- and (-)-20 as a white solid; yield 95%
ACCEPTED MANUSCRIPT
1
CHCl3) (CHMOXantho). H NMR (200 MHz, CDCl3): δ = 0.83 (dd,
J = 10.7 Hz & 6.4 Hz, 1H), 1.35 (m, 1H), 2.02- 2.24 (m, 2H), 2.34
(dd, J = 17.9 Hz & 6.7 Hz, 1H), 2.68 - 3.03 (m, 2H), 3.67 - 3.83
(m, 2H), 4.26 (t, J = 4.2 Hz, 1H), 4.97 (dd, J = 9.2 Hz & 4.7 Hz,
1H) ppm. 13C NMR (50 MHz, CDCl3): δ = 32.7, 34.8, 36.1, 44.3,
61.5, 64.9, 84.3 ppm.
4.15. (3aS,5S,6aS)-5-(Hydroxymethyl)tetrahydrofuro[3,2-b]furan-
2(3H)-one ((-)-17)
30
(CHMOXantho); yield 89% (CPMO); m.p. 78-81 °C, [α]D = +45.0
(c = 1.0, CHCl3) (CHMOXantho); [α]D = -32.4 (c = 0.3, CHCl3)
(CPMO). H NMR (200 MHz, CDCl3): δ = 1.06 (s, 9 H), 1.12 –
1.26 (m, 1 H), 1.65 – 1.75 (m, 1 H), 2.05 – 2.41 (m, 2 H), 2.66 –
2.81 (m, 2 H), 3.60 (dd, J = 10.0 Hz & 3.3 Hz, 1 H), 3.66 (dd, J =
10.0 Hz & 3.1 Hz, 1 H), 4.88 – 4.98 (m, 1 H), 7.36 – 7.44 (m, 6
H), 7.62 – 7.67 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
19.2, 26.7, 35.3, 35.5, 35.6, 39.1, 42.4, 66.3, 85.8, 127.6, 129.6,
133.5, 135.4, 177.0 ppm. C24H30O2Si (378.58): calcd. C 73.05, H
7.66; found C 73.04, H 7.59.
Tributyltin hydride (0.500 mL, 1.85 mmol) was added dropwise
to a solution of compound (-)-14 (0.190 g, 0.71 mmol) in dry
toluene (15 mL). The mixture was stirred for 48 h at 60 °C until
the starting material had reacted completely (checked by TLC).
Then, the solvent was concentrated in vacuo and the crude mass
was purified by column chromatography (Hexane/EtOAc) to yield
30
1
25
compound (-)-17 as a colorless oil; yield 99%, [α]D = -53.3 (c =
0.42, MeOH). H NMR (200 MHz, CDCl3): δ = 1.89 (bs, 1 H),
1
2.12 (ddd, J = 14.6 Hz & 7.1 Hz & 3.2 Hz, 1 H), 2.39 (ddd, J =
14.6 Hz & 7.8 Hz & 6.9 Hz, 1 H), 2.75 (d, J = 3.2 Hz, 2 H), 3.60
(dd, J = 11.8 Hz & 6.3 Hz, 1 H), 3.74 (dd, J = 11.9 Hz & 3.2 Hz, 1
H), 4.18 (ddd, J = 10.4 Hz & 7.2 Hz & 3.2 Hz, 1 H), 4.63 (dd, J =
7.3 Hz & 3.2 Hz, 1 H), 5.05 (ddd, J = 6.3 Hz & 4.2 Hz & 1.7 Hz, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 34.0, 36.4, 64.6, 79.0,
80.7, 84.4, 175.2 ppm.
4.19. (1R,6S,7R,8S)—7,8-Dihydroxy-3,9-
dioxabicyclo[4.2.1]nonan-4-one (21)
To a solution of compound (+)-6 (109 mg, 0.78 mmol) in
dichloromethane (11 mL) and tert-Butanol (2 mL) was added
NMO (163 mg, 1.39 mmol) followed by a crystal of OsO4. The
reaction was stirred at room temperature until TLC analysis
showed complete consumption of starting material (3-6 h). The
reaction was quenched with 2 mL of a 10% solution of Na2SO3
and the mixture was stirred for an additional 45 min. Then it was
filtered through a pad of Celite® which was washed with
dichloromethane. The aqueous phase was extracted 5 times with
dichloromethane. The combined organic layers were dried over
Na2SO4 and the solvent was removed in vacuo. Purification of the
crude mass by column chromatography (stepwise gradient
LP/EtOAc = 100% LP to 100% EtOAc, followed by a stepwise
gradient EtOAc/EtOH = 100% EtOAc to 10% EtOH) gave
compound 21; yield 55%; 1H NMR (200 MHz, CD3OD): δ = 2.81
(dd, J= 16.3 Hz & 5.0 Hz, 1 H), 2.95 (dd, J = 16.3 Hz & 2.4 Hz, 1
H), 3.90 – 4.40 (m, 6 H), 4.8 (s, 2 H) ppm. 13C NMR (50 MHz,
CD3OD): δ = 43.8, 73.1 (2C), 76.0, 82.1, 86.6, 175.7 ppm.
4.16. 5-(Hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one
((+)- and (-)-18)
Tributyltin hydride (208 µL, 0.78 mmol) was added dropwise
to a solution of compound (+)- or (-)-15 (85 mg, 0.30 mmol) in dry
toluene (1.5 mL). The mixture was stirred for 43 h at 60 °C under
nitrogen atmosphere until the starting material had reacted
completely (checked by TLC). The reaction mixture was directly
adsorbed on silica gel and after purification by column
chromatography (LP/EtOAc = 1/3 – 1/5) compounds (+)- and (-)-
18 were obtained as a colorless oil; yield 85% (CHMOXantho); yield
21
81% (CPMO); [α]D = +57.5 (c = 1.0, CHCl3) (CHMOXantho);
21
1
[α]D = -61.5 (c = 0.4, CHCl3) (CPMO). H NMR (200 MHz,
CDCl3): δ = 1.15 – 1.45 (m, 2 H), 1.55 – 1.80 (m, 1 H), 2.00 - 2.42
(m, 4 H), 2.67 - 2.84 (m, 2 H), 3.50 – 3.65 (m, 2 H), 4.92 (m, 1 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 35.5, 35.6, 39.1, 42.1, 65.6,
86.0, 177.3 ppm. C8H12O3 (156.18): calcd. C 61.52, H 7.74; found
C 57.63, H 6.30.
4.20. 7,8-Dihydroxy-3-oxabicyclo[4.2.1]nonan-4-one ((+)- and (-
)-22)
4.17. (3aS,5S,6aS)-5-(((tert-
Butyldiphenylsilyl)oxy)methyl)tetrahydrofuro[3,2-b]furan-2(3H)-
one ((-)-19)
To a solution of compound (+)- or (-)-7 (140 mg, 1.01 mmol) in
dichloromethane/tert-Butanol (6 mL, 2/1) was added NMO•H2O
(172 mg, 1.27 mmol) under nitrogen atmosphere followed by a
crystal of OsO4. The reaction was stirred at room temperature until
TLC analysis showed complete consumption of starting material
(24 h). The reaction was quenched with 2 mL of a 10% solution of
Na2SO3 and the mixture was stirred for an additional 1 h. The
reaction mixture was directly adsorbed on silica gel and after
purification by column chromatography (EtOAc) compounds (+)-
and (-)-22, respectively, were obtained as a colorless oil; yield
Imidazole (20.0 mg, 0.29 mmol) was added to a solution of
compound (-)-17 (8.5 mg, 0.05 mmol) in dry DMF (0.5 mL)
followed by tert-butylchlorodiphenylsilane (30 mg, 0.11 mmol).
The mixture was stirred for 24 h at room temperature until the
starting material had reacted completely (checked by TLC). Crude
mass was purified by column chromatography (Hexane/EtOAc) to
yield compound (-)-19 as a colorless oil; yield 92%; [α]D26 = -23.8
(c = 0.75, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.05 (s, 9 H),
2.10 – 2.26 (m, 1 H), 2.26 – 2.45 (m, 1 H), 2.68 – 2.72 (m, 2 H),
3.63 – 3.79 (m, 2 H), 4.05 – 4.20 (m, 1 H), 4.54 – 4.61 (m, 1 H),
4.97 – 5.05 (m, 1 H), 7.30 – 7.45 (m, 6 H), 7.61 – 7.72 (m, 4 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 19.2, 26.8, 34.6, 36.4, 65.6,
78.9, 80.7, 84.3, 127.7, 129.7, 133.3, 133.4, 135.5, 135.6, 175.2
ppm.
21
50% (CHMOXantho); yield 56% (CPMO); [α]D = -71.5 (c = 0.06,
21
EtOH) (CHMOXantho); [α]D = +73.1 (c = 1.27, EtOH) (CPMO).
1H NMR (200 MHz, CD3OD): δ = 1.48 (d, J = 11.1 Hz, 1 H), 2.21
– 2.37 (m, 3 H), 2.63 (dd, J = 15.8 & 1.8 Hz, 1 H), 2.84 (ddd, J =
15.8 Hz & 7.7 Hz & 1.3 Hz, 1 H), 3.87 (d, J = 6.0 Hz, 1 H), 4.12 –
4.38 (m, 3 H) ppm. 13C NMR (50 MHz, CD3OD): δ = 37.2, 41.1,
42.8, 47.9, 72.7, 73.9, 76.7, 177.7 ppm.
4.21. (1S,2S,6R,7R)-4,4-Dimethyl-3,5,9,12-
4.18. 5-(((tert-Butyldiphenylsilyl)oxy)methyl)hexahydro-2H-
cyclopenta[b]furan-2-one ((+)- and (-)-20)
tetraoxatricyclo[5.4.1.02,6]dodecan-10-one ((+)-23)

9
To a solution of compound 21 (50 mg, 0.29 mmol) in acetone
(3 mL) under nitrogen atmosphere, 2-methoxypropene (1.50 mL,
15.7 mmol) and a catalytic amount of p-Toluenesulfonic acid were
added. When TLC proved all starting material to be gone, the
reaction was hydrolyzed with saturated bicarbonate solution. The
aqueous phase was extracted 5 times with EtOAc. The combined
organic layers were dried over Na2SO4 and the solvent was
removed in vacuo. The crude material was purified by column
chromatography (basic SiO2, stepwise gradient LP/EtOAc = 100%
LP to 100% EtOAc) yielding compound (+)-23 as colorless
crystals; yield 76%, m.p. 163 – 167 °C, [α]D20: +73.0 (c = 0.66,
on silica gel (CHCl3/MeOH) gave compounds (+)- and (-)-26 as
ACCEPTED MANUSCRIPT
oils, each; yield 50% (CHMOXantho); yield 43% (CPMO); [α]D24 = -
24
104.1 (c = 1.0, MeOH) (CHMOXantho); [α]D = +97.1 (c = 1.0,
MeOH) (CPMO). 1H NMR (200 MHz, CD3OD): δ = 1.28 (s, 3 H),
1.50 (s, 3 H), 2.05 – 2.17 (m, 3 H), 2.31 – 2.57 (m, 2 H), 3.55 –
3.70 (m, 4 H), 4.19 – 4.41 (m, 2 H) ppm. 13C NMR (50 MHz,
CD3OD): δ = 25.4, 27.9, 34.9, 38.4, 43.4, 52.0, 64.5, 84.2, 86.7,
113.7, 174.6 ppm.
4.25. ((2R,5R)-5-((3-Amino-1H-1,2,4-triazol-5-yl)methyl)-2,5-
dihydrofuran-2-yl)methanol ((-)-27)
1
CHCl3). H NMR (CDCl3): δ 1.32 (s, 3H, CH3), 1.49 (s, 3H,
Aminoguanidine bicarbonate (90 mg, 0.67 mmol) was added to
a mixture of compound (+)-6 (90 mg, 0.64 mmol) in pyridine (5
mL) at room temperature. The reaction mixture was refluxed for 2
h under argon atmosphere until no starting material could be
detected by TLC. After that, the pyridine was removed and
purification of the liquid residue by column chromatography on
silica gel (CHCl3/MeOH) gave compound (-)-27 as colorless
crystals; yield 67%; m.p. 87 - 89°C; [α]D = -45.5 (c = 0.22,
MeOH). H NMR (200 MHz, CD3OD): δ = 2.59 – 2.85 (m, 2 H),
3.10 – 3.27 (m, 2 H), 3.30 – 3.55 (m, 2 H), 4.60 – 4.85 (m, 3 H),
4.85 – 5.05 (m, 1 H), 5.70 – 5.77 (m, 1 H), 5.80 – 5.95 (m, 1 H)
ppm. 13C NMR (50 MHz, CD3OD + CDCl3): δ = 34.4, 64.5, 84.4,
87.8, 128.4, 131.0, 156.5, 158.8 ppm.
CH3), 2.96 (d, J = 4 Hz, 2H, H-2), 4.23-4.30 (m, 3H), 4.31-4.39
(m, 1H), 4.65 (d, J=5.0 Hz, 2H), 4.95 (d, J = 5.0 Hz, 2H); 13C-
NMR (CDCl3): δ 24.3, 25.9, 42.5, 71.5, 78.3, 81.5, 82.4, 83.5,
112.4, 172.2;
4.22. 4,4-Dimethyl-3,5,9-triaoxatricyclo[5.4.1.02,6]dodecan-10-
one ((+)- and (-)-24)
21
1
To a solution of compound (+)- or (-)-22 (43 mg, 0.25 mmol) in
acetone (3 mL) under nitrogen atmosphere, 2,2-dimethoxypropane
(1.50 mL, 12.2 mmol) and a catalytic amount of p-Toluenesulfonic
acid were added. When TLC proved all starting material to be
gone (after 26 h), the reaction was hydrolyzed with saturated
bicarbonate solution. The aqueous phase was extracted 5 times
with EtOAc. The combined organic layers were dried over Na2SO4
and the solvent was removed in vacuo. The crude material was
purified by column chromatography (LP/EtOAc = 6/1) yielding
compounds (+)- and (-)-(+)- and (-)-24 as a white solids, each;
yield 80% (CHMOXantho); yield 60% (CPMO); m.p. 115 - 119 °C,
4.26. (4-((3-Amino-1H-1,2,4-triazol-5-yl)methyl)cyclopent-2-en-1-
yl)methanol ((+)- and (-)-28)
Aminoguanidine bicarbonate (62 mg, 0.46 mmol) was added to
a mixture of compound (+)- or (-)-7 (50 mg, 0.36 mmol) in
pyridine (3 mL) at room temperature. The reaction mixture was
refluxed for 1 h under argon atmosphere until no starting material
could be detected by TLC. After that, the pyridine was removed
and purification of the liquid residue by column chromatography
on silica gel (CHCl3/MeOH) gave compounds (+)- and (-)-28,
22
22
[α]D = -74.2 (c = 1.0, CHCl3) (CHMOXantho); [α]D = +69.2 (c =
1
1.0, CHCl3) (CPMO). H NMR (200 MHz, (CD3)2CO): δ = 1.26
(d, J = 0.5 Hz, 3 H), 1.36 (d, J = 0.5 Hz, 3 H), 1.59 (d, J = 11.3
Hz, 1 H), 2.22 – 2.30 (m, 2 H), 2.42 – 2.52 (m, 1 H), 2.70 – 2.83
(m, 2 H), 4.17 – 4.36 (m, 3 H), 4.69 (dd, J = 5.3 Hz & 1.4 Hz, 1 H)
ppm. 13C NMR (50 MHz, (CD3)2CO): δ = 23.6, 26.2, 36.8, 39.4,
39.9, 44.2, 71.0, 82.4, 84.5, 109.8, 174.1 ppm.
21
respectively; yield 71% (CHMOXantho); yield 71% (CPMO); [α]D
22
= 6.63 (c = 1.0, MeOH) (CHMOXantho); [α]D = -10.1 (c = 0.8,
MeOH) (CPMO). H NMR (200 MHz, CD3OD): δ = 1.04 – 1.18
1
(m, 1 H), 2.03 – 2.15 (m, 1 H), 2.35 – 2.56 (m, 1 H), 2.59 – 3.06
(m, 1 H), 3.19 – 3.22 (m, 2H), 3.25(bs, 2 H), 5.58 (dd, J = 7.8 Hz
& 1.4 Hz, 1 H), 5.65 (dd, J = 7.8 Hz & 1.4 Hz, 1 H) ppm. 13C
NMR (50 MHz, CD3OD): δ = 34.0, 35.3, 45.8, 49.1, 67.5, 133.6,
136.2 ppm.
4.23. ((3aR,4R,6S,6aS)-6-((3-Amino-1H-1,2,4-triazol-5-
yl)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl)methanol ((-)-25)
Aminoguanidine bicarbonate (58 mg, 0.43 mmol) was added to
a mixture of compound (+)-23 (90 mg, 0.41 mmol) in pyridine (5
mL) at room temperature. The reaction mixture was refluxed for
1.5 h under argon atmosphere until no starting material could be
detected by TLC. After that, the pyridine was removed and
purification of the liquid residue by column chromatography on
silica gel (CHCl3/MeOH) gave compound (-)-25 as colorless
4.27. 3-Oxabicyclo[4.2.1]nonan-4-one ((+)- and (-)-29)
Compound (+)- or (-)-7 (100 mg, 0.72 mmol) and Pd/C (10%
w/w) were suspended in dry EtOAc (10 mL) and hydrogenated at
rt overnight using a balloon filled with hydrogen. The conversion
was determined by TLC analysis and after completion, the
reaction mixture was filtered through a pad of Celite®. The
residue was washed thoroughly with EtOAc and the filtrate was
concentrated in vacuo. The purity of the product was determined
to be >95% by NMR so no further purification was necessary.
Compounds (+)- and (-)-29 were obtained as a pale yellow oil,
each; yield 79% (CHMOXantho); yield 83% (CPMO); [α]D22 = -12.4
(c = 1.0, EtOAc) (CHMOXantho); [α]D22 = +105.1 (c = 1.67, CHCl3)
(CPMO). 1H-NMR and 13C-NMR data are according to the
previous results in our group (Kandioller Wolfgang Diploma
Thesis)
21
crystals; yield 78%; m.p. 65 – 67°C; [α]D = -11.8 (c = 0.22,
1
MeOH). H NMR (200 MHz, CD3OD): δ = 1.12 – 1.20 (m, 2 H),
1.31 (s, 3 H), 1.51 (s, 3 H), 2.66 (s, 1 H) 2.78 – 2.84 (m, 2 H), 3.50
– 3.70 (m, 3 H), 3.91 – 3.99 (m, 1 H), 4.18 – 4.25 (m, 1 H), 4.46 –
4.52 (m, 1 H), 4.59 – 4.67 (m, 1 H) ppm. 13C NMR (50 MHz,
CD3OD): δ = 16.1, 23.4, 25.4, 61.1, 80.8, 81.8, 83.4, 84.2, 113.0
ppm.
4.24. (6-((3-Amino-1H-1,2,4-triazol-5-yl)methyl)-2,2-
dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol
((+)- and (-)-26)
4.28. (3-((5-Amino-4H-1,2,4-triazol-3-
yl)methyl)cyclopentyl)methanol ((+)- and (-)-30)
Aminoguanidine bicarbonate (33 mg, 0.25 mmol) was added to
a mixture of compound (+)- or (-)-24 (30 mg, 0.15 mmol) in
pyridine (3 mL) at room temperature. The reaction mixture was
refluxed for 1 h under argon atmosphere until no starting material
could be detected by TLC. After that, the pyridine was removed
and purification of the liquid residue by column chromatography
Aminoguanidine bicarbonate (100 mg, 0.74 mmol) was added
to a mixture of compound (+)- or (-)-29 (90 mg, 0.64 mmol) in
pyridine (5 mL) at room temperature. The reaction mixture was
refluxed for 1 h under argon atmosphere until no starting material

10
Tetrahedron
ACCEPTED MANUSCRIPT
22. de Gonzalo, G.; Mihovilovic, M. D.; Fraaije, M. W.
could be detected by TLC. After that, the pyridine was removed
ChemBioChem 2010, 11, 2208.
and purification of the liquid residue by column chromatography
23. Kamerbeek, N. M.; Janssen, D. B.; van Berkel, W. J. H.;
Fraaije, M. W. Adv. Synth. Catal. 2003, 345, 667.
24. Mihovilovic, M. D.; Muller, B.; Stanetty, P. Eur. J. Org.
Chem. 2002, 3711.
25. Leisch, H.; Morley, K.; Lau, P. C. K. Chem. Rev. 2011, 111,
4165.
26. Mihovilovic, M. D. Curr. Org. Chem. 2006, 10, 1265.
27. Balke, K.; Kadow, M.; Mallin, H.; Sass, S.; Bornscheuer, U.
T. Org. Biomol. Chem. 2012, 10, 6249.
on silica gel (CHCl3/MeOH) gave compounds (+)- and (-)-30 as
22
oils, each; yield 69% (CHMOXantho); yield 67% (CPMO); [α]D
=
21
+3.4 (c = 1.0, EtOAc) (CHMOXantho); [α]D = -1.9 (c = 1.67,
1
MeOH) (CPMO). H NMR (200 MHz, CD3OD): δ = 0.80 – 1.00
(m, 1 H), 1.20 – 1.50 (m, 2 H), 1.60 – 1.83 (m, 2 H), 1.85 – 2.40
(m, 3 H), 2.54 (d, J = 7.5 Hz, 2 H), 3.15 – 3.25 (m, 1 H), 3.35 (d, J
= 6.7 Hz, 2 H) ppm. 13C NMR (50 MHz, CD3OD): δ = 29.1, 32.5,
34.3, 37.4, 40.4, 43.2, 67.6, 160.0 ppm.
28. Fink, M. J.; Rial, D. V.; Kapitanova, P.; Lengar, A.;
Rehdorf, J.; Cheng, Q.; Rudroff, F.; Mihovilovic, M. D.
Adv. Synth. Catal. 2012, 354, 3491.
29. Iwaki, H.; Hasegawa, Y.; Wang, S.; Kayser, M. M.; Lau, P.
C. Appl. Environ. Microbiol. 2002, 68, 5671.
30. Griffin, M.; Trudgill, P. W. Eur J Biochem 1976, 63, 199.
31. van Beilen, J. B.; Mourlane, F.; Seeger, M. A.; Kovac, J.;
Li, Z.; Smits, T. H. M.; Fritsche, U.; Witholt, B. Environ.
Microbiol. 2003, 5, 174.
Acknowledgments
This work was funded by the Austrian Science Fund (F.W.F.
Lise-Meitner fellowship project number: M883-B10) and by
Vienna University of Technology. N.I. acknowledges financial
support by the Higher Education Commission (HEC), Pakistan, for
receiving an international PhD fellowship. R.M.-R. was recipient
of a predoctoral fellowship from the Spanish Ministry of Science
and Technology enabling an abroad research internship.
32. Chen, G.; Kayser, M. M.; Mihovilovic, M. D.; Mrstik, M.
E.; Martinez, C. A.; Stewart, J. D. New J. Chem. 1999, 23,
827.
Supplementary Material
33. Doig, S. D.; O'Sullivan, L. M.; Patel, S.; Ward, J. M.;
Woodley, J. M. Enzyme Microb. Technol. 2001, 28, 265.
34. Mihovilovic, M. D.; Bianchi, D. A.; Rudroff, F. Chem.
Commun. 2006, 3214.
35. Bianchi, D. A.; Moran-Ramallal, R.; Iqbal, N.; Rudroff, F.;
Mihovilovic, M. D. Bioorg. Med. Chem. Lett. 2013, 23,
2718.
36. Mihovilovic, M. D.; Rudroff, F.; Grotzl, B.; Kapitan, P.;
Snajdrova, R.; Rydz, J.; Mach, R. Angew. Chem., Int. Ed.
2005, 44, 3609.
37. Kim, H.; Hoffmann, H. M. R. Eur. J. Org. Chem. 2000,
2195.
38. Rappe, C. Arkiv foer Kemi 1963, 21, 503.
39. Le Goff, E. J. Org. Chem. 1964, 29, 2048.
40. Bremner, D. H. Ultrason. Sonochem. 1994, 1, S119.
41. Montana, A. M.; Grima, P. M. Tetrahedron Lett. 2001, 42,
7809.
42. Mihovilovic, M. D.; Groetzl, B.; Kandioller, W.; Snajdrova,
R.; Muskotal, A.; Bianchi, D. A.; Stanetty, P. Adv. Synth.
Catal. 2006, 348, 463.
43. Rial, D. V.; Bianchi, D. A.; Kapitanova, P.; Lengar, A.; van
Beilen, J. B.; Mihovilovic, M. D. Eur. J. Org. Chem. 2008,
1203.
44. Rudroff, F.; Alphand, V.; Furstoss, R.; Mihovilovic, M. D.
Organic Process Research & Development 2006, 10, 599.
45. Gutierrez, M.-C.; Furstoss, R.; Alphand, V. Adv. Synth.
Catal. 2005, 347, 1051.
Supplementary data related to this article can be found at …
References and notes
1. Matsuura, S.; Shiratori, O.; Katagiri, K. J. Antibiotics) 1964,
17, 234.
2. Nishimura, H.; Mayama, M.; Komatsu, Y.; Kato, H.;
Shimaoka, N.; Tanaka, Y. J. Antibiotics 1964, 17, 148.
3. Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990,
1655.
4. Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem.
Soc. 1991, 113, 5378.
5. Osumi, K.; Sugimura, H. Tetrahedron Lett. 1995, 36, 5789.
6. Lee, E.; Yoo, S.-K.; Cho, Y.-S.; Cheon, H.-S.; Chong, Y. H.
Tetrahedron Lett. 1997, 38, 7757.
7. Boukouvalas, J.; Fortier, G.; Radu, I.-I. J. Org. Chem. 1998,
63, 916.
8. Chandler, C. L.; Phillips, A. J. Org. Lett. 2005, 7, 3493.
9. Watanabe, K. In Chemistry of Nucleosides and Nucleotides;
Townsend, L. Ed.; Springer US, 1994; pp. 421.
10. Miller, P. S. In Bioorganic Chemistry: Nucleic Acids;
Hecht, S. M. Ed.; Oxford University Press: New York and
Oxford, 1996; pp. 347
11. Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett 1998,
700.
12. Guntaka, R. V.; Varma, B. R.; Weber, K. T. Int. J Biochem.
Cell B 2003, 35, 22.
13. Navarre, J.-M.; Guianvarc'h, D.; Farese-Di Giorgio, A.;
Condom, R.; Benhida, R. Tetrahedron Lett. 2003, 44, 2199.
14. Baeyer, A.; Villiger, V. Chem. Berichte 1899, 32, 3625.
15. Michelin, R. A.; Sgarbossa, P.; Scarso, A.; Strukul, G.
Coord. Chem. Rev. 2010, 254, 646.
46. Hilker, I.; Gutierrez, M. C.; Alphand, V.; Wohlgemuth, R.;
Furstoss, R. Org. Lett. 2004, 6, 1955.
47. Afarinkia, K.; Mahmood, F. Tetrahedron Lett. 2000, 41,
1287.
48. Ma, E.; Kim, J. Molecules [online computer file] 2003, 8,
886.
16. Krow, G. R. Organic Reactions (New York) 1993, 43, 251.
17. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737.
18. Brink, G. J. t.; Arends, I. W. C. E.; Sheldon, R. A. Chem.
Rev. 2004, 104, 4105.
49. Murphy, P. J. J. Chem. Soc., Chem. Commun. 1992, 1096.
50. Murphy, P. J.; Dennison, S. T. Tetrahedron 1993, 49, 6695.
51. Gadikota, R. R.; Callam, C. S.; Lowary, T. L. J. Org. Chem.
2001, 66, 9046.
19. Mihovilovic, M. D.; Rudroff, F.; Groetzl, B. Curr. Org.
Chem. 2004, 8, 1057.
52. Noyori, R.; Sato, T.; Hayakawa, Y. J. Am. Chem. Soc. 1978,
100, 2561.
20. Bolm, C. In Peroxide Chemistry; Adam, W. Ed.; Wiley-
VCH Verlag GmbH & Co. KGaA, 2005; pp. 494.
21. Strukul, G. Angew. Chem., Int. Ed. 1998, 37, 1199.
53. Sato, T.; Noyori, R. Bull. Chem. Soc. Jpn. 1978, 51, 2745.
54. Gracza, T.; Hasenohrl, T.; Stahl, U.; Jager, V. Synthesis
1991, 1108.