Efficient 1,8- and 1,9-asymmetric inductions in the Grignard reaction of δ- and ε-keto esters of 1,1′-binaphthalen-2-ols with an oligoether tether as the 2′-substituent: Application to the synthesis of (-)-malyngolide

Article abstract of DOI:10.1039/b100497m

Efficient 1,8- and 1,9-asymmetric inductions in the Grignard reaction of podand-type δ- (3,4) and ε-keto esters (5,6) are achieved in the presence of MgBr₂·OEt₂ with up to 97 and 82% optical yields, respectively, by using 2′-[3-(2-methoxyethoxy)propoxy]-1,1′-binaphthalen-2-ol as the chiral auxiliary. The 1,8-asymmetric inductive Grignard reaction has been advantageously utilized in the key step of a synthesis of (-)-malyngolide.

Full text of DOI:10.1039/b100497m

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Efficient 1,8- and 1,9-asymmetric inductions in the Grignard
reaction of ꢀ- and ꢁ-keto esters of 1,1Ј-binaphthalen-2-ols with an
oligoether tether as the 2Ј-substituent: application to the synthesis
of (Ϫ)-malyngolide
1
Masamitsu Date,a Yasufumi Tamai,*b Tetsutaro Hattori,*a Hideki Takayama,a
Yoshinori Kamikuboa and Sotaro Miyano*a
a Department of Biomolecular Engineering, Graduate School of Engineering,
Tohoku University, Aramaki-Aoba 07, Aoba-ku, Sendai 980-8579, Japan
b Department of Material Chemistry and Engineering, College of Engineering,
Nihon University, Tokusada-Nakagawara 1, Tamura-machi, Koriyama 963-8642, Japan
Received (in Cambridge, UK) 15th January 2001, Accepted 22nd February 2001
First published as an Advance Article on the web 15th March 2001
Efficient 1,8- and 1,9-asymmetric inductions in the Grignard reaction of podand-type δ- (3,4) and ε-keto esters (5,6)
are achieved in the presence of MgBr2ؒOEt2 with up to 97 and 82% optical yields, respectively, by using 2Ј-[3-(2-
methoxyethoxy)propoxy]-1,1Ј-binaphthalen-2-ol as the chiral auxiliary. The 1,8-asymmetric inductive Grignard
reaction has been advantageously utilized in the key step of a synthesis of (Ϫ)-malyngolide.
Introduction
Remote asymmetric induction is a challenging subject in the
field of asymmetric synthesis,1 and it has a potential for
shortening the synthetic routes to complex chiral molecules.
Although several methodologies for highly efficient remote
asymmetric induction up to a 1,7-relationship have been
developed, little is known about the asymmetric induction
beyond a 1,7-relationship.2 Recently, we have reported that
butan-4-olides (γ-lactones) with a quaternary carbon center at
the 4-position are synthesized with up to 99% optical yield via
the diastereoselective Grignard reaction of γ-keto esters of 1,1Ј-
binaphthalen-2-ol derivatives 1 in the presence of an excess of
MgBr2ؒOEt2, followed by a spontaneous lactonization of the
resulting hydroxy esters.3 This highly efficient 1,7-asymmetric
induction was attributed to the formation of a pseudo-
macrocyclic magnesium chelate composed of the podand-type
keto ester and MgBr2 (e.g. complex 27), which would fix the
orientation of the keto carbonyl group to make the nucleo-
phile attack preferentially from the outside of the pseudo-
macrocycle. Herein, we report the effective extension of the
methodology to 1,8- and 1,9-asymmetric inductive Grignard
reactions of δ- and ε-keto esters 3–6.4 Also reported is an
advantageous utilization of the 1,8-asymmetric induction
protocol in a short-step synthesis of (Ϫ)-malyngolide.
Results and discussion
Diastereoselective Grignard reaction of ꢂ-keto esters 3–7
The prerequisite ω-keto esters 3–7 were readily prepared by
DCC condensation of chiral auxiliaries 1a–f with ω-keto
acids 2a–e (Scheme 1). The Grignard reaction was performed
as follows: a keto ester 3–7 was treated with 3.0 equiv. of
MgBr2ؒOEt2 in dichloromethane at room temperature for 1 h to
preorganize the substrate–Lewis acid complex, which was then
treated with a diethyl ether solution of an excess of a Grignard
reagent 8 at Ϫ78 ЊC until the keto ester had disappeared by
monitoring on TLC. In the reaction of δ-keto esters 3 and 4,
the initially produced δ-hydroxy esters spontaneously cyclized
during work-up to afford lactone 9 in good yields after purifi-
Scheme 1 Reagents: i, DCC, PPy, CH2Cl2; ii, MgBr2ؒOEt2, CH2Cl2–
Et2O; iii, LAH, Et2O.
DOI: 10.1039/b100497m
J. Chem. Soc., Perkin Trans. 1, 2001, 645–653
This journal is © The Royal Society of Chemistry 2001
645

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Table 1 Grignard reaction of ω-keto esters 3–7
Entry
Substrate
R1
R2
R3
Product
Yield (%)
Ee (%) (Abs. confign.)
1
2
3a
3b
3c
3c
3c
3d
3e
3f
ME
MP
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Ph
9
9
73
56
80
77
85
79
82
88
70
90
63
83
75
75
87
46
89
96
96
59(S)
7 (S)
93 (R)
85 (R)
95 (R)
74 (R)
92 (R)
80 (R)
92 (S)
82 (S)
56 (S)
41 (S)
45 (S)
6 (S)
6 (S)
82 (R)
4
3
MEP
MEP
MEP
MEB
IBEP
MEEE
MEP
MEP
MEP
MEB
MEB
MEEE
MEEE
MEP
MEP
MEB
MEEE
9
4a
9
5b
9
6
7
8
9
10
11a
12
13a
14
15a
16
17
18
19
9
9
9
4c
5c
5c
5d
5d
5f
9
10
10
10
10
10
10
12
11
11
11
5f
6c
7c
7d
7f
Me
Me
Me
7
9
a The reaction was conducted in the absence of MgBr2ؒOEt2. b ZnCl2 was employed instead of MgBr2ؒOEt2.
cation by preparative TLC (PLC), while the reaction of ε- and
ζ-keto esters 5–7 gave the diastereomeric hydroxy esters by the
same treatment. In order to assess the stereoselectivity of
the Grignard addition with care to avoid diastereomeric
enrichment, the hydroxy esters obtained from the reaction
of benzoyl esters 5, 7 with methylmagnesium bromide 8a
were methylated in situ to diols 10, 11 by treatment with an
additional amount of the Grignard reagent, and the hydroxy
ester obtained from acetyl ester 6 and the phenyl Grignard
reagent 8b was reduced to diol 12 by treatment with LAH. The
ees of the isolated products 9–12 were determined by chiral
GLC or HPLC analyses.
Table 1 lists the results of the Grignard reactions. The
diastereoselectivity of the reaction between δ-keto esters 3a–f
and the methyl Grignard reagent 8a varied depending on the
structure of the 2Ј-substituent of the chiral auxiliaries (entries
1–3 and 6–8). The keto esters with a mono(alkylene glycol)-type
oligoether tether 3a, b showed lower diastereoselectivity and
opposite diastereoface selection compared with keto esters with
a di- or tri(alkylene glycol)-type substituent 3c–f, though the
mono(alkylene glycol)-type chiral auxiliary of ester 3a gave the
highest de in the corresponding Grignard reaction of γ-keto
esters.3 Consideration of the distinct difference in stereo-
selectivity between the reactions of ester 3b and ester 3c (entries
2 and 3) shows that the 3-(2-methoxyethoxy)propoxy (MEP-O)
group of keto ester 3c, which showed the best performance
among the chelating groups examined, coordinates to the Lewis
acid in a bidentate manner through the terminal ethylenedioxy
moiety rather than the internal propylenedioxy moiety. The
4-(2-methoxyethoxy)butoxy (MEB-O) group of keto ester 3d
should also coordinate through the terminal ethylenedioxy
moiety (entry 6). These observations may indicate that the
optimal chelating group for the remote asymmetric induction
varies with the distance between the keto and ester carbonyl
groups and that δ-keto esters require a longer oligoether tether
to achieve high stereoselectivity than γ-keto esters do. On the
other hand, the steric bulk of the terminal alkoxy moiety did
not have much effect on the stereoselectivity (compare entry 7
and entry 3).
with opposite stereochemistry of the adduct to that of the corre-
sponding ω-benzoyl esters 3c and 5c with the methyl Grignard
reagent 8a, suggesting that the orientation of the keto carbonyl
group in the chelated complex is identical in these reactions
(compare entry 9 with entry 3 and entry 16 with entry 10).
In our previous paper,3 it was shown that the relevant
Grignard reaction of γ-keto esters proceeded with fairly
good diastereoselectivity even if the preorganization step
had been omitted. This was rationalized as ligation of the
substrate to MgBr2 present in the reaction mixture by the
Schlenk equilibrium prior to the attack of the Grignard
reagent. Similar results were obtained in the reaction of δ-
and ε-keto esters (entries 4, 11, 13 and 15). The Grignard
reaction of ester 3c with ZnCl2 as the Lewis acid showed
almost equal stereoselectivity to that in the presence of
MgBr2ؒOEt2 (entry 5). In this case, however, at least 10 equiv.
of the Grignard reagent was required to complete the reac-
tion, suggesting the formation of an organozinc reagent
from the Grignard reagent and ZnCl2. A control reaction
with methylzinc chloride instead of methylmagnesium bromide
did not afford lactone 9. Therefore, it may be concluded that
the Grignard reagent, after the consumption of ZnCl2 to
form methylzinc chloride, added to the keto ester ligated
to MgBr2.
Determination of the absolute configurations of lactone 9 and
diols 10, 12
Scheme 2 illustrates the determination of the absolute configur-
ations of lactone 9 and diols 10 and 12.
Enantiomerically pure lactone (R)-(+)-16 was reduced with
LAH to give diol 17, which was converted into tosylate 21 by
the following sequential reactions: initial esterification of the
diol 17 with acetic anhydride to hydroxy ester 18, protection of
its hydroxy group as the tert-butyldimethylsilyl ether (19),
reduction of the siloxy ester 19 to alcohol 20, followed by
esterification of the alcohol 20 with toluene-p-sulfonyl chloride.
Homologation5 of the tosylate 21 with a Gilman reagent gave
(R)-2-phenylhexan-2-ol 15, after removal of the TBDMS-
protecting group. On the other hand, lactone (+)-9 of 90% ee
was reduced to give diol 13, the terminal hydroxy group of
which was converted into the tosylate (14), and then reduced
with LAH to give dextrorotatory alcohol 15. Comparison of
the elution behavior of the sample in HPLC with that of the
authentic sample determined the absolute configuration of
the alcohol (+)-15 to be R. Thus, the R absolute stereo-
chemistry of lactone (+)-9 was established.
The MEP-O chelating group was also highly effective in the
reaction of ε-keto esters 5 with the methyl Grignard reagent 8a
(entries 10, 12 and 14). However, the reaction of ζ-keto esters
7 resulted in low stereoselectivity even using the chelating
group varying from MEP-O to a longer oligoether tether
(entries 17–19).
The reaction of ω-acetyl esters 4c and 6c with the phenyl
Grignard reagent 8b showed almost equal diastereoselectivity
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The tosylate (R)-21 was coupled with ethylmagnesium
6
bromide in the presence of Li2CuCl4 to give authentic (R)-2-
phenylheptan-2-ol 24, after removal of the TBDMS-protecting
group. On the other hand, a control reaction of the ε-keto ester
(Ra)-5d with methylmagnesium bromide under the standard
conditions (vide supra) was quenched to give a diastereomeric
mixture of esters 25, reduction of which with LAH gave
levorotatory diol 12 of 43% ee. Tosylation of the diol 12,
followed by LAH reduction of the resulting ester 26 gave
levorotatory alcohol 24. Comparison of the elution behavior
of the sample in HPLC with that of the authentic sample
determined the absolute configuration of the alcohol (Ϫ)-24, as
well as that of the diol (Ϫ)-12, to be S. This analysis, combined
with the result that the diastereomeric mixture of the esters 25
gave levorotatory diol 10, established that the absolute stereo-
chemistry of the diol 10 should be (S)-(Ϫ).
Fig. 1 Downfield shifts in ppm of the 13C NMR signals for keto esters
3c, 5c and 7c upon complexation with MgBr2ؒOEt2 in
[2H2]dichloromethane. The downfield shifts of the complexes after
addition of 7 vol% of diethyl ether are shown in parentheses.
Mechanistic consideration of the remote asymmetric induction
In order to gain insight into the mechanism of the remote
asymmetric induction, complexation experiments were carried
out (Fig. 1). The δ-, ε- and ζ-keto esters with a MEP-O chelating
group 3c, 5c and 7c were treated with an excess of MgBr2
in [2H2]dichloromethane and the resulting complexes were
subjected to 13C NMR analyses. The spectra of the MgBr2
chelates 27–29 showed considerable downfield shifts of both
carbonyl carbons and the terminal carbon of the oligoether
tether. The chemical shift values of the complexes 27 and 28
were only slightly changed by the addition of 7 vol% of diethyl
ether, the amount of which is almost equal to that in the reac-
tion mixture, while the complex 29 showed considerable
decrease in the downfield shifts after the same treatment. These
observations indicate that the stability of the magnesium
chelates in the presence of diethyl ether changes according to
the length of the carbon chain between the two carbonyl
groups on the keto acid component. Therefore, it may be
concluded that the more stable the pseudo-macrocyclic
complex is, the higher the diastereoselectivity obtained by
fixing the orientation of the keto carbonyl group and that the
carbon chain of the ζ-keto acid moiety in ester 7c is too long to
construct a stable pseudo-macrocyclic chelate with MgBr2.
Detailed CPK and Dreiding molecular model inspections
gave the structure of the pseudo-macrocyclic complex 27 of the
δ-keto ester 3c as schematically visualized in Fig. 2. It is of
interest to note that the preferred diastereoface of the ε-keto
ester 5c in the Grignard reaction is same as that of the relevant
γ-keto ester3 and is opposite to that of the δ-keto ester 3c.
Although the three-dimensional structure of the pseudo-
Scheme 2 Reagents: i, LAH, Et2O; ii, TsCl, pyridine; iii, Ac2O, Et3N, DMAP, Et2O; iv, TBDMS-OTf, 2,6-lutidine, CH2Cl2; v, Me2CuLi, Et2O; vi,
TBAF, THF; vii, EtMgBr, Li2CuCl4, THF; viii, CH2Cl2–Et2O.
J. Chem. Soc., Perkin Trans. 1, 2001, 645–653
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successfully extended to the 1,8- and 1,9-asymmetric inductive
reactions of δ- and ε-keto esters by changing the 2Ј-oligoether
tether of the chiral auxiliaries and that the former reaction can
be advantageously utilized in the synthesis of (Ϫ)-malyngolide.
Experimental
Microanalyses were carried out in the Microanalytical Labor-
atory of the Institute for Chemical Reaction Science, Tohoku
University. Optical rotations were measured on a Union Giken
PM-101 or JASCO DIP-100 polarimeter and are given in units
of 10Ϫ1 deg cm2 gϪ1. IR spectra were recorded on a Shimadzu
IR-460 spectrophotometer. 1H and 13C NMR spectra were
recorded on a Bruker AC-250T, DPX-400 or DRX-500
spectrometer using tetramethylsilane as the internal standard
and CDCl3 as the solvent unless otherwise noted. J Values are
given in Hz. Silica gel columns were prepared by use of Nacalai
silica gel 60 (70–230 mesh). Merck silica gel 60GF254 was used
for analytical and preparative TLC (PLC). Densities (d) are
given in units of g cmϪ3. Na2SO4 was employed for the drying
of extracts. Water- and air-sensitive reactions were routinely
carried out under nitrogen. Diethyl ether and THF were
distilled from sodium diphenyl ketyl just before use. Dichloro-
methane, DMF and pyridine were distilled from CaH2. Other
solvents for experiments requiring anhydrous conditions were
purified by usual methods. The complexation experiments were
carried out by the same procedure as previously reported.3
Chiral auxiliaries 1a–c, e, f were obtained as before.3
Fig. 2 Schematic view of the pseudo-macrocyclic complex 27
composed of keto ester 3c and MgBr2.
macrocyclic complex 28 of the ε-keto ester 5c is unclear at
present, the structure seems to be similar to that of the γ-keto
ester3 and different from that of the δ-keto ester. Neither the
γ- nor the ε-keto acid component can make a zigzag structure
as observed for the δ-keto acid component (27), upon ligation
to MgBr2. Therefore, although further studies must be done to
know the precise origin of the diastereoface selection, the
attack of the nucleophile seems to occur preferentially from
outside of the pseudo-macrocycles in all these cases to give the
observed diastereoselectivity.
Synthesis of (Ϫ)-malyngolide
The δ-lactone (Ϫ)-malyngolide 36, an antibiotic discovered
from the marine blue-green alga Lyngbya majuscula, exhibits
significant activity against Mycobacterium smegmatis and
Streptococcus pyogenes.7 Although a number of papers have
dealt with the synthetic strategies, the methods require many
steps and/or suffer from low yields.8
It occurred to us that the remote asymmetric inductive
Grignard reaction of the δ-keto ester 3 could be advantageously
utilized for an improved synthesis of malyngolide 36 with a
quaternary carbon center (Scheme 3). Our synthetic strategy
(Ra)-2Ј-[4-(2-Methoxyethoxy)butoxy]-1,1Ј-binaphthalen-2-ol 1d
The starting alcohol, 4-(2-methoxyethoxy)butanol, was pre-
pared according to the method described by Okano et al.12
Thus, 1-chloro-2-methoxyethane (17.6 g, 186 mmol) was added
dropwise over a period of 30 min to a boiling solution of
butane-1,4-diol (25.0 g, 277 mmol) and NaOH (93%; 11.1 g,
258 mmol) in distilled water (10 cm3). After being refluxed for
25 h, the mixture was allowed to cool to room temperature and
neutralized by addition of conc. HCl. The resulting salt
was filtered off and the filtrate was evaporated to leave a pale
yellow oil, which was distilled through a Widmer fractionating
column. In contrast to the original report, the fractionated
distillate (17.6 g; bp 123–124 ЊC/15 Torr, 1 Torr = 133.3 N mϪ2
)
was a mixture of the desired 4-(2-methoxyethoxy)butanol
and butane-1,4-diol. Therefore, the mixture was used in the
following step without further purification.
To a stirred solution of the mixed alcohols (5.03 g) in dry
pyridine (40 cm3) was added toluene-p-sulfonyl chloride (14.3 g,
75.0 mmol) at 0 ЊC and the mixture was stirred at this temper-
ature overnight. The mixture was poured into ice-cold 6 mol
dmϪ3 HCl and extracted with dichloromethane. The organic
layer was dried and evaporated. The residue was dissolved in
the minimum amount of diethyl ether and the solution was
cooled in a refrigerator to induce crystallization of butane-1,4-
diyl ditosylate, which was removed by filtration. The mother
liquid was evaporated and the residue was chromatographed on
a silica gel column with hexane–ethyl acetate (3 : 2) as the
eluent to give 4-(2-methoxyethoxy)butyl toluene-p-sulfonate
(5.17 g, 32% based on 1-chloro-2-methoxyethane) as a colorless
oil, νmax(neat)/cmϪ1 1360 (SO2) and 1173 (SO2); δH(250 MHz)
1.56–2.04 (4 H, m, TsOCH2CH2CH2), 2.45 (3 H, s, ArMe),
3.36–3.64 (9 H, m, CH2OC2H4OMe), 4.05 (2 H, t, J 6.2,
TsOCH2), 7.35 (2 H, d, J 8.3, ArH) and 7.78 (2 H, d, J 8.3,
ArH).
Scheme 3 Reagents: i, MgBr2ؒOEt2, CH2Cl2–Et2O; ii, LDA, MeI,
THF–HMPA; iii, HIO4ؒ2H2O, RuCl3ؒ3H2O, CCl4–MeCN–H2O; iv,
CH2N2, Et2O; v, LiI, pyridine; vi, ClCO2Et, Et3N, Et2O; vii, Zn(BH4)2.
started with the reaction of δ-keto ester (Sa )-3c with nonyl-
magnesium bromide 8c. The Grignard reaction afforded the
corresponding δ-lactone 30 of high enantiomeric purity (97%
ee), which was methylated by treatment with LDA and
iodomethane to give a mixture of epimers 31 and 32. The RuO4
oxidation9 of the mixture gave acids 33 and 34 after chroma-
tographic purification as the methyl esters. The acids were then
treated with ethyl chloroformate and the resulting acid
10
anhydrides were reduced with Zn(BH4)2
to give (Ϫ)-
malyngolide 36 and epi-malyngolide 35 in the ratio of 8 : 1. It is
well known that these epimers are readily separated by chroma-
tography and that epi-malyngolide 35 can be epimerized to
malyngolide 36 by treatment with potassium tert-butoxide.11
Therefore, the present method provides an easy access to (Ϫ)-
malyngolide 36.
In conclusion, we have shown here that our previously
reported methodology to realize the highly efficient 1,7-
asymmetric inductive Grignard reaction of γ-keto esters can be
To a solution of (R)-BINOL (1.56 g, 5.45 mmol) in dry DMF
(15 cm3) was added NaH (60%; 219 mg, 5.48 mmol) portion-
wise and the mixture was stirred at room temperature for 3 h to
give a yellow solution, to which was added a solution of the
tosylate (1.66 g, 5.49 mmol) in DMF (15 cm3) and the mixture
was heated at 100 ЊC for 30 min. The cooled mixture was
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poured into 2 mol dmϪ3 HCl and the mixture was extracted
with diethyl ether. The extracts were washed successively with
saturated aqueous NaHCO3, distilled water and brine, dried
and evaporated. The residue was chromatographed on a silica
gel column with hexane–ethyl acetate (1 : 2) as the eluent to
give auxiliary 1d (1.71 g, 75%) as a pale yellow oil (Found: C,
77.7; H, 6.6. C27H28O4 requires C, 77.9; H, 6.8%); [α]1D8 Ϫ12.3
(c 1.06 in CHCl3); νmax(neat)/cmϪ1 3330 (OH); δH(250 MHz)
1.22–1.60 (4 H, m, ArOCH2C2H4), 3.13–3.41 (9 H, m, CH2-
OC2H4OMe), 3.96–4.10 (2 H, m, ArOCH2), 5.25 (1 H, br s, OH)
and 7.02–8.02 (12 H, m, ArH).
Ester (Ra)-4c. Hexane–ethyl acetate (1 : 1) as the eluent; a
pale yellow oil (87%) (Found: C, 74.6; H, 6.7. C32H34O6 requires
C, 74.7; H, 6.7%); [α]2D1 Ϫ8.2 (c 1.06, CHCl3); νmax(neat)/cmϪ1
1756 (CO) and 1714 (CO); δH(250 MHz) 1.25–1.41 (2 H, m,
OCOCH2CH2), 1.72–1.80 (4 H, m, ArOCH2CH2 and
OCOCH2), 1.88 (3 H, s, Ac), 2.04–2.11 (2 H, m, OCO-
C2H4CH2), 2.96–3.41 (9 H, m, CH2OC2H4OMe), 4.02–4.14
(2 H, m, ArOCH2), 7.17–7.44 (8 H, m, ArH) and 7.91–7.99
(4 H, m, ArH).
Ester (Ra)-5c. Benzene–ethyl acetate (9 : 1) as the eluent; a
pale yellow oil (98%) (Found: C, 77.2; H, 6.5. C38H38O6 requires
C, 77.3; H, 6.5%); [α]D18 +19.1 (c 1.10, CHCl3); νmax(neat)/cmϪ1
1757 (CO) and 1687 (CO); δH(250 MHz) 0.95–1.48 (4 H, m,
OCOCH2C2H4), 1.71 (2 H, quint, J 6.6, ArOCH2CH2), 1.99–
2.17 (2 H, m, OCOCH2), 2.48–2.72 (2 H, m, CH2COPh),
2.83–3.49 (6 H, m, CH2OC2H4O), 3.30 (3 H, s, OMe), 3.91–4.18
(2 H, m, ArOCH2) and 7.10–8.12 (17 H, m, ArH).
General procedure for preparation of the ꢀ-, ꢁ- and ꢃ-keto esters
3–7
Esters 3–7 were prepared by DCC condensation of auxiliaries
1a–f with ω-keto acids 2a–e in dichloromethane in the presence
of 4-pyrrolidin-1-ylpyridine (PPy), according to the procedure
reported before.3 The eluents for the chromatographic puri-
fication, the isolated yields and the physical and spectral
characteristics of the esters are given below.
Ester (Ra)-5d. As a colorless oil (76%) (Found: C, 77.7; H,
6.8. C39H40O6 requires C, 77.5; H, 6.7%); [α]1D8 +26.9 (c 0.97,
CHCl3); νmax(neat)/cmϪ1 1757 (CO) and 1687 (CO); δH(250
MHz) 0.95–1.65 (8 H, m, OCH2C2H4 and OCOCH2C2H4), 2.09
(2 H, t, J 7.4, OCOCH2), 2.60 (2 H, t, J 7.4, CH2COPh), 3.00–
3.50 (6 H, m, CH2OC2H4O), 3.34 (3 H, s, OMe), 3.87–4.08 (2 H,
m, ArOCH2) and 7.08–8.08 (17 H, m, ArH).
Ester (Ra)-3a. As a colorless oil (88%) (Found: C, 78.93; H,
5.92. C34H30O5 requires C, 78.74; H, 5.83%); [α]2D2 Ϫ13.4 (c 1.41,
CHCl3); νmax(neat)/cmϪ1 1755 (CO) and 1688 (CO); δH(250
MHz) 1.35–1.71 (2 H, m, CH2), 2.00–2.54 (4 H, m, CH2), 2.98
(3 H, m, OMe), 3.17–3.45 (2 H, m, CH2), 3.88–4.10 (2 H, m,
CH2) and 7.17–7.99 (17 H, m, ArH).
Ester (Ra)-5f. Benzene–ethyl acetate (7 : 3) as the eluent; a
pale yellow oil (66%) (Found: C, 75.5; H, 6.6. C39H40O7 requires
C, 75.5; H, 6.5%); [α]D18 +31.8 (c 0.98, CHCl3); νmax(neat)/cmϪ1
1757 (CO) and 1687 (CO); δH(250 MHz) 0.96–1.42 (4 H, m,
OCOCH2C2H4), 2.09 (2 H, t, J 7.3, OCOCH2), 2.61 (2 H, t,
J 7.5, CH2COPh), 3.33 (3 H, s, OMe), 3.38–3.62 (10 H, m,
CH2OC2H4OC2H4O), 3.97–4.22 (2 H, m, ArOCH2) and 7.10–
8.04 (17 H, m, ArH).
Ester (Ra)-3b. Benzene–ethyl acetate (8 : 1) as the eluent; a
colorless oil (88%) (Found: C, 78.9; H, 6.1. C35H32O5 requires C,
78.9; H, 6.1%); [α]D16 Ϫ17.3 (c 1.04, CHCl3); νmax(neat)/cmϪ1 1756
(CO) and 1684 (CO); δH(250 MHz) 1.45–1.71 (4 H, m,
OCH2CH2 and OCOCH2CH2), 2.16–2.51 (4 H, m, OCOCH2-
CH2CH2), 2.85–3.02 (5 H, m, CH2OMe), 3.97–4.11 (2 H, m,
ArOCH2) and 7.17–7.99 (17 H, m, ArH).
Ester (Ra)-6c. Benzene–ethyl acetate (4 : 1) as the eluent; a
colorless oil (90%) (Found: C, 74.7; H, 7.0. C33H36O6 requires
C, 75.0; H, 6.9%); [α]D19 +21.1 (c 1.26, CHCl3); νmax(neat)/cmϪ1
1754 (CO) and 1714 (CO); δH(250 MHz) 0.87–1.28 (4 H, m,
OCOCH2C2H4), 1.59–1.78 (2 H, m, ArOCH2CH2), 1.77–2.33
(4 H, m, OCOCH2 and CH2Ac), 2.00 (3 H, s, Ac), 2.88–3.50
(6 H, m, CH2OC2H4O), 3.31 (3 H, s, OMe), 3.92–4.20 (2 H, m,
ArOCH2), 7.00–7.60 (8 H, m, ArH) and 7.78–8.10 (4 H, m,
ArH).
Ester (Ra)-3c. Benzene–ethyl acetate (4 : 1 to 2 : 1) and then
hexane–ethyl acetate (3 : 2); a colorless oil (95%) (Found: C,
77.0; H, 6.4. C37H36O6 requires C, 77.1; H, 6.30%); [α]1D6 Ϫ21.3
(c 1.08, CHCl3); νmax(neat)/cmϪ1 1756 (CO) and 1684 (CO);
δH(250 MHz) 1.40–1.55 (4 H, m, ArOCH2CH2 and OCO-
CH2CH2), 2.16–2.52 (4 H, m, OCOCH2CH2CH2), 2.93–3.37
(9 H, m, CH2OC2H4OMe), 3.95–4.12 (2 H, m, ArOCH2) and
7.12–8.00 (17 H, m, ArH).
Ester (Ra)-3d. Hexane–ethyl acetate (3 : 2) and then benzene–
ethyl acetate (4 : 1) as the eluent; a pale yellow oil (73%)
(Found: C, 77.0; H, 6.6. C38H38O6 requires C, 77.3; H, 6.5%);
[α]D18 Ϫ22.4 (c 1.07, CHCl3); νmax(neat)/cmϪ1 1756 (CO) and 1685
(CO); δH(250 MHz) 1.23–1.62 (6 H, m, ArOCH2C2H4 and
OCOCH2CH2), 2.13–2.47 (4 H, m, OCOCH2CH2CH2), 3.08–
3.15 (2 H, m, OC3H6CH2), 3.28–3.44 (7 H, m, C2H4OMe),
3.91–4.01 (2 H, m, ArOCH2) and 7.12–7.99 (17 H, m, ArH).
Ester (Ra)-7c. Hexane–ethyl acetate (1 : 1); a colorless oil
(37%) (Found: C, 77.3; H, 6.9. C39H40O6 requires C, 77.5; H,
6.7%); [α]1D5 +9.7 (c 1.05, CHCl3); νmax(neat)/cmϪ1 1754 (CO)
and 1682 (CO); δH(250 MHz) 0.80–1.74 (8 H, m, ArOCH2CH2
and OCOCH2C3H6), 2.07 (2 H, t, J 7.2, OCOCH2), 2.62–2.83
(2 H, m, CH2COPh), 2.88–3.39 (6 H, m, CH2OC2H4O), 3.30
(3 H, s, OMe), 3.92–4.22 (2 H, m, ArOCH2), 7.03–7.67 (11 H,
m, ArH) and 7.72–8.03 (6 H, m, ArH).
Ester (Ra)-3e. Hexane–ethyl acetate (2 : 1) as the eluent; a
colorless oil (85%) (Found: C, 77.9; H, 6.9. C40H42O6 requires C,
77.6; H, 6.8%); [α]D18 Ϫ23.0 (c 1.00, CHCl3); νmax(neat)/cmϪ1 1757
(CO) and 1686 (CO); δH(250 MHz) 0.81 (6 H, d, J 6.7, Me),
1.44–1.85 (5 H, m, CHMe2, ArOCH2CH2 and OCOCH2CH2),
2.16–2.43 (4 H, m, OCOCH2CH2CH2), 2.97–3.40 (8 H, m,
CH2OC2H4OCH2), 4.00–4.09 (2 H, m, ArOCH2) and 7.16–7.99
(17 H, m, ArH).
Ester (Ra)-7d. Hexane–ethyl acetate (4 : 1) as the eluent; a
colorless oil (46%) (Found: C, 77.55; H, 6.9. C40H42O6 requires
C, 77.6; H, 6.8%); [α]D15 +11.0 (c 1.00, CHCl3); νmax(neat)/cmϪ1
1755 (CO) and 1684 (CO); δH(250 MHz) 0.78–1.55 (10 H, m,
ArOCH2C2H4 and OCOCH2C3H6), 2.03–2.17 (2 H, m,
OCOCH2), 2.62–2.85 (2 H, m, CH2COPh), 3.03–3.50 (6 H, m,
CH2OC2H4O), 3.33 (3 H, s, OMe), 3.89–4.07 (2 H, m,
ArOCH2), 7.12–7.65 (11 H, m, ArH) and 7.73–8.05 (6 H, m,
ArH).
Ester (Ra)-3f. Hexane–ethyl acetate (3 : 1) as the eluent; a
pale yellow oil (77%) (Found: C, 75.0; H, 6.3. C38H38O7 requires
C, 75.2; H, 6.3%); [α]D16 Ϫ16.4 (c 1.22, CHCl3); νmax(neat)/cmϪ1
1755 (CO) and 1682 (CO); δH(250 MHz) 1.38–1.65 (2 H, m,
OCOCH2CH2), 2.15–2.45 (4 H, m, OCOCH2CH2CH2), 3.09–
3.58 (13 H, m, CH2OC2H4OC2H4OMe), 4.08 (2 H, t, J 5.0,
ArOCH2) and 7.16–7.97 (17 H, m, ArH).
Ester (Ra)-7f. Hexane–ethyl acetate (1 : 2) as the eluent; a
colorless oil (53%) (Found: C, 75.6; H, 6.7. C40H42O7 requires C,
75.7; H, 6.7%); [α]D15 +13.6 (c 1.05, CHCl3); νmax(neat)/cmϪ1 1754
(CO) and 1684 (CO); δH(250 MHz) 0.80–1.52 (6 H, m, OCO-
CH2C3H6), 2.06 (2 H, t, J 7.1, OCOCH2), 2.68–2.82 (2 H, m,
J. Chem. Soc., Perkin Trans. 1, 2001, 645–653
649

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CH2COPh), 3.04–3.58 (10 H, m, CH2OC2H4OC2H4O), 3.37
(3 H, s, OMe), 4.05–4.17 (2 H, m, ArOCH2), 7.13–7.68 (11 H,
m, ArH) and 7.75–8.04 (6 H, m, ArH).
crushed ice and 2 mol dmϪ3 HCl and the mixture was
extracted with chloroform. The extracts were washed with
brine, dried and evaporated. The residue was purified by PLC
with benzene–ethyl acetate (1 : 1) as the developer to give diol
12 (9.6 mg, 46%) as a colorless oil (Found: C, 74.8; H, 9.75.
C13H20O2 requires C, 75.0; H, 9.7%); νmax(neat)/cmϪ1 3355
(OH); δH(250 MHz) 1.00–2.23 (8 H, m, CH2), 1.55 (3 H, s, Me),
3.57 (2 H, t, J 6.5, CH2OH) and 7.12–7.69 (5 H, m, ArH). The
enantiomeric excess of the diol 12 was determined to be 82% by
HPLC analysis on a Daicel Chiralcel OB column (4.6 mm
id × 25 cm) with 5% propan-2-ol in hexane as the eluent.
General procedure for the Grignard reaction of keto esters 3 and
4
To a solution of a keto ester 3 or 4 (100 µmol) in
dichloromethane (5.0 cm3) was added MgBr2ؒOEt2 (300 µmol)
and the dispersion was stirred for 1 h and then cooled to
Ϫ78 ЊC. After 1 h, 3.0 equiv. of a Grignard reagent 8a or b (1.0
mol dmϪ3 in diethyl ether) was added to the dispersion. The
progress of the reaction was monitored by TLC and an
additional amount of the Grignard reagent was added to the
mixture, if necessary. After the substrate had disappeared on
TLC, acetone (1.0 cm3) was added to the mixture, which was
then gradually warmed to room temperature over a period of
1 h. To the mixture was added distilled water and the two layers
were separated. The water layer was extracted with chloroform
and the combined organic layer was dried and evaporated. The
crude product was purified by PLC with hexane–ethyl acetate
or benzene–ethyl acetate as the developer to give lactone 9 as
colorless crystals (Found: C, 75.75; H, 7.4. C12H14O2 requires
C, 75.8; H, 7.4%); νmax(KBr)/cmϪ1 1717 (CO); δH(250 MHz)
1.35–1.78 (2 H, m, CH2), 1.57 (3 H, s, Me), 1.80–2.04 (1 H, m,
CH2), 2.07–2.52 (3 H, m, CH2) and 7.24–7.41 (5 H, m, ArH).
The enantiomeric excess was determined by GLC analysis on
ASTEC Chiraldex G-TA column (0.25 mm id × 20 m) at
150 ЊC. See Table 1 for the yield and enantiomeric excess of the
lactone 9 obtained in each reaction.
Determination of the absolute configuration of lactone 9
Conversion of lactone 9 into alcohol 15. To a solution of the
lactone (+)-9 of 90% ee { [α]1D2 +39.8 (c 1.01, CHCl3); 34.7 mg,
182 µmol} in diethyl ether (9.0 cm3) was added LAH (23.0 mg,
606 µmol) and the mixture was stirred at room temperature for
15 min. The mixture was cooled in an ice bath and quenched by
successive addition of crushed ice and 2 mol dmϪ3 HCl. The
mixture was extracted with chloroform and the extracts were
dried and evaporated. The residue was purified by PLC with
benzene–ethyl acetate (1 : 1) as the eluent to give diol 13 (31.1
mg, 88%) as a colorless oil (Found: C, 74.3; H, 9.3. C12H18O2
requires C, 74.2; H, 9.3%); [α]2D3 +15.6 (c 1.04, CHCl3);
νmax(neat)/cmϪ1 3355 (OH); δH(250 MHz) 1.10–2.03 (7 H, m,
CH2 and OH), 1.53 (3 H, s, Me), 2.10 (1 H, br s, OH), 3.57 (2 H,
t, J 6.8, CH2OH) and 7.16–7.53 (5 H, m, ArH).
To a solution of the diol 13 (24.0 mg, 124 µmol) in pyridine
(1.2 cm3) was added toluene-p-sulfonyl chloride (45.3 mg, 238
µmol) at 0 ЊC and the mixture was stirred at this temperature
overnight. The reaction was quenched with ice-cold 6 mol dmϪ3
HCl and the resulting mixture was extracted with chloroform.
The extracts were washed successively with 2 mol dmϪ3 HCl,
water and brine, dried and evaporated to give tosylate 14, which
was used in the next step without further purification.
General procedure for the Grignard reaction of keto esters 5 and
7
The reaction procedure was the same as that for the Grignard
reaction of keto esters 3 and 4, unless otherwise noted. After
the substrate had disappeared by monitoring on TLC (vide
supra), an additional amount of methylmagnesium bromide 8a
(1.0 mol dmϪ3 in diethyl ether; 1.0 cm3, 1.0 mmol) was added to
the mixture. The resulting mixture was gradually warmed to
room temperature before the addition of distilled water. After
the work-up, the crude product was purified by PLC with
hexane–ethyl acetate or benzene–ethyl acetate as the developer.
The ee values of the products were determined by HPLC
analyses on a Daicel Chiralcel OB (for diol 10) or OJ (for diol
11) column (4.6 mm id × 25 cm) with 10% propan-2-ol in
hexane as the eluent. See Table 1 for the yield and enantiomeric
excess of the diol 10 or 11 obtained in each reaction. The
physical and spectral characteristics of the diols are given below.
To a solution of the tosylate in diethyl ether (2.0 cm3) was
added LAH (18.0 mg, 474 µmol) at 0 ЊC and the mixture was
stirred at this temperature for 1 h. The reaction was quenched
by successive addition of ethyl acetate, distilled water and 2 mol
dmϪ3 HCl. The mixture was extracted with chloroform and the
extracts were dried and evaporated. The residue was purified by
PLC with benzene–ethyl acetate (7 : 1) as the eluent to give
dextrorotatory alcohol 15 (10.3 mg, 47%) as a colorless oil
(Found: C, 80.7; H, 10.1. C12H18O requires C, 80.9; H, 10.2%);
[α]1D9 +10.3 (c 0.53, CHCl3); νmax(neat)/cmϪ1 3415 (OH); δH(250
MHz) 0.91 (3 H, t, J 6.7, C3H6Me), 1.04–1.49 (4 H, m, CH2),
1.62 (3 H, s, Me), 1.74–2.00 (3 H, m, CH2 and OH) and
7.20–7.63 (5 H, m, ArH).
Diol 10. As crystals (Found: C, 76.35; H, 10.2. C15H24O2
requires C, 76.2; H, 10.2%); νmax(KBr)/cmϪ1 3360 (OH); δH(250
MHz) 1.16 (6 H, s, Me), 1.05–1.48 (6 H, m, CH2), 1.56 (3 H, s,
Me), 1.68–2.00 (2 H, m, CH2) and 7.13–7.64 (5 H, m, ArH).
Conversion of lactone 16 into alcohol 15. To a solution of
lactone (R)-(+)-1613 of 99% ee (267 mg, 1.52 mmol) in diethyl
ether (16 cm3) was added LAH (124 mg, 3.27 mmol) at 0 ЊC
and the mixture was stirred at this temperature for 30 min. The
reaction was quenched with 2 mol dmϪ3 HCl and the mixture
was extracted with chloroform. The extracts were washed
successively with saturated aqueous NaHCO3 and brine, dried,
and evaporated. The residue was purified by column chroma-
tography on a silica gel column with hexane–ethyl acetate (1 : 2
to 4 : 1) as the eluent to give diol 17 (257 mg, 94%) as a colorless
oil (Found: C, 73.3; H, 9.2. C11H16O2 requires C, 73.3; H, 9.0%);
[α]2D0 +21 (c 0.74, CHCl3); νmax(neat)/cmϪ1 3340 (OH); δH(250
MHz) 1.32–1.63 (2 H, m, CH2), 1.57 (3 H, s, Me), 1.80–2.10
(2 H, m, CH2), 2.09 (1 H, br s, OH), 2.89 (1 H, br s, OH), 3.60
(2 H, t, J 5.8, CH2OH) and 7.08–7.53 (5 H, m, ArH).
Diol 11. As crystals (Found: C, 76.9; H, 10.5. C16H26O2
requires C, 76.8; H, 10.5%); νmax(KBr)/cmϪ1 3400 (OH); δH(250
MHz) 1.17 (6 H, s, Me), 1.21–1.47 (8 H, m, CH2), 1.55 (3 H, s,
Me), 1.70–1.95 (2 H, m, CH2) and 7.20–7.50 (5 H, m, ArH).
Reaction of keto ester 6c with the Grignard reagent 8b
The reaction procedure was the same as that for the Grignard
reaction of keto esters 3 and 4, unless otherwise noted.
After the substrate had disappeared by monitoring on TLC
(vide supra), the reaction mixture was quenched with distilled
water and worked up. The crude product was purified by PLC
with hexane–ethyl acetate (1 : 1) as the developer to give the
corresponding hydroxy ester, which was dissolved in diethyl
ether (1.0 cm3) and treated with a large excess of LAH at 0 ЊC
for 1 h. The reaction was quenched by successive addition of
To an ice-cold solution of the diol 17 (257 mg, 1.43 mmol) in
diethyl ether (7.0 cm3) was added acetic anhydride (d 1.08; 175
mm3, 1.85 mmol), triethylamine (d 0.726; 250 mm3, 1.79 mmol)
and DMAP (47.1 mg, 386 µmol) and the mixture was stirred at
room temperature for 10 min. The reaction was quenched by
650
J. Chem. Soc., Perkin Trans. 1, 2001, 645–653

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addition of 2 mol dmϪ3 HCl dropwise at 0 ЊC and the mixture
was extracted with chloroform. The extracts were washed
successively with saturated aqueous NaHCO3 and brine, dried
and evaporated. The residue was purified by column chroma-
tography on a silica gel column with ethyl acetate as the eluent
to give acetate 18 (294 mg, 93%) as a colorless oil (Found: C,
70.2; H, 8.2. C13H18O3 requires C, 70.2; H, 8.2%); [α]1D9 +3.6
(c 1.67, CHCl3); νmax(neat)/cmϪ1 3475 (OH) and 1734 (CO);
δH(250 MHz) 1.32–1.74 (2 H, m, CH2), 1.61 (3 H, s, Me), 1.74–
1.93 (2 H, m, CH2), 2.00 (3 H, s, Ac), 2.05 (1 H, br s, OH), 3.99
(2 H, t, J 6.6, CH2OAc) and 7.12–7.53 (5 H, m, ArH).
C, 73.9; H, 11.0%); [α]1D9 +16.0 (c 1.25, CHCl3); νmax(neat)/cmϪ1
2940, 1492, 1470, 1446, 1374, 1254, 1171, 1130, 1071, 995, 772
and 698; δH(250 MHz) 0.06 (3 H, s, SiMe), 0.17 (3 H, s, SiMe),
0.87 (3 H, t, J 6.9, C3H6Me), 1.02 (9 H, s, But), 1.07–1.44 (4 H,
m, CH2), 1.65 (3 H, s, Me), 1.66–1.94 (2 H, m, CH2) and 7.17–
7.51 (5 H, m, ArH).
To an ice-cold solution of the silyl ether 22 (75.8 mg, 259
µmol) in THF (1.5 cm3) was added TBAF (1.0 mol dmϪ3 in
THF; 1.28 cm3, 1.3 mmol) and the mixture was stirred at room
temperature for 66 h. The reaction was quenched by successive
addition of crushed ice and 2 mol dmϪ3 HCl and the mixture
was extracted with chloroform. The extracts were washed suc-
cessively with saturated aqueous NaHCO3 and brine, dried and
evaporated. The residue was chromatographed on a silica gel
column with hexane–ethyl acetate (4 : 1) as the eluent to give
authentic alcohol (R)-15 (24.5 mg, 53%).
The elution behavior of the sample in HPLC on a Daicel
Chiralcel OB with 1% propan-2-ol in hexane as the eluent was
identical with that of the slower running major isomer of the
alcohol 15 derived from the lactone (+)-9 of 90% ee, which
determined the absolute configuration of the alcohol (+)-15 to
be R. Thus, the R absolute stereochemistry of the lactone (+)-9
was established.
To an ice-cold solution of the acetate 18 (260 mg, 1.17 mmol)
in dichloromethane (1.2 cm3) was added 2,6-lutidine (d 0.920;
275 mm3, 2.36 mmol) and tert-butyldimethylsilyl trifluoro-
methanesulfonate (d 1.15; 400 mm3, 1.74 mmol) and the
mixture was stirred at 0 ЊC for 20 min. The reaction was
quenched with 2 mol dmϪ3 HCl and the mixture was extracted
with chloroform. The extracts were washed successively with 2
mol dmϪ3 HCl, saturated aqueous NaHCO3 and brine and
dried. The solvents were evaporated and the residue was
chromatographed on a silica gel column with hexane–benzene–
ethyl acetate (15 : 1 : 1) as the eluent to give a mixture (304 mg)
of silyl ether 19 and a by-product, a small portion of which was
purified by PLC with hexane–benzene as the developer to give
analytically pure ether 19 as a colorless oil (Found: C, 67.9; H,
9.6. C19H32O3Si requires C, 67.8; H, 9.6%); [α]2D0 +6.6 (c 1.23,
CHCl3); νmax(neat)/cmϪ1 1742 (CO); δH(250 MHz) 0.08 (3 H, s,
SiMe), 0.19 (3 H, s, SiMe), 1.03 (9 H, s, But), 1.24–1.52 (1 H, m,
CH2), 1.69 (3 H, s, Me), 1.59–2.00 (3 H, m, CH2), 2.06 (3 H, s,
Ac), 4.00 (2 H, t, J 6.6, CH2OAc) and 7.17–7.58 (5 H, m, ArH).
To an ice-cold solution of the mixture (269 mg) in diethyl
ether (9.0 cm3) was added LAH (88.5 mg, 2.33 mmol) and the
mixture was stirred at 0 ЊC for 10 min. The reaction was
quenched with 2 mol dmϪ3 HCl and the mixture was extracted
with chloroform. The extracts were washed successively with
saturated aqueous NaHCO3 and brine, dried and evaporated.
The residue was chromatographed on a silica gel column with
hexane–ethyl acetate (6 : 1 to 5 : 1) as the eluent to give alcohol
20 (200 mg, 66% based on acetate 18) as a colorless oil (Found:
C, 69.3; H, 10.2. C17H30O2Si requires C, 69.3; H, 10.3%); [α]D19
+19.0 (c 0.87, CHCl3); νmax(neat)/cmϪ1 3350 (OH); δH(250
MHz) 0.06 (3 H, s, SiMe), 0.18 (3 H, s, SiMe), 1.02 (9 H, s, But),
1.21–2.07 (4 H, m, CH2), 1.69 (3 H, s, Me), 3.57 (2 H, t, J 6.5,
CH2OH) and 7.14–7.57 (5 H, m, ArH).
To an ice-cold solution of the alcohol 20 (153 mg, 520 µmol)
in pyridine (5.0 cm3) was added toluene-p-sulfonyl chloride
(210 mg, 1.10 mmol) portionwise and the mixture was stirred at
0 ЊC overnight. The reaction was quenched with ice-cold 4 mol
dmϪ3 HCl and the mixture was extracted with chloroform.
The extracts were washed successively with 4 mol dmϪ3 HCl,
saturated aqueous NaHCO3 and brine, dried, and evaporated.
The residue was purified by column chromatography on silica
gel with hexane–benzene (1 : 1) as the eluent to give spectro-
metrically pure tosylate 21 (190 mg, 82%) as a colorless oil,
δH(250 MHz) 0.02 (3 H, s, SiMe), 0.12 (3 H, s, SiMe), 0.97 (9
H, s, But), 1.24–1.50 (1 H, m, CH2), 1.63 (3 H, s, Me), 1.68–1.95
(3 H, m, CH2), 2.49 (3 H, s, ArMe), 3.94 (2 H, t, J 6.4, CH2OTs),
7.20–7.50 (7 H, m, ArH) and 7.71–7.88 (2 H, m, ArH).
Determination of the absolute configurations of diols 10 and 12
Conversion of tosylate 21 into alcohol 24. The tosylate (R)-21
(69.2 mg, 154 µmol) derived from lactone (R)-16 of 99% ee was
dissolved in THF (340 mm3) and the solution was cooled to
0 ЊC. To the solution was added ethylmagnesium bromide
(1.0 mol dmϪ3 in THF; 300 mm3, 300 µmol) and Li2CuCl4
(1.0 mol dmϪ3 in THF; 100 mm3, 100 µmol) at once and the
mixture was stirred at this temperature for 3 h. The reaction was
quenched by successive addition of crushed ice and 2 mol dmϪ3
HCl and the mixture was extracted with chloroform. The
extracts were washed with saturated aqueous NaHCO3 and
then brine, dried and evaporated. The residue was purified by
column chromatography on silica gel eluting with hexane to
give silyl ether 23 (42.0 mg, 89%) as a colorless oil (Found: C,
74.2; H, 11.5. C19H34OSi requires C, 74.4; H, 11.2%); [α]2D0 +15.7
(c 0.65, CHCl3); νmax(neat)/cmϪ1 2935, 1492, 1462, 1254, 1169,
1086, 1003, 833, 771 and 698; δH(250 MHz) 0.04 (3 H, s, SiMe),
0.16 (3 H, s, SiMe), 0.86 (3 H, t, J 7.0, C4H6Me), 1.01 (9 H, s,
But), 1.12–1.42 (6 H, m, CH2), 1.64 (3 H, s, Me), 1.70–1.96 (2 H,
m, CH2) and 7.12–7.62 (5 H, m, ArH).
A mixture of the silyl ether 23 (21.5 mg, 70.1 µmol) and
TBAF (1.0 mol dmϪ3 in THF; 210 mm3, 210 µmol) was stirred
at room temperature for 21 h. The reaction was quenched by
successive addition of crushed ice and 2 mol dmϪ3 HCl and
the mixture was extracted with chloroform. The extracts were
washed successively with saturated aqueous NaHCO3 and
brine, dried and evaporated. The residue was purified by PLC
with hexane–ethyl acetate (4 : 1) as the developer to give
authentic alcohol (R)-24 (6.1 mg, 45%) as a colorless oil. The
spectral data were identical with those of alcohol 24 obtained
from ester (Ra)-5d (vide infra).
Conversion of ester 5d into alcohol 24. To a solution of the
keto ester (Ra)-5d (350 mg, 579 µmol) in dichloromethane (29
cm3) was added dropwise an excess of methylmagnesium brom-
ide (0.88 mol dmϪ3 in diethyl ether; 2.6 cm3, 2.3 mmol) at
Ϫ78 ЊC and the mixture was stirred at this temperature for 5 h.
After the reaction had been quenched with distilled water, the
mixture was extracted with chloroform and the extracts were
dried and evaporated. The crude product was purified by
column chromatography on silica gel with benzene–ethyl
acetate (4 : 1 to 2 : 1) as the eluent to give hydroxyester 25 (305
mg, 85%) as a colorless oil (Found: C, 77.15; H, 7.0. C40H44O6
requires C, 77.4; H, 7.1%); νmax(neat)/cmϪ1 3460 (OH) and 1757
(CO); δH(250 MHz) 0.69–1.63 (10 H, m, OCH2C2H4 and OCO-
The Gilman reagent was prepared by addition of methyl-
lithium (1.5 mol dmϪ3 in diethyl ether; 5.6 cm3, 8.4 mmol) to an
ice-cold suspension of CuI (802 mg, 4.21 mmol) in diethyl ether
(2.0 cm3). To the cold solution was added a solution of the
tosylate 21 (190 mg, 423 µmol) in diethyl ether (4 cm3) over a
period of 5 min and the mixture was stirred at 0 ЊC for 30 min.
The reaction was quenched with saturated aqueous NH4Cl and
the mixture was extracted with chloroform. The extracts were
washed with water and then brine, dried and evaporated. The
residue was purified by column chromatography on silica gel
with hexane as the eluent to give compound 22 (105 mg, 85%)
as a colorless oil (Found: C, 73.4; H, 11.3. C18H32OSi requires
J. Chem. Soc., Perkin Trans. 1, 2001, 645–653
651

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CH2C3H6), 1.45 (3 H, s, Me), 1.94 (2 H, t, J 7.0, OCOCH2),
2.98–3.50 (6 H, m, CH2OC2H4O), 3.32 (3 H, s, OMe), 3.83–4.06
(2 H, m, ArOCH2), 7.05–7.58 (13 H, m, ArH) and 7.78–8.10 (4
H, m, ArH).
1.80 (1 H, m, CH2), 1.82–1.94 (2 H, m, CH2), 1.96–2.08 (1 H, m,
CH2), 2.24–2.33 (1 H, m, CH2), 2.35–2.50 (2 H, m, COCH2),
7.25–7.32 (3 H, m, ArH) and 7.32–7.41 (2 H, m, ArH).
The enantiomeric excess of the lactone 30 was determined to be
97% ee by HPLC analysis on a Daicel Chiralpak AD column
(4.6 mm id × 25 cm) with 3% propan-2-ol in hexane as the
eluent. On the other hand, by the same procedure as used for
the transformation of lactone 31 into malyngolide 36 (vide
infra), a portion of the sample was transformed into (S)-5-
hydroxymethyltetradecan-5-olide, [α]2D0 Ϫ2.2 (c 0.51, CHCl3)
{lit.,14 [α]D19 Ϫ2.37 (c 1.10, CHCl3) for (S)-isomer of 100% ee}.
This determined the absolute configuration of the lactone (Ϫ)-
30 to be S.
To a solution of LDA, which had been prepared from
diisopropylamine (d 0.722; 70 mm3, 499 µmol) and butyllithium
(1.62 mol dmϪ3 in hexane; 310 mm3, 502 µmol) in THF (500
µm3), was added a solution of lactone 30 (102 mg, 337 µmol) in
THF (2.0 cm3) at Ϫ78 ЊC and the mixture was stirred for 1 h. To
the mixture was added iodomethane (d 2.28; 90 mm3, 1.45
mmol) and HMPA (90 mm3). After 2 h, the mixture was
warmed to Ϫ45 ЊC, stirred overnight and then quenched with
saturated aqueous NH4Cl. The mixture was extracted with
diethyl ether and the extracts were dried and evaporated. The
residue was purified by column chromatography on silica gel
eluting with hexane–chloroform (1 : 1) to give a mixture of
epimers 31 and 32 (90.6 mg, 85%) as a colorless oil (Found: C,
79.4; H, 10.4. C21H32O2 requires C, 79.7; H, 10.2%); νmax(neat)/
cmϪ1 1732 (CO); δH(400 MHz) 0.86 (3 H, t, J 6.9, C8H16Me),
0.98–1.14 (1 H, m, CH2), 1.15–1.39 (16 H, m, CH2 and Me),
1.48–1.59 (1 H, m, CH2), 1.77–1.97 (3 H, m, CH2), 2.07–2.18
(1 H, m, CH2), 2.22–2.37 (2 H, m, CH2 and CH) and 7.24–7.40
(5 H, m, ArH).
To an ice-cold solution of 25 (274 mg, 441 µmol) in diethyl
ether (9.0 cm3) was added LAH (44.3 mg, 1.17 mmol) portion-
wise and the mixture was stirred at 0 ЊC for 30 min before being
quenched with 2 mol dmϪ3 HCl. The mixture was extracted
with chloroform and the extracts were dried and evaporated.
The residue was purified by column chromatography on silica
gel with chloroform–ethyl acetate (5 : 1 to 1 : 1) as the eluent to
give levorotatory diol 12 (82.4 mg, 90%), [α]1D8 Ϫ5.3 (c 0.91,
CHCl3), 43% ee. To a stirred solution of the diol 12 (53.9 mg,
259 µmol) in pyridine (2.6 cm3) was added toluene-p-sulfonyl
chloride (148 mg, 776 µmol) at 0 ЊC and the mixture was stirred
overnight. The reaction was quenched with ice-cold 6 mol dmϪ3
HCl and the resulting mixture was extracted with chloroform.
The extracts were washed successively with 2 mol dmϪ3 HCl,
water and brine, dried and evaporated to give tosylate 26, which
was used without further purification in the next step.
To a solution of the tosylate 26 in diethyl ether (4.0 cm3) was
added LAH (33.6 mg, 885 µmol) portionwise at 0 ЊC and the
mixture was stirred at this temperature for 1 h. The reaction was
quenched by successive addition of ethyl acetate, distilled water
and 2 mol dmϪ3 HCl. The mixture was extracted with chloro-
form and the extracts were dried and evaporated. The residue
was purified by PLC with benzene–ethyl acetate (8 : 1) as the
developer to give alcohol 24 (35.9 mg, 72% based on diol 12) as
a colorless oil (Found: C, 81.2; H, 10.5. C13H20O requires C,
81.2; H, 10.5%); [α]D19 Ϫ2.4 (c 1.18, CHCl3); νmax(neat)/cmϪ1 3415
(OH); δH(250 MHz) 0.90 (3 H, t, J 6.7, C4H8Me), 1.05–1.47
(6 H, m, CH2), 1.62 (3 H, s, Me), 1.71–2.04 (2 H, m, CH2) and
7.11–7.76 (5 H, m, ArH).
The mixture of epimers 31 and 32 (51.6 mg, 163 µmol) were
mixed with tetrachloromethane (2.0 cm3), acetonitrile (2.0 cm3),
distilled water (3.0 cm3) and HIO4ؒ2H2O (500 mg, 2.19 mmol)
to give a biphasic solution, to which was added RuCl3ؒ3H2O
(7.0 mg, 27 µmol) and the mixture was stirred at 35 ЊC for 1 d.
The cooled mixture was extracted with diethyl ether and the
extracts were washed with brine, dried and evaporated. The
residue was treated with an excess of diazomethane in diethyl
ether at room temperature to give, after purification by PLC
with hexane–dichloromethane (1 : 1) as the developer, a mix-
ture of the methyl esters of 33 and 34. This mixture was boiled
with LiI (92.2 mg, 689 µmol) in pyridine (1.0 cm3) for 8 h. To the
cooled mixture was added water and the mixture was acidified
by addition of 2 mol dm3 HCl. The mixture was extracted with
diethyl ether and the extracts were washed with water, dried and
evaporated. The residue was passed through a silica gel plug
with ethyl acetate as the eluent to give a mixture of acids 33 and
34 (27.0 mg, 58% based on the mixture of 31 and 32) as a
colorless oil, δH(500 MHz) 0.88 (3 H, t, J 6.9, C8H16Me), 1.17–
1.34 (15 H, m, CH2 and Me), 1.52–1.68 (2 H, m, CH2), 1.75–
2.07 (4 H, m, CH2), 2.18–2.28 (1 H, m, CH2), 2.43–2.67 (2 H, m,
CH2 and CH) and 8.54 (1 H, br s, OH). The 1H NMR spectrum
was identical with that of the authentic sample 33.10
Comparison of the elution behavior of the sample in HPLC
on a Chiralcel OB column with 1% propan-2-ol in hexane as the
eluent with that of the authentic alcohol (R)-24 derived from
tosylate (R)-21 determined the absolute configuration of the
major isomer running faster than the minor to be S, which
established the absolute configuration of the diol 12 as (S)-(Ϫ).
On the other hand, the reaction of the ester (Ra)-5d with the
Grignard reagent 8a under the conditions of entry 10 in Table 1
gave levorotatory diol 10 of 82% ee, [α]1D8 Ϫ5.5 (c 1.11, CHCl3).
These results determine the absolute configuration of the diol
(Ϫ)-10 to be S.
Synthesis of (Ϫ)-malyngolide
The antipode of the keto ester (Ra)-3c was obtained as above by
the DCC condensation of chiral auxiliary (Sa )-1c with 5-oxo-5-
phenylpentanoic acid. To a solution of the keto ester (Sa )-3c
(450 mg, 780 µmol) in dichloromethane (40 cm3) was added
MgBr2ؒOEt2 (609 mg, 2.36 mmol) and the mixture was stirred
at room temperature for 1 h and then cooled to Ϫ78 ЊC.
After 1 h, a quarter aliquot (900 mm3) of a solution of the
Grignard reagent 8c (1.05 mol dmϪ3 in diethyl ether; 3.60 cm3,
3.78 mmol) was added dropwise to the mixture. The reaction
was monitored by TLC and 900 mm3 each of the Grignard
solution was added to the mixture after 6, 12 and 24 h. The
mixture was stirred for a further 6 h before addition of acetone
(2.0 cm3). The mixture was allowed to warm to room tem-
perature, stirred for 2 h and then cooled in an ice bath. To the
mixture was added 2 mol dmϪ3 HCl and the resulting mixture
was extracted with chloroform. The extracts were dried and
evaporated and the residue was chromatographed on a silica gel
column eluting with hexane–chloroform (1 : 3) to give lactone
30 (193 mg, 82%) as a colorless oil (Found: C, 79.2; H, 9.9.
C20H30O2 requires C, 79.4; H, 10.0%); [α]2D2 Ϫ27.8 (c 0.81,
CHCl3); νmax(neat)/cmϪ1 1736 (CO); δH(400 MHz) 0.86 (3 H, t, J
6.9, C8H16Me), 1.00–1.13 (1 H, m, CH2), 1.15–1.32 (12 H, m,
CH2), 1.35–1.46 (1 H, m, CH2), 1.48–1.65 (1 H, m, CH2), 1.70–
To a solution of the mixture of acids 33 and 34 (38.7 mg, 136
µmol) in diethyl ether (1.0 cm3) were added triethylamine
(d 0.726; 20 mm3, 143 µmol) and ethyl chloroformate (d 1.14; 20
mm3, 210 µmol) at 0 ЊC and the mixture was stirred at this
15
temperature for 30 min. To the mixture was added Zn(BH4)2
(145 mmol dmϪ3 in diethyl ether; 1.1 cm3, 160 µmol) and the
resulting mixture was stirred for 30 min before being quenched
with saturated aqueous NH4Cl. The mixture was extracted with
diethyl ether and the extracts were washed with water, dried and
evaporated. The residue was purified by PLC with hexane–ethyl
acetate (2 : 1) as the developer to give a 8 : 1 mixture of malyn-
golide 36 and epi-malyngolide 35 (19.0 mg, 52%) as a colorless
oil, δH(500 MHz) 0.88 (3 H, t, J 6.9, C8H16Me), 1.15–1.49 (17 H,
m, CH2 and Me), 1.53–1.84 (4 H, m, CH2), 1.91–2.07 (2 H, m,
CH2), 2.37–2.55 (1 H, m, CH), 3.48 (8/9 H, d, J 12.0, CH2OH),
652
J. Chem. Soc., Perkin Trans. 1, 2001, 645–653

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5 C. R. Johnson and G. A. Dutra, J. Am. Chem. Soc., 1973, 95,
3.60 (2/9 H, s, CH2OH) and 3.65 (8/9 H, d, J 12.0, CH2OH).
1
7777.
The H NMR spectrum was composed of the spectra of the
6 G. Fouquet and M. Schlosser, Angew. Chem., Int. Ed. Engl., 1974,
13, 82.
authentic samples 35 and 36.8f
7 J. H. Cardllina II, R. E. Moore, E. V. Arnold and J. Clardy, J. Org.
Chem., 1979, 44, 4039.
Acknowledgements
8 (a) K. Matsuo, T. Matsumoto and K. Nishiwaki, Heterocycles,
1998, 48, 1213; and references therein. More recent examples:
(b) M. Carda, E. Castillo, S. Rodríguez and J. A. Marco, Tetrahedron
Lett., 2000, 41, 5511; (c) R. M. Kanada, T. Taniguchi and
K. Ogasawara, Tetrahedron Lett., 2000, 41, 3631; (d) N. Maezaki,
Y. Matsumori, T. Shogaki, M. Soejima, H. Ohishi, T. Tanaka and
C. Iwata, Tetrahedron, 1998, 54, 13087; (e) E. Winter and D. Hoppe,
Tetrahedron, 1998, 54, 10329; ( f ) S. Ohira, T. Ida, M. Moritani
and T. Hasegawa, J. Chem. Soc., Perkin Trans. 1, 1998, 293.
9 M. T. Nuñez and V. S. Martín, J. Org. Chem., 1990, 55, 1928.
10 S. Kim, C. Y. Hong and Y. C. Moon, J. Org. Chem, 1982, 47, 4350.
11 Y. Sakito, S. Tanaka, M. Asami and T. Mukaiyama, Chem. Lett.,
1980, 1223.
12 T. Okano, K. Morimoto, H. Konishi and J. Kiji, Nippon Kagaku
Kaishi, 1985, 486; Chem. Abstr.,1986, 104, 109773w.
13 A. Albinati, P. Bravo, F. Ganazzoli, G. Resnati and F. Viani,
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14 I. Ichimoto, K. Machiya, M. Kirihara and H. Ueda, Agric. Biol.
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This work was supported by Grants-in-Aid for Scientific
Research from the Ministry of Education, Science and Culture,
Japan (No. 08405058 and No. 10555318) and JSPS Research for
the Future Program.
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