Control of diastereoselectivity in orthoester Johnson-Claisen rearrangement of tartrate-based allyl alcohol: An efficient synthesis of arundic acid, a potential therapeutic agent for Alzheimer's disease

Article abstract of DOI:10.1002/ejoc.201101420

A diastereoselective orthoester Johnson-Claisen rearrangement has been employed in the synthesis of both enantiomers of arundic acid, a potential therapeutic agent against Alzheimer's disease. The effect of solvent, olefin geometry and alcohol chirality on the diastereoselectivity of the orthoester Johnson-Claisen rearrangement of a tartrate-based allyl alcohol has been studied. A diastereoselective orthoester Johnson-Claisen rearrangement has been employed in the synthesis of both enantiomers of arundic acid, a potential therapeutic agent for Alzheimer's disease. The effect of solvent, olefin geometry and alcohol chirality on the diastereoselectivity of the orthoester Johnson-Claisen rearrangement ofa tartrate-based allyl alcohol has beenstudied. Copyright

Full text of DOI:10.1002/ejoc.201101420

FULL PAPER
DOI: 10.1002/ejoc.201101420
Control of Diastereoselectivity in Orthoester Johnson–Claisen Rearrangement
of Tartrate-Based Allyl Alcohol: An Efficient Synthesis of Arundic Acid, a
Potential Therapeutic Agent for Alzheimer’s Disease
Rodney A. Fernandes,*[a] Arun B. Ingle,[a] and Dipali A. Chaudhari[a]
Keywords: Rearrangement / Allylic compounds / Asymmetric synthesis / Diastereoselectivity
A diastereoselective orthoester Johnson–Claisen rearrange-
ment has been employed in the synthesis of both enantio-
mers of arundic acid, a potential therapeutic agent against
Alzheimer’s disease. The effect of solvent, olefin geometry
and alcohol chirality on the diastereoselectivity of the ortho-
ester Johnson–Claisen rearrangement of a tartrate-based al-
lyl alcohol has been studied.
moto and Nakai[3] synthesized 1 by using the optical resolu-
tion method. They used recrystallization cycles to obtain a
final purity of 90% ee with 27% yield. The same group
disclosed another synthesis based on the asymmetric alkyl-
ation of chiral enolates using l-prolinol as the chiral auxil-
iary giving 20% overall yield and 96% ee after a single
recrystallization.[4] Hasegawa et al.[5a,5b] used Oppolzer’s
camphor sultam to obtain 1 in 59% overall yield and Ͼ99%
ee after two recrystallizations. However, the expensive chiral
auxiliary could not be recycled. The same group[5c] devel-
oped another method by using the chiral auxiliary derived
from (S)-(–)-1-phenylethylamine, which allowed the synthe-
sis of crystalline intermediates with moderate diastereo-
selectivities of 50–69%, which was increased to 99% after
two recrystallizations (10% overall yield). A diastereoselec-
tive photodeconjugation of a chiral diacetone d-glucosyl
α,β-unsaturated ester was employed by Piva and co-
workers[6] to give the acid 1 in 47% overall yield and 88%
ee after eight steps. Hasegawa et al.[7] also reported a syn-
thesis based on (R)-1,2-epoxyoctane, which gave the acid 1
in 52% overall yield and 99.8% ee. A metal-mediated cro-
tylation of (R)-2,3-cyclohexylideneglyceraldehyde and chro-
matographic isolation of the desired diastereomer from a
mixture of three isomers (eight steps, 13% overall yield) was
executed by Goswami and Chattopadhyay[8] to obtain enan-
tiomerically pure (R)-arundic acid. It has also been synthe-
sized by Garcia et al.[9] in 52% overall yield and 98% ee by
diastereoselective asymmetric alkylation of (1R)-(+)-cam-
phor-derived α-hydroxy ketones. Recently, Cozzi and co-
workers synthesized arundic acid by organocatalytic alkyl-
ation of octanal in 82% overall yield and 93% ee.[10] Thus,
the major synthetic attempts towards the target molecule
are through diastereoselective synthesis.
Introduction
A stroke is a medical emergency caused by the depletion
or deprivation of blood flow to the brain leading to rapid
nerve cell death and dysfunction of the body part controlled
by the affected nerve cells. It is responsible for serious long-
term disability, for example, paralysis, cognitive deficits, de-
mentia, dizziness, vertigo, impaired vision, language defi-
cits, emotional difficulties, pain, and is a major cause of
death worldwide. Research towards the synthesis of new
therapeutic agents and analogues of inhibitors to prevent
and treat stroke is today a priority. The Minase Research
Institute of Ono Pharmaceutical Co. Ltd., Osaka, Japan
during a screening process discovered a novel non-natural
compound, (R)-(–)-arundic acid 1 (Ono-2506,[1] Figure 1),
which has shown efficacy in preventing the expansion of
cerebral infarction by improving astrocyte function.
Arundic acid is undergoing phase II development for the
treatment of acute ischemic stroke as well as clinical devel-
opment in other neurodegenerative diseases including Alz-
heimer’s and Parkinson’s disease.[2]
Figure 1. Enantiomers of arundic acid.
Arundic acid has been a synthetic target in recent years
and a few syntheses are reported in the literature.[3–9] Kishi-
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, Maharashtra, India
Fax: +91-22-25767152
In continuation of our research efforts in the asymmetric
synthesis of bioactive natural products[11] by the orthoester
Johnson–Claisen rearrangement[12] of allyl alcohols with a
E-mail: rfernand@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101420.
Eur. J. Org. Chem. 2012, 1047–1055
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R. A. Fernandes, A. B. Ingle, D. A. Chaudhari
FULL PAPER
vicinal chiral diol moiety we recently completed the synthe- tage was overshadowed by the poor diastereoselectivity,
sis of both isomers of arundic acid[11b] (Scheme 1). The which was a major concern to us and thus we undertook a
strategy was based on the separation of a 1:1 diastereomeric detailed study on improvement. The allyl alcohol 3 dis-
mixture of 4 obtained by orthoester Johnson–Claisen re- played three important stereochemical aspects: a) the olefin
arrangement of 3 (Scheme 1). Although the diastereomers geometry, b) the allyl alcohol stereochemistry, and c) the
were separable after conversion into 5a and 5b, this advan- vicinal diol functionality. The latter being fixed we thought
to vary the former two aspects along with varying the sol-
vent (and hence reaction temperature). Herein we report a
detailed account of the diastereoselectivity of the orthoester
Johnson–Claisen rearrangement of tartrate-derived allyl
alcohols and its application towards an efficient synthesis
of the two enantiomers of arundic acid.
Results and Discussion
We synthesized four possible diastereomeric allyl
alcohols 3a–d as shown in Scheme 2. The known alcohol
6[13] was converted into α,β-unsaturated ketone 7a in 82%
yield.[11b] The Swern oxidation of alcohol 6 to the aldehyde
and subsequent Wittig reaction with Ph3P=CHCOCH3 in
MeOH furnished an E/Z mixture of 7a/7b in a ratio of
1:1.5. The mixture was separated to obtain 7a and 7b in
yields of 31 and 52%, respectively. The reduction of 7a with
(R)-CBS as catalyst[14] gave 3a in 89% yield and 19:1 dr.[15]
A similar reduction of 7a using (S)-CBS as catalyst deliv-
ered 3b in 89% yield and 16:1 dr.[15] The reduction of 7b
with (R)-CBS as catalyst gave a mixture of 3c/3d in a ratio
of 2:1. The diastereomeric mixture was separated by flash
column chromatography to yield 3c (56%) and 3d (29%).
On the other hand, the reduction of 7b with (S)-CBS as
catalyst provided 3d as a single diastereomer in 89% yield.
We subjected the four diastereomeric allyl alcohols to or-
thoester Johnson–Claisen rearrangement to investigate the
extent of chirality transfer based on the chirality of the allyl
Scheme 1. Previous synthesis of arundic acid enantiomers.[11b]
alcohols and the geometry of the double bond. The results
Scheme 2. Synthesis of diastereomeric allyl alcohols 3a–d.
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Orthoester Johnson–Claisen Rearrangement
are shown in Tables 1–4. The allyl alcohol 3a with E olefin provided 8a/8b as a 1:16 mixture in 81% yield (entry 1,
bond and C-6 S chirality after orthoester Johnson–Claisen Table 3). The diastereoselectivity gradually decreased
rearrangement in benzene and subsequent lactonization towards the higher-boiling decalin (entries 2–6) providing
provided 8a and 8b as a 4:1 mixture (entry 1, Table 1). The 8a/8b in a 1:5 ratio and 80% yield (entry 6). A similar reac-
diastereoselectivity gradually increased with higher-boiling tion with allyl alcohol 3d (Table 4) gave results opposite to
solvents (entries 2–6) with decalin providing 8a/8b in a 9:1 those with 3c: a mixture of 8a/8b in a 5:1 ratio and 81%
ratio and 80% yield (entry 6). The lactonization was carried yield was obtained in benzene (entry 1, Table 4) and the dia-
out to determine the diastereoselectivity easily by 1H NMR stereoselectivity gradually increased towards higher-boiling
spectroscopy. In lactone 8b the proton Ha is syn to the decalin (entries 2–6) to provide 8a/8b in a 10:1 ratio and
double bond and appears at δ = 4.17 ppm whereas the same 80% yield (entry 6).
proton in 8a is anti to the double bond and appears down-
field at δ = 4.37 ppm.[11c] The lactones 8a and 8b were easily
Table 3. Diastereoselective orthoester Johnson–Claisen rearrange-
ment of 3c.
separable by flash column chromatography. The similar or-
thoester Johnson–Claisen rearrangement of 3b and subse-
quent lactonization (Table 2) gave trends opposite to those
observed with 3a: lactone 8b was obtained as the major
diastereomer in benzene (1:8 8a/8b, 81%, entry 1, Table 2).
The diastereoselectivity gradually decreased towards deca-
lin (entries 2–6) giving 8a/8b in a 1:4 ratio (entry 6).
Entry Solvent
Reaction time [h] Yield [%]
8a/8b[a]
Table 1. Diastereoselective orthoester Johnson–Claisen rearrange-
ment of 3a.
1
2
3
4
5
6
benzene
CH3C(OMe)3
toluene
xylene
mesitylene
decalin
60
24
12
4
2
1
81
82
85
90
80
80
1: 16
1: 8
1: 7.5
1: 6
1: 5
1: 5
1
[a] Determined by H NMR.
Table 4. Diastereoselective orthoester Johnson–Claisen rearrange-
ment of 3d.
Entry Solvent
Reaction time [h] Yield [%]
8a/8b[a]
1
2
3
4
5
6
benzene
CH3C(OMe)3
toluene
xylene
mesitylene
decalin
60
24
12
4
2
1
81
82
85
90
80
80
4: 1
5: 1
6: 1
7: 1
7: 1
9: 1
1
[a] Determined by H NMR.
Entry Solvent
Reaction time [h] Yield [%]
8a/8b[a]
Table 2. Diastereoselective orthoester Johnson–Claisen rearrange-
ment of 3b.
1
2
3
4
5
6
benzene
CH3C(OMe)3
toluene
xylene
mesitylene
decalin
60
24
12
4
81
82
85
90
80
80
5: 1
6: 1
7: 1
9: 1
9: 1
10: 1
2
1
1
[a] Determined by H NMR.
The observed diastereoselectivity is in accordance with
literature reports.[12] Considering chair-like transition states,
A derived from (6S,E)-3a and B derived from (6R,Z)-3d
(Scheme 3) would be favored as they have the smallest
number of nonbonding interactions; both A and B yield the
same product 8a after lactonization of the intermediate es-
ter 4a (8a is the major diastereomer, see Table 1 and
Table 4). Similarly, (6R,E)-3b and (6S,Z)-3c produce 8b as
the major diastereomer (see Tables 2 and 3; transition states
Entry
Solvent
Reaction time [h] Yield [%] 8a/8b[a]
1
2
3
4
5
6
benzene
CH3C(OMe)3
toluene
xylene
mesitylene
decalin
60
24
12
4
81
82
85
90
80
80
1:8
1:6
1:6
1:5
1:4
1:4
2
1
1
[a] Determined by H NMR.
The allyl alcohol 3c with a Z olefin bond and C-6 S are not shown in Scheme 3, see the Supporting Infor-
chirality after orthoester Johnson–Claisen rearrangement in mation). The diastereoselectivity observed in the orthoester
benzene and subsequent lactonization diastereoselectively Johnson–Claisen rearrangement is mainly due to chirality
Eur. J. Org. Chem. 2012, 1047–1055
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R. A. Fernandes, A. B. Ingle, D. A. Chaudhari
FULL PAPER
transfer, as shown by the lowest-energy transition states. 5b from which 5a was obtained in 73% yield. Similar ortho-
The increase in diastereoselectivity for 8a with increasing ester Johnson–Claisen rearrangement of 3b with trimethyl
reaction temperature (Tables 1 and 4) could be due to the orthoacetate in benzene at reflux temperature over 60 h
formation of the thermodynamically favored product (8a is gave a mixture of 4a/4b in a 1:8 ratio and 86% yield (for
more stable than 8b) at higher temperature. The increase in the ratio after lactonization, see Table 2, entry 1). The mix-
diastereoselectivity for 8b with decreasing reaction tempera- ture on DIBALH reduction and Wittig olefination provided
ture (Tables 2 and 3) could be due to the formation of the 5b in 72% yield. Acetonide deprotection of 5a and 5b pro-
kinetically favored product (8b) at lower temperature.
vided 9a and 9b, respectively, each in 90% yield. Diol cleav-
age and subsequent oxidation gave the acids 10 and ent-10
Scheme 3. Transition states for the orthoester Johnson–Claisen re-
arrangement of 3a and 3d to give 8a.
After complete screening of the diastereoselectivity based
on olefin geometry and allyl alcohol stereochemistry we
used the optimum results for an efficient synthesis of the
two enantiomers of arundic acid. From the above study it
can been seen that compound 8a can best be obtained by
the
sequence
6Ǟ7aǞ3aǞ8a
as
opposed
to
6Ǟ7bǞ3dǞ8a because the synthesis of 7b from 6 was
achieved in a lower yield of 52%. Similarly, compound 8b
can best be obtained by the sequence 6Ǟ7aǞ3bǞ8b as
opposed to 6Ǟ7bǞ3cǞ8b. In the latter sequence, the
syntheses of 7b from 6 and of 3c from 7b gave lower yields,
although the best diastereoselectivity of 1:16 (8a/8b,
Table 3) was obtained in the orthoester Johnson–Claisen re-
arrangement of 3c as against 1:8 (8a/8b, Table 2) for the
corresponding reaction of 3b. The synthesis of the two
enantiomers of arundic acid is shown in Scheme 4. The or-
thoester Johnson–Claisen rearrangement of 3a with tri-
methyl orthoacetate in decalin at reflux temperature over
1 h gave a mixture of 4a/4b in a ratio of 9:1 in 85% yield
(for the ratio after lactonization, see Table 1, entry 6). The
mixture of 4a/4b was not completely separable at this stage
although a pure sample of 4a could be obtained for analysis
by column chromatography. DIBAL-H reduction of the
mixture to the corresponding aldehyde and subsequent
Wittig reaction with the ylide generated from
Scheme 4. Synthesis of the two enantiomers of arundic acid. Rea-
gents and conditions: a) MeC(OMe)3 (10.0 equiv.), EtCO2H (cat.),
decalin, reflux, 1 h, 85%; b) MeC(OMe)3 (10.0 equiv.), EtCO2H
(cat.), benzene, reflux, 60 h, 86%; c) i. DIBAL-H (1.1 equiv.),
–80 °C, CH2Cl2, 2 h; ii. Ph3P+CH2CH2CH2CH3Br– (1.3 equiv.),
nBuLi (1.4 equiv.), THF, –80 °C, 15 min, aldehyde from 4, warmed
to room temp., 8 h, 5a (73%), 5b (72%); d) 3 n HCl, MeOH, room
temp., 6 h, 90%; e) i. NaIO4 (2.0 equiv.), NaHCO3, CH2Cl2, room
temp., 6 h; ii. NaClO2 (10 equiv.), NaH2PO4·H2O (7.0 equiv.), cy-
clohexene (5.0 equiv.), tBuOH, room temp., 12 h, 66% (two steps);
Ph3P+CH2CH2CH2CH3Br– gave a separable mixture of 5a/ f) H2 (4 atm), Pd/C, MeOH, 2 h, 96%.
1050 Eur. J. Org. Chem. 2012, 1047–1055
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Orthoester Johnson–Claisen Rearrangement
3018, 2995, 2934, 2867, 1679, 1635, 1455, 1380, 1372, 1251, 1167,
(each in 66% yield). The final hydrogenation of 10 gave (R)-
(–)-arundic acid (1) in 96% yield {[α]2D5 = –6.8 (c = 0.82,
EtOH); ref.[7]: [α]2D5 = –6.1 (c = 2, EtOH)}.[16] Similarly, ent-
1
1093, 980, 908, 861, 699 cm–1. H NMR (400 MHz, CDCl3/TMS):
δ = 1.44 (s, 3 H), 1.46 (s, 3 H), 2.25 (s, 3 H), 3.63–3.65 (m, 2 H),
3.93–3.97 (m, 1 H), 4.42–4.46 (m, 1 H), 4.59 (d, J = 2.8 Hz, 2 H),
6.31 (dd, J = 16.0, 1.3 Hz, 1 H), 6.71 (dd, J = 16.0, 5.5 Hz, 1 H),
7.29–7.38 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.7,
26.9, 27.4, 69.3, 73.7, 77.7, 79.5, 110.3, 127.7, 127.79, 127.8, 128.4
(2 C), 131.1, 137.7, 142.7, 198.0 ppm. HRMS (ESI+): calcd. for
[C17H22O4 + Na]+ 313.1416; found 313.1416.
10 gave (S)-(+)-arundic acid (ent-1) in 96% yield {[α]D25
=
+6.6 (c = 0.54, EtOH)}. The 1H NMR and HPLC analyses
of the diastereomers obtained by converting 1 and ent-1
separately into (S)-α-methylbenzyl amides indicated over
99% ee. The spectroscopic and analytical data, including
the optical rotations of 1 and ent-1, are in full agreement
with those reported.[7,9]
(5S,6S,Z)-7-Benzyloxy-5,6-(isopropylidenedioxy)hept-3-en-2-one
(7b): Oxalyl chloride (0.83 mL, 9.51 mmol, 1.2 equiv.) was added
to a solution of DMSO (0.85 mL, 11.9 mmol, 1.5 equiv.) in dry
CH2Cl2 (50 mL) at –78 °C over 10 min. The reaction mixture was
stirred for 10 min and then alcohol 6 (2 g, 7.92 mmol) in CH2Cl2
(20 mL) was added dropwise. The reaction mixture was stirred at
–78 °C for 30 min, –40 °C for 30 min, and Et3N (4.42 mL,
31.7 mmol, 4.0 equiv.) was then added and the mixture stirred for
1 h. Water (30 mL) was added and the organic layer separated. The
aqueous layer was extracted with CH2Cl2 (3ϫ40 mL) and the com-
bined organic layers were washed with water and brine, dried
(Na2SO4), and concentrated to give the crude aldehyde.
Conclusions
We have synthesized chiral allyl alcohols 3a–d based on
diethyl tartrate and studied the effect of solvent, olefin ge-
ometry, and allyl alcohol chirality on the diastereoselectiv-
ity of their orthoester Johnson–Claisen rearrangement. An
efficient stereoselective synthesis of the two enantiomers of
arundic acid, a potential therapeutic agent for Alzheimer’s
disease, was completed in seven steps from known alcohol
6 in overall yields of 26% for both enantiomers. Further
application of this strategy towards the synthesis of other
natural products is in progress in our laboratory.
The crude aldehyde was dissolved in MeOH (25 mL) and CH3C(O)
CHPPh3 (3.02 g, 9.5 mmol, 1.2 equiv.) was added. The reaction
mixture was stirred at –78 °C for 2 h and then at –40 °C for 12 h.
It was warmed to room temperature and concentrated. The residue
was purified by flash column chromatography using petroleum
ether/EtOAc (9:1) as eluent to afford 7b (1.196 g, 52%) as a color-
less oil. Further elution gave 7a (0.713 g, 31%) as a colorless oil.
Experimental Section
Data for 7a: [α]2D5 = –12.6 (c = 1.5, CHCl3). Spectroscopic data are
General: Reaction flasks were oven- or flame-dried and cooled in
a desiccator. Dry reactions were carried out under Ar or N2. Sol-
vents and reagents were purified by standard methods. Thin-layer
chromatography was performed on EM 250 Kieselgel 60 F254 sil-
ica gel plates. The spots were visualized by staining with KMnO4
the same as above.
Data for 7b: [α]2D5 = 65.8 (c = 1.0, CHCl ). IR (CHCl ): ν = 3019,
˜
3
3
2934, 2868, 1698, 1625, 1455, 1410, 1383, 1373, 1182, 1163, 1080,
1036, 912, 860, 699 cm–1. H NMR (400 MHz, CDCl3/TMS): δ =
1
1.44 (s, 3 H), 1.45 (s, 3 H), 2.20 (s, 3 H), 3.70–3.72 (m, 2 H), 3.93–
3.97 (m, 1 H), 4.50–4.66 (m, 2 H), 5.20 (td, J = 8.3, 1.2 Hz, 1 H),
6.03 (dd, J = 11.6, 8.4 Hz, 1 H), 6.29 (dd, J = 11.6, 1.0 Hz, 1 H),
7.27–7.36 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.0,
27.1, 31.1, 70.7, 73.4, 73.8, 80.3, 110.2, 127.4, 127.6, 127.7, 128.2,
128.3, 129.6, 138.1, 143.3, 198.2 ppm. HRMS (ESI+): calcd. for
[C17H22O4 + H]+ 291.1596; found 291.1598.
1
or by using a UV lamp. H and 13C NMR spectra were recorded
with a Bruker AvanceIII 400 spectrometer and the chemical shifts
1
are given relative to the peak of TMS (δ = 0.00 ppm) for H NMR
and the CDCl3 peak (δ = 77.00 ppm, t) for 13C NMR spectroscopy.
IR spectra were obtained with a Perkin–Elmer Spectrum One FT-
IR spectrometer. Optical rotations were measured with a Jasco P-
2000 polarimeter. HRMS were recorded with a Micromass Q-Tof
micro (YA-105) spectrometer. HPLC was performed with a Jasco
PU-2089PLUS quaternary gradient pump with an MD-2010PLUS
multiwavelength detector.
(2S,3S,6S,E)-1-Benzyloxy-2,3-(isopropylidenedioxy)hept-4-en-6-ol
(3a): A solution of 7a (0.15 g, 0.52 mmol) in THF (1 mL) was
added dropwise over 10 min to a solution of (R)-2-methyl-CBS-
oxazaborolidine (0.52 mL, 1 m solution in toluene, 0.52 mmol,
1.0 equiv.) and BH3·SMe2 (0.059 mL, 0.62 mmol, 1.2 equiv.) in
THF (3 mL) at 0 °C. The mixture was stirred for 15 min and then
quenched by the slow addition of MeOH (1 mL) at 0 °C. The solu-
tion was stirred for 15 min at room temperature and concentrated.
The residue was purified by flash column chromatography using
petroleum ether/EtOAc (7:3) as eluent to afford alcohol 3a (134 mg,
(5S,6S,E)-7-Benzyloxy-5,6-(isopropylidenedioxy)hept-3-en-2-one
(7a): Oxalyl chloride (0.83 mL, 9.51 mmol, 1.2 equiv.) was added
to a solution of DMSO (0.84 mL, 11.89 mmol, 1.5 equiv.) in dry
CH2Cl2 (50 mL) at –78 °C over 10 min. The reaction mixture was
stirred for 10 min and then alcohol 6 (2 g, 7.92 mmol) in CH2Cl2
(20 mL) was added dropwise. The reaction mixture was stirred at
–78 °C for 30 min, –40 °C for 30 min, and then Et3N (4.41 mL,
31.70 mmol) was added and stirred for 1 h. Water (30 mL) was
added and the organic layer separated. The aqueous layer was ex-
tracted with CH2Cl2 (3ϫ40 mL) and the combined organic layers
were washed with water and brine, dried (Na2SO4), and concen-
trated to give the crude aldehyde.
89%) as a colorless oil. HPLC analysis indicated 19:1 dr. [α]2D5
–7.9 (c = 0.4, CHCl ). IR (CHCl ): ν = 3436, 3012, 2986, 2934,
=
˜
3
3
2869, 1638, 1495, 1454, 1379, 1371, 1246, 1168, 1128, 1079, 1028,
972, 944, 908, 865, 699 cm–1. H NMR (400 MHz, CDCl3/TMS):
1
δ = 1.25 (d, J = 6.3 Hz, 3 H), 1.44 (s, 6 H), 3.55–3.60 (m, 2 H),
3.88–3.93 (m, 1 H), 4.25 (t, J = 7.7 Hz, 1 H), 4.27–4.37 (m, 1 H),
4.59 (d, J = 2.4 Hz, 2 H), 5.66 (ddd, J = 15.8, 7.7, 1.2 Hz, 1 H),
The crude aldehyde was dissolved in THF (25 mL) and CH3C(O)-
CHPPh3 (3.02 g, 9.5 mmol, 1.2 equiv.) was added. The reaction
mixture was stirred at room temperature for 12 h and concentrated.
The residue was purified by flash column chromatography using
petroleum ether/EtOAc (9:1) as eluent to afford 7a (1.89 g, 82%)
5.83 (ddd, J = 15.4, 5.7, 0.8 Hz, 1 H), 7.27–7.35 (m, 5 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 23.1, 26.9, 27.0, 67.8, 69.3, 73.5,
78.5, 80.0, 109.4, 126.3, 127.7 (3 C), 128.4 (2 C), 137.9, 139.1 ppm.
HRMS (ESI+): calcd. for [C17H24O4 + Na]+ 315.1572; found
315.1585.
as a colorless oil. [α]2D5 = –12.8 (c = 1.5, CHCl ). IR (CHCl ): ν =
˜
3
3
Eur. J. Org. Chem. 2012, 1047–1055
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1051

R. A. Fernandes, A. B. Ingle, D. A. Chaudhari
FULL PAPER
(2S,3S,6R,E)-1-Benzyloxy-2,3-(isopropylidenedioxy)hept-4-en-6-ol
(3b): The title compound was prepared from 7a (0.15 g, 0.52 mmol)
by a similar procedure to that described for the synthesis of 3a,
using (S)-2-methyl-CBS-oxazaborolidine, to give 3b (134 mg, 89%)
as a colorless oil. HPLC analysis indicated 16:1 dr. [α]2D5 = –22.6 (c
was added and stirred for 12 h. It was then quenched with
NaHCO3 (0.1 g) and methanol was removed. Water (10 mL) was
added, the aqueous layer was extracted with EtOAc (3ϫ10 mL),
the combined organic layers were washed with water and brine,
dried (Na2SO4), and concentrated. The residue was purified by sil-
ica gel column chromatography using petroleum ether/EtOAc (7:3)
= 0.4, CHCl ). IR (CHCl ): ν = 3432, 3030, 2985, 2929, 2869, 1638,
˜
3
3
1
1605, 1492, 1454, 1379, 1371, 1240, 1168, 1130, 1077, 1028, 972,
941, 908, 866, 699 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ =
1.24 (d, J = 6.4 Hz, 3 H), 1.44 (s, 6 H), 1.75 (br. s, 1 H, OH), 3.54–
3.61 (m, 2 H), 3.87–3.92 (m, 1 H), 4.23 (t, J = 7.9 Hz, 1 H), 4.27–
4.34 (m, 1 H), 4.59 (d, J = 2.5 Hz, 2 H), 5.66 (ddd, J = 15.8, 7.4,
1.2 Hz, 1 H), 5.83 (ddd, J = 15.4, 5.7, 0.7 Hz, 1 H), 7.27–7.35 (m,
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.0, 26.9, 27.0, 67.8,
69.2, 73.5, 78.4, 80.0, 109.4, 126.3, 127.68 (2 C), 127.7, 128.3 (2
C), 137.9, 139.0 ppm. HRMS (ESI+): calcd. for [C17H24O4 + Na]+
315.1572; found 315.1580.
to give a mixture of 8a/8b (75.6 mg, 80%, 9:1 by H NMR). This
was efficiently separated by flash column chromatography using
petroleum ether/EtOAc (7:3) as eluent to afford 8a (65 mg, 69%)
as a colorless oil. Further elution gave 8b (6.6 mg, 7%) as a color-
less oil.
Data for 8a: [α]2D5 = 62.6 (c = 0.36, CHCl ). IR (CHCl ): ν = 3452,
˜
3
3
3033, 2919, 2868, 1777, 1625, 1495 1454, 1419, 1366, 1309, 1276,
1174, 1087, 1029, 977, 909 cm–1 1H NMR (400 MHz, CDCl3/
.
TMS): δ = 1.70 (d, J = 5.0 Hz, 3 H), 2.45 (dd, J = 17.2, 9.2 Hz, 1
H), 2.75 (dd, J = 17.2, 11.0 Hz, 1 H), 3.25 (quint., J = 8.4 Hz, 1
H), 3.53–3.65 (m, 2 H), 3.98–4.02 (m, 1 H), 4.37 (dd, J = 8.3,
1.7 Hz, 1 H), 4.55 (d, J = 5.6 Hz, 2 H), 5.55–5.63 (m, 2 H), 7.28–
7.38 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7, 34.6,
41.8, 69.6, 70.9, 73.4, 81.5, 127.1, 127.7 (2 C), 127.8, 128.3 (2 C),
(2S,3S,6S,Z)-1-Benzyloxy-2,3-(isopropylidenedioxy)hept-4-en-6-ol
(3c) and (2S,3S,6R,Z)-1-Benzyloxy-2,3-(isopropylidenedioxy)hept-4-
en-6-ol (3d): The title compounds were prepared from 7b (0.15 mg,
0.52 mmol) by a similar procedure to that described for 3a, using
(R)-2-methyl-CBS-oxazaborolidine, to give a mixture of 3c/3d in a
2:1 ratio (by 1H NMR). The mixture was separated by flash column
chromatography using petroleum ether/EtOAc (7:3) as eluent to
afford 3d (43.8 mg, 29%) as a colorless oil. Further elution gave 3c
(84.6 mg, 56%) as a colorless oil.
129.9, 137.4, 177.6 ppm. HRMS (ESI+): calcd. for [C16H20O4
H]+ 277.1440; found 277.1440.
+
Data for 8b: [α]2D5 = 43.0 (c = 0.36, CHCl ). IR (CHCl ): ν = 3443,
˜
3
3
3022, 2919, 2863, 1777, 1599, 1492, 1454, 1418, 1366, 1264, 1202,
1
1165, 1118, 1043, 1029, 972 cm–1. H NMR (400 MHz, CDCl3/
Data for 3c: [α]2D5 = –8.5 (c = 1.5, CHCl ). IR (CHCl ): ν = 3459,
˜
3
3
TMS): δ = 1.68 (dd, J = 6.4, 1.5 Hz, 3 H), 2.37 (dd, J = 17.6,
9.7 Hz, 1 H), 2.75 (dd, J = 17.6, 8.8 Hz, 1 H), 3.25 (quint., J =
8.8 Hz, 1 H), 3.55–3.64 (m, 2 H), 3.85–3.89 (m, 1 H), 4.17 (dd, J
= 8.0, 2.1 Hz, 1 H), 4.56 (d, J = 2.4 Hz, 2 H), 5.34 (dd, J = 15.1,
8.4 Hz, 1 H), 5.60 (dq, J = 15.0, 6.5 Hz, 1 H), 7.29–7.38 (m, 5
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8, 35.5, 40.2, 69.1,
71.2, 73.5, 83.8, 127.8 (2 C), 127.9, 128.5 (2 C), 128.7, 129.2, 137.5,
176.1 ppm. HRMS (ESI+): calcd. for [C16H20O4 + H]+ 277.1440;
found 277.1441.
2885, 2931, 2868, 1641, 1608, 1495, 1455, 1379, 1372, 1243, 1167,
1
1076, 925, 903, 862, 699 cm–1. H NMR (400 MHz, CDCl3/TMS):
δ = 1.16 (d, J = 6.3 Hz, 3 H), 1.43 (s, 6 H), 1.77 (br. s, 1 H, OH),
3.53–3.61 (m, 2 H), 3.85–3.89 (m, 1 H), 4.54–4.62 (m, 3 H), 4.73
(td, J = 8.4, 1.0 Hz, 1 H), 5.44 (ddd, J = 11.1, 8.8, 0.9 Hz, 1 H),
5.69 (ddd, J = 11.1, 8.5, 1.1 Hz, 1 H), 7.27–7.37 (m, 5 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 23.0, 26.9, 27.1, 63.8, 69.0, 73.6,
73.7, 80.0, 109.5, 126.9, 127.7 (2 C), 127.74, 128.4 (2 C), 137.7,
139.4 ppm. HRMS (ESI+): calcd. for [C17H24O4 + Na]+ 315.1572;
found 315.1583.
(4S,5S)-5-[2-Benzyloxy-(S)-1-hydroxyethyl]-4-[(E)-1-propenyl]-4,5-
dihydro-2(3H)-furanone (8a) and (4R,5S)-5-[2-Benzyloxy-(S)-1-
hydroxyethyl]-4-[(E)-1-propenyl]-4,5-dihydro-2(3H)-furanone (8b):
Reaction conditions as in entry 1, Table 2. Trimethyl orthoacetate
(0.411 g, 3.42 mmol, 10.0 equiv.) and propionic acid (2 mg, cata-
lytic) were added to a solution of allyl alcohol 3b (0.1 g,
0.342 mmol) in benzene (1 mL). The reaction mixture was heated
at reflux for 60 h. It was then cooled and concentrated. The residue
was dissolved in MeOH (5 mL) and 4 m HCl (0.5 mL) was added
and stirred for 12 h. It was then quenched with NaHCO3 (0.1 g)
and methanol was removed. Water (10 mL) was added and the
aqueous layer was extracted with EtOAc (3ϫ10 mL). The com-
bined organic layers were washed with water and brine, dried
(Na2SO4), and concentrated. The residue (76.5 mg, 81%, virtually
Data for 3d: [α]2D5 = –6.0 (c = 0.4, CHCl ). IR (CHCl ): ν = 3443,
˜
3
3
3027, 2985, 2931, 2868, 1638, 1498, 1454, 1379, 1371, 1245, 1167,
1
1075, 1045, 925, 908, 862, 699 cm–1. H NMR (400 MHz, CDCl3/
TMS): δ = 1.24 (d, J = 6.2 Hz, 3 H), 1.42 (s, 3 H), 1.43 (s, 3 H),
3.63–3.71 (m, 2 H), 3.83–3.88 (m, 1 H), 4.54–4.62 (m, 3 H), 4.75
(td, J = 8.4, 1.0 Hz, 1 H), 5.46 (ddd, J = 11.1, 8.8, 1.1 Hz, 1 H),
5.68 (ddd, J = 11.1, 8.5, 1.0 Hz, 1 H), 7.27–7.37 (m, 5 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 23.1, 26.9, 27.0, 63.3, 69.6, 73.7,
75.0, 79.1, 109.4, 127.6, 127.7, 127.9, 128.0, 128.4, 128.5, 137.3,
138.8 ppm. HRMS (ESI+): calcd. for [C17H24O4 + Na]+ 315.1572;
found 313.1582.
(2S,3S,6R,Z)-1-Benzyloxy-2,3-(isopropylidenedioxy)hept-4-en-6-ol
(3d): The title compound was prepared from 7b (0.15 mg,
0.52 mmol) by a similar procedure to that described for 3a, using
(S)-2-methyl-CBS-oxazaborolidine, to give 3d (135 mg, 89%) as a
colorless oil (single diastereomer by 1H NMR). [α]2D5 = –6.2 (c =
0.5, CHCl3). The spectroscopic data are the same as above.
1
pure) was analyzed by H NMR, which indicated a mixture of 8a/
8b in a 1:8 ratio. This was efficiently separated by flash column
chromatography using petroleum ether/EtOAc (7:3) as eluent to
afford 8a (7.5 mg, 8%) as a colorless oil. Further elution gave 8b
(61.3 mg, 65%) as a colorless oil. Data for 8a: [α]2D5 = 64.5 (c = 0.3,
CHCl3). The spectroscopic data are the same as before. Data for
8b: [α]2D5 = 42.8 (c = 0.3, CHCl3). The spectroscopic data are the
same as before.
(4S,5S)-5-[2-Benzyloxy-(S)-1-hydroxyethyl]-4-[(E)-1-propenyl]-4,5-
dihydro-2(3H)-furanone (8a) and (4R,5S)-5-[2-Benzyloxy-(S)-1-
hydroxyethyl]-4-[(E)-1-propenyl]-4,5-dihydro-2(3H)-furanone (8b):
Reaction conditions as in entry 6, Table 1. Trimethyl orthoacetate
(0.411 g, 3.42 mmol, 10.0 equiv.) and propionic acid (2 mg, cata-
lytic) were added to a solution of allyl alcohol 3a (0.1 g,
0.342 mmol) in decalin (1 mL). The reaction mixture was heated at
reflux for 1 h in a preheated oil bath, cooled, and concentrated.
The residue was dissolved in MeOH (5 mL) and 4 m HCl (0.5 mL)
Methyl 3-[(3S)-3-Benzyloxy-(1S,2S)-1,2-(isopropylidenedioxy)prop-
yl]hex-4-enoate (4a): Trimethyl orthoacetate (4.52 g, 37.6 mmol,
10.0 equiv.) and propionic acid (20 mg, catalytic) were added to a
solution of allyl alcohol 3a (1.1 g, 3.76 mmol) in decalin (5 mL).
The reaction mixture was heated at reflux for 1 h in a preheated
oil bath, cooled, and concentrated. The residue was purified by
1052
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1047–1055

Orthoester Johnson–Claisen Rearrangement
flash column chromatography using petroleum ether/EtOAc (9:1)
as eluent to afford a mixture of 4a/4b (1.11 g, 85%, 9:1 ratio as
determined earlier through lactonization) as a colorless oil. The
mixture of 4a/4b could not be separated at this stage. However a
sample of pure 4a was obtained by flash column chromatography
for analysis.
dried (Na2SO4), and concentrated. The residue was purified by
flash column chromatography using petroleum ether/EtOAc (19:1)
as eluent to afford 5a (0.53 g, 73%) as a colorless oil. Further elu-
tion gave 5b (57 mg, 8%) as a colorless oil.
Data for 5a: [α]2D5 = –20.2 (c = 1.1, CHCl ). IR (CHCl ): ν = 3012,
˜
3
3
2983, 2932, 2863, 1600, 1495, 1455, 1379, 1251, 1215, 1169, 1087,
Data for 4a: [α]2D5 = –5.0 (c = 0.3, CHCl ). IR (CHCl ): ν = 3019,
971, 905, 856, 758, 697 cm–1. H NMR (400 MHz, CDCl3/TMS):
1
˜
3
3
2989, 2933, 2863, 1740, 1588, 1455, 1435, 1379, 1370, 1243, 1167,
δ = 0.89 (t, J = 7.3 Hz, 3 H), 1.21–1.35 (m, 2 H), 1.39 (s, 6 H), 1.67
(d, J = 5.2 Hz, 3 H), 1.96–2.06 (m, 2 H), 2.07–2.12 (m, 2 H), 2.13–
1
1097, 1045, 971, 911, 861, 699 cm–1. H NMR (400 MHz, CDCl3/
TMS): δ = 1.37 (s, 3 H), 1.38 (s, 3 H), 1.65 (dd, J = 6.3, 1.4 Hz, 3 2.28 (m, 1 H), 3.53 (d, J = 4.9 Hz, 2 H), 3.88 (dd, J = 8.4, 2.3 Hz,
H), 2.43 (dd, J = 15.3, 8.9 Hz, 1 H), 2.54 (dd, J = 15.3, 5.8 Hz, 1
H), 2.68–2.72 (m, 1 H), 3.54–3.55 (m, 2 H), 3.64 (s, 3 H), 3.82 (dd,
J = 8.4, 2.9 Hz, 1 H), 3.93–3.99 (m, 1 H), 4.58 (d, J = 7.4 Hz, 2
H), 5.36 (ddq, J = 15.4, 8.8, 1.5 Hz, 1 H), 5.50 (dq, J = 15.4, 6.3 Hz,
1 H), 3.97–4.01 (m, 1 H), 4.59 (d, J = 7.0 Hz, 2 H), 5.22–5.3 (m, 1
H), 5.31–5.42 (m, 3 H), 7.27–7.36 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.8, 18.0, 22.7, 26.9, 27.0, 29.3, 30.4, 44.5,
70.7, 73.4, 77.3, 80.0, 108.7, 127.5 (2 C), 127.53, 127.8, 128.3 (3 C),
1 H), 7.28–7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 129.9, 131.1, 138.1 ppm. HRMS (ESI+): calcd. for [C23H34O3
+
18.0, 26.9, 27.0, 37.3, 40.7, 51.5, 70.6, 73.5, 77.2, 79.9, 109.0, 127.6
(3 C), 128.0, 128.4 (2 C), 129.0, 138.0, 172.8 ppm. HRMS (ESI+):
calcd. for [C20H28O5 + H]+ 349.2015; found 349.2007.
H]+ 359.2586; found 359.2583. The characterization of 5b follows
the next reaction.
(2S,3S,4R)-1-Benzyloxy-2,3-(isopropylidenedioxy)-4-[(E)-1-propen-
yl]-(Z)-dec-6-ene (5b): The title compound was prepared from a
mixture of 4a/4b (1:8, 0.1 g, 0.28 mmol) by a similar procedure to
that described for 5a to give 5b (74 mg, 72%) and 5a (7.2 mg, 7%)
as colorless oils.
Methyl 3-[(3R)-3-Benzyloxy-(1S,2S)-1,2-(isopropylidenedioxy)prop-
yl]hex-4-enoate (4b): Trimethyl orthoacetate (0.822 mg, 6.84 mmol,
10 equiv.) and propionic acid (2 mg, catalytic) were added to a solu-
tion of allyl alcohol 3b (0.2 g, 0.684 mmol) in benzene (5 mL). The
reaction mixture was heated at reflux for 60 h and then cooled and
concentrated. The residue was purified by flash column chromatog-
raphy using petroleum ether/EtOAc (9:1) as eluent to afford a mix-
ture of 4a/4b (205 mg, 86%, 1:8 ratio as determined earlier through
lactonization) as a colorless oil. The mixture of 4a/4b could not be
separated at this stage. However a sample of pure 4b was obtained
by flash column chromatography for analysis.
Data for 5b: [α]2D5 = –17.2 (c = 3.2, CHCl ). IR (CHCl ): ν = 3019,
˜
3
3
2868, 1602, 1451, 1380, 1372, 1216, 1163, 1084, 1040, 971, 916,
858, 757, 667 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ = 0.88
(t, J = 7.3 Hz, 3 H), 1.31–1.38 (m, 2 H), 1.41 (s, 3 H), 1.42 (s, 3
H), 1.55 (dd, J = 6.4, 1.5 Hz, 3 H), 1.95–2.0 (m, 2 H), 2.0–2.1 (m,
1 H), 2.15–2.2 (m, 1 H), 2.38–2.41 (m, 1 H), 3.41–3.43 (m, 1 H),
3.57 (dd, J = 10.5, 2.6 Hz, 1 H), 3.65 (t, J = 8.1 Hz, 1 H), 3.94–
3.98 (m, 1 H), 4.58 (d, J = 6.4 Hz, 2 H), 4.99–5.04 (m, 1 H), 5.25–
5.5 (m, 3 H), 7.31–7.35 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.8, 17.8, 22.7, 27.1, 27.2, 29.3, 29.4, 48.1, 70.8, 73.2,
79.3, 79.6, 108.8, 127.0, 127.5 (2 C), 127.6, 127.8, 128.3 (2 C), 130.2,
Data for 4b: [α]2D5 = –25.0 (c = 0.5, CHCl ). IR (CHCl ): ν = 3033,
˜
3
3
2987, 2936, 2863, 1739, 1587, 1495, 1455, 1432, 1379, 1371, 1244,
1169, 1088, 1043, 973, 908, 860, 699 cm–1. 1H NMR (400 MHz,
CDCl3/TMS): δ = 1.39 (s, 3 H), 1.40 (s, 3 H), 1.65 (dd, J = 6.5,
1.7 Hz, 3 H), 2.29 (dd, J = 14.3, 8.5 Hz, 1 H), 2.61–2.77 (m, 1 H), 130.9, 138.1 ppm. HRMS (ESI+): calcd. for [C23H34O3 + Na]+
2.70 (dd, J = 14.3, 4.5 Hz, 1 H), 3.44 (dd, J = 10.5, 6.2 Hz, 1 H),
3.56 (dd, J = 10.4, 2.9 Hz, 1 H), 3.63 (s, 3 H), 3.67 (t, J = 7.9 Hz,
1 H), 3.94–3.98 (m, 1 H), 4.57 (d, J = 3.4 Hz, 2 H), 5.08 (ddq, J =
15.3, 9.1, 1.7 Hz, 1 H), 5.55 (dq, J = 15.3, 6.5 Hz, 1 H), 7.28–7.36
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8, 26.9, 27.1,
37.1, 44.3, 51.4, 70.6, 73.3, 79.0, 79.7, 109.1, 127.6 127.7 (2 C),
128.3 (2 C), 128.8 (2 C), 138.0, 172.7 ppm. HRMS (ESI+): calcd.
for [C20H28O5 + H]+ 349.2015; found 349.2013.
381.2406; found 381.2401.
(2S,3S,4S)-1-Benzyloxy-4-[(E)-1-propenyl]-(Z)-dec-6-ene-2,3-diol
(9a): A solution of 3 m HCl (0.5 mL) was added to a solution of
5a (0.1 g, 0.28 mmol) in MeOH (5 mL) at room temperature and
the mixture was stirred for 6 h. It was then quenched with NaHCO3
(0.1 g) and methanol was removed. Water (10 mL) was added and
the aqueous layer extracted with EtOAc (3ϫ10 mL). The com-
bined organic layers were washed with water and brine, dried
(2S,3S,4S)-1-Benzyloxy-2,3-(isopropylidenedioxy)-4-[(E)-1-propen- (Na2SO4), and concentrated. The residue was purified by flash col-
yl]-(Z)-dec-6-ene (5a): DIBAL-H (2.1 mL, 2.1 mmol, 1 m solution umn chromatography using petroleum ether/EtOAc (7:3) as eluent
in hexane, 1.05 equiv.) was added dropwise to a solution of the
mixture of 4a/4b (9:1, 0.7 g, 2.01 mmol) in CH2Cl2 (25 mL) at
–80 °C over a period of 1 h. The reaction mixture was stirred at
–80 °C for 2 h, quenched with MeOH (2 mL), and stirred for
15 min. It was warmed to room temperature and a saturated solu-
tion of Rochelle’s salt (5 mL) was added and stirred for 2 h. The
mixture was extracted with CH2Cl2 (3ϫ25 mL). The combined or-
ganic layers were washed with water and brine, dried (Na2SO4),
and concentrated to give the crude aldehyde which was used in the
next reaction.
to afford 9a (80 mg, 90%) as a colorless oil. [α]2D5 = –16.5 (c = 1,
CHCl ). IR (CHCl ): ν = 3445, 3011, 2956, 2929, 2868, 1649, 1605,
˜
3
3
1
1492, 1454, 1405, 1375, 1254, 1094, 974, 916, 699 cm–1. H NMR
(400 MHz, CDCl3/TMS): δ = 0.89 (t, J = 7.3 Hz, 3 H), 1.31–1.38
(m, 2 H), 1.68 (dd, J = 6.1, 1.3 Hz, 3 H), 1.97–2.04 (m, 2 H), 2.06–
2.19 (m, 2 H), 2.25–2.32 (m, 1 H), 3.51–3.57 (m, 2 H), 3.60 (dd, J
= 9.7, 3.9 Hz, 1 H), 3.77–3.81 (m, 1 H), 4.56 (d, J = 4.0 Hz, 2 H),
5.28–5.35 (m, 1 H), 5.37–5.44 (m, 2 H), 5.47 (dd, J = 16.4, 6.1 Hz,
1 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.8, 18.0, 22.7, 29.4, 29.5, 45.8, 71.0, 71.8, 73.2, 73.4, 127.2, 127.7
(2 C), 127.8, 128.1, 128.4 (2 C), 130.6, 131.0, 137.7 ppm. HRMS
(ESI+): calcd. for [C20H30O3 + H]+ 319.2273; found 319.2274.
nBuLi (1.12 mL, 2.81 mmol, 2.5 m solution in THF, 1.4 equiv.) was
added to a slurry of butyltriphenylphosphonium bromide (1.04 g,
2.61 mmol, 1.3 equiv.) in THF (20 mL) at –80 °C. The mixture was (2S,3S,4R)-1-Benzyloxy-4-[(E)-1-propenyl]-(Z)-dec-6-ene-2,3-diol
stirred for 15 min and then a solution of the above aldehyde in
THF (10 mL) was added. After stirring the reaction mixture for 8 h
at room temperature it was quenched by adding saturated aqueous
NH4Cl (2 mL). The solution was extracted with EtOAc (3ϫ25 mL)
and the combined organic layers were washed with water and brine,
(9b): The title compound was prepared from 5b (0.1 mg,
0.28 mmol) by a similar procedure to that described for 9a, to give
9b (80 mg, 90%) as a colorless oil. [α]2D5 = 2.52 (c = 1.2, CHCl3).
IR (CHCl ): ν = 3436, 3008, 2956, 2929, 2870, 1665, 1653, 1605,
˜
3
1492, 1454, 1402, 1375, 1306, 1264, 1207, 1100, 1075, 1029, 971,
Eur. J. Org. Chem. 2012, 1047–1055
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1053

R. A. Fernandes, A. B. Ingle, D. A. Chaudhari
FULL PAPER
1
908, 870, 698 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ = 0.89
(t, J = 7.4 Hz, 3 H), 1.31–1.38 (m, 2 H), 1.65 (dd, J = 6.4, 1.6 Hz,
3 H), 1.94–2.08 (m, 3 H), 2.27–2.35 (m, 1 H), 2.41–2.47 (m, 1 H),
2.53 (br. s, 1 H, OH), 2.61 (d, J = 5.8 Hz, 1 H, OH), 3.40–3.44 (m,
1 H), 3.60–3.62 (m, 2 H), 3.86–3.83 (m, 1 H), 4.55 (d, J = 2.4 Hz,
2 H), 5.13–5.20 (ddq, J = 15.3, 9.2, 1.7 Hz, 1 H), 5.31–5.42 (m, 2
H), 5.51 (dq, J = 15.3, 9.2 Hz, 1 H), 7.28–7.38 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.7, 17.9, 22.7, 28.6, 29.4, 46.4,
69.2, 73.5, 73.6, 74.1, 127.5, 127.6, 127.7 (2 C), 127.8, 128.4 (2 C),
96%) as a colorless oil. [α]2D5 = 6.6 (c = 0.54, EtOH). IR, H and
13C NMR, and HRMS analytical data are the same as those for 1.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra for compounds 7a, 7b,
3a, 3b, 3c, 3d, 8a, 8b, 4a, 4b, 5a, 5b, 9a, 9b, 10 and 1; transition
states for orthoester Johnson–Claisen rearrangement of 3b and 3c
giving 8b.
130.6, 131.2, 137.6 ppm. HRMS (ESI+): calcd. for [C20H30O3
H]+ 319.2273; found 319.2271.
+
Acknowledgments
(R)-2-[(E)-1-Propenyl]-(Z)-oct-4-enoic Acid (10): NaIO4 (107 mg,
0.50 mmol, 2.0 equiv.) and saturated aq. NaHCO3 (0.5 mL) were
added to a solution of 9a (80 mg, 0.25 mmol) in CH2Cl2 (10 mL)
at room temperature and the mixture was stirred for 6 h. Na2SO4
(1 g) was added, the mixture was filtered through cotton, and the
residual cake was washed with CH2Cl2 (2ϫ20 mL). The filtrate
was concentrated and the crude aldehyde used directly in the next
reaction. The crude aldehyde was dissolved in tBuOH (2 mL) and
cyclohexene (0.13 mL, 1.25 mmol, 5 equiv.) and a solution of
NaH2PO4·H2O (241 mg, 1.75 mmol, 7.0 equiv.) and NaClO2
(226 mg, 2.5 mmol, 10.0 equiv.) in water (2 mL) were added drop-
wise. The mixture was stirred at room temperature for 12 h and
then quenched with aq. NH4Cl. The aqueous phase was extracted
with CH2Cl2 (3ϫ20 mL) and the combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by flash column chromatography using petroleum
ether/EtOAc (7:3) as eluent to afford 10 (30 mg, 66%) as a colorless
The authors are indebted to the Industrial Research and Consul-
tancy Centre (IRCC), IIT Bombay and the Department of Science
and Technology, New Delhi (grant number SR/S1/OC-25/2008) for
financial support. A. B. I. is grateful to the Council of Scientific
and Industrial Research (CSIR), New Delhi for a research fellow-
ship.
[1] N. Tateishi, T. Mori, Y. Kagamiishi, S. Satoh, N. Katsube, E.
Morikawa, T. Morimoto, T. Matsui, T. Asano, J. Cereb. Blood
Flow Metab. 2002, 22, 723.
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oil. [α]2D5 = 31.4 (c = 0.18, CHCl ). IR (CHCl ): ν = 3011, 2962,
˜
3
3
[5] a) T. Hasegawa, H. Yamamoto, Bull. Chem. Soc. Jpn. 2000, 73,
423; b) T. Hasegawa, Y. Kawanaka, E. Kasamatsu, Y. Iguchi,
Y. Yonekawa, M. Okamoto, C. Ohta, S. Hashimoto, S. Ohuch-
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Yamamoto, Synthesis 2003, 1181.
2934, 2874, 2578, 1709, 1449, 1438, 1418, 1377, 1284, 1246, 1043,
967 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ = 0.89 (t, J =
7.4 Hz, 3 H), 1.31–1.38 (m, 2 H), 1.69 (dd, J = 6.3, 1.4 Hz, 3 H),
2.0 (q, J = 7.3 Hz, 2 H), 2.28 (dt, J = 7.1, 14.9 Hz, 1 H), 2.49 (dt,
J = 7.1, 14.3 Hz, 1 H), 3.0 (q, J = 7.6 Hz, 1 H), 5.27–5.34 (m, 1
H), 5.41–5.50 (m, 2 H), 5.51 (dq, J = 15.2, 6.4 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.7, 17.9, 22.7, 29.3, 30.1 49.2,
125.5, 127.8, 128.8, 132.2, 180.4 ppm. HRMS (ESI+): calcd. for
[C11H18O2 + H]+ 183.1385; found 183.1392.
[6] B. Pelotier, T. Holmes, O. Piva, Tetrahedron: Asymmetry 2005,
16, 1513.
[7] T. Hasegawa, Y. Kawanaka, E. Kasamatsu, C. Ohta, K. Naka-
bayashi, M. Okamoto, M. Hamano, T. Takahashi, S. Ohuch-
ida, Y. Hamada, Org. Process Res. Dev. 2005, 9, 774.
[8] D. Goswami, A. Chattopadhyay, Lett. Org. Chem. 2006, 12,
922.
[9] J. M. Garcia, J. M. Odriozola, A. Lecumberri, J. Razkin, A.
Gonzalez, Tetrahedron 2008, 64, 10664.
(S)-2-[(E)-1-Propenyl]-(Z)-oct-4-enoic Acid (ent-10): The title com-
pound was prepared from 9b (76 mg, 0.24 mmol) by a similar pro-
cedure to that described for 10, to give ent-10 (28.7 mg, 66%) as a
colorless oil. [α]2D5 = –32.2 (c = 0.2, CHCl3). IR, 1H and 13C NMR,
and HRMS analytical data are the same as those for 10.
[10] A. Gualandi, E. Emer, M. G. Capdevila, P. G. Cozzi, Angew.
Chem. Int. Ed. 2011, 50, 7842.
[11] a) R. A. Fernandes, A. B. Ingle, Tetrahedron Lett. 2009, 50,
1122; b) R. A. Fernandes, A. Dhall, A. B. Ingle, Tetrahedron
Lett. 2009, 50, 5903; c) R. A. Fernandes, A. K. Chowdhury, J.
Org. Chem. 2009, 74, 8826; d) R. A. Fernandes, A. B. Ingle,
V. P. Chavan, Tetrahedron: Asymmetry 2009, 20, 2835; e) R. A.
Fernandes, A. K. Chowdhury, Eur. J. Org. Chem. 2011, 1106; f)
R. A. Fernandes, A. K. Chowdhury, Tetrahedron: Asymmetry
2011, 22, 1114.
[12] For Johnson–Claisen rearrangement, see: a) W. S. Johnson, L.
Werthemann, W. R. Bartlett, T. J. Brocksom, T.-T. Li, D. J.
Faulkner, M. R. Peterson, J. Am. Chem. Soc. 1970, 92, 741; b)
T. Hiyama, K. Kobayashi, M. Fujita, Tetrahedron Lett. 1984,
25, 4959; c) F. Ziegler, Chem. Rev. 1988, 88, 1423; d) C. Agami,
F. Couty, G. Evano, Tetrahedron Lett. 2000, 41, 8301; e) E.
Brenna, C. Fuganti, F. G. Gatti, M. Passoni, S. Serra, Tetrahe-
dron: Asymmetry 2003, 14, 2401; f) K.-K. Chan, N. Cohen,
J. P. De Noble, A. C. Specian Jr, G. Saucy, J. Org. Chem. 1976,
41, 3497.
(R)-2-Propyloctanoic Acid [(R)-(–)-arundic Acid (1)]: 10% Pd/C
(3 mg) was added to a solution of 10 (25.5 mg, 0.14 mmol) in
MeOH (2 mL) at room temperature and the mixture was stirred
under H2 (4 atm). After stirring for 2 h, the reaction mixture was
filtered through a pad of Celite and washed with MeOH. The fil-
trate was concentrated and the residue purified by silica gel flash
column chromatography using petroleum ether/EtOAc (7:1) as elu-
ent to give 1 (25 mg, 96%) as a colorless oil. [α]2D5 = –6.8 (c = 0.82,
EtOH). IR (CHCl ): ν = 3016, 2958, 2930, 2859, 2642, 1706, 1466,
˜
3
1416, 1380, 1284, 1251, 1235, 1111, 1026, 948 cm–1. 1H NMR
(400 MHz, CDCl3/TMS): δ = 0.88 (t, J = 7.4 Hz, 3 H), 0.91 (t, J
= 7.4 Hz, 3 H), 1.21–1.40 (m, 10 H), 1.40–1.46 (m, 2 H), 157–1.66
(m, 2 H), 2.32–2.39 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 14.0, 14.1, 20.6, 22.6, 27.3, 29.2, 31.7, 32.2, 34.3, 45.3, 182.8 ppm.
HRMS (ESI+): calcd. for [C11H22O2 + H]+ 187.1698; found
187.1702.
[13] R. A. Fernandes, Eur. J. Org. Chem. 2007, 5064.
[14] For CBS reduction, see: a) E. J. Corey, E. C. J. Helal, Angew.
Chem. 1998, 110, 2092; Angew. Chem. Int. Ed. 1998, 37, 1986;
b) J. Garcia, M. López, J. Romeu, Tetrahedron: Asymmetry
1999, 10, 2617.
(S)-2-Propyloctanoic Acid [(S)-(+)-Arundic Acid (ent-1)]: The title
compound was prepared from ent-10 (15 mg, 0.082 mmol) by a
similar procedure to that described for 1, to give ent-1 (14.7 mg,
1054
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1047–1055

Orthoester Johnson–Claisen Rearrangement
[15] The diastereomeric ratio was determined by chiral HPLC (col-
umn: Chiralcel OD-H, Column No. ODHOCE-NB035, Daicel
Chemical Ind. Ltd.; eluent: n-hexane/iPrOH, 95:5; flow rate:
1 mL/min; tR = 12.1 min (3a), tR = 13.6 min (3b).
[16] The signs of the optical rotations reported in ref.[9] is the re-
verse for each enantiomer.
Received: September 28, 2011
Published Online: December 14, 2011
Eur. J. Org. Chem. 2012, 1047–1055
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1055