A practical asymmetric synthesis of enantiopure spiro[4,4]nonane-1,6-dione

Article abstract of DOI:10.1002/adsc.201100089

A practical asymmetric synthesis of enantiopure spiro[4,4]nonane-1,6-dione, a valuable precursor for chiral ligand development, is reported. This synthetic strategy includes a kinetic resolution of the readily synthesized ketone precursor with a chiral qu

Full text of DOI:10.1002/adsc.201100089

FULL PAPERS
DOI: 10.1002/adsc.201100089
A Practical Asymmetric Synthesis of Enantiopure
Spiro[4,4]nonane-1,6-dione
G
Zhaobin Han,a Zheng Wang,a and Kuiling Dinga,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: kding@mail.sioc.ac.cn
Received: February 5, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100089.
Abstract: A practical asymmetric synthesis of enan- prevent its racemization under basic conditions. This
tiopure spiro
ACHTUNGTRENNUNG
cursor for chiral ligand development, is reported. enantiomers of spiroAHCTNUGTRENNNUG
This synthetic strategy includes a kinetic resolution excellent enantiopurities (up to >99% ee) in the
of the readily synthesized ketone precursor with a overall yields of 54% [(R)-1] and 42% [(S)-1], re-
chiral quaternary carbon center by bioreduction with spectively. The practicality of the present synthetic
bakerꢀs yeast as the key step, followed by a hydrofor- procedure has provided a fundamental platform for
mylation, oxidation, esterification and Dieckmann the development of spiro
cyclization reaction sequence to generate the spiro chiral chemistry.
five-membered ring. It was found that the masking
ACHTUNGTNER[NUNG 4,4]nonane-1,6-dione-based
of the b-ketone carbonyl group of enantiopure ethyl
1-allyl-2-oxocyclopentanecarboxylate via formation Keywords: asymmetric synthesis; bioreduction; catal-
of a ketal with 1,3-diol derivative is necessary during ysis; Dieckmann condensation; hydroformylation;
the process of Dieckmann condensation in order to ketones; spiro compounds
Introduction
ment of chiral auxiliaries or ligands in asymmetric
synthesis or catalysis.
Spirocarbocyclic structures are common subunits
found in many natural products, drugs, other useful
materials and, more recently, chiral ligands.[1] Spiro-
ACHTUNGTRENNUNG[4,4]nonane-1,6-dione (1), an important intermediate
with high functionality, has served as a valuable pre-
cursor of chiral auxiliaries or ligands in asymmetric
synthesis or catalysis. For example, cis,cis-spiro-
ACHTUNGTRENNUNG
Since the first report on the synthesis of racemic
chiral ketones with LiAlH4.[2] SpirOP, a diphosphinite spiro
ligand derived from enantiopure spiro
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
diol shows excellent asymmetric induction in the to access it in enantiopure form.[6–12] The resolution of
Rh(I)-catalyzed hydrogenation of a variety of func- racemic 1 was realized in 1977 by repeated recrystalli-
tionalized olefins.[3] SpinPHOX, a type of P,N ligand zation of the hydrazone diastereomers of (S)-2-oxo-2-
synthesized from 1, was found to be highly efficient in (1-phenylethylamino)acetohydrazide, followed by re-
the Ir(I)-catalyzed asymmetric hydrogenations of moval of the hydrazone in refluxing acetone/water.
imines and a,b-unsaturated carboxylic acid deriva- Enantiopure BINOL was also found to be able to
tives.[4] These results clearly demonstrate that the separate two enantiomers of racemic 1 through enan-
spiro
ACHTUNGTRENNUNG[4,4]nonane or spiroACHTUNGTRENN[UGN 4,4]nona-1,6-diene back- tioselective molecular complexation, affording opti-
bone represents a promising motif for the develop- cally pure BINOL·1 in up to 19% yield after recrys-
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Adv. Synth. Catal. 2011, 353, 1584 – 1590

A Practical Asymmetric Synthesis of Enantiopure SpiroACHTNUTRGNE[NUG 4,4]nonane-1,6-dione
tallization.[7] Alternatively, the enantiopure 1 can be
prepared by oxidation of the corresponding enantio-
pure trans,trans-spiro
spiro[4,4]nonane-1,6-diol. However, the enantiopure
trans,trans-spiro[4,4]nonane-1,6-diol or cis,cis-spiro-
[4,4]nonane-1,6-diol has to be separated by formation
ACHTUNGTRNE[NUNG 4,4]nonane-1,6-diol or cis,cis-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
of their diastereomers with optically pure chiral auxil-
iaries, such as (1S)-(À)-camphanic chloride,[8] d-10-
camphorsulfonyl chloride,[9] or (+)-(R)-camphor,[10]
followed by removal of the auxiliary. The optically
active 1 and trans,trans-spiroACTHNUGRTNEUNG[4,4]nonane-1,6-diol have
also been prepared through kinetic resolution of 1 via
reduction with microbial[11a] or chiral Lewis acidic cat-
alysts in moderate selectivities.[11b] The direct asym-
metric synthesis from readily available starting mate-
rials represents the most straightforward approach to
optically active 1, in which enantioselective construc-
tion of a quaternary carbon center is the key step.
Stoichiometric amounts of optically pure 1,2-diols
have been used to form a chiral ketal auxiliary for
asymmetric induction in the allylation of 2-oxocyclo-
pentanecarboxylate ester with allyl bromide to gener-
ate a quaternary carbon center.[12] As described
above, although a variety of methodologies for the
synthesis of optically active 1 has been reported,[6–13]
the accessibility of both (R)-1 and (S)-1 with >99%
ee values still remains a challenging issue in terms of
practicality. In the present work, we report a concise
asymmetric synthesis of enantiopure (R)-1 and (S)-1
from readily available starting material with facile
manipulations.
Results and Discussion
As shown in Scheme 1, the synthetic route that we in-
itially tried includes the kinetic resolution of ethyl 1-
allyl-2-oxocyclopentanecarboxylate (3) by bioreduc-
tion with bakerꢀs yeast as the key step, followed by a
hydroformylation, oxidation, esterification and Dieck-
Scheme 1. Synthesis of optically active spiro
dione (1).
ACHTUNGTREN[NUGN 4,4]nonane-1,6-
mann cyclization reaction sequence as the key steps duction on various substrate scales, the reaction con-
to generate the spiro five-membered ring. The final ditions were further optimized in detail. As shown in
removal of the methoxycarbonyl group from the the Supporting Information (Table S1), the bioreduc-
Dieckmann cyclization product 6 would give the tion of (Æ)-3 on a 2-gram scale proceeds smoothly in
target spiro
N
3 can be easily prepared on a large scale (39 grams) bakerꢀs yeast and CuO at room temperature. The
in 99% yield from commercially available ethyl progress of the reaction was monitored by chiral GC
2-oxocyclopentanecarboxylate (2) and allylic bromide analysis, and the conversion of the starting material
in the presence of K2CO3 as base.[13] Although the ki- remains unchanged after 24 h. Although the ee values
netic reduction of the (Æ)-3 with bakerꢀs yeast has of both (R)-3 and (S,S)-4 are very high (ꢀ99%), the
been reported to be a feasible and inexpensive ap- diastereoselectivity (dr) of the reduction for the for-
proach to furnish (1S,2S)-ethyl 1-allyl-2-hydroxycyclo- mation of (S,S)-4 was only 98/2. Considering that
pentanecarboxylate [(S,S)-4] in >99% ee, the diaste- (S,S)-4 will be re-oxidized into its ketone form, a
reoselectivity of the bioreduction process and enan- higher dr value of 4 is critically important for attain-
tiomeric excess of the remaining (R)-3 were not de- ing a high ee in (S)-5 after oxidation due to the diffi-
tailed in the literature.[14] As part of an effort to culty in the separation of diastereomers of 4. It is ex-
achieve the maximum stereoselectivity of the biore- pected that the diastereoselectivity of the reaction can
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be improved by avoiding the overreduction of (Æ)-3. lective removal of the methoxycarbonyl functional
Indeed, when 6 g of (Æ)-3 were submitted to the reac- group from (R)-6 to afford the target molecule (R)-1
tion with the control of the reaction time, the dr of 4 represents a challenging step in the present synthetic
was improved to 99/1 albeit with a slight loss of enan- procedure due to the sensitivity of 1,3-dicarbonyl
tiomeric excess in (R)-3 (97% ee). The enantiomeric fragments to the strong base in the substrate. There-
excess of recovered unreduced (R)-3 (97%) can be fore, neutral reaction conditions should be beneficial
readily increased to >99% ee by a second run of the to the selective decarboxylation. As expected, under
bioreduction under the same experimental conditions the optimized reaction conditions (2 equiv. LiCl,
in 95% yield. To our delight, this enzymatic kinetic 5 equiv. H2O, 1258C, 30 min) following a method re-
resolution process still works equally well on a 12- ported by Krapcho,[17] the methoxycarbonyl group in
gram scale of (Æ)-3. Accordingly, both (R)-3 and (R)-6 can be readily removed to afford (R)-1 in 75%
(S,S)-4 can be conveniently prepared on a gram scale yield. Following the same reaction sequence men-
in the laboratory on the basis of the above-mentioned tioned above, (S)-1 can be prepared from (S)-5 in the
optimized kinetic resolution process.
same yield. To our surprise, the enantiomeric excess
With both enantiopure (R)-3 and (S,S)-4 in hand, of finally obtained (R)-1 or (S)-1 from the reaction of
we next explored ways to extend a carboxylate group enantiopure (R)-5 or (S)-5 is only 92%, indicating
at the terminal carbon of the 1-allyl side chain. The some extent of loss of enantioselectivity in the step of
Rh(I)-catalyzed hydroformylation of terminal alkenes either the Dieckmann cyclization or the decarboxyla-
represents a highly efficient and regioselective ap- tion. In order to elucidate the underlying reason for
proach for the introduction of a formyl group in a the partial racemization, (S)-5 with 99% ee was treat-
highly atom-economic manner.[15] As shown in ed with 1 equivalent of LDA and 2 equivalents of
Scheme 1, the Rh(I) complex of a racemic BINOL- HMPA in THF under the same conditions of the
based diphosphoramidite ligand {2,2’-bis[di(1H- Dieckmann condensation, and the enantiomeric
pyrrol-1-yl)phosphinooxy]-1,1’-binaphthyl, L} was excess of the recovered (S)-5 (25% yield) was found
chosen for the catalysis of the hydroformylations of to drop to 90%. This result clearly indicates that
(R)-3 and (S,S)-4.[16] Under 20 atm of H2/CO (1:1) enantiopure (S)-5 or (R)-5 undergoes partial racemi-
with 0.05 mol% of Rh(I) catalyst in toluene at 808C, zation under the experimental conditions before cycli-
the hydroformylation of (R)-3 or (S,S)-4 proceeds ef- zation. A plausible racemization pathway of (S)-5
ficiently to give the aldehydes in almost quantitative under basic conditions is thus proposed, which is
yield and >99% linear regioselectivity in 5 h. The shown in Scheme 2. Although (S)-5 can be deproton-
crude linear aldehydes without purification were di- ated in a selective manner under the experimental
rectly submitted to the oxidation with Jones reagent conditions to mostly generate intermediate 7, a small
to afford the corresponding acid. The resultant acid amount of intermediate 8 might be formed via either
was treated with TMSCl and MeOH, furnishing the direct deprotonation at the a-position of the ester
keto diester (R)-5 in an overall yield of 85% (3 steps) group in (S)-5 or an exchange equilibrium with inter-
with >99% ee. In the oxidation of the aldehyde de- mediate 7. An intramolecular aldol reaction of inter-
rived from (S,S)-4, the 2-hydroxy group is oxidized si- mediate 8 and then retro-aldol reaction of intermedi-
À
multaneously to afford the keto diester (S)-5 with ate 9 may break the C C bond connected with the
>99% ee after esterification with methanol. The total chiral center to form intermediate 10. Accordingly,
yield of (S)-5 for this three-step reaction sequence the partial racemization will take place through the
starting from (S,S)-4 is 70%.
interchange between 9 and 11 via 10 in this process.
In the Dieckmann cyclization step, the deprotona- The intermediate 11 undergoes a retro-aldol reaction
tion of the a position of the ester carbonyl group in to form the intermediate 12 or 13, the enolate form of
(R)-5 is critically important to guarantee the succes- (R)-5.
sive intramolecular nucleophilic condensation. Con-
On the basis of the proposed plausible racemization
sidering the acidity difference of the a protons of pathway mentioned above, we envisioned that protec-
keto and ester carbonyl groups in (R)-5, we envi- tion of the keto carbonyl group in (R)-5 would cir-
sioned that the choice of an appropriate amount of cumvent this problem. Accordingly, we decided to
base and reaction conditions are very important for mask the keto carbonyl group in (R)-5 with diols in-
achieving a high yield of cyclization product 6. After cluding glycol or 2,2-dimethylpropane-1,3-diol in the
careful optimization of the reaction conditions includ- presence of p-TsOH under Dean–Stark conditions.
ing reaction temperature, bases and additives, as well The desired products were obtained in less than 60%
as their stoichiometry, it was found that the reaction yields due to the transesterification of the methyl car-
of (R)-5 in THF at À788C to room temperature in the boxylate group of (R)-5 with the diol. We were
presence of 3.5 equivalents of lithium diisopropyl- pleased to find that the condensation of (R)-5 and
ACHTUNGTRENNUNG
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A Practical Asymmetric Synthesis of Enantiopure SpiroACHTNUTRGNE[NUG 4,4]nonane-1,6-dione
Scheme 2. Proposed racemization pathway of (S)-5 in the presence of LDA as the base.
methanesulfonate (TMSOTf)[18] afforded the ketal de- Conclusions
rivative (R)-14 in 99% yield. Dieckmann cyclization
of (R)-14 in the presence of 2.1 equivalents of lithium An efficient and practical synthetic procedure has
hexamethyldisilazide (LiHMDS) provides two spiro been developed to access both enantiomers of spiro-
compounds 15a and 15b in a combined yield of 96%.
ACHTUNGTREN[NGNU 4,4]noane-1,6-dione (1) with a kinetic resolution of
The formation of ethyl ester derivative 15b was prob- the readily synthesized ketone precursor with a chiral
ably caused by the transesterification of either 15a or quaternary carbon center by bioreduction with
unreacted (R)-14 with the ethoxy anion generated by bakerꢀs yeast as the key step, followed by a hydrofor-
the Dieckmann condensation step. The dealkoxycar- mylation, oxidation, esterification and Dieckmann
boxylation of a mixture of 15a and 15b was then real- cyclization reaction sequence to generate the five-
ized by treatment with LiCl in wet DMSO at 1308C, membered ring. It was found that the enantiopure
affording (R)-16 in 75% yield. Finally, deprotection of key intermediate keto diester (5) underwent partial
the ketal moiety in (R)-16 by an acidic hydrolysis in a racemization under Dieckmann condensation condi-
CH2Cl2-H2O two-phase system afforded (R)-1 in 90% tions, which is a problematic issue for the synthesis of
yield with >99% ee (Scheme 3). Following the same enantiopure 1. Alternatively, the protection of the b-
reaction sequence described above, (S)-1 can be pre- ketone carbonyl group of enantiopure ethyl 1-allyl-2-
pared from (S)-5 in an overall yield of 60% with oxocyclopentanecarboxylate 5 via formation of a
>99% ee. Although two extra protection and depro- ketal with a 1,3-diol derivative has circumvented this
tection steps have to be carried out in the present syn- problem. Accordingly, both enantiomers of spiro-
thetic procedure, the total of yield of (R)-1 or (S)-1 is
ACHTUNGTREN[NUGN 4,4]nonane-1,6-dione (1) have been successfully pre-
comparable or even higher than that attained on the pared on gram scales with excellent enantiopurities
basis of the procedure shown in Scheme 1, and most (>99% ee) in the overall yields of 54% [(R)-1] and
importantly the racemization can be completely 42% [(S)-1] from (R)-3 and (S,S)-4, respectively. The
avoided.
present synthetic protocol has the advantages of high
overall yield, excellent ees of both enantiomers and
simple manipulation of the procedures, which will
Scheme 3. An alternative synthetic procedure for enantiopure 1.
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Bioreduction of (R)-3 with 97% ee (5.29 g, 27.0 mmol)
with bakerꢀs yeast (30 g), CuO (2.1 g, 26.4 mmol) in 20%
aqueous sucrose solution (400 mL) afforded (R)-3 with
>99% ee under the same experimental conditions; yield:
95%. The enantiomeric excess was determined by GC anal-
ysis (Chiralcel Supelco GAMMA-DEXTM 225 column, N2
flow rate=1 mLminÀ1, 1308C): tR =18.1 min (minor), tR =
19.1 min (major).
stimulate future research on the asymmetric catalysis
with spiroACHTUNGTRENNUNG[4,4]nonane-based chiral ligands.
Experimental Section
General
AHCTUNGTRENNUNG
(S,S)-4: yield: 5.86 g (49%); [a]2D0: +26.8 (c 1.75, CHCl3),
THF was dried with sodium benzophenone ketyl and
CH2Cl2 with CaH2 under an atmosphere of argon. Melting
points were measured on an X-4 apparatus and are uncor-
rected. All other solvents and reagents were used as re-
>99% ee; 99/1 dr. The enantiomeric excess was determined
by GC analysis (Chiralcel Supelco GAMMA-DEXTM 225
column, N2 flow rate=1 mLminÀ1, 1108C): tR =41.3 min
1
1
ceived. H and 13C NMR spectra were recorded on Varian
(major), tR =49.6 min (minor). H NMR (400 MHz, CDCl3):
d=5.79–5.68 (m, 1H), 5.07–5.02 (m, 2H), 4.18 (d, J=6.8 Hz,
2H), 4.08–4.05 (m, 1H), 2.39 (dd, J=6.8 Hz, 14.0 Hz, 1H),
2.22–2.15 (m, 2H), 2.04–1.80 (m, 4H), 1.73–1.59 (m, 3H),
1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
175.5, 133.5, 117.7, 78.5, 60.5, 58.1, 40.2, 32.0, 30.7, 20.3, 14.1;
HR-MS (EI): m/z=198.1261, calcd. for C11H18O3: 198.1256.
Mercury 300 MHz or 400 MHz spectrometers. Chemical
shifts (d values) are reported in ppm using TMS (1H NMR,
d=0 ppm) or CDCl3 (13C NMR, d=77 ppm) as internal
standard, respectively. Optical rotations were determined
using a Perkin–Elmer 341 MC polarimeter. HR-MS [EI
(70 eV)] were determined on a Waters Micromass GCT Pre-
mier spectrometer. GC analyses were performed on an Agi-
lent 6890 gas chromatograph by using a Chiralcel Supelco
gamma-DEXTM 225 column or a Varian Chirasil-DEX CB
column.
Preparation of (R)-5
A glass vessel containing a solution of Rh(CO)
2ACHTUNGTRENNUNG(acac)
(6.6 mg,0.025 mmol), {2,2’-bis[di(1H-pyrrol-1-yl)phosphi-
nooxy]-1,1’-binaphthyl} (62.6 mg, 0.10 mmol) and (R)-3
(10.0 g, 51 mmol) in 110 mL toluene was placed in a high-
pressure autoclave. After the autoclave had been purged
with syngas (H2/CO=1:1) three times, the final pressure was
adjusted to 20 atm. The reactor was heated to 808C while
stirring at 500 rpm. After stirring at that temperature for
5 h, the reaction mixture was cooled down in an ice/water
Synthesis of Racemic 1-Allyl-2-oxocyclopentane-
carboxylate [(Æ)-3][13]
To a 500-mL single-neck flask containing K2CO3 (110 g, 0.8
mol) and acetone (250 mL) were added ethyl 2-oxocyclo-
pentanecarboxylate 2 (29.8 mL, 0.2 mol) and allylic bromide
(34.6 mL, 0.4 mol). The reaction mixture was refluxed for
20 h. The mixture was filtered to remove KBr and K2CO3
after cooling to room temperature. After removal of the sol-
vent, the residue was purified by vacuum distillation (100–
1028C/oil pump) to afford pure product (Æ)-3 as colorless
oil; yield: 39.1 g (99%). 1H NMR (300 MHz, CDCl3): d=
5.74–5.64 (m, 1H), 5.14–5.08 (m, 2H), 4.17 (q, J=7.2 Hz,
2H), 2.67 (dd, J=14.1 Hz, 7.5 Hz, 1H), 2.49–2.20 (m, 4H),
2.05–1.88 (m, 3H), 1.25 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=214.3, 170.7, 132.9, 118.8, 61.2, 59.7,
37.9, 37.5, 31.9, 19.3, 13.9; HR-MS (EI): m/z=196.1100,
calcd. for C11H16O3: 196.1099.
1
bath and then the syngas was released carefully. H NMR
analysis of the crude reaction mixture indicated a complete
conversion of (R)-3 and only the linear aldehyde was ob-
served. Removal of toluene by vacuum evaporation afford-
ed the desired linear aldehyde, which was then dissolved in
acetone (60 mL) for the next oxidation. Jonesꢀ reagent
[22 mL, containing CrO3 (6.1 g, 61 mmol)] was added drop-
wise at 08C until the red color of the solution did not disap-
pear. The reaction mixture was stirred for additional 1 h at
08C, and then the reaction was quenched with i-PrOH
(5 mL). After addition of H2O (100 mL), the mixture was
extracted with EtOAc (50 mLꢂ3). The combined organic
phase was washed with water and brine, dried over anhy-
drous sodium sulfate. Removal of the solvent by vacum
evaporation afforded the crude acid product, which was sub-
mitted to esterification without further purification.
Kinetic Resolution of (Æ)-3
To a suspension of dry bakerꢀs yeast (66 g) in 20% aqueous
sucrose solution (1 L) was added CuO (4.8 g, 60 mmol) at
room temperature. The reaction mixture was stirred vigo-
rously before1-allyl-2-oxocyclopentanecarboxylate (Æ)-3
(12 g, 61 mmol) was added in one portion. After 24 h, Celite
(70 g) was added and the suspension was filtered to separate
the solids and aqueous phase. The solids obtained were sub-
jected to extraction with hot CHCl3 (300 mLꢂ5), and the
aqueous filtrate with EtOAc (300 mLꢂ5). The combined or-
ganic phase was washed with brine and dried over anhy-
drous sodium sulfate. After removal of the solvent by
vacum evaporation, the residue was submitted to column
chromtography separation on silica gel using petroleum
ether/EtOAc (10/1–3/1) as eluent to afford optically active
(R)-3 and (S, S)-4.
To a solution of the acid in MeOH (120 mL) was added
TMSCl (14.5 mL, 113 mmol). The reaction mixture was
stirred for 16 h at room temperature. After removal of the
solvent by vacum evaporation, the residue was submitted to
column chromtography separation on silica gel using petro-
leum ether/EtOAc (20/1–5/1) as eluent to afford (R)-5 as a
pale yellow oil; yield: 11.1 g (85%); [a]2D0: À15.0 (c 0.94,
CHCl3), >99% ee. The enantiomeric excess was determined
by GC analysis (Varian Chirasil-DEX CB column, N2 flow
rate=1 mLminÀ1, 608C, 2 min, 18CminÀ1, 1508C, 10 min,
38CminÀ1, 1808C, 30 min): tR =105.4 min (major), tR =
1
105.7 min (minor). H NMR (300 MHz, CDCl3): d=4.17 (q,
J=7.2 Hz, 2H), 3.67 (s, 3H), 2.58–2.20 (m, 5H), 2.06–1.87
(m, 4H), 1.72–1.52 (m, 3H), 1.25 (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=214.7, 173.5, 170.8, 61.3,
(R)-3:[14a] yield: 5.29 g (44%); [a]2D0: À34.5 (c 1.01,
CHCl3); 97% ee.
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A Practical Asymmetric Synthesis of Enantiopure SpiroACHTNUTRGNE[NUG 4,4]nonane-1,6-dione
60.2, 51.5, 37.8, 33.9, 33.0, 32.6, 20.2, 19.5, 14.0; HR-MS
(EI): m/z=256.1306, calcd. for C13H20O5: 256.1311.
Preparation of (S)-1 from (S)-6
Following the procedure described above using (S)-6 instead
of (R)-6, (S)-1 was obtained; yield: 71%; mp 63–648C; [a]2D0:
À115.1 (c 0.81, cyclohexane), 92% ee. The enantiomeric
excess was determined by GC analysis (Chiralcel Supelco
GAMMA-DEXTM 225 column, N2 flow rate=1 mLminÀ1,
1508C): tR =10.0 min (minor), tR =15.5 min (major).
Preparation of (S)-5
Following the procedure described above using (S,S)-4 in-
stead of (R)-3, (S)-5 was obtained; total yield: 70%. [a]2D0:
+17.8 (c 0.91, CHCl3); >99% ee. The enantiomeric excess
was determined by GC analysis (Varian Chirasil-DEX CB
column, N2 flow rate=1 mLminÀ1, 608C, 2 min, 18CminÀ1,
1508C, 10 min, 38CminÀ1, 1808C, 30 min): tR =104.4 min
(minor), tR =105.7 min (major).
Preparation of (R)-14
To a solution of (R)-5 (9.35 g, 36.5 mmol) and 2,2-dimethyl-
1,3-bis(trimethylsilyloxy)propane (18.1 g, 73.7 mmol) in
CH2Cl2 (60 mL) was added TMSOTf (0.67 mL, 3.7 mmol) at
À208C. After stirring for additional 15 h at the same tem-
perature, the reaction was quenched by addition of pyridine
(8 mL). After addition of saturated aqueous NaHCO3 solu-
tion, the mixture was extracted with CH2Cl2 (40 mLꢂ3).
The combined organic phase was dried over anhydrous
sodium sulfate and then filtered. After removal of the sol-
vent by vacum evaporation, the residue was submitted to
column chromtography separation on silica gel using petro-
leum ether/EtOAc (20:1–10:1) as eluent to afford (R)-14 as
a pale yellow oil; yield: 12.4 g (99%); [a]2D0: À6.4 (c 1.5
Preparation of (R)-6
To a solution of (R)-5 (1.92 g, 7.5 mmol) and HMPA
(9.1 mL, 52.9 mmol) in THF (120 mL) was added LDA (2M
in THF, 13.3 mL, 26.6 mmol) dropwise at À788C. The reac-
tion mixture was stirred for 1 h at the same temperature
before being allowed to warm to room temperature. After
stirring for additional 20 h, the reaction was quenched with
saturated aqueous NH4Cl solution and the mixture was ex-
tracted with EtOAc (50 mLꢂ3). The combined organic
phase was washed with brine and dried over anhydrous
sodium sulfate. After removal of the solvent by vacum evap-
oration, the residue was submitted to column chromtogra-
phy separation on silica gel using petroleum ether/EtOAc
(30:1–10:1) as eluent to afford (R)-6 as pale yellow oil;
1
CHCl3); H NMR (300 MHz, CDCl3): d=4.31–4.09 (m, 2H),
3.74–3.45 (m, 7H), 2.42–2.24 (m, 4H), 2.13–2.05 (m, 1H),
1.73–1.60 (m, 5H), 1.38–1.25 (m, 5H), 1.16 (s, 3H), 0.71 (s,
3H); 13C NMR (100 MHz, CDCl3): d=173.8, 173.4, 109.1,
72.5, 71.1, 60.5, 60.4, 51.4, 34.3, 30.9, 30.2, 29.2, 27.6, 22.6,
22.0, 20.4, 19.1, 14.2; HR-MS (EI): m/z=342.2043, calcd. for
C18H30O6: 342.2042.
yield: 1.12 g (71%). [a]2D0: +65.3 (c 0.79, CHCl3); H NMR
1
(300 MHz, CDCl3): d=3.76 (s, 3H), 3.40 (t, J=8.1 Hz, 1H,
major isomer), 3.31 (t, J=9.0 Hz, 1H, minor isomer), 2.71–
2.10 (m, 7H), 2.00–1.72 (m, 3H); 13C NMR (100 MHz,
CDCl3): d (major isomer)=215.9, 209.4, 169.4, 64.6, 54.9,
52.5, 38.2, 34.4, 32.2, 24.1, 19.6; HR-MS (EI): m/z=
210.0895, calcd. for C11H14O4: 210.0892.
Preparation of (R)-15
To a solution of (R)-14 (11.6 g, 33.9 mmol) in 250 mL THF
was added LiHMDS (1M solution in THF, 71.1 mL,
71.1 mmol) dropwise at 08C. The reaction mixture was al-
lowed to warm to room temperature and then stirred for ad-
ditional 3 h. Saturated aqueous NH4Cl solution was added
to to quench the reaction and the mixture was extracted
with EtOAc (80 mLꢂ3). The combined organic phase was
washed with brine and dried over anhydrous sodium sulfate.
After removal of the solvent by vacum evaporation, the resi-
due was submitted to column chromtography separation on
silica gel using petroleum ether/EtOAc (20:1–10:1) as eluent
to afford a mixture of (R)-15a and (R)-15b (15a/15b=2/1)
as a pale yellow oil; yield: 9.84 g (96%).
Preparation of (S)-6
Following the procedure described above using (S)-5 instead
of (R)-5, (S)-6 was obtained; yield: 70%; [a]2D0: À72.3 (c
0.83, CHCl3).
Preparation of (R)-1 from (R)-6
A mixture of (R)-6 (821 mg, 3.9 mmol), LiCl (332 mg,
7.9 mmol) and H2O (356 mL, 19.8 mmol) in DMSO (14 mL)
was heated at 1258C for 0.5 h. After cooling to room tem-
peature, water was added to the reaction mixture, which was
then extracted with EtOAc (20 mLꢂ3). The combined or-
ganic phase was washed with water (15 mLꢂ3), brine, and
then dried over anhydrous sodium sulfate. After removal of
the solvent by vacum evaporation, the residue was submit-
ted to column chromtography separation on silica gel using
petroleum ether/EtOAc (20:1) as eluent to afford (R)-1 as a
white solid; yield: 390 mg (66%); mp 63–648C; [a]2D0: +113.5
(c 1.01, cyclohexane), 92% ee. The enantiomeric excess was
determined by GC analysis (Chiralcel Supelco GAMMA-
DEXTM 225 column, N2 flow rate=1 mLminÀ1, 1508C): tR =
1
(R)-15a: [a]2D0: +68.3 (c 0.81, CHCl3); H NMR (400 MHz,
CDCl3): d=3.74–3.14 (m, 8H), 2.79–2.24 (m, 3H), 2.15–1.84
(m, 5H), 1.70–1.53 (m, 2H), 1.22 (s, 3H, minor isomer), 1.18
(s, 3H, major isomer), 0.71 (s, 3H, major isomer), 0.70 (s,
3H, minor isomer); 13C NMR (100 MHz, CDCl3): d (major
isomer)=212.8, 170.5, 109.1, 72.7, 70.7, 62.5, 55.8, 52.8, 32.3,
30.0, 29.0, 26.8, 23.6, 22.9, 22.0, 19.6; HR-MS (EI): m/z=
296.1622, calcd. for C16H24O5: 296.1624.
1
15b: H NMR (400 MHz, CDCl3): d=4.17–4.06 (m, 2H),
3.67–3.57 (m, 1H), 3.40–3.06 (m, 4H), 2.70–2.17 (m, 3H),
2.09–1.77 (m, 5H), 1.61–1.46 (m, 2H), 1.25–1.17 (m, 3H),
1.15 (s, 3H, minor isomer), 1.12 (s, 3H, major isomer), 0.66–
0.62 (m, 3H); 13C NMR (100 MHz, CDCl3): d (major
isomer)=212.9, 170.0, 109.0, 72.7, 70.6, 62.4, 60.9, 55.9, 32.2,
29.9, 28.9, 26.7, 23.6, 22.9, 21.9, 19.5, 14.0; HR-MS (EI):
m/z=310.1783, calcd. for C17H26O5: 310.1780.
1
9.2 min (major), tR =15.4 min (minor). H NMR (300 MHz,
CDCl3): d=2.40–2.16 (m, 8H), 1.95–1.80 (m, 4H); 13C NMR
(75 MHz, CDCl3): d=216.8, 64.3, 38.4, 34.2, 19.7; HR-MS
(EI): m/z=152.0833, calcd. for C9H12O2: 152.0837.
Adv. Synth. Catal. 2011, 353, 1584 – 1590
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1589

Zhaobin Han et al.
FULL PAPERS
References
Preparation of (R)-16
A solution of (R)-15 (7.78 g, 25.9 mmol), LiCl (3.92 g,
93.3 mmol) and H2O (4.65 mL, 258 mmol) in DMSO
(50 mL) was heated at 1308C for 1 h. After cooling to room
temperature, water was added to quench the reaction. The
mixture was extracted with EtOAc (50 mLꢂ3). The com-
bined organic phase was washed with water three times and
then brine, dried over anhydrous sodium sulfate and filtered.
After removal of the solvent by vacum evaporation, the resi-
due was submitted to column chromtography separation on
silica gel using petroleum ether/EtOAc (20:1–10:1) as eluent
to afford a mixture of (R)-16 as a pale yellow oil; yield:
4.62 g (75%); [a]D20: +58.4 (c 1.08, CHCl3); 1H NMR
(400 MHz, CDCl3): d=3.66 (d, J=11.2 Hz, 1H); 3.45 (d, J=
11.2 Hz, 1H); 3.40 (dd, J=11.2 Hz, 2.8 Hz, 1H), 3.33 (dd,
J=11.2 Hz, 2.8 Hz, 1H), 2.65–2.58 (m, 1H), 2.43–2.27 (m,
2H), 2.24–2.14 (m, 1H), 2.12–2.05 (m, 1H), 1.96–1.80 (m,
3H), 1.79–1.46 (m, 4H), 1.20 (s, 3H), 0.71 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=221.0, 109.1, 72.7, 61.6, 39.1, 32.1,
31.0, 30.0, 27.0, 22.9, 22.0, 19.7, 19.4; HR-MS (EI): m/z=
238.1538, calcd. for C14H22O3: 238.1569.
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Preparation of (R)-1 from (R)-16
A mixture of (R)-16 (4.1 g, 17.2 mmol) in a mixure of CH2Cl2
(36 mL) and 5M HCl (12 mL) was stirred for 6 h at room
temperature. The mixture extracted with CH2Cl2 (20 mLꢂ3)
and the combined organic phase was washed with saturated
aqueous NaHCO3 solution and brine, dried over anhydrous
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chromtography separation on silica gel using petroleum
ether/EtOAc (20:1–10:1) as eluent to afford (R)-1 as a white
solid; yield: 2.36 g (90%); mp 64–658C; [a]2D0: +123.8 (c 0.91,
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flow rate=1 mLminÀ1, 1508C): tR =9.0 min (major), tR =
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1
15.1 min (minor); H NMR (300 MHz, CDCl3): d=2.40–2.16
(m, 8H), 1.95–1.80 (m, 4H); 13C NMR (75 MHz, CDCl3): d=
216.8, 64.3, 38.4, 34.2, 19.7; HR-MS (EI): m/z=152.0833,
calcd. for C9H12O2: 152.0837.
Preparation of (S)-1
Following the same reaction sequence described above by
using (S)-5 as starting material instead of (R)-5, (S)-1 was
obtained; overall yield: 60%; mp 64–658C; [a]2D0: À131.7 (c
0.70, cyclohexane); >99% ee. The ee was determined by GC
analysis (Chiralcel Supelco GAMMA-DEXTM 225 column,
N2 flow rate=1 mLminÀ1, 1508C): tR =9.1 min (minor), tR =
13.4 min (major).
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Financial support from the National Natural Science Founda-
tion of China (Nos. 20821002, 20972176, 20923005), the Chi-
nese Academy of Sciences, the Major Basic Research Devel-
opment Program of China (Grant No. 2010CB833300), and
the Science and Technology Commission of Shanghai Munic-
ipality is gratefully acknowledged.
1590
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1584 – 1590