Enantiomeric scaffolding of α-tetralone and related scaffolds by EKR (Enzymatic Kinetic Resolution) and stereoselective ketoreduction with ketoreductases

Article abstract of DOI:10.1039/c1ob06545a

Stereochemically pure compounds containing an all carbon quaternary stereocenter based on 1-tetralone, 1-indanone and 4-chromanone scaffolds have been synthesized by employing Lipase PS (Burkholderia cepacia) catalyzed kinetic resolution. These scaffolds

Full text of DOI:10.1039/c1ob06545a

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2012, 10, 536
www.rsc.org/obc
PAPER
Enantiomeric scaffolding of a-tetralone and related scaffolds by EKR
(Enzymatic Kinetic Resolution) and stereoselective ketoreduction with
ketoreductases†
Rajib Bhuniya and Samik Nanda*
Received 8th September 2011, Accepted 3rd October 2011
DOI: 10.1039/c1ob06545a
Stereochemically pure compounds containing an all carbon quaternary stereocenter based on
1-tetralone, 1-indanone and 4-chromanone scaffolds have been synthesized by employing Lipase PS
(Burkholderia cepacia) catalyzed kinetic resolution. These scaffolds are further functionalized by
microbial ketoreductase enzymes (Geotrichum candidum, Candida parapsilosis and Aspergillus niger) to
access stereochemically pure diols which, on further synthetic manipulation, yield novel cyclic
compounds.
the literature till today.5 Enzymatic kinetic resolution (EKR),
Introduction
desymmetrization of meso or prochiral substrates (enantioselective
Natural products and their analogues provide the inspiration for
enzymatic desymmetrization) are different approaches which can
an array of strategies used in the diversity oriented synthesis
be used successfully to create all carbon quaternary stereocenters
of novel small molecule libraries.1 These libraries are generally
focused on core scaffolds from individual natural products or
specific substructures found across a class of natural products
or altogether a new chemotype.2 Increasing evidence supports the
utility of these strategies for identifying new biologically active
small organic molecules. These efforts also have led to noteworthy
advances in several novel strategies in synthetic organic chemistry.3
The introduction of chemical diversity in compound collection
libraries according to different strategies of organic synthesis is
essential for the identification of small organic molecules with
diverse biological activities. The ongoing development of novel
synthetic methodology, both on solid phase and in solution,
enables the creation of small molecule libraries with well de-
fined substituent, stereochemical and scaffold diversity to yield
new lead molecules (after biological screening) from relatively
small compound collections. Generation of carbon containing
quaternary stereocenters is a challenging and daunting task
in asymmetric organic synthesis. There exist many well-defined
chemical strategies for creating a quaternary stereocenter in an
organic molecule.4 Still, the quest for newer methods for the above
mentioned theme is ongoing. Though there exist many chemocat-
alyst based strategies for generation of quaternary stereocenters,
very few efficient biocatalytic approaches have been known in
in small organic molecules.6 We have earlier demonstrated an
efficient method to generate all carbon quaternary stereocenters
by EKR based on a-tetralone, a-indanone and chroman-4-
one scaffolds.7 The methodology has been successfully applied
to the synthesis of 2,2-dialkylated tetralones and indanones
in an asymmetric fashion. We have chosen chromanone, a-
tetralone and a-indanone based scaffolds as there exist many
natural products based on chromanone (flavonoids and ho-
moisoflavonoids) and a-tetralone.8 The generality of our method
is well explored for many substrates. In the present work we intend
to extend our strategies for further stereoselective biocatalytic
functionalization on the existing scaffolds in a diverse way
(Scheme 1).
Results and discussion
Enzymatic kinetic resolution of tetralone/indanone and
chromanone scaffolds
The initial EKR has been optimized in our lab by taking many
substrates based on a-tetralone, a-indanone and chroman-4-
one.7b The enantioselectivity and absolute configuration for the
fast reacting acetate enantiomer and the slow reacting alcohol
in the EKR reaction has been established by the Kazlauskas
empirical rule. In our earlier article we did have minor problems
using the deacetylation reaction from the acetate compounds
(obtained from the fast reacting enantiomer) to access the
stereochemically pure alcohols, mainly due to the fact that in
some cases slight racemization is observed under the reaction
conditions (K2CO3/MeOH). The problem of this racemization
has been taken care of by performing an enzyme (lipase, Porcine
Department of Chemistry, Indian Institute of Technology, Kharagpur,
721302, India. E-mail: snanda@chem.iitkgp.ernet.in
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra and HPLC chromatograms for all new compounds. The cif files
for the two crystals reported in this article have been deposited with
the Cambridge Crystallographic Data Centre. CCDC reference numbers
830577 and 830578. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06545a
536 | Org. Biomol. Chem., 2012, 10, 536–547
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Scheme 1 Proposed biocatalytic functionalization of tetralone and indanone scaffolds.
Table 1 Lipase-PS catalyzed transesterification of compounds 2–4 and
pancreatic lipase) mediated deacetylation reaction. Though the
enzyme-mediated (PPL) deacetylation is a little time consuming,
the reaction is extremely efficient in terms of chemical yield
as well as stereochemical purity of the obtained alcohols (as
no racemization was observed during enzymatic deacetylation).
So, by changing the deacetylation conditions we have access to
both the enantiomeric hydroxymethylated compounds bearing
all carbon quaternary stereocenters based on a-tetralones, a-
indanones and chroman-4-one. The enantiomeric excess (ee) for
the product acetates of 1–14 (Scheme 2) as well as the parent
alcohols was determined by chiral-HPLC measurements. In all
the cases we have synthesized racemic acetates of compounds
1–14 by means of chemical acylation and recorded their HPLC
data, which allows us to assign the retention time for major and
minor enantiomers respectively. The reaction was monitored by
TLC and the reaction was stopped after an appreciable amount
of conversion was achieved (as indicated by quantitative HPLC
analysis; the presence of approximately 1 : 1 ratio of alcohol and
acetate was indicated). The selectivity factor (E) for the EKR
reaction is shown in Table 1 for all the substrates (2–4 and 8–
12, data for substrates 1, 5–7, 13–14 was presented in our earlier
article).7b
8–12
a
Entry
Substrate
Conversion(c)
Eesa (%)
Eep (%)
Eb
1
2
3
4
5
6
7
8
2
3
4
8
49
49
49
49
49
49
49.9
49.9
97
96
96
94
96
94
93
94
99
98
98
97
99
99
94
95
> 200
> 200
> 200
> 200
> 200
> 200
110
9
10
11
12
139
a Ees were calculated by chiral HPLC (Diacel, Chiral OD-H and OJ-H
column, hexane–isopropanol, 9 : 1). b Enantioselectivities of the reactions
(E) were determined from the following equation: E = ln [1 - c(1 + eep)]/ln[1
- c(1 - eep)], where eep = product ee, ees = substrate ee; c = ees/(ees +
eep)%. Enantioselectivities of the reaction (E) were determined using the
“Selectivity” program developed by K. Faber, H. Ho¨nig, and A. Kleewein,
(http://www.cis.TUGraz.at/orgc/).
Microbial ketoreductase isolation and assay
Next we focused our attention on applying several ketoreductase
classes of enzymes for the asymmetric reduction of the keto
Scheme 2 Monoalkylated hydroxymethylated tetralone, indanone and chromanone based scaffolds for EKR reaction.
The Royal Society of Chemistry 2012 Org. Biomol. Chem., 2012, 10, 536–547 | 537
This journal is
©

View Article Online
functionality in compounds 1–14 (to both the enantiomers).
Several microbial ketoreductases were screened for that purpose.9
As the enantioselectivity of many of the ketoreductases was not
known, we thought to develop an enantioselective assay based
on chiral HPLC for all the ketoreductase enzymes employed in
our work. a-Tetralone was taken as a model substrate as the
corresponding reduced product 1,2,3,4-tetrahydro-naphthalen-1-
ol is known in the literature,10 and the HPLC retention times
are also known for both the enantiomers (tR = 7.55; tS = 6.29;
Chiral OJ-H column; hexane : i-PrOH = 9 : 1, flow rate: 1 ml
min-1; Fig. 1). We found that the ketoreductase enzyme isolated
from Geotrichum candidum (NBRC 5767) reduces 1-tetralone in
an anti-Prelog fashion to afford the corresponding alcohol (R-
1,2,3,4-tetrahydro-napthalen-1-ol). Whereas ketoreductases from
Candida parapsilosis (NBRC 1396) and Aspergillus niger (NBRC
4415) afford the corresponding alcohols in Prelog fashion for the
reduction of 1-tetralone to yield (S)-1,2,3,4-tetrahydro-napthalen-
1-ol (Scheme 3).
fashion. Ketroreductase strains were obtained from NBRC, Osaka
and stored in glycerol (50% v/v) at -20 ◦C. The cells were grown
in specified medium (as mentioned in the manual) in 500 mL
conical flasks for 24 h. Substrates (tetralones/indanones and chro-
manones) were directly added to the growing cells of ketoreductase
solution. Reactions were monitored periodically by TLC analysis.
It usually takes 2–3 days for quantitative conversion and after
that the product alcohols can be extracted in organic solvents and
purified by standard techniques. The stereochemistries of the final
alcohols were confirmed by X-ray crystal analysis by preparing
the corresponding PNBz (para-nitrobenzoate) derivatives (Scheme
4).† The chemical yield and enantiomeric purity of the reduction
process of both the enantiomers of compound 1 are listed
in Scheme 4. It was observed that the growing cells of the
above mentioned microbial ketoreductase strains afford excellent
enantioselection in the final alcohols, though the chemical yield is
somewhat less in a few cases. It is also important to note that
ketoreductases from G. candidum and C. parapsilosis/A. niger
are stereocomplementary with respect to the product alcohols
(as the hydride is transferred to Re- and Si- face subsequently).
This methodology was successfully applied to all of the other
compounds (2–13). In all the cases stereochemically pure diols
were obtained in good yield. Therefore a series of stereochemically
pure 1,3-diols have been prepared biocatalytically with PKR
(Candida parapsilosis/Aspergillus niger) and APKR (Geotrichum
candidum).
The structures of all the diols (19–44) are presented in Scheme
5. In general, good chemical yield and excellent diastereoselec-
tivity were obtained for the synthesized diols by using those
microbial ketoreductase strains. It is worth mentioning that,
though ketoreductase from G. candidum has a wide application in
synthetic biotransformation, ketoreductases from A. niger (NBRC
4415) and C. parapsilosis (NBRC 1396) are not explored well in
synthetic biocatalysis.11 Both of these ketoreductases follow the
Prelog’s rule for the hydride transfer to a prochiral carbonyl com-
pound and provide excellent enantioselection for the synthesized
diols.
Fig. 1 HPLC chromatogram of (R)-enantiomer, racemic compound and
(S)-enantiomer of 1,2,3,4-tetrahydro-naphthalen-1-ol (Chiral OJ-H; flow
rate: 1 ml min-1; mobile phase: hexane–iPrOH = 9 : 1).
Generation of stereochemically pure novel tricyclic scaffolds from
biocatalytically derived diols
Next we focused our attention on creating further molecular com-
plexity from the biocatalytically synthesized diols. We intended to
create a dihydropyran ring from the two hydroxyl appendages by
using a RCM (ring closing metathesis) reaction followed by an AD
reaction (asymmetric dihydroxylation), to access stereochemically
pure tricyclic diols. For that reason we have chosen diols 18 and
37.
Diol 18 was monoprotected as its TBS ether (tert-butyldimethyl
silyl) to yield compound 45 in 90% yield. The secondary hydroxyl
group in 45 was protected as its PNBz (4-nitrobenzoate) ester
on treatment with 4-nitrobenzoic acid with EDC·HCl–DMAP
to afford 46 in 88% yield. Upon exposure to PPTS in methanol
compound 46 furnished alcohol 47 with removal of the TBS group
in 82% yield.12 Oxidation of alcohol 47 under Swern conditions 13
afforded the aldehyde 48 in 90% yield. Wittig olefination of
aldehyde 48 with methyltriphenylphosphonium iodide in the
presence of LHMDS at -5 ◦C afforded compound 49 in 78% yield.
Deprotection of the PNBz group in compound 49 was achieved
Scheme 3 Enantioselective assay of microbial ketoreductase by using
1-tetralone as a substrate.
Biocatalytic reduction of both the enantiomers of 1–14 to access
various stereochemically pure diols
Next we focused our attention on applying the above microbial
strains of the ketoreductase class of enzymes for the asymmetric
reduction of the keto functionality in compounds 1–14. Several
microbial ketoreductases were employed for that purpose, and we
found that the ketoreductase enzyme isolated from Geotrichum
candidum (NBRC 5767) reduces the ketones in an anti-Prelog
fashion to afford the corresponding alcohols. Whereas ketore-
ductases from Candida parapsilosis (NBRC 1396) and Aspergillus
niger (NBRC 4415) affords the corresponding alcohols in Prelog
538 | Org. Biomol. Chem., 2012, 10, 536–547
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Scheme 4 Biocatalytic reduction of both the enantiomers of 1 for synthesis of all the possible stereoisomers of the diol, and ORTEP presentation of the
bis-PNBz derivatives of diols 18 and 27.
on treatment with 10% aq. NaOH 14 and afforded 50 in 86% yield.
The secondary hydroxyl group in 50 was converted to its O-allyl
ether upon treatment with allyl bromide and Ag2O15 to furnish
compound 51 in 88% yield. Ring closing metathesis reaction
(RCM) of compound 51 with Grubbs 1st generation catalyst 16 in
DCM solvent at room temperature afforded compound 52 in 77%
yield. Asymmetric dihydroxylation with AD mix-b 17 of compound
52 afforded the tricyclic diol 53 in 78% yield (overall yield = 21%
from the diol 18, Scheme 6). The same reaction sequence was
performed with indanone based diol 37 to provide the tricyclic
diol 62 as a single stereoisomer (overall yield = 19% from the
diol 37, Scheme 6). The synthesized tricyclic diol scaffold found in
compounds 53 and 62 is unique, as these types of compounds have
not been reported elsewhere, and can serve as a new chemotype.
a-indanone and chroman-4-one scaffolds by employing two
consecutive biocatalytic steps. The first one allows us to fix
a quaternary stereocenter by lipase catalyzed EKR strategy
whereas the second one involves a unique microbial carbonyl
reductase induced alcohol synthesis with absolute stereocontrol.
The synthesized diols can serve as potential chiral building blocks
for novel tricyclic compounds as demonstrated by us in this
article.
Experimental section
General information
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF
and diethylether were distilled from sodiumbenzophenone ketyl.
Dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were
distilled from calcium hydride. Microbial ketoreductases strains
G. candidum (NBRC 5767), C. parapsilosis (NBRC 1396) and
A. niger (NBRC 4415) were obtained from NBRC, Japan and
Conclusion
In conclusion we have described an efficient asymmetric syn-
thetic strategy for a diverse set of diols based on a-tetralone,
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 536–547 | 539
©

View Article Online
Scheme 5 Biocatalytically synthesized diols (synthesis from one set of enantiomer is only shown) by applying PKR (Candida parapsilosis-NBRC 1396)
and APKR (Geotrichum candidum NBRC 5767. Yields and enantiomeric purity are given under each compound.
maintained in Petri dishes as well as in glycerol slants periodically.
Bioreductions were performed in an incubator shaker at 35 ◦C.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates (Merck) with UV
light, ethanolic anisaldehyde and phosphomolybdic acid/heat as
developing agents. Silicagel 100–200 mesh was used for column
chromatography. Yields refer to chromatographically and spectro-
scopically homogeneous materials unless otherwise stated. NMR
spectra were recorded on 200 & 400 MHz spectrometers at 25 ◦C
in CDCl3 using TMS as the internal standard. Chemical shifts
are shown in d. 13C NMR spectra were recorded with a complete
proton decoupling environment. The chemical shift value is listed
Growing conditions for microbial ketoreductases: G. candidum
(NBRC 5767)
The dried cells obtained from the culture collection were moist-
ened with the rehydration fluid (peptone 5 g, yeast extract 3 g,
MgSO4·7H2O 1 g, distilled water 1 L, pH 7.0). It was streaked into
several Petri dishes (Growth medium: PSA medium) and then
incubated at 25 ◦C in an incubator for 24 h.
Recipe for PSA (potato sucrose agar) medium: potatoes were
washed with tap water, peeled and cut into 1 cm small cubes. Then
they were rinsed with tap water quickly and 200 g of potato cubes
were boiled with 1 L of distilled water for 20 min. After that they
were mashed and squeezed through a muslin bag. Finally agar was
added to it and boiled till melted. Sucrose (20 g) was added to the
solution and stirred well till dissolved. The final volume made was
1 L (pH = 5.6) and then it was autoclaved to sterilize it.
1
as dH and dC for H and 13C, respectively. Optical rotations were
measured on a digital polarimeter. Chiral HPLC was performed
using Chiral OJ-H, AS-H and OD-H column (0.46 ¥ 25 cm) with
LC-20AT chromatograph coupled with UV–vis detector (254 nm).
Eluting solvent used was different ratios of hexane and 2-propanol.
HRMS data are collected from University of Hyderabad, and
IACS-Kolkata, India.
For the biotransformation purpose with NBRC 5767, PS liquid
medium was prepared without agar, and then the grown cells of G.
candidum were transferred to this medium through an inoculating
540 | Org. Biomol. Chem., 2012, 10, 536–547
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Scheme 6 Synthesis of stereochemically pure tricyclic diols from biocatalytically derived diols 18 and 37. Reagents and conditions: a) TBS-Cl, imidazole,
rt, 90%; b) 4-nitrobenzoic acid, EDC·HCl–DMAP, rt, 88%; c) PPTS, MeOH, rt, 82%; d) (COCl)2, Me2SO, Et3N, -78 ◦C, 90%; e) Ph3P+MeI-, LHMDS,
-5 ◦C, 78%; f) 10% aq. NaOH, rt, 6h, 86%; g) CH2 CH–CH2Br, Ag2O, rt, 48 h, 88%; h) Grubbs 1st generation catalyst, DCM, rt, 77%; i) AD mix-b,
MeSO2NH2, tBuOH–H2O (1 : 1), rt, 24 h, 78%.
loop. The content was incubated in an incubator shaker for 24 h,
and after that substrates were directly added to the growing culture
medium.
growing culture of ketoreductase medium. The reaction mixture
was incubated with an incubator shaker at 30 ◦C. The reaction
was monitored with periodical TLC analysis. After all the starting
materials had been consumed (usually took 2–3 days) the reaction
mixture was extracted several times with EtOAc, and the organic
layer was dried (Na2SO4) followed by evaporation and purification
by means of silica gel chromatography (SGC) affording the pure
diols.
C. parapsilosis (NBRC 1396)
The dried cells obtained from the culture collection were moist-
ened with the rehydration fluid (YM liquid medium: glucose 10 g,
peptone 5 g, yeast extract 3 g, malt extract 3 g, distilled water 1 L,
pH 7.0). It was streaked into several Petri dishes (growth medium:
YM agar) and then incubated at 25 ◦C in an incubator for 24 h.
For the biotransformation purpose with NBRC 1396, YM
liquid medium was prepared without agar, and then the grown
cells of C. parapsilosis were transferred to this medium through
an inoculating loop. The content was incubated in an incubator
shaker for 24 h, and after that period substrates were directly
added to the growing culture medium.
(1R,2S)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-2-
methylnaphthalen-1-ol (15)
dH (CDCl3, 400 MHz): 7.56 (d, J = 7.6 Hz, 1H), 7.23–7.08 (m,
3H), 4.76 (s, 1H), 3.65 (d, J = 10.4 Hz, 1H), 3.61 (d, J = 10.4 Hz,
1H), 2.90–2.76 (m, 2H), 1.59–1.51 (m, 2H), 0.98 (s, 3H).
dC (CDCl3, 100 MHz): 138.6, 134.7, 127.3, 126.3, 125.6, 125.1,
72.3, 70.3, 37.5, 28.6, 24.6, 14.0.
[a]2D9 = +14.36 (c = 1, MeOH).
HRMS (ESI) Calcd for C12H16O2Na [M + Na]+, 215.1047;
Found, 215.1050.
A. niger (NBRC 4415)
The dried cells obtained from the culture collection were moist-
ened with the rehydration fluid (same as NBRC 5767). It was
streaked into several Petri dishes (growth medium: PSA medium)
and then incubated at 25 ◦C in an incubator for 24 h.
For the biotransformation purpose with NBRC 4415 similar
procedures to those for NBRC 5767 were followed.
(1S,2S)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-2-
methylnaphthalen-1-ol (16)
dH (CDCl3, 200 MHz): 7.42 (d, J = 7.6 Hz, 1H), 7.23–6.86 (m,
3H), 4.56 (s, 1H), 3.43 (d, J = 10.6 Hz, 1H), 3.3 (d, J = 10.6 Hz,
1H), 2.72–2.57 (m, 2H), 1.59–1.28 (m, 2H), 0.7 (s, 3H).
dC (CDCl3, 50 MHz): 138.9, 135.2, 127.9, 126.6, 126.3, 125.8,
73.5, 71.6, 38.0, 29.2, 25.1, 14.2.
Experimental conditions for bioreductions
The strains of different microbial ketoreductases were grown on
specific media as described earlier. Substrates (1–14, 100 mg)
were dissolved in minimum amount of EtOH and added to the
[a]2D9 = +4.36 (c = 0.5, MeOH).
HRMS (ESI) Calcd for C12H16O2Na[M + Na]+, 215.1047;
Found, 215.1050.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 536–547 | 541
©

View Article Online
(1S,2R)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-5-methoxy-2-
(1R,2R)-2-Ethyl-1,2,3,4-tetrahydro-2-(hydroxymethyl)naphthalen-
methylnaphthalen-1-ol (19)
1-ol (24)
dH (CDCl3, 400 MHz): 7.26–7.17 (m, 2H), 6.74 (d, J = 7.6 Hz, 1H),
4.73 (s, 1H), 3.82 (s, 3H), 3.6 (s, 2H), 2.77–2.57 (m, 2H), 1.57–1.54
(m, 2H), 0.96 (s, 3H).
dH (CDCl3, 200 MHz): 7.52 (d, J = 6.4 Hz, 1H), 7.22–7.07 (m,
3H), 4.81 (s, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.56 (d, J = 10.8 Hz,
1H), 2.83–2.72 (m, 2H), 1.83–1.6 (m, 2H), 1.5–1.22 (m, 2H), 1.25
(t, J = 7.4 Hz, 3H).
dC (CDCl3, 50 MHz): 156.9, 139.8, 127.0, 124.5, 118.8, 108.4,
75.2, 72.9, 55.5, 37.9, 28.8, 19.8, 14.2.
dC (CDCl3, 50 MHz): 138.1, 135.6, 128.3, 127.0, 126.6, 126.3,
76.5, 68.9, 40.2, 25.2, 24.9, 17.6, 7.2.
[a]2D9 -7.88 (c 0.8, MeOH).
HRMS (ESI) Calcd for C13H18O3Na[M + Na]+, 245.1153;
Found, 245.1161.
[a]2D9 -7.28 (c 0.8, MeOH).
HRMS (ESI) Calcd for C13H18O2Na[M + Na]+, 229.1204;
Found, 229.1197.
(1R,2R)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-5-methoxy-2-
methylnaphthalen-1-ol (20)
(1R,2R)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-5,8-dimethoxy-2-
methylnaphthalen-1-ol (25)
dH (CDCl3, 400 MHz): 7.28–7.16 (m, 2H), 6.72 (d, J = 7.6 Hz, 1H),
4.76 (s, 1H), 3.80 (s, 3H), 3.6 (s, 2H), 2.77–2.52 (m, 2H), 1.57–1.54
(m, 2H), 0.92 (s, 3H).
dH (CDCl3, 200 MHz): 6.69 (s, 2H), 4.9 (s, 1H), 3.83 (s, 3H), 3.73
(s, 3H), 3.56 (d, J = 10.6 Hz, 1H), 3.48 (d, J = 10.6 Hz, 1H), 2.65
(m, 2H), 1.65–1.38 (m, 2H), 1.15 (s, 3H).
dC (CDCl3, 50 MHz): 152.4, 151.6, 127.8, 127.0, 108.5, 108.1,
72.2, 71.8, 55.9, 55.8, 37.7, 28.3, 20.3, 16.2.
[a]2D9 = 5.08 (c = 1.0, MeOH).
dC (CDCl3, 50 MHz): 156.8, 139.8, 127.2, 124.6, 118.9, 108.3,
75.2, 73.0, 55.4, 37.8, 28.7, 19.8, 14.2.
[a]2D9 -3.45 (c 0.6, MeOH).
HRMS (ESI) Calcd for C13H18O3Na[M + Na]+, 245.1153;
Found, 245.1161.
(1S,2R)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-6-methoxy-2-
methylnaphthalen-1-ol (21)
(1S,2R)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-5,8-dimethoxy-2-
methylnaphthalen-1-ol (26)
dH (CDCl3, 200 MHz): 7.44 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.6,
2.6 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 4.68 (s, 1H), 3.78 (s, 3H),
3.64 (s, 2H), 2.97–2.63 (m, 2H), 1.68–1.45 (m, 2H), 1.0 (s, 3H).
dC (CDCl3, 50 MHz): 158.4, 136.6, 130.5, 128.1, 113.2, 112.4,
74.7, 72.3, 55.4, 38.1, 29.2, 25.3, 14.3.
dH (CDCl3, 200 MHz): 6.66 (s, 2H), 4.87 (s, 1H), 3.8 (s, 3H), 3.75
(s, 3H), 3.53 (d, J = 10.4 Hz, 1H), 3.48 (d, J = 10.4 Hz, 1H), 2.62
(m, 2H), 1.59–1.38 (m, 2H), 1.06 (s, 3H).
dC (CDCl3, 50 MHz): 152.4, 151.6, 127.9, 127.1, 108.6, 108.2,
72.2, 71.8, 55.9, 55.8, 37.7, 28.3, 20.3, 16.2.
[a]2D9 = 12.3 (c = 0.9, MeOH).
[a]2D9 = 0.88 (c = 1.0, MeOH).
HRMS (ESI) Calcd for C13H18O3Na[M + Na]+, 245.1153;
Found, 245.1161.
(1R,2R)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-6-methoxy-2-
(1S, 2R)-2,3-Dihydro-2-(hydroxymethyl)-2-methyl-1H-inden-1-ol
methylnaphthalen-1-ol (22)
(27)
dH (CDCl3, 200 MHz): 7.45 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.6,
2.6 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 4.69 (s, 1H), 3.78 (s, 3H),
3.6 (s, 2H), 2.93–2.63 (m, 2H), 1.62–1.52 (m, 2H), 0.98 (s, 3H).
dC (CDCl3, 50 MHz): 158.6, 136.7, 130.6, 128.1, 113.0, 112.4,
74.6, 72.5, 55.2, 38.2, 29.1, 25.4, 14.3.
dH (CDCl3, 200 MHz): 6.99 (s, 1H), 6.87–6.82 (m, 2H), 4.82 (s,
1H), 3.41 (s, 2H), 2.6 (d, J = 14.4 Hz, 1H), 2.34 (d, J = 14.4 Hz,
1H), 2.14 (s, 3H), 0.8 (s, 3H).
dC (CDCl3, 50 MHz): 144.6, 137.4, 135.7, 128.1, 124.8, 124.5,
78.8, 69.0, 50.4, 39.7, 21.2, 17.1.
[a]2D9 = 11.2 (c = 1.0, MeOH).
[a]2D9 -4.68 (c 1.0, MeOH).
HRMS (ESI) Calcd for C13H18O3Na[M + Na]+, 245.1153;
Found, 245.1162.
HRMS (TOF) Calcd for C11H14O2Na [M + Na]+,201.0892;
Found, 201.0892.
(1S,2R)-2-Ethyl-1,2,3,4-tetrahydro-2-(hydroxymethyl)naphthalen-
1-ol (23)
(1R,2R)-2,3-Dihydro-2-(hydroxymethyl)-2-methyl-1H-inden-1-ol
(28)
dH (CDCl3, 200 MHz): 7.53 (d, J = 7.0 Hz, 1H), 7.26–7.07 (m,
3H), 4.81 (s, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.56 (d, J = 10.8 Hz,
1H), 2.83–2.66 (m, 2H), 1.83–1.6 (m, 2H), 1.5–1.22 (m, 2H), 1.15
(t, J = 7.4 Hz, 3H).
dH (CDCl3, 200 MHz): 7.18 (s, 1H), 7.05 (m, 2H), 5.04 (s, 1H),
3.70 (s, 2H), 2.76 (d, J = 15.6 Hz, 1H), 2.57 (d, J = 15.6 Hz, 1H),
2.34 (s, 3H), 1.05 (s, 3H).
dC (CDCl3, 50 MHz): 138.1, 135.6, 128.3, 126.9, 126.5, 126.3,
76.4, 68.9, 40.2, 25.2, 24.9, 17.6, 7.2.
dC (CDCl3, 50 MHz): 143.9, 137.3, 136.5, 128.8, 124.8, 124.7,
80.1, 70.3, 50.2, 39.9, 21.3, 16.9.
[a]2D9 = 2.2 (c = 0.4, MeOH).
[a]2D9 -18.9 (c 1.0, MeOH).
HRMS (ESI) Calcd for C13H18O2Na[M + Na]+, 229.1204;
Found, 229.1197.
HRMS (TOF) Calcd for C11H14O2Na, 201.0892; Found,
201.0892.
542 | Org. Biomol. Chem., 2012, 10, 536–547
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
(1S,2R)-2-Ethyl-2,3-dihydro-2-(hydroxymethyl)-1H-inden-1-ol
(29)
(1R,2R)-5-Fluoro-2,3-dihydro-2-(hydroxymethyl)-2-methyl-1H-
inden-1-ol (34)
dH (CDCl3, 200 MHz): 7.38–7.34 (m, 1H), 7.25–7.14 (m, 3H), 5.1
(s, 1H), 3.72 (d, J = 10.6 Hz, 1H), 3.57 (d, J = 10.6 Hz, 1H), 2.78
(d, J = 15.8 Hz, 1H), 2.58 (d, J = 15.8 Hz, 1H), 1.83–1.69 (m, 1H),
1.55–1.4 (m, 1H), 0.89 (t, J = 7.4 Hz, 3H).
dH (CDCl3, 200 MHz): 7.34–7.27 (m, 1H), 6.95–6.85 (m, 2H), 5.03
(s, 1H), 3.68 (s, 2H), 2.79 (d, J = 15.8 Hz, 1H), 2.59 (d, J = 15.8 Hz,
1H), 1.05 (s, 3H).
dC (CDCl3, 100 MHz): 162.9 (d, J = 243.2 Hz), 142.7 (d, J =
8.4 Hz), 139.24 (d, J = 2.2 Hz), 125.42 (d, J = 9.1 Hz), 113.73 (d,
J = 22.5 Hz), 111.1 (d, J = 22.5 Hz), 79.1, 69.8, 50.3, 40.0, 29.6,
16.8.
dC (CDCl3, 50 MHz): 144.3, 141.0, 128.3, 126.9, 125.1, 124.4,
80.8, 67.2, 52.6, 37.4, 21.5, 8.9.
[a]2D9 -2.85 (c 1.0, MeOH).
HRMS (ESI) Calcd for C12H16O2Na[M + Na]+, 215.1047;
Found, 215.1043.
[a]2D9 -4.43 (c 1.0, MeOH).
(1S,2R)-5-Bromo-2,3-dihydro-2-(hydroxymethyl)-2-methyl-1H-
(1R,2R)-2-Ethyl-2,3-dihydro-2-(hydroxymethyl)-1H-inden-1-ol
inden-1-ol (35)
(30)
dH (CDCl3, 200 MHz): 7.26–7.12 (m, 3H), 4.93 (s, 1H), 3.55 (s,
2H), 2.72 (d, J = 15.8 Hz, 1H), 2.44 (d, J = 15.8 Hz, 1H), 0.91 (s,
3H).
dH (CDCl3, 200 MHz): 7.38–7.34 (m, 1H), 7.25–7.14 (m, 3H), 5.1
(s, 1H), 3.71 (d, J = 10.6 Hz, 1H), 3.58 (d, J = 10.6 Hz, 1H), 2.77
(d, J = 15.8 Hz, 1H), 2.58 (d, J = 15.8 Hz, 1H), 1.83–1.69 (m, 1H),
1.55–1.4 (m, 1H), 0.89 (t, J = 7.4 Hz, 3H).
dC (CDCl3, 50 MHz): 143.5, 142.8, 129.5, 128.0, 125.8, 121.2,
78.0, 69.1, 50.6, 29.6, 16.9.
dC (CDCl3, 50 MHz): 144.1, 140.8, 128.2, 126.8, 124.9, 124.2,
80.7, 67.1, 52.4, 37.2, 21.3, 8.8.
[a]2D9 -6.78 (c 0.9, MeOH).
HRMS (TOF) Calcd for C11H13BrO2Na [M + Na]+, 278.9997;
Found, 278.9672.
[a]2D9 -7.55 (c 0.75, MeOH).
HRMS (ESI) Calcd for C12H16O2Na[M + Na]+, 215.1047;
Found, 215.1043.
(1R,2R)-5-Bromo-2,3-dihydro-2-(hydroxymethyl)-2-methyl-1H-
inden-1-ol (36)
(1S,2R)-2,3-Dihydro-2-(hydroxymethyl)-5-methoxy-2-methyl-1H-
inden-1-ol (31)
dH (CDCl3, 200 MHz): 7.26–7.12 (m, 3H), 4.93 (s, 1H), 3.55 (s,
2H), 2.72 (d, J = 15.8 Hz, 1H), 2.44 (d, J = 15.8 Hz, 1H), 0.91 (s,
3H).
dH (CDCl3, 200 MHz): 7.24 (m, 1H), 6.75–6.69 (m, 2H), 4.95 (s,
1H), 3.79 (s, 3H), 3.57 (s, 2H), 2.77 (d, J = 15.8 Hz, 1H), 2.54 (d,
J = 15.8 Hz, 1H), 1.05 (s, 3H).
dC (CDCl3, 50 MHz): 143.4, 142.7, 129.5, 128.2, 125.6, 121.3,
78.3, 69.4, 50.8, 29.5, 16.7.
dC (CDCl3, 50 MHz): 159.9, 142.4, 136.1, 125.2, 126.7, 110.4,
78.9, 69.5, 55.4, 50.1, 40.4, 17.2.
[a]2D9 -9.95 (c 0.8, MeOH).
HRMS (TOF) Calcd for C11H13BrO2Na [M + Na]+, 278.9997;
Found, 278.9672.
[a]2D9 -8.45 (c 1.0, MeOH).
HRMS (ESI) Calcd for C12H16O3Na [M + Na]+,231.0997;
Found, 231.0991.
(1S,2R)-2,3-Dihydro-2-(hydroxymethyl)-2,6-dimethyl-1H-inden-
1-ol (37)
(1R,2R)-2,3-Dihydro-2-(hydroxymethyl)-5-methoxy-2-methyl-1H-
inden-1-ol (32)
dH (CDCl3, 200 MHz): 6.99 (s, 1H), 6.87–6.82 (m, 2H), 4.82 (s,
1H), 3.41 (s, 2H), 2.59 (d, J = 15.6 Hz, 1H), 2.33 (d, J = 15.6 Hz,
1H), 2.14 (s, 3H), 0.81 (s, 3H).
dH (CDCl3, 200 MHz): 7.23 (m, 1H), 6.76–6.69 (m, 2H), 4.95 (s,
1H), 3.76 (s, 3H), 3.63 (s, 2H), 2.73 (d, J = 15.8 Hz, 1H), 2.57 (d,
J = 15.8 Hz, 1H), 1.05 (s, 3H).
dC (CDCl3, 50 MHz): 144.6, 137.5, 135.7, 128.1, 124.8, 124.5,
78.8, 69.0, 50.4, 39.7, 21.2, 17.1.
dC (CDCl3, 50 MHz): 160.3, 142.6, 136.2, 125.4, 112.9, 110.7,
79.7, 70.3, 55.6, 50.3, 40.6, 17.3.
[a]2D9 -16.7 (c 0.9, MeOH).
HRMS (TOF) Calcd for C12H16O2Na [M + Na]+, 215.1048;
Found, 215.1047.
[a]2D9 -11.6 (c 1.0, MeOH).
HRMS(ESI) Calcd for C12H16O3Na[M + Na]+, 231.0997;
Found, 231.0991.
(1R,2R)-2,3-Dihydro-2-(hydroxymethyl)-2,6-dimethyl-1H-inden-
1-ol (38)
(1S,2R)-5-Fluoro-2,3-dihydro-2-(hydroxymethyl)-2-methyl-1H-
inden-1-ol (33)
dH (CDCl3, 200 MHz): 7.18 (s, 1H), 7.05 (m, 2H), 5.04 (s, 1H),
3.70 (s, 2H), 2.74 (d, J = 15.6 Hz, 1H), 2.57 (d, J = 15.6 Hz, 1H),
2.34 (s, 3H), 1.05 (s, 3H).
dH (CDCl3, 200 MHz): 7.27–7.2 (m, 1H), 6.86–6.77 (m, 2H), 4.95
(s, 1H), 3.57 (s, 2H), 2.77–2.46 (m, 2H), 0.96 (s, 3H).
dC (CDCl3, 50 MHz): 162.82 (d, J = 242.5 Hz), 142.78 (d, J =
8.5 Hz), 139.73 (d, J = 2.0 Hz), 125.45 (d, J = 9.0 Hz), 113.46 (d,
J = 22.5 Hz), 111.96 (d, J = 22.0 Hz), 78.7, 69.4, 50.6, 40.1, 17.0.
[a]2D9 -1.22 (c 0.5, MeOH).
dC (CDCl3, 50 MHz): 143.4, 137.3, 136.5, 128.9, 124.8, 124.7,
80.1, 70.3, 50.1, 39.9, 21.3, 16.9.
[a]2D9 -8.56 (c 0.66, MeOH).
HRMS (TOF) Calcd for C12H16O2Na [M + Na]+, 215.1048;
Found, 215.1047.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 536–547 | 543
©

View Article Online
(1S,2R)-2-Ethyl-2,3-dihydro-2-(hydroxymethyl)-6-methyl-1H-
(7R,8R)-7,8-Dihydro-7-(hydroxymethyl)-7-methyl-6H-
inden-1-ol (39)
[1,3]dioxolo[4,5-g]chromen-8-ol (44)
d
H (CDCl3, 200 MHz): 7.21–7.01 (m, 3H), 5.02 (s, 1H), 3.68 (d, J =
dH (DMSO-d6, 200 MHz): 6.74 (s, 1H), 6.32 (s, 1H), 5.83 (s, 2H),
4.24 (s, 1H), 3.78 (s, 2H), 3.25–3.16 (m, 2H), 0.77 (s, 3H).
dC (DMSO-d6, 50 MHz): 148.6, 147.2, 141.4, 117.9, 108.8, 101.2,
97.6, 69.6, 60.4, 64.4, 39.1, 14.7.
10.6 Hz, 1H), 3.54 (d, J = 10.6 Hz, 1H), 2.7 (d, J = 15.8 Hz, 1H),
2.5 (d, J = 15.8 Hz, 1H), 2.3 (s, 3H), 1.76–1.62 (m, 1H), 1.47–1.22
(m, 1H), 0.86 (t, J = 7.4 Hz, 3H).
dC (CDCl3, 50 MHz): 144.2, 137.7, 136.4, 128.9, 124.7, 124.6,
80.6, 67.1, 52.6, 36.8, 21.3, 21.2, 8.7.
[a]2D9 = +20.4 (c = 1.0, MeOH).
[a]2D9 -12.22 (c 1.1, MeOH).
(1S,2R)-2-((tert-Butyldimethylsilyloxy)methyl)-2-methyl-1,2,3,4-
tetrahydronaphthalen-1-ol (45)
HRMS (TOF) Calcd for C13H18O2Na [M + Na]+, 229.1204;
Found, 229.1205.
The diol 18 (480 mg, 2.5◦mmol) was taken in anhydrous DCM
(10 mL) and cooled to 0 C. Imidazole (170 mg, 2.5 mmol) and
DMAP (catalytic) were added to the reaction mixture followed by
the addition of TBS-Cl (377 mg, 2.5 mmol). The reaction mixture
was allowed to warm to room temperature for 1 h, after that time
water was added to it and it was extracted with DCM, the organic
layer was washed with brine and dried over Na2SO4. Evaporation
and purification yielded the mono TBDMS-protected compound
45, in 90% yield.
dH (CDCl3, 200 MHz): 7.6 (d, J = 7.0 Hz, 1H), 7.22–7.06 (m,
3H), 4.78 (s, 1H), 3.62 (d, J = 9.4 Hz, 1H), 3.58 (d, J = 9.4 Hz,
1H), 2.96–2.66 (m, 2H), 1.66–1.42 (m, 2H), 0.95 (s, 12H), 0.1 (s,
6H).
1S,2R)-2-Ethyl-2,3-dihydro-2-(hydroxymethyl)-6-methyl-1H-
inden-1-ol (40)
dH (CDCl3, 200 MHz): 7.20–7.01 (m, 3H), 5.04 (s, 1H), 3.66 (d,
J = 10.6 Hz, 1H), 3.52 (d, J = 10.6 Hz, 1H), 2.74 (d, J = 15.8 Hz,
1H), 2.52 (d, J = 15.8 Hz, 1H), 2.3 (s, 3H), 1.76–1.65 (m, 1H),
1.47–1.22 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).
dC (CDCl3, 50 MHz): 144.2, 137.8, 136.5, 128.9, 124.4, 124.2,
80.5, 67.1, 52.6, 36.8, 21.4, 21.2, 8.7.
[a]2D9 -9.8 (c 1.0, MeOH).
HRMS (TOF) Calcd for C13H18O2Na [M + Na]+, 229.1204;
Found, 229.1205.
dC (CDCl3, 50 MHz): 138.4, 134.9, 128.1, 126.73, 126.6, 126.2,
75.0, 73.84, 38.0, 29.3, 25.91, 25.17, 18.2, 14.3, -5.5, -5.6.
[a]2D9 = +16.4 (c = 0.8, MeOH).
(3S,4R)-3,4-Dihydro-3-(hydroxymethyl)-3-methyl-2H-chromen-4-
ol (41)
d
H (CDCl3, 200 MHz): 7.43 (d, J = 7.2 Hz, 1H), 7.20 (m, 1H), 6.96
(1S,2R)-2-((tert-Butyldimethylsilyloxy)methyl)-2-methyl-1,2,3,4-
tetrahydronaphthalen-1-yl 4-nitrobenzoate (46)
(m, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.72 (s, 1H), 4.0 (d, J = 11.2 Hz,
1H), 3.9 (d, J = 11.2 Hz, 1H), 3.59 (d, J = 11.0 Hz, 1H), 3.4 (d, J =
11.0 Hz, 1H), 1.0 (s, 3H).
4-Nitrobenzoic acid (131 mg, 0.784 mmol) was taken in dry DCM
(5 mL). Dicyclohexylcarbodiimide (DCC, 162 mg, 0.784 mmol),
DMAP (cat. amount) and compound 45 (160 mg, 0.523 mmol)
were sequentially added to the reaction mixture. The reaction
mixture was kept at room temperature for 3 h. After that time it was
directly loaded into a silica gel column. The ester was purified by
flash chromatography (40 : 1; hexane–EtOAc) to afford compound
46 in 88% yield.
dC (CDCl3, 50 MHz): 153.6, 128.7, 124.6, 120.7, 116.0, 70.0,
68.1, 66.3, 37.9, 13.7.
[a]2D9 = +34.06 (c = 1.0, MeOH).
HRMS (ESI) Calcd for C11H14O3Na [M + Na]+, 217.0841;
Found, 217.0846.
(3S,4S)-3,4-Dihydro-3-(hydroxymethyl)-3-methyl-2H-chromen-4-
ol (42)
dH (CDCl3, 200 MHz): 8.28–8.17 (m, 4H), 7.24–7.1 (m, 4H),
6.26 (s, 1H), 3.56–3.3 (m, 2H), 2.98–2.72 (m, 2H), 1.91–1.77 (m,
2H), 1.04 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H).
d
H (CDCl3, 200 MHz): 7.38 (d, J = 7.4 Hz, 1H), 7.05 (m, 1H), 6.86
(m, 1H), 6.7 (d, J = 8.0 Hz, 1H), 4.64 (s, 1H), 3.95 (d, J = 11.0 Hz,
1H), 3.83 (d, J = 11.0 Hz, 1H), 3.5 (d, J = 11.2 Hz, 1H), 3.31 (d,
J = 11.2 Hz, 1H), 0.91 (s, 3H).
dC (CDCl3, 50 MHz): 164.3, 150.5, 136.6, 135.9, 134.0, 130.8,
129.0, 128.8, 127.9, 126.6, 123.5, 75.1, 67.7, 39.0, 28.4, 25.8, 25.5,
18.7, 18.2, -5.67.
dC (CDCl3, 50 MHz): 153.6, 128.8, 128.5, 124.8, 120.5, 115.8,
70.1, 67.8, 66.1, 37.9, 13.7.
[a]2D9 = +22.45 (c = 1.2, MeOH).
[a]2D9 = +24.3 (c = 0.8, MeOH).
HRMS (ESI) Calcd for C11H14O3Na [M + Na]+, 217.0841;
Found, 217.0846.
(1S,2R)-2-(Hydroxymethyl)-2-methyl-1,2,3,4-
tetrahydronaphthalen-1-yl 4-nitrobenzoate (47)
The para-nitrobenzoate ester prepared in the previous step, 46
(240 mg, 0.528 mmol) was dissolved in absolute methanol (4 mL)
and PPTS (70 mg, 0.3 mmol) was added in one portion. The
reaction was stirred at rt for 2.5 h. After that time the solvent was
removed in vacuo and the residue was dissolved in ethyl acetate.
The organic layer was washed with brine and dried over Na2SO4.
The crude residue was purified by flash column chromatography
(1 : 10 EtOAc–Hexane) to afford the compound 47 (82%).
(7S,8R)-7,8-Dihydro-7-(hydroxymethyl)-7-methyl-6H-
[1,3]dioxolo[4,5-g]chromen-8-ol (43)
dH (DMSO-d6, 200 MHz): 6.73 (s, 1H), 6.3 (s, 1H), 5.85 (s, 2H),
4.2 (s, 1H), 3.75 (s, 2H), 3.25–3.1 (m, 2H), 0.77 (s, 3H).
dC (DMSO-d6, 50 MHz): 148.5, 147.3, 141.3, 117.9, 108.7, 101.1,
97.6, 69.7, 60.3, 64.4, 39.1, 14.7.
[a]2D9 = +28.9 (c = 1.0, MeOH).
544 | Org. Biomol. Chem., 2012, 10, 536–547
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
d
H (CDCl3, 200 MHz): 8.29 (m, 4H), 7.25–7.15 (m, 4H), 6.32 (s,
was stirred at room temperature for 2 h. The solvent was removed
in vacuo and the residue was dissolved in ethyl acetate. The
organic layer was washed with brine and dried over Na2SO4. The
crude residue was purified by flash column chromatography (1 : 10
EtOAc–Hexane) to afford the compound 50 (86%).
dH (CDCl3, 200 MHz): 7.52 (m, 1H), 7.24–7.09 (m, 3H), 5.88
(dd, J = 17.6, 10.6 Hz, 1H), 5.15 (m, 2H), 4.5 (s, 1H), 2.88–2.8 (m,
2H), 1.89–1.71 (m, 2H), 1.09 (s, 3H).
1H), 3.5 (d, J = 8.6 Hz, 1H), 3.42 (d, J = 8.6 Hz, 1H), 2.96–2.87 (m,
2H), 2.56 (br, 1H, -OH), 2.16–2.09 (m, 1H), 1.83–1.76 (m, 1H),
1.06 (s, 3H).
dC (CDCl3, 50 MHz): 165.5, 150.7, 136.3, 135.2, 133.7, 131.0,
129.4, 128.9, 127.8, 126.2, 123.7, 74.8, 67.9, 39.0, 28.9, 25.3, 16.7.
[a]2D9 = +8.26 (c = 0.5, MeOH).
dC (CDCl3, 50 MHz): 145.2, 137.8, 135.6, 128.6, 128.1, 127.3,
126.2, 113.5, 74.4, 40.4, 31.0, 25.7, 18.2.
(1S,2S)-2-Formyl-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl
4-nitrobenzoate (48)
[a]2D9 = +12.66 (c = 0.5, MeOH).
Oxalyl chloride (0.12 mL, 1.329 mmol) was taken in anhydrous
DCM (5 mL). Then DMSO (0.19 mL, 2.66 mmol) was added
to the solution and kept at -78 ◦C. After 15 min alcohol 47
(220 mg, 0.886 mmol) was added to it, and the solution was stirred
at the same temperature for a further 45 min. After this time Et3N
(0.74 mL, 5.316 mmol) was added slowly to the reaction mixture
at the same temperature. The reaction mixture was allowed to
attain room temperature. Water was added to the solution, and
the mixture was extracted with DCM. The organic extract was
washed with water, NaHCO3 solution and brine. The organic
layer was dried (Na2SO4) and evaporated. Purification by silica
gel chromatography yielded the aldehyde 48 in 90% yield.
dH (CDCl3, 200 MHz): 9.57 (s, 1H), 8.27–8.14 (m, 4H), 7.33–
7.11 (m, 4H), 6.57 (s, 1H), 3.07–2.87 (m, 2H), 2.24–1.91 (m, 2H),
1.19 (s, 3H).
HRMS(ESI) Calcdfor C13H16ONa[M + Na]+, 211.1098; Found,
211.1103.
(1R,2R)-1-(Allyloxy)-2-methyl-2-vinyl-1,2,3,4-
tetrahydronaphthalene (51)
The compound 50 (25 mg, 0.133 mmol) was dissolved in 1 mL
of dry DMF. Silver oxide (74 mg, 0.319 mmol) and allyl bromide
(35 mL, 0.4 mmol) were added subsequently. The reaction mixture
was stirred at room temperature for 4 days. After completion of the
reaction, as indicated by TLC, the mixture was quenched with cold
water (2 mL), and extracted with AcOEt. The combined organic
layer was washed with brine and dried over Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (Hexane–EtOAc, 20 : 1) afforded 51 (72% yield).
dH (CDCl3, 200 MHz): 7.29–7.11 (m, 4H), 6.07–5.88 (m, 2H),
5.37–5.0 (m, 4H), 4.17–4.07 (m, 3H), 2.91–2.8 (m, 2H), 2.0 (m,
1H), 1.77–1.6 (m, 1H), 1.21 (s, 3H).
dC (CDCl3, 50 MHz): 202.1, 164.28, 150.7, 135.8, 135.1, 132.6,
131.2, 130.9, 129.0, 128.7, 126.6, 123.6, 72.9, 49.8, 26.7, 25.1, 16.2.
[a]2D9 = +32.0 (c = 1.5, MeOH).
dC (CDCl3, 50 MHz): 144.7, 136.4, 136.3, 135.4, 129.1, 128.9,
127.4, 125.3, 116.4, 112.6, 82.2, 71.7, 40.5, 30.2, 29.7, 21.7.
[a]2D9 = +18.45 (c = 0.6, MeOH).
(1R,2R)-2-Methyl-2-vinyl-1,2,3,4-tetrahydronaphthalen-1-yl
4-nitrobenzoate (49)
HRMS(ESI) Calcdfor C16H20ONa[M + Na]+, 251.1412; Found,
251.1404.
Wittig reaction of compound 48 was done by using KOtBu as
a base. To a suspension of freshly prepared KOtBu (177 mg,
1.578 mmol) in 5 mL of diethyl ether was added methyltriph-
enylphosphonium iodide (709 mg, 1.752 mmol) in two portions.
The bright yellow mixture was heated at reflux for 1 h. The yellow
mixture was allowed to cool to room temperature. A solution
of aldehyde 48 (180 mg, 0.796 mmol) in 5 mL of Et2O was
added to the reaction mixture. The solution was stirred at room
temperature. After completion of the reaction, as indicated by
TLC, the reaction was quenched with water and the layers were
separated. The aqueous layer was extracted with 20 mL of Et2O.
The organic layers were combined, dried with Na2SO4, filtered,
and the solvent was removed in vacuo. The crude residue was
purified by flash column chromatography to afford the compound
49 (1 : 20 EtOAc–Hexane) in 78% yield.
dH (CDCl3, 200 MHz): 8.31–8.19 (m, 4H), 7.34–7.12 (m, 4H),
6.22 (s, 1H), 5.84 (dd, J = 17.6, 10.6 Hz, 1H), 5.12–5.01 (m, 2H),
2.97–2.90 (m, 2H), 2.15–1.81 (m, 2H), 1.26 (s, 3H).
dC (CDCl3, 50 MHz): 165.3, 150.5, 142.5, 136.6, 135.8, 133.7,
130.8, 129.3, 128.9, 128.2, 126.2, 123.5, 114.0, 76.4, 39.8, 30.8,
25.8, 21.5.
[a]2D9 = +20.8 (c = 1.1, MeOH).
(4aR,10bR)-4a-Methyl-4a,5,6,10b-tetrahydro-2H-
benzo[h]chromene (52)
Compound 51 (15 mg, 0.0657 mmol) was taken in anhydrous
degassed DCM (30 mL). Grubbs first generation metathesis
catalyst (4 mg, 0.005 mmol) was then added and the solution
was stirred at rt for 3 h. The solution was evaporated and the
content of the flask was directly loaded onto a silica gel column.
Flash chromatography with hexane : EtOAc (1 : 30) afforded the
compound 52 in 77% yield.
dH (CDCl3, 400 MHz): 7.51 (d, J = 6.8 Hz, 1H), 7.22–7.15 (m,
2H), 7.08 (d, J = 6.8 Hz, 1H), 5.79 (d, J = 9.6 Hz, 1H), 5.66 (td, J =
9.6, 2.4 Hz, 1H), 4.44–4.39 (m, 3H), 2.95–2.81 (m, 2H), 1.76–1.71
(m, 2H), 0.88 (s, 3H).
dC (CDCl3, 100 MHz): 136.7, 136.3, 135.1, 128.1, 126.4, 125.7,
124.4, 124.3, 79.1, 67.3, 33.7, 31.7, 25.3, 17.6.
[a]2D9 = +28.6 (c = 0.33, MeOH).
HRMS(ESI) Calcd for C14H16ONa[M + Na]+, 223.1099; Found,
223.1093.
(3S,4R,4aR,10bS)-4a-Methyl-3,4,4a,5,6,10b-hexahydro-2H-
benzo[h]chromene-3,4-diol (53)
(1R,2R)-2-Methyl-2-vinyl-1,2,3,4-tetrahydronaphthalen-1-ol (50)
A methanolic solution of 1% NaOH (212 mg, 5.313 mmol, 30 mL)
At first, t-BuOH (0.2 mL), H2O (0.2 mL) and AD-mix-b (87 mg)
was added to the olefinic compound 49 and the reaction mixture
were mixed and the mixture was stirred for 15 min. Methane
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 536–547 | 545
©

View Article Online
sulfonamide (9 mg) was then added and stirring was continued
for a further 15 min. Compound 52 (12 mg, 0.06 mmol) was then
added in one portion. The slurry was stirred vigorously at 20 ◦C for
24 h. After that time, sodium sulfite (96 mg) was added and stirring
was continued for a further 1 h. The reaction mixture was extracted
with EtOAc. The organic layer was dried (Na2SO4) and evaporated
in vacuo. The diol was purified by flash chromatography (5 : 1;
hexane : EtOAc) to afford diol 53 in 78% yield.
(2R,3R)-2,3-Dihydro-2,5-dimethyl-2-vinyl-1H-inden-3-yl
4-nitrobenzoate (58)
dH (CDCl3, 200 MHz): 8.33–8.18 (m, 4H), 7.25–7.14 (m, 3H), 6.3
(s, 1H), 6.06 (dd, J = 16.0, 10.6 Hz, 1H), 5.17–5.03 (m, 2H), 3.0 (s,
2H), 2.34 (s, 3H), 1.33 (s, 3H).
dC (CDCl3, 50 MHz): 164.4, 150.6, 144.0, 140.0, 136.7, 135.8,
130.8, 129.9, 126.2, 125.5, 124.7, 123.6, 113.16, 84.1, 50.2, 43.5,
21.3, 20.0.
[a]2D9 = +24.33 (c = 0.5, MeOH).
d
H (CDCl3, 400 MHz): 7.49 (m, 1H), 7.20–7.07 (m, 3H), 4.62 (s,
1H), 4.28 (m, 1H), 4.09 (m, 1H), 3.8–3.71 (m, 2H), 2.86–2.7 (m,
2H), 2.2 (m, 2H), 1.6 (m, 2H), 0.88 (s, 3H).
(1R,2R)-2,3-Dihydro-2,6-dimethyl-2-vinyl-1H-inden-1-ol (59)
dC (CDCl3, 100 MHz): 136.2, 134.5, 128.2, 126.5, 125.8, 125.4,
74.8, 74.4, 67.5, 64.9, 37.7, 29.6, 28.4, 22.6, 14.7.
[a]2D9 = +38.2 (c = 0.1, MeOH).
dH (CDCl3, 200 MHz): 7.26–7.06 (m, 3H), 6.09 (dd, J = 16.0,
10.6 Hz, 1H), 5.18–5.05 (m, 2H), 4.91 (s, 1H), 2.88 (d, J = 16.0 Hz,
1H), 2.7 (d, J = 16.0 Hz, 1H), 2.35 (s, 3H), 1.1 (s, 3H).
dC (CDCl3, 50 MHz): 145.3, 143.7, 143.2, 137.8, 136.4, 128.8,
124.7, 112.7, 82.0, 51.5, 42.7, 21.3, 18.0.
HRMS (ESI) Calcd for C14H18O3Na [M+Na]+, 257.1153;
Found, 257.1158.
[a]2D9 = +12.56 (c = 1.2, MeOH).
(1S,2R)-2-((tert-Butyldimethylsilyloxy)methyl)-2,3-dihydro-2,5-
dimethyl-1H-inden-1-ol (54)
HRMS(ESI) Calcdfor C13H16ONa[M + Na]+, 211.1099; Found,
211.1104.
dH (CDCl3, 200 MHz): 7.25–7.04 (3H), 5.06 (s, 1H), 3.6 (s, 2H),
2.81–2.54 (2H), 2.4 (s, 3H), 0.9 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H).
dC (CDCl3, 50 MHz): 144.0, 137.5, 136.2, 128.5, 124.7, 80.0,
70.2, 50.5, 39.7, 25.9, 21.3, 18.3, 17.1, -5.48.
(1R,2R)-1-(Allyloxy)-2,3-dihydro-2,6-dimethyl-2-vinyl-1H-indene
(60)
[a]2D9 = +8.62 (c = 0.5, MeOH).
dH (CDCl3, 400 MHz): 7.14 (s, 1H), 7.04 (m, 2H), 6.12 (dd, J =
160, 10.8 Hz, 1H), 6.01–5.94 (m, 1H), 5.32 (d, J = 17.2 Hz, 1H),
5.15 (m, 2H), 5.03 (d, J = 10.8 Hz, 1H), 4.66 (s, 1H), 4.24 (dd, J =
12.8, 5.2 Hz, 1H), 4.14 (dd, J = 12.8, 5.2 Hz, 1H), 2.84 (d, J =
16.0 Hz, 1H), 2.68 (d, J = 16.0 Hz, 1H), 2.33 (s, 3H), 1.14 (s, 3H).
dC (CDCl3, 100 MHz): 146.5, 142.7, 137.8, 135.9, 135.0, 128.5,
125.2, 124.4, 116.6, 112.1, 88.4, 71.4, 51.3, 43.7, 21.2, 18.1.
[a]2D9 = +46.4 (c = 0.8, MeOH).
(1S,2R)-2-((tert-Butyldimethylsilyloxy)methyl)-2,3-dihydro-2,5-
dimethyl-1H-inden-1-yl 4-nitrobenzoate (55)
dH (CDCl3, 200 MHz): 8.3–8.21 (m, 4H), 7.25–7.08 (m, 3H), 6.39
(s, 1H), 3.58 (d, J = 9.6 Hz, 1H), 3.5 (d, J = 9.6 Hz, 1H), 2.96 (d,
J = 16.0 Hz, 1H), 2.8 (d, J = 16.0 Hz, 1H), 2.33 (s, 3H), 1.2 (s, 3H),
0.86 (s, 9H), 0.03 (s, 6H).
HRMS(ESI) Calcd for C16H20ONa[M + Na]+, 251.1412; Found,
251.1404.
dC (CDCl3, 50 MHz): 164.4, 150.5, 140.4, 139.8, 136.5, 136.0,
130.8, 129.9, 126.3, 124.8, 123.5, 81.8, 68.8, 49.6, 40.6, 25.8, 21.3,
18.5, 18.2, -5.5.
(4aR,9bR)-8-Dimethyl-2,4a,5,9b-tetrahydro-indeno[1,2-b]pyran
(61)
[a]2D9 = +13.9 (c = 0.5, MeOH).
dH (CDCl3, 200 MHz): 7.11–6.96 (m, 3H), 6.26 (td, J = 10.0,
2.4 Hz, 1H), 5.58 (td, J = 10.0, 2.4 Hz, 1H), 4.79 (s, 1H), 4.52 (t,
J = 2.2 Hz, 2H), 2.57 (s, 2H), 2.34 (s, 3H), 0.87 (s, 3H).
dC (CDCl3, 50 MHz): 141.6, 137.7, 135.9, 134.8, 127.2, 125.4,
125.2, 122.5, 85.6, 68.3, 45.4, 38.2, 21.2, 20.6.
[a]2D9 = +18.2 (c = 0.4, MeOH).
(1S,2R)-2,3-Dihydro-2-(hydroxymethyl)-2,5-dimethyl-1H-inden-
1-yl 4-nitrobenzoate (56)
dH (CDCl3, 200 MHz): 8.26 (m, 4H), 7.15 (m, 3H), 6.38 (s, 1H),
3.6 (s, 2H), 2.98 (d, J = 16.0 Hz, 1H), 2.65 (d, J = 16.0 Hz, 1H),
2.32 (s, 3H), 1.2 (s, 3H).
dC (CDCl3, 50 MHz): 165.3, 150.7, 139.8, 138.9, 136.8, 135.6,
130.9, 130.1, 126.0, 125.0, 123.7, 81.9, 68.6, 50.1, 40.8, 21.3, 18.3.
[a]2D9 = +2.45 (c = 0.2, MeOH).
HRMS(ESI) Calcd for C14H16ONa[M + Na]+, 223.1099; Found,
223.1093.
(3S,4R,4aR,9bR)-8-Dimethyl-2,3,4,4a,5,9b-hexahydro-
indeno[1,2-b]pyran-3,4-diol (62)
d
H (CDCl3, 400 MHz): 7.07 (2H), 6.97 (d, J = 7.6 Hz, 1H), 5.01 (s,
(1S,2S)-2-Formyl-2,3-dihydro-2,5-dimethyl-1H-inden-1-yl
4-nitrobenzoate (57)
1H), 4.24 (m, 1H), 4.05 (m, 2H), 3.62 (t, J = 10.8 Hz, 1H), 2.94 (d,
J = 14.0 Hz, 1H), 2.36 (d, J = 14.0 Hz, 1H), 2.32 (s, 3H), 1.6 (br,
2H, -OH), 0.88 (s, 3H).
dH (CDCl3, 200 MHz): 9.77 (s, 1H), 8.3–8.21 (m, 4H), 7.25–7.17
(m, 3H), 6.55 (s, 1H), 3.38 (d, J = 16.0 Hz, 1H), 2.89 (d, J = 16.0 Hz,
1H), 2.35 (s, 3H), 1.25 (s, 3H).
dC (CDCl3, 50 MHz): 201.6, 164.5, 150.8, 138.8, 137.4, 136.2,
135.0, 130.9, 130.6, 126.0, 124.8, 123.7, 80.4, 58.7, 39.1, 21.3, 15.3.
[a]2D9 = +6.82 (c = 0.5, MeOH).
dC (CDCl3, 100 MHz): 140.8, 137.1, 136.4, 127.8, 125.9, 123.4,
80.6, 73.4, 69.3, 64.9, 50.7, 36.3, 21.6, 17.6.
[a]2D9 = +23.96 (c = 0.13, MeOH).
HRMS (ESI) Calcd for C14H18O3Na [M+Na]+, 257.1154;
Found, 257.1158.
546 | Org. Biomol. Chem., 2012, 10, 536–547
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
5 Enzyme catalysis in organic synthesis (Vol 1-3)., Ed by K. Drauz and
H. Waldmann, Wiley-VCH, Weinheim, 2002.
Acknowledgements
6 E. Garcia-Urdiales, I. Alfonso and V. Gotor, Chem. Rev., 2005, 105,
Financial support from DST-India is gratefully acknowledged
(Grant: SR/S1/OC-55/2009, IRPHA for NMR instrument and
for X-ray diffractometer). One of the authors RB is thankful to
CSIR-India for providing research fellowship.
313–354.
7 (a) T. Mahapatra, T. Das and S. Nanda, Tetrahedron: Asymmetry, 2008,
19, 2497–2507; (b) T. Mahapatra, N. Jana and S. Nanda, Tetrahedron:
Asymmetry, 2008, 19, 1224–1232; (c) T. Mahapatra, N. Jana and S.
Nanda, Adv. Synth. Catal., 2011, 353, 2152–2168.
8 (a) S. Kesavan, J. S. Panek and J. A. Jr. Porko, Org. Lett., 2007, 9,
5203–5206; (b) W. Gu, H. M. Ge, Y. C. Song, H. Ding, H. L. Zhu, X.
A. Zhao and R. X. Tan, J. Nat. Prod., 2007, 70(1), 114–117; (c) Rene
Beugelmans, Jacqueline Chastanet, Helene Ginsburg, Leticia Quintero-
Cortes and Georges Roussi, J. Org. Chem., 1985, 50, 4933–4938.
9 (a) D. C. Demirjian, P. C. Shah and F. Moris-Varas, In Biocatalysis From
Discovery to Application, (Ed: W. D Fessner), Springer-Verlag, Berlin,
2000, pp. 1–29; (b) Y. Yasohara, N. Kizaki, J. Hasegawa, M. Takahashi,
M. Wada, M. Kataoka and S. Shimizu, Appl. Microbiol. Biotechnol.,
1999, 51, 847–851; (c) S. Shimizu, H. Hata and H. Yamada, Agric. Biol.
Chem., 1984, 48, 2285–2291; (d) M. Kataoka, S. Shimizu, Y. Doi, K.
Sakamoto and H. Yamada, Biotechnol. Lett., 1990, 12, 357–360; (e) H.
Miya, M. Kawada and Y. Sugiyama, Biosci., Biotechnol., Biochem.,
1996, 60, 95–98; (f) A. Shafiee, H. Motamedi and A. King, Appl.
Microbiol. Biotechnol., 1998, 49, 709–717; (g) M. Wada, M. Kataoka,
H. Kawabata, Y. Yasohara, N. Kizaki, J. Hasegawa and S. Shimizu,
Biosci., Biotechnol., Biochem., 1998, 62, 280–285; (h) M. Wada, H.
Kawabata, A. Yoshizumi, M. Kataoka, S. Nakamori, Y. Yasohara,
N. Kizaki, J. Hasegawa and S. Shimizu, J. Biosci. Bioeng., 1999, 87,
144–148.
References
1 (a) R. A. Bauer, J. M. Wurst and D. S. Tan, Curr. Opin. Chem. Biol.,
2010, 14, 308–314; (b) M. E. Welsch, S. A. Snyder and B. R. Stockwell,
Curr. Opin. Chem. Biol., 2010, 14, 347–361; (c) S. Shang and D. Tan,
Curr. Opin. Chem. Biol., 2002, 6, 161–167; (d) A. Reayi and P. Arya,
Curr. Opin. Chem. Biol., 2005, 9, 240–247; (e) R. Breinbauer, I. R.
Vetter and H. Waldmann, Angew. Chem., Int. Ed, 2002, 41, 2879–2890;
(f) D J. Ecker and S, T. Crooke, Biotechnology, 1995, 13, 351–60; (g) P.
Arya, R. Joseph, Z. Gan and B. Rakic, Chemistry & Biology, 2005, 12,
163–180; (h) S. Shang and D. S. Tan, Curr. Opin. Chem. Biol., 2005, 9,
248–258; (i) D. S. Tan, Nat. Chem. Biol., 2005, 1, 74–84; (j) M. Oikawa,
M. Ikoma and M. Sasaki, Tetrahedron Lett., 2005, 46, 5863–5866;
(k) L. Weber, Methods in Molecular Biology, 2005, 310, 11–24; (l) D.
E. G. Shuker, Annual Reports on the Progress of Chemistry, Section
B:, Organic Chemistry, 2005, 101, 137–147; (m) S. Hotha, Chemical
Industry Digest, 2006, 19, 51–56; (n) D. S. Tan, Eds by S. L. Schreiber,
T. M. Kapoor and G. Wess, Chemical Biology: From Small Molecules
to Systems Biology and Drug Design, Wiley-VCH, 2007, Vol 2, 483-518.
2 (a) G. Klebe, Drug Discovery Today, 2006, 11, 580–594; (b) J. C.
Hermann, R. Marti-Arbona, A. A. Fedorov, E. Fedorov, S. C. Almo,
B. K. Shoichet and F. M. Raushel, Nature, 2007, 448, 775–779; (c) P.
Willet, Drug Discovery Today, 2006, 11, 1046–1053; (d) J. Rosen, J.
Gottfries, S. Muresan, A. Backlund and T. I. Opera, J. Med. Chem.,
2009, 52, 1953–1962; (e) D. J. Newman and G. M. Cragg, J. Nat. Prod.,
2007, 70, 461–477; (f) M. A. Koch, A. Schuffenhauer, M. Scheck, S.
Wetzel, M. Casaulta, A. Odermatt, P. Ertl and H. Waldmann, Proc.
Natl. Acad. Sci. U. S. A., 2005, 102, 17272–17277; (g) S. Wetzel, A.
Schuffenhauer, S. Roggo, P. Ertl and H. Waldmann, Chimia, 2007, 61,
355–360; (h) C. M. Dobson, Nature, 2004, 431, 931–945; (i) C. Lipinski
and A. Hopkins, Nature, 2004, 432, 855–861.
3 (a) S. Dandapani and L. A. Marcaurelle, Curr. Opin. Chem. Biol., 2010,
14, 362–370; (b) J. E. Biggs-Houck, A. Younai and J. T. Shaw, Curr.
Opin. Chem. Biol., 2010, 14, 371–382; (c) M. Vendrell, J. S. Lee and Y.
T. Chang, Curr. Opin. Chem. Biol., 2010, 14, 383–389; (d) S. Goldman,
Curr. Opin. Chem. Biol., 2010, 14, 390–395; (e) B. Lepenies, J. Yin and
P. H. Seeberger, Curr. Opin. Chem. Biol., 2010, 14, 404–411; (f) I. R.
J. Correa, A. Noren-Muller, H.-D. Ambrosi, S. Jakupovic, K. Saxena,
H. Schwalbe, M. Kaiser and H. Waldmann, Chem.–Asian. J., 2007, 2,
1109–1126; (g) C. Rosenbaum, P. Baumhot, R. Mazitschek, O. Muller,
A. Giannis and H. Waldmann, Angew. Chem., Int. Ed., 2004, 43, 224–
228; (h) F. Wehner, A. Noren-Muller, O. Muller, I. Jr. Reis-Correa, A.
Giannis and H. Waldmann, ChemBioChem, 2008, 9, 401–405; (i) A.
Noren-Muller, W. Wilk, K. Saxena, H. Schwalbe, M. Kaiser and H.
Waldmann, Angew. Chem., Int. Ed., 2008, 47, 5973–5977; (j) W. Wilk, A.
Noren-Muller, M. Kaiser and H. Waldmann, Chem.–Eur. J., 2009, 15,
11976–11984; (k) M. A. Koch, L.-O. Wittenberg, S. Basu, D. A. Jeyaraj,
E. Gourzoulidou, K. Reinecke, A. Odermatt and H. Waldmann, Proc.
Natl. Acad. Sci. U. S. A., 2004, 101, 16271–16276; (l) M. Scheck, M.
A. Koch and H. Waldmann, Tetrahedron, 2008, 64, 4792–4802; (m) S.
Wetzel, K. Klein, S. Renner, D. Rauh, T. I. Oprea, P. Mutzel and H.
Waldmann, Nat. Chem. Biol., 2009, 5, 581–583; (n) S. Renner, W. A.
van Otterlo, M. Dominguez Seoana, S. Mocklinghoff, B. Hofmann,
S. Wetzel, A. Schuffenhauer, P. Ertl, T. I. Oprea, D. Steinhilber, L.
Brunsveld, D. Rauh and H. Waldmann, Nat. Chem. Biol., 2009, 5,
585–592; (o) K. Kumar and H. Waldmann, Angew. Chem., Int. Ed.,
2009, 48, 3224–3242; (p) J. P. Nandy, M. Prakesch, S. Khadem, P. T.
Reddy, U. Sharma and P. Arya, Chem. Rev., 2009, 109, 1990–2060; (q) T.
E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed., 2008, 47, 48–56;
(r) H. Waldmann, M. Kuhn, W. Lui and K. Kumar, Chem. Commun.,
2008, 10, 1211–1213; (s) A. Ulaczyk-Lesanko and D. G. Hall, Curr.
Opin. Chem. Biol., 2005, 9, 266–276; (t) O. Ramstrom and J. M. Lehn,
Nat. Rev. Drug Discovery, 2002, 1, 26–36; (u) R A. Goodnow, W. Guba
and W. Haap, Comb. Chem. High Throughput. Screen., 2003, 6, 649–90.
4 New frontiers in asymmetric catalysis, Ed by K. Mikami and M.
Lautens, Wiley-Interscience, New Jersey, 2007.
10 Y. N. Niu, Z. Y. Yan, G. Q. Li, H. L. Wei, G. L. Gao, L. Y. Wu and Y.
M. Liang, Tetrahedron: Asymmetry, 2008, 19, 912–920.
11 (a) K Nakamura, R Yamanaka, T Matsuda and T Harada, Tetra-
hedron: Asymmetry, 2003, 14, 2659–2681; (b) K. Nakamura and T.
Matsuda, J. Org. Chem., 1998, 63, 8957–8964; (c) K. Nakamura, K.
Kitano, T. Matsuda and A. Ohno, Tetrahedron Lett., 1996, 37, 1629–
1632; (d) D. Buisson, R. Azerad, C. Sanner and M. Larcheveque,
Biocatalysis., 1992, 5, 249–265; (e) D. Buisson, R. Azerad, C. Sanner
and M. Larcheveque, Tetrahedron: Asymmetry, 1991, 2, 987–988; (f) D.
Buisson, R. Azerad, C. Sanner and M. Larcheveque, Biocatalysis.,
1990, 3, 85–93; (g) K. Nakamura, Y. Inoue, T. Matsuda and I. Misawa,
J. Chem. Soc., Perkin Trans. 1, 1999, 2397–2402; (h) K. Nakamura,
M. Fujii and Y. Ida, J. Chem. Soc., Perkin Trans 1., 1997, 2375; (i) K.
Nakamura, S. Takano and A. Ohno, Tetrahedron Lett., 1993, 34, 6087–
6090; (j) K. Nakamura, J. Mol. Catal B: Enzymatic., 1998, 5, 129–132;
(k) Z. L. Wie, G. Q. Lin and Z. Y. Li, Bioorg. Med. Chem., 2000, 8,
1129–1137; (l) R. N. Patel, C. G. Mcnamee, A. Banerje, J. M. Howell,
R. S. Robison and L. Szarka, J. Enzyme Microb. Technol., 1992, 14,
731–738; (m) T. Kitayama, Tetrahedron: Asymmetry, 1997, 8, 3765–
3774; (n) R. Azerad and D. Buisson, In: Microbial Reagents in Organic
Synthesis, (Ed: S. Servi), Kluwer Academic Publishers, Netherlands,
1992, pp. 421–440; (o) K. Nakamura, T. Matsuda, T. Itoh and A. Ohno,
Tetrahedron Lett., 1996, 37, 5727–5730; (p) T. Matsuda, T. Harada, N.
Nakajima, T. Itoh and K. Nakamura, J. Org. Chem., 2000, 65, 157–
163; (q) A. Arnone, R. Bernardi, F. Blasco, R. Cardillo, R. Resnati,
I. I. Gerus and V. P. Kukhar, Tetrahedron, 1998, 54, 2809–2818; (r) T.
Kitazume and T. Kobayashi, Synthesis, 1987, 187–188; (s) T. Kitazume
and Y. Nakayama, J. Org. Chem., 1986, 51, 2795–2799; (t) T. Kitazume
and T. Sato, J. Fluorine Chem., 1985, 30, 189–202; (u) T. Fujisawa, K.
Ichikawa and M. Shimizu, Tetrahedron: Asymmetry, 1993, 4, 1237–
1240; (v) T. Fujisawa, T. Sugimoto and M. Shimizu, Tetrahedron:
Asymmetry, 1994, 5, 1095–1098; (w) T. Fujisawa, Y. Onogawa, A. Sato,
T. Mitsuya and M. Shimizu, Tetrahedron, 1998, 54, 4267–4276; (x) K.
Nakamura, T. Matsuda, M. Shimizu and T. Fujisawa, Tetrahedron,
1998, 54, 8393–8402; (y) Y. Ohtsuka, O. Katoh, T. Sugai and H. Ohta,
Bull. Chem. Soc. Jpn., 1997, 70, 483–491; (z) A. Sakai, M. Bakke, H.
Ohta, H. Kosugi and T. Sugai, Chem. Lett., 1999, 1255–1256.
12 C. Prakash, S. Saleh and A. I. Blair, Tetrahedron Lett., 1989, 30,
19.
13 A. J. Mancuso, D. S. Brownfain and D. Swern, J. Org. Chem., 1979, 44,
4148.
14 K. Mashimo and Y. Sato, Tetrahedron, 1970, 26, 803.
15 L. Van Hijfte and R. D. Little, J. Org. Chem., 1985, 50, 3940.
16 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,
100.
17 L. F. Tietze, T. Eicher, U. Diederichsen and A. Speicher, In Reactions
and Syntheses, Wiley-VCH, Weinheim, 2007, pp. 211.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 536–547 | 547
©