Catalytic enantioselective synthesis of (S)-8-hydroxy-3-[(S)-2′- hydroxypentyl]-6-methoxyisochroman-1-one, (S)-3-Hydroxy-3-[(S)-2′- hydroxypentyl]-6,8-dimethoxyisochroman-1-one, and their epimers

Article abstract of DOI:10.1002/ejoc.201301708

The total synthesis of (S)-8-hydroxy-3-[(S)-2′-hydroxypentyl]-6- methoxyisochroman-1-one, (S)-3-hydroxy-3-[(S)-2′-hydroxypentyl]-6,8- dimethoxyisochroman-1-one, and their epimers has been successfully achieved. The key reactions include a catalytic enantioselective asymmetric epoxidation to introduce the chirality, and an Alder-Rickert reaction for the construction of the substituted phenyl ring. Copyright

Full text of DOI:10.1002/ejoc.201301708

FULL PAPER
DOI: 10.1002/ejoc.201301708
Catalytic Enantioselective Synthesis of (S)-8-Hydroxy-3-[(S)-2Ј-hydroxypentyl]-
6-methoxyisochroman-1-one, (S)-3-Hydroxy-3-[(S)-2Ј-hydroxypentyl]-6,8-
dimethoxyisochroman-1-one, and Their Epimers
Gullapalli Kumaraswamy,*[a,b] Kukkadapu Ankamma,[a] Nimmakayala Raghu,[a] and
Dasa RamBabu[a]
Keywords: Organocatalysis / Asymmetric synthesis / Oxygen heterocycles / Natural products / Cyclization
The total synthesis of (S)-8-hydroxy-3-[(S)-2Ј-hydroxy-
pentyl]-6-methoxyisochroman-1-one, (S)-3-hydroxy-3-[(S)-
tions include a catalytic enantioselective asymmetric epoxid-
ation to introduce the chirality, and an Alder–Rickert reaction
for the construction of the substituted phenyl ring.
2Ј-hydroxypentyl]-6,8-dimethoxyisochroman-1-one,
and
their epimers has been successfully achieved. The key reac-
of catalytic enantioselective strategies for the synthesis of
biologically active molecules,[7] we proposed a diastereo-
divergent route to (S)-8-hydroxy-3-[(S)-2Ј-hydroxypentyl]-6-
methoxyisochroman-1-one 1a and its stereoisomers.
Introduction
In 2010, Isaka and co-workers reported the isolation of
the cyclodepsipeptide cordycommunin together with two
unnamed dihydroisocoumarin natural products (1a and 1b)
from the extracts of fungus Ophiocordyceps communis
BCC16475.[1] Later, the structures assigned to these anony-
mous dihydroisocoumarins were found to be already known
in the literature .[2] The total synthesis of one of these di-
hydroisocoumarins, i.e., 7-demethoxyfusarentin 1a and its
methyl ether 1b was reported by Reddy et al.[3]
Recently, Jennings et al. not only achieved the total syn-
thesis of dihydroisocoumarin 1a, but also named compound
1a as 7-deoxy-6-O-methylfusarentin and 1b as 7-deoxy-6,8-
O-dimethylfusarentin, in analogy with the fusarentin parent
skeleton[4] (Figure 1). The family of fusarentin molecules
comprises a 4-oxy-isochroman-1-one motif connected to a
pendant stereogenic hydroxy alkyl group or a substituted
pyrone ring. Owing to the biological properties of these nat-
ural molecules,[5] several strategies have appeared for the
synthesis of this class of compounds.[2–4,6] Most of these
approaches use chiral synthons for the introduction of chi-
rality. Published routes to (S)-8-hydroxy-3-[(S)-2Ј-hydroxy-
pentyl]-6-methoxyisochroman-1-one and (S)-3-hydroxy-3-
[(S)-2Ј-hydroxypentyl]-6,8-dimethoxyisochroman-1-one
lack flexibility for stereochemical modification (Figure 1).
As a result of our continued interest in the development
Figure 1. Dihydroisocoumarin natural products.
Results and Discussion
Recently, we reported a highly diastereoselective route to
1,3,5-skipped polyols based on an iterative catalytic enan-
tioselective asymmetric epoxidation.[8] We intended to use
this method to install the requisite 1,3-diol stereogenic
centres, either syn or anti, as required for the fusarentin
family, and in particular for (S)-8-hydroxy-3-[(S)-2Ј-
hydroxypentyl]-6-methoxyisochroman-1-one and (S)-3-
hydroxy-3-[(S)-2Ј-hydroxypentyl]-6-8-dimethoxyisochrom-
an-1-one. A retrosynthetic plan is shown in Scheme 1.
Similarly to the previous synthesis of 1a, we planned to
construct the highly substituted phenyl ring by using an
Alder–Rickert reaction between alkyne ester 3 and 1,5-di-
methoxycyclohexa-1,4-diene (4). Key intermediate 3 can be
accessed by ring-opening of a terminal epoxide 5 with an
[a] Organic & Biomolecular Chemistry Division, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500607, India
www.iictindia.org
[b] Academy of Scientific and Innovative Research,
2 Rafi Marg, New Delhi 110001, India
E-mail: gkswamy_iict@yahoo.co.in
www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301708.
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Synthesis of Fusarentin Derivatives
appropriately functionalized lithium acetylide. In turn, hy- When aldehyde 10 was subjected to the catalytic epoxid-
droxy-protected terminal epoxide 5 could be synthesized by ation using ent-A, terminal epoxide anti-11 was formed in
an organocatalytic Macmillan epoxidation[9] starting from 90% yield with a 90:10 diastereomeric ratio, as estimated
achiral aldehyde 6 (Scheme 1).
by 13C NMR spectroscopy. Similarly, when catalyst A
(20 mol-%) was used under otherwise identical conditions,
terminal epoxide syn-11 was formed with a Ͼ99:1 dia-
stereomeric ratio. This indicates that the catalyst directs the
stereochemical outcome of the reaction, inducing a high
diastereoselectivity, consistant with our previous observa-
tions (Scheme 3).[8]
Scheme 1. Retrosynthesis of (S)-8-hydroxy-3-[(S)-2Ј-hydroxy-
pentyl]-6-methoxyisochroman-1-one and (S)-3-hydroxy-3-[(S)-2Ј-
hydroxypentyl]-6,8-dimethoxyisochroman-1-one.
Accordingly, enantioenriched terminal epoxide 7 with
95% ee was prepared from benzyloxy pentanal 6 by a cata-
lytic asymmetric epoxidation. The ee of 7 was determined
by comparison of its optical rotation value, and its absolute
configuration was assigned based on the sign of the specific
rotation reported in the literature.[9] CuI-catalysed regiose-
lective ring opening[10] of (R)-oxirane 7 with ethylmagne-
sium bromide gave secondary alcohol 8. The secondary
alcohol was protected as its TBS (tert-butyldimethylsilyl)
ether, and subsequent debenzylation with Li in liquid NH3
gave compound 9 in 79% yield. Subsequent oxidation of
alcohol 9 gave aldehyde 10, which was used in the next cata-
lytic asymmetric epoxidation (Scheme 2).
Scheme 3. Diastereodivergent synthesis of terminal epoxides.
Subsequent addition of lithium ethyl propiolate to ter-
minal epoxide anti-11 led to acetylene alcohol 12,[11] and
subsequent protection of the secondary alcohol with
TBSOTf under basic conditions gave silyl ether 3 in 97%
yield. Next, we carried out a typical Alder–Rickert cycload-
dition reaction[12] to construct the substituted aromatic
moiety. The reaction of 3 with diene 4 was heated in a
sealed tube under neat conditions at 200 °C with a catalytic
amount of N,N-dimethylaniline to produce the desired aro-
matic ester (i.e., 13) in 60% yield (Scheme 4).
Scheme 2. Synthesis of enantioenriched TBS-protected aldehyde;
TFA = trifluoroacetate.
Having established a route to aldehyde 10, we planned to
evaluate the catalyst-directed iterative MacMillan asymmet-
ric epoxidation and the diastereoselectivity of this reaction. fluoride.
Scheme 4. Synthesis of 1a and 1b. TBAF = tetrabutylammonium
Eur. J. Org. Chem. 2014, 2168–2173
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2169

G. Kumaraswamy, K. Ankamma, N. Raghu, D. RamBabu
(R)-2-[3-(Benzyloxy)propyl]oxirane (7): Aldehyde (5.418 g,
FULL PAPER
6
Finally, fluoride-induced deprotection of the silyl groups
and concomitant lactonization gave (S)-3-hydroxy-3-[(S)-
2Ј-hydroxypentyl]-6,8-dimethoxyisochroman-1-one 1b in
90% yield. Selective demethylation[13] of the 8-methoxy
group in 1b using boron trichloride in dichloromethane at
–78 °C gave target molecule 1a in 80% yield. The analytical
data (1H and 13C NMR spectroscopic data) and specific
rotation {[α]D32 = –15.7 (c = 0.5, CHCl3); ref.[1] [α]2D6 = –14.0
(c = 0.13, CHCl3)} of 1a were in good agreement with the
reported values (Scheme 4).
We went on to carry out the stereoselective synthesis of
syn variants epi-1b and epi-1a. Thus, exposure of syn-11 to
conditions similar to those described above for the conver-
sion of anti-11 into 1b and 1a led to the expected epi-1b
and epi-1a in 73 and 68% yields, respectively (Scheme 5).
28.2 mmol) was added to a stirred solution of catalyst A (1.60 g,
5.63 mmol), lithium chloride (1.73 g, 42.25 mmol), copper tri-
fluoroacetate hydrate (4.17 g, 14.08 mmol), and sodium persulfate
(6.706 g, 28.2 mmol) in acetonitrile (200 mL) and water (1.12 mL)
at 10 °C, and the resulting mixture was stirred vigorously for 2 h.
The reaction mixture was cooled to 0 °C, and then NaBH4 (2.68 g,
70.42 mmol) was added. After 10 min, the mixture was warmed to
room temperature. A freshly prepared ethanolic aqueous solution
of KOH [KOH (20 g) dissolved in EtOH (20 mL) and distilled H2O
(40 mL)] was added, and the resulting mixture was stirred vigor-
ously for 30 min. Distilled water (200 mL) was then added, and the
mixture was extracted with pentane (3ϫ 150 mL). The combined
organic extracts were washed with brine (1ϫ 50 mL), dried with
anhydrous Na2SO4, filtered, and concentrated, with the bath tem-
perature kept at 30 °C. The resulting residue was purified by col-
umn chromatography on silica gel (pentane/ether) to give epoxide
7 (4.58 g, 85%) as a colourless oil. [α]3D1 = +10.2 (c = 1.0, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.33–7.26 (m, 5 H), 4.51 (s, 2
H), 3.57–3.48 (m, 2 H), 2.96–2.92 (m, 1 H), 2.74 (t, J = 4.88 Hz, 1
H), 2.47 (dd, J = 2.75, 5.03 Hz, 1 H), 1.83–1.56 (m, 4 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 138.3, 128.2, 127.4, 72.7, 69.6, 51.9,
46.9, 29.1, 26.0 ppm. MS (ESI): m/z = 193 [M + H]+, 215 [M +
Na]+. HRMS (ESI): calcd. for C12H17O2 193.1223; found 193.1217.
(4S)-(1-Benzyloxy-4-hydroxy)heptane (8): Magnesium (2.5 equiv.,
0.63 g, 26 mmol) was put into a flame-dried two-necked round-
bottomed flask capped with septa and with an argon balloon, and
the magnesium was activated by heating the flask to 80 °C for
20 min. The flask was cooled to room temp., then THF (15 mL)
and a few iodine crystals were added. Bromoethane (2.5 equiv.,
1.94 mL, 26 mmol) was dissolved in THF (30 mL), and a small
portion of this solution was added to the flask containing the mag-
nesium while stirring gently until the brown iodine colour disap-
peared. Subsequently, the remaining bromoethane/THF solution
was added dropwise to the reaction mixture over a period of
10 min. After the addition was complete, the reaction mixture was
stirred for a further 20 min, then it was cooled to 0 °C. Copper
iodide (0.07 equiv., 0.98 g, 1.04 mmol) was added, and the resulting
mixture was stirred for 20 min. A solution of oxirane (S)-7 (2.0 g,
10.4 mmol) in THF (30 mL) was added dropwise over a period of
Scheme 5. Synthesis of the 2Ј-epimer of (S)-8-hydroxy-3-[(S)-2Ј-
hydroxypentyl]-6-methoxyisochroman-1-one 1a.
Conclusions
In conclusion, a diastereodivergent total synthesis of (S)-
8-hydroxy-3-[(S)-2Ј-hydroxypentyl]-6-methoxyisochroman-
1-one (1a) and (S)-3-hydroxy-3-[(S)-2Ј-hydroxypentyl]-6,8-
dimethoxyisochroman-1-one (1b) and their unnatural dia-
stereomers has been accomplished. Compound 1a was syn-
thesised in 10 steps and 20% overall yield. This strategy
facilitates the synthesis of diastereomeric analogues by 10 min to the resulting purple-black suspension. The reaction mix-
ture was gradually allowed to warm to r.t. and stirred for 30 min.
Subsequently, the reaction mixture was cooled to 0 °C, and pre-
cooled (0 °C) saturated aqueous NH4Cl solution (30 mL) was
added for quenching. The aqueous layer was extracted with Et2O
(3ϫ 20 mL), and the combined organic extracts were dried with
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (EtOAc/hexane, 1:9) to give 8
(1.76 g, 76%) as a colourless oil. [α]3D5 = 0.61 (c = 1.25, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 7.33–7.26 (m, 5 H), 4.52 (s, 2 H),
3.65–3.58 (m, 1 H), 3.51 (t, J = 6.10 Hz, 2 H), 2.24 (br. s, 1 H),
1.79–1.67 (m, 3 H), 1.66–1.59 (m, 1 H), 1.49–1.31 (m, 4 H), 0.92
(t, J = 7.17 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 138.0,
128.2, 127.5, 72.8, 71.0, 70.4, 39.5, 34.4, 26.0, 18.8, 14.0 ppm. IR
using a complementary chiral catalyst. Further work in-
volving the application of this strategy for the synthesis of
related biologically active natural products is in progress.
Experimental Section
General Information: Reactions were carried out under an inert ar-
gon atmosphere where specified. The apparatus used for reactions
was completely dried in an oven. CH3CN was distilled from CaH2.
Diethyl ether was distilled from sodium benzophenone ketyl. 1H
and 13C NMR spectra were recorded with Bruker 300 MHz
(Avance) and Varian Unity 500 MHz (Innova) spectrometers in
CDCl3. J values are given in Hertz, and chemical shifts (δ) are
reported relative to tetramethylsilane (δ = 0.0 ppm), which was used
as an internal standard. The following abbreviations are used: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad.
IR data were measured using an FTIR spectrometer using KBr
pellets or as films. Mass spectral (MS and HRMS) data were re-
(KBr): ν = 3364, 2929, 1452, 1097, 772, 697 cm–1. MS (ESI): m/z
˜
= 223 [M + H]+, 245 [M + Na]+. HRMS (ESI): calcd. for C14H23O2
223.1692; found 223.1685.
(4S)-[1-Benzyloxy-4-tert-butyldimethylsilyloxy]heptane (8a): tBu-
Me2SiCl (1.3 equiv., 0.99 g, 6.6 mmol) was added portionwise to a
stirred solution of 8 (1.0 equiv., 1.13 g, 5 mmol) and 1H-imidazole
corded using the electrospray ionization (ESI) method. Optical ro- (2.0 equiv., 0.69 g, 10.2 mmol) in dry CH2Cl2 (15 mL) at 0 °C. The
tations were recorded with a digital polarimeter at 589 nm (sodium
d-line).
reaction mixture was stirred at 0 °C for 2 h, then it was quenched
with saturated aqueous NH4Cl. The mixture was extracted with
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Synthesis of Fusarentin Derivatives
CH2Cl2 (2ϫ 15 mL). The combined organic extracts were washed
with H2O and brine (10 mL), dried (Na2SO4), and concentrated,
and the residue was purified by column chromatography (EtOAc/
1.12 mL, 61.97 mmol) at 10 °C, and the mixture was stirred vigor-
ously for 2 h at same temperature. The mixture was then cooled to
0 °C, and NaBH4 (2.5 equiv., 2.68 g, 70.42 mmol) was added. After
hexanes, 1:9) to give (S)-8a (1.52 g, 89.4%) as a colourless oil. a further 10 min, the mixture was warmed to room temperature. A
[α]3D5 = –4.2 (c = 2.5, CHCl3). 1H NMR (CDCl3, 500 MHz): δ =
7.34–7.33 (m, 3 H), 7.30–7.26 (m, 2 H), 4.50 (s, 2 H), 3.69–3.64 (m,
1 H), 3.46 (t, J = 6.56 Hz, 2 H), 1.74–1.59 (m, 2 H), 1.59–1.53 (m,
freshly prepared solution of KOH [KOH (20 g) dissolved in EtOH
(20 mL) and distilled water (40 mL)] was added, and the resulting
mixture was stirred vigorously for 30 min. Distilled water (200 mL)
2 H), 1.43–1.24 (m, 4 H), 0.90–0.87 (m, 15 H), 0.03 (s, 6 H) ppm. was added, and the mixture was extracted with pentane (3ϫ
13C NMR (CDCl3, 75 MHz): δ = 138.6, 128.3, 127.5, 127.4, 72.7, 150 mL). The combined organic extracts were washed with brine
71.8, 70.6, 39.4, 33.5, 25.9, 18.5, 18.1, 14.3, –4.4 ppm. IR (KBr): ν
(1ϫ 50 mL), dried with anhydrous Na2SO4, filtered, and concen-
˜
= 2954, 2929, 2855, 1457, 1035, 833, 773 cm–1. MS (ESI): m/z = trated, with the bath temperature kept at 30 °C. The residue was
337 [M + H]+, 359 [M + Na]+. HRMS (ESI): calcd. for C20H37O2Si purified by silica gel column chromatography (pentane/ether) to
337.2557; found 337.2549.
give epoxide anti-11 (6.20 g, 90%) as a colourless oil. [α]3D1 = +15.45
1
(c = 2.2, CHCl3). H NMR (CDCl3, 300 MHz): δ = 3.92–3.84 (m,
(S)-4-(tert-Butyldimethylsilyloxy)-1-heptanol (9): Lithium metal
(0.325 g, 46.5 mmol) was added to freshly condensed liquid NH3
(50 mL) at –78 °C. Then, a solution of 8a (5.21 g, 15.5 mmol) in
THF (50 mL) was added at –78 °C. The resulting mixture was
stirred for 10 min at –78 °C, and then it was quenched by the ad-
dition of solid NH4Cl. The NH3 was then allowed to evaporate.
The residue was partitioned between H2O (50 mL) and Et2O
(50 mL), and the aqueous phase was extracted with Et2O (2ϫ
50 mL). The combined organic extracts were washed with H2O
(50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (hexane/EtOAc,
7:3) to give 9 (3.47 g, 91%) as a clear colourless liquid. [α]3D5 = –18
(c = 0.25, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 3.77–3.70 (m,
1 H), 3.69–3.55 (m, 1 H), 2.19 (br. s, 1 H), 1.65–1.51 (m, 4 H),
1.50–1.39 (m, 2 H), 1.39–1.23 (m, 2 H), 0.92–0.90 (m, 12 H), 0.06
(s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 71.8, 63.2, 38.7,
1 H), 3.04–2.98 (m, 1 H), 2.79 (t, J = 5.29 Hz, 1 H), 2.47 (q, J =
2.27 Hz, 1 H), 1.68–1.55 (m, 2 H), 1.54–1.43 (m, 2 H), 1.40–1.25
(m, 2 H), 0.92–0.87 (m, 12 H), 0.06 (s, 6 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 69.9, 49.9, 47.7, 40.2, 40.1, 25.8, 18.2, 18.0,
14.2, –4.4, –4.7 ppm. IR (KBr): ν = 2928, 2855, 1253, 1074, 834,
˜
773 cm–1. MS (ESI): m/z = 245 [M + H]+, 267 [M + Na]+. HRMS
(ESI): calcd. for C13H28O2NaSi 267.1750; found 267.1749.
Ethyl (5S,7S)-7-(tert-Butyldimethylsilyloxy)-5-hydroxydec-2-ynoate
(12): A solution of n-butyllithium (1.6 m in toluene; 3.76 mL,
6.02 mmol) was added dropwise to a THF (6 mL) solution of ethyl
propiolate (0.58 mL, 5.7 mmol) at –78 °C under an argon atmo-
sphere. After 45 min, a THF (5 mL) solution of anti-5 (0.35 g,
1.43 mmol) was added dropwise, followed by BF3·OEt2 (0.23 mL,
1.86 mmol). The resulting solution was stirred at same temperature
for 30 min. The reaction mixture was then quenched with saturated
aqueous NH4Cl. The layers were separated, and the aqueous phase
was extracted with diethyl ether (3ϫ 10 mL). The combined or-
ganic extracts were washed with brine, dried with Na2SO4, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (EtOAc/hexane, 3:97) to give 12 (0.41 g,
85%) as a colourless dense liquid. [α]3D1 = +10.2 (c = 2.0, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 4.21 (q, J = 7.17 Hz, 2 H), 4.05–
4.01 (m, 1 H), 3.91 (d, J = 1.98 Hz, 1 H), 2.57–2.52 (dd, J = 5.65,
17.09 Hz, 1 H), 2.46 (dd, J = 6.56, 16.94 Hz, 1 H), 1.76–1.73 (m,
2 H), 1.64–1.51 (m, 2 H), 1.37–1.26 (m, 5 H), 0.92 (t, J = 7.32 Hz,
3 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 153.5, 85.7, 74.7, 71.4, 66.5, 61.8, 40.1, 38.0,
33.3, 28.0, 25.8, 18.7, 18.0, 14.2, –4.5 ppm. IR (KBr): ν = 2955,
˜
2925, 2856, 1219, 1039, 772 cm–1. MS (ESI): m/z = 247 [M + H]+,
269 [M + Na]+. HRMS (ESI): calcd. for C13H31O2Si 247.2087;
found 247.2080.
(S)-4-(tert-Butyldimethylsilyloxy)heptanal (10): A solution of oxalyl
chloride (0.66 mL) in CH2Cl2 (8.0 mL) was cooled to –78 °C, and
dry DMSO (1.12 mL) was added. The mixture was stirred for
15 min, then a solution of alcohol 9 (8.0 mL) in CH2Cl2 (7.0 mL)
was added, and the resulting solution was stirred at same tempera-
ture for 45 min. Then, Et3N (3.6 mL) was added, and the mixture
was stirred for 15 min at –78 °C. Thereafter, the reaction mixture
was removed from the cooling bath and allowed to stir at room
temperature for 1 h. Finally, the reaction was quenched with water.
The mixture was partitioned between H2O (50 mL) and CH2Cl2
(50 mL), and the aqueous phase was extracted with CH2Cl2 (2ϫ
50 mL). The combined organic extracts were dried, and the sol-
vents were evaporated. The residue was purified by silica gel col-
umn chromatography (acetone/hexanes, 4:96) to give (S)-10 (0.61 g,
89.4%) as a yellow oil. [α]3D9 = +7.0 (c = 1.9, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ = 9.78 (s, 1 H), 3.76–3.68 (m, 1 H), 2.51–
2.44 (m, 2 H), 1.89–1.78 (m, 1 H), 1.75–1.64 (m, 1 H), 1.51–1.25
(m, 4 H), 0.92–0.88 (m, 12 H), 0.04–0.03 (d, J = 2.08 Hz, 6 H)
ppm. 13C NMR (CDCl3,75 MHz): δ = 202.7, 70.8, 39.6, 39.2, 28.8,
27.6, 25.7, 18.9, 17.8, 14.1, 13.9, –4.6, –4.8 ppm. IR (KBr): ν =
˜
3501, 2930, 2236, 1712, 1252, 1072, 773 cm–1. MS (ESI): m/z =
343 [M + H]+, 365 [M + Na]+. HRMS (ESI): calcd. for C18H35O4
343.2299; found 343.2286.
Ethyl (5S,7S)-5,7-Bis(tert-butyldimethylsilyloxy)dec-2-ynoate (3):
2,6-Lutidine (0.2 mL, 1.75 mmol) and (tert-butyldimethylsilyl)tri-
fluoromethanesulfonate (0.33 mL, 1.46 mmol) were added to a
stirred solution of 11 (0.5 g, 1.46 mmol) in anhydrous CH2Cl2
(5 mL) at 0 °C. The reaction mixture was allowed to stir for 15 min
at 0 °C, and then it was quenched with a saturated aqueous solu-
tion of NaHCO3 (25 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (3ϫ 5 mL). The com-
bined organic layers were washed with brine (10 mL), dried with
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(EtOAc/Hexane, 1:99) to give 3 (0.65 g, 97%) as a colourless oil.
25.8, 18.4, 18.0, 14.2, –4.5 ppm. IR (KBr): ν = 2955, 2928, 2856,
˜
2712, 1728, 1253, 1070, 835, 774 cm–1. MS (ESI): m/z = 245 [M +
H]+. HRMS (ESI): calcd. for C13H29O2Si 245.1933; found
245.1931.
1
(R)-[(S)-2-(tert-Butyldimethylsilyloxy)pentyl]oxirane (anti-11): Al-
dehyde 10 (6.89 g, 28.2 mmol) was added to a stirred solution of
[α]3D3 = +8.33 (c = 2.1, CHCl3). H NMR (CDCl3, 300 MHz): δ =
4.21 (q, J = 7.18 Hz, 2 H), 4.0–3.91 (m, 1 H), 3.8–3.72 (m, 1 H),
catalyst
A (20 mol-%, 1.60 g, 5.63 mmol), lithium chloride 2.56–2.4 (m, 2 H), 1.74–1.67 (m, 2 H), 1.47–1.25 (m, 7 H), 0.88 (m,
(1.5 equiv., 1.73 g, 42.25 mmol), copper trifluoroacetate hydrate
(50 mol-%, 4.17 g, 14.08 mmol), and sodium persulfate (1 equiv.,
6.706 g, 28.2 mmol) in acetonitrile (200 mL) and water (2.2 equiv.,
21 H), 0.10–0.06 (m, 12 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 153.6, 86.4, 69.9, 68.4, 61.6, 45.3, 40.2, 28.4, 25.7, 25.9, 18.3,
17.9, 14.1, 14.0, –3.3, –4.1, –4.2, –4.4 ppm. IR (KBr): ν = 2924,
˜
Eur. J. Org. Chem. 2014, 2168–2173
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2171

G. Kumaraswamy, K. Ankamma, N. Raghu, D. RamBabu
FULL PAPER
2237, 1715, 1465, 1250, 1072, 773 cm–1. MS (ESI): m/z = 479 [M
+ Na]+. HRMS (ESI): calcd. for C24H48O4NaSi2 479.2983; found
479.2979.
(CDCl3, 75 MHz): δ = 169.7, 165.7, 164.4, 141.0, 106.1, 101.6, 99.4,
76.2, 66.9, 55.5, 42.2, 40.1, 33.7, 18.6, 14.0 ppm. IR (KBr): ν =
˜
3443, 1661, 1628, 1512, 1420, 1161, 672 cm–1. MS (ESI): m/z = 281
[M + H]+, 298 [M + NH4]+. HRMS (ESI): calcd. for C15H21O5
281.1367; found 281.1383.
Ethyl
2-[(2S,4S)-2,4-Bis(tert-butyldimethylsilyloxy)heptyl]-4,6-di-
methoxybenzoate (13): A mixture of acetylenic ester 3 (0.20 g,
0.45 mmol), diene 4 (0.19 g, 1.36 mmol), and a catalytic amount of
N,N-dimethylaniline (0.01 g, 0.09 mmol) was heated in a sealed
tube at 200 °C for 48 h under an inert atmosphere. After TLC indi-
cated that the reaction was complete, the residue was purified by
column chromatography over silica gel (EtOAc/hexane, 1:9) to give
compound 13 (0.15 g, 60%) as a colourless oil. [α]3D0 = –25.0 (c =
0.9, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 6.38 (d, J =
2.14 Hz, 1 H), 6.32 (d, J = 2.14 Hz, 1 H), 4.34 (q, J = 7.17 Hz, 2
H), 3.98–3.92 (m, 1 H), 3.78 (d, J = 3.81 Hz, 6 H), 3.72–3.68 (m,
1 H), 2.79 (dd, J = 5.49, 13.58 Hz, 1 H), 2.63 (dd, J = 7.63,
13.58 Hz, 1 H), 1.59 (t, J = 6.26 Hz, 3 H), 1.49–1.23 (m, 6 H), 0.90
(t, J = 7.02 Hz, 3 H), 0.84 (s, 9 H), 0.82 (s, 9 H), 0.02 (s, 3 H),
0.003 (s, 3 H), –0.03 (s, 3 H), –0.18 (s, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 168.2, 160.8, 158.0, 138.9, 117.3, 107.4, 96.9, 70.6,
69.8, 60.8, 55.9, 55.2, 46.0, 41.8, 39.8, 25.9, 18.4, 14.2, –4.2,
(S)-[(S)-2-(tert-Butyldimethylsilyloxy)pentyl]oxirane (syn-11): A
similar procedure to that described for compound anti-11 was fol-
lowed, except instead of catalyst A, ent-A was used, yield 3.10 g,
90%. [α]3D3 = –15.3 (c = 1.9, CHCl3). 1H NMR (CDCl3, 300 MHz):
δ = 3.89–3.82 (m, 1 H), 3.04 (t, J = 4.53 Hz, 1 H), 2.44 (dd, J =
2.64, 4.91 Hz, 1 H), 1.76–1.55 (m, 2 H), 1.50 (t, J = 6.80 Hz, 2 H),
1.44–1.25 (m, 2 H), 0.93–0.89 (m, 12 H), 0.05 (s, 3 H), 0.04 (s, 3
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 70.1, 49.4, 46.7, 40.1,
39.3, 25.7, 18.6, 14.1, –4.6 ppm. IR (KBr): ν = 2928, 2855, 1253,
˜
1074, 834, 773 cm–1. MS (ESI): m/z = 245 [M + H]+, 267
[M + Na]+. HRMS (ESI): calcd. for C13H28O2NaSi 267.1750;
found 267.1749.
Ethyl (5R,7S)-7-(tert-Butyldimethylsilyloxy)-5-hydroxydec-2-ynoate
(14): An analogous procedure to that described above for com-
pound 11 was followed, yield 0.20 g, 85%. [α]3D4 = +8.5 (c = 1.0,
1
–4.6 ppm. IR (KBr): ν = 2924, 2853, 1726, 1604, 1463, 1330, 1255,
˜
CHCl3). H NMR (CDCl3, 500 MHz): δ = 4.23 (q, J = 7.17 Hz, 2
1155, 1099, 834, 774 cm–1. MS (ESI): m/z = 569 [M + H]+, 591 [M
+ Na]+. HRMS (ESI): calcd. for C30H56O6NaSi2 591.3507; found
591.3487.
H), 4.01–3.94 (m, 2 H), 3.6 (d, J = 1.83 Hz, 1 H), 2.56 (dd, J =
5.50, 17.09 Hz, 1 H), 2.49 (dd, J = 6.71, 16.94 Hz, 1 H), 1.83–1.79
(m, 1 H), 1.69–1.59 (m, 2 H), 1.52–1.48 (m, 2 H), 1.30 (t, J =
7.17 Hz, 3 H), 1.25 (s, 1 H), 0.93–0.90 (m, 12 H), 0.11 (s, 3 H), 0.09
(s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 153.5, 85.7, 74.7,
72.8, 68.9, 61.8, 41.5, 40.0, 29.6, 27.4, 25.7, 17.8, 17.7, 14.1, 13.9,
(S)-3-Hydroxy-3-[(S)-2Ј-hydroxypentyl]-6,8-dimethoxyisochroman-
1-one (1b): TBAF (1 m in THF; 1.12 mL, 1.12 mmol) was added to
a stirred solution of 13 (0.16 g, 0.28 mmol) in anhydrous THF
(10 mL) at 0 °C. The reaction mixture was warmed to room tem-
perature, and stirring was continued for 6 h. After TLC indicated
that the reaction was complete, it was quenched by the addition of
H2O (5 mL). The THF was removed under reduced pressure, and
the aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL). The
combined organic layers were washed with brine (15 mL), dried
with anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica column chromatography (EtOAc/
hexane, 80:20) to give lactone 1b (0.05 g, 90%) as a colourless oil.
–4.7, –4.0 ppm. IR (KBr): ν = 3501, 2930, 2236, 1712, 1252, 1072,
˜
773 cm–1. MS (ESI): m/z = 343 [M + H]+, 365 [M + Na]+. HRMS
(ESI): calcd. for C18H35O4Si 343.2299; found 343.2286.
Ethyl (5R,7S)-5,7-Bis(tert-butyldimethylsilyloxy)dec-2-ynoate (epi-
3): A similar procedure to that described above for TBS protection
was followed, yield 0.32 g, 97%. [α]3D6 = –8.0 (c = 1.25, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 4.20 (q, J = 7.18 Hz, 2 H), 4.0–3.92
(m, 1 H), 3.80–3.72 (m, 1 H), 2.57–2.40 (m, 2 H), 1.72 (t, J =
6.23 Hz, 2 H), 1.47–1.25 (m, 4 H), 0.92–0.88 (m, 21 H), 0.09–0.04
(m, 12 H) ppm. 13C NMR (CDCl3, 300 MHz): δ = 153.6, 86.5,
74.7, 69.1, 67.6, 61.6, 44.5, 39.3, 27.8, 25.8, 18.3, 17.9, 14.3, 14.0,
[α]3D0 = –47.0 (c = 1.0, CHCl3). H NMR ([D6]acetone, 500 MHz):
1
δ = 6.53 (d, J = 2.29 Hz, 1 H), 6.47 (d, J = 2.29 Hz, 1 H), 4.60–
4.55 (m, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.74 (d, J = 5.65 Hz, 1
H), 2.92–2.80 (m, 2 H), 1.82 (dd, J = 2.29, 9.31 Hz, 1 H), 1.59 (dd,
J = 3.20, 10.07 Hz, 1 H), 1.53–1.36 (m, 4 H), 0.93 (t, J = 7.02 Hz,
3 H) ppm. 13C NMR ([D6]acetone, 125 MHz): δ = 166.1, 164.8,
162.7, 146.2, 109.0, 105.9, 99.4, 75.9, 67.9, 57.1, 56.9, 44.6, 42.2,
–4.6 ppm. IR (KBr): ν = 2924, 2237, 1715, 1465, 1250, 1072,
˜
773 cm–1. MS (ESI): m/z = 479 [M + Na]+. HRMS (ESI): calcd.
for C24H48O4NaSi2 479.2983; found 479.2979.
Ethyl 2-[(2R,4S)-2,4-Bis(tert-butyldimethylsilyloxy)heptyl]-4,6-di-
methoxybenzoate (epi-13): A similar procedure to that described for
compound 12 was followed, yield 0.30 g, 60%. [α]3D5 = –10.6 (c =
0.85, CHCl3); 1H NMR (CDCl3, 300 MHz): δ = 6.38 (d, J =
2.27 Hz, 1 H), 6.32 (d, J = 2.27 Hz, 1 H), 4.34 (q, J = 6.80 Hz, 2
H), 4.01–4.92 (m, 1 H), 3.78 (d, J = 3.02 Hz, 7 H), 2.81–2.68 (m,
2 H), 1.74–1.41 (m, 2 H), 1.34 (t, J = 7.55 Hz, 3 H), 1.29–1.21 (m,
2 H), 0.86 (d, J = 6.04 Hz, 21 H), 0.04–0.02 (m, 9 H), –0.15 (s, 3
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 168.2, 160.7, 157.9,
138.8, 117.5, 107.1, 96.7, 70.1, 69.2, 64.2, 60.9, 55.8, 55.2, 44.8,
42.1, 38.9, 25.8, 25.2, 18.3, 18.0, 17.8, 14.2, –4.3, –4.5, –4.7,
37.0, 20.4, 15.4 ppm. IR (KBr): ν = 3423, 2922, 1701, 1603, 1462,
˜
1245, 1161, 1086, 772 cm–1. MS (ESI): m/z = 295 [M + H]+, 317
[M + Na]+. HRMS (ESI): calcd. for C16H23O5 295.1540; found
295.1532.
(S)-8-Hydroxy-3-[(S)-2Ј-hydroxypentyl]-6-methoxyisochroman-1-
one (1a): A solution of BCl3 in hexane (1.0 m; 1.36 mL, 1.36 mmol)
was added dropwise to a stirred solution of 1b (0.2 g, 0.68 mmol)
in CH2Cl2 (80 mL) at –78 °C, and the mixture was stirred for
30 min at the same temperature. NaOH solution (5 % aq.) was
added, the organic layer was separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were washed
with H2O and brine, dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica column
–4.8 ppm. IR (KBr): ν = 2924, 2853, 1726, 1604, 1463, 1330, 1255,
˜
1155, 1099, 834, 774 cm–1. MS (ESI): m/z = 569 [M + H]+, 591 [M
+ Na]+. HRMS (ESI): calcd. for C30H56O6NaSi2 591.3507; found
591.3487.
chromatography (EtOAc/hexane, 35:65) to give diol 1a (0.15 g, (R)-3,4-Dihydro-3-[(S)-2-hydroxypentyl]-6,8-dimethoxyisocoumarin
80%) as a colourless oil. [α]3D2 = –15.7 (c = 0.5, CHCl3). H NMR
(CDCl3, 500 MHz): δ = 11.15 (s, 1 H), 6.33 (d, J = 2.0 Hz, 1 H),
6.22 (br. s, 1 H), 4.85–4.79 (m, 1 H), 4.06–4.02 (m, 1 H), 3.82 (s, 3
H), 2.93–2.82 (m, 2 H), 2.03–1.82 (m, 2 H), 1.70–1.65 (m, 1 H),
(epi-1b): The lactonization procedure described above was fol-
lowed, yield 0.10 g, 90%. [α]3D3 = +48.6 (c = 0.35, CHCl3). 1H NMR
([D6]acetone, 300 MHz): δ = 6.54 (d, J = 2.08 Hz, 1 H), 6.48 (s, 1
H), 4.60–4.51 (m, 1 H), 3.86 (d, J = 8.69 Hz, 6 H), 3.62 (d, 1 H),
1
1.51–1.23 (m, 4 H), 0.95 (t, J = 7.01 Hz, 3 H) ppm. 13C NMR 3.04–2.82 (m, 2 H), 1.95–1.86 (m, 1 H), 1.82–1.74 (m, 1 H), 1.52–
2172
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2168–2173

Synthesis of Fusarentin Derivatives
1.29 (m, 4 H), 0.91 (t, J = 7.18 Hz, 3 H) ppm. 13C NMR ([D6]-
acetone, 125 MHz): δ = 166.1, 164.9, 162.5, 146.0, 106.0, 99.5, 76.8,
[4] T. N. Trotter, A. M. M. Albury, M. P. Jennings, J. Org. Chem.
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2863.
68.9, 57.1, 56.9, 44.0, 41.7, 36.2, 20.4, 15.3 ppm. IR (KBr): ν =
˜
3423, 2922, 1701, 1603, 1462, 1245, 1161, 1086, 772 cm–1. MS
(ESI): m/z = 295 [M + H]+, 317 [M + Na]+. HRMS (ESI): calcd.
for C16H23O5 295.1540; found 295.1532.
(R)-3,4-Dihydro-8-hydroxy-3-[(S)-2-hydroxypentyl]-6-methoxyiso-
coumarin (epi-1a): A similar procedure to that described for com-
pound 1a was followed, yield 0.07 g, 80%. [α]3D2 = –15.0 (c = 0.04,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 11.17 (s, 1 H), 6.37 (d,
J = 2.0 Hz, 1 H), 6.26 (br. s, 1 H), 4.81–4.72 (m, 1 H), 3.96–3.89
(m, 1 H), 3.83 (s, 3 H), 2.96–2.93 (m, 2 H), 2.09–1.99 (m, 2 H),
1.90–1.82 (m, 2 H), 1.58–1.40 (m, 4 H), 0.95 (t, J = 6.99 Hz, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 169.4, 165.8, 164.6, 140.8,
106.3, 101.6, 99.4, 77.8, 68.7, 55.5, 41.9, 39.8, 33.2, 18.6, 13.9 ppm.
IR (KBr): ν = 3443, 1661, 1628, 1512, 1420, 1161, 672 cm–1. MS
˜
(ESI): m/z = 281 [M + H]+, 294 [M + NH4]+. HRMS (ESI): calcd.
[7] a) G. Kumaraswamy, A. N. Murthy, V. Narayanarao, S. P.
Babu, B. Jagadeesh, Org. Biomol. Chem. 2013, 11, 6751–6765;
b) G. Kumaraswamy, D. Rambabu, Tetrahedron: Asymmetry
2013, 24, 196–201; c) G. Kumaraswamy, K. Sadaiah, Tetrahe-
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raswamy, G. Ramakrishna, R. Raju, M. Padmaja, Tetrahedron
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for C15H21O5 281.1367; found 281.1383.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
Acknowledgments
[8] G. Kumaraswamy, A. N. Murthy, K. Sadaiah, Tetrahedron
2012, 68, 3179–3186.
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Konoki, M. Yotsu-Yamashita, M. Sasaki, Chem. Eur. J. 2013,
19, 8100–8110.
The authors are grateful to Dr. Lakshmi Kantham, Director, IICT,
for her constant encouragement. Financial support was provided
by the Department of Science and Technology (DST), New Delhi
(grant number SR/S1/OC-08:2011) and by the Council of Scientific
and Industrial Research (CSIR) (ORGIN programme CSC-0108 of
XII five-year plan). The Council of Scientific and Industrial Re-
search and the University Grant Commission (UGC), New Delhi
are gratefully acknowledged for awarding an RA fellowship to
K. A., and fellowships to N. R. and D. R.
[11] The relative stereochemistries of 12 and 14 were assigned by
analogy; see ref.[8]
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Received: November 13, 2013
Published Online: January 30, 2014
Eur. J. Org. Chem. 2014, 2168–2173
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2173