Total synthesis of (+)-aspicilin by an alkyne-based approach and its biological evaluation

Article abstract of DOI:10.1002/ejoc.201101673

The stereoselective total synthesis of (+)-aspicilin is described. The pivotal step in this approach is the generation of an enyne intermediate by the coupling of an alkyne with vinyl iodide, which constructed the C6-C7 bond. Conversion of the enyne to th

Full text of DOI:10.1002/ejoc.201101673

FULL PAPER
DOI: 10.1002/ejoc.201101673
Total Synthesis of (+)-Aspicilin by an Alkyne-Based Approach and Its
Biological Evaluation
Chada Raji Reddy,*[a] Nagavaram Narsimha Rao,[a] Pombala Sujitha,[b] and
Chityal Ganesh Kumar[b]
Keywords: Natural products / Total synthesis / C–C coupling / Aspicilin / Alkynes
The stereoselective total synthesis of (+)-aspicilin is de-
scribed. The pivotal step in this approach is the generation
of an enyne intermediate by the coupling of an alkyne with
vinyl iodide, which constructed the C6–C7 bond. Conversion
of the enyne to the desired macrolide was achieved through
Sharpless asymmetric dihydroxylation and Yamaguchi
macrolactonization as the key steps. Additionally, the bio-
logical activity of (+)-aspicilin was evaluated on A549, HeLa,
and MCF7 cancer cell lines.
explore alkyne-based approaches to macrolides[5] prompted
us to develop a new strategy for the total synthesis of 1 and
evaluate its biological activity.
Introduction
The 18-membered macrocyclic lactone (+)-aspicilin (1,
Figure 1) was initially isolated in 1900 from a lichen of the
Lecanoraceae family,[1] and its basic structure was eluci-
dated in 1973.[2] The determination of both relative and ab-
solute configurations was attained in 1985 by NMR spec-
troscopy, single-crystal X-ray analysis, and the degradation
and synthesis of a fragment.[3] With four stereocenters,
which include one contiguous syn–anti triol skeleton, 1 has
fascinated synthetic organic chemists.[4] The first synthesis
of 1 was accomplished in 1988 with photolactonization as
Results and Discussion
In this synthesis, we aimed to use alkyne chemistry,
which has various advantages such as the easy accessibility
of the desired alkyne fragments in high yields, the assembly
of the two subunits can be accomplished under mild reac-
tion conditions, and the generation of the desired stereocen-
ters using alkyne functionality. Thus, total synthesis of 1 is
envisaged by Yamaguchi macrolactonization of seco-acid 2,
which was delivered from two key fragments 3 and 4 using
Sonogashira coupling and Sharpless asymmetric dihydrox-
ylation as the key reactions. Subunit 3 was obtained from
the key step.[4q] Subsequently, various strategies have been
[4a–4n]
developed for the total synthesis of 1
and its iso-
mers.[4o–4q] The design and execution of a new synthetic
route that enables easy access to substrates, which proceeds
with high selectivity, in good yield, and requires mild reac-
tion conditions, is still important. To date, the biological
activity of 1 has not been investigated. Hence, our work to
Figure 1. Structure of 1.
[a] Division of Natural Products Chemistry, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500007, India
Fax: +91-40-2716-0512
E-mail: rajireddy@iict.res.in
[b] Chemical Biology Laboratory, CSIR – Indian Institute of
Chemical Technology,
Hyderabad 500007, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101673.
Scheme 1. Retrosynthetic analysis of 1.
Eur. J. Org. Chem. 2012, 1819–1824
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1819

C. Raji Reddy, N. N. Rao, P. Sujitha, C. G. Kumar
FULL PAPER
oxirane 5 by an alkyne-zipper reaction, and 4 was achieved
from hydrozirconation–iodination of the known precursor
6 (Scheme 1).
Firstly, 3 was obtained from (S)-propylene oxide 5
(Scheme 2). Epoxide 5 was opened with 1-nonyne with
nBuLi/hexamethylphosphoramide (HMPA) in tetra-
hydrofuran (THF) to provide homopropargylic alcohol 7 in
86% yield. The internal alkyne of 7 was transformed to
terminal alkyne 3 through a zipper reaction using KH and
1,3-diaminopropane.[6]
Scheme 3. Synthesis of 4. Reagents and conditions: (a) PPh3, CCl4,
80 °C, 12 h, 95%; (b) nBuLi, THF, HMPA, –30 °C, 1 h, 96%; (c)
TBSCl, imidazole, N,N-dimethylformamide (DMF), 0 °C to room
temp., 12 h, 96%; (d) Cp2ZrCl2, super hydride, I2, room temp., 2 h,
76%.
Sonogashira coupling[10] between 3 and 4 was particu-
larly effective to form the key C6–C7 bond and provide
enyne 11 in good yield. Compound 11 with the unprotected
Scheme 2. Synthesis of 3. Reagents and conditions: (a) 1-nonyne,
nBuLi, THF, HMPA, –40 to 0 to –20 °C to room temp., 14 h, 86%;
(b) KH, 1,3-diaminopropane, 40 °C to room temp., 16 h, 83%.
The synthesis of Sonogashira coupling precursor 4 began hydroxy group was further transformed to 1. The key
with the known alcohol 6, derived from (–)-2,3-O-isopro- Sharpless asymmetric dihydroxylation[11] of 11 was ac-
pylidene-d-threitol.[7] The chlorination of 6 using Ph3P/ complished using AD-mix-β/MeSO2NH2, tBuOH/H2O to
CCl4 gave 8 in 95% yield, which was subjected to an elimi- obtain polyol 12 in 72% yield as a separable 9:1 dia-
nation reaction with nBuLi/HMPA in THF to afford the stereomeric mixture. Protection of the newly generated 1,2-
propargylic alcohol 9 in 96% yield.[8] The protection of 9 diol as acetonide 13 followed by hydrogenation using 10%
[tert-butyldimethylsilyl chloride (TBSCl)/imidazole] to give Pd/C in EtOH in the presence of hydrogen (one-pot debenz-
TBS-ether 10 proceeded in 96% yield. Hydrozirconation– ylation and alkyne reduction) afforded the diol 14. Selective
iodination of 10 using Cp2ZrCl2/super hydride/I2 reaction oxidation of the primary alcohol in 14 was attained with
conditions[9] provided 4 (76% yield) ready for the coupling 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO)/bis-
(Scheme 3).
(acetoxy)iodobenzene (BAIB) in CH2Cl2 to aldehyde, which
Scheme 4. Synthesis of 1. Reagents and conditions: (a) CuI, PdCl2(PPh3)2, Et3N, 0 °C to room temp., 3 h, 84%; (b) AD-mix-β, Me-
SO2NH2, tBuOH/H2O, 0 °C, 72 h, 72%; (c) 2,2-dimethoxypropane, camphorsulfonic acid (CSA, 20 mg), CH2Cl2, 0 °C to room temp.,
1 h, 88%; (d) H2/PdC (10%), EtOH, room temp., 12 h, 82%; (e) i) TEMPO, BAIB, CH2Cl2, room temp., 2 h; ii) PPh3=CHCO2Et, CH2Cl2,
0 °C to room temp., 2 h, 78%; (f) LiOH, THF/MeOH/H2O (8:1:1), room temp., 8 h (g) 2,4,6-trichlorobenzoyl chloride, Et3N, 0 °C, 4 h,
DMAP, toluene, 100 °C, 10 h, 68% over two steps; (h) 2 m HCl in MeOH, 0 °C, 5 h, 86%.
1820
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Eur. J. Org. Chem. 2012, 1819–1824

Total Synthesis of (+)-Aspicilin and Its Biological Evaluation
(5, 2.4 mL, 34.5 mmol) in HMPA (8 mL) over 15 min. The reaction
mixture was stirred at –20 °C for 30 min, warmed to room tempera-
ture over 4 h, and stirred for 12 h at room temperature. The reac-
tion mixture was poured into iced water (50 mL) and extracted with
diethyl ether (4ϫ50 mL). The combined organic layer was washed
with brine (50 mL), dried with Na2SO4, concentrated, and purified
by column chromatography (hexanes/diethyl ether, 80:20) to pro-
vide 7 (5.4 g, 86%) as a yellow liquid. [α]2D0 = +11.7 (c = 1.12,
was subsequently exposed to a one-pot two-carbon Wittig
olefination (PPh3=CHCOOEt) to obtain α,β-unsaturated
1
ester 15 (E/Z ratio 40:1 by H NMR) in 78% yield.[12] The
hydrolysis of 15 by LiOH in THF/MeOH/H2O gave seco-
acid 2 for the macrolactonization reaction. The hydroxy
acid 2 was exposed to Yamaguchi reaction conditions
[2,4,6-trichlorobenzoyl chloride/Et3N/4-(dimethylamino)-
pyridine (DMAP), 100 °C][13] to provide the protected mac-
rolide 16. Treatment of 16 with 2 m HCl in MeOH afforded
CHCl ). IR (KBr): ν
= 3383, 2927, 2857, 1459, 1114, 1082, 938
˜
3
max
cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.8 (sext, J = 5.7 Hz, 1 H),
1 [m.p. 153–155 °C. [α]D20 = +37.9 (c = 0.64, CHCl3)] in 86% 2.37–2.29 (m, 1 H), 2.27–2.19 (m, 1 H), 2.17–2.12 (m, 2 H), 1.86
(br. s, OH), 1.54–1.44 (m, 2 H), 1.41–1.24 (m, 8 H), 1.22 (d, J =
5.4 Hz, 3 H), 0.89 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 82.7, 76.0, 66.4, 31.5, 29.1, 28.8, 28.7, 28.6, 22.4, 21.9,
18.5, 13.8 ppm.
yield (Scheme 4). The characterization of our synthetic
sample was identical to literature data (1H and 13C NMR
spectroscopy and optical rotation).
Compound 1 was tested against various cancer cell lines
using an MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5-di-
(S)-Dodec-11-yn-2-ol (3): Potassium hydride (35% suspension in
phenyltetrazolium bromide].[14] It showed promising inhibi- mineral oil, 2.05 g, 15.4 mmol) was weighed in an oven-dried
round-bottomed flask and washed with diethyl ether (3ϫ5 mL)
under nitrogen. To the oil-free potassium hydride was added 1,3-
diaminopropane (15 mL) at room temperature, and the mixture
was heated for 1 h at 40 °C. The reaction mixture was cooled to
0 °C, and 7 (700 mg, 3.85 mmol) was added. The reaction mixture
was warmed to room temperature and stirred for 15 h. After com-
pletion of the reaction (monitored by TLC), the reaction mixture
was cooled to 0 °C and quenched with ice. The aqueous layer was
extracted with diethyl ether (2ϫ25 mL). The combined organic
layer was washed with 2 m HCI (25 mL) and water (25 mL) and
dried with Na2SO4. The organic solvent was evaporated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (hexanes/diethyl ether, 80:20) to give 3 (581 mg, 83%) as a
tory activity on the proliferation of A549 (IC50 = 14.7 μm
over 24 h), HeLa (IC50 = 17.9 μm over 24 h), and MCF7
(IC50 = 12.0 μm over 24 h) cancer cell lines. It did not exhi-
bit any cytotoxicity towards Neuro2a or MDA-MB-231
cancer cell lines. Furthermore, antibacterial and antifungal
activities were also evaluated and showed no potential ac-
tivity.[15]
Conclusions
An efficient strategy has been developed for the total
synthesis of (+)-aspicilin (1) in 12 linear steps in 13.2%
colorless oil. [α]2D0 = +7.3 (c = 1.20, CHCl ). IR (KBr): νmax = 3309,
˜
3
overall yield from the known alcohol 6. The characteristic 2929, 2856, 2116, 1461, 1373, 1125, 629 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 3.79–3.72 (m, 1 H), 2.15 (td, J = 7.0, 2.0 Hz, 2 H),
1.84 (t, J = 2.0 Hz, 1 H), 1.55–1.48 (m, 2 H), 1.46–1.26 (m, 12 H),
1.17 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
84.4, 67.9, 67.6, 39.0, 29.4, 29.2, 28.8, 28.5, 28.2, 25.5, 23.1, 18.1
ppm.
features of this alkyne-based approach included: (i) synthe-
sis of the desired fragments by alkyne chemistry, (ii) as-
sembly of the two subunits by Sonogashira coupling, (iii)
generation of the required stereocenters by Sharpless asym-
metric dihydroxylation, and (iv) Yamaguchi macrolatoni-
zation to construct the 18-membered macrolactone ring. (4R,5S)-4-(Benzyloxymethyl)-5-(chloromethyl)-2,2-dimethyl-1,3-di-
oxolane (8): To a stirred solution of 6 (5.0 g, 19.8 mmol) in CCl4
(100 mL) was added triphenyl phosphane (10 g, 39.6 mmol) at
room temperature, and the mixture was heated to reflux for 12 h.
The reaction mixture was cooled to 0 °C, diluted with hexanes
(100 mL), and stirred for 30 min. The precipitate was filtered, and
the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes/EtOAc, 97:3) to
give 8 (5.07 g, 95%) as a colorless oil. [α]2D0 = –2.6 (c = 1.00,
The cytotoxic actitivity towards A549, HeLa, and MCF7
cancer cells has also been disclosed.
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 with
300, 400, 500, or 75 MHz spectrometers at ambient temperature.
FTIR spectra were recorded as KBr discs or neat. Optical rotations
were measured with a digital polarimeter using a 2 mL cell with a
1 dm path length. All the reagents and solvents were reagent grade
and used without purification unless specified otherwise. Technical
grade ethyl acetate and hexanes used for column chromatography
were distilled prior to use. When used as a reaction solvent, THF
was freshly distilled from sodium benzophenone ketyl. Column
chromatography was carried out using silica gel (60–120 mesh and
100–200 mesh) packed in glass columns. All the reactions were per-
formed under an atmosphere of nitrogen in flame-dried or oven-
dried glassware with magnetic stirring.
CHCl ). IR (KBr): νmax = 2988, 2864, 1373, 1245, 1216, 1085, 741,
˜
3
698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.36–7.21 (m, 5 H),
4.57 (s, 2 H), 4.11–3.99 (m, 2 H), 3.68–3.54 (m, 4 H), 1.41 (s, 3 H),
1.40 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 137.6, 128.3,
127.7, 127.5, 109.9, 78.0, 77.8, 73.5, 70.4, 44.4, 27.0, 26.9 ppm.
HRMS (ESI): calcd. for C14H19ClO3Na [M + Na]+ 293.0915;
found 293.0929.
(S)-1-(Benzyloxy)but-3-yn-2-ol (9): To
a solution of HMPA
(5.14 mL, 29.6 mmol) in THF (30 mL) was added nBuLi (2.5 m in
hexanes, 10.3 mL, 25.9 mmol) at –30 °C under a nitrogen atmo-
sphere. To this mixture was added 8 (1.0 g, 3.7 mmol) in THF
(5 mL) dropwise. The reaction mixture was stirred for 1 h at –30 °C.
After the completion of the reaction (monitored by TLC), the mix-
ture was treated with a saturated aqueous solution of NH4Cl
(25 mL) and extracted with diethyl ether (2ϫ25 mL). The com-
bined organic layer was washed with brine (20 mL), dried with
(S)-Dodec-4-yn-2-ol (7): To a stirred solution of 1-nonyne (8.5 mL,
51.7 mmol) in dry THF (30 mL) at –40 °C was added nBuLi (1.6 m
in hexane, 21.5 mL, 34.5 mmol) dropwise. The reaction mixture
was warmed to 0 °C over 30 min and then recooled to –20 °C. To
this was added dry HMPA (8 mL) followed by (S)propylene oxide
Eur. J. Org. Chem. 2012, 1819–1824
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C. Raji Reddy, N. N. Rao, P. Sujitha, C. G. Kumar
FULL PAPER
Na2SO4, and the organic solvents were evaporated under reduced
pressure. The residue was purified by flash column chromatography
(hexanes/EtOAc, 80:20) to give 9 (625 mg, 96%) as a colorless oil.
δ = 7.32–7.22 (m, 5 H), 6.00 (dd, J = 15.7, 5.5 Hz, 1 H), 5.69 (dt,
J = 15.7, 1.8 Hz, 1 H), 4.51 (s, 2 H), 4.36–4.30 (m, 1 H), 3.79–3.70
(m, 1 H), 3.35 (d, J = 6.4 Hz, 2 H), 2.27 (td, J = 6.4, 1.8 Hz, 2 H),
1.56–1.47 (m, 2 H), 1.47–1.24 (m, 12 H), 1.17 (d, J = 5.5 Hz, 3 H),
0.90 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
141.4, 138.1, 128.1, 127.5, 127.4, 110.4, 91.0, 78.5, 74.5, 73.2, 71.7,
[α]2D0 = +7.7 (c = 1.0, CHCl ). IR (KBr): ν
= 3290, 2917, 2865,
˜
3
max
2117, 1452, 1112, 743, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ
= 7.37–7.22 (m, 5 H), 4.59 (s, 2 H), 4.53–4.45 (m, 1 H), 3.62 (dd,
J = 9.6, 3.3 Hz, 1 H), 3.57–3.49 (m, 1 H), 2.47 (br. s, OH), 2.37 (d, 67.8, 39.2, 29.4, 29.3, 28.9, 28.7, 28.6, 25.7, 25.6, 23.3, 19.3, 18.1,
J = 1.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 137.4,
128.3, 127.7, 127.6, 81.7, 73.5, 73.3, 73.2, 61.2 ppm.
–4.8 ppm. HRMS (ESI): calcd. for C29H48O3NaSi [M + Na]+
495.32649; found 495.32566.
(2S,13R,14S,15R)-16-(Benzyloxy)-15-(tert-butyldimethylsilyloxy)-
hexadec-11-yne-2,13,14-triol (12): Compound 11 (600 mg,
1.27 mmol) was dissolved in a mixture of tert-butyl alcohol
(6.4 mL) and water (6.4 mL) and cooled to 0 °C. To this was added
methane sulfonamide (121 mg, 1.27 mmol) followed by AD-mix-β
(1.8 g), and the mixture was stirred for 72 h at 0 °C. After comple-
tion of the reaction (monitored by TLC), the reaction mixture was
quenched by adding solid sodium sulfite (2 g) and stirred for l h.
The mixture was diluted with water (25 mL) and extracted with
EtOAc (3ϫ25 mL). The combined organic layer was dried with
Na2SO4, and the solvents evaporated to dryness under reduced
pressure. The residue was purified by column chromatography
(hexanes/EtOAc, 85:15) to give 12 (462 mg, 72%) as a separable
diastereomeric mixture (9:1). Major isomer: [α]2D0 = –3.2 (c = 1.44,
(S)-[1-(Benzyloxy)but-3-yn-2-yloxy](tert-butyl)dimethylsilane (10):
To a stirred solution of 9 (575 mg, 3.26 mmol) in DMF (5 mL) was
added imidazole (776 mg, 11.4 mmol) followed by tert-butyldime-
thylsilyl chloride (740 mg, 4.9 mmol) at 0 °C. The reaction mixture
was warmed to room temperature and stirred for 12 h. After com-
pletion of the reaction, the mixture was diluted by saturated aque-
ous NaHCO3 solution (20 mL), and the aqueous phase was ex-
tracted with diethyl ether (2ϫ20 mL). The combined organic layer
was washed with brine (20 mL), dried with Na2SO4, and evapo-
rated under reduced pressure. The crude residue was purified by
flash column chromatography (hexanes/EtOAc, 95:5) to give 10
(907 mg, 96%) as a colorless oil. [α]2D0 = +23.3 (c = 1.20, CHCl3).
1
IR (KBr): ν
= 2932, 2858, 1462, 1253, 1101, 836, 778 cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 7.32–7.27 (m, 5 H), 4.58 (s, 2 H),
4.51 (ddd, J = 6.7, 5.2, 2.2 Hz, 1 H), 3.59–3.49 (m, 2 H), 2.33 (d,
J = 2.2 Hz, 1 H), 0.91 (s, 9 H), 0.13 (s, 3 H), 0.11 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 138.5, 128.3, 127.5, 83.1, 74.4,
73.4, 72.9, 62.8, 25.7, 18.2, –4.7, –4.9 ppm. HRMS (ESI): calcd.
for C17H26O2NaSi [M + Na]+ 313.15943; found 313.15894.
CHCl ). IR (KBr): νmax = 3446, 2927, 2855, 1631, 1458, 1251, 1092,
˜
3
836, 775 cm–1. H NMR (300 MHz, CDCl3): δ = 7.40–7.29 (m, 5
1
H), 4.54 (s, 2 H), 4.57–4.52 (m, 1 H), 4.01 (q, J = 5.3 Hz, 1 H),
3.84–3.74 (m, 1 H), 3.71 (dd, J = 6.0, 3.0 Hz, 1 H), 3.61 (d, J =
5.3 Hz, 1 H), 2.21 (td, J = 6.8, 2.2 Hz, 2 H), 1.54–1.24 (m, 14 H),
1.18 (d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.07 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 137.5, 128.3, 127.7, 127.6,
86.3, 78.6, 76.2, 73.5, 72.3, 71.1, 68.1, 62.6, 39.2, 29.4, 29.3, 28.9,
28.7, 28.5, 25.7, 25.6, 23.4, 18.7, 18.0, –4.5, –5.0 ppm. HRMS
(ESI): calcd. for C29H50O5NaSi [M + Na]+ 529.33197; found
529.33079. Minor isomer: [α]2D0 = –3.8 (c = 0.60, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 4.54 (s, 2 H), 4.32 (d,
J = 7.2 Hz, 1 H), 4.16 (t, J = 7.2 Hz, 1 H), 3.81–3.75 (m, 1 H),
3.61 (d, J = 7.2 Hz, 1 H), 3.57 (dd, J = 9.7, 6.4 Hz, 1 H), 3.50 (dd,
J = 9.7, 5.6 Hz, 1 H), 2.22 (td, J = 7.2, 1.6 Hz, 2 H), 1.54–1.47 (m,
2 H), 1.46–1.24 (m, 12 H), 1.18 (d, J = 6.6 Hz, 3 H), 0.89 (s, 9 H),
0.11 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
137.8, 128.3, 127.7, 127.6, 87.6, 77.2, 75.4, 73.4, 71.6, 70.2, 68.1,
64.3, 39.3, 29.5, 29.4, 28.9, 28.8, 28.4, 25.8, 25.6, 23.4, 18.7, 18.0,
–4.3, –5.0 ppm.
(S,E)-[1-(Benzyloxy)-4-iodobut-3-en-2-yloxy](tert-butyl)dimethylsil-
ane (4): To a solution of [Cp2ZrCl2] (2.32 g, 7.93 mmol) in THF
(32 mL) was added LiEt3BH (7.93 mL, 1 m in THF, 7.93 mmol) at
room temperature over 20 min. The reaction mixture was stirred
for 1 h before 10 (1.15 g, 3.97 mmol) in THF (16 mL) was added
dropwise. The mixture was stirred for 30 min before the addition
of I2 (1.5 g, 5.96 mmol) at 0 °C, and stirring continued for 30 min.
The reaction was quenched by the addition of saturated aqueous
NaHCO3 solution (30 mL). The aqueous phase was extracted with
diethyl ether (2ϫ25 mL). The combined organic layer was washed
with brine (20 mL), dried with Na2SO4, and evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (hexanes/EtOAc, 97:3) to give 4 (1.26 g, 76%) as a colorless
liquid. [α]2D0 = +3.2 (c = 1.30, CHCl ). IR (KBr): νmax = 2954, 2930,
˜
3
2891, 2856, 1464, 1362, 1253, 1096, 835, 777 cm–1
.
1H NMR
(S)-12-[(4R,5S)-5-{(R)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)-
ethyl}-2,2-dimethyl-1,3-dioxolan-4-yl]dodec-11-yn-2-ol (13): To 12
(440 mg, 0.87 mmol) in CH2Cl2 (5 mL) was added CSA (20 mg,
0.087 mmol) followed by 2,2-dimethoxypropane (0.32 mL,
2.6 mmol). The mixture was stirred for 1 h at room temperature.
After completion of the reaction (monitored by TLC), saturated
NaHCO3 solution (15 mL) was added to the reaction mixture and
(300 MHz, CDCl3): δ = 7.35–7.20 (m, 5 H), 6.57 (dd, J = 14.3,
5.1 Hz, 1 H), 6.32 (dd, J = 14.3, 1.3 Hz, 1 H), 4.50 (s, 2 H), 4.29–
4.21 (m, 1 H), 3.38–3.32 (m, 2 H), 0.89 (s, 9 H), 0.05 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 146, 138, 128.2, 127.5, 77.1, 74.1,
73.8, 73.3, 25.7, 18.2, –4.8 ppm. HRMS (ESI): calcd. for C17H27O2-
INaSi [M + Na]+ 441.07172; found 441.07239.
(2S,15S,E)-16-(Benzyloxy)-15-(tert-butyldimethylsilyloxy)hexadec- it was extracted with CH2Cl2 (2ϫ25 mL). The combined organic
13-en-11-yn-2-ol (11): To a solution of 4 (450 mg, 1.08 mmol) and
3 (196 mg, 1.08 mmol) in triethylamine (10 mL) was added bis(tri-
phenylphosphane)palladium(II) dichloride (76 mg, 0.11 mmol) at
0 °C. The mixture was stirred for 15 min at 0 °C before copper(I)
iodide (41.1 mg, 0.21 mmol) was added. After stirring for 10 min
at 0 °C, the reaction mixture was warmed to room temperature
and stirred for another 2.5 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (hexanes/
EtOAc, 90:10) to afford 11 (428 mg, 84%) as a light yellow oil.
layer was dried with Na2SO4, and the solvents evaporated to dry-
ness under reduced pressure. The residue was purified by column
chromatography (hexanes/EtOAc, 90:10) to give 13 (420 mg, 88%)
as a colorless oil. [α]2D0 = +12.2 (c = 1.00, CHCl ). IR (KBr): ν
˜
3
max
= 3447, 2929, 2856, 1461, 1372, 1252, 1152, 1064, 835, 777 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H), 4.68 (d, J =
7.0 Hz, 1 H), 4.52 (s, 2 H), 4.14 (dd, J = 7.0, 3.0 Hz, 1 H), 4.07–
4.02 (m, 1 H), 3.82–3.74 (m, 1 H), 3.57 (dd, J = 10.0, 6.0 Hz, 1 H),
3.48 (dd, J = 10.0, 6.0 Hz, 1 H), 2.18 (t, J = 7.0 Hz, 2 H), 1.52–
1.21 (m, 14 H), 1.47 (s, 3 H), 1.40 (s, 3 H), 1.18 (d, J = 6.0 Hz, 3
H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 138.1, 128.2, 127.5, 109.6, 86.9, 82.4, 78.2,
[α]2D0 = +1.2 (c = 1.00, CHCl ). IR (KBr): νmax = 3429, 2929, 2856,
˜
3
1719, 1271, 1118, 836, 779, 714 cm–1. 1H NMR (400 MHz, CDCl3):
1822
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1819–1824

Total Synthesis of (+)-Aspicilin and Its Biological Evaluation
73.3, 72.2, 70.8, 68.1, 66.3, 39.3, 29.5, 29.4, 29.0, 28.8, 28.4, 26.7,
26.0, 25.8, 25.7, 23.4, 18.8, 18.1, –4.5, –4.7 ppm. MS (ESI): m/z =
569.3588 [M + Na]+.
Macrolactone 16: To a solution of 2 (180 mg, 0.36 mmol) in THF
(10 mL) at 0 °C were added Et3N (0.3 mL, 2.16 mmol) and 2,4,6-
Cl3C6H2COCl (0.28 mL, 1.8 mmol). After stirring at room tem-
perature for 4 h, the reaction mixture was diluted with toluene
(10 mL) and added dropwise to a solution of DMAP (1.3 g,
10.8 mmol) in toluene (200 mL) at 100 °C over 10 h. After cooling
to room temperature, the mixture was concentrated to about
20 mL, diluted with EtOAc (25 mL), and the solution was success-
ively washed with 0.5 m aqueous HCl (10 mL), saturated aqueous
NaHCO3 solution (10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column
chromatography (hexanes/EtOAc, 98:2) to provide 16 (118 mg,
68%) as a colorless oil. [α]2D0 = +19.5 (c = 0.64, CHCl3). IR (KBr):
(S)-12-[(4R,5S)-5-{(R)-1-(tert-Butyldimethylsilyloxy)-2-
hydroxyethyl}-2,2-dimethyl-1,3-dioxolan-4-yl]dodecan-2-ol (14): Pal-
ladium on carbon (100 mg, 10% w/w) was added to a solution of
13 (250 mg, 0.46 mmol) in EtOH (5 mL), and the heterogeneous
mixture was stirred overnight under a hydrogen atmosphere. After
the completion of the reaction, the mixture was filtered through a
small pad of Celite, and the resulting filtrate was concentrated un-
der reduced pressure. The crude product was purified by flash col-
umn chromatography (hexanes/EtOAc, 80:20) to give 14 (172 mg,
82%) as a colorless liquid. [α]2D0 = +8.5 (c = 1.0, CHCl3). IR (KBr):
ν
max = 2929, 2858, 1718, 1457, 1372, 1255, 1115, 976, 835 cm–1. 1H
˜
ν
˜
max = 3428, 2927, 2856, 1463, 1372, 1251, 1066, 835, 775 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 6.82 (dd, J = 14.8, 4.9 Hz, 1 H),
6.01 (d, J = 14.8 Hz, 1 H), 5.08–4.99 (m, 1 H), 4.66–4.60 (m, 1 H),
4.05 (t, J = 5.9 Hz, 1 H), 3.72 (d, J = 7.9 Hz, 1 H), 1.62–1.22 (m,
20 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.25 (d, J = 5.9 Hz, 3 H), 0.94
(s, 9 H), 0.11 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.3, 146.1, 122.3, 108.0, 82.3, 74.5, 70.8, 70.3, 35.8,
32.8, 27.8, 27.3, 27.0, 26.9, 26.8, 25.9, 25.8, 24.4, 24.2, 20.5, 18.2,
–4.5, –4.8 ppm. HRMS (ESI): calcd. for C27H50O5SiNa [M +
Na]+ 505.3320; found 505.3338.
NMR (400 MHz, CDCl3): δ = 4.90–3.91 (m, 1 H), 3.80–3.73 (m, 1
H), 3.71–3.60 (m, 4 H), 2.07 (br. s, OH), 1.73–1.23 (m, 20 H), 1.37
(s, 3 H), 1.34 (s, 3 H), 1.17 (d, J = 5.5 Hz, 3 H), 0.90 (s, 9 H), 0.12
(s, 3 H), 0.10 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 108.7,
81.3, 80.4, 74.0, 68.0, 65.0, 39.3, 34.6, 29.7, 29.5, 29.4, 27.3, 27.1,
26.2, 25.7, 23.4, 17.9, –4.4, –4.5 ppm. HRMS (ESI): calcd. for
C25H52O5SiNa [M + Na]+ 483.3476; found 483.3432.
(R,E)-Ethyl 4-(tert-Butyldimethylsilyloxy)-4-[(4S,5R)-5-{(S)-11-hy-
droxydodecyl}-2,2-dimethyl-1,3-dioxolan-4-yl]but-2-enoate (15): To
14 (220 mg, 0.48 mmol) in CH2Cl2 (10 mL) at 0 °C was added
BAIB (178 mg, 0.55 mmol) and TEMPO (7.1 mg, 0.05 mmol). The
mixture was stirred for 2 h at room temperature, cooled to 0 °C,
and (ethocycarbonlymethylene)triphenylphosphorane (216 mg,
0.62 mmol) was added. The reaction mixture was warmed to room
temperature and stirred for 2 h. After completion of the reaction,
the mixture was concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes/EtOAc, 90:10)
to afford 15 (197 mg, 78%) as a colorless liquid. [α]2D0 = +10.0 (c =
(+)-Aspicilin (1): To a solution of 16 (90 mg, 0.18 mmol) in MeOH
(1 mL) at 0 °C was added 2 m HCl in MeOH (3 mL). The mixture
was stirred for 5 h at 0 °C. After completion of the reaction (moni-
tored by TLC), the solvent was evaporated under reduced pressure,
and the residue was purified by flash column chromatography (hex-
anes/EtOAc, 30:70) to give 1 (52 mg, 86%) as a colorless solid.
M.p. 153–155 °C. [α]2D0 = +37.9 (c = 0.64, CHCl3) {ref.[4g]: [α]2D2
+37.5 (c = 0.55, CHCl3), ref.[4i]: [α]2D3 = +38.5 (c = 0.22, CHCl3)}.
IR (KBr): ν = 3449, 3289, 2926, 2855, 1718, 1662, 1459, 1370,
=
˜
max
1245, 1179, 1075 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.91 (dd,
J = 16.3, 5.4 Hz, 1 H), 6.13 (d, J = 16.3 Hz, 1 H), 5.05 (sext, J =
6.2 Hz, 1 H), 4.62–4.55 (m, 1 H), 3.77 (td, J = 7.0, 2.3 Hz, 1 H),
3.66 (br. s, 1 H), 3.62–3.55 (m, 1 H), 3.36 (br. s, 1 H), 2.83 (br. s,
1 H), 1.56 (q, J = 6.2 Hz, 4 H), 1.47–1.15 (m, 16 H), 1.25 (d, J =
6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.5, 144.6,
123.0, 74.7, 73.3, 71.1, 69.9, 35.6, 32.0, 28.2, 27.7, 27.5, 27.2, 27.1,
26.3, 24.2, 23.6, 20.4 ppm. HRMS (ESI): calcd. for C18H32O5Na
[M + Na]+ 328.2142; found 328.2134.
1.0, CHCl ). IR (KBr): ν
= 3446, 2928, 2856, 1721, 1352, 1463,
˜
3
max
1372, 1257, 1166, 1072, 838, 777 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 6.96 (dd, J = 15.0, 5.0 Hz, 1 H), 6.03 (d, J = 15.0 Hz,
1 H), 4.34 (t, J = 5.0 Hz, 1 H), 4.24–4.16 (m, 2 H), 3.96 (td, J =
9.0, 4.0 Hz, 1 H), 3.82–3.76 (m, 1 H), 3.58 (t, J = 7.0 Hz, 1 H),
1.78–1.55 (m, 2 H), 1.52–1.22 (m, 18 H), 1.38 (s, 6 H), 1.19 (d, J
= 6.0 Hz, 3 H), 0.92 (s, 9 H), 0.09 (s, 3 H), 0.04 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.2, 147.8, 121.6, 108.7, 82.8, 78.6,
72.8, 68.1, 60.4, 39.3, 34.4, 29.6, 29.6, 29.5, 29.4, 27.4, 27.1, 26.1,
25.8, 25.7, 23.4, 18.1, 14.2, –4.5, –4.6 ppm. HRMS (ESI): calcd.
for C29H56O6SiNa [M + Na]+ 551.3738; found 551.3717.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all compounds.
(R,E)-4-(tert-Butyldimethylsilyloxy)-4-[(4S,5R)-5-{(S)-11-hydroxy-
dodecyl}-2,2-dimethyl-1,3-dioxolan-4-yl]but-2-enoic Acid (2): To a
solution of 15 (190 mg, 0.36 mmol) in THF/MeOH/H2O (8:1:1,
5 mL) was added LiOH (151 mg, 3.6 mmol). The reaction mixture
was stirred at room temperature for 8 h. The residue was diluted
with H2O (5 mL), and the resulting solution was acidified to about
pH 7 with 2 n HCl and extracted with EtOAc (2ϫ25 mL). The
combined organic extracts were dried with Na2SO4 and concen-
trated in vacuo, and the resulting crude seco-acid 2 (180 mg, quan-
titative) was used in the next step without further purification.
Acknowledgments
N. N. R. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship.
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˜
3
1704, 1376 cm–1. H NMR (500 MHz, CDCl3): δ = 7.06 (dd, J =
1
15.0, 4.6 Hz, 1 H), 6.05 (d, J = 15.0 Hz, 1 H), 4.40 (t, J = 4.6 Hz,
1 H), 4.00–3.94 (m, 1 H), 3.85–3.78 (m, 1 H), 3.60 (t, J = 6.9 Hz,
1 H), 1.62–1.22 (m, 20 H), 1.38 (s, 6 H), 1.19 (d, J = 5.7 Hz, 3 H),
0.93 (s, 9 H), 0.10 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.1, 150.0, 121.0, 108.7, 82.7, 78.3, 72.6, 68.3, 39.1,
34.3, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 27.4, 27.1, 26.0, 25.8, 25.5,
23.3, 18.1, –4.5, –4.6 ppm. MS (ESI): 523.3207 [M + Na]+.
Eur. J. Org. Chem. 2012, 1819–1824
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1823

C. Raji Reddy, N. N. Rao, P. Sujitha, C. G. Kumar
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Published Online: February 3, 2012
1824
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1819–1824