An asymmetric synthesis of (-)-prelactone B

Article abstract of DOI:10.1055/s-2005-916009

An efficient synthesis of (-)-prelactone B has been developed using 1,2-cyclohexylidene glyceraldehyde as the chiral template. The key features of the synthesis were stereoselective crotylation of 1,2-cyclohexylidene glyceraldehyde and enantioselective re

Full text of DOI:10.1055/s-2005-916009

PAPER
2777
An Asymmetric Synthesis of (–)-Prelactone B
An
A
symmetric Sy
v
nthesis of (–
i
)-Prela
n
ctone
B
ash A. Salaskar,a Narayan V. Mayekar,b Anubha Sharma,a Sandip K. Nayak,a Angshuman Chattopadhyaya,a
Subrata Chattopadhyay*a
a
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai – 400 085, India
Heavy Water Division, Bhabha Atomic Research Centre, Mumbai – 400 085, India
b
Fax +91(22)5505151; E-mail: schatt@apsara.barc.ernet.in
Received 20 January 2005; revised 11 May 2005
Earlier, we have shown6a–c that the addition of Grignard
reagents to glyceraldehyde derivative 2 provides easy ac-
cess to the C-3 epimers of alkanetriol derivatives which
are useful chirons for the synthesis of various classes of
Abstract: An efficient synthesis of (–)-prelactone B has been de-
veloped using 1,2-cyclohexylidene glyceraldehyde as the chiral
template. The key features of the synthesis were stereoselective cro-
tylation of 1,2-cyclohexylidene glyceraldehyde and enantioselec-
tive reduction of a ketone, as well as operational simplicity and use bioactive compounds. Extending this work, a Barbier-
of inexpensive reagents/chemicals.
type reaction of allylic halides with 2 was also devel-
oped.6d It was envisaged that the homoallylic alcohol 3a
Key words: chiral template, enantioselective synthesis, prelactone
B
obtained via crotylation of 2, would be suitable for a brief
synthesis of (–)-1a (Scheme 1).
The Zn-mediated crotylation of 1 afforded a mixture of
diastereomers 3a and 3b as the major products in a 64:34
ratio along with a trace amount of 3c. All the stereomers
could be separated easily by normal column chromatogra-
phy and were characterized from their 1H NMR spectra.6d
According to our synthetic plan, for (–)-1a, we required
the (2R,3R,4S)-stereomer 3d of the crotylated product,
while the major product 3a obtained by the above reaction
was the (2R,3S,4S)-stereomer. However, the stereorever-
sal of the carbinol centre could be easily accomplished
following our own method.7 Compound 3a was oxidized
with PCC8 to give the ketone 4, which on reduction with
K-selectride furnished 3d as the sole product. The three
1H NMR multiplets (1:1:2) at 3.25–4.10 ppm were in con-
formity with those reported earlier for the corresponding
isopropylidene derivative.9a,b Benzylation of 3d to 5 fol-
lowed by OsO4-mediated dihydroxylation gave 6 as an
epimeric mixture, which on NaIO4 cleavage gave the al-
dehyde 7. This on reaction with isopropylmagnesium bro-
mide furnished 8 as a mixture of inseparable C-5 epimers.
Fortunately, the epimers could be easily separated by col-
umn chromatography after acetylation to furnish 9a and
9b in a ratio of 3:7. Based on our previous experience the
more polar isomer 9b (major product) was assigned the
3,5-anti configuration. The stereochemical outcome of
the reaction was in accordance with earlier reports.9c Con-
firmation of the syn and anti configurations of 9a and 9b
could not be unambiguously assigned from their 13C NMR
resonances. Consequently, this was accomplished by their
derivatization to the corresponding 3,5-acetonides and an-
alyzing their 13C NMR signals. For this, 9a and 9b were
converted to the respective acetonides 10a and 10b by de-
benzylation, deacetylation, and acetalization. The 13C
NMR spectrum of 10a showed the methyl resonances
19.8 and 31.1 ppm along with a resonance at 98.6 ppm
(acetal carbon) of the six-membered acetonide moiety
confirming its 3,5-syn relationship.10a–c Likewise, the ace-
tonide methyl resonances at 23.8 and 24.1 ppm and the ac-
It has been proposed that the so called prelactones exist
for some macrolides and their production can be stimulat-
ed under certain conditions.1a The prelactone B 1a and
prelactone C 1b (Scheme 1) are two such microbial d-lac-
tones isolated1b from the culture-filtrate extract of Strepto-
myces griseus (strain Tü 2599 and 18) and the mycelium
extract of Streptomyces sp. (strain GÖ 22/15).
These are the first wild-strain derived metabolites repre-
senting the early steps of the polyketide pathway.2a Avail-
ability of all possible stereomers would assist the
mechanistic studies of the polyketide synthesis (PKS) of
avermectins and help their bioevaluation.2b In particular,
the stereomers would be useful standards to decipher the
selectivities of the PKS enzymes, ketoreductase and dehy-
dratase. Given that similar d-lactones are known3a,b to pos-
sess impressive cytotoxicity, compound 1a also appears
promising. Furthermore, these types of functionalized
chiral d-lactones serve as important structural motifs in
the asymmetric syntheses of a large number of bioactive
natural products such as mevinolin and compactin,4a
phomalactone,4b asperlin,4c massoialactone4d etc.
Several asymmetric syntheses of 1a have been reported.5a–j
Of these, the proline-catalyzed crossed-aldol strategy5d is
by far the best in terms of brevity and efficiency. Many of
the other methods suffer from the limitations of using ex-
pensive reagents, formation of side products, low yields
and/or poor selectivity requiring HPLC separation of the
desired enantiomer from a mixture of stereomers. In light
of the above, we developed an expeditious synthesis of
(–)-1a from easily accessible and inexpensive reagents. It
is worth noting that amongst the earlier syntheses, only
one synthesis of (–)-1a has been reported so far.5d
SYNTHESIS 2005, No. 16, pp 2777–2781
x
x.
x
x
.
2
0
0
5
Advanced online publication: 23.09.2005
DOI: 10.1055/s-2005-916009; Art ID: Z01605SS
© Georg Thieme Verlag Stuttgart · New York

2778
A. A. Salaskar et al.
PAPER
Scheme 1 i) Crotyl bromide, Zn, aq NH4Cl; ii) PCC, NaOAc, CH2Cl2; iii) K-selectride, THF, –78 °C; iv) NaH, BnBr, THF, D; v) OsO4, NMO,
acetone–H2O; vi) NaIO4, CH3CN–H2O; vii) i-PrMgBr, THF; viii) Ac2O, pyridine, column chromatography; ix) aq TFA; x) MsCl, pyridine; Zn,
NaI, DMF, D; xi) BMS, THF; Na2CrO4, H2SO4, D; xii) H2, 10% Pd/C, EtOH.
etal carbon resonance at 100.3 ppm in the 13C NMR thesis. It is worth noting that the synthetic protocol de-
spectrum of 10b established its 3,5-anti configuration.
scribed herein, can also be used for the syntheses of all the
stereomers of prelactone B. For example, the homoallylic
alcohol 3b produced during the synthesis can be elaborat-
ed to (+)-1a using the above sequence of reactions. Like-
wise, the other stereomers of 1a could be synthesized
from 9a or its other diastereomers that can be synthesized
from 3b. Furthermore, following this method, (+)-1a can
also be prepared using the aldehyde (S)-212 as the starting
material. Finally, our synthesis is very simple, requires in-
expensive reagents, and the stereomers produced at some
of the stages can be separated by normal column chroma-
tography.
The required isomer 9b was subsequently deacetalized to
11 by treatment with aqueous trifluoroacetic acid (TFA).
This was converted to olefin 12 by mesylation of the diol
followed by heating with NaI in the presence of Zn dust in
DMF. This on hydroboration with borane dimethyl sulfide
(BMS) followed by in situ oxidation11 with Na2CrO4 di-
rectly afforded the d-lactone 13. Finally catalytic hydro-
genolysis of 13 afforded the title compound (–)-1a, which
was characterized by comparing the chiroptical and spec-
tral data with those reported.5d
Thus, a simple synthesis of (–)-1a has been developed us-
ing the easily accessible aldehyde 2 as the chiral template.
The bulky cyclohexylidenedioxy group in 2 ensured gen-
eration of the stereogenic centers with good stereocontrol
and also provided the d-lactone moiety of the target com-
pound. Furthermore, the cyclohexylidene protection was
also stubborn to even mild acidic work-up and improved
the solubilities of the intermediates involved in the syn-
The IR spectra were scanned as thin films with a Jasco FT-IR spec-
trometer. The 1H NMR were recorded with a Bruker AC-200 (200
MHz for 1H NMR and 50 Hz for 13C NMR) instrument. Optical ro-
tations were measured with a Jasco DIP 360 polarimeter. All anhy-
drous reactions were carried out under an Ar atmosphere using
freshly dried solvents. Unless otherwise mentioned, the organic ex-
tracts were dried over anhydrous Na2SO4.
Synthesis 2005, No. 16, 2777–2781 © Thieme Stuttgart · New York

PAPER
An Asymmetric Synthesis of (–)-Prelactone B
2779
(2R,3S,4S)-1,2-Cyclohexylidenedioxy-4-methylhex-5-en-3-ol
(3a)
(10 mL). After the brisk evolution of H2 was over, the mixture was
refluxed for 0.5 h, warmed to r.t., and BnBr (0.907 g, 5.3 mmol) in
THF (10 mL) was added. The mixture was subsequently refluxed
until the reaction was complete (ca. 4 h, monitored by TLC). The re-
action was cooled to r.t., poured into ice–water (25 mL), the organic
layer separated, and the aqueous portion extracted with Et2O (2 × 15
mL). The combined organic extracts were washed with H2O (2 × 5
mL), brine (1 mL), dried, and the solvent was removed. Column
chromatography (silica gel, 0–10% EtOAc–hexane) afforded pure
5.
To a cooled and well stirred mixture of 2 (5.0 g, 0.029 mol), Zn dust
(5.7 g, 0.088 mol), and crotyl bromide (7.9 g, 0.059 mol) in THF (50
mL), was added dropwise aq sat. NH4Cl. After stirring the mixture
for 4 h at ambient temperature, the mixture was filtered and the res-
idue thoroughly washed with Et2O (25 mL). The filtrate was washed
with H2O (2 × 10 mL), brine (1 mL), and dried. The solvent was re-
moved in vacuo and column chromatography of the residue afford-
ed pure alcohols 3a–c (85% overall yield).
Yield: 1.14 g (82%); colorless oil; [a]D22 –7.4 (c 2.51, CHCl3).
IR (film): 3060, 1694, 990, 910 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.10 (d, J = 6.8 Hz, 3 H), 1.40–
1.62 (m, 10 H), 2.01–2.05 (m, 1 H), 3.48–3.57 (m, 1 H), 3.78–3.98
(m, 2 H), 4.10–4.14 (m, 1 H), 4.52–4.75 (m, 2 H), 4.88–5.10 (m, 2
H), 5.70–5.97 (m, 1 H), 7.33 (s, 5 H).
3a
Yield: 3.62 g (54.4%); colorless oil; [a]D22 +2.4 (c 1.21, CHCl3).
IR (film): 3408, 1657, 990 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.07 (d, J = 6.6 Hz, 3 H), 1.40–
1.59 (m, 10 H), 2.07 (br s, D2O exchange, 1 H), 2.20–2.43 (m, 1 H),
3.53–3.58 (m, 1 H), 3.82–4.06 (m, 3 H), 5.0–5.12 (m, 2 H), 5.71–
5.91 (m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 12.7, 16.4, 23.9, 25.1, 34.8, 36.2,
40.7, 65.1, 71.7, 74.8, 109.1, 115.9, 139.8.
13C NMR (CDCl3, 50 MHz): d = 13.7, 14.6, 25.7, 32.7, 37.5, 64.4,
65.7, 73.0, 83.1, 109.8, 114.2, 127.6, 128.1, 129.3, 130.4, 139.8.
Anal. Calcd for C20H28O3: C, 75.91; H, 8.92. Found: C, 76.09; H,
9.15.
(2R,4S)-1,2-Cyclohexylidenedioxy-4-methylhex-5-en-3-one (4)
To a cooled (0 °C) and stirred suspension of PCC (1.9 g, 8.85
mmol) and NaOAc (0.1 g, 1.2 mmol) in CH2Cl2 (80 mL) was added
3a (0.8 g, 3.54 mmol) in one portion. After stirring for 8 h, the reac-
tion was quenched with Et2O (80 mL) and the supernatant passed
through a pad of silica gel. Removal of the solvent afforded pure 4.
Yield: 0.658 g (83%); colorless oil; [a]D22 +5.7 (c 1.12, CHCl3).
IR (film): 1730 cm–1.
(2R,3R,4S,5RS)-3-Benzyloxy-1,2-cyclohexylidenedioxy-4-meth-
ylhexane-5,6-diol (6)
To a stirred solution of 5 (1.0 g, 3.2 mmol) and NMO (0.773 g, 6.4
mmol) in acetone–H2O (8:1, 10 mL) was added OsO4 (0.04 g, 0.16
mmol) in t-BuOH (1 mL). After stirring for 12 h, when the reaction
was complete (TLC), aq NaHSO3 (4 mL) was added to the mixture,
and the aqueous extracts were extracted with CHCl3 (2 × 15 mL).
The organic extracts were washed with H2O (2 × 10 mL), brine (1
mL), dried, and the solvent was removed. Column chromatography
of the residue (silica gel, 0–5% MeOH–CHCl3) afforded pure 6.
1H NMR (CDCl3, 200 MHz): d = 1.17 (d, J = 6.8 Hz, 3 H), 1.41–
1.65 (m, 10 H), 2.43–2.51 (m, 1 H), 3.98–4.19 (m, 2 H), 4.56 (d,
J = 7.4 Hz, 1 H), 5.13–5.24 (m, 2 H), 5.76–5.94 (m, 1 H).
Yield: 0.946 g (86%); colorless oil; [a]D22 +16.0 (c 1.98, CHCl3).
13C NMR (CDCl3, 50 MHz): d = 12.7, 16.4, 23.8, 25.0, 34.9, 36.1,
IR (film): 3431, 3060, 1060 cm–1.
43.6, 65.1, 71.7, 108.9, 116.8, 139.8, 177.1.
1H NMR (CDCl3, 200 MHz): d = 0.91 (two overlapping d, J = 6.4
Hz, 3 H), 1.29–1.59 (m, 10 H), 2.00–2.08 (m, 1 H), 3.18 (br s, D2O
exchangeable, 2 H), 3.42–3.78 (m, 5 H), 3.87–4.09 (m, 1 H), 4.24–
4.38 (m, 1 H), 4.62–4.89 (m, 2 H), 7.32 (s, 5 H).
Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.77; H,
9.12.
(2R,3R,4S)-1,2-Cyclohexylidenedioxy-4-methylhex-5-en-3-ol
(3d)
13C NMR (CDCl3, 50 MHz): d = 12.8, 14.1, 14.6, 25.2, 25.6, 35.3,
36.2, 36.8, 46.4, 64.6, 65.9, 73.0, 73.5, 73.6, 79.6, 81.2, 110.1,
128.3, 127.8, 138.5, 138.6.
To a cooled (–78 °C) and stirred suspension of 4 (0.62 g, 2.77
mmol) in THF (30 mL) was injected K-selectride (3.3 mL, 1.0 M in
THF). After stirring for 3 h at the same temperature, the reaction
mixture was allowed to warm to r.t., quenched with H2O (5 mL),
and extracted with EtOAc (2 × 20 mL). The organic layer was
washed with brine (1 mL), dried, and concentrated in vacuo. Col-
umn chromatography (silica gel, 0–15% EtOAc–hexane) of the res-
idue afforded pure 3d.
Yield: 0.470 g (75%); colorless oil; [a]D22 +12.1 (c 1.16, CHCl3).
IR (film): 3408, 1648, 990 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.07 (d, J = 6.8 Hz, 3 H), 1.33–
1.58 (m, 10 H), 1.96 (br s, D2O exchange, 1 H), 2.17–2.37 (m, 1 H),
3.25–3.36 (m, 1 H), 3.64–3.71 (m, 1 H), 3.92–4.10 (m, 2 H), 4.96–
5.09 (m, 2 H), 5.76–5.94 (m, 1 H).
Anal. Calcd for C20H30O5: C, 68.54; H, 8.63. Found: C, 68.71; H
8.67.
(2R,3R,4R)-3-Benzyloxy-4,5-cyclohexylidenedioxy-2-methyl-
pentanal (7)
To a cooled (0 °C) and stirred solution of 6 (0.9 g, 2.6 mmol) in
CH3CN (30 mL) and H2O (20 mL) was added NaIO4 (1.1 g, 5.2
mmol) in portions. After stirring for 1 h at the same temperature, the
mixture was filtered, and the filtrate was concentrated in vacuo. The
residue was taken in Et2O (25 mL) and the organic extract washed
successively with H2O (5 mL), aq NaHSO3 (2 mL), H2O (5 mL) ,
aq Na2S2O3 (2 mL), H2O (5 mL), and brine (2 mL). The ethereal
phase was concentrated in vacuo to afford pure 7, which was used
as such in the next step.
Yield: 0.754 g (92%); colorless oil; [a]D22 –1.6 (c 1.34, CHCl3).
IR (film): 3070, 2733, 1714 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.98 (d, J = 7.0 Hz, 3 H), 1.26–
1.55 (m, 10 H), 2.72–2.78 (m, 1 H), 3.81–3.86 (m, 2 H), 4.08–4.16
(m, 2 H), 4.49–4.65 (m, 2 H), 7.33 (s, 5 H), 9.67 (d, J = 1.5 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 12.4, 16.9, 23.9, 25.1, 35.0, 36.2,
41.3, 65.7, 74.6, 75.4, 109.6, 112.8, 139.6.
Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found: C, 68.87; H,
9.68.
(2R,3R,4S)-3-Benzyloxy-1,2-cyclohexylidenedioxy-4-methyl-
hex-5-ene (5)
To a stirred suspension of NaH (0.253 g, 5.28 mmol, 50% suspen-
sion in oil) in THF (20 mL) was added 3d (1.0 g, 4.4 mmol) in THF
13C NMR (CDCl3, 50 MHz): d = 13.5, 14.2, 25.2, 25.6, 36.8, 46.4,
66.5, 68.2, 73.9, 81.0, 109.8, 126.3, 126.7, 129.4, 138.0, 175.1.
Synthesis 2005, No. 16, 2777–2781 © Thieme Stuttgart · New York

2780
A. A. Salaskar et al.
PAPER
Anal. Calcd for C19H26O4: C, 71.67; H, 8.23. Found: C, 71.79; H,
8.08.
(2R,3R,4S,5S)-3-Benzyloxy-1,2-dihydroxy-4,6-dimethylheptyl-
5-acetate (11)
A mixture of 9b (0.246 g, 0.61 mmol) and 80% aq TFA (15 mL) in
CH2Cl2 (15 mL) was stirred at –20 °C for 24 h. The mixture was
concentrated in vacuo, the residue taken in CHCl3 (20 mL), the or-
ganic extract washed with H2O (2 × 5 mL), brine (1 mL), and dried.
Removal of the solvent followed by column chromatography of the
crude product (silica gel, 0–5% MeOH–CHCl3) afforded pure 11.
Yield: 0.158 g (80%); colorless thick syrup; [a]D22 –17.6 (c 1.78,
CHCl3).
IR (film): 3431, 3090, 1729 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.87 (d, J = 6.6 Hz, 6 H), 1.02 (d,
J = 7.0 Hz, 3 H), 1.15–1.22 (m, 1 H), 1.27–1.48 (m, 1 H), 2.03 (s, 3
H), 2.84 (br s, D2O exchange, 2 H), 3.32–3.42 (m, 1 H), 3.48–3.65
(m, 2 H), 3.99–4.22 (m, 1 H), 4.38–4.68 (m, 2 H), 4.86–4.92 (m, 1
H), 7.33 (s, 5 H).
13C NMR (CDCl3, 50 MHz): d = 13.7, 17.6, 19.1, 29.5, 30.9, 65.8,
67.4, 74.1, 74.3, 80.1, 127.6, 127.9, 137.4, 137.8, 170.7.
(2R,3R,4S,5RS)-3-Benzyloxy-1,2-cyclohexylidenedioxy-4,6-
dimethylheptan-5-ol (8)
To a cooled (0 °C) and stirred solution of isopropylmagnesium bro-
mide [prepared from 2-bromopropane (0.812 g, 6.6 mmol) and Mg
(0.193 g, 8.0 mmol)] in THF (20 mL) was added 7 (0.7 g, 2.2
mmol). After stirring the mixture for 2 h at 0 °C and 2 h at r.t., the
reaction was quenched by the addition of aq sat. NH4Cl (5 mL). The
organic layer was separated, the aqueous phase extracted with Et2O
(2 × 20 mL), the combined organic extracts were washed with brine
(1 mL), and dried. Removal of the solvent followed by column
chromatography of the residue (silica gel, 0–15% EtOAc–hexane)
afforded pure 8 as an epimeric mixture.
Yield: 0.555 g (70%); colorless oil; [a]D22 +2.8 (c 2.20, CHCl3).
IR (film): 3476, 1649, 1450, 1359, 1090 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.87 (d, J = 7.2 Hz, 3 H), 0.99
(two overlapping d, J = 6.2, 7.2 Hz, 6 H), 1.41–1.62 (m, 12 H), 2.70
(br s, D2O exchange, 1 H), 3.36–3.46 (m, 2 H), 3.50–3.54 (m, 1 H),
3.94–4.01 (m, 1 H), 4.38–4.42 (m, 1 H), 4.57 (d, J = 9.0 Hz, 1 H),
5.00 (d, J = 9.0 Hz, 1 H), 7.32 (s, 5 H).
Anal. Calcd for C18H28O5: C, 66.64; H, 8.70. Found: C, 66.84; H
8.86.
(3R,4S,5S)-3-Benzyloxy-4,6-dimethylhept-1-enyl-5-acetate (12)
To a cooled (0 °C) and stirred solution of 11 (0.36 g, 1.11 mmol) in
pyridine (5.0 mL) was injected MsCl (0.216 mL, 2.79 mmol) and
the mixture stirred for 12 h at r.t. The mixture was poured into ice-
cold H2O (15 mL), the organic layer separated, washed with H2O (2
× 5 mL), brine (1 mL), and dried. Removal of the solvent afforded
the mesylate, which was used as such for the next step.
Anal. Calcd for C22H34O4: C, 72.89; H, 9.45. Found: C, 72.72; H,
9.27.
(2R,3R,4S,5S)-3-Benzyloxy-1,2-cyclohexylidenedioxy-4,6-di-
methylheptyl-5-acetate (9b)
A mixture of 8 (0.5 g, 1.4 mmol), Ac2O (2 mL), and pyridine (2 mL)
was stirred overnight. The mixture was treated with ice–cold water,
stirred for 1 h, and extracted with Et2O (2 × 10 mL). The ethereal
layer was washed with 10% aq NH4Cl (5 mL), H2O (2 × 10 mL),
10% aq Na2CO3 (5 mL), H2O (2 × 10 mL), brine (2 mL), and dried.
Removal of the solvent followed by column chromatography of the
residue (silica gel, 0–10% EtOAc–hexane) afforded 9a (0.156 g)
and 9b (0.364 g, total yield 92%).
Yellowish oil.
IR (film): 1739, 1362, 1172 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.89 (d, J = 6.6 Hz, 6 H), 1.05 (d,
J = 7.0 Hz, 3 H), 1.15–1.18 (m, 1 H), 1.93–2.12 (m containing a s at
2.06, 4 H), 3.06 (s, 6 H), 3.63–3.77 (m, 1 H), 4.01–4.26 (m, 2 H),
4.48–4.62 (m, 3 H), 5.06–5.12 (m, 1 H), 7.34 (s, 5 H).
A mixture of the above mesylate, NaI (607.5 mg, 4.05 mmol) and
Zn dust (2.63 g, 4.05 mmol) in DMF (25 mL) was heated at 90 °C
for 8 h. The reaction mixture was cooled to r.t., diluted with Et2O
(25 mL), and the supernatant was passed through a pad (5 cm) of sil-
ica gel. The eluent was concentrated in vacuo, diluted with H2O (15
mL), and extracted with Et2O (2 × 15 mL). The ethereal layer was
washed with H2O (2 × 10 mL), brine (1 mL), and dried. The solvent
was removed in vacuo followed and column chromatography of the
residue (silica gel, 0–15% EtOAc–hexane) afforded pure 12.
Yield: 0.210 g (65%); colorless oil; [a]D22 –27.1 (c 2.5, CHCl3).
IR (film): 1740, 1230, 990, 910 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.89 (merged d, J = 6.4 Hz, 6 H),
1.04 (d, J = 6.5 Hz, 3 H), 1.22–1.32 (m, 1 H), 1.81–1.97 (m, 1 H),
2.16 (s, 3 H), 4.24–4.30 (m, 1 H), 4.54–4.62 (m, 1 H), 4.75–4.88 (m,
1 H), 4.99–5.15 (m, 1 H), 5.19–5.36 (m, 2 H), 5.57–5.86 (m, 1 H),
7.29–7.34 (m, 5 H).
9a
Colorless oil; [a]D22 +4.1 (c 1.41, CHCl3); Rf 0.42 (15% EtOAc–
hexane).
IR (film): 1730 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.85 (d, J = 7.8 Hz, 6 H), 0.98 (d,
J = 7.0 Hz, 3 H), 1.25–1.80 (m, 11 H), 1.96–2.06 (m containing a s
at 1.99, 4 H), 3.44 (t, J = 6.4 Hz, 1 H), 3.85 (t, J = 7.6 Hz, 1 H),
4.01–4.11 (m, 1 H), 4.20–4.26 (m, 1 H), 4.46–4.62 (m, 2 H), 5.10–
5.15 (m, 1 H), 7.25–7.32 (m, 5 H).
13C NMR (CDCl3, 50 MHz): d = 10.8, 17.5, 19.4, 21.0, 23.9, 24.0,
25.2, 29.5, 34.8, 36.2, 36.6, 66.1, 73.8, 75.7, 80.5, 109.4, 127.5,
127.7, 128.3, 138.6, 170.9.
9b
22
Colorless oil; [a]D +6.9 (c 1.70, CHCl3); Rf 0.35 (15% EtOAc–
hexane).
13C NMR (CDCl3, 50 MHz): d = 12.8, 17.3, 19.2, 29.5, 30.8, 73.9,
IR (film): 3070, 1729, 1242 cm–1.
80.1, 81.4, 116.2, 127.7, 128.6, 130.7, 135.1, 139.8, 170.7.
1H NMR (CDCl3, 200 MHz): d = 0.87 (d, J = 7.0 Hz, 6 H), 1.01 (d,
J = 7.1 Hz, 3 H), 1.27–1.48 (m, 3 H), 1.52–1.70 (m, 8 H), 1.97–2.12
(m containing a s at 1.99, 4 H), 3.37–3.43 (m, 1 H), 3.48–3.59 (m,
1 H), 3.94–4.03 (m, 1 H), 4.28–4.36 (m, 1 H), 4.57–4.63 (m, 1 H),
4.87–4.94 (m, 2 H), 7.28–7.36 (m, 5 H).
13C NMR (CDCl3, 50 MHz): d = 12.2, 16.1, 16.2, 19.6, 19.8, 23.9,
25.1, 28.8, 35.1, 36.5, 65.7, 72.7, 75.7, 78.6, 109.9, 127.3, 127.7,
128.1, 138.8, 170.8.
Anal. Calcd for C18H26O3: C, 74.45; H, 9.03. Found: C, 74.63; H
9.17.
(3S,4R,5S)-3-Benzyloxy-4-methyl-5-isopropyl-(5)-hexanolide
(13)
To a cooled (–78 °C) and stirred solution of 12 (0.12 g, 0.41 mmol)
in THF (10 mL) was injected BMS (0.7 mL). After stirring for 2 h,
a solution of Na2CrO4 (0.2 g, 1.23 mmol) and H2SO4 (0.2 mL) in
H2O (2.0 mL) was added to the mixture at 0 °C, and the mixture re-
fluxed for 1 h. The mixture was poured in iced-water (15 mL), ex-
Anal. Calcd for C24H36O5: C, 71.25; H, 8.97. Found: C, 71.17; H,
9.17.
Synthesis 2005, No. 16, 2777–2781 © Thieme Stuttgart · New York

PAPER
An Asymmetric Synthesis of (–)-Prelactone B
2781
tracted with Et2O (2 × 15 mL), the organic extract was washed with
H2O (2 × 5 mL), brine (1 mL), and dried. The solvent was removed
in vacuo and preparative TLC (silica gel, 10% EtOAc–hexane) af-
forded pure 13.
Yield: 51.6 mg (48%); colorless oil; [a]D22 –45.2 (c 0.72, CHCl3).
IR: 2880, 1727 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.92 (d, J = 6.8 Hz, 3 H), 1.06
(merged d, J = 6.1, 6.8 Hz, 6 H), 1.68–1.75 (m, 1 H), 1.98–2.06 (m,
1 H), 2.20–2.27 (m, 1 H), 2.94–2.99 (m, 1 H), 3.49–3.75 (m, 2 H),
4.46–4.59 (m, 2 H), 7.33 (s, 5 H).
13C NMR (CDCl3, 50 MHz): d = 13.5, 14.0, 19.9, 28.6, 38.9, 39.1,
68.8, 81.4, 86.2, 126.8, 127.2, 136.1, 139.2, 170.9.
References
(1) (a) Boddien, C.; Gerber-Nolte, J.; Zeeck, A. Leibigs Ann.
1996, 1381. (b) Bindseil, K. U.; Zeeck, A. Helv. Chim. Acta
1993, 76, 150.
(2) (a) Khosla, C.; Gokhale, R. S.; Jacobson, J. R.; Cane, D. E.
Ann. Rev. Biochem. 1999, 68, 219. (b) O’Hagen, D. In The
Polyketide Metabolites; O’Hagen, D., Ed.; Ellis Horwood:
New York, 1991, 116–137.
(3) (a) Falomir, E.; Murga, J.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2003, 44, 539. (b) Murga, J.; García-
Fortanet, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2003,
44, 1737.
(4) (a) Endo, J. A. J. Med. Chem. 1985, 28, 401. (b) Honda, T.;
Kametani, T.; Kanai, K.; Tatsuzaki, Y.; Tsubuki, M. J.
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R. H.; Gillman, K. W. Tetrahedron Lett. 1999, 40, 1257.
(d) Cavil, G. W. K.; Clark, D. V.; Whitefield, F. B. Aust. J.
Chem. 1968, 21, 2819.
(5) (a) Hanefeld, U.; Hooper, A. M.; Staunton, J. Synthesis
1999, 401. (b) Chakraborty, T. K.; Tapadar, S. Tetrahedron
Lett. 2003, 44, 2541. (c) Fournier, L.; Gaudel-Siri, A.;
Kocienski, P. J.; Pons, J. M. Synlett 2003, 107. (d) Pihko,
P.; Erkkila, A. Tetrahedron Lett. 2003, 44, 7607. (e) Csaky,
A. G.; Mba, M.; Plumet, J. Synlett 2003, 2092.
(f) Aggarwal, V. K.; Bae, I.; Lee, H. Y. Tetrahedron 2004,
60, 9725. (g) Yadav, J. S.; Reddy, K. B.; Sabitha, G.
Tetrahedron Lett. 2004, 45, 6475. (h) Fan, Q.; Lin, L.; Liu,
J.; Huang, Y.; Feng, X.; Zhang, G. Org. Lett. 2004, 6, 2185.
(i) Dias, L. C.; Steil, L. J.; Vasconcelos, V. D. Tetrahedron:
Asymmetry 2004, 15, 147. (j) Enders, D.; Haas, M. Synlett
2003, 2182.
(6) (a) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem.
1995, 60, 585. (b) Sharma, A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 1999, 10, 883. (c) Sharma, A.;
Chattopadhyay, S. Enantiomer 2000, 5, 175.
(d) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
(7) Dhotare, B.; Salaskar, A.; Chattopadhyay, A. Synthesis
2003, 2571.
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45, Found: C, 73.37; H,
8.61.
(3S,4R,5S)-Prelactone B (1a)
A mixture of 13 (0.1 g, 0.38 mmol) and 10% Pd/C (30 mg) in EtOH
(15 mL) was shaken under a positive pressure of H2; after the re-
quired uptake of H2, the mixture was passed through a pad of silica
gel (5 cm) and the pad was eluted with Et2O (20 mL). The combined
eluents were concentrated to furnish pure 1a.
Yield: 59.0 mg (90%); colorless oil; [a]D22 –41.7 (c 0.57, MeOH),
{lit.4d [a]D22 –46 (c 0.42, MeOH)}.
IR (film): 3370, 1728, 1063 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.93 (d, J = 7.0 Hz, 3 H), 1.05
(merged d, J = 6.3, 6.6 Hz, 6 H), 1.70–1.78 (m, 1 H), 1.88 (br s, D2O
exchange, 1 H), 1.97–2.04 (m, 1 H), 2.42–2.48 (m, 1 H), 2.89–2.96
(m, 1 H), 3.63–3.77 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 13.5, 13.9, 19.9, 28.7, 38.9, 39.1,
69.6, 86.3, 170.9.
(2R,3R,4S,5R)-1,2-Cyclohexylidenedioxy-3,5-isopropylidine-
dioxy-4,6-dimethylheptane (10a)
13C NMR (CDCl3, 50 MHz): d = 13.4, 13.9, 19.8, 23.6, 23.8, 24.6,
29.7, 31.1, 34.7, 36.3, 64.8, 66.8, 67.3, 67.9, 98.6, 109.9.
(8) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647.
(9) (a) Mulzer, J.; De Lasalle, P.; Freissler, A. Leibigs Ann.
Chem. 1986, 1152. (b) Roush, W. R.; Adam, M. A.; Walts,
A. E.; Harris, D. J. J. Am. Chem. Soc. 1986, 108, 3422.
(c) Baker, D. C.; Hawkins, L. D. J. Org. Chem. 1982, 47,
2179; and references cited therein.
(2R,3R,4S,5S)-1,2-Cyclohexylidenedioxy-3,5-isopropylidine-
dioxy-4,6-dimethylheptane (10b)
13C NMR: d = 13.5, 14.2, 23.8, 24.1, 24.8, 25.0, 25.1, 31.7, 34.8,
36.4, 66.2, 66.7, 66.9, 68.2, 100.3, 109.8.
(10) (a) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett.
1990, 31, 7099. (b) Rychnovsky, S. D.; Skalitzky, D. J.
Tetrahedron Lett. 1990, 31, 945. (c) Rychnovsky, S. D.;
Rogers, B. M.; Richardson, T. I. Acc. Chem. Res. 1998, 31,
9.
(11) Mandal, A. K.; Mahajan, S. W. Synthesis 1991, 311.
(12) Benagila, M.; Caporale, M.; Puglisi, A. Enantiomer 2002, 7,
383.
Synthesis 2005, No. 16, 2777–2781 © Thieme Stuttgart · New York