Stereodivergent total synthesis of (+)-aspergillide B and (+)-7-epi-aspergillide A

Article abstract of DOI:10.1002/ejoc.201201155

The stereoselective total syntheses of (+)-aspergillide B and (+)-7-epi-aspergillide A were achieved. The key reactions include Noyori's asymmetric transfer hydrogenation, an Achmatowicz rearrangement, a Ferrier-type alkynylation, a hydrosilylation-protodesilylation, a CBS (Corey-Bakshi-Shibata) oxazaborolidine reduction, a Yamaguchi macrolactonization, and a Mitsunobu macrolactonization. The stereoselective total syntheses of (+)-aspergillide B and (+)-7-epi-aspergillide A were achieved. The key reactions include Noyori's asymmetric transfer hydrogenation, an Achmatowicz rearrangement, a Ferrier-type alkynylation, a hydrosilylation-protodesilylation, a CBS (Corey-Bakshi-Shibata) oxazaborolidine reduction, a Yamaguchi macrolactonization, and a Mitsunobu macrolactonization. Copyright

Full text of DOI:10.1002/ejoc.201201155

FULL PAPER
DOI: 10.1002/ejoc.201201155
Stereodivergent Total Synthesis of (+)-Aspergillide B and (+)-7-epi-
Aspergillide A
Y. Sridhar[a] and P. Srihari*[a]
Keywords: Natural products / Total synthesis / Enantioselectivity / Asymmetric catalysis / Macrocycles / Lactones
The stereoselective total syntheses of (+)-aspergillide B and
(+)-7-epi-aspergillide A were achieved. The key reactions in-
clude Noyori’s asymmetric transfer hydrogenation, an
Achmatowicz rearrangement, a Ferrier-type alkynylation, a
hydrosilylation–protodesilylation, a CBS (Corey–Bakshi–Shi-
bata) oxazaborolidine reduction, a Yamaguchi macrolacton-
ization, and a Mitsunobu macrolactonization.
stereoselective synthesis. With this feature in mind, we be-
came interested in the syntheses of the enantiomers (both
natural and unnatural isomers) of aspergillides to examine
their activity.
Introduction
Nature produces a vast collection of natural products as
new chemical entities that exhibit specific functions in bio-
logical systems. Most current drugs are derived from these
natural products.[1] Marine microorganisms are a source for
numerous natural products that exhibit interesting bio-
logical properties with wide therapeutic applications.[2] The
work initiated by Kusumi and co-workers on the marine
derived fungus Aspergillus ostianus strain 01F313 has led to
the isolation of three new bicyclic 14-membered macrolides
with 2,6-cis- and 2,6-trans-fused dihydro- or tetrahydropyan
rings, namely aspergillides A, B, and C (1–3, see Figure 1).[3]
These molecules showed modest cytotoxicity against mouse
lymphatic leukemia cells. Further investigations showed
these compounds to exhibit cytotoxicity toward a number
of cancer cell lines including, HL-60 (human promyelocytic
leukemia), MDA-MB-231 (human breast carcinoma), and
HT1080 (human fibrosarcoma) cell lines.[4f] The striking
structural complexity together with the biological activity
of these macrolides has attracted several synthetic groups
to target their total synthesis,[4–7] which would allow the
confirmation/revision of the absolute stereostructure of the
molecules and also make them available to further investi-
gations of their biological properties. Although a specific
stereoisomer with one or more stereogenic centers can be
responsible for the biological activity, there are many times
that the other isomer could cause side effects or may be
more active than the parent isomer. This feature has in-
creased the necessity from the synthetic community for
Figure 1. Structures of aspergillides A–C.
In continuation of our efforts towards the total syntheses
of lactone-containing natural products,[8] we recently pub-
lished the total synthesis of both enantiomers of aspergil-
lide C and their C-4 epimers through a concise approach.[7a]
Herein, we describe the total syntheses of (+)-aspergillide B
and (+)-7-epi-aspergillide A.
Results and Discussion
We envisaged that both of the target macrolides (–)-as-
pergillide A (1) and (+)-aspergillide B (ent-2) could be pre-
pared from the corresponding seco acids 4 and 5 by lacton-
ization, removal of the tert-butyldimethylsilyl (TBS) group,
and epimerization at C-7 (for 1; see Scheme 1).
Both seco acids 4 and 5 could be synthesized from a com-
mon intermediate 6 through sequential reactions, that is, a
reduction of the alkyne to a trans alkene, a chemoselective
conjugate reduction of the α,β-unsaturated ketone to a
ketone, and a stereoselective keto reduction that is followed
by TBS protection and finally hydrolysis of the diester.
Compound 6 can be obtained from acetal 7 by a Ferrier-
type alkynylation with derivatized trimethylsilyl (TMS)-
acetylene 8. Acetal 7 could be obtained from chiral furfuryl
[a] Division of Natural Products Chemistry, CSIR – Indian
Institute of Chemical Technology,
Tarnaka, Hyderabad 500007, India
Fax: +91-4027160512
E-mail: srihari@iict.res.in
Homepage: www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201155.
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Total Synthesis of Aspergillides
Scheme 1. Retrosynthetic analysis of aspergillides A and B.
alcohol 9, and the alkyne fragment 8 can be accessed from ture (72:28), which was further activated through an acyl-
homopropargyl alcohol 11 through an alkyne zipper isom- ation to give a mixture of the corresponding acetates 7 (see
erization reaction, which in turn can be obtained from com- Scheme 2).
mercially available (R)-propylene oxide and 1-butyne (see
Scheme 1) through an epoxide ring-opening reaction.
Table 1. Optimization of asymmetric transfer hydrogenation of β-
Our synthesis commenced by treating the lithium enolate
of ethyl acetate (10) with 2-furoyl chloride to afford β-keto
ester 13. The ketone functionality was reduced chemo- and
enantioselectively with Noyori’s catalyst Ru[(1R,2R)-p-
TsNCH(Ph)CH(Ph)NH](η6-p-cymene) (14) in iPrOH.[9]
Initially, our efforts towards the reduction of 13 to the cor-
responding β-hydroxy ester 9 were not fruitful under con-
ventional Noyori’s asymmetric transfer hydrogenation con-
ditions. However, when a catalytic amount of tBuOK was
used along with the catalyst, the reaction worked remark-
ably well affording 9 in 98% yield and Ͼ95% ee[10] (see
Table 1, Entry 7). When subjected to an Achmatowicz oxi-
dative rearrangement[11] under standard conditions, furyl
keto ester 13.
[a] IPA = isopropyl alcohol. [b] Reduction with 100% transesteri-
alcohol 9 provided pyranone lactol 15 as an anomeric mix- fied product was formed.
Scheme 2. Synthesis of acetate 7 (LDA = lithium diisopropylamide).
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The required alkyne fragment 8 was synthesized in four addressed by following Trost’s protocol,[15] in which alkyne
steps with an overall yield of 74.8%. Thus, (R)-propylene 6 was trans hydrosilylated by treatment with triethoxysilane
oxide was exposed to the lithium acetylide of 1-butyne (12) in the presence of [Cp*Ru(MeCN)3]PF6 followed by proto-
in the presence of HMPA (hexamethylphosphoramide) to desilylation with HF/pyridine to yield trans olefin 18, exclu-
give homopropargyl alcohol 11. The internal alkyne of 11 sively.[16]
was isomerized to terminal alkyne 16 through a zipper
With the two olefins in the system, our attention then
isomerization[12] by using Li-tBuOK in the presence of 1,3- focused on the chemoselective reduction of the enone.
diaminopropane. The resulting alkynol 16 was appropri- Though the reaction was difficult in the beginning, we suc-
ately masked by treating it with TMSCl and Ac2O to afford ceeded in the chemoselective reduction reaction by mod-
8 (see Scheme 3). This sequence required a single column ifying Saegusa’s method to yield the desired keto compound
purification in the final step.
19 (see Table 2). Thus, compound 18 was treated with a
CuH complex, which was generated by treating LiAlH4
with CuI in tetrahydrofuran THF/HMPA system, to afford
compound 19 in 92% yield (see Scheme 5 and Table 2, En-
try 6).[17]
Table 2. Conjugate reduction of 18.
Scheme 3. Synthesis of alkyne 8.
Acetate 7 was then subjected to a Ferrier-type alk-
ynylation[13] by treatment with silylated alkyne 8 in the pres-
ence of SnCl4 to give alkyne 6 as the only product in 85%
The next stage was to proceed further with a stereoselec-
yield.[14] The diastereoselectivity in this reaction can be ex- tive reduction of the ketone functionality in 19. This reac-
plained by the formation during the course of reaction of a tion was achieved by using (S)-Me-CBS[18] [(S)-2-methyl-
cyclic oxocarbenium ion (see Scheme 4). Because the cyclic CBS-oxazaborolidine] as the catalyst and BH3–THF as the
oxocarbenium ion is almost planar in geometry with five hydride ion source to provide the easily separable chiral
sp2-hybridized centers in the ring, it facilitates the incoming allyl alcohols 20 and 20a in 93% yield with a diastereomeric
nucleophile to preferentially attack from the opposite face ratio (dr) of 88:12 (see Scheme 5).
(i.e., α face) to that of ester substituent, which is present on
Although the minor isomer 20a could be further utilized
the β face. The NOESY experiment for 6 did not reveal any for the synthesis of another analogue, the major alcohol
spatial relationship between 3- and 7-H (δ = 4.85 and 5.08), 20 was utilized in the synthesis of (+)-aspergillide B. Thus,
which infers the 3,7-anti geometry of the product.
compound 20 was protected by treatment with TBSOTf (Tf
With the requisite stereochemical configuration set at C- = trifluoromethylsulfonyl) as the corresponding silyl ether
3, C-7, and C-13, we further proceeded with the stereospe- 21, and the resulting diester 21 was hydrolyzed with NaOH
cific reduction of the alkyne moiety in 6 to an (E) alkene. in MeOH/H2O to give seco acid 5. Under Yamaguchi con-
Initial attempts with Li in liquid NH3 resulted in decompo- ditions,[19] seco acid 5 underwent lactonization to afford 22,
sition of starting material. However, the problem was later which contained the macrocyclic core of aspergillide B.
Scheme 4. Alkynylation of adduct 7.
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Total Synthesis of Aspergillides
Scheme 5. Synthesis of alcohol 20.
Compound 22 was further subjected to desilylation by
treatment with TBAF (tetra-n-butylammonium fluoride) to
give the target macrolide (+)-aspergillide B (see Scheme 6).
The spectroscopic data of this synthetic compound was
compared with previously known data and was identical
with that of the enantiomeric natural product.
Scheme 7. Synthesis of 7-epi-aspergillide A.
Scheme 6. Synthesis of (+)-aspergillide B.
By maneuvering the reaction conditions, we could also
accomplish the total synthesis of aspergillide A. Compound
20a (see Scheme 5) was also synthesized from 19 through a
reduction with NaBH4 to give a mixture of alcohols 20a
and 20 (7:3) that were easily separable by column
chromatography (see Scheme 7). The major diastereomer
20a was protected by treatment with TBSOTf to give the
corresponding TBS ether 23, and the diester was hydrolyzed
by using NaOH in MeOH/H2O to yield seco acid 4. The
resulting seco acid 4 was subjected to a Mitsunobu lacton-
ization[20] to yield the macrocyclic core in 24, which upon
treatment with TBAF yielded 7-epi-aspergillide A (25, see
Scheme 7). Our attempts to epimerize the vinyl-substituted
Scheme 8. Attempted epimerization of 7-epi-aspergillide A to as-
pergillide A (1).
Conclusions
Herein, a facile strategy for the total syntheses of 7-epi-
anomeric carbon in 25 with TfOH[21] did not succeed and aspergillide A and the unnatural enantiomer of aspergil-
resulted in decomposition of the starting material lide B has been developed with an overall yield of 18.3 and
(Scheme 8). Thus, we ended with the 7-epi-aspergillide A.
21.9%, respectively. Further employment of this strategy to
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Y. Sridhar, P. Srihari
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was continued until complete consumption of the starting material
was observed (indicated by TLC, approximately 24 h.). Water
(50 mL) was added to the reaction mixture, and the product was
extracted with CH2Cl2 (4ϫ20 mL). The combined extracts were
washed with brine (40 mL) and dried with anhydrous Na2SO4. The
solvents were removed in vacuo to give the ethyl ester, which was
purified by column chromatography through a short pad of silica
gel (hexane/EtOAc, 92:8) to give 9 (1.98 g, 98%) as a light yellow
oil; Rf = 0.40 (hexane/EtOAc, 4:1). [α]2D0 = +20.86 (c = 1.66,
obtain several other analogues of these new 14-membered
macrolides is currently being investigated.
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded with a 300 or 500 MHz spectrometer at ambient tempera-
ture. The samples were dissolved in either CDCl3 or C6D6. The
coupling constant (J) is given in Hz. The chemical shifts are re-
ported in ppm on a scale downfield from TMS, which was used as
an internal standard, and the signal patterns are indicated as s (sin-
glet), d (doublet), t (triplet), q (quartet), sext (sextet), m (multiplet),
and br. (broad). FTIR spectra were recorded by using KBr pellets
(neat) or a CHCl3 solution. The data 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 HRMS,
m/z ratios are reported in atomic mass units. Mass analysis was
carried out in ESI mode. All of the reagents were reagent grade
and used without further purification unless otherwise specified.
Solvents for the reactions were distilled prior to use. THF, toluene,
and diethyl ether were distilled from Na and benzophenone ketyl.
MeOH was distilled from Mg and I2, and CH2Cl2 was distilled
from CaH2. All air- or moisture-sensitive reactions were conducted
under nitrogen or argon in flame- or oven-dried glassware and were
magnetically stirred. Column chromatography was carried out with
silica gel (100–200 mesh) packed in glass columns. Technical grade
ethyl acetate and petroleum ether, which were used for column
chromatography, were distilled prior to use.
CHCl ). IR (KBr): ν = 3445, 2984, 2938, 1732, 1632, 1373, 1283,
˜
3
1217, 1163, 1012, 741 cm–1. 1H 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), 2.79 (dd, J
= 16.5, 4.5 Hz, 1 H), 1.28 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.6, 154.7, 141.9, 110.0, 106.0, 63.9, 60.7,
39.7, 13.8 ppm. MS (ESI): m/z = 207 [M + Na]+.
(R)-Ethyl
2-(6-Hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate
(15): To a magnetically stirred solution of furfuryl alcohol 9 (2.00 g,
10.87 mmol) in THF/H2O (24:6 mL) were added solid NaHCO3
(1.83 g, 21.74 mmol), NaOAc·3H2O (1.62 g, 11.96 mmol), and N-
bromosuccinimide (NBS, 1.93 g, 10.87 mmol) at 0 °C. The stirring
was continued at 0 °C until complete consumption of starting ma-
terial was observed (as monitored by TLC, 1 h). The reaction was
quenched with a saturated aqueous solution of NaHCO3 (10 mL),
and the resulting solution was extracted with EtOAc (2ϫ20 mL).
The combined extracts were washed with a saturated aqueous solu-
tion of Na2S2O4 (20 mL) followed by brine (20 mL). The organic
layer was dried with anhydrous Na2SO4 and concentrated in vacuo.
The residue obtained was purified by silica gel column chromatog-
raphy (hexane/EtOAc, 4:1) to give 15 (2.09 g, 96%; mixture of in-
separable anomers, 72:28) as a yellow oil; Rf = 0.40 (hexane/EtOAc,
Ethyl 3-(Furan-2-yl)-3-oxopropanoate (13): To a solution of diiso-
propylamine (7.95 mL, 56.75 mmol) in THF (40 mL) was added
nBuLi (1.60 m solution in hexane, 35.47 mL, 56.75 mmol) at –78 °C
under argon. The stirring was continued for 1 h, and then anhy-
3:2). [α]2D0 = +5.23 (c = 1.50, CHCl ). IR (KBr): ν = 3426, 2925,
˜
3
drous EtOAc (5.57 mL, 56.75 mmol) in THF (20 mL) was added 1729, 1695, 1374, 1292, 1180, 1028 cm–1. 1H NMR (300 MHz,
at –78 °C. After 1 h, 2-furoyl chloride (5.61 mL, 56.75 mmol) in
THF (20 mL) was slowly added over 30 min at –78 °C. The mixture
was stirred for 1 h and then quenched with an aqueous saturated
solution of NH4Cl (20 mL). The reaction mixture was diluted with
water (50 mL), and the resulting solution was extracted with EtOAc
CDCl3, major anomer): 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, dd, J = 7.2 Hz, 3
H) ppm. 1H NMR (300 MHz, CDCl3, visible resonances for minor
(3ϫ30 mL). The combined organic layers were washed with brine anomer): δ = 6.94 (dd, J = 10.5, 1.5 Hz, 1 H), 6.14 (dd, J = 10.5,
(40 mL), dried with anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (hexane/
EtOAc, 9:1) to give 13 (8.06 g, 78%; keto/enol tautomers, 20:1) as
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, major anomer): δ = 195.1, 170.9, 144.9,
126.7, 87.5, 70.5, 60.9, 35.1, 13.9 ppm. 13C NMR (75 MHz, CDCl3,
visible resonances for minor anomer): δ = 194.5, 148.7, 128.1, 90.8,
a pale red oil; R = 0.55 (hexane/EtOAc, 4:1). IR (KBr): ν = 3135,
˜
f
2984, 2939, 1739, 1679, 1570, 1468, 1325, 1154, 1026, 915,
769 cm–1. 1H NMR (500 MHz, CDCl3, keto tautomer): δ = 7.62 75.1, 61.0, 35.8 ppm. HRMS (ESI): calcd. for C9H12O5Na [M +
(dd, J = 1.6, 0.7 Hz, 1 H), 7.28 (dd, J = 3.6, 0.7 Hz, 1 H) 6.58 (dd,
J = 3.6, 1.7 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3.85 (s, 2 H),
Na]+ 223.0582; found 223.0579.
(S)-Ethyl 2-(6-Acetoxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (7):
To the magnetically stirred solution of lactol 15 (2.0 g, 10.0 mmol)
in CH2Cl2 (20 mL) was added pyridine (1.61 mL, 20.0 mmol) at
0 °C followed by Ac2O (1.12 mL, 11.0 mmol) at the same tempera-
ture. Within 1 h, the entire lactol was consumed, and the reaction
was then quenched with HCl (1 n solution, 20 mL) at 0 °C. The
resulting solution was extracted with CH2Cl2 (2ϫ20 mL). The or-
ganic layer was washed with water (30 mL) followed by a saturated
aqueous solution of NaHCO3 (20 mL) and then dried with anhy-
drous Na2SO4. Evaporation of the CH2Cl2 in vacuo gave the crude
product, which in turn was purified by column chromatography
1
1.26 (t, J = 7.1 Hz, 3 H) ppm. H NMR (500 MHz, CDCl3, visible
resonances for enol tautomer): δ = 12.17 (s, 1 H), 7.50 (dd, J = 1.7,
0.7 Hz, 1 H), 6.94 (dd, J = 3.4, 0.6 Hz, 1 H), 6.51 (dd, J = 3.5,
1.8 Hz, 1 H), 5.61 (s, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 1.33 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, keto tautomer): δ
= 180.9, 166.8, 151.8, 146.9, 118.2, 112.6, 61.3, 45.3, 13.9 ppm. 13
C
NMR (75 MHz, CDCl3, visible resonances for enol tautomer): δ =
172.9, 161.8, 148.1, 144.7, 111.9, 86.1, 60.2, 14.1 ppm. HRMS
(ESI): calcd. for C9H10O4Na [M
205.04727.
+
Na]+ 205.04713; found
(R)-Ethyl 3-(Furan-2-yl)-3-hydroxypropanoate (9): To a degassed (hexane/EtOAc, 9:1) to give the desired product 7 (2.18 g, 90%;
solution of β-keto ester 13 (2.00 g, 10.99 mmol) and Ru[(1R,2R)-p-
TsNCH(Ph)CH(Ph)NH](η6-p-cymene) (0.14 g, 0.22 mmol) in
iPrOH (20 mL) under argon was added tBuOK (1 m solution in
tBuOH, 1.10 mL, 1.10 mmol) at room temperature. The stirring
mixture of inseparable anomers, 75:25) as a yellow viscous oil; Rf
= 0.5 (hexane/EtOAc, 7:3). [α]2D0 = –20.56 (c = 1.10, CHCl3). IR
1
(KBr): ν = 2984, 1747, 1701, 1375, 1216, 1104, 939, 763 cm–1. H
˜
NMR (300 MHz, CDCl3, major anomer): δ = 6.86 (dd, J = 10.8,
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Total Synthesis of Aspergillides
3.7 Hz, 1 H), 6.45 (d, J = 3.7 Hz, 1 H), 6.23 (d, J = 9.8 Hz, 1 H), (R)-7-(Trimethylsilyl)hept-6-yn-2-ol (17): nBuLi (1.60 m solution in
4.86 (dd, J = 6.6, 4.2 Hz, 1 H), 4.15 (q, J = 7.5 Hz, 2 H), 2.92 (dd,
hexane, 36.83 mL, 58.93 mmol) was added dropwise to a magneti-
J = 17.7, 4.5 Hz, 1 H), 2.73 (dd, J = 16.5, 6.9 Hz, 1 H), 2.14 (s, 3 cally stirred solution of alcohol 16 (3.00 g, 26.79 mmol) in THF
H), 1.27 (t, J = 7.8 Hz, 3 H) ppm. 1H NMR (300 MHz, CDCl3,
visible resonances for the minor anomer): δ = 6.52 (d, J = 3.0 Hz,
1 H), 6.25 (d, J = 9.8 Hz, 1 H), 4.69 (dd, J = 8.3, 4.5 Hz, 1 H),
4.20 (q, J = 7.5 Hz, 2 H), 2.15 (s, 3 H), 1.28 (t, J = 6.9 Hz, 3
(40 mL) at –78 °C. The stirring was continued for 1 h, and then
freshly distilled TMSCl (7.49 mL, 58.93 mmol) was added at
–78 °C. After 1 h, the reaction mixture was warmed to 0 °C. HCl
(1 n aqueous solution, 50 mL) was added dropwise, and the stirring
H) ppm. 13C NMR (75 MHz, CDCl3, major anomer): δ = 193.7, was continued at room temperature for 30 min. The reaction mix-
169.7, 169.1, 141.2, 128.0, 86.4, 72.2, 60.6, 34.9, 20.6, 13.8 ppm.
13C NMR (75 MHz, CDCl3, visible resonances for the minor an-
omer): δ = 193.4, 169.3, 168.7, 143.7, 128.2, 87.2, 75.7, 60.7, 37.5,
20.7 ppm. HRMS (ESI): calcd. for C11H14O6Na [M + Na]+
265.0688; found 265.0701.
ture was extracted with diethyl ether (2ϫ10 mL). The combined
organic extracts were washed with water (30 mL) followed by a
saturated aqueous solution of NaHCO3 (50 mL) and then dried
with anhydrous Na2SO4. Evaporation of solvents in vacuo gave 17
(4.53 g, 92%) as a light yellow oil; Rf = 0.50 (hexane/diethyl ether,
4:1). [α]2D0 = –6.83 (c = 0.55, CHCl ). IR (KBr): ν = 3347, 2961,
˜
3
2928, 2174, 1249, 841, 760 cm–1. 1H NMR (500 MHz, CDCl3): δ =
3.82 (sext, 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.
(R)-Hept-4-yn-2-ol (11): Into a 500 mL, two-necked round-bot-
tomed flask was collected 1-butyne (12) (6.95 mL, 86.21 mmol),
which was diluted with dry THF (80 mL). The reaction mixture
was cooled to –78 °C and then treated with nBuLi (1.6 m solution
in hexanes, 32.40 mL, 51.72 mmol). After 30 min, the reaction mix-
ture was gradually warmed to 0 °C. The resulting grey solution was
stirred at 0 °C for 30 min. Then, dry HMPA (dried with CaH2,
8 mL) was added dropwise at 0 °C. After cooling the reaction mix-
ture to –20 °C and stirring for 30 min, (R)-propylene oxide
(3.01 mL, 43.10 mmol) in dry HMPA (8 mL) was added. The stir-
ring was continued for 1 h, and then the reaction mixture was
warmed to ambient temperature over 4 h and stirred for an ad-
ditional 12 h. A saturated aqueous solution of NH4Cl (50 mL) was
added at 0 °C followed by water (50 mL). The reaction mixture was
extracted with Et2O (4ϫ50 mL), and the combined extracts were
washed with brine and dried with anhydrous Na2SO4. The solvents
were removed in vacuo at room temperature to give alcohol 11
(4.67 g, 95%) as a pale yellow oil; Rf = 0.50 (hexane/EtOAc, 4:1).
(R)-7-(Trimethylsilyl)hept-6-yn-2-yl Acetate (8): To a magnetically
stirred solution of alcohol 17 (4.0 g, 21.74 mmol) in CH2Cl2
(40 mL) was added pyridine (3.50 mL, 43.48 mmol) at 0 °C fol-
lowed by the addition of DMAP [4-(N,N-dimethylamino)pyridine,
0.66 g, 5.43 mmol] and Ac2O (2.44 mL, 23.91 mmol) at the same
temperature. The mixture was stirred for 3 h and then quenched
with HCl (1 n aqueous solution, 60 mL) at 0 °C. The resulting solu-
tion was extracted with CH2Cl2 (3ϫ20 mL). The combined ex-
tracts were washed with water (40 mL) and a saturated aqueous
solution of NaHCO3 (40 mL) and then dried with anhydrous
Na2SO4. Evaporation of the CH2Cl2 in vacuo gave the crude prod-
uct, which in turn was purified by column chromatography (hex-
ane/diethyl ether, 9.5:0.5) through a short pad of silica gel to give
8 (4.57 g, 93%) as a colorless oil; Rf = 0.8 (hexane/diethyl ether,
[α]2D0 = –17.48 (c = 2.20, CHCl ). IR (KBr): ν = 3385, 2968, 2928,
˜
3
1905, 1530, 1350, 1249, 1083, 841, 760, 690 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 3.88–3.81 (m, 1 H), 2.34–2.20 (m, 2 H),
2.19–2.14 (m, 2 H), 2.00 (br. d, J = 3.2 Hz, OH), 1.22 (d, J =
6.4 Hz, 3 H), 1.14 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 84.0, 75.5, 66.3, 29.1, 21.9, 14.0, 12.2 ppm. C7H12O
(112.17): calcd. C 74.95, H 10.78; found C 74.73, H 10.33.
9:1). [α]2D0 = –1.96 (c = 0.93, CHCl ). IR (KBr): ν = 2926, 2854,
˜
3
2175, 1740, 1372, 1247, 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.
(R)-Hept-6-yn-2-ol (16): Lithium pieces (1.49 g, 21.43 mmol) were
intermittently added to vigorously stirring anhydrous 1,3-diamino-
propane (60 mL) at ambient temperature, and then the mixture was
warmed to 70 °C and stirred for 3 h. During this time, the reaction
mixture gradually changed from deep blue to grey. The reaction
mixture was cooled to ambient temperature, and tBuOK (16.00 g,
14.29 mmol) was added under argon. The resulting pale yellow
solution was stirred for 30 min. Then, alkyne 11 (4.00 g,
35.72 mmol) was added neat at ambient temperature, and the reac-
tion mixture changed from pale yellow to purple to dark brown.
After 30 min, the entire reaction mixture was poured into ice water
(200 mL), and the resulting solution was extracted with Et2O
(4ϫ50 mL). The combined extracts were washed with HCl (1 n
solution, 2ϫ50 mL) and a saturated aqueous solution of NaHCO3
(50 mL) and then dried with anhydrous Na2SO4. The Et2O was
removed in vacuo at ambient temperature to give terminal alkyne
16 (3.68 g, 92%) as a pale yellow oil; Rf = 0.40 (hexane/EtOAc,
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 (1.00 g, 4.13 mmol) and 8 (0.51 g, 4.55 mmol) in CH2Cl2
(20 mL) was added SnCl4 (1 m solution in heptane, 1.24 mL,
1.24 mmol) at 0 °C. The ice bath was removed, and the stirring was
continued at room temp. for 1 h. After that time, acetate 7 was
entirely consumed (monitored by TLC), and the reaction mixture
was quenched with a saturated aqueous solution of NaHCO3
(20 mL) at 0 °C and then diluted with water (20 mL). The resulting
mixture was stirred at room temp. for an additional 1 h and then
extracted with CH2Cl2 (3ϫ20 mL). The combined organic extracts
were washed with brine (20 mL) and dried with anhydrous Na2SO4.
Evaporation of the 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 (1.18 g, 85%) as a light yellow
oil; Rf = 0.50 (hexane/EtOAc, 4:1). [α]2D0 = –142.60 (c = 0.83,
4:1). [α]2D0 = –12.40 (c = 0.99, CHCl ). IR (KBr): ν = 3453, 2922,
˜
3
2851, 2180, 1128 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.84 (sext,
CHCl ). IR (KBr): ν = 2933, 2190, 1735, 1696, 1373, 1247, 1175,
˜
3
J = 5.9 Hz, 1 H), 2.25–2.21 (m, 2 H), 1.95 (t, J = 2.7 Hz, 1 H),
1024 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.90 (dd, J = 9.8,
1.71–1.54 (m, 4 H), 1.30 (br. s, OH), 1.21 (t, J = 6.2 Hz, 3 H) ppm. 4.5 Hz, 1 H), 6.04 (dd, J = 9.8, 1.5 Hz, 1 H), 5.08 (dt, J = 4.5,
13C NMR (75 MHz, CDCl3): δ = 84.3, 68.4, 67.4, 38.0, 24.6, 23.4,
18.3 ppm. C7H12O (112.17): calcd. C 74.95, H 10.78; found C
74.60, H 10.45.
2.3 Hz, 1 H), 4.90 (sext, 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
Eur. J. Org. Chem. 2013, 578–587
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
583

Y. Sridhar, P. Srihari
FULL PAPER
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, 13.9 ppm. HRMS (ESI): calcd. for
C18H24O6Na [M + Na]+ 359.1470; found 359.1475.
1 H), 2.14–1.93 (m, 3 H), 2.03 (s, 3 H), 1.66–1.35 (m, 4 H), 1.26 (t,
J = 7.2, Hz, 3 H), 1.20 (d, J = 6.3, Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 209.5, 170.7, 170.6, 132.9, 128.5, 73.9, 72.2,
70.7, 60.7, 35.6, 35.3, 34.9, 32.0, 27.7, 24.8, 21.3, 19.8, 14.1 ppm.
HRMS (ESI): calcd. for C18H29O6 [M + H]+ 341.19587; found
341.19560.
Ethyl 2-{(2S,6S)-6-[(S,E)-6-Acetoxyhept-1-enyl]-3-oxo-3,6-dihydro-
2H-pyran-2-yl}acetate (18): To a degassed stirred solution of alkyne
6 (0.50 g, 1.49 mmol) and (EtO)3SiH (1.09 mL, 5.95 mmol) in
CH2Cl2 (20 mL) was added [Cp*(MeCN)3Ru]PF6 (7 mg,
0.014 mmol) at 0 °C under argon. The reaction mixture was
warmed to room temperature, as it was stirred. After 1 h, alkyne 6
was entirely consumed (monitored by TLC), and the solvent was
evaporated under reduced pressure to give the crude mixture, which
was diluted with THF (20 mL). This mixture was cooled to 0 °C,
and to it was added pyridine (1.19 mL, 14.88 mmol) and then HF/
pyridine (70:30, 0.20 mL, 7.44 mmol) dropwise at 0 °C. After the
entire vinyl siloxane was consumed (monitored by TLC, 5 min),
the reaction mixture was quenched with water (5 mL) and then
neutralized with HCl (0.5 n solution, 35 mL). The resulting solu-
tion was extracted with EtOAc (3ϫ20 mL). The organic layers
were washed with water (20 mL) and a saturated aqueous solution
of NaHCO3 (10 mL) and then 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 desired product 18 (0.45 g, 90%) as a colorless oil; Rf =
0.50 (hexane/EtOAc, 4:1). [α]2D0 = –78.42 (c = 1.88, CHCl3). IR
Ethyl 2-{(2R,3R,6S)-6-[(R,E)-6-Acetoxyhept-1-en-1-yl]-3-hydroxy-
tetrahydro-2H-pyran-2-yl}acetate (20): To a magnetically stirred
solution of (S)-Me-CBS (1 m solution in toluene, 0.88 mL,
0.88 mmol) in anhydrous THF (10 mL) was added dropwise BH3–
THF (1 m solution in THF, 0.88 mL, 0.88 mmol) at 0 °C, and the
reaction mixture was stirred at room temperature for 30 min. The
generated complex was cooled to –78 °C, and then a solution of
ketone 19 (0.30 g, 0.88 mmol) in THF (2 mL) was added dropwise.
The stirring was continued until there was complete consumption
of starting material (indicated by TLC, approximately 6 h). The
reaction mixture was quenched with a saturated aqueous solution
of NH4Cl and then diluted with water (10 mL). The resulting solu-
tion was extracted with EtOAc (3ϫ10 mL). The combined extracts
were washed with brine (10 mL), dried with anhydrous Na2SO4,
filtered, and concentrated to give the crude product. Purification
by column chromatography (hexane/EtOAc, 85:15) gave 20
(0.246 g, 82%) and 20a (0.034 g, 11%) as colorless oils; Rf = 0.40
(hexane/EtOAc, 3:2). [α]2D0 = +27.30 (c = 0.23, CHCl3). IR (KBr):
ν = 3452, 2976, 2835, 1735, 1374, 1248, 1080, 1040, 981, 760 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 5.66 (dtd, J = 15.7, 6.5, 1.4 Hz,
1 H), 5.52 (ddt, J = 15.8, 4.6, 1.0 Hz, 1 H), 4.89 (sext, J = 6.20 Hz,
1 H), 4.30 (br. m, 1 H), 4.23 (td, J = 6.9, 2.6 Hz, 1 H), 4.15 (q, J
= 7.14 Hz, 2 H), 3.74 (br. s, 1 H), 2.62 (dd, J = 7.4, 2.4 Hz, 2 H),
2.09–1.95 (m, 4 H), 2.02 (s, 3 H), 1.89–1.83 (m, 1 H), 1.79–1.70 (m,
1 H), 1.63–1.33 (m, 4 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.20 (d, J =
6.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.8, 170.7,
132.8, 129.0, 72.0, 70.8, 70.3, 66.8, 60.6, 35.9, 35.4, 32.2, 26.4, 24.9,
24.2, 21.4, 19.9, 14.2 ppm. HRMS (ESI): calcd. for C18H30O6Na
[M + Na]+ 365.19346; found 365.19256.
(KBr): ν = 2982, 1745, 1698, 1375, 1246, 1104 cm–1. 1H 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,
1 H), 4.16 (q, J = 7.2, Hz, 2 H), 2.92 (dd, J = 16.2, 3.9 Hz, 1 H),
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): calcd. for C18H26O6Na
[M + Na]+ 361.1627; found 361.1641.
Ethyl 2-{(2R,3S,6S)-6-[(R,E)-6-Acetoxyhept-1-en-1-yl]-3-hydroxy-
tetrahydro-2H-pyran-2-yl}acetate (20a): To a magnetically stirred
solution of ketone 19 (0.10 g, 0.29 mmol) in THF/MeOH (3:1,
4 mL) was added NaBH4 (0.011 g, 0.29 mmol) portionwise at 0 °C.
The stirring was continued until there was a complete consumption
of starting material (monitored by TLC, approximately 10 min),
and the reaction mixture was quenched with a saturated aqueous
NH4Cl solution and then diluted with water (10 mL). The resulting
solution was extracted with EtOAc (3ϫ5 mL). The combined or-
ganic layers were washed with brine (5 mL), dried with anhydrous
Na2SO4, filtered, and concentrated to give the crude product. Puri-
fication by column chromatography (hexane/EtOAc, 85:15) gave
20a (0.069 g, 69%) and 20 (0.029 g, 29%) as colorless oils; Rf =
0.40 (hexane/EtOAc, 3:2). [α]2D0 = +23.07 (c = 1.09, CHCl3). IR
Ethyl 2-{(2R,6S)-6-[(R,E)-6-Acetoxyhept-1-en-1-yl]-3-oxotetrahy-
dro-2H-pyran-2-yl}acetate (19): Flame-dried CuI was dissolved in
HMPA at 50 °C, and the solution was cooled to room temperature.
To a vigorously stirred suspension of LiAlH4 (0.08 g, 2.22 mmol)
in anhydrous THF (20 mL) was added dropwise the solution of
CuI (0.42 g, 2.22 mmol) in HMPA (8 mL) at –78 °C. The generated
orange suspension gradually turned to brown. The stirring was
continued for an additional 1 h, and then compound 18 (0.50 g,
1.48 mmol) in anhydrous THF (2 mL) was added dropwise at the
same temperature. Within 15 min, the enone was entirely con-
sumed. The reaction mixture was quenched with an aqueous satu-
rated solution of NH4Cl (5 mL) at –78 °C, and the resulting mix-
ture was warmed to room temp. over 30 min. The reaction mass
was filtered through a wet pad of silica gel (EtOAc), which was
washed with EtOAc (4ϫ10 mL). The combined filtrates were
washed with water (2ϫ20 mL) and brine (20 mL), dried with anhy-
drous Na2SO4, and filtered. The solvents were evaporated under
reduced pressure to give the crude product, which was purified by
column chromatography (hexane/EtOAc, 9:1) to give 19 (0.46 g,
(KBr): ν = 3453, 2979, 2935, 1735, 1447, 1374, 1248, 1155, 1080,
˜
981, 760 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.66 (dtd, J =
15.9, 6.6, 1.5 Hz, 1 H), 5.49 (dd, J = 15.7, 4.0 Hz, 1 H), 4.88 (sext,
J = 6.2 Hz, 1 H), 4.34 (br. d, J = 2.8 Hz, 1 H), 4.17 (q, J = 7.2 Hz,
2 H), 3.95 (td, J = 8.1, 4.5 Hz, 1 H), 3.40 (td, J = 8.9, 3.8 Hz, 1
H), 2.79 (dd, J = 15.1, 4.3 Hz, 1 H), 2.52 (dd, J = 15.1, 8.50 Hz, 1
H), 2.18–2.01 (m, 4 H), 2.03 (s, 3 H), 1.95–1.78 (m, 2 H), 1.71–1.36
(m, 4 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.22 (d, J = 6.2 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.8, 170.9, 132.6, 129.4, 72.5,
71.6, 71.0, 69.8, 60.5, 37.9, 34.9, 32.1, 27.8, 27.3, 24.6, 21.3, 19.7,
14.1 ppm. HRMS (ESI): calcd. for C18H31O6 [M + H]+ 343.21152;
found 343.21096.
92%) as a colorless oil; Rf = 0.50 (hexane/EtOAc, 4:1). [α]2D0
=
+64.86 (c = 1.20, CHCl ). IR (KBr): ν = 2979, 2934, 2859, 1734
˜
3
(br.), 1374, 1248, 1185, 1025, 757 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 5.76 (dtd, J = 15.6, 6.6, 1.4 Hz, 1 H), 5.59 (ddt, J =
15.6, 5.0, 1.0 Hz, 1 H), 4.89 (sext, J = 6.4 Hz, 1 H), 4.52–4.45 (m,
2 H), 4.15 (q, J = 7.2 Hz, 2 H), 2.82 (dd, J = 16.3, 4.5 Hz, 1 H),
2.67 (dd, J = 16.3, 7.3 Hz, 1 H), 2.63–2.46 (m, 2 H), 2.34–2.17 (m,
Ethyl 2-{(2R,3R,6S)-6-[(R,E)-6-Acetoxyhept-1-en-1-yl]-3-[(tert-but-
yldimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}acetate (21): To
a
584
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 578–587

Total Synthesis of Aspergillides
magnetically stirred solution of alcohol 20 (0.20 g, 0.58 mmol) in
CH2Cl2 (5 mL) was added 2,6-lutidine (0.20 mL, 1.75 mmol) drop-
wise at 0 °C. After 10 min, TBSOTf (0.15 mL, 0.64 mmol) was
added at the same temperature. The stirring was continued until
there was complete consumption of starting material (monitored
by TLC, approximately 2 h), and the reaction mixture was
quenched with a saturated aqueous NH4Cl solution and then di-
luted with water (10 mL). The resulting solution was extracted with
CH2Cl2 (2ϫ10 mL). The combined organic layers were washed
with brine (10 mL), dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to give the crude product. Pu-
rification by column chromatography (hexane/EtOAc, 95:5) gave
21 (0.22 g, 84%) as a colorless oil; Rf = 0.55 (hexane/EtOAc, 9:1).
0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.9, 133.3, 129.5, 72.3, 70.9, 67.8, 38.3, 34.7, 32.0,
27.4, 27.0, 25.8, 25.0, 23.2, 18.0, –4.7, –4.9 ppm. HRMS (ESI):
calcd. for C20H38O5NaSi [M + Na]+ 409.23807; found 409.23727.
2-{(2R,3S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-[(R,E)-6-hydroxy-
hept-1-en-1-yl]tetrahydro-2H-pyran-2-yl}acetic Acid (4): Following
a similar procedure as that used for preparation of 5, diester 23
(0.3 g, 0.66 mmol) afforded seco acid 4 (0.249 g, 98%) as a colorless
oil; Rf = 0.35 (hexane/EtOAc, 1:1). [α]2D0 = +39.33 (c = 2.24,
CHCl ). IR (KBr): ν = 3409 (br.), 2932, 2858, 1715, 1464, 1367,
˜
3
1255, 1106, 1046, 838, 775, 668 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 5.77–5.62 (m, 2 H), 4.41–4.35 (m, 1 H), 3.91–3.78 (m, 2 H),
3.36 (td, J = 9.9, 4.4 Hz, 1 H), 2.83 (dd, J = 15.3, 2.8 Hz, 1 H),
2.33 (dd, J = 15.3, 9.8 Hz, 1 H), 2.22–1.98 (m, 2 H), 1.96–1.78 (m,
2 H), 1.75–1.55 (m, 2 H), 1.51–1.36 (m, 4 H), 1.19 (d, J = 6.19 Hz,
3 H), 0.88 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 176.0, 134.2, 128.5, 72.3, 72.2, 71.0, 68.2, 37.9, 37.7, 32.1, 29.0,
27.7, 25.7, 24.7, 22.9, 17.9, –4.1, –4.8 ppm. HRMS (ESI): calcd. for
C20H39O5Si [M + H]+ 387.25613; found 387.25600.
[α]2D0 = +18.25 (c = 0.84, CHCl ). IR (KBr): ν = 2933, 2858, 1737,
˜
3
1465, 1372, 1248, 1103, 974, 838, 777 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 5.62 (dt, J = 15.2, 6.8 Hz, 1 H), 5.44 (dd, J = 15.1,
5.3 Hz, 1 H), 4.88 (sext, J = 6.3 Hz, 1 H), 4.30–4.27 (m, 1 H), 4.19–
4.10 (m, 3 H), 3.85–3.81 (m, 1 H), 2.69 (dd, J = 15.0, 9.3 Hz, 1 H),
2.6 (dd, J = 15.2, 4.9 Hz, 1 H), 2.05–2.00 (m, 2 H), 2.02 (s, 3 H),
1.89–1.83 (m, 1 H), 1.81–1.73 (m, 1 H), 1.64–1.54 (m, 2 H), 1.51–
1.31 (m, 4 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.19 (d, J = 6.3 Hz, 3 H),
0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 172.0, 170.7, 132.0, 130.1, 72.7, 70.8, 70.2, 67.7, 60.3,
35.3, 33.3, 32.1, 27.9, 27.4, 25.7, 24.8, 21.3, 19.9, 18.0, 14.2, –4.8,
–4.9 ppm. HRMS (ESI): calcd for C24H44O6NaSi [M + Na]+
479.27994; found 479.27911.
(1R,5R,11S,14R,E)-14-[(tert-Butyldimethylsilyl)oxy]-5-methyl-
4,15-dioxabicyclo[9.3.1]pentadec-9-en-3-one (22): To a magnetically
stirred solution of seco acid 5 (0.05 mg, 0.13 mmol) in THF (5 mL)
was added Et3N (0.11 mL, 0.78 mmol) at 0 °C followed by the ad-
dition of 2,4,6-trichlorobenzoyl chloride (0.06 mL, 0.39 mmol).
The stirring was continued at 0 °C for 1 h and then at room temp.
for an additional 1 h. The reaction mixture was diluted with tolu-
ene (20 mL), and the stirring was continued for an additional 1 h.
The resulting mixture was added dropwise over 8 h by syringe
pump to a solution of DMAP (0.395 g, 3.23 mmol) in toluene
(40 mL) at 60 °C under argon. After the addition, the mixture was
stirred for another 15 min. The toluene was evaporated under re-
duced pressure, and the residue was diluted with EtOAc (10 mL).
The resulting mixture was neutralized with HCl (0.5 n aqueous
solution, 6.50 mL) at 0 °C, and the solution was extracted with
EtOAc (3ϫ10 mL). The combined extracts were washed with water
(20 mL) and brine (10 mL) and then dried with anhydrous Na2SO4.
Evaporation of the solvents in vacuo gave the crude lactone. Purifi-
cation by column chromatography (hexane/EtOAc, 95:5) afforded
the desired lactone 22 (0.036 g, 76%) as a colorless oil; Rf = 0.60
(hexane/EtOAc, 9:1). [α]2D0 = +47.59 (c = 0.21, CHCl3). IR (KBr):
Ethyl 2-{(2R,3S,6S)-6-[(R,E)-6-Acetoxyhept-1-en-1-yl]-3-[(tert-but-
yldimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}acetate (23): Follow-
ing a similar procedure as that used for the preparation of com-
pound 21, alcohol 20a (0.30 g, 0.87 mmol) afforded TBS ether 23
(0.35 g, 88%) as a colorless oil; Rf = 0.50 (hexane/EtOAc, 9:1).
[α]2D0 = +24.93 (c = 0.80, CHCl ). IR (KBr): ν = 2934, 2858, 1737,
˜
3
1371, 1249, 1102, 1046, 838, 775 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 5.65 (dt, J = 16.1, 5.7 Hz, 1 H), 5.5 (dd, J = 16.1,
4.2 Hz, 1 H), 4.90 (sext, J = 6.8 Hz, 1 H), 4.34 (br. s, 1 H), 4.16 (q,
J = 7.2 Hz, 2 H), 3.89 (td, J = 9.3, 3.2 Hz, 1 H), 3.37 (td, J = 9.6,
4.0 Hz, 1 H), 2.78 (dd, J = 14.9, 3.0 Hz, 1 H), 2.32 (dd, J = 14.9,
9.6 Hz, 1 H), 2.13–2.02 (m, 2 H), 2.03 (s, 3 H) 1.95–1.70 (m, 2 H),
1.67–1.35 (m, 6 H), 1.27 (t, J = 7.2, Hz, 3 H), 1.21 (d, J = 6.2, Hz,
3 H), 0.87 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 171.8, 170.8, 132.7, 129.2, 72.4, 71.9, 71.0, 70.8, 60.3, 38.1,
35.3, 32.3, 28.8, 27.6, 25.7, 24.9, 21.3, 20.0, 17.9, 14.2, –4.1,
–4.8 ppm. HRMS (ESI): calcd. for C24H44O6NaSi [M + Na]+
479.27994; found 479.27858.
ν = 2930, 2856, 1729, 1458, 1259, 1109, 837, 774, 668 cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 6.16 (dddd, J = 15.6, 10.9, 4.7,
1.8 Hz, 1 H), 5.63 (dd, J = 15.6, 4.1 Hz, 1 H), 5.07–5.02 (m, 1 H),
4.45–4.40 (br. m, 1 H), 4.08 (br. d, J = 11.00 Hz, 1 H), 3.64 (t, J =
3.0 Hz, 1 H), 2.45 (dd, J = 13.7, 1.61 Hz, 1 H), 2.23–2.16 (m, 2 H),
2.14 (dd, J = 13.6, 11.1 Hz, 1 H), 1.99–1.90 (m, 1 H), 1.86–1.76
(m, 3 H), 1.72–1.66 (m, 1 H), 1.64–1.56 (m, 1 H), 1.45–1.37 (m, 1
H), 1.31–1.25 (m, 1 H), 1.18 (d, J = 6.5 Hz, 3 H), 0.96 (s, 9 H),
0.05 (s, 3 H), 0.03 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.6, 137.6, 129.2, 71.1, 69.8, 69.7, 68.2, 40.2, 31.8, 30.6, 28.2,
26.0, 25.1, 22.7, 19.2, 18.3, –4.4, –4.8 ppm. HRMS (ESI): calcd. for
C20H37O4Si [M + H]+ 369.24556; found 369.24593.
2-{(2R,3R,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-[(R,E)-6-hydroxy-
hept-1-en-1-yl]tetrahydro-2H-pyran-2-yl}acetic Acid (5): To a vigor-
ously stirred solution of diester 21 (0.20 g, 0.44 mmol) in MeOH/
H2O (4:1, 8 mL) was added NaOH (0.07 g, 1.75 mmol) at 0 °C. The
stirring was continued until there was complete consumption of the
starting material (indicated by TLC, for 16 h). The reaction mixture
was neutralized by the addition of KHSO4 (0.24 g, 1.75 mmol) at
0 °C and then diluted with water (10 mL). The resulting solution
was extracted with CH2Cl2 (5ϫ10 mL). The organic layers were
separated, dried with anhydrous Na2SO4, and filtered. The solvent
was evaporated under reduced pressure to give seco acid 5 (0.165 g,
(1R,5R,11S,14S,E)-14-[(tert-Butyldimethylsilyl)oxy]-5-methyl-
4,15-dioxabicyclo[9.3.1]pentadec-9-en-3-one (24): To a vigorously
stirred solution of PPh3 (0.68 g, 2.59 mmol) in anhydrous toluene
(50 mL) at 0 °C was added diisopropylazodicarboxylate (DIAD,
0.513 mL, 2.59 mmol). The yellowish solution was stirred for
98%) as a colorless oil; Rf = 0.35 (hexane/EtOAc, 1:1). [α]2D0
=
+28.58 (c = 1.00, CHCl ). IR (KBr): ν = 3424 (br.), 2931, 2858,
˜
3
1724, 1601, 1456, 1255, 1107, 1032, 837, 757, 640 cm–1. H NMR
1
(300 MHz, CDCl3): δ = 5.69 (dtd, J = 15.5, 6.6, 1.2 Hz, 1 H), 5.49 30 min, and then a solution of seco acid 4 (0.10 g, 0.26 mmol) in
(br. dd, J = 15.5, 5.5 Hz, 1 H), 4.26–4.21 (m, 2 H), 3.77–3.83 (m,
2 H), 2.74 (dd, J = 15.5, 9.6 Hz, 1 H), 2.56 (dd, J = 15.4, 4.1 Hz,
1 H), 2.01–2.10 (m, 2 H), 1.93–1.99 (m, 1 H), 1.83–1.76 (m, 1 H),
anhydrous toluene (40 mL) was added dropwise at room tempera-
ture over 30 min. The reaction mixture was stirred for 48 h until
there was complete consumption of the starting material (moni-
1.70–1.59 (m, 1 H), 1.54–1.38 (m, 5 H), 1.18 (d, J = 6.20 Hz, 3 H), tored by TLC). The toluene was evaporated under reduced pres-
Eur. J. Org. Chem. 2013, 578–587
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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585

Y. Sridhar, P. Srihari
FULL PAPER
sure, and the crude mass was purified by column chromatography
(hexane/EtOAc, 95:5) to give lactone 24 as a colorless oil (0.069 g,
72%); Rf = 0.65 (hexane/EtOAc, 9:1). [α]2D0 = +85.52 (c = 0.22,
research grant sponsored through CSIR (Human Resources Re-
search Group, Young Scientist Award (P 81-113). The authors
thank Dr. J. S. Yadav, “CSIR-Bhatnagar Fellow, former Director,”
CSIR-IICT for his constant encouragement and support.
CHCl ). IR (KBr): ν = 2929, 2856, 1728, 1458, 1259, 1109, 837,
˜
3
774, 668 cm–1. H NMR (500 MHz, CDCl3): δ = 6.39 (dddd, J =
1
15.4, 11.1, 4.0, 1.5 Hz, 1 H), 5.64 (br. dd, J = 15.7, 4.5 Hz, 1 H),
4.66–4.60 (m, 1 H), 4.44–4.40 (br. m, 1 H), 3.76 (t, J = 9.1 Hz, 1
H), 3.33 (td, J = 9.9, 4.4 Hz, 1 H), 2.76 (d, J = 15.9 Hz, 1 H), 2.24
(dd, J = 15.9, 8.6 Hz, 1 H), 2.19–2.04 (m, 2 H), 2.00–1.88 (m, 3
H), 1.82–1.66 (m, 3 H), 1.63–1.55 (m, 2 H), 1.30 (d, J = 6.2 Hz, 3
H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.5, 138.4, 127.9, 73.2, 71.6, 71.4, 70.6,
37.9, 33.2, 32.1, 30.5, 28.5, 25.8, 25.6, 20.2, 18.0, –3.9, –4.7 ppm.
HRMS (ESI): calcd. for C20H37O4Si [M + H]+ 369.24556; found
369.24645.
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Manohar, Tetrahedron: Asymmetry 2012, 23, 252–263; b) Z.
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M. Sasaki, Tetrahedron 2010, 66, 7492–7503; h) G. Sabitha,
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(+)-Aspergillide B: To a magnetically stirred solution of silyl ether
22 (0.020 g, 54.34 μmol) in anhydrous THF (2 mL) was added tet-
rabutylammonium fluoride (1 m solution in THF, 0.11 mL,
108.70 μmol) at 0 °C. The ice bath was removed, and the stirring
was continued until there was complete consumption of the starting
material (indicated by TLC, approximately 3 h). Water was added
(5 mL), and the resulting solution was extracted with EtOAc
(3ϫ5 mL). The combined extracts were washed with brine (5 mL)
and dried with anhydrous Na2SO4. The solvent was evaporated un-
der reduced pressure to give the crude product. Purification by col-
umn chromatography (hexane/EtOAc, 6:4) afforded (+)-2 as a
white amorphous solid (12.70 mg, 92%), m.p. 83–85 °C; Rf = 0.50
(hexane/EtOAc, 1:1). [α]2D0 = +96.97 (c = 0.33, MeOH); ref.[6c]
[α]2D0 = +84 (c = 0.12, MeOH). IR (KBr): ν = 3440, 2924, 2853,
˜
1732, 1452, 1254, 1190, 1026, 969 cm–1. 1H NMR (300 MHz,
C6D6): δ = 6.18 (dddd, J = 15.7, 10.8, 4.8, 1.9 Hz, 1 H), 5.37 (br.
dd, J = 15.7, 4.3 Hz, 1 H), 5.08–4.99 (m, 1 H), 4.32–4.25 (m, 1 H),
4.06 (br. d, J = 11.3 Hz, 1 H), 3.20 (br. s, 1 H), 2.70 (dd, J = 13.7,
11.3 Hz, 1 H), 2.12 (dd, J = 13.66, 1.75 Hz, 1 H), 2.09–1.93 (m, 1
H), 1.90–1.65 (m, 2 H), 1.61–1.41 (m, 3 H), 1.42–1.21 (m, 3 H),
1.05 (d, J = 6.40 Hz, 3 H), 0.96 (dddd, J = 13.8, 4.9, 2.6, 1.3 Hz,
1 H) ppm. 13C NMR (75 MHz, C6D6): δ = 169.9, 138.2, 129.1,
71.6, 69.9, 69.6, 67.3, 39.9, 32.1, 30.8, 27.9, 25.3, 22.6, 19.2 ppm.
HRMS (ESI): calcd. for C14H23O4 [M + H]+ 255.15909; found
255.15939.
[5] For a review on the syntheses of aspergillides, see: T. Nagas-
awa, S. Kuwahara, Heterocycles 2012, 85, 587–613.
[6] For the synthesis of aspergillide B, see: a) B. M. Trost, M. J.
Bartlett, Org. Lett. 2012, 14, 1322–1325; b) A. J. M. Hendrix,
M. P. Jennings, Tetrahedron Lett. 2010, 51, 4260–4262; c) J. Liu,
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ref.[4a,4e–4g,4k]
[7] For the synthesis of aspergillide C, see: a) P. Srihari, Y. Sridhar,
Eur. J. Org. Chem. 2011, 6690–6697; b) H. Kobayashi, M.
Kanematsu, M. Yoshida, K. Shishido, Chem. Commun. 2011,
47, 7440–7442; c) M. Kanematsu, M. Yoshida, K. Shishido,
Tetrahedron Lett. 2011, 52, 1372–1374; d) J. D. Panarese, S. P.
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[8] For our recent contributions to natural products Synthesis see:
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829–832; b) K. Vamshikrishna, P. Srihari, Tetrahedron 2012,
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(+)-7-epi-Aspergillide A (25): Following a similar procedure as that
employed for product (+)-2, compound 24 (0.05 g, 0.135 mmol) af-
forded 25 (31.75 mg, 92%) as a colorless oil; Rf = 0.50 (hexane/
EtOAc, 1:1). [α]2D0 = +91.68 (c = 0.80, CHCl ). IR (KBr): ν = 3430,
˜
3
2926, 2854, 1724, 1454, 1265, 1078, 972, 757 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 6.44 (dddd, J = 15.5, 10.2, 3.6, 1.4 Hz, 1
H), 5.61 (br. dd, J = 15.8, 3.5 Hz, 1 H), 4.67–4.57 (m, 1 H), 4.49–
4.42 (m, 1 H), 3.77 (t, J = 9.0 Hz, 1 H), 3.35 (td, J = 9.9, 3.9 Hz,
1 H), 2.83 (d, J = 16.1 Hz, 1 H), 2.34 (dd, J = 16.1, 8.2 Hz, 1 H),
2.20–2.03 (m, 2 H), 2.05–1.93 (m, 2 H), 1.90–1.77 (m, 2 H), 1.73–
1.67 (m, 2 H), 1.59–1.51 (m, 2 H), 1.30 (d, J = 6.1 Hz, 3 H), 1.28–
1.16 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.6, 138.4,
127.5, 73.4, 71.4, 71.3, 69.6, 37.9, 33.3, 32.2, 30.0, 28.4, 25.7,
20.3 ppm. HRMS (ESI): calcd. for C14H23O4 [M + H]+ 255.15909;
found 255.15944.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
Acknowledgments
Y. S. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for financial assistance. P. S. acknowledges a
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586
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Total Synthesis of Aspergillides
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Received: August 25, 2012
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Published Online: November 27, 2012
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