Total synthesis of both enantiomers of macrocyclic lactone aspergillide C

Article abstract of DOI:10.1002/ejoc.201100917

A facile approach to the total synthesis of both enantiomers of the 14-membered macrolactone aspergillide C is described. The strategy employed was also utilized for the synthesis of C4-epimers of both the enantiomers of aspergillide C. The key reactions include Sharpless kinetic resolution, Achmatowicz reaction, Ferrier type alkynylation, hydrosilylation- protodesilylation, Corey-Bakshi-Shibata (CBS) mediated reduction, and Yamaguchi macrolactonization.

Full text of DOI:10.1002/ejoc.201100917

FULL PAPER
DOI: 10.1002/ejoc.201100917
Total Synthesis of Both Enantiomers of Macrocyclic Lactone Aspergillide C
P. Srihari*[a] and Y. Sridhar[a]
Keywords: Natural products / Total synthesis / Macrocycles / Lactones / Diastereoselectivity / Hydrosilylation / Kinetic
resolution
A facile approach to the total synthesis of both enantiomers
of the 14-membered macrolactone aspergillide C is de-
scribed. The strategy employed was also utilized for the syn-
thesis of C4-epimers of both the enantiomers of aspergil-
lide C. The key reactions include Sharpless kinetic resolu-
tion, Achmatowicz reaction, Ferrier type alkynylation, hydro-
silylation-protodesilylation, Corey–Bakshi–Shibata (CBS)
mediated reduction, and Yamaguchi macrolactonization.
In a continuation of our program on the synthesis of
lactone-containing biologically active natural products,[6]
we became interested in targeting aspergillide C for total
synthesis. We describe herein a strategy whereby the target
molecule and also other analogues become easily accessible.
Introduction
Marine natural products have been a continuous source
of biologically potent natural products that have attracted
significant interest over last two decades due to their inter-
esting biological properties and their therapeutic applica-
tions.[1] Very recently, Kusumi and co-workers isolated three
novel bicyclic 14-membered macrolides with 2,6-cis and
trans-fused dihydro- or tetrahydropyran rings, namely as-
pergillides A–C (1–3; Figure 1), from a marine-derived fun-
gus Aspergillus ostianus strain 01F313.[2] These molecules
were found to display potent cytotoxicity against mouse
lymphatic leukemia cells.[2] The absolute configurations of
these molecules were initially determined on the basis on
a combination of spectroscopic methods, and were finally
confirmed/revised based on their total syntheses.[3,4,5] The
architectural complexity combined with the potent activity
of these molecules has attracted a number of synthetic com-
munities to target them for total synthesis;[3,4,5] it was anti-
cipated that the availability of such compounds would allow
further investigations into their biological properties.
Results and Discussion
Retrosynthetically, we envisaged that the target macro-
lide (+)-aspergillide C could be achieved from precursor 4
in three steps involving di-ester hydrolysis, Yamaguchi
lactonization, and methoxymethyl (MOM) deprotection
(Scheme 1). The intermediate 4 could be synthesized from 5
through stereoselective enone reduction followed by MOM
protection. Compound 5 can be obtained from acetal 7 by
Ferrier type alkynylation with derivatized trimethylsilyl
(TMS) protected acetylene 8 followed by reduction of the
alkyne to the trans olefin. Whereas acetal 7 could be ob-
Figure 1. Structures of aspergillides A–C.
[a] Organic Chemistry Division I, Indian Institute of Chemical
Technology,
Tarnaka, Hyderabad 500607, India
Fax: +91-4027160512
E-mail: srihari@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100917.
Scheme 1. Retrosynthetic analysis of (+)-aspergillide C.
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Total Synthesis of Aspergillide C
tained from racemic furfuryl alcohol 9 by Sharpless-type
kinetic resolution, the alkyne fragment 8 can be accessed
from commercially available chiral epoxide 10 (Scheme 1).
Our synthesis began with addition of enolate 11, gener-
ated from ethyl acetate, to furfuraldehyde to generate the
racemic secondary furfuryl alcohol 9. Racemate 9 was ki-
netically resolved under Sharpless conditions[7] into two
heteromers, i.e., pyranone lactal 12 and an enantio-pure
furfuryl alcohol 13 (Scheme 2). Whereas lactal 12 could be
directly utilized for the total synthesis of the natural prod-
uct (+)-aspergillide C, compound 13 could be subjected to
Achmatowicz reaction[8] to obtain lactal 14 and then uti-
lized for the synthesis of (–)-aspergillide C.
Scheme 4. Alkynylation of adduct 7.
presence of [Cp*Ru(MeCN)3]PF6 and then protodesilylated
with HF-pyridine[13] to yield the trans olefin 5 exclusively.
Unfortunately, attempts to proceed further with the lacton-
ization at this point did not proceed as planned because the
ester hydrolysis proved to be difficult.[14] Enone reduction
under Luche’s conditions yielded 16[15] as the major prod-
uct along with the desired product 17 in minor amounts
(Scheme 5). The stereoselectivity of this enone reduction
was systematically tuned with the use of the Corey–Bakshi–
Shibata reagent S-CBS[16] as a catalyst in the presence of
catechol borane to provide easily separable chiral allyl
alcohol 17 (80% yield) along with the other diastereomer
16 (9% yield).
Scheme 2. Synthesis of intermediates 12, 13, and 14.
We initially focused on the synthesis of natural isomer
(+)-aspergillide C. Accordingly, the anomeric hydroxyl
functionality in adduct 12 was activated to the correspond-
ing acetate 7 and subjected to Ferrier-type alkynylation[9]
with silylated alkyne 8 (synthesized from commercially
available chiral epoxide following the four-step sequence
shown in Scheme 3 with an overall yield of 60%) in the
presence of SnCl4 (Scheme 4) to give alkyne 6 in 85% yield
as a single diastereomer.[10] The high diastereoselectivity of
this reaction may be due to preferential attack of the nu-
cleophile from the opposite face (β-face) to the C6 substitu-
ent (oriented on the α-face) following a similar mechanism
to that reported for C-glycosidation reactions.[11]
Scheme 5. Total synthesis of (+)-aspergillide C.
With the requisite stereochemistry at all the chiral centers
established, the stage was set to selectively deprotect the
protective groups and cyclize the product through lacton-
ization to generate the 14-membered ring skeleton. However,
anticipating five-membered lactone ring formation[5b,5c]
through the free hydroxyl group in 17, we first protected the
free hydroxyl moiety by conversion into the corresponding
Scheme 3. Synthesis of alkyne 8.
Chemoselective reduction of alkyne 6 to E-alkene 5 was MOM ether 4 with methylal (dimethoxymethane)[17] in the
successfully achieved following Trost’s protocol;[12] thus, presence of P2O5. Di-ester 4 was subjected to hydrolysis
alkyne 6 was trans hydrosilylated with triethoxysilane in the with LiOH·H2O to produce seco acid 18. Lactonization of
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P. Srihari, Y. Sridhar
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18 under Yamaguchi[18] conditions afforded lactone 19 in
70% yield. Finally, deprotection of the MOM moiety upon
exposure of 19 to 8 n HCl yielded (+)-aspergillide C
(Scheme 5). The spectroscopic data of this synthetic com-
pound was compared to previously reported data[2a,5b] and
found to be identical.
Following a similar reaction sequence, starting from 14
and alkyne ent-8 [obtained from (S)-propylene oxide],
(–)-aspergillide C (ent-3) was synthesized (Scheme 6). Thus,
compound 14, after acylation followed by Ferrier-type alk-
ynylation with ent-8, gave ent-6. Hydrosilylation followed
by protodesilylation of alkyne ent-6 gave ent-5, which, upon
stereoselective reduction with R-CBS catalyst, afforded
alcohol ent-17 as the major product. MOM protection fol-
lowed by ester hydrolysis of ent-17 yielded seco acid ent-18.
Compound ent-18, upon lactonization under Yamaguchi
conditions followed by MOM deprotection, afforded (–)-
aspergillide C (ent-3; Scheme 6).
Scheme 7. Synthesis of the C4 epimer of (+)-aspergillide C.
Scheme 8. Synthesis of the C4 epimer of (–)-aspergillide C.
Conclusions
The total syntheses of both enantiomers of aspergillide C
and also the C4-epimers of (+)- and (–)-aspergillide C have
been achieved. The adopted strategy has paved the way for
the synthesis of four target molecules, including the natural
and unnatural isomers of aspergillide C, involving a similar
reaction sequence. Application of similar strategies for the
synthesis of aspergillide A and B, and of other related mac-
rolides for screening further biological activities are being
investigated.
Scheme 6. Synthesis of (–)-aspergillide C.
With alcohol 16 in hand (Scheme 5), we proceeded fur-
ther to the synthesis of the C4 epimer of (+)-aspergillide C
(21). Accordingly, compound 16 was treated with methylal
to yield the corresponding MOM ether,[17] which was then
subjected to hydrolysis with LiOH·H2O to yield seco acid
20. Compound 20, upon lactonization followed by exposure
to 8 n HCl, underwent MOM deprotection to yield the C4
epimer of (+)-aspergillide C (21; Scheme 7).
Experimental Section
1
General: H and 13C NMR spectra were recorded at ambient tem-
perature in CDCl3 or C6D6 as solvent with 200, 300, or 500 MHz
spectrometers. Coupling constants (J) are given in Hz; chemical
shifts are reported in ppm downfield from TMS as internal stan-
dard, and signal patterns are indicated as follows: s = singlet, d =
doublet, t triplet, q quartet, sext sextet, m multiplet, br. broad.
FTIR spectra were recorded as KBr pellets (CHCl3/neat; as noted)
and are reported in wavenumbers (cm–1). Optical rotations were
measured with a digital polarimeter using a 1-mL cell with a 1-dm
path length. For low (MS) and high (HRMS) resolution mass spec-
tra, m/z ratios are reported as values in atomic mass units. Mass
analysis was performed in ESI mode. All reagents were reagent
Similarly, synthesis of the C4 epimer of (–)-aspergillide
C was also accomplished starting from ent-5. Thus, ent-5
was subjected to enone reduction following Luche’s proto-
col to afford ent-16 as an easily separable major product
along with ent-17 as a minor product. The desired isomer
ent-16 was protected as the corresponding MOM ether and
then subjected to diester hydrolysis to yield ent-20, which,
upon lactonization followed by MOM deprotection, af-
forded the C4 epimer of (–)-aspergillide C (ent-21) in 80%
yield (Scheme 8).
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Total Synthesis of Aspergillide C
grade and used without further purification unless specified other-
wise. Solvents for reactions were distilled prior to use: THF, tolu-
ene, and diethyl ether were distilled from Na and benzophenone
ketyl; MeOH from Mg and I2; CH2Cl2 from CaH2. All air- or
moisture-sensitive reactions were conducted under a nitrogen or
argon atmosphere in flame-dried or oven-dried glassware with mag-
netic stirring. Column chromatography was carried out using silica
gel (60–120 mesh or 100–200 mesh) packed in glass columns. Tech-
nical grade ethyl acetate and petroleum ether used for column
chromatography were distilled prior to use.
(3.24 mL, 25.54 mmol) was added at –78 °C. After 1 h, the reaction
mixture was warmed to 0 °C. 1 n aq. HCl (20 mL) was added drop-
wise and stirring was continued for 30 min at room temperature.
The reaction mixture was extracted with diethyl ether (2ϫ10 mL),
washed with water (30 mL) and brine (10 mL), and dried with an-
hydrous Na2SO4. Evaporation of solvents in vacuo gave a light-
yellow oil, which was purified through a short pad of silica gel
(hexane/diethyl ether, 4:1) to afford alcohol 15b as a colorless oil
(1.96 g, 92%); Rf = 0.5 (hexane/diethyl ether, 4:1). (+)-15b: [α]D23
=
+7.9 (c = 0.55, CHCl ). IR (neat): ν = 3347, 2961, 2928, 2174,
˜
3
1249, 841, 760 cm–1. H NMR (500 MHz, CDCl3): δ = 3.82 (sext.,
1
(S)-Hept-6-en-2-ol (15): To a mixture of (S)-propylene oxide (10;
2.41 mL, 34.48 mmol) and CuCN (0.31 g, 3.45 mmol) in THF
(30 mL), was added 3-butenylmagnesium bromide (2.06 m in THF,
20 mL, 41.38 mmol) over 20 min at –78 °C. Stirring was continued
for 6 h at –78 °C, then the reaction mixture was warmed to room
temperature over 2 h. The reaction was quenched with saturated
aq. NH4Cl solution (5 mL), diluted with water (50 mL), and ex-
tracted with diethyl ether (3ϫ20 mL). The combined extracts were
washed with brine (20 mL), dried with anhydrous Na2SO4, and
evaporated in vacuo to give the crude product. Purification by col-
umn chromatography through a short pad of silica gel (hexane/
J = 7.0 Hz, 1 H), 2.23 (t, J = 7.0 Hz, 2 H), 1.69–1.49 (m, 4 H),
1.20 (d, J = 7.0 Hz, 3 H), 0.14 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 107.2, 84.8, 67.6, 38.3, 24.8, 23.5, 19.8, 0.12 ppm.
C10H20OSi (184.35): calcd. C 65.15, H 10.94; found C 64.52, H
10.56. (–)-15b: [α]2D3 = –8.6 (c = 0.45, CHCl3).
(S)-7-(Trimethylsilyl)hept-6-yn-2-yl Acetate (8): To a magnetically
stirring solution of alcohol 15b (2.0 g, 10.86 mmol) in CH2Cl2
(20 mL), pyridine (1.75 mL, 21.73 mmol) was added at 0 °C fol-
lowed by addition of DMAP (0.331 g, 2.71 mmol), and finally
Ac2O (1.21 mL, 11.95 mmol) at the same temperature. The mixture
diethyl ether, 4:1) afforded the desired alcohol as a colorless oil was stirred for 3 h then quenched with 1 n aq. HCl (30 mL) at 0 °C,
(3.26 g, 83%); Rf = 0.5 (hexane/diethyl ether, 4:1). (+)-15: [α]D25
and extracted with CH2Cl2 (3ϫ10 mL). The combined extracts
+10.0 (c = 0.75, CHCl ). IR (KBr): ν = 3358, 2957, 2937, 2810, were washed with water (20 mL), brine (10 mL), and dried with
=
˜
3
1634, 1458, 1375, 1219, 1060 cm–1. 1H NMR (300 MHz, CDCl3):
anhydrous Na2SO4. Evaporation of CH2Cl2 in vacuo gave the
δ = 5.83–5.69 (m, 1 H), 5.02–4.90 (m, 2 H), 3.76 (sext., J = 6.0 Hz, crude product, which was purified through a short pad of silica gel
1 H), 2.10–2.02 (m, 2 H), 1.57–1.36 (m, 4 H), 1.17 (d, J = 6.0 Hz, (hexane/diethyl ether, 9.5:0.5) to give 8 as a colorless oil (2.28 g,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.6, 114.4, 67.6,
38.5, 33.6, 24.9, 23.2 ppm. C7H14O (114.19): calcd. C 73.63, H
12.36; found C 72.96, H 12.10. (–)-15: [α]2D5 = –10.9 (c = 1.10,
CHCl3).
93%); Rf = 0.8 (hexane/diethyl ether, 9:1). (+)-8: [α]2D5 = +2.3 (c =
0.65, CHCl ). IR (KBr): ν = 2926, 2854, 2175, 1740, 1372, 1247,
˜
3
842, 771 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.89 (sext., J =
6.0 Hz, 1 H), 2.21 (t, J = 6.9 Hz, 2 H), 2.02 (s, 3 H), 1.67–1.46 (m,
4 H), 1.23 (d, J = 6.3 Hz, 3 H), 0.14 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.2, 106.5, 84.5, 70.1, 34.7, 24.2, 20.9,
19.7, 19.4, 0.1 ppm. C12H22O2Si (226.39): calcd. C 63.66, H 9.80;
found C 63.73, H 9.52. (–)-8: [α]2D4 = –1.9 (c = 0.45, CHCl3).
(S)-Hept-6-yn-2-ol (15a): Bromine (0.45 mL, 8.77 mmol) was added
dropwise to a pre-cooled (0 °C) solution of alcohol 15 (1.0 g,
8.77 mmol) in CCl4 (10 mL), and stirring was continued for 1 h at
room temp. When TLC analysis indicated complete consumption
of alcohol 15, the CCl4 was evaporated in vacuo. The residue was
dried under high vacuum and the product was used without purifi-
cation for the next step. Sodium pieces (2.0 g, 87.77 mmol) were
added slowly to liq. NH3 (50 mL) at –78 °C, then a small amount
of ferric nitrate was added to allow complete formation of NaNH2
(indicated by a color change from deep-blue to grey). To the re-
sulting mixture was added a solution of the above dibromide in
THF (10 mL) at –33 °C. After 30 min, the reaction was quenched
with solid NH4Cl (3.0 g) then aq. sat. NH4Cl (10 mL) at –33 °C.
The reaction mixture was allowed to come to room temperature
over 3 h (during which time the NH3 completely evaporated), then
diluted with water (50 mL) and extracted with diethyl ether
(3ϫ20 mL). The organic layer was dried with anhydrous Na2SO4,
evaporated in vacuo, and purified through a short pad of silica gel
(hexane/diethyl ether, 4:1) to give the desired alcohol 15a as a color-
less oil (0.835 g, 85%); Rf = 0.4 (hexane/diethyl ether, 4:1). (+)-15a:
Ethyl 3-(Furan-2-yl)-3-hydroxypropanoate (9): To a solution of di-
isopropylamine (8.02 mL, 57.29 mmol) in THF (40 mL) was added
nBuLi (1.60 m in hexane, 35.80 mL, 57.29 mmol) at –78 °C under
a nitrogen atmosphere. Stirring was continued for 1 h, then anhy-
drous EtOAc (7.52 mL, 57.29 mmol) in THF (20 mL) was added
at –78 °C. After 1 h, furfuraldehyde (4.31 mL, 52.08 mmol) in THF
(20 mL) was added at –78 °C, and the mixture was stirred for 1 h
before being quenched with aq. sat. NH4Cl (20 mL). The reaction
mixture was diluted with water (50 mL), extracted with EtOAc
(3ϫ30 mL) and the combined organic layer was washed with brine
(40 mL), dried with anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (hexane/
EtOAc, 9:1) to give 9 as a yellow oil (9.0 g, 94%); Rf = 0.4 (hexane/
EtOAc, 4:1). IR (KBr): ν = 3445, 2984, 2938, 1732, 1632, 1373,
˜
1
1283, 1217, 1163, 1012, 741 cm–1. H NMR (300 MHz, CDCl3): δ
= 7.34 (d, J = 1.8 Hz, 1 H), 6.30 (dd, J = 3.3, 1.8 Hz, 1 H), 6.25
(d, J = 3.3 Hz, 1 H), 5.09 (dt, J = 7.8, 4.5 Hz, 1 H), 4.18 (q, J =
7.2 Hz, 2 H), 3.19 (br. s, OH), 2.86 (dd, J = 16.2, 7.5 Hz, 1 H),
[α]2D3 = +11.5 (c = 0.13, CHCl ). IR (KBr): ν = 3453, 2922, 2851,
˜
3
2180, 1128 cm–1. H NMR (300 MHz, CDCl3): δ = 3.84–3.74 (m,
1
1 H), 2.19 (td, J = 6.4, 2.8 Hz, 2 H), 1.86 (t, J = 2.4 Hz, 1 H), 2.79 (dd, J = 16.5, 4.5 Hz, 1 H), 1.28 (t, J = 7.2 Hz, 3 H) ppm. 13
C
1.68–1.48 (m, 4 H), 1.18 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 84.3, 68.4, 67.4, 38.0, 24.6, 23.4, 18.2 ppm.
C7H12O (112.17): calcd. C 74.95, H 10.78; found C 74.60, H 10.45.
(–)-15a: [α]2D4 = –11.9 (c = 0.25, CHCl3).
NMR (75 MHz, CDCl3): δ = 171.6, 154.7, 141.9, 110.0, 106.0, 63.9,
60.7, 39.7, 13.8 ppm. C9H12O4 (184.19): calcd. C 58.69, H 6.57;
found C 58.62, H 6.49.
(S)-Ethyl
2-(6-Hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate
(S)-7-(Trimethylsilyl)hept-6-yn-2-ol (15b): nBuLi (1.60 m in hexane,
(12): To flame-dried 4 Å molecular sieves (2.50 g) in CH2Cl2
16 mL, 25.54 mmol) was added dropwise to a magnetically stirring (40 mL), was added (+)-DIPT (2.75 mL, 13.04 mmol). The solution
solution of alcohol 15a (1.30 g, 11.60 mmol) in THF (20 mL) at
was cooled to –21 °C and Ti(OiPr)4 (3.24 mL,10.86 mmol) was
–78 °C. Stirring was continued for 1 h, then freshly distilled TMSCl
added dropwise. Stirring was continued for 30 min, and the reac-
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P. Srihari, Y. Sridhar
FULL PAPER
tion mixture was cooled to –30 °C. To this mixture was added race-
mic furyl alcohol 9 (10 g, 54.35 mmol) in CH2Cl2 (30 mL) dropwise
169.1, 141.2, 128.0, 86.4, 72.2, 60.6, 34.9, 20.6, 13.8 ppm. Minor
anomer: H NMR (300 MHz, CDCl3): δ = 6.52 (d, J = 3.0 Hz, 1
1
at –30 °C. After 30 min, TBHP (4.2 m in toluene, 7.12 mL, H), 6.25 (d, J = 9.8 Hz, 1 H), 4.69 (dd, J = 8.3, 4.5 Hz, 1 H), 4.20
29.89 mmol) was added slowly at –30 °C. The reaction mixture was
warmed to –21 °C and stirring was continued for 24 h at –21 °C.
The reaction was quenched with dimethyl sulfide (2 mL) and
stirred for 1 h at room temp. The reaction mixture was filtered
through a pad of Celite and the filtrate was washed with water
(100 mL), brine (20 mL), dried with anhydrous Na2SO4, and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (hexane/EtOAc, 9:1 to 8:2) to give unreacted (R)-enantiomer
of 9 (ee Ͼ99% determined by chiral HPLC analysis; Chiralpak OJ-
H; iPrOH/hexanes, 4%; λ = 210 nm; flow rate = 1.0 mL/min; Rt =
28.3 min) and (+)-DIPT as an inseparable mixture (7.20 g), and 12
(72:28 mixture of inseparable anomers) as a yellow viscous oil
(4.56 g, 42%); Rf (hexane/EtOAc, 3:2) = 0.7 and 0.4. (–)-12: [α]D24
(q, J = 7.5 Hz, 2 H), 2.15 (s, 3 H), 1.28 (t, J = 6.9 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 193.4, 169.3, 168.7, 143.7, 128.2,
87.2, 75.7, 60.7, 37.5, 20.7 ppm. HRMS (ESI): m/z calcd. for
C11H14O6Na [M + Na]+ 265.0688; found 265.0701. (–)-7: [α]2D3
–24.0 (c = 1.00, CHCl3).
=
Ethyl 2-{(2S,6R)-6-[(S)-6-Acetoxyhept-1-ynyl]-3-oxo-3,6-dihydro-
2H-pyran-2-yl}acetate (6): To a magnetically stirred solution of
acetate 7 (0.50 g, 2.06 mmol) and 8 (0.51 g, 2.27 mmol) in CH2Cl2
(20 mL), SnCl4 (1 m in heptane, 0.52 mL, 0.52 mmol) was added at
0 °C. The ice bath was then removed and stirring was continued at
room temp. Within 1 h all acetate 7 was consumed (reaction moni-
tored by TLC) and the reaction was quenched with sat. aq.
NaHCO3 (10 mL) at 0 °C, diluted with water (10 mL), stirred at
room temp. for 1 h, then extracted with CH2Cl2 (3ϫ10 mL),
washed with brine (10 mL), and dried with anhydrous Na2SO4.
Evaporation of CH2Cl2 in vacuo gave the crude product, which
was subjected to silica gel column chromatography (hexane/EtOAc,
9:1) to give the desired product 6 as light-yellow oil (0.59 g, 85%);
Rf = 0.5 (hexane/EtOAc, 4:1). (+)-6: [α]2D5 = +161.0 (c = 0.70,
= –4.84 (c = 1.10, CHCl ). IR (KBr): ν = 3426, 2925, 1729, 1695,
˜
3
1374, 1292, 1180, 1028 cm–1; Major anomer: H NMR (300 MHz,
1
CDCl3): δ = 6.88 (dd, J = 10.2, 3.3 Hz, 1 H), 6.09 (d, J = 10.2 Hz,
1 H), 5.56 (d, J = 3.3 Hz, 1 H), 4.97 (dd, J = 8.1, 3.6 Hz, 1 H),
4.14 (q, J = 7.2 Hz, 2 H), 2.98 (dd, J = 16.8, 3.9 Hz, 1 H), 2.65
(dd, J = 16.8, 8.1 Hz, 1 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 195.1, 170.9, 144.9, 126.7, 87.5, 70.5,
60.9, 35.1, 13.9 ppm. Minor anomer: 1H NMR (300 MHz, CDCl3):
δ = 6.94 (dd, J = 10.5, 1.5 Hz, 1 H), 6.14 (dd, J = 10.5, 1.5 Hz, 1
H), 5.69 (br. s, 1 H), 4.52 (dd, J = 7.8, 3.6 Hz, 1 H), 4.15 (q, J =
7.2 Hz, 2 H), 2.74 (dd, J = 16.5, 8.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 194.5, 148.7, 128.1, 90.8, 75.1, 61.0,
35.8 ppm. HRMS (ESI): m/z calcd. for C9H12O5Na [M + Na]+
223.0582; found 223.0579.
CHCl ). IR (neat, KBr): ν = 2933, 2190, 1735, 1696, 1373, 1247,
˜
3
1175, 1024 cm–1. H NMR (300 MHz, CDCl3): δ = 6.90 (dd, J =
1
9.8, 4.5 Hz, 1 H), 6.04 (dd, J = 9.8, 1.5 Hz, 1 H), 5.08 (dt, J = 4.5,
2.3 Hz, 1 H), 4.90 (sext., dd, J = 6.0 Hz, 1 H), 4.85 (dd, J = 7.3,
4.2 Hz, 1 H), 4.16 (qt, J = 4.7, 7.5 Hz, 2 H), 2.95 (dd, J = 16.6,
4.5 Hz, 1 H), 2.66 (dd, J = 16.8, 7.5 Hz, 1 H), 2.28 (td, J = 6.8,
2.3 Hz, 2 H), 2.01 (s, 3 H), 1.69–1.52 (m, 4 H), 1.28 (t, J = 6.9 Hz,
3 H), 1.22 (d, J = 6.6, Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 194.0, 170.3, 170.0, 146.7, 124.7, 88.5, 73.0, 72.6, 70.0, 63.0,
60.5, 35.0, 34.7, 24.0, 21.0, 19.7, 18.3, 13 ppm. (–)-6: [α]2D5 = –150.2
(c = 0.42, CHCl3). HRMS (ESI): m/z calcd. for C18H24O6Na [M +
Na]+ 359.1470; found 359.1475.
(R)-Ethyl
2-(6-Hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate
(14): To a magnetically stirred solution of (R)-furfuryl alcohol (ob-
tained from the above resolution; 3.0 g, 16.30 mmol) in THF/H2O
(24:6 mL), solid NaHCO3 (2.73 g, 32.61 mmol), NaOAc·3H2O
(2.44 g, 17.93 mmol), and finally NBS (2.93 g, 16.30 mmol) were
added at 0 °C. Stirring was continued at 0 °C until complete con-
sumption of starting material was observed (1 h; reaction moni-
tored by TLC). The reaction was quenched with saturated aq.
NaHCO3 (10 mL) and extracted with EtOAc (2ϫ20 mL). The or-
ganic layer was dried with anhydrous Na2SO4, concentrated in
vacuo, and the residue was purified by column chromatography
(hexane/EtOAc, 4:1) to give 14 (72:28 mixture of inseparable ano-
mers) as a yellow oil (2.99 g, 92%); Rf = 0.4 (hexane/EtOAc, 3:2).
(+)-14: [α]2D4 = +4.20 (c = 0.95, CHCl3).
Ethyl 2-{(2S,6S)-6-[(S,E)-6-Acetoxyhept-1-enyl]-3-oxo-3,6-dihydro-
2H-pyran-2-yl}acetate (5): To a vigorously stirring solution of al-
kyne 6 (0.50 g, 1.49 mmol) and (EtO)3SiH (1.09 mL, 5.95 mmol)
in CH2Cl2 (20 mL), [Cp*(MeCN)3Ru]PF6 (7 mg, 0.014 mmol) was
added at 0 °C under an argon atmosphere, and the ice bath was
then removed. Within 1 h, all alkyne 6 was consumed (reaction
monitored by TLC). Evaporation of CH2Cl2 in vacuo gave the
crude vinyl siloxanes, which was diluted with THF (20 mL) cooled
to 0 °C. To this mixture, pyridine (1.19 mL, 14.88 mmol) followed
by HF/pyridine (70:30 solution, 0.20 mL, 7.44 mmol) were added
dropwise at 0 °C. After all vinyl siloxane was consumed (5 min;
reaction monitored by TLC), the reaction was quenched with water
(5 mL), neutralized with 0.5 n HCl (35 mL), and extracted with
(S)-Ethyl 2-(6-Acetoxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (7):
To a magnetically stirred solution of lactol 12 (2.0 g, 10.0 mmol) in
CH2Cl2 (20 mL), pyridine (1.61 mL, 20.0 mmol) was added at 0 °C
followed by Ac2O (1.12 mL, 11.0 mmol) at the same temperature. EtOAc (3ϫ20 mL). The organic layers were washed with water
All lactol was consumed within 1 h, and the reaction was then
quenched with 1 n HCl (20 mL) at 0 °C and extracted with CH2Cl2
(2ϫ20 mL). The organic layer was washed with water (30 mL) and
brine (20 mL), and dried with anhydrous Na2SO4. Evaporation of
CH2Cl2 in vacuo gave the crude product, which was purified by
column chromatography (hexane/EtOAc, 9:1) to give the desired
product 7 (75:25 mixture of inseparable anomers) as a yellow vis-
cous oil (2.170 g, 90%); Rf = 0.5 (hexane/EtOAc, 4:1). (+)-7: [α]D23
(20 mL) and brine (10 mL), and dried with anhydrous Na2SO4.
Evaporation of solvent in vacuo gave the crude product, which was
subjected to silica gel column chromatography (hexane/EtOAc, 9:1)
to give the desired product 5 as a light-yellow oil (0.45 g, 90%); Rf
= 0.5 (hexane/EtOAc, 4:1). (+)-5: [α]2D5 = +74.2 (c = 1.05, CHCl3).
1
IR (KBr): ν = 2982, 1745, 1698, 1375, 1246, 1104 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 6.96 (dd, J = 10.2, 3.9 Hz, 1 H), 6.10 (dd,
J = 10.5, 1.8 Hz, 1 H), 5.76 (dt, J = 15.6, 6.6 Hz, 1 H), 5.58 (dd, J
= 15.6, 5.1 Hz, 1 H), 4.81–4.92 (m, 2 H), 4.61 (dd, J = 8.1, 3.9 Hz,
= +18.0 (c = 1.75, CHCl ). IR (neat, KBr): ν = 2984, 1747, 1701,
˜
3
1375, 1216, 1104, 939, 763 cm–1; Major anomer: 1H NMR 1 H), 4.16 (q, J = 7.2, Hz, 2 H), 2.92 (dd, J = 16.2, 3.9 Hz, 1 H),
(300 MHz, CDCl3): δ = 6.86 (dd, J = 10.8, 3.7 Hz, 1 H), 6.45 (d,
J = 3.7 Hz, 1 H), 6.23 (d, J = 9.8 Hz, 1 H), 4.86 (dd, J = 6.6,
4.2 Hz, 1 H), 4.15 (q, J = 7.5 Hz, 2 H), 2.92 (dd, J = 17.7, 4.5 Hz,
1 H), 2.73 (dd, J = 16.5, 6.9 Hz, 1 H), 2.14 (s, 3 H), 1.27 (t, J =
7.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.7, 169.7,
2.60 (dd, J = 16.5, 8.1 Hz, 1 H), 2.16–2.09 (m, 2 H), 2.0 (s, 3 H),
1.64–1.39 (m, 4 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.20 (d, J = 6.3 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.5, 170.5, 170.4,
149.4, 136.3, 125.6, 124.0, 72.2, 72.0, 70.5, 60.5, 35.3, 35.1, 32.0,
24.5, 21.2, 19.8, 14.0 ppm. HRMS (ESI): m/z calcd. for
6694
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6690–6697

Total Synthesis of Aspergillide C
C18H26O6Na [M + Na]+ 361.1627; found 361.1641. (–)-5: [α]2D3
–83.2 (c = 0.50, CHCl3).
=
stirring solution of alcohol 17 (0.120 g, 0.35 mmol) in (MeO)2CH2
(5 mL), P2O5 (0.20 g, 1.41 mmol) was added at 0 °C under an atmo-
sphere of argon. Within 3 h all the starting material was consumed
and the reaction mass was decanted from the black tar type mate-
rial and rinsed with EtOAc (3ϫ5 mL). The combined organic layer
was washed with saturated aq. NaHCO3 (10 mL) and brine
(10 mL) and dried with anhydrous Na2SO4. Evaporation of sol-
vents in vacuo gave the crude product, which was purified by col-
umn chromatography (hexane/EtOAc, 9:1) to give 4 as a colorless
Ethyl 2-{(2S,3S,6S)-6-[(S,E)-6-Acetoxyhept-1-enyl]-3-hydroxy-3,6-
dihydro-2H-pyran-2-yl}acetate (17): To a 25 mL two-necked round-
bottomed flask charged with a magnetic stir bar, was added (S)-
CBS catalyst (1 m in toluene, 0.59 mL, 0.59 mmol). The toluene was
evaporated under high vacuum and the residue was purged with
argon and diluted with CH2Cl2 (5 mL), cooled to 0 °C, and cate-
cholborane (1 m in THF, 0.59 mL, 0.59 mmol) was added. The re-
action mixture was warmed to room temperature, stirred for
30 min, then cooled to –78 °C. To this reaction mixture, a solution
of enone 5 (0.10 g, 0.29 mmol) dissolved in CH2Cl2 (3 mL) was
added dropwise. The reaction was stirred for 24 h at –78 °C until
TLC analysis indicated complete consumption of the starting mate-
rial. MeOH (2 mL) was carefully added and the reaction was di-
luted with sat. NH4Cl (5 mL) and extracted with CH2Cl2
(2ϫ10 mL). The combined extracts were washed with brine
(10 mL), dried with anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by silica gel column chromatography (hex-
ane/EtOAc, 9:1 to 8:2) to give 16 (9 mg, 9%) as the minor isomer,
and the desired alcohol 17 (80 mg, 80%) as the major isomer. Rf =
0.4 (hexane/EtOAc, 3:2). (+)-17: [α]2D4 = +105.0 (c = 0.50, CHCl3).
oil (0.121 g, 90%); Rf = 0.5 (hexane/EtOAc, 7:3). (+)-4: [α]D23
=
+120.0 (c = 0.12, CHCl ). IR (KBr): ν = 2926, 2850, 1735, 1373,
˜
3
1246, 1149, 1038 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.01 (ddd,
J = 10.5, 4.8, 1.8 Hz, 1 H), 5.92 (dd, J = 10.5, 3.0, Hz, 1 H), 5.61
(dt, J = 15.6, 6.3, Hz, 1 H), 5.48 (dd, J = 15.6, 5.7, Hz, 1 H), 4.86
(sex, J = 6.6, Hz, 1 H), 4.73 (d, J = 6.8 Hz, 1 H), 4.64 (br. s, 1 H),
4.60 (d, J = 6.8 Hz, 1 H), 4.20 (dd, J = 7.2, 2.7 Hz, 1 H), 4.13 (q,
J = 7.2 Hz, 2 H), 3.83 (br. t, J = 3.6 Hz, 1 H), 3.36 (s, 3 H), 2.62
(dd, J = 7.2, 2.7 Hz, 2 H), 2.11–2.04 (m, 2 H), 2.01 (s, 3 H), 1.64–
1.37 (m, 4 H), 1.27 (t, J = 6.9 Hz, 3 H), 1.20 (d, J = 6.0 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.3, 170.7, 134.0,
132.1, 127.3, 124.6, 95.8, 72.8, 70.8, 68.2, 68.1, 60.4, 55.6, 35.9,
35.4, 32.1, 24.8, 21.4, 19.9, 14.2 ppm. HRMS (ESI): m/z calcd. for
C20H32O7Na [M + Na]+ 407.2045; found 407.2052. (–)-4: [α]2D3
–115.1 (c = 0.20, CHCl3).
=
IR (KBr): ν = 3446, 2979, 2930, 1733, 1376, 1248, 1220, 1026 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 6.06 (ddd, J = 10.2, 5.4, 2.1 Hz,
1 H), 5.90 (dd, J = 10.2, 3.6 Hz, 1 H), 5.60 (dt, J = 16.2, 6.3 Hz, 1
H), 5.50 (dd, J = 15.9, 5.1 Hz, 1 H), 4.86 (sext., J = 6.3 Hz, 1 H),
4.60 (br. s, 1 H), 4.17–4.07 (m, 3 H), 3.72 (br. s, 1 H), 2.61 (d, J =
6.6 Hz, 2 H), 2.07 (td, J = 11.4, 3.9 Hz, 2 H), 2.01 (s, 3 H), 1.69–
1.37 (m, 4 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.20 (d, J = 6.3 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.3, 170.7, 134.2,
131.6, 126.7, 126.8, 73.1, 70.7, 68.7, 63.2, 60.4, 36.2, 35.3, 32.1,
24.8, 21.3, 19.8, 14.1 ppm. HRMS (ESI): m/z calcd. for
2-{(2S,3S,6S)-6-[(S,E)-6-Hydroxyhept-1-enyl]-3-(methoxymethoxy)-
3,6-dihydro-2H-pyran-2-yl}acetic Acid (18): LiOH·H2O (33 mg,
0.78 mmol) was added to a magnetically stirred solution of ester 4
(50 mg, 0.13 mmol) in THF/H2O (7:3, 5 mL) at 0 °C. Stirring was
continued until complete consumption of starting material was ob-
served (ca. 24 h). The reaction mixture was cooled to 0 °C and
acidified with KHSO4 to pH 5, diluted with water (10 mL), and
extracted with EtOAc (3ϫ10 mL). The combined organic layer was
washed with brine (10 mL) and dried with anhydrous Na2SO4.
Evaporation of solvents in vacuo gave the crude acid, which was
purified by silica gel column chromatography (hexane/EtOAc, 7:3
to 100% EtOAc) to afford seco acid 18 as a colorless oil (38 mg,
95%); Rf = 0.2 (hexane/EtOAc, 1:1). (+)-18: [α]2D4 = +163.3 (c =
C18H28O6Na [M + Na]+ 363.1783; found 363.1789. (–)-17: [α]2D4
–110.0 (c = 0.85, CHCl3).
=
Ethyl 2-{(2S,3R,6S)-6-[(S,E)-6-Acetoxyhept-1-enyl]-3-hydroxy-3,6-
dihydro-2H-pyran-2-yl}acetate (16): To a magnetically stirred solu-
tion of enone 5 (0.50 g, 1.48 mmol) in MeOH (10 mL), CeCl3·7H2O
(0.83 g, 2.22 mmol) was added at 0 °C. After 5 min, the reaction
mixture was cooled to –78 °C and NaBH4 (56 mg, 1.48 mmol) was
added. Within 5 min, all enone 5 was consumed and the reaction
was quenched with sat. NH4Cl (10 mL), diluted with water
(10 mL), extracted with EtOAc (5ϫ10 mL) and the combined ex-
tracts were washed with brine (10 mL) and dried with anhydrous
Na2SO4. Evaporation of the solvent in vacuo gave the crude prod-
uct, which was purified by column chromatography (hexane/
EtOAc, 9:1 to 8:2) to give colorless alcohol 16 (0.39 g, 77%) as the
major isomer and 17 (96 mg, 19%) as the minor isomer. Rf = 0.4
(hexane/EtOAc, 3:2). (+)-16: [α]2D5 = +24.2 (c = 1.50, CHCl3) IR
0.35, CHCl ). IR (KBr): ν = 3448, 2926, 2851, 1719, 1375, 1219,
˜
3
1
1032 cm–1. HNMR (300 MHz, CDCl3): δ = 6.08 (ddd, J = 10.5,
5.1, 1.8 Hz, 1 H), 5.99 (dd, J = 10.2, 3.0 Hz, 1 H), 5.66 (dt, J =
15.3, 5.7 Hz, 1 H), 5.54 (dd, J = 15.6, 5.1 Hz, 1 H), 4.80 (d, J =
7.2, Hz, 1 H), 4.76–4.70 (br. m, 1 H), 4.65 (d, J = 6.6, Hz, 1 H),
4.24 (dt, J = 8.4, 3.6 Hz, 1 H), 3.88–3.78 (m, 2 H), 3.39 (s, 3 H),
2.77 (dd, J = 15.9, 9.0 Hz, 1 H), 2.59 (dd, J = 15.9, 3.9 Hz, 1 H),
2.17–1.99 (m, 2 H), 1.68–1.56 (m, 1 H), 1.48–1.32 (m, 3 H), 1.18
(d, J = 6.3, Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.8,
134.7, 132.3, 127.2, 124.5, 95.6, 73.0, 68.4, 68.1, 68.0, 55.7, 37.6,
36.2, 31.6, 24.4, 22.7 ppm. HRMS (ESI): m/z calcd. for
C16H26O6Na [M + Na]+ 337.1627; found 337.1642. (–)-18: [α]2D4
–155.4 (c = 0.25, CHCl3).
=
(KBr): ν = 3435, 2980, 2938, 1731, 1373, 1247, 1219, 1025 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 5.83 (ddd, J = 10.2, 5.7, 1.8 Hz,
1 H), 5.77 (ddd, J = 10.2, 2.4, 1.2 Hz, 1 H), 5.61 (dt, J = 15.6,
7.0 Hz, 1 H), 5.51 (dd, J = 15.6, 4.5 Hz, 1 H), 4.87 (sext., J =
6.0 Hz, 1 H), 4.56 (br. s, 1 H), 4.15 (q, J = 6.5 Hz, 2 H), 3.88 (dd,
J = 7.8, 1.5 Hz, 1 H), 3.80 (ddd, J = 15.9, 7.8, 4.2 Hz, 1 H), 2.75
(dd, J = 15.5, 4.5 Hz, 1 H), 2.49 (dd, J = 15.5, 8.0 Hz, 1 H), 2.10–
2.06 (m, 2 H), 2.01 (s, 3 H), 1.65–1.40 (m, 4 H), 1.28 (t, J = 7.0 Hz,
3 H), 1.21 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 171.3, 170.7, 134.2, 131.6, 126.7, 126.8, 73.1, 70.7, 68.7, 63.2,
60.4, 36.2, 35.2, 32.1, 24.8, 21.3, 19.8, 14.1 ppm. MS (ESI): m/z =
363 [M + Na]+. (–)-16: [α]D23 = –27.4 (c = 0.45, CHCl3).
2-{(2S,3R,6S)-6-[(S,E)-6-Hydroxyhept-1-enyl]-3-(methoxymethoxy)-
3,6-dihydro-2H-pyran-2-yl}acetic Acid (20): Following a procedure
similar to that followed for 4, alcohol 16 (0.20 g, 0.59 mmol) gave
MOM ether 16a as a colorless oil (0.21 g, 92%); Rf = 0.5 (hexane/
EtOAc, 7:3). Compound 16a, upon hydrolysis following a protocol
similar to that employed for compound 18, gave seco acid 20 as a
colorless oil (47 mg, 95%); Rf = 0.2 (hexane/EtOAc, 1:1). (+)-16a:
[α]2D4 = +13.8 (c = 0.70, CHCl ). IR (KBr): ν = 2979, 2938, 1732,
˜
3
1373, 1247, 1035 cm–1. H NMR (300 MHz, CDCl3): δ = 5.88 (dt,
1
J = 10.5, 1.8 Hz, 1 H), 5.77 (ddd, J = 10.2, 2.7, 1.5 Hz, 1 H), 5.64
(dt, J = 15.6, 6.3 Hz, 1 H), 5.53 (dd, J = 15.6, 5.4 Hz, 1 H), 4.86
Ethyl
2-{(2S,3S,6S)-6-[(S,E)-6-Acetoxyhept-1-enyl]-3-(methoxy- (sext., J = 6.6 Hz, 1 H), 4.71 (d, J = 7.2 Hz, 1 H), 4.64 (d, J =
methoxy)-3,6-dihydro-2H-pyran-2-yl}acetate (4): To a vigorously
6.9 Hz, 1 H), 4.55 (br. m, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.95 (td,
Eur. J. Org. Chem. 2011, 6690–6697
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6695

P. Srihari, Y. Sridhar
FULL PAPER
J = 8.4, 3.6 Hz, 1 H), 3.86 (dd, J = 8.1, 1.8 Hz, 1 H), 3.37 (s, 3 H),
2.69 (dd, J = 15.3, 3.9 Hz, 1 H), 2.42 (dd, J = 15.0, 6.7 Hz, 1 H),
white solid (6.8 mg, 80%); Rf = 0.5 (hexane/EtOAc, 7:3); m.p. 114–
116 °C. (+)-3: [α]D25 = +76.8 (c = 0.18, MeOH) {ref.[2a] [α]2D5 = +66.2
2.11–2.04 (m, 2 H), 2.01 (s, 3 H), 1.64–1.33 (m, 4 H), 1.27 (t, J = (c = 0.19, MeOH); ref.[5b] [α]2D5 = +83.0 (c = 0.14, MeOH)}. IR
7.2 Hz, 3 H), 1.20 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.0, 170.7, 133.9, 130.5, 127.6, 126.1, 95.8, 72.5,
72.3, 70.8, 68.7, 60.4, 55.6, 37.7, 35.3, 32.1, 24.8, 21.3, 19.9,
14.1 ppm. HRMS (ESI): m/z calcd. for C20H32O7Na [M + Na]+
407.2045; found 407.2058. (–)-16a: [α]2D4 = –15.0 (c = 0.85, CHCl3).
(KBr): ν = 3290, 2925, 1720, 1219, 1083, 1036 cm–1 1H NMR
.
˜
(500 MHz, C6D6): δ = 5.94 (dddd, J = 15.6, 9.2, 5.9, 1.5 Hz, 1 H),
5.74 (ddd, J = 9.8, 5.4, 2.0 Hz, 1 H), 5.42 (dd, J = 10.0, 3.7 Hz, 1
H), 5.18 (dd, J = 15.6, 3.9 Hz, 1 H), 5.15–5.09 (m, 1 H), 4.47–4.44
(m, 1 H), 4.04 (d, J = 11.2 Hz, 1 H), 3.25–3.21 (br. m, 1 H), 2.86
(dd, J = 14.0, 11.2 Hz, 1 H), 2.24 (dd, J = 13.9, 1.7 Hz, 1 H), 1.98–
1.92 (m, 1 H), 1.64–1.54 (m, 2 H), 1.46–1.37 (m, 1 H), 1.35–1.24
(m, 2 H, 1 H, OH), 1.20–1.12 (m, 1 H), 0.99 (d, J = 6.8 Hz, 3
(+)-20: [α]2D3 = +20.6 (c = 0.80, CHCl ). IR (KBr): ν = 3444, 2926,
˜
3
1713, 1219, 1066 cm–1. H NMR (500 MHz, CDCl3): δ = 5.91 (dt,
1
J = 10.5, 1.5 Hz, 1 H), 5.83 (ddd, J = 10.2, 2.5, 1.5 Hz, 1 H), 5.71
(dt, J = 15.6, 7.0 Hz, 1 H), 5.59 (dd, J = 15.6, 6.0 Hz, 1 H), 4.77 H) ppm. 13C NMR (75 MHz, C6D6): δ = 170.0, 135.0, 131.8, 128.3,
(d, J = 7.0 Hz, 1 H), 4.68 (d, J = 7.0 Hz, 1 H), 4.63 (br. s, 1 H),
4.01 (td, J = 9.5, 3.0 Hz, 1 H), 3.91 (dd, J = 8.5, 2.0 Hz, 1 H), 3.83
(sext., J = 6.2 Hz, 1 H), 3.41 (s, 3 H), 2.84 (dd, J = 15.0, 2.5 Hz, 1
H), 2.46 (dd, J = 15.5, 10.0 Hz, 1 H), 2.17–2.01 (m, 2 H), 1.67–
1.58 (m, 1 H), 1.48–1.41 (m, 2 H), 1.40–1.34 (m, 1 H), 1.19 (d, J
= 6.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.9, 134.5,
130.1, 127.6, 126.6, 95.8, 72.8, 72.6, 68.3, 68.1, 55.7, 37.5, 37.4,
126.2, 72.0, 69.8, 69.5, 64.6, 38.8, 32.1, 31.0, 23.7, 18.7 ppm.
HRMS (ESI): m/z calcd. for C14H20O4Na [M + Na]+ 275.1259;
found 275.1256. (–)-3: [α]2D5 = –79.8 (c = 0.20, MeOH).
(1S,5S,11S,14R,E)-14-Hydroxy-5-methyl-4,15-dioxabicyclo[9.3.1]-
pentadeca-9,12-dien-3-one (21): Following a procedure similar to
that followed for compound 19, seco acid 20 (40 mg, 0.13mmol)
gave lactone 20a as a colorless oil (25 mg, 68%); Rf = 0.6 (hexane/
EtOAc, 3:2). Compound 20a was subjected to MOM deprotection,
following the procedure given for the preparation of 3, to yield 21
as a colorless oil (10.2 mg, 80%); Rf = 0.5 (hexane/EtOAc, 7:3).
31.5, 24.3, 22.5 ppm. MS (ESI): m/z = 337 [M + Na]+. (–)-20: [α]
24
= –26.0 (c = 0.50, CHCl3).
D
(1S,5S,11S,14S,E)-14-(Methoxymethoxy)-5-methyl-4,15-dioxabicy-
clo[9.3.1]pentadeca-9,12-dien-3-one (19): To a magnetically stirred
solution of seco acid 18 (38 mg, 0.12 mmol) in THF (5 mL), Et3N
(0.14 mL, 0.97 mmol) was added at 0 °C, followed by addition of
2,4,6-trichlorobenzoyl chloride (0.10 mL, 0.61 mmol). Stirring was
continued at 0 °C for 1 h then at room temp. for a further 1 h. The
reaction mixture was diluted with toluene (20 mL) and stirring was
continued for an additional 1 h. The resulting mixture was added
dropwise over 8 h by syringe pump to a refluxing solution of
DMAP (0.369 g, 3.03 mmol) in toluene (40 mL) under argon. After
addition, the mixture was stirred for 15 min, then toluene was evap-
orated under reduced pressure and the residue was diluted with
EtOAc (10 mL), neutralized with 0.5 n HCl (6 mL) at 0 °C, and
extracted with EtOAc (3 ϫ10 mL). The combined extracts were
washed with water (20 mL) and brine (10 mL) and dried with anhy-
drous Na2SO4. Evaporation of solvents in vacuo gave the crude
lactone, which was purified by column chromatography (hexane/
EtOAc, 9:1) to afford the desired lactone 19 as a colorless oil
(25 mg, 70%); Rf = 0.6 (hexane/EtOAc, 3:2). (+)-19: [α]2D5 = +84.1
(–)-20a: [α]2D4 = –11.6 (c = 0.50, CHCl ). IR (KBr): ν = 2928, 1731,
˜
3
1268, 1249, 1104, 1044 cm–1. 1H NMR (300 MHz, CDCl3): δ =
6.00 (dddd, J = 15.6, 10.2, 6.4, 1.2 Hz, 1 H), 5.92 (dt, J = 10.2,
1.5 Hz, 1 H), 5.79 (ddd, J = 10.2, 3.0, 1.5 Hz, 1 H), 5.54 (dd, J =
15.9, 4.5 Hz, 1 H), 5.18–5.09 (m, 1 H), 4.78 (d, J = 6.9 Hz, 1 H),
4.67 (d, J = 6.9 Hz, 1 H), 4.65 (br. m, 1 H), 4.00 (td, J = 9.2,
1.8 Hz, 1 H), 3.92 (dd, J = 9.0, 1.5 Hz, 1 H), 3.41 (s, 3 H), 2.87
(dd, J = 13.5, 1.5 Hz, 1 H), 2.27 (dd, J = 13.5, 11.1 Hz, 1 H), 2.25–
2.17 (m, 1 H), 1.87–1.57 (m, 5 H), 1.19 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 170.8, 135.2, 130.0, 128.2, 127.2,
95.9, 73.2, 71.8, 70.1, 68.4, 55.7, 38.7, 31.8, 30.7, 23.1, 18.6 ppm.
HRMS (ESI): m/z calcd. for C16H24O5Na [M + Na]+ 319.1521;
found 319.1528. (+)-20a: [α]2D4 = –14.0 (c = 0.45, CHCl3). (+)-21:
[α]2D3 = +25.1 (c = 0.95, MeOH). IR (KBr): ν = 3344, 2924, 2853,
˜
1729, 1220, 1049 cm–1. 1H NMR (500 MHz, C6D6): δ = 5.97 (dddd,
J = 15.6, 9.3, 6.0, 1.6 Hz, 1 H), 5.59 (dt, J = 10.2, 1.7 Hz, 1 H),
5.40 (ddd, J = 10.2, 3.0, 1.8 Hz, 1 H), 5.28 (dd, J = 15.6, 4.2 Hz,
1 H), 5.22–5.13 (m, 1 H), 4.56–4.51 (m, 1 H), 3.90 (ddd, J = 11.1,
9.0, 1.8 Hz, 1 H), 3.66 (dd, J = 8.8, 1.5 Hz, 1 H), 2.85 (dd, J =
13.5, 1.8 Hz, 1 H), 2.38 (dd, J = 13.5, 11.4 Hz, 1 H), 1.99–1.90 (m,
1 H), 1.63–1.51 (m, 2 H), 1.45–1.13 (m, 3 H), 0.98 (d, J = 6.3 Hz,
3 H) ppm. 13C NMR (75 MHz, C6D6): δ = 170.4, 134.7, 131.3,
131.2, 129.8, 71.8, 71.0, 69.7, 67.5, 38.9, 32.0, 31.0, 23.4, 18.7 ppm.
HRMS (ESI): m/z calcd. for C14H20O4Na [M + Na]+ 275.1259;
found 275.1256. (–)-21: [α]2D3 = –29.3 (c = 0.30, MeOH).
(c = 0.45, CHCl ). IR (KBr): ν = 2924, 2852, 1731, 1362, 1248,
˜
3
1
1148, 1039 cm–1. H NMR (300 MHz, CDCl3): δ = 6.09 (ddd, J =
10.2, 5.1, 1.8 Hz, 1 H), 5.99 (dd, J = 10.2, 3.3 Hz, 1 H), 5.94 (dddd,
J = 15.3, 9.1, 6.4, 1.5 Hz, 1 H), 5.46 (dd, J = 15.3, 3.9 Hz, 1 H),
5.19–5.10 (m, 1 H), 4.81 (d, J = 6.9 Hz, 1 H), 4.79–4.74 (br. m, 1
H), 4.63 (d, J = 6.9 Hz, 1 H), 4.23 (dt, J = 11.1, 1.8 Hz, 1 H), 3.73
(dd, J = 5.1, 2.1 Hz, 1 H), 3.39 (s, 3 H), 2.70 (dd, J = 14.1, 11.1 Hz,
1 H), 2.42 (dd, J = 14.1, 2.1 Hz, 1 H), 2.26–2.17 (m, 1 H), 1.91–
1.59 (m, 5 H), 1.19 (d, J = 6.6, Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.5, 135.0, 133.0, 125.8, 125.0, 95.4, 71.8, 70.1, 69.0,
68.3, 55.6, 38.6, 31.8, 30.8, 23.2, 18.6 ppm. HRMS (ESI): m/z calcd.
for C16H24O5Na [M + Na]+ 319.1521; found 319.1516. (–)-19:
[α]2D3 = –86.0 (c = 0.25, CHCl3).
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra; NOESY spectrum of
compound 6.
(1S,5S,11S,14S,E)-14-Hydroxy-5-methyl-4,15-dioxabicyclo[9.3.1]-
pentadeca-9,12-dien-3-one (3): To a magnetically stirred solution of
MOM ether 19 (10 mg, 0.03 mmol) in THF (3 mL), 8 n HCl (1 mL)
was added dropwise at 0 °C and stirring was continued at room
temp. until complete consumption of starting material (ca. 4 h) was
observed. Saturated aq. NaHCO3 (5 mL) was added at 0 °C and
the reaction mixture was extracted with EtOAc (2ϫ10 mL). The
organic layer was washed with brine (5 mL) and dried with anhy-
drous Na2SO4. Evaporation of solvent in vacuo and purification
by column chromatography (hexane/EtOAc, 8:2) afforded 3 as a
Acknowledgments
Y. S. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for financial assistance. P. S. acknowledges a
research grant from the Human Resources Research Group-New
Delhi through the Council of Scientific & Industrial Research
(CSIR) Young Scientist Award (P 81-113). The authors thank Dr.
J. S. Yadav, Director, IICT for his constant encouragement and sup-
port
6696
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6690–6697

Total Synthesis of Aspergillide C
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Received: June 23, 2011
Published Online: September 21, 2011
Eur. J. Org. Chem. 2011, 6690–6697
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6697