Chemoenzymatic approach to the total synthesis of (+)-bourgeanic acid

Article abstract of DOI:10.1055/s-0031-1289699

A highly stereoselective total synthesis of (+)-bourgeanic acid has been accomplished by an enzymatic desymmetrization approach to create two methyl chiral centers. Other key steps involved in this approach are a Wittig reaction, a Gilman reaction, and TE

Full text of DOI:10.1055/s-0031-1289699

788
PAPER
Chemoenzymatic Approach to the Total Synthesis of (+)-Bourgeanic Acid
C
hemoenz
h
ymatic
A
pp
i
lTotal
lSynthe
u
sis of (+)-Bourgean
S
ic
A
cid . Yadav,*a Tenneti Srinivasa Rao,a Nagendra Nath Yadav,a Kovvuru V. Raghavendra Rao,a Basi V. Subba
Reddy,a Ahmad Al Khazim Al Ghamdib
a
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
b
Received 11 October 2011; revised 17 December 2011
vors the formation of eight-membered structure
Abstract: A highly stereoselective total synthesis of (+)-bourgean-
ic acid has been accomplished by an enzymatic desymmetrization
approach to create two methyl chiral centers. Other key steps in-
volved in this approach are a Wittig reaction, a Gilman reaction, and
TEMPO/iodobenzene diacetate mediated selective oxidation of the
1,3-diol, Yamaguchi lactonization and lithium hydroxide mediated
partial hydrolysis (saponification) of the eight-membered cyclic di-
lactone
(Figure 1).7
The first total synthesis of (+)-bourgeanic acid (1) was re-
ported by White et al. using methodology developed by
Evans and Sonnet.7 Subsequently, Breit et al. reported the
total synthesis of 1 using o-DPPB [o-(diphenylphosphi-
no)benzoyl]-directed copper-mediated allylic substitution
as the key step.8 Inspired by its fascinating structural fea-
tures, recently we reported the total synthesis of (+)-
bourgeanic acid (1).9 In continuation of our research on
total synthesis of polydeoxypropionate natural products,10
we herein report a highly stereoselective total synthesis of
(+)-bourgeanic acid (1) via an enzymatic desymmetriza-
tion approach.
Key words: enzymatic desymmetrization, aliphatic depside,
(+)-bourgeanic acid, bourgeanic lactone, (–)-hemibourgeanic acid,
Wittig reaction, Gilman reaction, Yamaguchi lactonization
Natural products derived from polydeoxypropionates are
known to exhibit promising biological activity.1–3 (+)-
Bourgeanic acid (1), a structurally unique aliphatic dep-
side, was isolated by the Bodo group in 1973 from the spe-
cies of lichen Ramalina.4 The structure of 1 was
established by the same group, as an esterification product
of two molecules of (–)-hemibourgeanic acid (3), i.e.
(2S,3S,4R,6R)-2,4,6-trimethyl-3-hydroxyoctanoic acid,
and was confirmed by saponification of 1. The absolute
configuration of 1 was proposed by X-ray analysis of its
p-bromophenacyl ester.5,6 The formation of an eight-
membered dilactone 2 takes place rapidly from compound
1 under mild dehydrating conditions, which was noted by
Bodo et al. Based on conformational analysis, the dilac-
tone exists as eight-membered ring that adopts a crown
shaped conformation with C2 axis of symmetry and all the
substituents positioned in equatorial orientation, which fa-
The retrosynthetic route for the (+)-bourgeanic acid (1) is
depicted in Scheme 1. (+)-Bourgeanic acid (1) was pro-
posed to be synthesized from seco acid 3, which could
easily be prepared from diol 13. The diol 13 was assumed
to be prepared from compound 11 by Sharpless asymmet-
ric epoxidation followed by epoxide ring opening. Com-
pound 11 could in turn be obtained from known
compound 4 by a sequence of reactions such as protection,
deprotection, and Wittig olefination and diisobutylalumi-
num hydride reduction.
OH
1
OH
O
OH OH
3
13
O
OH
OAc
OH
OH
O
O
4
11
OH
Scheme 1 Retrosynthetic analysis of (+)-bourgeanic acid (1)
O
1
O
Our synthesis began with the known precursor 4 which
was synthesized in four steps starting from cis-4,6-di-
methylcyclohexane-1,3-dione.11 Accordingly, cis-diketone
was converted into the diacid using periodate oxidation.12
Reduction of the diacid with lithium aluminum hydride in
tetrahydrofuran at room temperature gave meso-2,4-di-
methylpentane-1,5-diol in 98% yield. Desymmetrization
of the meso-diol was achieved using a lipase (derived
from porcine pancrease; PPL) and vinyl acetate in tetrahy-
drofuran at room temperature to afford the mono-acetate
O
OH
O
OH
O
2
3
Figure 1 Representative structures of (+)-bourgeanic acid (1),
bourgeanic lactone (2), and (–)-hemibourgeanic acid (3)
SYNTHESIS 2012, 44, 788–792
Advanced online publication: 10.02.2012
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x
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x
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0
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DOI: 10.1055/s-0031-1289699; Art ID: Z96911SS
© Georg Thieme Verlag Stuttgart · New York

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Chemoenzymatic Approach to Total Synthesis of (+)-Bourgeanic Acid
789
4 in 47% yield with >95% ee along with the meso-diace-
tate.13 It is noteworthy to mention that the meso-diacetate
was again converted back into the meso-diol by treatment
with sodium methoxide in methanol. The mono-acetate 4
was then protected as its silyl ether 5 using tert-butyl-
diphenylsilyl chloride and imidazole in dichloromethane.
The mono-acetate 5 was treated with sodium methoxide in
methanol to furnish the alcohol 6, which was then protect-
ed as the tosylate 7 using tosyl chloride, triethylamine,
and a catalytic amount of 4-(dimethylamino)pyridine. The
tosylate 7 was then subjected to a Gilman reaction using
lithium dimethylcuprate (6 equiv) to give the methyl de-
rivative 8 in 92% yield.14 Further desilylation of com-
a
b
OH
OH
1
OH
O
OH
13
3
Scheme 3 Reagents and conditions: (a) (i) TEMPO, PhI(OAc)2,
CH2Cl2, 5 h, (ii) NaClO2, NaH2PO4·2 H2O, 2-methylbut-2-ene, t-
BuOH–H2O (3:1), 75% over 2 steps; (b) (i) 2,4,6-Cl3C6H2COCl,
Et3N, DMAP, 85%, (ii) LiOH, THF–H2O (1:1), 0.5 h, 54%.
In conclusion, we have demonstrated the total synthesis of
(+)-bourgeanic acid (1) in a highly stereoselective man-
ner. The synthesis involves very simple and straightfor-
ward reactions such as enzymatic desymmetrization of a
meso-diol, Sharpless asymmetric epoxidation, Gilman’s
dimethylcuprate addition to an epoxide, 2,2,6,6-tetra-
methylpiperidinoxyl/iodobenzene diacetate oxidation of
the primary alcohol, Yamaguchi lactonization, and lithi-
um hydroxide mediated partial hydrolysis of the lactone
as key steps.
pound
8
using tetrabutylammonium fluoride in
tetrahydrofuran gave the alcohol 9 in 95% yield. The re-
sulting alcohol 9 was then subjected to Swern oxidation
followed by Wittig olefination using ethyl (triphenylphos-
phoranylidene)acetate to afford the a,b-unsaturated ester
10. Reduction of compound 10 using diisobutylaluminum
hydride gave an allylic alcohol 11 in 92% yield, which
was then subjected to Sharpless asymmetric epoxidation
using titanium(IV) isopropoxide, (+)-diethyl tartrate, and
tert-butyl hydroperoxide to afford epoxide 12 in 85%
yield.15 Ring opening of the epoxide 12 with dilithium cy-
ano(dimethyl)cuprate gave 1,3-diol 13 in 84% yield
(Scheme 2).16
All solvents were purified by standard techniques. IR spectra were
recorded on Perkin-Elmer FT-IR 240-c spectrophotometer using
KBr optics. 1H and 13C NMR spectra were recorded on Bruker-300
spectrometer (300 MHz) and Varian Unity 500 spectrometer (500
MHz) in CDCl3 using TMS as internal standard. Mass spectra were
recorded on Finnigan MAT 1020 mass spectrometer operating at 70
eV. Column chromatography was performed using E. Merck 60–
120, mesh silica gel. Melting points were recorded on Buchi R-535
apparatus and are uncorrected. Optical rotations were measured
with JASCO DIP-370 polarimeter at 25 °C.
Selective oxidation of 1,3-diol 13 using 2,2,6,6-tetrameth-
ylpiperidinoxyl (TEMPO) and iodobenzene diacetate af-
forded (2S,3S,4R,6R)-3-hydroxy-2,4,6-trimethyloctanal,
which was further oxidized under Pinnick’s conditions
(NaClO2, NaH2PO4·2 H2O)17 to give (–)-hemibourgeanic
acid (3) in 75% yield.18 The Yamaguchi macrolactoniza-
tion of (–)-hemibourgeanic acid (3) using 2,4,6-trichloro-
benzoyl chloride, triethylamine, and 4-(dimethyl-
amino)pyridine under dilute conditions afforded
bourgeanic lactone (2) in 85% yield.19 Partial hydrolysis
of 2 using 1.0 equivalents of lithium hydroxide in tetrahy-
drofuran–water (1:1) over 30 minutes gave the target nat-
ural product 1 in 54% yield as a white solid (Scheme 3).
The analytical and spectral data of the target molecule 1
were in good agreement with the literature.7–9
(2S,4R)-5-Hydroxy-2,4-dimethylpentyl Acetate (4)
To a stirred soln of meso-2,4-dimethylpentane-1,5-diol (4.0 g, 30.2
mmol) in THF (130 mL) and H2O (170 mL) were added PPL (11.6
gm) and vinyl acetate at r.t. The resulting mixture was stirred for 6
h at 25 °C. After complete conversion, the product was extracted
with EtOAc. The organic extracts were dried (Na2SO4) and concen-
trated in vacuo and then purified by column chromatography
(EtOAc–n-hexane, 1:5) to afford the monoacetate 4 (2.47 g, 47%)
as a colorless liquid.
[a]D25 +9.8 (c 0.6, CHCl3).
IR (neat): 3431, 2957, 2924, 1738, 1462, 1391, 1371, 1243, 1030
cm–1.
a
c
ref. 10,11,12
b
d
O
OAc
OH
OAc
OTBDPS
OH
OTBDPS
OTs
OTBDPS
4
5
6
7
e
g
f
h
OEt
OH
OTBDPS
OH
O
8
9
10
11
i
OH
OH
O
OH
12
13
Scheme 2 Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 °C to r.t., 2 h, 98%; (b) NaOMe, MeOH, r.t., 1 h, 97%; (c) TsCl,
Et3N, DMAP, CH2Cl2, 0 °C to r.t., 4 h, 98%; (d) Me2LiCu, –30 °C to 0 °C, 92%; (e) TBAF, THF, 3 h, 95%; (f) (1) (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C, 3 h; (2) Ph3PCHCO2Et, benzene, 80 °C, 2 h, 80% over 2 steps; (g) DIBAL-H, CH2Cl2, 0 °C to r.t., 1 h, 92%; (h) L-(+)-DET,
Ti(Oi-Pr)4, TBHP, CH2Cl2, –20 °C, 6 h, 85%; (i) Me2Cu(CN)Li2, anhyd Et2O, –78 °C to r.t., 3 h, 84%.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 788–792

790
J. S. Yadav et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 3.97 (dd, J = 10.5, 5.2 Hz, 1 H),
3.85 (dd, J = 10.5, 6.7 Hz, 1 H), 3.49 (dd, J = 10.5, 6.0 Hz, 1 H),
3.42 (dd, J = 10.5, 6.0 Hz, 1 H), 2.05 (s, 3 H), 1.82–1.96 (m, 1 H),
1.64–1.78 (m, 1 H), 1.43 (br, 1 H), 1.39–1.49 (m, 1 H), 1.15–1.30
(m, 1 H), 0.96 (d, J = 6.7 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H).
CH2Cl2 (3 × 25 mL). The combined organic layers were washed
with sat. NaCl soln, dried (Na2SO4), and concentrated in vacuo. The
crude product was then purified by column chromatography
(EtOAc–n-hexane, 1:9) to give the tosylate 7 (6.42 g, 98%) as a col-
orless oil.
13C NMR (CDCl3, 75 MHz): d = 171.3, 69.1, 67.9, 37.2, 32.9, 29.9,
[a]D25 +3.8 (c 1.7, CHCl3).
20.9, 17.8, 17.2.
IR (neat): 3063, 2958, 2930, 2859, 2360, 1463, 1361, 1179, 1104,
965, 701 cm–1.
(2S,4R)-5-(tert-Butyldiphenylsiloxy)-2,4-dimethylpentyl
Acetate (5)
1H NMR (300 MHz, CDCl3): d = 7.79–7.74 (m, 4 H), 7.61 (m, 2 H),
7.42–7.34 (m, 6 H), 7.29 (m, 2 H), 3.85–3.80 (m, 1 H), 3.71–3.66
(m, 1 H), 3.44–3.33 (m, 2 H), 2.43 (s, 3 H), 1.85–1.77 (m, 1 H),
1.66–1.59 (m, 1 H), 1.44–1.38 (m, 1 H), 1.04 (s, 9 H), 0.92 (m, 1 H),
0.89 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.5, 135.5, 134.7, 133.7, 129.7,
129.5, 127.8, 127.5, 75.1, 68.3, 36.7, 32.7, 30.3, 26.8, 21.5, 19.2,
17.5, 17.1.
To a stirred soln of alcohol 4 (2.35 g, 13.5 mmol), imidazole (1.47
g, 21.6 mmol), and DMAP (cat.) in CH2Cl2 (30 mL) was added
TBDPSCl (4.45 g, 16.2 mmol) slowly at 0 °C. The resulting mixture
was allowed to stir at r.t. for a further 2 h. Upon completion, the
mixture was quenched with sat. NH4Cl soln and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo; the crude product was purified
by column chromatography (EtOAc–n-hexane, 1:9) to give the silyl
ether 5 (5.45 g, 98%) as a colorless oil.
MS (ESI): m/z = 547 [M + Na].
HRMS (ESI): m/z [M + Na] calcd for C30H40O4NaSiS: 547.2314;
found: 547.2325.
[a]D25 +7.9 (c 1.0, CHCl3).
IR (neat): 3061, 2955, 2860, 1737, 1465, 1389, 1376, 1240, 1112
cm–1.
tert-Butyl[(2R,4R)-2,4-dimethylhexyloxy]diphenylsilane (8)
To a solution of Me2CuLi, prepared from CuI (13.8 g, 72.6 mmol)
and MeLi (96.7 mL, 145.1 mmol, 1.5 M in Et2O) in Et2O (60 mL)
at –25 °C was added tosylate 7 (6.35 g, 12.1 mmol) in Et2O and the
reaction mixture was slowly warmed to 0 °C. After 3 h stirring at
r.t., the mixture was quenched with sat. aq NH4Cl and extracted
with Et2O (2 × 100 mL). The combined organic extract was washed
with brine and dried over anhyd Na2SO4. Solvent removal then gave
the crude product which was purified by column chromatography
(EtOAc–hexane, 1:19) to give compound 8 (4.09 g, 92%) as a col-
orless oil.
1H NMR (300 MHz, CDCl3): d = 0.88 (d, J = 6.8 Hz, 3 H), 0.94 (m,
1 H), 0.95 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.46–1.55 (m, 1 H),
1.68–1.86 (m, 2 H), 2.0 (s, 3 H), 3.44 (ddd, J = 17.4, 9.8, 6.0 Hz, 2
H), 3.74–3.78 (m, 1 H), 3.87–3.92 (m, 1 H), 7.32–7.40 (m, 6 H),
7.65 (dd, J = 7.5, 1.5 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 17.6, 19.3, 20.9, 26.8, 29.9, 33.0,
37.3, 68.5, 69.3, 127.5, 129.5, 133.9, 135.6, 171.3.
MS (ESI): m/z = 435 [M + Na].
HRMS (ESI): m/z [M + Na] calcd for C25H36NaO3Si: 435.2331;
found: 435.2340.
[a]D25 +4.9 (c 1.3, CHCl3).
IR (neat): 3069, 2959, 2858, 1465, 1385, 1108, 703 cm–1.
(2S,4R)-5-(tert-Butyldiphenylsiloxy)-2,4-dimethylpentan-1-ol
(6)
1H NMR (500 MHz, CDCl3): d = 7.7 (m, 4 H), 7.45–7.38 (m, 6 H),
3.56–3.42 (m, 2 H), 1.76 (m, 1 H), 1.42–1.29 (m, 3 H), 1.08 (s, 9 H),
0.96 (d, J = 7 Hz, 3 H), 0.93–0.89 (m, 2 H), 0.76 (d, J = 7 Hz, 3 H),
0.74 (t, J = 6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 135.6, 133.9, 129.5, 127.6, 68.7,
40.3, 33.1, 31.8, 29.1, 26.8, 19.7, 19.3, 17.7, 11.1.
To a stirred soln of acetate 5 (5.41 g, 13.13 mmol) in MeOH (20
mL) was added NaOMe (1.4 g, 26.26 mmol). The resulting mixture
was allowed to stir for 1.5 h at r.t. It was then quenched with sat.
NH4Cl soln and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were washed with sat. NaCl soln and then dried (an-
hyd Na2SO4). Removal of the solvent followed by purification by
column chromatography (silica gel, EtOAc–n-hexane, 3:7) gave the
alcohol 6 (4.71 g, 97%) as a colorless oil.
MS (ESI): m/z = 391 [M + Na]+.
(2R,4R)-2,4-Dimethylhexan-1-ol (9)
[a]D25 +1.1 (c 1.3, CHCl3).
To a stirred soln of compound 8 (3.91 g, 10.62 mmol) in THF (20
mL) was added 1.0 M TBAF in THF (17 mL, 17 mmol) dropwise.
The resulting mixture was allowed to stir at r.t. for 6 h. Removal of
the solvent followed by purification by column chromatography
(silica gel, EtOAc–hexane, 2:8) gave the alcohol 9 (1.31 g, 95%) as
a colorless oil.
[a]D25 +4.1 (c 2.3, CHCl3).
IR (neat): 3380, 2959, 2925, 1686, 1461, 1031 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.51–3.31 (m, 2 H), 1.74–1–64 (m,
1 H), 1.46–1.28 (m, 3 H), 1.14–1.05 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3
H), 0.88 (t, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 68.4, 40.6, 33.1, 31.5, 29.0, 19.8,
17.3, 11.1.
IR (neat): 3353, 3073, 3053, 2954, 2849, 1461, 1421, 1077, 813
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87 (d, J = 6.8 Hz, 3 H), 0.91 (m,
1 H), 0.94 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.42–1.50 (m, 1 H),
1.55–1.63 (m, 1 H), 1.68–1.76 (m, 1 H), 3.28–3.34 (m, 1 H), 3.39–
3.51 (m, 3 H), 7.34–7.41 (m, 6 H), 7.60–7.64 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 135.6, 133.9, 129.5, 127.6, 68.7,
68.3, 37.1, 33.1, 26.9, 26.5, 19.3, 17.9, 17.4.
MS (ESI): m/z = 393 [M + Na].
HRMS (ESI): m/z [M + Na] calcd for C23H34NaO2Si: 393.2225;
found: 393.2223.
(2S,4R)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethylpentyl
4-Methylbenzenesulfonate (7)
To a stirred soln of alcohol 6 (4.62 g, 12.48 mmol) in CH2Cl2 at 0
°C were added Et3N (2.25 mL, 16.23 mmol), DMAP (cat.), and
TsCl (2.61 g, 13.7 mmol) successively. The resulting mixture was
stirred at r.t. for 4 h and then quenched with H2O and extracted with
Ethyl (4R,6R,E)-4,6-Dimethyloct-2-enoate (10)
To a stirred soln of oxalyl chloride (1.85 mL, 19.38 mmol) in anhyd
CH2Cl2 (20 mL) at –78 °C was added DMSO (2.06 mL, 29.07
mmol) slowly dropwise under a N2 atmosphere. After 15 min stir-
ring, a soln of alcohol 9 (1.26 g, 9.69 mmol) in anhyd CH2Cl2 (20
mL) was added. After 45 min of stirring at –78 °C, Et3N (6.7 mL,
Synthesis 2012, 44, 788–792
© Thieme Stuttgart · New York

PAPER
Chemoenzymatic Approach to Total Synthesis of (+)-Bourgeanic Acid
791
48.46 mmol) was added and the mixture was stirred for 0.5 h at –78
°C and then 0.5 h at 0 °C. The mixture was then quenched with sat.
NH4Cl soln (300 mL) and extracted with CH2Cl2 (2 × 800 mL). The
combined organic layers were washed with H2O (500 mL), fol-
lowed by brine (300 mL) soln, dried (Na2SO4), and concentrated in
vacuo. To a stirred soln of the above crude aldehyde in benzene was
added stabilized ylide, Ph3PCHCO2Et (4.52 g, 8.12 mmol) and the
mixture was allowed to reflux for 2 h. It was then concentrated in
vacuo. Purification of the crude ester by column chromatography
(silica gel, EtOAc–hexane, 1:9) gave the pure unsaturated ester 10
(1.53 g, 80% over 2 steps) as a colorless liquid.
[a]D25 –40.2 (c 0.4, CHCl3).
IR (neat): 2962, 2921, 1722, 1651, 1460, 1181 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83 (d, J = 6.4 Hz, 3 H), 0.85 (t,
J = 7.3 Hz, 3 H), 0.97 (d, J = 6.7 Hz, 3 H), 1.05–1.15 (m, 4 H),
1.22–1.40 (m, 3 H), 1.57 (br s, 1 H), 2.24 (m, 1 H), 4.10 (dd, J = 5.8,
0.6 Hz, 2 H), 5.51 (ddt, J = 15.4, 7.6, 1.0 Hz, 1 H), 5.60 (dtd,
J = 15.4, 5.8, 0.6 Hz, 1 H).
1.50 (m, 4 H), 1.89 (br s, 1 H), 2.64 (dd, J = 7.4, 2.3 Hz, 1 H), 2.92
(dt, J = 4.5, 2.4 Hz, 1 H), 3.53–3.62 (m, 1 H), 3.83–3.91 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 11.1, 17.7, 19.4, 29.4, 31.6, 32.8,
40.9, 58.7, 60.7, 61.8.
HRMS (ESI): m/z [M + Na] calcd for C10H20NaO2: 195.1360;
found: 195.1368.
(2R,3S,4R,6R)-2,4,6-Trimethyloctane-1,3-diol (13)
A soln Me2Cu(CN)Li2 was prepared by addition of 1.5 M MeLi in
Et2O (36.7 mL, 55.1 mmol) to a suspension of anhyd CuCN (2.46
g, 27.5 mmol) in anhyd Et2O (10 mL) at –78 °C under argon. The
mixture was stirred at –30 °C until it became homogeneous. To this
soln was added a soln of the epoxy alcohol 12 (0.79 g, 4.59 mmol)
in Et2O (5 mL) at –78 °C. The resulting mixture was allowed to
warm slowly to r.t. over 3 h. Upon completion, the mixture was
treated with sat. NH4Cl (28 mL), aq 25% NH3 (7 mL), H2O (50 mL),
and Et2O (90 mL). The resulting mixture was then allowed to stir for
30 min. The layers were separated and the aqueous phase was satu-
rated with NaCl and extracted with Et2O (4 × 50 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated in
vacuo. The residue was dissolved in CH2Cl2 (20 mL) and treated
with NaIO4 (0.5 g, 2.3 mmol) at r.t. for 1 h. The mixture was filtered
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (EtOAc–n-hexane, 3:7) to furnish the
diol 13 (0.72 g, 84%) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 11.3, 19.1, 21.5, 30.0, 31.9, 34.1,
44.2, 64.0, 127.2, 139.3.
HRMS (ESI): m/z [M + Na] calcd for C12H22NaO2: 221.1517;
found: 221.1525.
(4R,6R,E)-4,6-Dimethyloct-2-en-1-ol (11)
[a]D25 –9.5 (c 0.6, CHCl3).
To a stirred soln of ester 10 (1.47 g, 7.42 mmol) in anhyd CH2Cl2
(20 mL) at 0 °C was added 1.0 M DIBAL-H in toluene (8.9 mL, 8.9
mmol) dropwise. The resulting mixture was stirred for 1 h at r.t. and
then quenched with MeOH and sat. sodium potassium tartarate soln
(15 mL) at 0 °C. The organic layer was washed with brine, dried
(anhyd Na2SO4), and purified by column chromatography (EtOAc–
hexane, 3:7) to give the allyl alcohol 11 (1.06 g, 92%) as oil.
[a]D25 –25.3 (c 0.5, CHCl3).
IR (neat): 3357, 2960, 2917, 2872, 1459 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83 (d, J = 6.4 Hz, 3 H), 0.85 (t,
J = 7.3 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.04–1.16 (m, 2 H),
1.22–1.38 (m, 3 H), 1.59 (br s, 1 H), 2.24 (m, 1 H), 4.08 (dd, J = 5.1,
0.6 Hz, 2 H), 5.47–5.64 (m, 2 H).
IR (neat): 3372, 2960, 2924, 1460, 1379, 1278, 1076, 1027, 979
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.81 (d, J = 7.5 Hz, 3 H), 0.86 (d,
J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.88 (t, J = 7.5 Hz, 3 H),
1.0–1.15 (m, 2 H), 1.30–1.47 (m, 3 H), 1.71–1.81 (m, 1 H), 1.83–
1.93 (m, 2 H), 3.46 (dd, J = 9.1, 2.5 Hz, 1 H), 3.66 (dd, J = 10.6, 7.5
Hz, 1 H), 3.72 (dd, J = 10.6, 3.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 11.2, 12.7, 13.5, 19.5, 29.4, 31.4,
32.1, 37.5, 40.9, 68.9, 79.7.
MS (EI): m/z = 188 [M].
HRMS: m/z [M] calcd for C11H24O2: 188.1776; found: 188.1781.
13C NMR (75 MHz, CDCl3): d = 11.2, 18.9, 21.3, 29.8, 31.8, 33.9,
(2S,3S,4R,6R)-3-Hydroxy-2,4,6-trimethyloctanoic Acid (3)
PhI(OAc)2 (0.77 g, 2.39 mmol) and TEMPO (54 mg, 0.32 mmol)
were added sequentially to a stirred soln of the diol 12 (0.30 g, 1.59
mmol) in CH2Cl2 (6 mL) at r.t. After completion, the mixture was
treated with sat. Na2S2O3. The separated organic phase was washed
with sat. NaHCO3 soln and brine soln, followed by dried (anhyd
Na2SO4), and concentrated under reduced pressure. The crude alde-
hyde was used in next step without purification. The aldehyde was
dissolved in t-BuOH–H2O (3:1). To the mixture were added
NaH2PO4·2 H2O (0.44 g, 3.22 mmol) and 2-methylbut-2-ene (0.11
g, 1.61 mmol) followed by NaClO2 (0.29 g, 3.22 mmol). The result-
ing mixture was stirred at 0 °C. After completion, the solvent was
evaporated under reduced pressure and the residue was diluted with
EtOAc. The organic layer was washed once with brine and dried
(Na2SO4) and concentrated to afford the crude acid which was puri-
fied by column chromatography (silica gel, EtOAc–n-hexane, 1:1)
to give the pure b-hydroxy acid 3 (0.24 g, 75%).
44.1, 63.8, 127.1, 139.1.
LC-MS: m/z = 174 [M + NH4].
{(2S,3S)-3-[(2R,4R)-4-Methylhexan-2-yl]oxiran-2-yl}methanol
(12)
To a stirred suspension of powdered 4Å molecular sieves in CH2Cl2
(15 mL) at –20 °C were added L-(+)-DET (0.15 mL, 0.86 mmol)
and Ti(Oi-Pr)4 (0.2 mL, 0.69 mmol). After 30 min, a soln of allylic
alcohol 11 (0.9 g, 5.77 mmol) in CH2Cl2 (10 mL) was added to the
above suspension, and then 4–5 M TBHP in toluene (2.5 mL, 11.5
mmol) was added. The resulting mixture was stirred at –20 °C for 6
h and then quenched with H2O (20 mL). The above mixture was
treated with 3 M NaOH and then saturated with solid NaCl and the
resulting mixture was stirred vigorously for 30 min. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The crude product was purified
by column chromatography (EtOAc–n-hexane, 3:7) to afford the
epoxy alcohol 12 (0.86 g, 85%) as a colorless liquid.
[a]D25 –3.5 (c 1.0, CHCl3).
IR (neat): 3439, 2961, 2923, 1712, 1459, 1380, 1262, 1212, 982,
769 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.64 (dd, J = 8.4, 3.0 Hz, 1 H),
2.7–2.60 (m, 1 H), 1.78–1.69 (m, 1 H), 1.47–1.23 (m, 5 H), 1.18 (d,
J = 7.1 Hz, 3 H), 1.13–1.01 (m, 1 H), 0.87 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 181.2, 75.1, 43.2, 40.8, 31.6, 31.3,
29.2, 19.4, 14.1, 12.9, 11.1.
[a]D25 –34.8 (c 2.0, CHCl3).
IR (neat): 3424, 2962, 2922, 2874, 1461 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, J = 7.4 Hz, 3 H), 0.88 (d,
J = 6.4 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 1.05–1.16 (m, 2 H), 1.26
© Thieme Stuttgart · New York
Synthesis 2012, 44, 788–792

792
J. S. Yadav et al.
PAPER
MS (ESI): m/z = 201 [M – H].
Raeppel, F. J. Am. Chem. Soc. 2003, 125, 13784.
(e) Nagamitsu, T.; Takano, D.; Marumoto, K.; Fukuda, T.;
Furuya, K.; Otoguro, K.; Takeda, K.; Kuwajima, I.;
Harigaya, Y.; Omura, S. J. Org. Chem. 2007, 72, 2744.
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Kuwajima, I.; Harigaya, Y.; Omura, S. Org. Lett. 2004, 6,
1865. (g) Vong, B. G.; Kim, S. H.; Abraham, S.;
Theodorakis, E. A. Angew. Chem. Int. Ed. 2004, 43, 3947.
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P.; Cribb, B. W.; Allsopp, P. G.; Moore, C. J.; Kitching, W.
Org. Lett. 2003, 5, 5083. (b) Des Mazery, R.; Pullez, M.;
Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B.
L. J. Am. Chem. Soc. 2005, 127, 9966.
HRMS: m/z [M – H] calcd for C11H21O3: 201.1490; found:
201.1486.
(+)-Bourgeanic Acid (1)
To a stirred solution of bourgeanic lactone 2 (60 mg, 0.163 mmol)
in THF–H2O (1:1; 4 mL) was added LiOH (3.8 mg, 0.163 mmol) at
r.t. After 30 min, the formation of the required acid was observed by
TLC. The mixture was then acidified to pH 2 with 2 M HCl and then
THF was removed under reduced pressure. The combined organic
phase was dried over Na2SO4, and the solvent was removed under
vacuum. The resulting aqueous layer was extracted with EtOAc
(3 × 10 mL), concentrated under vacuum, and the residue was puri-
fied by silica gel chromatography (EtOAc–hexane, 1:1) to afford 1
(33 mg, 54%) as a white solid; mp 123–124 °C.
(4) Bodo, B.; Hebrard, B.; Molho, L.; Molho, D. Tetrahedron
Lett. 1973, 14, 1631.
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[a]D25 +7.0 (c 1.0, CHCl3).
IR (KBr): 3446, 2923, 2854, 1728, 1639, 1460 cm–1.
349, 23.
(6) Bodo, B.; Trowitzch-Kienast, W.; Schomburg, D.
Tetrahedron Lett. 1986, 27, 847.
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Eur. J. Org. Chem. 2011, 58.
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B. V. S. Synthesis 2010, 4300. (b) Yadav, J. S.; Yadav, N.
N.; Rao, T. S.; Reddy, B. V. S.; Ghamdi, A. A. K. A. Eur. J.
Org. Chem. 2011, 4603.
1H NMR (300 MHz, CDCl3): d = 5.16 (dd, J = 9.0, 3.0 Hz, 1 H),
3.70 (dd, J = 9.8, 2.2 Hz, 1 H), 2.86–2.74 (m, 1 H), 2.67–2.54 (m, 1
H), 1.96–1.85 (m, 1 H), 1.79–1.59 (m, 2 H), 1.54–1.38 (m, 2 H),
1.34–1.23 (m, 3 H), 1.18 (d, J = 6.7 Hz, 3 H), 1.10 (d, J = 7.5 Hz, 3
H), 1.14–1.01 (m, 3 H), 0.94 (d, J = 7.5 Hz, 3 H), 0.96–0.90 (m, 1
H), 0.89 (t, J = 6.7 Hz, 3 H), 0.87 (d, J = 6.0 Hz, 3 H), 0.85 (d, J =
6.0 Hz, 3 H), 0.84 (t, J = 7.5 Hz, 3 H), 0.82 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 177.1, 175.7, 76.5, 74.8, 44.0, 41.9,
41.0, 40.6, 31.2, 30.9, 30.9, 29.4, 29.2, 19.4, 19.3, 14.4, 13.8, 12.7,
11.2, 11.1.
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2489.
MS (ESI): m/z = 385 [M – H].
HRMS: m/z [M – H] calcd for C22H42O5: 385.2953; found:
385.2966.
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Acknowledgment
T.S.R., N.N.Y., and K.V.R. thank the CSIR, New Delhi for the fi-
nancial support in the form of fellowships. Partial support was also
supplied by King Saud University for Global Research Network for
Organic Synthesis (GRNOS).
(14) (a) Hiyoshizo, K.; Isao, K.; Masamitsu, O. J. Org. Chem.
1990, 55, 4417. (b) Ghosh, A. K.; Bilcer, G.; Schiltz, G.
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5974.
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Synthesis 2012, 44, 788–792
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