Synthesis and synthesis-based structural elucidation of (-)-macrosphelides J and K

Article abstract of DOI:10.3987/COM-15-13195

The structures of (-)-macrosphelides J and K have been elucidated via asymmetric total syntheses. Key points of the structure elucidation include an initial prediction of the stereochemistries of (-)-macrosphelides J and K based on the structural relation

Full text of DOI:10.3987/COM-15-13195

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HETEROCYCLES, Vol. 91, No. 5, 2015
HETEROCYCLES, Vol. 91, No. 5, 2015, pp. 970 - 988. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 16th February, 2015, Accepted, 25th March, 2015, Published online, 9th April, 2015
DOI: 10.3987/COM-15-13195
SYNTHESIS AND SYNTHESIS-BASED STRUCTURAL ELUCIDATION
OF (‒)-MACROSPHELIDES J AND K
Hongchan An,a Seung-Hee Kim,a Heegyu Kim,b Kyeojin Kim,a Jaehoon Sim,a
Jaebong Jang,a Seung-Mann Paek,c Young-Ger Suh,a and Hwayoung Yunb*
aCollege of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu,
151-742, Korea; bCollege of Pharmacy, Pusan National University, Geumjeong-gu,
Busan 609-735, Korea; cCollege of Pharmacy, Research Institute of
Pharmaceutical Science, Gyeongsang National University, Jinju daero, Jinju,
660-751, Korea
E-mail: hyun@pusan.ac.kr
Abstract – The structures of (‒)-macrosphelides J and K have been elucidated via
asymmetric total syntheses. Key points of the structure elucidation include an
initial prediction of the stereochemistries of (‒)-macrosphelides J and K based on
the structural relationship of the macrosphelides and molecular modeling of
macrosphelide B. Our synthetic approach features an isoxazoline-based route
involving a diastereoselective olefin-nitrile oxide cycloaddition, an intricate
reductive N-O bond cleavage of an isoxazoline and O-alkylation of the labile
β-hydroxy ketone intermediate.
INTRODUCTION
Natural products are frequently promising candidates for drug discovery.1 In addition, the total syntheses
of biologically active natural products play an important role in the elucidation of their intriguing
molecular structure as well as their structure-activity relationships. Although structural analyses utilizing
spectrometry efficiently allow the structural determination of complex molecules, the final structures have
occasionally been confirmed via extensive synthetic studies.2 Indeed, the originally reported structures of
many natural products have been revised based on the results of total syntheses, although a number of
structures of bioactive natural products remain to be elucidated.2b
The stereochemistries of the macrosphelides, which are considered novel lead compounds for the
development of anticancer and immunosuppressant agents, have not been completely elucidated thus

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971
far.3b-d Thirteen macrosphelides have been reported over the past two decades (Figure 1).3,4
Macrosphelides A, B, C, D, J and K were discovered by Ōmura et al. from the fermentation broth of
Microsphaeropsis sp. FO-5050.3 Macrosphelides E, F, G, H, I, L and M were isolated by Numata et al.
from a strain of Periconia byssoides, which was originally separated from the sea hare Aplysia kurodai.4
Macrosphelides are unique polyketides consisting of a 16-membered macrolactone backbone with the
exception of macrosphelides D and M,4d,5t which are 15-membered macrocyclic polyketides. They
commonly consist of three core fragments including a γ-keto- or γ-hydroxy-trans-α,β-unsaturated acid
moiety connected via an ester linkage.3,4 Macrolides possess four or five stereocenters, and the number of
stereocenters depends on the presence of a secondary alcohol.3,4 Since the initial isolation and structural
elucidation of macrosphelides in the 1990s, these unique polyketides have attracted interest from
synthetic5 and medicinal6 chemists due to their potent tumor metastasis-suppressing and
immune-modulating activities.3-7 However, the stereochemistries of macrosphelides J and K had not been
confirmed until we elucidated them.3c
Figure 1. The macrosphelide family
Macrosphelides J and K are structurally unique compared to other macrosphelides.3c Notably, they
possess a γ-keto-α-alkoxy ester moiety, which could be a challenge late in the total synthesis because the
alkoxy unit is readily eliminated to form a favored conjugated system.8 In this work, the first total
syntheses of (‒)-macrosphelides J (1) and K (2) via an isoxazoline-based route,9 which we recently
reported, is described.5s Moreover, the stereochemistries of the five stereocenters were elucidated for the
first time through these syntheses.5s Throughout the synthetic studies, we took special note of the

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HETEROCYCLES, Vol. 91, No. 5, 2015
structural similarities between macrosphelide B and macrosphelides J and K.5p With the assistance of a
molecular modeling study, one isomer was rationally deduced from thirty-two possible diastereomers. In
this paper, we provide a full account of the structural elucidation of (‒)-macrosphelides J and K through
total synthesis.
RESULT AND DISCUSSION
Structural prediction of (‒)-macrosphelides J and K
Unlike all other macrosphelide isotypes, macrosphelides J and K possess an oxygenated C-12 carbon
(Figure 2). Based on the common framework of this family, it was envisioned that macrosphelides J and
K would be derived from conjugated addition process of C-12=C-13 alkene moiety of mother
macrosphelide molecule. Actually this type of biological conjugated addition, as metabolism or small
molecule-protein interaction or other processes in vivo, is prevailing in bioactive natural product.10
Interesting was all of other macrosphelide molecules favor conjugated addition at C-13 position except
for macrosphelide B which has C-14 ketone moiety to stay C-12 electron deficient. This hypothesis made
to deduce absolute configuration of other chiral centers in macrosphelides J and K as identical as those in
macrosphelide B, except for C-12 chiral center. It also meant, instead of 32 possible stereoisomers, just 2
suspicious stereoisomers were necessary to confirm our hypothesis and full structure of natural product
macrosphelides J and K.
Figure 2. Conjugated addition to macrosphelides J and K from other macrosphelide

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973
In addition, a preliminary molecular modeling study revealed that addition of the alkoxy unit to the
γ-keto-trans-α,β-unsaturated ester moiety from the α-face was favored (Figure 3).11 The two axial methyl
substituents may hinder attack from the β-face.
Figure 3. Preliminary molecular modeling shown from different angles
We then commenced the syntheses of predicted structures 1 and 2 to confirm the structures of
macrosphelides J and K, respectively. The syntheses of the C-12 epimers of 1 and 2 were also carried out
to confirm our hypothesis regarding facial selectivity on C-12 carbon.
Synthetic strategy for 1 and 2
The synthetic strategy for 1 and 2 is illustrated in Scheme 1. Our previous synthetic strategy for
(+)-macrosphelide B was employed for the initial synthetic approach because of the structural similarities
between the compounds.5o,r An intramolecular olefin-nitrile oxide cycloaddition (INOC) was utilized for
the key macrocyclization step in the synthesis of (+)-macrosphelide B. In this particular case, the
diastereoselectivity of the INOC was not crucial for the synthesis of (+)-macrosphelide B because the
newly formed stereogenic center is not present in the natural product. However, the moderate
diastereoselectivity of the INOC was not sufficient for stereoselective introduction of the C-12 alkoxy
group in the syntheses of (‒)-macrosphelides J and K.3c We extensively investigated other reaction
conditions to increase the stereoselectivity of the INOC, including utilization of a metal catalyst12 or a
phase transfer catalyst (PTC). Sufficiently high stereoselectivities were not obtained in spite of isolating
the isoxazoline products in high yields.13 Therefore, alternative routes for the stereoselective introduction
of the alkoxy unit were investigated.

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Scheme 1. Initial synthetic approach for macrosphelides J and K
Revised synthetic strategy for 1 and 2
We intended to maximize the diastereoselectivity by performing the intramolecular cycloaddition at an
early stage in the syntheses of macrosphelides J and K. As shown in Scheme 2, the revised synthetic
strategy for macrosphelides J and K focused on the stereoselective elaboration of a sensitive β-alkoxy
ketone.5s The C-12 alkoxy group would be installed in a high diastereoselective procedure though
reductive N-O bond cleavage of the isoxazoline, which would be prepared by a chiral auxiliary-assisted
cycloaddition14 and subsequent O-alkylation of the resulting secondary alcohol.
Scheme 2. Revised synthetic strategy
Preparation of the isoxazoline intermediate 3
Preparation of isoxazoline intermediate 3 is outlined in Scheme 3. The known aldehyde 815 was
condensed with hydroxylamine hydrochloride to afford oxime 6.16 The key intermolecular cycloaddition
of oxime 6 and acrylate 717 in the presence of aqueous NaOCl afforded isoxazoline 5 in 78% yield with
high diastereoselectivity (>10:1).14b Only the desired regioisomer was observed. Upon reaction of

HETEROCYCLES, Vol. 91, No. 5, 2015
975
isoxazoline 5 with excess allyl alcohol in the presence of Ti(Oi-Pr)4, the desired ester 4 was obtained, and
the sultam auxiliary could be recovered in 90% yield.18 Diester 11 was obtained by PMB deprotection of
4 and esterification of the resulting alcohol with acid 10. The lactonization precursor 15 was conveniently
prepared by deprotection of 11 and esterification of the resulting alcohol with acid 13. The deprotection
of allyl ester 15 and subsequent macrolactonization of the resulting ω-hydroxy acid under Yamaguchi
conditions afforded the 16-membered macrolide 3 in 60% yield for two steps.19
Scheme 3. Preparation of isoxazoline intermediate 3
Reductive N-O bond cleavage of 3
Having accomplished the diastereoselective synthesis of isoxazoline 3, we turned our attention to the
intricate N-O bond cleavage20 and O-alkylation21 of the labile β-hydroxy ketone. Several metal-mediated
reductions have been studied for cleavage of the N-O bond of isoxazolines. Numerous reductive
conditions were examined to obtained the β-hydroxy ketone unit from the isoxazoline (Table 1). Reaction
utilizing Zn, Sm, Cu and Ni (entries 1 - 4)20a-d did not result in a recognizable reaction. Treatment of
isoxazoline 3 with molybdenum led to complete decomposition of the substrate (entries 5 and 6).20e,f
Treatment of isoxazoline 3 with Pd/C afforded exclusively the olefin-reduced product in 80% yield (entry
7).20g Finally, reduction of isoxazoline 3 was accomplished with Ti(Oi-Pr)4/EtMgBr (entry 8).20h It should
be noted that only the supernatant of the Kulinkovich reagent should be used for successful reduction.

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HETEROCYCLES, Vol. 91, No. 5, 2015
Table 1. Reductive N-O bond cleavage
O-Alkylation of hydroxy ketone 16 and completion of the syntheses
For the final stage of the syntheses, O-alkylations of the γ-keto-α-hydroxy unit of intermediate 16 were
carefully explored because of potential complications resulting from the presence of labile ester moieties
(Table 2). Treatment of 16 with KOt-Bu or KHCO3 as bases in the presence of MeI/EtI (entries 1 and 2)
did not provide the desired product. Treatment of 16 with Ag2O or NaH led to complete decomposition of
the substrate (entries 3 and 4).21a,b Other methylations were not successful (entries 5 and 6).21c,d
O-Alkylations of 16 were finally achieved with ROTf/2,6-di-tert-butylpyridine (DTBP) (entries 7 and
8).21e Interestingly, no epimerization or ester hydrolysis were observed when using DTBP as base.
Table 2. O-Alkylation

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977
The final deprotection of MEM ethers 17 and 18 proceeded smoothly to give the synthetic
(‒)-macrosphelides J (1) and K (2) in excellent yields (Scheme 4). Their spectral data (1H NMR, 13C
NMR, HR-MS and IR) and optical rotations were identical to the reported data for the natural products.5s
Scheme 4. Completion of the total syntheses of 1 and 2
Total syntheses of 12-epi-macrosphelides J (epi-1, 30) and K (epi-2, 31)
The structures of (‒)-macrosphelides J (1) and K (2) were further confirmed by the total syntheses of
12-epi-macrosphelides J (30) and K (31) (Schemes 5 and 6). The syntheses of 12-epi-macrosphelides J
and K were achieved via intermolecular olefin-nitrile oxide cycloaddition using ent-7.14 The
well-established isoxazoline synthesis efficiently provided the C-12 stereocenters. The moderate
stereoselectivity (>5:1) is likely due to the mismatch of oxime ether 6 and ent-7 in the cycloaddition. The
16-membered macrolactone 26 was conveniently prepared in high yield using the previously described
procedure.5s
O
O
OH
O
N
O
Ce(NH4)2(NO3)6
Ti(i-PrO)4
ent-7, NaOCl
O
N
N
N
SO2
MeCN/H2O(4:1)
86%
toluene, rt
88%
allyl alcohol, 4Å MS, 130 °C
PMBO
76%
OPMB
PMBO
6
19 (d.r. > 5 : 1)
20
O
O
O
O
OMEM
O RO
O
N
O
N
O
O
O
N
10, EDCI, DMAP
13, EDCI, DMAP
O
CH2Cl2, rt
79%
CH2Cl2, rt
66%
O
OR
OH
21
O
O
O
DDQ
DDQ
CH2Cl2/pH 7 buffer (10:1), 88%
24 R = PMB
25 R = H
22 R = PMB
23 R = H
CH2Cl2/pH 7 buffer (10:1), 94%
O
OMEM
O
O
(1) morpholine, Pd(PPh3)4, THF, rt
N
O
(2) Cl3C6H2COCl, Et3N, DMAP, toluene, rt
63% for 2 steps
O
O
O
26
Scheme 5. Preparation of 16-membered lactone 26

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HETEROCYCLES, Vol. 91, No. 5, 2015
With the desired isoxazoline 26 available, transformation of 26 into β-hydroxy ketone 27 was carried out
using excess Mo(CO)6.20e In the case of substrate 26, reduction of the Kulinkovich reagent was
unsuccessful. Again, the β-hydroxy group of 27 was alkylated with ROTf in the presence of DTBP.21e
Treatment of the resulting ether intermediates with TFA in CH2Cl2 afforded 12-epi-macrosphelides J (30)
and K (31). As anticipated, the spectral data for 30 and 31 did not match the reported spectral data for
natural macrosphelides J and K. Thus, the absolute configurations of (‒)-macrosphelides J (1) and K (2)
were clearly elucidated.
Scheme 6. Completion of the total syntheses of 30 and 31
Plausible biosynthetic pathway
Hypothesis on biosynthetic pathway of macrosphelides J and K is suggested below (Scheme 7). Because
of sterically demanding C-15 and C-9 methyl group, β-face of the C-12=C-13 olefin is thought to be
totally hindered. Consequently, conjugate addition of alkoxide or alcohol moiety induces stereoselective
formation of C-12 chiral center. This hypothesis matches well with the previous report by Kobayashi
group and Nemoto group. During the synthesis of macrosphelide A from macrosphelide B, Kobayashi
group tried to induce C-14 hydroxyl group from stereoselective reduction of C-14 ketone group.5d
Unfortunately, treatment of NaBH4 afforded a trace amount of desired macrosphelide A (34), whereas
14-epi-macrosphelide A (33) was obtained as a major isomer. This unexpected result shows to what
extent the β-face of macrosphelide framework is blocked. Similar results were also observed in allylic
oxidation strategy for macrosphelide derivatives synthesis. Nemoto group planned to prepare
macrosphelide derivatives directly via allylic oxidation of simply substituted macrosphelide skeleton 35.6c
After extensive reaction screening and X-ray crystallography analysis of 35, it was possible to produce
macrosphelide A (34) and macrosphelide C (36) in high yield, along with 14-epi macrosphelide C (37) as
a minor product. During epoxidation strategy for macrosphelide-derivatives synthesis, similar facial

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979
selectivity was also observed. Introduction of epoxide group to the conjugated alkene in macrosphelide
skeleton afforded α-face addition product 38 and its isomer 39 as major products. These
stereoselectivities are regarded as results from steric hindrance of β-face in macrosphelide skeleton and
concomitant nucleophilic addition from α-face, which is more open than β-face. Our study also shows
macrosphelides J and K might be prepared from β-face addition of alcohol to the mother molecule 32 as
usually observed in reactions of macrosphelide framework. This hypothesis is valuable as it can be
applied to further research such as development of more advanced immunomodulator or preparation of
chemical probes for target protein identification.
Scheme 7. Structural environment of macrosphelide skeleton and its synthetic features
CONCLUSION
In summary, the convergent syntheses of (‒)-macrosphelides J and K from the acrylated camphorsultam 7
were achieved in 12 linear steps. In addition, the predicted stereochemistries of both macrosphelides were
confirmed by the total syntheses of natural (‒)-macrosphelides J and K as well as their C12-epimers. The
key part of the syntheses involved diastereoselective preparation of the isoxazoline intermediates, which
were later transformed into the requisite β-hydroxy ketones. Specifically, intricate N-O bond cleavage of

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the isoxazoline intermediates was successfully achieved utilizing the in-situ generated Kulinkovich
reagent. Appropriate reaction conditions for O-alkylation of the labile β-hydroxy ketones were also found.
(12S)-Alkoxy-12,13-dihydromacrosphelide B, which seem conjugated addition products of
macrosphelide B were proved to be real structure of these natural products. It can be also deduced that
conjugated addition of biomolecules, such as proteins, nucleic acids or other constituents, triggers
pharmacological pathway of macrosphelide B, as simple alcohol generates macrosphelides J and K.
Overall, the structural elucidation of (‒)-macrosphelides J and K based on their hypothetical biosynthetic
routes greatly facilitates our current work regarding their mode of action.
EXPERIMENTAL
Unless noted otherwise, all starting materials and reagents were obtained from commercial suppliers and
were used without further purification. Tetrahydrofuran and Et2O were distilled from sodium
benzophenone ketyl. Dichloromethane, chloroform, triethylamine, acetonitrile and pyridine were freshly
distilled from calcium hydride. All solvents used for routine isolation of products and chromatography
were reagent grade and glass distilled. Reaction flasks were dried at 100 °C. Air and moisture sensitive
reactions were performed under argon atmosphere. Flash column chromatography was performed using
silica gel 60 (230-400 mesh, Merck) with the indicated solvents. Thin-layer chromatography was
performed using 0.25 mm silica gel plates (Merck). Optical rotations were measured with JASCO
DIP-1000 digital polarimeter at ambient temperature using 100 nm cell of 2 mL capacity. Infrared spectra
were recorded on a Perkin-Elmer 1710 FT-IR spectrometer. Mass spectra were obtained with VG Trio-2
GC-MS instrument. High resolution mass spectra were obtained with JEOL JMS-AX 505WA instrument.
1H-and 13C-NMR spectra were recorded on either a JEOL JNM-GCX 400 or JEOL JNM-LA 300
spectrometer as solutions in deuteriochloroform (CDCl3). Chemical shifts are expressed in parts per
million (ppm, δ) downfield from tetramethylsilane and are referenced to the deuterated solvent (CHCl3).
1H-NMR data were reported in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet and/or multiple resonance), number of protons, and coupling constant in hertz (Hz).
Preliminary molecular modeling: The study was carried out using SYBYL 6.8. (+)-Macrosphelide B was
minimized using Tripos forcefield parameters and the conjugate gradient algorithm with a gradient
convergence value of 0.005 kcal/mol ଈ. Low energy conformation was searched by a systematic
conformational search.
Isoxazoline (19). To a solution of aldoxime 6 (2.80 g, 13.4 mmol) and acrylate ent-7 (3.0 g, 11.1 mmol) in
toluene (120 mL) were added aqueous NaOCl (13.2 mL, 22.2 mmol, c.a. 10%) at ambient temperature.

HETEROCYCLES, Vol. 91, No. 5, 2015
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The reaction mixture was stirred for 1 h at the same temperature and diluted with H2O. The aqueous layer
was extracted with EtOAc and the combined organic layers were dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 2)
to afford 4.66 g (88%) of isoxazoline 19 (d.r. > 5 : 1) as pale yellow and foamy solid: [α]2D5 -249 (c 0.373,
1
CHCl3); FT-IR (thin film, neat) νmax 2959, 1699, 1612, 1514, 1335 cm-1; H-NMR (CDCl3, 300 MHz) δ
7.23 (d, 2H, J = 8.8 Hz), 6.85 (d, 2H, J = 8.6 Hz), 5.47 (dd, 1H, J = 11.1, 6.9 Hz), 4.44 (q, 1H, J = 6.6 Hz),
4.38 (m, 2H), 3.90 (dd, 1H, J = 7.7, 5.0 Hz), 3.78 (s, 3H), 3.48 (m, 2H), 3.27 (m, 2H), 2.15 (m, 1H), 2.05
(m, 2H), 1.90 (m, 2H), 1.40 (m, 2H), 1.37 (d, 3H, J = 6.6 Hz), 1.17 (s, 3H), 0.96 (s, 3H); 13C-NMR
(CDCl3, 100 MHz) δ 168.3, 159.4, 159.3, 129.6, 129.6, 129.6, 113.8, 113.8, 77.0, 70.6, 69.2, 65.3, 55.2,
52.9, 49.0, 47.8, 44.6, 38.1, 36.8, 32.9, 26.4, 20.9, 19.8, 19.2; LR-MS (FAB+) m/z 477 (M+H+); HR-MS
(FAB+) calcd for C24H33N2O6S (M+H+) 477.2059; found 477.2051.
Allyl ester (20). To a solution of isoxazoline 19 (939 mg, 2.0 mmol) in the presence of 4ଈ molecular
sieves (493 mg, 250 mg/mmol) in allyl alcohol (39.4 mL, 0.05 M) was added Ti(Oi-Pr)4 (1.73 mL, 5.9
mmol) at 130 °C. The reaction mixture was vigorously stirred for 1 h at the same temperature and was
quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined
organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc : n-hexane = 1 : 3) to afford 479 mg (76%) of allyl ester 20
as a yellow oil: [α]2D5 -187 (c 2.25, CHCl3); FT-IR (thin film, neat) νmax 2937, 1744, 1613, 1514, 1444,
1375 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 7.22 (d, 2H, J = 8.6 Hz), 6.85 (d, 2H, J = 8.6 Hz), 5.90 (m, 1H),
5.32 (dd, 1H, J = 17.2, 1.5 Hz), 5.25 (dd, 1H, J = 10.4, 1.3 Hz), 4.96 (dd, 1H, J = 11.0, 7.3 Hz), 4.65 (dt,
2H, J = 5.9, 1.2 Hz), 4.45 (q, 1H, J = 6.6 Hz), 4.38 (m, 2H), 3.77 (s, 3H), 3.24 (m, 2H), 1.36 (d, 3H, J =
6.6 Hz) ; 13C-NMR (CDCl3, 75 MHz) δ 169.6, 159.5, 159.3, 131.2, 129.4, 129.4, 129.4, 119.1, 113.8,
113.8, 77.2, 70.5, 69.3, 66.1, 55.2, 36.9, 19.1 ; LR-MS (FAB+) m/z 320 (M+H+); HR-MS (FAB+) calcd
for C17H22NO5 (M+H+) 320.1498; found 320.1494.
Alcohol (21). To a solution of allyl ester 20 (3.26 g, 10.2 mmol) in MeCN (120 mL) and H2O (30 mL)
was added ammonium cerium nitrate (8.39 g, 15.3 mmol) at ambient temperature. After stirring for 3 h at
the same temperature, the reaction mixture was quenched with H2O. The aqueous layer was extracted
with EtOAc and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 1) to afford
1.75 g (86%) of alcohol 21 as a pale yellow oil: [α]2D5 -153 (c 1.15, CHCl3); FT-IR (thin film, neat) νmax
3419, 2982, 2938, 1743, 1649, 1438, 1375, 1330 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 5.88 (m, 1H), 5.31
(dd, 1H, J = 17.2, 1.1 Hz), 5.24 (dd, 1H, J = 10.4, 0.7 Hz), 5.01 (dd, 1H, J = 10.6, 7.5 Hz), 4.67 (m, 1H),
4.63 (d, 2H, J = 5.9 Hz), 3.31 (m, 2H), 2.92 (s, 1H), 1.39 (d, 3H, J = 6.6 Hz); 13C-NMR (CDCl3, 75 MHz)

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HETEROCYCLES, Vol. 91, No. 5, 2015
δ 170.0, 161.3, 131.1, 119.1, 77.4, 66.2, 63.4, 37.6, 20.8; LR-MS (FAB+) m/z 200 (M+H+); HR-MS
(FAB+) calcd for C9H14NO4 (M+H+) 200.0923; found 200.0918.
Ester (22). To a solution of alcohol 21 (2.63 g, 13.2 mmol) and acid 10 (4.44 g, 19.8 mmol) in CH2Cl2
(200 mL) were added EDCI (5.06 g, 26.4 mmol) and DMAP (3.23 g, 26.4 mmol) at ambient temperature.
After stirring for 2 h at the same temperature, the reaction mixture was quenched with H2O. The aqueous
layer was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc :
n-hexane = 1 : 3) to afford 4.22 g (79%) of ester 22 as a yellow oil: [α]2D5 -101 (c 1.35, CHCl3); FT-IR
(thin film, neat) νmax 2937, 1742, 1613, 1514, 1454, 1377 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 7.19 (d, 2H,
J = 8.6 Hz), 6.83 (d, 2H, J = 8.8 Hz), 5.89 (m, 1H), 5.71 (q, 1H, J = 6.6 Hz), 5.32 (dd, 1H, J = 17.1, 1.4
Hz), 5.25 (dd, 1H, J = 10.4, 1.2 Hz), 4.84 (dd, 1H, J = 11.6, 6.8 Hz), 4.63 (d, 2H, J = 5.9 Hz), 4.41 (m,
2H), 3.99 (m, 1H), 3.76 (s, 3H), 3.12 (m, 2H), 2.52 (m, 2H), 1.45 (d, 3H, J = 6.6 Hz), 1.23 (d, 3H, J = 6.1
Hz); 13C-NMR (CDCl3, 100 MHz) δ 170.3, 169.4, 159.2, 158.0, 131.2, 130.4, 129.2, 129.2, 119.0, 113.8,
113.8, 77.6, 71.8, 70.6, 66.2, 65.5, 55.2, 42.1, 37.9, 19.6, 18.1; LR-MS (FAB+) m/z 428 (M+Na+);
HR-MS (FAB+) calcd for C21H27NO7Na (M+Na+) 428.1685; found 428.1673.
Alcohol (23). To a solution of PMB ether 22 (3.48 g, 8.6 mmol) in CH2Cl2 (120 mL) and phosphate
buffer solution (12 mL, pH 7.0) was added DDQ (5.83 g, 25.7 mmol) at ambient temperature. The
reaction mixture was stirred for 3 h and diluted with CH2Cl2. The mixture was filtered under reduced
pressure and washed with H2O. The aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc : n-hexane = 1 : 1) to afford 2.30 g (94%) of alcohol 23 as a yellow
oil: [α]2D5 -127 (c 1.39, CHCl3); FT-IR (thin film, neat) νmax 3444, 3088, 2977, 2938, 1739, 1649, 1453,
1377 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 5.86 (m, 1H), 5.68 (q, 1H, J = 6.7 Hz), 5.29 (dd, 1H, J = 17.1,
1.4 Hz), 5.22 (dd, 1H, J = 10.4, 1.2 Hz), 5.00 (dd, 1H, J = 11.2, 7.3 Hz), 4.62 (dt, 2H, J = 5.9, 1.3 Hz),
4.15 (m, 1H), 3.23 (m, 2H), 2.85 (s, 1H), 2.41 (m, 2H), 1.45 (d, 3H, J = 6.6 Hz), 1.18 (d, 3H, J = 6.4 Hz);
13C-NMR (CDCl3, 75 MHz) δ 171.4, 169.3, 157.6, 131.1, 119.0, 77.7, 66.2, 65.6, 64.3, 43.0, 38.0, 22.6,
17.9; LR-MS (FAB+) m/z 286 (M+H+); HR-MS (FAB+) calcd for C13H20NO6 (M+H+) 286.1291; found
286.1286.
Ester (24). To a solution of alcohol 23 (1.02 g, 3.6 mmol) and acid 13 (1.78 g, 5.0 mmol) in CH2Cl2 (50
mL) were added EDCI (1.37 g, 7.16 mmol) and DMAP (875.0 g, 7.16 mmol) at ambient temperature.
After stirring for 3 h at the same temperature, the reaction mixture was quenched with H2O and the
aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc :

HETEROCYCLES, Vol. 91, No. 5, 2015
983
n-hexane = 1 : 1) to afford 1.47 g (66%) of ester 24 as a yellow oil: [α]2D5 -80.0 (c 0.347, CHCl3); FT-IR
(thin film, neat) νmax 2937, 1743, 1658, 1613, 1514, 1454, 1378 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 7.21
(d, 2H, J = 8.7 Hz), 6.85 (m, 1H), 6.84 (d, 2H, J = 8.4 Hz), 5.98 (dd, 1H, J = 16.1, 1.4 Hz), 5.90 (m, 1H),
5.68 (q, 1H, J = 6.5 Hz), 5.33 (dd, 1H, J = 17.1, 1.5 Hz), 5.33 (m, 1H), 5.26 (dd, 1H, J = 10.2, 0.9 Hz),
5.01 (dd, 1H, J = 11.4, 7.2 Hz), 4.71 (m, 2H), 4.66 (dt, 2H, J = 6.0, 1.2 Hz), 4.48 (s, 2H), 4.30 (m, 1H),
3.77 (s, 3H), 3.74 (m, 1H), 3.60 (m, 2H), 3.47 (m, 2H), 3.34 (s, 3H), 3.21 (m, 2H), 2.62 (m, 2H), 1.43 (d,
3H, J = 6.9 Hz), 1.32 (d, 3H, J = 6.6 Hz), 1.15 (d, 3H, J = 6.6 Hz); 13C-NMR (CDCl3, 100 MHz) δ 169.4,
168.9, 165.0, 159.1, 157.5, 145.7, 131.2, 130.4, 129.2, 129.2, 123.0, 119.2, 113.7, 113.7, 94.0, 77.8, 77.6,
77.2, 76.0, 71.6, 70.8, 67.2, 66.3, 65.8, 59.0, 55.2, 40.8, 37.9, 19.9, 18.0, 15.6; LR-MS (FAB+) m/z 622
(M+H+); HR-MS (FAB+) calcd for C31H44NO12 (M+H+) 622.2864; found 622.2869.
Alcohol (25). To a solution of PMB ether 24 (2.72 g, 4.4 mmol) in CH2Cl2 (80 mL) and phosphate buffer
solution (8 mL, pH 7.0) was added DDQ (2.97 g, 13.1 mmol) at ambient temperature. The reaction
mixture was stirred for 2 h, diluted with CH2Cl2 and filtered under reduced pressure. The organic layer
was washed with H2O and aqueous layer was extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography
on silica gel (EtOAc : n-hexane = 3 : 2) to afford 1.93 g (88%) of alcohol 25 as a yellow oil: [α]2D5 -98.2
(c 0.747, CHCl3); FT-IR (thin film, neat) νmax 3464, 2929, 1741, 1652, 1453, 1376 cm-1; 1H-NMR (CDCl3,
300 MHz) δ 6.83 (dd, 1H, J = 15.8, 6.2 Hz), 5.99 (dd, 1H, J = 15.8, 1.3 Hz), 5.90 (m, 1H), 5.69 (q, 1H, J
= 6.5 Hz), 5.33 (d, 1H, J = 15.8 Hz), 5.31 (m, 1H), 5.26 (d, 1H, J = 10.4 Hz), 5.03 (dd, 1H, J = 11.2, 7.1
Hz), 4.72 (m, 2H), 4.66 (d, 2H, J = 5.7 Hz), 4.19 (m, 1H), 3.92 (m, 1H), 3.73 (m, 2H), 3.53 (t, 2H, J = 4.4
Hz), 3.36 (s, 3H), 3.24 (m, 2H), 2.62 (m, 2H), 2.20 (s, 1H), 1.45 (d, 3H, J = 6.6 Hz), 1.31 (d, 3H, J = 6.2
13
Hz), 1.12 (d, 3H, J = 6.6 Hz); C-NMR (CDCl3, 100 MHz) δ 169.4, 169.0, 164.9, 157.5, 144.4, 131.2,
123.6, 119.3, 94.4, 80.8, 77.7, 71.6, 68.9, 67.5, 67.3, 66.4, 65.8, 59.0, 40.8, 38.0, 19.9, 18.0, 17.7; LR-MS
(FAB+) m/z 502 (M+H+); HR-MS (FAB+) calcd for C23H36NO11 (M+H+) 502.2288; found 502.2299.
16-Membered lactone (26). To a solution of alcohol 25 (91.2 mg, 0.2 mmol) in THF (3 mL) were added
Pd(PPh3)4 (63.1 mg, 0.1 mmol) and morpholine (32 μL, 40 μmol) at ambient temperature. The mixture
was stirred for 12 h at the same temperature, quenched with 1N HCl and extracted with EtOAc three
times. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude acid
was used for next step without further purification. To a solution of above acid in toluene (4 mL) were
o
added Et3N (166 μL, 1.1 mmol) and 2,4,6-trichlorobenzoyl chloride (142 μL, 0.9 mmol) at 0 C. The
mixture was warmed to ambient temperature and stirred for 2 h before removing THF under reduced
pressure. The residue was solved in toluene (30 mL) and the mixture was added slowly to a rapidly stirred
solution of DMAP (556 mg, 4.6 mmol) in toluene (40 mL). The reaction mixture was stirred for 24 h and

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HETEROCYCLES, Vol. 91, No. 5, 2015
quenched with H2O. The reaction mixture was extracted with EtOAc and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc : n-hexane = 2 : 1) to afford 80.7 mg (63%) of ester 26 as a pale
yellow oil.
β-Hydroxy ketone (27). To a solution of macrolactone 26 (8.0 mg, 18 μmol) in MeCN (1 mL) and H2O
(10 μL) was added Mo(CO)6 (47.8 mg, 180 μmol) at ambient temperature. The reaction mixture was
refluxed for 12 h and cooled to room temperature. The reaction mixture was filtered through a pad of
silica gel and concentrated in vacuo. The residue was purified by flash column chromatography on silica
gel (EtOAc : n-hexane = 3 : 2) to afford 5.8 mg (71%) of ester 27 as a pale yellow oil: [α]2D0 -30.5 (c
1
0.220, CHCl3); FT-IR (thin film, neat) νmax 3397, 2924, 2853, 1736, 1541, 1459 cm-1; H-NMR (CDCl3,
400 MHz) δ 6.75 (dd, 1H, J = 15.7, 6.6 Hz), 6.02 (d, 1H, J = 15.9 Hz), 5.41 (m, 1H), 5.05 (q, 1H, J = 7.0
Hz), 4.87 (m, 1H), 4.71 (m, 2H), 4.56 (dd, 1H, J = 7.5, 1.9 Hz), 4.28 (t, 1H, J = 6.9 Hz), 3.75 (m, 1H),
3.64 (m, 1H), 3.52 (t, 2H, J = 4.5 Hz), 3.36 (s, 3H), 2.93 (dd, 1H, J = 18.2, 7.8 Hz), 2.72 (dd, 1H, J = 15.4,
10.8 Hz), 2.61 (m, 2H), 1.43 (d, 3H, J = 6.4 Hz), 1.38 (d, 3H, J = 7.0 Hz), 1.34 (d, 3H, J = 6.3 Hz);
13C-NMR (CDCl3, 100 MHz) δ 205.4, 171.7, 170.3, 164.5, 144.2, 124.4, 94.0, 77.2, 75.1, 73.4, 71.6, 68.0,
67.5, 66.9, 59.0, 42.0, 40.8, 19.9, 17.3, 15.7; LR-MS (FAB+) m/z 469 (M+Na+); HR-MS (FAB+) calcd
for C20H30O11Na (M+Na+) 469.1686; found 469.1685.
β-Methoxy ketone (28). To a solution of β-hydroxy ketone 27 (9.0 mg, 20 μmol) in CHCl3 (1 mL) were
added 2,6-di-t-butylpyridine (136 μL, 0.6 mmol) and MeOTf (67 μL, 0.6 mmol) at ambient temperature.
The mixture was warmed to 80 °C and stirred for 12 h. The mixture was quenched with saturated aqueous
NH4Cl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc :
n-hexane = 1 : 1) to afford 7 mg (75%) of β-methoxy ketone 28 as a colorless oil: [α]2D0 -34.6 (c 0.067,
1
CH3OH); FT-IR (thin film, neat) νmax 2927, 2855, 1739, 1660, 1453, 1373 cm-1; H-NMR (CDCl3, 500
MHz) δ 6.71 (dd, 1H, J = 15.9, 7.9 Hz), 6.00 (d, 1H, J = 15.9 Hz), 5.38 (m, 1H), 4.93 (q, 1H, J = 6.4 Hz),
4.90 (m, 1H), 4.70 (m, 2H), 4.28 (dd, 1H, J = 10.3, 1.7 Hz), 4.18 (t, 1H, J = 8.5 Hz), 3.69 (m, 2H), 3.52 (t,
2H, J = 4.6 Hz), 3.36 (s, 3H), 3.34 (s, 3H), 2.90 (dd, 1H, J = 17.6, 10.3 Hz), 2.72 (dd, 1H, J = 14.7, 11.2
Hz), 2.54 (dd, 1H, J = 14.7, 2.2 Hz), 2.21 (dd, 1H, J = 17.6, 1.6 Hz), 1.44 (d, 3H, J = 6.4 Hz), 1.36 (d, 3H,
13
J = 7.1 Hz), 1.33 (d, 3H, J = 6.3 Hz); C-NMR (CDCl3, 75 MHz) δ 204.3, 171.0, 171.0, 164.1, 145.5,
124.9, 93.9, 78.0, 71.5, 71.1, 68.8, 67.4, 59.0, 58.7, 51.7, 41.1, 40.1, 29.7, 20.1, 17.5, 15.7; LR-MS
(FAB+) m/z 461 (M+H+); HR-MS (FAB+) calcd for C21H33O11 (M+ H+) 461.2023; found 461.1997.
β-Ethoxy ketone (29). To a solution of ș-hydroxy ketone 27 (12 mg, 26 μmol) in CHCl3 (1 mL) were
added 2,6-di-t-butylpyridine (0.18 mL, 0.9 mmol) and EtOTf (0.10 mL, 0.8 mmol) at ambient

HETEROCYCLES, Vol. 91, No. 5, 2015
985
temperature. The mixture was warmed to 80 °C and stirred for 12 h. The mixture was quenched with
saturated aqueous NH4Cl and extracted with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica
gel (EtOAc : n-hexane = 1 : 1) to afford 8 mg (68%) of β-ethoxy ketone 29 as a colorless oil: [α]2D5 -34.9
1
(c 1.67, CHCl3); FT-IR (thin film, neat) νmax 2978, 2925, 2855, 1739, 1662, 1452, 1371 cm-1; H-NMR
(CDCl3, 300 MHz) δ 6.71 (dd, 1H, J = 15.9, 8.0 Hz), 6.00 (d, 1H, J = 15.7 Hz), 5.37 (m, 1H), 4.91 (m,
1H), 4.86 (q, 1H, J = 7.2 Hz), 4.70 (q, 2H, J = 7.2 Hz), 4.36 (dd, 1H, J = 10.4, 1.7 Hz), 4.19 (t, 1H, J =
8.6 Hz), 3.68 (m, 2H), 3.52 (t, 2H, J = 4.8 Hz), 3.52 (m, 2H), 3.36 (s, 3H), 2.92 (dd, 1H, J = 17.3, 10.5
Hz), 2.72 (dd, 1H, J = 14.7, 11.2 Hz), 2.53 (dd, 1H, J = 14.6, 2.2 Hz), 2.15 (dd, 1H, J = 17.3, 1.8 Hz),
1.42 (d, 3H, J = 6.2 Hz), 1.36 (d, 3H, J = 7.1 Hz), 1.32 (d, 3H, J = 6.2 Hz), 1.13 (t, 3H, J = 7.1 Hz);
13C-NMR (CDCl3, 75 MHz) δ 204.5, 171.4, 171.1, 164.1, 145.5, 124.9, 93.9, 78.0, 74.5, 71.5, 71.1, 68.8,
67.4, 66.7, 59.0, 41.1, 39.9, 30.2, 20.1, 17.5, 15.7, 15.0; LR-MS (FAB+) m/z 475 (M+H+); HR-MS
(FAB+) calcd for C22H35O11 (M+H+) 475.2179; found 475.2150.
12-epi-Macrosphelide J (30). To a solution of β-methoxy ketone 28 (7 mg, 15 μmol) in CH2Cl2 (0.5 mL)
was added trifluoroacetic acid (0.5 mL) at ambient temperature. After stirring for 12 h, the reaction
mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (EtOAc :
n-hexane = 1 : 1) to afford 6 mg (99%) of 12-epi-macrosphelide J 30 as a colorless oil: [α]2D4 10.9 (c
0.373, CHCl3); FT-IR (thin film, neat) νmax 3471, 2927, 2854, 1737, 1662, 1452, 1375, 1336 cm-1;
1H-NMR (CDCl3, 300 MHz) δ 6.83 (dd, 1H, J = 15.8, 5.5 Hz), 6.04 (dd, 1H, J = 15.8, 1.5 Hz), 5.42 (m,
1H), 4.93 (q, 1H, J = 6.9 Hz), 4.87 (m, 1H), 4.26 (m, 1H), 4.25 (dd, 1H, J = 10.1, 1.8 Hz), 3.34 (s, 3H),
2.95 (dd, 1H, J = 17.6, 10.3 Hz), 2.76 (dd, 1H, J = 15.3, 11.1 Hz), 2.66 (s, 1H), 2.57 (dd, 1H, J = 15.3, 2.5
Hz), 2.21 (dd, 1H, J = 17.6, 1.8 Hz), 1.48 (d, 3H, J = 6.4 Hz), 1.36 (d, 3H, J = 7.1 Hz), 1.33 (d, 3H, J =
13
6.6 Hz); C-NMR (CDCl3, 100 MHz) δ 204.3, 172.0, 170.8, 164.3, 145.4, 123.2, 76.2, 76.1, 74.8, 74.3,
68.5, 58.7, 40.9, 40.0, 20.0, 17.7, 15.8; LR-MS (FAB+) m/z 373 (M+H+); HR-MS (FAB+) calcd for
C17H25O9 (M+H+) 373.1499; found 373.1511.
12-epi-Macrosphelide K (31). To a solution of β-ethoxy ketone 29 (3 mg, 7 μmol) in CH2Cl2 (0.5 mL)
was added trifluoroacetic acid (0.5 mL) at ambient temperature. After stirring for 12 h, the reaction
mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (EtOAc :
n-hexane = 1 : 1) to afford 3 mg (99%) of 12-epi-macrosphelide K 31 as a colorless oil: [α]2D0 31.6 (c
0.140, CH3OH); FT-IR (thin film, neat) νmax 3471, 2980, 2933, 2877, 2856, 1737, 1663, 1450, 1373, 1335
cm-1; 1H-NMR (CDCl3, 300 MHz) δ 6.82 (dd, 1H, J = 15.6, 5.5 Hz), 6.05 (dd, 1H, J = 15.7, 1.0 Hz), 5.42
(m, 1H), 4.90 (q, 1H, J = 7.1 Hz), 4.85 (m, 1H), 4.34 (dd, 1H, J = 10.4, 1.6 Hz), 4.25 (m, 1H), 3.49 (m,
2H), 2.97 (dd, 1H, J = 17.3, 10.4 Hz), 2.77 (dd, 1H, J = 15.2, 11.4 Hz), 2.66 (s, 1H), 2.56 (dd, 1H, J =

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HETEROCYCLES, Vol. 91, No. 5, 2015
15.2, 2.2 Hz), 2.16 (dd, 1H, J = 17.2, 1.7 Hz), 1.47 (d, 3H, J = 6.4 Hz), 1.36 (d, 3H, J = 7.5 Hz), 1.33 (d,
3H, J = 7.0 Hz), 1.13 (t, 3H, J = 7.1 Hz); 13C-NMR (CDCl3, 75 MHz) δ 204.5, 172.5, 170.9, 164.2, 145.3,
123.2, 76.3, 75.0, 74.6, 74.4, 68.5, 66.8, 40.8, 39.9, 20.0, 17.7, 15.7, 15.0; LR-MS (FAB+) m/z 387
(M+H+); HR-MS (FAB+) calcd for C18H27O9 (M+H+) 387.1655; found 387.1674.
ACKNOWLEDGEMENTS
This work was supported by the National Research Foundation of Korea (NRF) grant for the Global Core
Research Center (GCRC) funded by the Korea government (MSIP) (No. 2011-0030001) and Pusan
National University Research Grant, 2014.
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