A facile synthesis and enzymatic resolution of naturally occurring remotely functionalized alkylmethylmaleic anhydrides from Aspergillus wentii: Aspergillus acids A-D

Article abstract of DOI:10.1055/s-2006-926326

The first synthesis of four new naturally occurring remotely functionalized secondary mould metabolite anhydrides 1a-d is described starting from N-p-tolyl citraconimide (5) in three to six steps and 20-65% overall yields. The condensation of triphenylphosphine-maleimide adduct 6 with aldehyde 4 furnished the exoimide 7, which after isomerization, hydrolysis, and acylation gave aspergillus acid A (1a) in 54% overall yield in four steps. The condensation of adduct 6 with aldehyde 15 similarly afforded the desired imide 17 in two steps. The acid-catalyzed hydrolysis of imide 17 directly furnished aspergillus acid B (1b), exposing the latent methyl ketone present as the terminal acetylene. Sodium borohydride induced chemoselective reduction of aspergillus acid B (1b) gave aspergillus acid C (1c), which upon acetic anhydride induced acylation, furnished aspergillus acid D (1d). A facile Amano PS catalyzed acylation of aspergillus acid C (1c) gave, in good yield, the desired (+)-aspergillus acid C (1e) in 70% ee and (-)-aspergillus acid D (1f) in 72% ee. In the present enzymatic reaction, the anhydride moiety presumably plays a crucial role in the substrate recognition, binding, and resolution process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926326

PAPER
831
A Facile Synthesis and Enzymatic Resolution of Naturally Occurring
Remotely Functionalized Alkylmethylmaleic Anhydrides from Aspergillus
wentii: Aspergillus Acids A–D1
R
emotely Fun
r
ctionaliz
i
ed
A
lky
n
lmethylmale
i
ic Anh
v
ydride
s
asan Easwar, Narshinha P. Argade*
Combi Chem-Bio Resource Centre, Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25893153; E-mail: np.argade@ncl.res.in
Received 20 July 2005; revised 12 September 2005
tabolites aspergillus acids A–D produced by the mould
Aspergillus wentii when grown on a yeast–glucose medi-
um; these natural products were also established to be
derivatives of citraconic anhydride with remotely func-
Abstract: The first synthesis of four new naturally occurring re-
motely functionalized secondary mould metabolite anhydrides 1a–
d is described starting from N-p-tolyl citraconimide (5) in three to
six steps and 20–65% overall yields. The condensation of triphen-
ylphosphine-maleimide adduct 6 with aldehyde 4 furnished the exo- tionalized long hydrocarbon chains (Figure 1). On the ba-
imide 7, which after isomerization, hydrolysis, and acylation gave
sis of the Horeau method, the chiral centre in acids 1c and
1d has been assigned the S configuration.9
aspergillus acid A (1a) in 54% overall yield in four steps. The con-
densation of adduct 6 with aldehyde 15 similarly afforded the de-
To date, the synthesis of these achiral/chiral natural prod-
ucts 1a–d has not been reported. We believe that the re-
mote functional groups on the hydrophobic long chain
hydrocarbon units of these acids 1a–d will anchor the
binding process with target enzymes, resulting in a boost
in activity.17,19 The tremendous clinical potential of such
compounds, as mentioned above, makes them attractive
synthetic targets and the provision of a facile synthetic
sired imide 17 in two steps. The acid-catalyzed hydrolysis of imide
17 directly furnished aspergillus acid B (1b), exposing the latent
methyl ketone present as the terminal acetylene. Sodium borohy-
dride induced chemoselective reduction of aspergillus acid B (1b)
gave aspergillus acid C (1c), which upon acetic anhydride induced
acylation, furnished aspergillus acid D (1d). A facile Amano PS cat-
alyzed acylation of aspergillus acid C (1c) gave, in good yield, the
desired (+)-aspergillus acid C (1e) in 70% ee and (–)-aspergillus
acid D (1f) in 72% ee. In the present enzymatic reaction, the anhy-
dride moiety presumably plays a crucial role in the substrate recog- route to these molecules is an imperative task of current
nition, binding, and resolution process.
interest. In the past decade, we have in our group designed
several bioactive natural and unnatural compounds using
cyclic anhydrides as potential precursors20 and we have
also accomplished some important enzymatic resolu-
tions.21 In continuation of our earlier studies,20,21 starting
from maleimide 5, herein we report the first synthesis of
these naturally occurring acids 1a–d formed by the ele-
gant introduction of remote functional groups and an en-
zymatic resolution of acid 1c (Schemes 1 and 2).
Key words: citraconimide, Wittig condensation, chemoselective
reduction, aspergillus acid, enzymatic resolution
In the past decade, several structurally interesting com-
pounds with dialkyl substituted maleic anhydride moi-
eties have been isolated as bioactive natural products and
were synthesized in view of their promising bioactivi-
ties;2–4 of these, alkylmethylmaleic anhydrides are among
the most popular (Figure 1).5–15 One can surmise that na-
ture might design these alkylmethylmaleic anhydrides by
employing the condensation between pyruvic acid and
other carboxylic acids. A specific example is that of chae-
tomellic acid A, which was isolated from Chaetomella
acutiseta8 (genesis pyruvic acid and palmitic acid).16
Structure activity relationship studies have revealed that
the hydrophilic dianion of chaetomellic acid A binds with
the phosphate group of the enzyme and the hydrophobic
tetradecyl group coils with the farnesyl chain thus deacti-
vating the enzyme. Hence, such compounds highlighting
the regiochemical dichotomy are known to be potent and
highly specific inhibitors of ras-farnesyl-protein trans-
ferase (Ras-FPTase)8,17 and presently chaetomellic acid A
is of commercial interest as a bioactive natural product.18
Assante et al., in 1979, isolated9 four new secondary me-
Aspergillus acid A (1a) is 2-(17-acetoxyheptadecyl)-3-
methylmaleic anhydride while aspergillus acids B–D
(1b–d) contain a 16-carbon chain with carbonyl, hydrox-
yl, and acetyl groups at carbon-15, respectively. In 1997,
we developed elegant reaction conditions to couple citra-
conimide–triphenylphosphine adduct with aliphatic alde-
hydes leading to alkyl methyl substituted maleic
anhydrides.17c,22 We assumed that this coupling reaction
would be useful for the preparation of the remotely func-
tionalized anhydrides 1a–d.
With this in mind we prepared the appropriate 17-acet-
oxyhexadecanal (4) in two steps starting from 1,17-hepta-
decanediol (2) via monoacetylation and Swern oxidation
in 70% overall yield (Scheme 1). The triphenylphos-
phine-induced Wittig olefination of citraconimide 5 with
acetoxyaldehyde 4 in refluxing acetic acid gave the corre-
1
sponding exo-alkylidene succinimide 7 (E/Z, 90:10; H
NMR spectroscopy) in 70% yield. The carbon–carbon
double-bond migration from a trisubstituted exocyclic to
a tetrasubstituted endocyclic was effected by triethyl-
amine furnishing the desired maleimide 8 in 92% yield.
SYNTHESIS 2006, No. 5, pp 0831–0838
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926326; Art ID: Z14605SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
6

832
S. Easwar, N. P. Argade
PAPER
O
O
O
O
CH2CH3
CH3
CH2(CH2)4CH3
CH3
CH2(CH2)6CH3
CH3
CH2(CH2)12CH3
O
O
O
O
CH3
O
O
O
O
2-Ethyl-3-methylmaleic
2-Hexyl-3-methylmaleic
2-Octyl-3-methylmaleic
Chaetomellic acid A
(ras farnesyl-protein
transferase inhibitor)8
anhydride (flavouring agent)5
anhydride (flavouring agent)6
anhydride (flavouring agent)7
HO
O
O
O
O
O
COOH
CH(CH2)7CH3
(CH2)6CH
CH3
CH2(CH2)13
R
CH2(CH2)14CH2
O
O
O
O
O
CH3
CH3
CH3
CH3
O
O
O
O
O
cis-Chaetomellic acid B
(ras farnesyl-protein
transferase inhibitor)8
1a: Aspergillus acid A [R = (CH2)3OAc]9
1b: Aspergillus acid B [R = COCH3]9
Maleic anhydride
segment of tautomycin
(antifungal,
Tyromycin A
(aminopeptidase inhibitor,
potential cytostatic
activity)11
1c: (S)-Aspergillus acid C [R = CH(OH)CH3]9
1d: (S)-Aspergillus acid D [R = CH(OAc)CH3]9
antibiotic)10
(activity unknown)
O
O
O
O
O
O
O
O
COOH
OH
O
O
O
H
R
CH3
CH3
CH3
CH3
Graphenone
O
O
O
Lindenanolide E (R =
CHO)
Telfairic anhydride
(activity
Itaconitin
(activity
(activity
(HIV-1 integrase
unknown)13
unknown)14
unknown)15
inhibitor)12
Figure 1 Naturally occurring alkyl methyl substituted maleic anhydrides and their bioactivities
Base-catalyzed hydrolysis of maleimide 8 furnished the 2- At this stage, we had two options for the synthesis of as-
(17-hydroxytetradecyl)-3-methylmaleic anhydride (9) in pergillus acids B–D, (i) start with a suitable w-substituted
94% yield. Acetic anhydride mediated acylation of anhy- 16-carbon aldehyde, perform the selective remote func-
dride 9 gave the naturally occurring aspergillus acid A tionalization, and then attempt a new enzymatic resolu-
(1a) in 89% yield. The analytical and spectral data ob- tion, or (ii) directly design and start with a protected
tained for acid 1a were in complete agreement with the re- enantiomerically pure remotely functionalized 16-carbon
ported data9 and the overall yield of 1a, for the four steps, aldehyde. We reasoned and chose the former, as the latter
was 54%. The successful synthesis of 1a proved that our would involve (i) stoichiometric use of costly reagents for
present synthetic route would allow the preparation of the enantioselective reduction of alkyl methyl ketone,23,24
chiral acids 1c and 1d via acid 1b.
(ii) appropriate protection–deprotection of the secondary
i
ii
HOCH2(CH2)15CH2OH
H3CCOOCH2(CH2)14CH2CHO
H3CCOOCH2(CH2)15CH2OH
(89%)
O
(79%)
2
3
4
H
O
O
PPh3
CH2(CH2)14CH2OAc
CH3
iii
(70%)
iv
Ar
N
Ar
N
Ar
N
(92%)
CH3
CH3
O
O
O
5
6
7
(E:Z = 90:10)
O
O
O
O
CH2(CH2)15CH2OAc
CH3
CH2(CH2)15CH2OH
CH2(CH2)15CH2OAc
CH3
v
vi
Ar
N
O
(89%)
(94%)
CH3
O
O
O
8
9
Aspergillus acid A (1a)
Ar = p-Tolyl
Scheme 1 Reagents and conditions: (i) Ac2O (0.98 equiv), py, r.t., 6 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, –60 °C, 90 min; (iii) PPh3, AcOH,
4, reflux, 18 h; (iv) Et3N, THF, reflux, 48 h; (v) (a) KOH (30% aq), THF–MeOH (1:2), reflux, 12 h, (b) H+/HCl; (vi) Ac2O, py, r.t., 8 h.
Synthesis 2006, No. 5, 831–838 © Thieme Stuttgart · New York

PAPER
Remotely Functionalized Alkylmethylmaleic Anhydrides
833
alcohol moiety, and (iii) possible loss of enantiomeric pu- now left with two important tasks, converting the maleim-
rity during the course of the total synthesis.
ide 17 to the anhydride and exposing the latent methyl ke-
tone present as the terminal acetylene. Both steps were
achieved in one pot in 90% yield upon treatment of imide
17 with a mixture of acetic acid and 6 M sulfuric acid (2:1)
at 100 °C. Under these conditions, the imide was hydro-
lyzed to the anilic acid, which subsequently underwent
ring-closure to the anhydride; simultaneous addition of a
water molecule to the carbon–carbon triple bond in a
Markovnikov fashion led to the generation of an alkyl
methyl ketone, thus furnishing the natural product 1b. We
were also able to successfully isolate the intermediate
acetylinic anhydride 18 by carrying out base-catalyzed
hydrolysis of the corresponding maleimide 17. The anhy-
dride 18 on acid-catalyzed hydration gave the desired as-
pergillus acid B (1b) in 90% yield. The overall yield of
aspergillus acid B for the three steps was 65%.
In our efforts to functionalize the remote carbon in accor-
dance with the established structures of the target mole-
cules, we envisaged a Markovnikov hydration of a
terminal acetylene as the key step in the synthesis of these
mould metabolites 1b–d. In this context, 1,14-tetradecane
diol (10) was transformed in two steps to the w-bromo-O-
THP protected alcohol 12 via the corresponding bromo-
hydrin in 79% overall yield. The bromo compound 12 was
then converted using standard functional group intercon-
versions to the desired aldehyde 15 in three steps (69%)
with incorporation of an acetylene unit at the terminal po-
sition of the chain (Scheme 2). The overall yield of alde-
hyde 15 for the five steps was 54%. Wittig condensation
of aldehyde 15 with the imide–triphenylphosphine adduct
generated in situ from citraconimide 5 proceeded smooth-
ly in refluxing acetic acid to yield the exo-imide 16 Chemoselective reduction of the ketone carbonyl in 1b
(E/Z, 85:15; 1H NMR spectroscopy) in 78% yield with the was now necessary to obtain the corresponding hydroxyl
carbon–carbon triple bond intact. Subsequently, triethyl- compound 1c. In our hands, sodium borohydride reduc-
amine efficiently catalyzed the isomerization of the exo- tion of 1b in organic solvents under a variety of conditions
cyclic trisubstituted carbon–carbon double bond in exo- failed to provide us with the required chemoselectivity.
alkylidene succinimide 16 to afford the tetrasubstituted We always observed the reduction of the anhydride car-
endocyclic maleimide 17 in 93% yield. To complete the bonyl as well as the ketone moiety and obtained a mixture
synthesis of the second metabolite in the series, we were of the corresponding butyrolactones 19a/19b (26:74) with
i
ii
iii
BrCH2(CH2)12CH2OH
HOCH2(CH2)12CH2OH
BrCH2(CH2)12CH2OTHP
(85%)
(93%)
(85%)
10
11
12
iv
(95%)
v
HC CCH2(CH2)12CH2OTHP
HC CCH2(CH2)12CH2OH
14
HC CCH2(CH2)11CH2CHO
(85%)
13
15
H
O
O
O
O
x
CH2(CH2)12CH2C CH
CH2(CH2)12CH2COCH3
CH3
ix
vii
CH
CH2(CH2)11CH2C
CH3
vi
X
O
Ar N
Ar
(81%)
N
(90%)
(93%)
(78%)
CH3
CH3
O
O
O
O
16
17 (x = N-Ar)
Aspergillus acid B (1b)
(E:Z = 85:15)
5
viii
ix
18 (x = O)
(90%)
(95%)
OH
OR
OH
OCOCH3
O
O
O
O
CH2(CH2)12CH2
CH3
CH2(CH2)12CH2
CH3
CH2(CH2)12CH2
CH2(CH2)12CH2
xiii
xii
O
O
O
+
O
[for (–)-1f]
(90%)
(for 1c)
CH3
CH3
O
O
O
O
Aspergillus acid C (1c, R = H)
Aspergillus acid D (1d, R = Ac)
xi (91%)
(–)-Aspergillus acid D (1f)
(–)-Aspergillus acid C (1g)
(+)-Aspergillus acid C (1e)
(43% yield 72% ee)
(45% yield, 70% ee)
Ar = p-Tolyl
Scheme 2 Reagents and conditions: (i) HBr (47% aq), toluene, reflux, 96 h; (ii) DHP, PPTS (cat.), CH2Cl2, r.t., 4 h; (iii) NaC≡CH, THF,
HMPA, –78 °C to r.t., 40 h; (iv) p-TsOH, MeOH, r.t., 2 h; (v) (COCl)2, DMSO, Et3N, CH2Cl2, –60 °C, 90 min; (vi) PPh3, AcOH, 15, reflux,
24 h; (vii) Et3N, THF, reflux, 48 h; (viii) (a) KOH (30% aq), THF–MeOH (1:2), reflux, 12 h, (b) H+/HCl; (ix) 6 M H2SO4–AcOH (1:2), 100 °C,
8 h; (x) (a) NaOH (aq), THF, 50 °C, 2 h, (b) NaBH4, 0 °C to r.t., 3 h, (c) H+/HCl; (xi) Ac2O, py, r.t., 12 h; (xii) Amano PS, vinyl acetate, hexane–
benzene (2:1), 45 °C, 72 h; (xiii) (a) NaOH (aq), THF, 50 °C, 4 h, (b) H+/HCl.
Synthesis 2006, No. 5, 831–838 © Thieme Stuttgart · New York

834
S. Easwar, N. P. Argade
PAPER
the remote hydroxyl functional group (Scheme 3). The enzymatic resolution of a secondary alcohol coupled with
structural assignment of regioisomers 19a and 19b was a maleic anhydride moiety.
1
deduced on the basis of H NMR signals for the vinylic
In summary, a facile route for the synthesis of four new
methyl group. As expected, the b-methyl group signal in
secondary metabolites 1a–d has been described in three to
the major isomer 19b appeared at 2.02 ppm, while the a-
five steps in very good overall yields. In the present syn-
thesis, a terminal acetylene group is employed to bring
methyl group in the minor isomer 19a appeared at 1.83
ppm. Finally, the desired chemoselectivity was obtained
about an elegant means of remote functionalization; the
by carrying out a sodium borohydride reduction of the
chemoselective sodium borohydride reduction and
Amano PS catalyzed enzymatic resolution are both note-
worthy. The Amano PS catalyzed enzymatic resolution of
corresponding di-sodium salt of 1b followed by quench-
ing the reaction with dilute hydrochloric acid to afford,
exclusively, the natural product 1c in 81% yield. We be-
( )-1c gave the (+)-aspergillus acid C (1e) in 45% yield
lieved that the hydroxy anhydride 1c was a potential pre-
and 70% ee and (–)-aspergillus acid D (1f) in 43% yield
cursor for the synthesis of the macrocyclic lactone
and 72% ee. We feel that the present approach is general
skeleton via intramolecular lactonization pathway. Acet-
in nature and will be useful for the design of several ana-
ylation of hydroxy anhydride 1c with acetic anhydride–
logues of these metabolites for structure activity relation-
ship studies.
pyridine furnished the fourth metabolite in the series, 1d,
in 91% yield. The overall yield of aspergillus acid C was
53% (four steps) and that of aspergillus acid D was 48%
Stereochemical assignments are based on the optical rotation of
(five steps). The analytical and spectral data obtained for
known compounds.9 Amano PS-1360 U was obtained from Amano
natural products 1b–d were in complete agreement with
Pharmaceuticals, Japan. The activity of the lipase powder used is
expressed in terms of units, 1 unit corresponding to micromoles of
the reported data.9
butyric acid liberated (estimation by GC) from glyceryl tributyrate
The conversion of methyl alkyl ketones to enantiomeri-
per minute per milligram of enzyme powder.28 Mps are uncorrected.
cally pure secondary alcohols using Baker’s yeast and
NMR spectra were recorded in CDCl3 using TMS as an internal
other microorganisms is known to be unsatisfactory24,25
standard on a Brucker AC 200, MSL 300, and MSL 500 NMR spec-
and enzymatic resolution is a better option in such cases.
trometers. FT-IR spectra were recorded on a FT-IR-8300 Shimadzu
We felt that the presence of a remote anhydride moiety in
aspergillus acid C would improve the recognition and
binding of the substrate acids 1c/1d during resolution and
hence we systematically studied both the enzyme-cata-
lyzed hydrolysis of ( )-1d and the enzyme-catalyzed acy-
lation of ( )-1c using vinyl acetate as an acyl donor. The
biphasic Amano PS catalyzed hydrolysis of ( )-1d pro-
ceeded rather slowly and after a prolonged reaction time
(seven days), we observed only 8–10% of the hydrolyzed
product (by 1H NMR spectroscopy). Following our earlier
observation,21a we performed the Amano PS catalyzed
acylation of ( )-1c in hexane–benzene (2:1) and observed
a very clean acylation at 45 °C to obtain the acids (+)-1e
(45%) and (–)-1f (43%), after separation by column chro-
matography. The base-catalyzed hydrolysis of (–)-as-
pergillus acid D (1f) furnished (–)-aspergillus acid C (1g)
in 90% yield. 1H NMR spectra of the MTPA derivatives26
of both (+)-aspergillus acid C (1e) and (–)-aspergillus acid
C (1g) showed a very clean separation of the two diaste-
reomeric methoxy group singlet signals, revealing that the
acids (+)-1e and (–)-1g formed in 70% ee and 72% ee, re-
spectively. To the best of our knowledge27 this is the first
spectrometer. Column chromatographic separations were done on
ACME silica gel (60–120 mesh/100–200 mesh). Commercially
available 1,14-tetradecanediol, Cl(CO)2Cl, PPh3, dihydropyran,
Ac2O, sodium acetylide, DCC, and (R)-Mosher’s acid were used.
Petroleum ether (PE) with a bp range 60–80 °C was used.
17-Acetoxyheptadecan-1-ol (3)
Ac2O (0.92 mL, 9.80 mmol) was added to a cool (ice bath) solution
of 1,17-heptadecanediol (2)29 (2.72 g, 10.00 mmol) in anhyd pyri-
dine (10 mL) with stirring. The reaction mixture was allowed to
warm to r.t., stirred for a further 6 h, then poured into ice-water (30
mL), and extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with a solution of CuSO4 (5% aq, 30 mL), H2O
(30 mL), brine (30 mL), and dried over Na2SO4. The organic phase
was concentrated in vacuo and the residue was purified by column
chromatography (PE–EtOAc, 8:2) to give 3; yield: 2.48 g (79%);
white solid; mp 60–61 °C.
IR (CHCl3): 3447, 1726 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 26 H), 1.50–1.70 (m, 5
H), 2.05 (s, 3 H), 3.64 (t, J = 6 Hz, 2 H), 4.05 (t, J = 6 Hz, 2 H).
17-Acetoxyheptadecan-1-al (4)
A solution of Cl(CO)2Cl (0.88 mL, 10.00 mmol) in anhyd CH2Cl2
(5 mL) was placed in a two-necked round-bottom flask and kept un-
der argon at –60 °C. A solution of DMSO (1.42 mL, 20.00 mmol)
in anhyd CH2Cl2 (5 mL) was added dropwise over a period of 5 min.
O
O
(i) NaBH4, MeOH
–5 °C, 10 min
CH2(CH2)12CH2COCH3
CH2(CH2)12CH2CH(OH)CH3
CH2(CH2)12CH2CH(OH)CH3
O
O
+
O
(ii) H+/HCl
(77%)
CH3
CH3
CH3
O
O
19b
Aspergillus acid B (1b)
19a
19a:19b = 26:74
Scheme 3
Synthesis 2006, No. 5, 831–838 © Thieme Stuttgart · New York

PAPER
Remotely Functionalized Alkylmethylmaleic Anhydrides
835
Alcohol 3 (1.57 g, 5.00 mmol) in anhyd CH2Cl2 (5 mL) was added
dropwise over a period of 5 min and stirred at –60 °C for 90 min.
Et3N (4.17 mL, 30.00 mmol) was added, the reaction mixture was
allowed to warm to r.t., and stirred for a further 45 min. The reaction
was quenched by the addition of H2O (20 mL) and the aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The combined organic lay-
ers were washed with H2O (20 mL), brine (20 mL), and dried over
Na2SO4. The organic phase was concentrated in vacuo and the res-
idue was purified by column chromatography (PE–EtOAc, 9:1) to
give 4; yield: 1.39 g (89%); thick oil.
2-Heptadec-(17-acetoxy)yl-3-methyl-N-(p-tolyl)maleimide (8)
A solution of 7 (994 mg, 2.00 mmol) in THF (3 mL) and Et3N (3
mL) was stirred under reflux for 48 h, then the reaction was allowed
to cool to r.t. The reaction mixture was concentrated in vacuo and
the residue was purified by column chromatography (PE–EtOAc,
9:1) to give 8; yield: 915 mg (92%); white solid; mp 70–71 °C.
IR (CHCl3): 1736, 1707 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 26 H), 1.50–1.70 (m, 4
H), 2.05 (s, 6 H), 2.37 (s, 3 H), 2.46 (t, J = 6 Hz, 2 H), 4.05 (t, J = 6
Hz, 2 H), 7.15–7.30 (m, 4 H).
13C NMR (CDCl3, 50 MHz): d = 8.7, 20.8, 20.9, 23.7, 25.8, 28.1,
28.5, 29.1, 29.2, 29.4, 29.5 (9 × CH2), 64.5, 125.5, 129.3, 129.4,
137.0, 137.1, 141.2, 170.7, 170.9, 171.0.
IR (CHCl3): 2716, 1740, 1729 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.28 (br s, 24 H), 1.50–1.75 (m, 4
H), 2.05 (s, 3 H), 2.43 (dt, J = 8, 2 Hz, 2 H), 4.05 (t, J = 6 Hz, 2 H),
9.77 (s, 1 H).
Anal. Calcd for C31H47NO4: C, 74.81; H, 9.52; N, 2.81. Found: C,
74.65; H, 9.41; N, 2.92.
Hexadec-15-yne-1-al (15)
Prepared from 14 (1.50 g, 6.30 mmol) using the same procedure as
described for 4; yield: 1.26 g (85%); thick oil.
IR (neat): 3310, 2718, 2116, 1726, cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.28 (br s, 20 H), 1.45–1.80 (m, 2
H), 1.94 (br s, 1 H), 2.19 (t, J = 7 Hz, 2 H), 2.43 (t, J = 7 Hz, 2 H),
9.77 (s, 1 H).
2-Hexadec-(15-yne)yl-3-methyl-N-(p-tolyl)maleimide (17)
Prepared from 16 (945 mg, 2.25 mmol) using the same procedure as
described for 8; yield: 880 mg (93%); white solid; mp 71–72 °C.
IR (CHCl3): 3308, 2116, 1709 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.27 (br s, 20 H), 1.40–1.70 (m, 4
H), 1.94 (t, J = 2 Hz, 1 H), 2.05 (s, 3 H), 2.18 (dt, J = 7, 2 Hz, 2 H),
2.37 (s, 3 H), 2.46 (t, J = 7 Hz, 2 H), 7.23 (br s, 4 H).
13C NMR (CDCl3, 50 MHz): d = 8.9, 18.4, 21.1, 23.8, 28.2–29.6 (12
× CH2), 68.0, 84.8, 125.7, 129.3, 129.6, 137.1, 137.4, 141.3, 170.9,
171.2.
( )-2-Heptadec-(17-acetoxy)ylidene-3-methyl-N-(p-tolyl)suc-
cinimide (7)
A mixture of citraconimide 5 (603 mg, 3.00 mmol) and PPh3 (0.95
g, 3.60 mmol) in glacial AcOH (15 mL) was stirred at r.t. for 1 h.
Aldehyde 4 (1.31 g, 4.20 mmol) in glacial AcOH (7 mL) was added
and the reaction was refluxed with stirring for 18 h. AcOH was dis-
tilled off in vacuo at 50 °C and the residue was dissolved in EtOAc
(30 mL). The organic layer was washed successively with H2O (15
mL), an aq solution of NaHCO3 (15 mL), brine (15 mL), and dried
over Na2SO4. The organic phase was concentrated in vacuo and the
residue was purified by column chromatography (PE–EtOAc, 9:1)
to give 7; yield: 1.04 g (70%); yellow solid; mp 60–61 °C.
Anal. Calcd for C28H39NO2: C, 79.76; H, 9.32; N, 3.32. Found: C,
79.62; H, 9.25; N, 3.20.
2-Heptadec-(17-hydroxy)yl-3-methylmaleic Anhydride (9)
To a solution of imide 8 (745 mg, 1.50 mmol) in THF–MeOH (1:2,
12 mL) was added an aq solution of KOH (30%; 10 mL) and the re-
action mixture was heated under reflux for 12 h with stirring. The
reaction mixture was concentrated in vacuo, the residue was acidi-
fied with dilute HCl, and extracted with Et2O (3 × 50 mL). The or-
ganic layer was washed with H2O (50 mL), brine (50 mL), and dried
over Na2SO4. The organic phase was concentrated in vacuo and the
residue was purified by column chromatography (PE–EtOAc, 9:1)
to give 9; yield: 516 mg (94%); white solid; mp 63 °C.
IR (CHCl3): 1771, 1713, 1672 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 24 H), 1.50–1.70 (m, 4
H), 1.52 (d, J = 8 Hz, 3 H), 2.05 (s, 3 H), 2.20–2.40 (m, 2 H), 2.38
(s, 3 H), 3.46 (q, J = 8 Hz, 1 H), 4.05 (t, J = 6 Hz, 2 H), 6.25 (dt,
J = 8, 2 Hz, 0.1 H), 6.92 (dt, J = 8, 2 Hz, 0.9 H), 7.15–7.30 (m, 4 H).
13C NMR (CDCl3, 50 MHz): d = 16.4, 20.9, 21.1, 25.8, 28.5, 29.1,
29.4–29.5 (12 × CH2), 37.4, 64.5, 126.1, 129.3, 129.6, 130.5, 138.3,
140.5, 145.0 (Z-CH=C), 168.8, 171.1, 177.3.
IR (CHCl3): 3404, 1765, 1707 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.25 (br s, 26 H), 1.50–1.70 (m, 5
H), 2.07 (s, 3 H), 2.45 (t, J = 6 Hz, 2 H), 3.64 (t, J = 4 Hz, 2 H).
Anal. Calcd for C31H47NO4: C, 74.81; H, 9.52; N, 2.81. Found: C,
74.93; H, 9.33; N, 2.86.
13C NMR (CDCl3, 50 MHz): d = 9.4, 24.3, 25.7, 27.5, 29.1, 29.3–
29.5 (11 × CH2), 32.7, 62.9, 140.4, 144.7, 165.8, 166.2.
Anal. Calcd for C22H38O4: C, 72.09; H, 10.45. Found: C, 71.97; H,
10.36.
( )-2-Hexadec-(15-yne)ylidene-3-methyl-N-(p-tolyl)succin-
imide (16)
Prepared from 5 (603 mg, 3.00 mmol) using the same procedure as
described for 7; yield: 985 mg (78%); thick oil.
IR (CHCl3): 3306, 2116, 1771, 1713, 1672 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.29 (br s, 18 H), 1.45–1.65 (m, 4
H), 1.52 (d, J = 6 Hz, 3 H), 1.94 (t, J = 2 Hz, 1 H), 2.18 (dt, J = 7, 2
Hz, 2 H), 2.25–2.35 (m, 2 H), 2.38 (s, 3 H), 3.45 (q, J = 6 Hz, 1 H),
6.23 (dt, J = 8, 2 Hz, 0.15 H), 6.91 (dt, J = 8, 2 Hz, 0.85 H), 7.10–
7.30 (m, 4 H).
2-Hexadec-(15-yne)yl-3-methylmaleic Anhydride (18)
Prepared from 17 (210 mg, 0.50 mmol) using the same procedure
described for 9; yield: 157 mg (95%); thick oil.
IR (CHCl3): 3314, 2116, 1765, 1713 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 20 H), 1.45–1.65 (m, 4
H), 1.94 (t, J = 2 Hz, 1 H), 2.07 (s, 3 H), 2.19 (dt, J = 6, 2 Hz, 2 H),
2.46 (t, J = 6 Hz, 2 H).
13C NMR (CDCl3, 125 MHz): d = 9.5, 18.4, 24.4, 27.6, 28.5, 28.7,
29.1, 29.2, 29.4–29.5 (6 × CH2), 29.7, 68.0, 84.8, 140.4, 144.8,
165.9, 166.3.
13C NMR (CDCl3, 50 MHz): d = 16.4, 18.3, 21.1, 28.4–29.4 (12 ×
CH2), 37.5, 68.0, 84.7, 126.2, 129.3, 129.6, 130.5, 138.4, 140.5,
144.4 (Z-CH=C), 168.8, 177.3.
Anal. Calcd for C21H32O3: C, 75.86; H, 9.70. Found: C, 76.01; H,
9.63.
Anal. Calcd for C28H39NO2: C, 79.76; H, 9.32; N, 3.32. Found: C,
79.81; H, 9.36; N, 3.27.
Synthesis 2006, No. 5, 831–838 © Thieme Stuttgart · New York

836
S. Easwar, N. P. Argade
PAPER
2-Heptadec-(17-acetoxy)yl-3-methylmaleic Anhydride
(Aspergillus Acid A, 1a)
IR (CHCl3): 1462, 1215 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.27 (br s, 20 H), 1.45–1.75 (m, 6
H), 1.75–2.00 (m, 4 H), 3.41 (t, J = 7 Hz, 2 H), 3.30–3.60 (m, 2 H),
3.65–3.95 (m, 2 H), 4.58 (t, J = 2 Hz, 1 H).
To a stirred solution of alcohol 9 (366 mg, 1.00 mmol) in pyridine
(4 mL) was added Ac2O (0.47 mL, 5 mmol) and the reaction mix-
ture was kept in the dark at r.t. for 8 h. The reaction mixture was
poured into H2O (20 mL) and extracted with EtOAc (3 × 15 mL).
The combined organic layers were washed with an aq solution of
CuSO4 (20 mL), H2O (20 mL), brine (20 mL), and dried over
Na2SO4. The organic phase was concentrated in vacuo and the res-
idue was purified by column chromatography (PE–EtOAc, 9:1) to
give 1a; yield: 363 mg (89%); white solid; mp 43–44 °C (lit.9 mp
45–46 °C).
1-Tetrahydropyranyloxypentadec-15-yne (13)
A sodium acetylide slurry in xylene (18%, 0.84 g, 17.50 mmol) and
THF (20 mL) under argon was cooled to –78 °C, and a solution of
12 (3.30 g, 8.75 mmol) in HMPA (10 mL) and THF (4 mL) was
slowly injected into the reaction mixture with stirring. The reaction
mixture was allowed to warm to r.t. and stirred for a further 40 h.
The reaction was slowly quenched by the addition of a sat. solution
of NaHCO3 (5%, 15 mL), then a solution of NH4OAc (15 mL) was
added to dissolve the white precipitate formed. The reaction mix-
ture was extracted with EtOAc (3 × 30 mL), the combined organic
layers were washed with H2O (25 mL), brine (25 mL), and dried
over Na2SO4. The organic phase was concentrated in vacuo and the
residue was purified by column chromatography (PE–EtOAc, 9:1)
to give 13; yield: 2.40 g (85%); thick oil.
IR (CHCl3): 1857, 1774, 1726, 1472, 1250 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 26 H), 1.45–1.70 (m, 4
H), 2.05 (s, 3 H), 2.07 (s, 3 H), 2.45 (t, J = 6 Hz, 2 H), 4.05 (t, J = 6
Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 9.4, 20.9, 24.4, 25.9, 27.5, 28.6,
29.2–29.6 (12 × CH2), 64.6, 140.4, 144.7, 165.8, 166.2, 171.1.
IR (CHCl3): 3310, 2118, 1466, 1454 cm–1.
Anal. Calcd for C24H40O5: C, 70.55; H, 9.87. Found: C, 70.61; H,
10.00.
1H NMR (CDCl3, 200 MHz): d = 1.27 (br s, 20 H), 1.40–1.65 (m, 8
H), 1.94 (t, J = 2 Hz, 1 H), 2.18 (dt, J = 7, 2 Hz, 2 H), 3.30–3.60 (m,
3 H), 3.65–3.95 (m, 3 H), 4.58 (t, J = 2 Hz, 1 H).
2-Hexadec-(15-acetoxy)yl-3-methylmaleic Anhydride
(Aspergillus Acid D, 1d)
Prepared from 1c (106 mg, 0.30 mmol) using the same procedure
described for 1a; yield: 108 mg (91%); thick oil.
Hexadec-15-yn-1-ol (14)
To a solution of 13 (2.19 g, 6.80 mmol) in MeOH (20 mL) was add-
ed p-TsOH·H2O (129 mg, 0.68 mmol) and the reaction mixture was
stirred for 2 h at r.t. NaHCO3 (500 mg) was added and the reaction
mixture was stirred for a further 30 min. The reaction mixture was
filtered through celite and the filtrate was concentrated in vacuo.
The residue was diluted with H2O (20 mL) and the aqueous phase
was extracted with EtOAc (3 × 30 mL). The combined organic ex-
tracts were washed with H2O (30 mL), a sat. solution of NaHCO3
(30 mL), brine (30 mL), and dried over Na2SO4. The organic phase
was concentrated in vacuo and the residue was purified by column
chromatography (PE–EtOAc, 8:2) to give 14; yield: 1.54 g (95%);
white solid; mp 35 °C.
IR (CHCl3): 1767, 1732 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.20 (d, J = 8 Hz, 3 H), 1.26 (br s,
22 H), 1.40–1.70 (m, 4 H), 2.03 (s, 3 H), 2.07 (s, 3 H), 2.46 (t, J = 7
Hz, 2 H), 4.89 (sext, J = 6 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): d = 9.4, 19.8, 21.2, 24.3, 25.3, 27.5,
29.1, 29.3–29.4 (9 × CH2), 35.8, 70.9, 140.4, 144.6, 165.8, 166.2,
170.7.
Anal. Calcd for C23H38O5: C, 70.02; H, 9.71. Found: C, 70.09; H,
9.82.
14-Bromotetradecan-1-ol (11)
IR (CHCl3): 3381, 3310, 2116, 1464, 1433 cm–1.
To a mixture of diol 10 (3.45 g, 15.00 mmol) and toluene (60 mL)
was added concd HBr (48% aq solution; 2 mL, 17.65 mmol). The
heterogeneous mixture was stirred and heated at reflux for 48 h. A
second portion of HBr (0.75 mL, 6.62 mmol) was added and the re-
action mixture was heated at reflux for a further 48 h. When the
starting diol had been completely consumed (TLC), the reaction
mixture was allowed to cool to r.t., and the phases were separated.
The organic layer was diluted with EtOAc (60 mL) and washed with
NaOH (1 M; 40 mL), brine (40 mL), and dried over Na2SO4. The
organic phase was concentrated in vacuo to afford a thick oil, which
was purified by column chromatography (PE–EtOAc, 8:2) to give
11; yield: 3.74 g (85%); white solid; mp 52–54 °C.
1H NMR (CDCl3, 200 MHz): d = 1.28 (br s, 20 H), 1.45–1.75 (m, 5
H), 1.95 (t, J = 2 Hz, 1 H), 2.18 (dt, J = 7, 2 Hz, 2 H), 3.64 (t, J = 6
Hz, 2 H).
2-Hexadec-(15-oxo)yl-3-methylmaleic Anhydride (Aspergillus
Acid B, 1b)
A solution of 17 (632 mg, 1.50 mmol) in AcOH (6 mL) and H2SO4
(6 M; 3 mL) was heated at 100 °C for 8 h with stirring. The reaction
mixture was allowed to cool to r.t., concentrated in vacuo, the resi-
due was diluted with H2O (20 mL), and extracted with EtOAc (3 ×
30 mL). The combined organic extract was washed successively
with H2O (30 mL), brine (30 mL), and dried over Na2SO4. The or-
ganic phase was concentrated in vacuo and the residue was purified
by column chromatography (PE–EtOAc, 8:2) to give 1b; yield: 473
mg (90%); white solid; mp 43–44 °C (lit.9 mp 43 °C).
IR (CHCl3): 3393 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 20 H), 1.50–1.70 (m, 3
H), 1.86 (quint, J = 7 Hz, 2 H), 3.42 (t, J = 7 Hz, 2 H), 3.65 (t, J =
7 Hz, 2 H).
IR (CHCl3): 1765, 1713 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 20 H), 1.45–1.65 (m, 4
H), 2.07 (s, 3 H), 2.14 (s, 3 H), 2.42 (t, J = 8 Hz, 2 H), 2.45 (t, J = 8
Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 9.5, 23.8, 24.4, 27.6, 29.1–29.4
(10 × CH2), 29.8, 43.8, 140.4, 144.7, 165.9, 166.3, 209.4.
14-Bromo-1-(tetrahydropyranyloxy)tetradecane (12)
To a solution of 11 (3.30 g, 11.26 mmol) in anhyd CH2Cl2 (20 mL)
were added dihydropyran (1.54 mL, 16.90 mmol) and PPTS (28
mg, 0.11 mmol). The reaction mixture was stirred at r.t. for 4 h. The
reaction was diluted with CH2Cl2 (15 mL) the reaction mixture was
washed with a sat. aq solution of NaHCO3 (15 mL), brine (15 mL),
and dried over Na2SO4. The organic phase was concentrated in vac-
uo and the residue was purified by column chromatography (PE–
EtOAc, 9:1) to give 12; yield: 3.95 g (93%); thick oil.
Anal. Calcd for C21H34O4: C, 71.96; H, 9.78. Found: C, 71.81; H,
9.90.
Synthesis 2006, No. 5, 831–838 © Thieme Stuttgart · New York

PAPER
Remotely Functionalized Alkylmethylmaleic Anhydrides
837
2-Hexadec-(15-hydroxy)yl-3-methylmaleic Anhydride
(Aspergillus Acid C, 1c)
(+)-1e
Yield: 79 mg (45%); white solid; mp 52 °C; [a]58920 +1.3 (c 1.0,
CHCl3) {lit.9 [a] +1.83 (c 0.38, CHCl3)}.
A solution of 1b (350 mg, 1.00 mmol) in aq NaOH (30%, 5 mL) and
THF (5 mL) was stirred for 2 h at 50 °C. The reaction mixture was
cooled to 0 °C and then NaBH4 (76 mg, 2.00 mmol) was added in
one portion. The reaction mixture was allowed to warm to r.t. and
stirred for 3 h. The reaction mixture was concentrated in vacuo,
acidified by the slow addition of dilute HCl, extracted with EtOAc
(3 × 30 mL). The combined organic extracts were washed with H2O
(30 mL), brine (30 mL), and dried over Na2SO4. The organic phase
was concentrated in vacuo and the residue was purified by column
chromatography (PE–EtOAc, 8:2) to give 1c; yield: 285 mg (81%);
white solid; mp 51–52 °C (lit.9 mp 50 °C).
Analytical and spectral data obtained were identical with 1c.
(–)-1f
Yield: 85 mg (43%); thick oil; [a]58920 +2.0 (c 1.0, CHCl3) {lit.9
(+)-1f [a] +2.70 (c 0.22, CHCl3)}.
Analytical and spectral data obtained were identical with 1d.
(–)-(R)-2-Hexadec-(15-hydroxy)yl-3-methylmaleic Anhydride
(1g)
A solution of acetate (–)-1f (60 mg, 0.15 mmol) in an aq solution of
NaOH (30%; 3 mL) and THF (3 mL) was stirred for 4 h at 50 °C.
The reaction mixture was cooled to r.t., concentrated in vacuo, acid-
ified by the addition of dilute HCl, and extracted with EtOAc (3 ×
15 mL). The combined organic layers were washed successively
with H2O (15 mL), brine (15 mL), and dried over Na2SO4. The or-
ganic phase was concentrated in vacuo and the residue was purified
by column chromatography (PE–EtOAc, 9:1) to give (–)-1g.
IR (CHCl3): 3398, 1765 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.18 (d, J = 8 Hz, 3 H), 1.26 (br s,
22 H), 1.45–1.65 (m, 4 H), 2.07 (s, 3 H), 2.45 (t, J = 7 Hz, 2 H), 3.80
(sext, J = 6 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): d = 9.0, 23.0, 24.0, 25.4, 27.1, 28.8,
29.2–29.3 (9 × CH2), 38.9, 67.5, 140.2, 144.3, 165.5, 165.9.
Anal. Calcd for C21H36O4: C, 71.55; H, 10.29. Found: C, 71.62; H,
10.36.
Yield: 48 mg (90%); thick oil; [a]58920 –1.4 (c 1.0, CHCl3).
Analytical and spectral data obtained were identical with 1c.
4-(15¢-Hydroxyhexadecyl)-3-methyl-2(5H)-furanone (19a) and
3-(15¢-Hydroxyhexadecyl)-4-methyl-2(5H)-furanone (19b)
Anhydride 1b (35 mg, 0.10 mmol) was dissolved in MeOH (4 mL).
NaBH4 (10 mg, 0.26 mmol) was added to the above solution at –5
°C and stirred for 10 min. The reaction was then quenched by the
slow addition of dilute HCl and extracted with EtOAc (3 × 15 mL).
The combined organic extracts were washed successively with H2O
(15 mL), brine (15 mL), and dried over Na2SO4. The organic phase
was concentrated in vacuo and the residue was purified by column
chromatography (PE–EtOAc, 8:2) to give 19b and 19a.
MTPA Ester; General Procedure
To a solution of (R)-Mosher’s acid (15 mg, 0.06 mmol), alcohol (+)-
1e or (–)-1g (18 mg, 0.05 mmol) and DMAP (cat.) in anhyd CH2Cl2
(3 mL) was added a solution of DCC (12 mg, 0.06 mmol) in anhyd
CH2Cl2 (2 mL) at 0 °C. The reaction mixture was allowed to warm
to r.t. and stirred for 8 h. The urea formed was removed by filtration,
the organic phase was concentrated in vacuo, and the residue was
purified by column chromatography (PE–EtOAc, 9.5:0.5) to give
the MTPA ester as a thick oil in quantitative yield.
19a
MTPA Ester of (+)-(S)-2-Hexadec-(15-hydroxy)yl-3-methyl-
maleic Anhydride (1e)
Yield: 7 mg (21%); white solid; mp 72–73 °C (lit.9 mp 72–74 °C).
1H NMR (CDCl3, 500 MHz): d = 1.15–1.35 (m, 25 H), 1.55–1.70
(m, 4 H), 2.07 (s, 3 H), 2.45 (t, J = 10 Hz, 2 H), 3.55 (s, 0.45 H),
3.57 (s, 2.55 H), 5.16 (sext, J = 5 Hz, 1 H), 7.35–7.43 (m, 3 H),
7.50–7.55 (m, 2 H).
IR (nujol): 3500, 1765 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.19 (d, J = 6 Hz, 3 H), 1.30 (br s,
22 H), 1.40–1.60 (m, 4 H), 1.83 (s, 3 H), 2.41 (t, J = 8 Hz, 2 H), 3.80
(sext, J = 6 Hz, 1 H), 4.66 (s, 2 H).
MTPA Ester of (–)-(R)-2-Hexadec-(15-hydroxy)yl-3-methyl-
maleic Anhydride (1g)
Anal. Calcd for C21H38O3: C, 74.51; H, 11.31. Found: C, 74.39; H,
11.22.
1H NMR (CDCl3, 500 MHz): d = 1.20–1.35 (m, 25 H), 1.50–1.63
(m, 4 H), 2.07 (s, 3 H), 2.45 (t, J = 10 Hz, 2 H), 3.55 (s, 2.58 H),
3.57 (s, 0.42 H), 5.14 (sext, J = 5 Hz, 1 H), 7.35–7.43 (m, 3 H),
7.50–7.55 (m, 2 H).
19b
Yield: 19 mg (56%); white solid; mp 53–54 °C (lit.9 mp 53–55 °C).
IR (nujol): 3472, 1734 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.19 (d, J = 6 Hz, 3 H), 1.30 (br s,
22 H), 1.40–1.60 (m, 4 H), 2.02 (s, 3 H), 2.25 (t, J = 7 Hz, 2 H), 3.80
(sext, J = 6 Hz, 1 H), 4.62 (s, 2 H).
Acknowledgment
S.E. thanks UGC New Delhi, for the award of a research fellowship
and N.P.A. thanks Department of Science and Technology, New
Delhi, for financial support. We thank Amano Pharmaceuticals Co.,
Japan for a generous gift of enzyme Amano PS.
Anal. Calcd for C21H38O3: C, 74.51; H, 11.31. Found: C, 74.62; H,
11.29.
Amano PS Catalyzed Acylation of ( )-1c
A solution of alcohol ( )-1c (176 mg, 0.50 mmol) in n-hexane–ben-
zene (2:1; 9 mL) was added to Amano PS lipase (100 mg) followed
by vinyl acetate (0.23 mL, 2.50 mmol). The reaction mixture was
stirred at 45 °C for 72 h and then allowed to cool to r.t. The enzyme
was removed by filtration, and washed with EtOAc. The organic
layer was dried (Na2SO4), concentrated in vacuo, and the residue
was purified by column chromatography (PE–EtOAc, 9:1) to give
(+)-1e and (–)-1f.
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Synthesis 2006, No. 5, 831–838 © Thieme Stuttgart · New York

838
S. Easwar, N. P. Argade
PAPER
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