Concise syntheses of (+)-macrosphelides A and B: Studies on the macro-ring closure strategy

Article abstract of DOI:10.1021/jo8016692

Highly concise syntheses of (+)-macrosphelides A and B were accomplished in this study. The key feature of our synthetic route involved the direct three-carbon homologation of the readily available Weinreb amide 6 by the addition of a trans-vinylogous est

Full text of DOI:10.1021/jo8016692

Concise Syntheses of (+)-Macrosphelides A and B: Studies on the
Macro-Ring Closure Strategy
Seung-Mann Paek,† Hwayoung Yun,† Nam-Jung Kim,† Jong-Wha Jung,† Dong-Jo Chang,†
Sujin Lee,† Jakyung Yoo,‡ Hyun-Ju Park,‡ and Young-Ger Suh*,†
College of Pharmacy, Seoul National UniVersity, Gwanak-ro 599, Gwanak-gu, Seoul 151-742, Korea, and
College of Pharmacy, Sungkyunkwan UniVersity, Suwon 440-746, South Korea
ygsuh@snu.ac.kr
ReceiVed August 9, 2008
Highly concise syntheses of (+)-macrosphelides A and B were accomplished in this study. The key
feature of our synthetic route involved the direct three-carbon homologation of the readily available
Weinreb amide 6 by the addition of a trans-vinylogous ester anion equivalent and facile construction of
the 16-membered macrolide skeleton of macrosphelides via an intramolecular nitrile oxide-olefin
cycloaddition. The syntheses of macrosphelides A and B were completed with a 30 and 20% overall
yield, respectively. This paper describes the details of our syntheses.
Introduction
From the first isolation4 and structural elucidation5 of
macrosphelides from a culture broth of the fungus Microsphaerop-
sis sp. FO-5050 by the Omura group4a and from the strain
Periconia byssoides separated from the sea hare Aplysia kurodai
by the Numata group,4c these marine polyketides have attracted
much interest from biologists because of their potent biological
activities.4,5 (+)-Macrosphelide A selectively prohibits the
adhesion of human leukemia HL-60 cells to human umbilical
vein endothelial cells (HUVEC) in a dose-dependent fashion
(IC50 3.5 µM).4a (+)-Macrosphelide A also exhibits oral
Naturally occurring macrolides continuously have been the
focus of potential sources of drug leads because of their unique
biological activities and structural features.1 However, the
enthalpic and entropic disadvantage of the macrocyclization
process has hampered the development of efficient synthetic
routes of biologically attractive natural macrolides and their
analogs. A variety of macrocyclization technologies such as
macrolactonization, ring-closing metathesis, and Pd(0)-catalyzed
cross-coupling have been studied,2 and these have been applied
to the syntheses of synthetically and biologically attractive
macrolides.3 However, the need for an efficient macrocyclization
process, which retains versatility and selectivity, still exists.
(4) (a) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.; Takamatsu, S.;
j
Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995, 48,
1435–1439. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Iraoka, H.; Natori,
j
M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95–98. (c) Numata, A.;
Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo, T.
Tetrahedron Lett. 1997, 38, 8215–8218. (d) Yamada, T.; Iritani, M.; Doi, M.;
Minoura, K.; Ito, T.; Numata, A. J. Chem. Soc., Perkin Trans. 1 2001, 3046–
3053. (e) Yamada, T.; Iritani, M.; Minoura, K.; Numata, A.; Kobayashi, Y.;
Wang, Y.-G. J. Antibiot. 2002, 55, 147–154.
† Seoul National University.
‡ Sungkyunkwan University.
(1) Dewick, P. M. Medicinal Natural Products, 2nd ed.; Wiley and Sons:
Sussex, U.K., 2001.
(5) (a) Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.; Hayashi, M.;
j
Komiyama, K.; Omura, S.; Sprengeler, P. A.; Smith, A. B., III J. Am. Chem.
(2) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006, 106 (3),
Soc. 1997, 119, 10247–10248. (b) Sunazuka, T.; Hirose, T.; Chikaraishi, N.;
911–939.
Harigaya, Y.; Hayashi, M.; Komiyama, K.; Sprengeler, P. A.; Smith, A. B., III;
j
(3) Kang, E. J.; Lee, E. Chem. ReV. 2005, 105 (12), 4348–4378.
Omura, S. Tetrahedron 2005, 61 (15), 3789–3803.
554 J. Org. Chem. 2009, 74, 554–561
10.1021/jo8016692 CCC: $40.75 2009 American Chemical Society
Published on Web 12/16/2008

Syntheses of (+)-Macrosphelides A and B
antitumor activity against lung metastasis of B16/BL6 melanoma
in mice (50 mg/kg).5 Importantly, no acute toxicity was
produced by the injection of macrosphelide A into BDF mice
intraperitoneally at 200 mg/kg for 5 days (Figure 1).4 In addition
to anticancer activity, it also has been reported that the
immunosuppressant activity of (+)-macrosphelide B is equally
potent to that of cyclosporin, which is currently used clinically.6
Because of their anticancer and immunosuppressant properties,
macrosphelides have been identified as a new lead target for
the development of novel anticancer drugs and immunomodu-
lators.7
readily available Weinreb amide 6. Employing this strategy,
concise synthesis of 2 via sequential MEM deprotection and
oxidation of the bis-protected acid 3 at the adequate stage
was anticipated.
SCHEME 1. Retrosynthesis of (+)-Macrosphelide A
FIGURE 1. Structures of (+)-macrosphelides A and B.
Our initial approach involved the addition of the trans-
vinylogous acyl anion, prepared from 7, to the corresponding
Weireb amide and the chelation-controlled reduction of the
resulting ketone. Thus, we commenced our syntheses with
the model study of the known Weinreb amide 916 (Scheme
2). Commercially available ethyl-(S)-lactate 8 was trans-
formed into Weinreb amide 9, which was subjected to the
key three-carbon homologation. Gratifyingly, the addition of
the vinyl anion prepared from 715 to the solution of 9 in Et2O
afforded the desired product 10 with a 90% yield. This one-
step procedure afforded the entire carbon architecture of the
key monomeric fragment 3. After examination of the
representative reduction conditions17-19 for the stereoselec-
tive ketone reduction of 10 with the latent ortho ester intact,
the chelation-controlled 1,2-anti reduction was adapted for
the requisite allylic alcohol 11.
From a chemical perspective, macrosphelides are attractive
because of their unique structural features.8-12 Macrosphelides
consist of a 16-membered macrolide skeleton with three ester
linkages connecting three fragments. Two of these fragments
possess similar carbon frameworks and oxidation states. These
unique structural features have prompted synthetic chemists to
focus on the development of efficient synthetic methodologies
for each fragment and for the macrocyclic ring closure.
Previously, we reported the formal synthesis of (+)-mac-
rosphelide A and the total synthesis of (+)-macrosphelide B.
The methodology that was reported employed an efficient
synthesis of the monomeric fragment by the direct addition of
a trans-vinylogous ester anion equivalent to the corresponding
carbonyl unit and an uncommon intramolecular nitrile oxide-
olefin cycloaddition for the final macrolactonization reaction.13
ThisprocessappearstobesuperiortoYamaguchilactonization8d,14
for labile cyclization precursors. The present report fully
describes our synthetic efforts toward the syntheses of (+)-
macrosphelides A and B.
SCHEME 2. Vinylogous Ester Anion Addition to a Weinreb
Amide
Results and Discussion
Retrosynthesis toward 1. Our synthetic plan toward 1 is
summarized in Scheme 1. First, we designed a unified strategy
toward (+)-macrosphelides A (1) and B (2) because of their
structural similarity. Therefore, we pursued the late-stage
differentiation. From this point of view, our strategy envis-
aged a synthetic efficiency, including assembling key frag-
ments 3, 4, and 5 through iterative esterification, followed
by final macrolactonization. Key monomeric fragments 3 and
4 would be prepared conveniently through three-carbon
homologation by addition of the trans-vinylogous acyl anion
precursor 7, which was developed by our group,15 to the
Initial reduction under Overman’s condition17 (LAH, Et2O,
-10 °C) afforded poor selectivity (1.5:1). Addition of LiI18 as
an additive elevated the diastereoselectivity slightly. However,
super hydride reduction of 10 in CH2Cl2 enhanced the facial
selectivity dramatically. This excellent facial selectivity is
supported by Faucher’s report.19
j
(6) Omura, S.; Komiyama, K. Immunosuppressants. PCT Int. Appl. WO
0147516 A1, 2001.
(7) For recent examples of medicinal research on marcosphelides, see: (a)
Ishihara, K.; Kawaguchi, T.; Matsuya, Y.; Sakurai, H.; Saiki, I.; Nemoto, H.
Eur. J. Org. Chem. 2004, 3973–3978. (b) Matsuya, Y.; Kawaguchi, T.; Nemoto,
H.; Nozaki, H.; Hamada, H. Heterocycles 2003, 59, 481–484. (c) Matsuya, Y.;
Kawaguchi, T.; Nemoto, H. Heterocycles 2003, 61, 39–43. (d) Matsuya, Y.;
Ishihara, K.; Funamori, N.; Kawaguchi, T.; Nemoto, H. Heterocycles 2003, 61,
59–63. (e) Matsuya, Y.; Nemoto, H. Heterocycles 2005, 65, 1741–1749. (f)
Matsuya, Y.; Kawaguchi, T.; Ishihara, K.; Ahmed, K.; Zhao, Q.-L.; Kondo, T.;
Nemoto, H. Org. Lett. 2006, 8, 4609–4612. (g) Wang, B.-L.; Jiang, Z.-X.; You,
Z.-W.; Qing, F.-L. Tetrahedron 2007, 63, 12671–12680.
Lactic acid 1320 with the selectively cleavable PMB protecting
group was transformed into Weinreb amide 6. Subjection of 6
to the trans-vinylogous ester anion addition afforded the addition
product 14 with a high yield. The diastereoselective reduction
of 14 under the established conditions from the model study
provided the 1,2-anti allylic alcohol 15 as a single detectable
diastereomer. Finally, hydrolysis of the ortho ester after MEM
J. Org. Chem. Vol. 74, No. 2, 2009 555

Paek et al.
TABLE 1. Chelation-Controlled Carbonyl Reduction
The structure of monomeric fragment 3 was confirmed as
outlined in Scheme 4. Esterification of 3 with allyl bromide
and oxidative cleavage of the PMB ether afforded homoallylic
alcohol 4 with a 74% yield over two steps. Alcohol protection
of 4, followed by allyl deprotection, gave known acid 165 in a
quantitative yield. The 1,2-anti diol 16 was identical to the
reported 16 in all aspects, including optical rotation. This
confirmation prompted us to complete the synthesis of 1 by the
coupling of 3 with intermediate 4 (Scheme 5).
entry
reagent
solvent
yield (%)
ratio (11:12)a
1
2
3
LAH
LAH, Lil
LiEt3BH
Et2O
Et2O
CH2Cl2
79
80
80
1.5:1
3:1
>20:1
a
1
Diastereomeric ratio was determined by H NMR.
Synthesis of 1 commenced with the coupling of fragments 3
and 4 (Scheme 5). Acid 3 and homoallylic alcohol 4 were
coupled by esterification under Keck conditions,21 and the PMB
ether was deprotected by DDQ to produce alcohol 18. Again,
esterification of acid 522 and alcohol 18 afforded trimeric ester
19 with a yield of 88%. Finally, PMB deprotection of 19,
protection of the secondary alcohol afforded the bis-protected
acid 3. This five-step sequence allowed us to secure a multigram
quantity of the common fragment 3, which was utilized for the
total syntheses of both (+)-macrosphelides A and B.
SCHEME 3. Preparation of Key Fragment 3
SCHEME 4. Structural Confirmation of Fragment 3
SCHEME 5. Formal Synthesis of (+)-Macrosphelide A
556 J. Org. Chem. Vol. 74, No. 2, 2009

Syntheses of (+)-Macrosphelides A and B
FIGURE 2. First synthetic plan for (+)-macrosphelide B.
followed by allyl ester cleavage in the presence of Pd(PPh3)4,
afforded the known seco acid 20 in a near quantitative yield.
The structure of seco acid 20 was confirmed by comparison of
its spectral data with that reported for compound 20.5
instead of Yamaguchi lactonization, which is known to induce
a partial racemization.8d Nitrile oxide 22 would readily be
prepared in situ from the intermediate obtained by esterification
of oxime ether 23 and key fragment 3.
Synthetic Study toward 2. After completion of the formal
synthesis of 1, we turned our attention toward the total synthesis
of 2 (Figure 2). The structural similarity of 1 and 2 envisioned
the utilization of fragment 3′ as a coupling partner for the
synthesis of 2, using the same strategy employed for the
synthesis of macrosphelide A. However, the highly electron-
deficient character as well as the free acid function of 3′
hampered this approach.23 Thus, an alternative route employing
a masked variant of the reactive γ-keto-R,ꢀ-unsaturated carbonyl
moiety was necessary.
SCHEME 6. Revised Synthetic Strategy for
(+)-Macrosphelide B
Revised Retrosynthesis toward 2. Because the instability
of the R,ꢀ-unsaturated γ-keto acid moiety rendered our initial
iterative approach toward 2 unsuccessful, we decided to expose
it at the late stage of our synthesis. Therefore, we chose an
isoxazoline unit as a suitable equivalent in terms of stability
and facile conversion to 2 (Scheme 6). The isoxazoline
intermediate 21 envisaged an efficient synthesis of (+)-
macrosphelide B (2) upon facile N-O bond cleavage24 of 21
and subsequent dehydration of the secondary alcohol at the final
stage. For isoxazoline 21, we planned to employ an intramo-
lecular nitrile oxide-olefin cycloaddition (INOC) because the
previous macrocyclic INOC executed by Asaoka and Kim25
provided the desired regioselectivity. The INOC enabled the
introduction of the masked γ-keto-R,ꢀ-unsaturated acid moiety
at the late stage and also constructed the core 16-membered
lactone skeleton of macrosphelide as the final ring closure
Preparation of INOC Precursor 29. Preparation of INOC
precursor 29 is described in Scheme 7. Known aldehyde 2426
was condensed with commercially available TBS-protected
hydroxylamine to give oxime ether 25. Although separation of
the E/Z mixture of 25 was possible by careful column chro-
matography on silica gel, it was directly used for the next step
because both isomers could be transformed into nitrile oxide
22. PMB deprotection of 25 and esterification of the resulting
alcohol with acid 5 followed by PMB removal of the resulting
ester 26 afforded a 59% yield of alcohol 23 in three steps.
Alcohol 23 was coupled with key fragment 3 under Yamaguchi
conditions to afford diester 27 with a 74% yield.27 Oxidative
cleavage of the PMB ether of 27 and subsequent acryloylation
of the resulting alcohol gave TBS oxime 28. Deprotection of
(8) (a) Kobayashi, Y.; Kumar, B. G.; Kurachi, T. Tetrahedron Lett. 2000,
41, 1559–1563. (b) Kobayashi, Y.; Kumar, G. B.; Kurachi, T.; Acharya, H. P.;
Yamazaki, T.; Kitazume, T. J. Org. Chem. 2001, 66, 2011–2018. (c) Kobayashi,
Y.; Acharya, H. P. Tetrahedron Lett. 2001, 42, 2817–2820. (d) Kobayashi, Y.;
Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381–4384.
J. Org. Chem. Vol. 74, No. 2, 2009 557

Paek et al.
SCHEME 7. Preparation of INOC Precursor 29
TABLE 2. Intramolecular Cycloaddition of Olefin and Nitrile
Oxide
substrate in the N-O bond cleavage, which lowered the overall
efficiency of our synthesis (Scheme 8). The low reaction
temperature improved the facial selectivity, although the chemi-
cal yield was not satisfactory (Table 2, entries 2-4). Cycload-
dition under reflux conditions did not work (Table 2, entry 5).
However, cycloaddition in 1,4-dioxane instead of THF (Table
2, entry 6) or benzene (Table 2, entry 7) afforded a high facial
selectivity as well as an excellent yield.
Structural assignments of the INOC adducts, 21-r and 21-ꢀ,
are outlined in Scheme 9. Major adduct 21-r was treated with
a catalytic amount of NaH in MeOH to give the methanolysis
product 30. The free hydroxyl group of 30 was removed by
tosylation and subsequent super hydride treatment, which also
reduced the methyl ester to give the primary alcohol 32. The
optical rotation of isoxazoline 32 was identical to that of
authentic 32,28 and this confirmed the absolute stereochemistry
of 12-C of major adduct 21-r. Stereochemical elucidation of
the new stereocenter seems interesting in terms of understanding
the INOC pattern for the macrocyclic ring closure of this unique
system. Furthermore, from the viewpoint of medicinal chemistry,
a variety of structural variants of macrosphelides could be
derived from these INOC intermediates.
entry
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
temperature (°C) ratio (21-r:21-ꢀ) yield (%)
1
2
3
4
5
6
7
8
rt
-78
66:33
96
-
no reaction
83: 17
83: 17
54: 46
88: 12
93: 17
91: 9
-30
-15
40
50
79
37
47
22
89
-15
benzene
1,4-dioxane
-15
rt
The plausible transition state of INOC for oxime 29 is
illustrated in Figure 3. Exposure of oxime 29 to NaOCl
produces the nitrile oxide 22 in situ, which undergoes [3 +
2] intramolecular nitrile oxide-olefin cycloaddition to pro-
oxime 28 under the buffered TBAF conditions provided requisite
free oxime 29 with the other labile functional groups intact in
a near quantitative yield.
Intramolecular Nitrile Oxide Cycloaddition (INOC). With
the desired free oxime 29 available, we investigated a variety
of conditions to produce the desired INOC adduct (Table 2).
Gratifyingly, use of NaOCl as an oxidant in CH2Cl2 at room
temperature afforded the INOC adducts as a mixture of 21-r
and 21-ꢀ with a 96% yield and without detection of the
undesired regioisomers. The facial selectivity was moderate (2:
1), and both diastereomers were separated by column chroma-
tography (Table 2, entry 1). Considering the ultimate disap-
pearance of the newly formed stereogenic center in our
synthesis, the moderate facial selectivity seems unimportant.
However, we improved the diastereoselectivity of the INOC
because we discovered that minor adduct 21-ꢀ was a poor
(9) (a) Ono, M.; Nakamura, H.; Konno, F.; Akita, H. Tetrahedron: Asymmetry
2000, 11, 2753–2764. (b) Nakamura, H.; Ono, M.; Shiba, Y.; Akita, H.
Tetrahedron: Asymmetry 2002, 13, 705–713. (c) Nakamura, H.; Ono, M.; Makino,
M.; Akita, H. Heterocycles 2002, 57, 327–336.
(10) Sharma, G. V. M.; Mouli, C. C. Tetrahedron Lett. 2002, 43, 9159–
9161.
(11) (a) Takahashi, T.; Kusaka, S.-i.; Doi, T.; Sunazuka, T.; Omura, S. Angew.
Chem., Int. Ed. 2003, 42, 5230–5234. (b) Kusaka, S.-I.; Dohi, S.; Doi, T.;
Takahashi, T. Tetrahedron Lett. 2003, 44, 8857–8859.
(12) (a) Matsuya, Y.; Kawaguchi, T.; Nemoto, H. Org. Lett. 2003, 5, 2939–
2941. (b) Kawaguchi, T.; Funamori, N.; Matsuya, Y.; Nemoto, H. J. Org. Chem.
2004, 69, 505–509.
(13) Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.; Jung, J.-W.; Lee, Y.-S.; Jung, J.-
K.; Suh, Y.-G. Org. Lett. 2005, 7, 3159–3162.
(14) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
558 J. Org. Chem. Vol. 74, No. 2, 2009

Syntheses of (+)-Macrosphelides A and B
SCHEME 8. Structural Confirmation of INOC Major Adduct 21-r
SCHEME 9. Completion of (+)-Macrosphelide B Synthesis
duce isoxazoline intermediates 21-r and 21-ꢀ. During the
cycloaddition of nitrile oxide and olefin, the R-face approach
of the acrylate moiety of 22 toward the nitrile oxide seems
to suffer a steric interaction between the two vinyl hydrogens
of the acrylate and the 15-H of the nitrile oxide. In contrast,
the ꢀ-face approach of the acrylate moiety creates a severe
steric repulsion of the vinyl hydrogens of the acrylate and
15-CH3 group of the nitrile oxide. This difference in the steric
repulsion of the two transition states seems to induce
production of 21-R as a favorable adduct, and this facial
selectivity is consistent with the previous report by Sh-
ishido.29
FIGURE 3. Transition state for INOC.
J. Org. Chem. Vol. 74, No. 2, 2009 559

Paek et al.
FIGURE 4. Energy-minimized transition states for INOC.
Further analysis of our proposed mechanism is in Figure 3.
Molecular modeling was conducted to generate transition state
geometries in the INOC. A conformational search of transition
state 22, performed by molecular dynamics using a simulated
annealing method, provided a conformer library containing more
than 500 conformations. From the conformer library of 22, the
structures that mimic the transition state for the attack from R
face and ꢀ face in the INOC were selected. The selected
structures were energy minimized, and these structures are in
Figure 4. As we anticipated, the transition state for the attack
from the R face was energetically more favorable than that from
the ꢀ face, when comparing energies and the distances between
the oxygen atom of the nitrile oxide and the vinyl carbon of
the acrylate moiety. These results support the experimental
results obtained with INOC, in which isomer 21-r was obtained
as the major product.
yield and the total synthesis of (+)-macrosphelide B through
13 linear steps with a 20% overall yield. The synthetic approach
used the efficient preparation of key fragments and the highly
convergent assembly of these fragments, including the 16-
membered ring formation by INOC from the highly labile
precursors. The key architecture of the monomeric fragment
involves the direct addition of the trans-vinylogous ester anion
to the corresponding Weinreb amide, followed by a chelation-
controlled stereoselective carbonyl reduction. In particular, the
INOC-induced ring closure for the synthesis of (+)-mac-
rosphelide B would be highly suitable for the versatile and
practical syntheses of macrosphelide analogs. Employing this
practical synthetic route, our intensive work on the mac-
rosphelide analogs with promising pharmacological properties
is currently in progress.
Completion of Synthesis toward 2. The mixture of INOC
adduct 21-r and 21-ꢀ was treated with Mo(CO)6 in wet CH3CN
to give the secondary alcohol 33 (Scheme 9). Spectral analysis
(13C NMR) confirmed the structure of 33, which consists of a
single diastereomer. Production of a single diastereomer is likely
due to the favorable reaction profile for 21-r compared to that
for 21-ꢀ.30 Dehydration of alcohol 33 afforded a known MEM-
protected (+)-macrosphelide B 34 with a yield of 81%, and
the final MEM deprotection of 3412 provided 2 in an excellent
yield. This synthetic (+)-macrosphelide B (2) exhibited spectral
data (1H NMR, 13C NMR, HR-MS, IR) and optical rotation
identical to those of the authentic natural product.
Experimental Section
Addition of the Vinylogous Ester Anion. (S,E)-4-(4-Methoxy-
benzyloxy)-1-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)pent-
1-en-3-one 14: To a solution of t-BuLi (1.5 M solution in pentane,
3.8 mL, 5.7 mmol) in Et2O (10 mL) at -78 °C was added a solution
of iodovinyl ortho ester 7 (810 mg, 2.9 mmol) in Et2O (10 mL).
After the mixture was stirred for 5 h at - 40 °C, a solution of
Weinreb amide 6 (170 mg, 0.70 mmol) in Et2O (10 mL) was added
at -78 °C. The reaction mixture was warmed to rt and stirred for
12 h, after which it was quenched with H2O. The reaction mixture
was extracted with EtOAc, and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (EtOAc/n-hexane/Et3N, 25:75:2) to afford 220 mg (90%) of
ketone 14 as a colorless oil: [R]D20 -3.75 (c 0.5, MeOH); 1H NMR
(CD3OD, 300 MHz) δ 7.19 (d, 2H, J ) 8.8 Hz), 6.82 (d, 2H, J )
8.8 Hz), 6.75 (d, 1H, J ) 15.7 Hz), 6.51 (d, 1H, J ) 15.9 Hz),
Conclusion
In summary, we achieved the formal synthesis of (+)-
macrosphelide A through 12 linear steps with a 30% overall
(23) Although Y. Kobayashi reported the synthesis of 3′, we couldn’t handle
that compound. This difference is thought to be derived from the highly labile
character of 3′. See ref 8.
(24) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni, D.
Synthesis 1987, 276–278.
(15) (a) Suh, Y.-G.; Seo, S.-Y.; Jung, J.-K.; Park, O.-H.; Jeon, L.-O.
Tetrahedron Lett. 2001, 42, 1691–1694. (b) Suh, Y.-G.; Jung, J.-K.; Seo, S.-Y.;
Min, K.-H.; Shin, D.-Y.; Lee, Y.-S.; Kim, S.-H.; Park, H.-J. J. Org. Chem. 2002,
67, 4127–4137.
(16) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994,
35, 9083–9086.
(17) Overman, L. E.; McCready, R. J. Tetrahedron Lett. 1982, 23, 2355–
2358.
(18) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988,
29, 5419–5422.
(19) Faucher, A.-M.; Brochu, C.; Landry, S. R.; Duchesne, I.; Hantos, S.;
Roy, A.; Myles, A.; Legault, C. Tetrahedron Lett. 1998, 39, 8425–8428.
(20) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4573–4576.
(25) (a) Asaoka, M.; Abe, M.; Mukata, T.; Takei, H. Chem. Lett. 1982, 11,
215–218. (b) Kim, D.; Lee, J.; Shim, P. J.; Doi, T.; Kim, S. J. Org. Chem.
2002, 67, 772–781.
(26) Maezaki, N.; Hirose, Y.; Tanaka, T. Org. Lett. 2004, 6, 2177–2180.
(27) Esterification under other various conditions such as EDCI-DMAP,
DCC-DMAP, or DCC-DMAP-CSA was unsuccessful.
(28) Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron
Lett. 1988, 29, 3555–3558.
(29) Irie, O.; Fujiwara, Y.; Nemoto, H.; Shishido, K. Tetrahedron Lett. 1996,
37, 9229–9232.
(21) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
(22) Eh, M.; Schomburg, D.; Schicht, K.; Kalesse, M. Tetrahedron 1995,
51, 8983–8992.
(30) When pure 21-ꢀ was transformed to 34, the two-step yield was 5-
10%. This may be a result from the reluctance of 21-ꢀ to bond with N-O
cleavage.
560 J. Org. Chem. Vol. 74, No. 2, 2009

Syntheses of (+)-Macrosphelides A and B
4.33 (dd, 2H, J ) 10.9, 24.0 Hz), 4.05 (q, 1H, J ) 7.0 Hz), 3.91
(s, 6H), 3.71 (s, 3H), 1.21 (d, 3H, J ) 7.0 Hz), 0.75 (s, 3H); 13C
NMR (CD3OD, 125 MHz) δ 203.6, 161.6, 140.9, 131.6 (2C), 128.3,
115.5, 107.6, 81.3, 74.6, 73.3, 56.4, 32.2, 18.6, 15.0; IR (neat) νmax
3744, 2877, 1701, 1649, 1512, 1461, 1324, 1247 cm-1; LRMS
(FAB) m/z 349 (M + H+); HRMS (FAB) calcd for C19H25O6 (M
+ H+) 349.1651, found 349.1657.
164.5, 157.4, 144.5, 125.1, 93.6, 78.1, 77.2, 77.1, 72.3, 71.5, 67.9,
67.4, 65.9, 59.0, 40.6, 40.4, 19.7, 17.4; IR (neat) νmax 2924, 1739,
1455, 1371, 1272, 1187, 1051, 852 cm-1; LRMS (EI) m/z 443 (M
+ Na+); HRMS (FAB) calcd for C20H30NO10 (M + H+) 444.1870,
20
1
found 444.1881. 21-ꢀ: [R]D -55.1 (c 1.16, CHCl3); H NMR
(CDCl3, 300 MHz) δ 6.67 (dd, 1H, J ) 7.8, 15.9 Hz), 5.99 (d, 1H,
J ) 15.9 Hz), 5.77 (q, 1H, J ) 6.9 Hz), 5.45-5.39 (m, 1H), 4.95
(dd, 1H, J ) 8.4, 12.2 Hz), 4.94 (dq, 1H, J ) 6.2, 9.3 Hz), 4.74
(dd, 2H, J ) 7.1, 16.1 Hz), 4.05 (t, 1H, J ) 8.7 Hz), 3.78-3.72
(m, 1H), 3.65-3.58 (m, 1H), 3.53-3.50 (m, 2H), 3.38-3.26 (m,
1H), 3.36 (s, 3H), 2.82 (dd, 1H, J ) 8.2, 17.5 Hz), 2.66-2.53 (m,
2H), 1.48 (d, 3H, J ) 6.7 Hz), 1.36 (d, 3H, J ) 6.2 Hz), 1.30 (d,
3H, J ) 6.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 169.6, 167.8,
164.0, 158.3, 145.3, 125.3, 93.8, 77.6, 76.4, 71.5, 71.4, 68.1, 67.4,
66.5, 58.9, 40.9, 39.0, 19.9, 19.1, 17.6; IR (neat) νmax 2925, 2854,
1742, 1455, 1374, 1252, 1192, 1104, 1051 cm-1; LRMS (FAB)
m/z 444 (M + H+); HRMS (FAB) calcd for C20H30NO10 (M +
H+) 444.1870, found 444.1854.
IntramolecularNitrileOxideCycloaddition.(2S,6S,11R,12S,15R)-
11-[(2-Methoxyethoxy)methoxy]-2,6,12-trimethyl-3,7,13,16-tetraoxa-
17-azabicyclo[13.2.1]octadeca-1(17),9-diene-4,8,14-trione 21-r and
(2S,6S,11R,12S,15S)-11-[(2-methoxyethoxy)methoxy]-2,6,12-tri-
methyl-3,7,13,16-tetraoxa-17-azabicyclo[13.2.1]octadeca-1(17),9-
diene-4,8,14-trione 21-ꢀ: To a solution of aldoxime 29 (3.0 mg,
6.7 µmol) in dioxane (1 mL) was added aqueous NaOCl (about
10%, 5 drops) at ambient temperature. The reaction mixture was
stirred for 10 min at the same temperature and diluted 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, 2:3 f 3:2) to afford 2.5 mg (83%) of
isoxazoline 21-r and 0.2 mg (6.6%) of isoxazoline 21-ꢀ as colorless
Acknowledgment. This research was supported by the Center
for Bioactive Molecular Hybrids, Yonsei University, and in part
by the Research Institute of Pharmaceutical Science, Seoul
National University.
20
1
oils. 21-r: [R]D -107.5 (c 0.8, CHCl3); H NMR (CDCl3, 400
MHz) δ 6.68 (dd, 1H, J ) 4.7, 15.7 Hz), 6.00 (d, 1H, J ) 15.7
Hz), 5.47 (q, 1H, J ) 6.5 Hz), 5.33-5.30 (m, 1H), 5.00 (dd, 1H,
J ) 7.5, 11.7 Hz), 4.89 (dq, 1H, J ) 4.0, 6.4 Hz), 4.69 (dd, 2H, J
) 7.0, 13.2 Hz), 4.21 (t, 1H, J ) 8.0 Hz), 3.78-3.73 (m, 1H),
3.64-3.59 (m, 1H), 3.55-3.51 (m, 2H), 3.37 (s, 3H), 3.22 (dd,
1H, J ) 11.9, 17.6 Hz), 3.07 (dd, 1H, J ) 7.5, 17.6 Hz), 2.69-2.59
(m, 2H), 1.56 (d, 3H, J ) 6.6 Hz), 1.42 (d, 3H, J ) 6.2 Hz), 1.33
(d, 3H, J ) 6.3 Hz); 13C NMR (CDCl3, 100 MHz) δ 170.3, 169.1,
Supporting Information Available: Experimental proce-
dures and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO8016692
J. Org. Chem. Vol. 74, No. 2, 2009 561