Total synthesis of methyl sarcophytoate, a marine natural biscembranoid

Article abstract of DOI:10.1021/jo802249k

(Chemical Equation Presented) The total synthesis of methyl sarcophytoate (1), a marine natural biscembranoid, has been achieved by the thermal Diels-Alder reaction between the 14-membered dienophile unit, methyl sarcoate (2), and the 14-membered diene unit 64. Methyl sarcoate (2) was prepared using n-BuLi-Bu₂Mg-mediated dithiane coupling, Kosugi-Migita-Stille coupling, and Grubbs ring-closing metathesis. The diene unit 64 was prepared using Sharpless asymmetric epoxidation, Grubbs ring-closing metathesis, 6-exo-tet epoxide opening, and n-BuLi-Bu₂Mg-mediated Ito-Kodama cyclization. The final Diels-Alder reaction between 2 and 64 proceeded with high site, endo/exo, π-face, and regioselectivities. During this reaction, partial E → Z isomerization at the C4 position was observed.

Full text of DOI:10.1021/jo802249k

Total Synthesis of Methyl Sarcophytoate, a Marine Natural
Biscembranoid
Takahiro Ichige, Yusuke Okano, Naoki Kanoh,† and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio UniVersity, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
msynktxa@applc.keio.ac.jp
ReceiVed October 8, 2008
The total synthesis of methyl sarcophytoate (1), a marine natural biscembranoid, has been achieved by
the thermal Diels-Alder reaction between the 14-membered dienophile unit, methyl sarcoate (2), and
the 14-membered diene unit 64. Methyl sarcoate (2) was prepared using n-BuLi-Bu2Mg-mediated dithiane
coupling, Kosugi-Migita-Stille coupling, and Grubbs ring-closing metathesis. The diene unit 64 was
prepared using Sharpless asymmetric epoxidation, Grubbs ring-closing metathesis, 6-exo-tet epoxide
opening, and n-BuLi-Bu2Mg-mediated Ito-Kodama cyclization. The final Diels-Alder reaction between
2 and 64 proceeded with high site, endo/exo, π-face, and regioselectivities. During this reaction, partial
E f Z isomerization at the C4 position was observed.
Introduction
cembranoids, there were no additional reports of isolating
biscembranoids for 10 years. However, from 2004 to 2008, 17
biscembranoids have been reported, i.e., nyalolide,6 methyl
tortuoates A and B,7 bisglaucumlides A (Figure 1), B (Figure
1), C, and D,8 ximaolides A-E,9 bislatumlides A and B,10
desacetylnyalolide,11 diepoxynyalolide,11 and dioxanyalolide.11
Thus, the biscembranoids are a growing family of marine natural
products.
Marine organisms produce diverse secondary metabolites
having unique biological activities and chemical structures.1
Biscembranoid (tetraterpenoid) natural products have been
isolated from several soft corals. In 1986, Su, Clardy, and their
co-workers isolated methyl isosartortuoate2 from the Chinese
soft coral Sarcophyton tortuosum as the first member of the
biscembranoids. Two years later, Su, Zheng, and their co-
workers isolated methyl sartortuoate3 from the same soft coral.
In 1990, the Kusumi-Kakisawa group isolated two biscem-
branoids (Figure 1), methyl sarcophytoate (1)4a and methyl
chlorosarcophytoate,4a from the Okinawan soft coral Sarcophy-
ton glaucum. In 1993, Bowden et al. isolated methyl neosar-
tortuate acetate5 (Figure 1) from the Australian soft coral
Sarcophyton tortuosum. After the isolation of these five bis-
The biscembranoids are considered to be biogenetically
synthesized by the Diels-Alder reaction between two different
(4) (a) Kusumi, T.; Igari, M.; Ishitsuka, M. O.; Ichikawa, A.; Itezono, Y.;
Nakayama, N.; Kakisawa, H. J. Org. Chem. 1990, 55, 6286–6289. (b) Ishitsuka,
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Schleyer, M.; Kashman, Y. J. Nat. Prod. 2004, 67, 1303–1308.
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Y.-J.; Yang, X.-P. J. Nat. Prod. 2004, 67, 1915–1918.
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Hou, D.-X.; Fujii, M.; Doe, M.; Morimoto, Y.; Takemura, K. J. Nat. Prod. 2006,
69, 1130–1133.
† Present address: Graduate School of Pharmaceutical Sciences, Tohoku
University, Aobayama, Sendai 980-8578, Japan.
(1) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35–94, and the corresponding previous
reviews.
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Soc. 1986, 108, 177–178.
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Y. Sci. Sin., Ser. B 1988, 31, 1172–1184.
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Cimino, G. J. Nat. Prod. 2007, 70, 1158–1166.
230 J. Org. Chem. 2009, 74, 230–243
10.1021/jo802249k CCC: $40.75 2009 American Chemical Society
Published on Web 11/16/2008

Total Synthesis of Methyl Sarcophytoate
FIGURE 1. Biscembranoids built from methyl sarcoate (2) as a dienophile unit, the isolated dienophile units, and the sole-isolated diene unit of
biscembranoids.
SCHEME 1. Hypothetical Biosynthesis of Methyl
Sarcophytoate (1)
the diene unit has been isolated only from the soft coral which
produces methyl neosartortuate acetate5 (Figure 1).
Structurally, the biscembranoids are categorized into three
groups depending on the dienophile unit: methyl sarcoate
(including its double-bond isomers),4a,5,8 methyl tortuosoate
(methyl tetrahydrosarcoate, including slightly different
derivatives),2,3,6,7,9,11 and isosarcophytonolide D (including its
double-bond isomer).10 Among the 22 isolated biscembranoids,
20 compounds, except for the isosarcophytonolide D group,10
have the same configuration in the cyclohexene junction,
probably derived via the CO2Me-endo transition state in the
biosynthetic Diels-Alder reaction shown in Scheme 2. The
structures and relative stereochemistry of the biscembranoids
were determined by spectroscopic methods, including X-ray
crystallographic analysis; however, the absolute configuration
has been elucidated only in the cases of methyl sarcophytoate
(1)4c and the bisglaucumlides8 on the basis of the differences
in the CD spectra.
Besides the intriguing chemical structures, several biological
activities have been reported, including cytotoxicity against
several cancer cell lines,4a,6-8,10 antimicrobial activity against
Escherichia coli,11 lethal toxicity against the brine shrimp
Artemia salina,11 and in vivo effects on mice and rats.3
The structural complexity of the biscembranoids, in conjunc-
tion with their biogenetic hypothesis, first captured our attention
in the early 1990s and has since led to the asymmetric syntheses
of the diene unit 312a,b and the dienophile unit 2 (methyl
sarcoate)12cof methyl sarcophytoate (1) (Scheme 1). It is
reasonable to conclude that our asymmetric synthesis of 212c
revealed the absolute configuration of not only 2 but also 1.4
Armed with these experiences, we have recently accomplished
cembranes: the 14-membered dienophile and diene units [Scheme
1, example of methyl sarcophytoate (1)]. Evidence for such a
biogenetic hypothesis is the isolation of the dienophile unit from
the original coral; i.e., methyl sarcoate (2),4b,5 methyl tortuo-
soate9 (methyl tetrahydrosarcoate),11 and isosarcophytonolide
D10 have been isolated along with their biscembranoids (Figure
1). In contrast, probably because of its highly reactive nature,
J. Org. Chem. Vol. 74, No. 1, 2009 231

Ichige et al.
in the presence of a catalytic amount of DMF,16 was treated
SCHEME 2. Configuration of the Biscembranoid
Cyclohexene Core
with (3-methyloxetan-3-yl)methanol17 to give oxetane ester 13
17
in 92% yield from 10. Treatment of 13 with BF3 ·OEt2
afforded ortho ester 14 in 61% yield. Allylic bromination of 14
with NBS and benzoic peroxide (BPO) in benzene afforded the
desired allyl bromide 7 in 75% yield.
Synthesis of the C10-C13 Dithiane Segment 8. The
synthesis of the C10-C13 dithiane segment 8 commenced with
the Asami-Mukaiyama chiral aminal 1118 (Scheme 5). Cu(I)-
catalyzed 1,4-addition of i-PrMgCl to 11 followed by acidic
hydrolysis of the aminal function afforded the chiral aldehyde
1518 in 60% yield. At this stage, the optical purity and the
absolute configuration of 15 were firmly determined as follows
(Scheme 6). Pentenylation of 15 by the Wipf method19 using
1-pentyne, Cp2Zr(H)Cl, and Me2Zn gave a 4:1 inseparable
mixture of lactone 17. The mixture of 17 was reduced with
LiAlH4, and the resulting diol was selectively silylated with
TBSCl and imidazole to afford a separable mixture of 18a and
18b. The major isomer 18a was transformed into Mosher esters
19a and 19b. At this stage, the modified Mosher ester analysis20
shown in Scheme 6 revealed the optical purity of these
compounds to be >95% and the absolute configuration of the
hydroxy-substituted carbon of 19a and 19b to be R. In addition,
the relative configuration of both diastereomers of 17 was
determined by the transformation to the known separable
lactones 20a (major)21 and 20b (minor)22 by ozonolysis followed
by NaBH4 reduction. Taken together, these results established
the optical purity and the absolute configuration of 15 to be
>95% and S, respectively.
the biogenesis-inspired and to date only13 asymmetric total
synthesis of methyl sarcophytoate (1).14 It has been of great
interest to us whether the biscembranoids are biogenetically
synthesized by the enzymatic Diels-Alder reaction.15 Therefore,
we planned the total synthesis of 1 featuring the intermolecular
Diels-Alder reaction between the diene and dienophile units.
In this article, we describe this program in detail.
Results and Discussion
Dithioacetalization of 15 with 1,3-propanedithiol in the
presence of BF3 ·OEt2 gave 16 in 75% yield (Scheme 5), which
was reduced with LiAlH4 (96% yield), and the resulting alcohol
was silylated with TBSCl and imidazole to afford the desired
dithiane 8 in 97% yield.
Retrosynthetic Analysis of Methyl Sarcoate (2). Scheme
3 outlines the synthetic plan of methyl sarcoate (2). We
anticipated that the final step would be realized by the Grubbs
ring-closing metathesis (RCM) between the C8 and C9 positions.
The precursor 4 would be obtained by the Kosugi-Migita-Stille
coupling between the C1-C3, C9-C14 acid chloride 5 and the
C4-C8 vinyl stannane 6. Acid chloride 5 was dissected at
the C13-C14 bond into the C1-C3, C14 allyl bromide 7 and
the C10-C13 dithiane 8, featuring the dithiane coupling
followed by the elongation at the C10 position using the
Grignard reagent 9. Allyl bromide 7 would be derived from
mesaconic acid (10) via Corey ortho ester formation. We
selected the Asami-Mukaiyama aminal 11 as the starting
material for the synthesis of dithiane 8, which has the only chiral
center found in methyl sarcoate (2). Vinyl stannane 6 would be
obtained from 4-pentyn-1-ol (12) via Negishi carbometalation.
Synthesis of the C1-C3, C14 Allyl Bromide Segment 7.
A key functionality of this segment is its ortho ester, which
was constructed using Corey’s method (Scheme 4). Acid
chloride, derived from mesaconic acid (10) and oxalyl chloride
Synthesis of the C4-C8 Vinyl Stannane Segment 6.
Negishi methyl alumination23 of 4-pentyn-1-ol (12) with
Cp2ZrCl2 and Me3Al in ClCH2CH2Cl followed by iodination
with I2 gave vinyl iodide 21 in 90% yield (Scheme 7). Lithiation
of 21 with 2.4 equiv of n-BuLi followed by treatment with 2.4
equiv of n-Bu3SnCl gave vinyl stannane 22 in 72% yield.
Oxidation of 22 with tetrapropylammonium perruthenate
(TPAP)24 and NMO (81% yield) followed by Wittig methyl-
enation gave the desired vinyl stannane 6 in 91% yield.
Dithiane Coupling between Segments 7 and 8. Prior to the
first crucial coupling between allyl bromide 7 and dithiane 8,
we investigated the metalation of dithiane 8 as shown in Table
1. Initial attempts using n-BuLi as a base were unsatisfactory.
When n-BuLi (1.2 equiv) was added at rt to a solution of 8
(1.0 equiv) in THF and the resulting anion lifetime was analyzed
(10) Yan, X.-H.; Gavagnin, M.; Cimino, G.; Guo, Y.-W. Tetrahedron Lett.
2007, 48, 5313–5316.
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(12) (a) Yasuda, M.; Ide, M.; Matsumoto, Y.; Nakata, M. Synlett 1997, 899–
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1998, 71, 1417–1429. (c) Ichige, T.; Kamimura, S.; Mayumi, K.; Sakamoto, Y.;
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Xu, X. Tetrahedron Lett. 2000, 41, 4641–4644. (b) Gao, Y.; Nan, F.; Xu, X.
Tetrahedron Lett. 2000, 41, 4811–4813. (c) Hong, Z.; Chen, X.; Xu, X.
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1991, 113, 4092–4096.
(21) Enantiomer of 20a: Blazis, V. J.; Hawkins, E. S.; Baker, D. C.
Carbohydr. Res. 1994, 253, 225–233.
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232 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of Methyl Sarcophytoate
SCHEME 3. Retrosynthetic Analysis of Methyl Sarcoate (2)
SCHEME 4. Synthesis of the C1-C3, C14 Segment 7
SCHEME 6. Structure Determination of Aldehyde 15a
SCHEME 5. Synthesis of the C10-C13 Segment 8
by D2O quenching, the percentage of deuterium incorporation
(% D) decreased from 55 (after 2 min) to 48 (after 5 min) and
to 29 (after 15 min) (Table 1, entries 1-3). To improve the
anion generating conditions, a premixed reagent of n-BuLi-
Bu2Mg then was utilized. We have previously demonstrated that
the n-BuLi-Bu2Mg-mediated Ito-Kodama cyclization was one
of the key steps for the synthesis of the diene unit 3.12a,b In
addition, we also have demonstrated that dithiane anions
generated by the n-BuLi-Bu2Mg-mixed organometallic reagent
are long-lived and maintain a good nucleophilicity.25 Indeed,
when the premixed organometallic reagent prepared from 1.2
equiv of n-BuLi and 0.3 equiv of Bu2Mg was used for lithiation,
the % D value stayed at a high level (67%), even the resulting
anion was quenched after 1 h (Table 1, entries 4-7).
Encouraged by this experiment, we treated 2.0 equiv of
dithiane 8 in THF with 2.4 equiv of n-BuLi and 0.6 equiv of
Bu2Mg at rt for 0.5 h. To this mixture was added at -78 °C
1.0 equiv of allyl bromide 7, and the resulting solution was
gradually warmed to 0 °C over a period of 1.5 h, giving the
coupling product 23 in 56% reproducible yield (Scheme 8). In
contrast, when the metalation was conducted with only n-BuLi,
the coupling yield was less than 30% without reproducibility.
We believe that this example will broaden the synthetic
usefulness of the n-BuLi-Bu2Mg-mediated dithiane coupling.26,27
Instead of ortho ester 7, each dimethyl, diethyl, and di-t-butyl
(25) (a) Ide, M.; Yasuda, M.; Nakata, M. Synlett 1998, 936–938. (b) Ide,
M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491–2499.
J. Org. Chem. Vol. 74, No. 1, 2009 233

Ichige et al.
SCHEME 7. Synthesis of the C4-C8 Segment 6
1.0 equiv of n-BuLi and 3.0 equiv of (COCl)2, which was
subjected to Kosugi-Migita-Stille coupling. The relevant
results of this coupling are listed in Table 2. When a mixture
of 1.0 equiv of 5 and 2.0 equiv of 6 in the presence of a catalytic
30
amount of Pd(PPh3)4 was heated at 50 °C under an argon
atmosphere, only the decarbonylative coupling product 28 was
obtained in 28% yield (Table 2, entry 1). To suppress this
decarbonylation, the reaction was conducted under an atmo-
spheric pressure of CO;31 however, no improvement was
observed (Table 2, entry 2). Next, we used a highly active Pd(0)
catalyst prepared from 1:1 Pd(OAc)2/n-Bu3P32 (Table 2, entries
3-6). In THF, under a CO atmosphere, the coupling reaction
proceeded at rt to afford the desired product 4SS in 30% yield
(Table 2, entry 3). Without CO, a trace amount of 28
accompanied the desired product (Table 2, entry 4). When less
polar toluene was used as a solvent, the reaction proceeded
within 3 h, and the yield of 4SS was 43% (Table 2, entry 5).
Finally, it was found that benzene was the best solvent, affording
4SS in 71% yield within 1 h (Table 2, entry 6).
TABLE 1. Generation and Lifetime of the Dithiane Anion of 8
entry
base
n-BuLi
n-BuLi
n-BuLi
time (min)
% Da
Ring-Closing Metathesis: Final Stage for Total Synthesis
12c
1
2
3
4
5
6
7
2
5
15
5
15
30
60
55
48
29
52
61
70
67
of Methyl Sarcoate (2).
The total synthesis of methyl
sarcoate (2) reached the final stage, which was ring-closing
metathesis. Initially, we attempted RCM using dithiane 4SS and
15 mol % of the Grubbs second-generation catalyst 2933 in
CH2Cl2 at 40 °C for 12 h (Scheme 10). However, these
conditions failed to generate the desired macrocycle 30; instead,
dimer 31 was obtained in 38% yield as a mixture of the
stereoisomers together with 58% yield of the recovered starting
material 4SS. Instead of CH2Cl2, toluene was used, and the
reaction was conducted at 100 °C for 6 h, resulting in failure
(19% of 31 and 64% of 4SS). We speculated that this unfavorable
result came from the restricted conformation of 4SS because of
the dithiane group. On the basis of this analysis, the dithiane
group in 4SS was transformed into the carbonyl group by our
recently reported method,34 which was oxidative dedithioac-
etalization using NaClO2 and NaH2PO4, affording 4O in 70%
yield (Scheme 11). The results of RCM of 4O are listed in Table
3. Under the catalytic (15 mol %) conditions in CH2Cl2 or
toluene, dimer 32 was obtained as the major product; however,
it was found that a trace amount of methyl sarcoate (2) existed
(Table 3, entry 1 or 2). When a stoichiometric amount of the
Grubbs catalyst 29 was used in CH2Cl2 at 40 °C for 20 h, the
yield of 2 increased to 13%, but dimer 32 was still the major
product (Table 3, entry 3). Finally, methyl sarcoate (2) was
obtained in 43% yield under the conditions of toluene, 100 °C,
and 0.5 h (Table 3, entry 4). The synthetic methyl sarcoate (2)
was identical (1H NMR, 13C NMR, and CD spectra) to the
natural methyl sarcoate (2).4b
n-BuLi-Bu2Mgb
n-BuLi-Bu2Mgb
n-BuLi-Bu2Mgb
n-BuLi-Bu2Mgb
a Deuterium incorporation determined by 1H NMR analysis of the
crude products. b n-BuLi in hexane and Bu2Mg in heptane (Aldrich)
were mixed before addition to 8 in THF.
ester was used for this coupling; however, only a complex
mixture was obtained.
Ortho ester 23 then was subjected to the acid conditions
achieving the deprotection of the TBS group and the partial
hydrolysis of the ortho ester, and the subsequent alkaline
hydrolysis afforded carboxylic acid, which was treated with
diazomethane to afford dimethyl ester 24 in 84% yield from
23. Oxidation of 24 with o-iodoxybenzoic acid (IBX)28 gave
aldehyde 25 in 97% yield, which was successively subjected
to coupling with vinyl Grignard reagent 9 and IBX oxidation,
generating 26 in 62% yield. For the sake of introducing the
C4-C8 portion into this segment, selective hydrolysis of one
of the two methyl esters in 26 was needed. Probably because
of a steric reason, the less-hindered methyl ester in 26 was
hydrolyzed using 2.0 equiv of LiOH in a 2:1 THF/H2O mixture
selectively producing carboxylic acid 27 in 78% yield. The
structure of 27 was confirmed by HMBC NMR analysis.
Kosugi-Migita-Stille Coupling between Segments 5
and 6. The next crucial step was Kosugi-Migita-Stille
coupling29 of the C1-C3, C9-C14 acid chloride 5 (derived
from 27) with the C4-C8 vinyl stannane 6 (Scheme 9).
Carboxylic acid 27 was transformed into acid chloride 5 with
The success of the asymmetric synthesis of 212c revealed the
absolute configuration not only of 2 but also of methyl
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234 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of Methyl Sarcophytoate
SCHEME 8. Dithiane Coupling and the Grignard Reaction
SCHEME 9. Kosugi-Migita-Stille Coupling between 5 and 6
37 would be constructed efficiently by RCM of the diene
obtained by condensation of the optically active allyl alcohol
39 and the C28-C30 carboxylic acid 40. Allyl alcohol 39 could
be derived from geraniol (41) via SAE.
Synthesis of Aldehyde 36. Geraniol (41) was treated with
PMBCl and NaH in DMF, and the resulting PMB ether was
subjected to SeO2 oxidation35 to afford alcohol 4236 in 41%
overall yield (Scheme 13). SAE37 of 42 afforded epoxy alcohol
43 in 75% yield. Treatment of 43 with iodine, triphenylphos-
phine, and imidazole provided epoxy iodide 44 (79% yield),
which was treated with n-BuLi in THF to give allyl alcohol
39a in 98% yield. Allyl alcohol 39a could be directly obtained
from 43 in 81% yield by treatment of the intermediate iodide
with water38 in one pot. The enantiomeric excess (94% ee) and
absolute configuration (S) of 39a, and hence 43, were determined
by the modified Mosher ester analysis20 using Mosher esters
39S and 39R shown in Scheme 13. To improve the % ee, 39a
was subjected to kinetic resolution conditions,37 giving 39b in
88% yield with >98% ee. Condensation of the resulting 39b
with vinylacetic acid (40) by DCC in the presence of a catalytic
amount of DMAP gave 45 in 97% yield, which was subjected
to RCM using Grubbs reagent 29,33 affording lactone 37 in 74%
yield. As anticipated, this RCM reaction effectively constructed
the C27-C28 Z-olefin. Reduction of 37 with DIBALH afforded
lactol, which was subjected to the Wittig reaction with 38 (94%
yield from 37), silylation with triethylsilyl chloride (TESCl),
and DIBALH reduction to give allyl alcohol 46 in 90% two-
step yield. SAE of 46 provided epoxy alcohol 47 (>95% de)
in 92% yield, which was oxidized with SO3-pyridine and DMSO
to afford epoxy aldehyde 36 in 99% yield.
sarcophytoate (1).4 Aiming at confirming the biogenesis-inspired
Diels-Alder reaction, we continued our experiment.
Previous Synthesis of the Diene Unit 3. Our previous first-
generation synthesis of the diene unit 3 demonstrated that all
of the carbon skeleton of 3 was derived only from geraniol
(Figure 2).12a,b Although this was a unique synthesis, some
unsatisfactory stereo- and regioselectivities in the dihydropyran
formation steps led to a low overall yield (Figure 2). Therefore,
the refinement on the dihydropyran formation steps was our
first concern.
Retrosynthetic Analysis of the New Synthesis of the
Diene Unit 3. Scheme 12 reveals a plan for the new synthesis
of the diene unit 3. We adopted the previous route as the final
stage of the synthesis of 3, i.e., the modified Ito-Kodama
cyclization between the C21-C34 bond and the triene formation
from epoxy allyl sulfide 33.12a,b This cyclization precursor 33
would be derived from olefin 34 or 35 by epoxidation at the
C34-C35 double bond. To definitely construct the dihydropyran
ring in 34 or 35, we selected the 6-exo-tet opening of the
C30-C31 epoxide by the C26-hydroxy group, which led to
epoxy aldehyde 36, following dissection of the C32-C33 bond.
Epoxy aldehyde 36 would be secured from ꢀ,γ-unsaturated
δ-lactone 37 by the Wittig reaction using the C31-C32 Wittig
reagent 38 followed by Sharpless asymmetric epoxidation
(SAE). We anticipated that the crucial C27-C28 Z-olefin in
Second-Generation Synthesis of Epoxy Allyl Sulfide 33.
To introduce the C32-hydroxy group with the correct config-
uration, epoxy aldehyde 36 was subjected to Brown asymmetric
allylation39 using allylmagnesium bromide and (-)-B-chloro-
diisopinocampheylborane [(-)-DIPCl], giving the desired al-
cohol 48a and its epimer 48b in 83 and 10% yields, respectively
(35) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526–
5528.
(36) Zhang, T.; Li, Y.; Peng, L. Z.; Liu, H. W.; Mei, T. S.; Li, Y. L. Chin.
Chem. Lett. 2004, 15, 141–142.
(37) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(38) (a) Dorta, R. L.; Rodr´ıguez, M. S.; Salazar, J. A.; Sua´rez, E. Tetrahedron
Lett. 1997, 38, 4675–4678. (b) Liu, Z.; Lan, J.; Li, Y. Tetrahedron: Asymmetry
1998, 9, 3755–3762.
J. Org. Chem. Vol. 74, No. 1, 2009 235

Ichige et al.
TABLE 2. Kosugi-Migita-Stille Coupling between 5 and 6
entry
catalyst
Pd(PPh3)4
solvent
atmosphere
temp (°C)
time (h)
yield (%) of 4SS
yield (%) of 28
1
2
3
4
5
6
THF
THF
THF
THF
toluene
benzene
Ar
50
50
rt
rt
rt
36
16
12
12
3
0
0
30
36
43
71
28
27
0
trace
0
Pd(PPh3)4
CO
CO
Ar
CO
CO
1:1 Pd(OAc)2:n-Bu3P
1:1 Pd(OAc)2:n-Bu3P
1:1 Pd(OAc)2:n-Bu3P
1:1 Pd(OAc)2:n-Bu3P
rt
1
0
SCHEME 10. Ring-Closing Metathesis of 4SS
acetonide 50 in 97% yield. The stereochemistry at the C32
position and the trans dihydropyran configuration were con-
firmed at this stage by NOE measurements (Scheme 14).
Conversion of the terminal vinyl group to the 2-methylpropenyl
group was realized by treatment of 50 with Grubbs catalyst 29
in 2-methyl-2-butene, providing 34 in 78% yield. According to
our first-generation synthesis,12a,b regioselective epoxidation of
34 with m-CPBA in CH2Cl2 afforded a 2:1 inseparable mixture
of diastereomers 51a (ꢀ epoxide) and 51b (R epoxide) in 34%
yield along with the recovered 34 (45%). This mixture 51a,b
was further transformed into the cyclization precursor 33a,b
by PMB deprotection with DDQ (81% yield) followed by
phenylsulfidation with diphenyl disulfide and n-Bu3P (91%
yield). The resulting 33a,b was identical to our previous sample
of 33a,b in all respects.12a,b The overall yield of 33a,b from
geraniol (41) in this second-generation route was about 5 times
greater than that of the first-generation route.12a,b We learned
in our previous synthesis12a,b that the C34-C35 ꢀ-epoxide 33a
is much more desirable than R epoxide 33b for the later stage.
Hence, to obtain only ꢀ epoxide 33a, we investigated the third-
generation synthesis starting from epoxy aldehyde 36.
SCHEME 11. Ring-Closing Metathesis of 4O to Give Methyl
Sarcoate (2)
Third-Generation Synthesis of Epoxy Allyl Sulfide 33. The
anion derived from tert-butyl acetate and LDA was added to
epoxy aldehyde 36 to afford alcohols 52a and 52b in 63 and
27% yields, respectively (Scheme 15). The structure of these
alcohols was confirmed as follows. Each 52a and 52b was
treated with TBAF, and the resulting diol was subjected to the
(i-PrO)4Ti-mediated 6-exo-tet epoxide opening to give dihy-
dropyran, which was acetonized with 2,2-dimethoxypropane and
PPTS to afford 53. The NOE measurement of 53a and 53b
shown in Scheme 15 revealed their stereochemistries. The
undesired 52b could be converted into the desired 52a by
Dess-Martin periodinane (DMP) oxidation (97% yield) and
NaBH4 reduction (52a, 64%; 52b, 26%).
TABLE 3. Ring-Closing Metathesis of 4O
29
temp time yield (%) yield (%) recovered
entry solvent (mol %) (°C) (h)
of 2
of 32
(%) 4O
1
2
3
4
CH2Cl2
toluene
CH2Cl2
toluene
15
15
100
100
40 24
100 12
40 20
trace
trace
13
32
24
27
0
58
54
trace
0
100
0.5
43
(Scheme 14). The 6-exo-tet opening of the epoxide function in
48a was first realized using camphorsulfonic acid (CSA) in
CH2Cl2 at rt to give diol 49 in 65% yield. In contrast, treatment
of 48a with BF3 ·OEt2 in MeOH40 afforded 49 in 89% yield.
Acetonization of 49 with 2,2-dimethoxypropane and PPTS gave
FIGURE 2. Inconvenient steps in our previous first-generation synthesis
of the diene unit 3.
236 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of Methyl Sarcophytoate
SCHEME 12. Retrosynthetic Analysis of the New Synthesis of the Diene Unit 3
SCHEME 13. Synthesis of Aldehyde 36
Silylation of 52a with TESCl (97% yield) followed by
DIBALH reduction of the resulting 54 afforded aldehyde 55 in
75% yield (Scheme 16). Wittig elongation of 55 with 38 gave
56 in 96% yield, which was reduced with DIBALH, furnishing
allyl alcohol 57 in 94% yield. The 6-exo-tet cyclization using
BF3 ·OEt2 in MeOH40 (97% yield) followed by acetonization
of the resulting 58 gave allyl alcohol 35 in 91% yield. To secure
the desired ꢀ epoxide, allyl alcohol 35 was subjected to SAE37
to expectedly furnish only ꢀ epoxide 59 in 95% yield.
Deoxygenation of 59 was realized via iodination (93% yield)
followed by NaBH3CN reduction41 (73% yield) of the resulting
iodide 60 affording 51a, which was further converted into the
cyclization precursor 33a, as described above (Scheme 14) by
deprotection of the PMB ether (89% yield) followed by
(39) (a) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432–439. (b) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org.
Chem. 1989, 54, 1570–1576.
(40) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3, 333–336.
(41) Hutchins, R. O.; Kandasamy, D.; Maryanoff, C. A.; Masilamani, D.;
Maryanoff, B. E. J. Org. Chem. 1977, 42, 82–91.
J. Org. Chem. Vol. 74, No. 1, 2009 237

Ichige et al.
SCHEME 14. Second-Generation Synthesis of Epoxy Allyl Sulfide 33
SCHEME 15. Aldol Reaction of 36
phenylsulfidation (89% yield). As compared to the first-
generation route,12a,b an improved overall yield by about 10
times was secured by this third-generation route.
the intermolecular Diels-Alder reaction between the 14-
membered dienophile unit 65 and diene unit 66.42 Under the
thermal conditions in toluene at 110 °C, all four possible adducts
67-70 were obtained in a ratio of 4.5:2.1:1.6:1.0, among which
the CO2Me-endo adduct 67, having the same cyclohexene
configuration as the natural biscembranoids, was the major
product. In contrast, under the Et2AlCl-promoted conditions,
the CO2Me-endo adduct 68 and the CO-endo adduct 70 were
obtained in the ratio of 2.5-20:1 depending on the amount of
Et2AlCl used. According to these model studies, we investigated
the Diels-Alder reaction in the real system.
Synthesis of the Diene Unit 64. According to the procedure
described for the first-generation route,12a,b epoxy allyl sulfide
33a was transformed into the diene unit 64 by the following
four-step sequence (Scheme 17): (1) n-BuLi-Bu2Mg-mediated
cyclization (33a f 62), (2) oxidation of sulfide, (3) syn
ꢀ-elimination (62 f 63), and (4) dehydration (63 f 64).
Although 64 could be converted into the intact diene unit 3,12a,b
we chose 64 as the diene unit for the final Diels-Alder reaction
because of the high instability of 3.
Diels-Alder Reaction between 2 and 64 and End
Game. The results of the Diels-Alder reaction between methyl
Model Diels-Alder Reaction of the 14-Membered
Dienophile and Diene Pair. We have previously investigated
238 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of Methyl Sarcophytoate
SCHEME 16. Third-Generation Synthesis of Epoxy Allyl Sulfide 33a
SCHEME 17. Synthesis of the Diene Unit 64
the latter was confirmed by NOE and HMBC analyses.
Similarly, 71 gave a 70:30 mixture of 71:72, and 72 gave a
74:26 mixture of 72:71 after 1.5 days (Scheme 20). These facts
indicate that the isomerization during Diels-Alder reaction
occurred both in the starting material and in the products. In
addition, the 4Z-adduct 72 could be converted into the desired
adduct 71 by treatment of 72 with AcOH at rt for 6.5 days in
45% yield (72:71 ) 52:48). Therefore, the total isolated yield
of 71 amounted to 34%. Interestingly, the recently isolated
bisglaucumlides C and D have the Z-configuration at the C4-
position.8
Finally, the acetonide group in 71 was deprotected with
aqueous AcOH to afford methyl sarcophytoate (1) in 50% yield
(Scheme 20). The spectral data of the synthetic sample were
identical to those of the natural one.4a
It is noteworthy that this Diels-Alder reaction proceeded with
high site, endo/exo, π-face, and regioselectivities except for the
E f Z isomerization at the C4-position. Plausible explanations
for these selectivities are as follows. The C1-C2 doubly
activated (by both the ketone and ester groups) double bond in
2 is more reactive than the C4-C5 and C8-C9 double bonds.
The C34-C21 and C22-C23 double bonds in 64 do not
have the s-cis conformation because of the steric repulsion
between the 38-methyl and 33-methylene groups. Although the
planar figures are depicted as such a structure, it is for the sake
of simplicity. In contrast, the C21-C34 and C35-C36 double
bonds easily reside in the s-cis conformation under the given
reaction conditions. Hence, the desired site-selective Diels-Alder
reaction would occur. The CO2Me-endo transition states are
more favorable than the CO-endo (and/or CO2Me-exo) transition
states because both reactants in the latter reside in a more
crowded position, i.e., the reactants overlap each other. In order
to account for the π-face and regioselectivities, the solution
conformations of 2 and 64 in toluene-d8 at 50 °C were
investigated by 1H NMR analysis. The representative NOEs and
coupling constants are depicted in Figure 4. The upper region
of the π-face in the dienophile unit 2 is shielded by the
C11-C13 portion; therefore, the lower region in 2 is a reactive
face. In the case of the diene unit 64, the π-face and
regioselectivities are a delicate issue. Two possible transition
states, TS A and TS B, are depicted in Figure 5. The only
significant difference between the two transition states is the
40-methyl group which probably makes TS B more crowded
sarcoate (2) and the diene unit 64 were compiled in Table 4. A
mixture of 2 (1.0 equiv) and 64 (1.0 equiv) was stored in toluene
at 25 °C for 4 days, resulting in no reaction (Table 4, entry 1).
At 60 °C, only a gradual decomposition of 64 occurred (Table
4, entry 2). Gratifyingly, at 100 °C for 1.5 days, the desired
adduct 71 and its 4Z-isomer 72 were obtained in 22 and 27%
yields, respectively (Table 4, entry 3). Other stereoisomers were
not found, and the starting materials 2 (39%) and 64 (30%)
were recovered. The structure of 72 was determined by the
precise NMR analysis shown in Figure 3. The longer the reaction
time, the lower the isolated yield of the adducts due to partial
decomposition. At 140 °C for 1 day in 1,2-dichlorobenzene,
only decomposition of 2 and 64 occurred (Table 4, entry 4).
Additionally, under Lewis acid-promoted conditions (i.e.,
Et2AlCl, BF3 ·OEt2, TiCl4, ZnCl2), only decomposition of 64
occurred (Table 4, entries 5-8). In water, no improvement
occurred (Table 4, entry 9).
In order to clarify the timing of the E f Z isomerization, 2,
71, and 72 were separately subjected to Diels-Alder reaction
conditions (toluene, 100 °C). The ratio of 2 and its Z-isomer
73 reached 71:29 after 12 h (Scheme 19), and the structure of
(42) Nakata, M.; Yasuda, M.; Suzuki, S.; Ohba, S. Synlett 1994, 71–74.
J. Org. Chem. Vol. 74, No. 1, 2009 239

Ichige et al.
SCHEME 18. Model Diels-Alder Reaction between 65 and 66
TABLE 4. Diels-Alder Reaction between 2 and 64
entry
solvent
toluene
toluene
toluene
1,2-dichlorobenzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Lewis acid (1.0 equiv)
temp (°C)
time (days)
ratioa of 2:64:71:72
1
2
3
4
5
6
7
8
9
-
25
60
4
1:1:0:0b
-
2.5
1.5
1
1
1
1
1
1.5
1:0.47:0:0c
-
100
140
-20
-20
-20
-20
25
1:0.68:0.43:0.65 (71, 22%; 72, 27%)d
e
-
-
Et2AlCl
BF3 ·OEt2
TiCl4
ZnCl2
-
1:0.44:0:0c
1:0:0:0c
trace:0:0:0e
1:0.50:0:0c
1:0.20:0:0c
H2O
a Determined by 1H NMR analysis of the crude products. b No reaction. c Decomposition of 64. d Recovery of 2 (39%) and 64 (30%).
e Decomposition of 2 and 64.
SCHEME 19. Thermal Isomerization of 2 to 73
FIGURE 3. NOE measurement of 72.
the acetonide protecting group, our results suggest that 1 could
be biosynthesized by the inherent reactivity of 2 and 3, possibly
than TS A. All of these factors make TS A leading to the desired
without the aid of an enzyme.15
adduct most favorable.
Experimental Section
Conclusion
Dithiane Coupling Product 23. To a solution of 8 (50.0 mg,
0.149 mmol) in dry THF (0.745 mL) was added a premixed solution
of a 1.57 M hexane solution of n-BuLi (0.114 mL, 0.179 mmol)
and a 1.0 M heptane solution of Bu2Mg (0.0447 mL, 0.0447 mmol)
We have succeeded in the first total synthesis of methyl
sarcophytoate (1) via the intermolecular Diels-Alder reaction
between the 14-membered dienophile unit, methyl sarcoate (2),
and the diene unit 64 with a high stereoselectivity. It is striking
at rt. The solution was stirred at rt for 0.5 h to afford a yellow
and interesting that only the natural type of cyclohexene core
skeleton was obtained. Although the Diels-Alder reaction
proceeded only at high temperature, and the diene unit bears
solution. This was cooled to -78 °C, and a solution of 7 (28.2 mg,
0.0747 mmol) in dry THF (0.377 mL) was added. The resulting
solution was allowed to warm to 0 °C during a period of 1.5 h,
240 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of Methyl Sarcophytoate
SCHEME 20. Isomerization between 71 and 72 and Final
Step
2880, 1470, 1395, 1350, 1310, 1255, 1195, 1085, 1055, 1020, 990,
910, 890, 840, 780; H NMR (300 MHz, CDCl3) δ 0.08 (6H, s),
1
0.76 (3H, s), 0.79 (3H, s), 0.91 (9H, s), 0.96 (3H, d, J ) 7.0 Hz),
1.02 (3H, d, J ) 7.0 Hz), 1.52-3.26 (12H, m), 3.63-3.81 (2H,
m), 3.89 (6H, s), 3.90 (6H, s), 6.10 (1H, s); 13C NMR (75 MHz,
CDCl3) δ -5.1, 14.6, 14.7, 18.5, 19.7, 24.9, 26.2, 26.4, 26.5, 27.3,
27.5, 29.9, 30.4, 32.0, 32.7, 43.7, 60.4, 64.2, 72.6, 72.8, 107.2,
107.5, 130.4, 138.1; MS (EI) m/z 631 (M+); HRMS (EI) m/z calcd
for C31H54O7S2Si (M+) 630.3080, found 630.3084.
Coupling Product 4SS. To a solution of 27 (18.0 mg, 0.0449
mmol) in dry THF (0.360 mL) was added a 1.57 M hexane solution
of n-BuLi (0.0286 mL, 0.0449 mmol) at -78 °C. After 5 min at
-78 °C, the solution was warmed to 0 °C, and oxalyl chloride
(0.0120 mL, 0.135 mmol) was added. After 0.5 h at rt, solvents
and excess oxalyl chloride were carefully evaporated under reduced
pressure to afford the crude acid chloride 5. To a mixture of this
crude 5 in dry benzene (0.360 mL) were added a solution of 6
(34.6 mg, 0.0899 mmol) in dry benzene (0.180 mL) and about a
0.1 M benzene solution of 1:1 Pd(OAc)2:(n-Bu)3P (0.0449 mL,
0.00449 mmol). The reaction mixture was degassed with CO gas
and then stirred at rt for 1 h under a CO atmosphere. A saturated
aqueous solution of NaHCO3 (0.2 mL) and water (1.0 mL) were
added, and the mixture was extracted with EtOAc (1.0 mL × 3).
The extracts were washed with brine (1.0 mL), dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified
with silica-gel column chromatography (2.0 g, 10:1 hexane:EtOAc
including 1% Et3N) to afford 4SS (15.3 mg, 71%) as a yellow syrup:
25
Rf ) 0.78 (1:1 hexane:EtOAc); [R]D +12.5 (c 1.53, CHCl3); IR
(neat, cm-1) 2950, 2930, 1720, 1670, 1620, 1435, 1370, 1280, 1230,
1090, 995, 910, 860, 760; 1H NMR (300 MHz, CDCl3) δ 0.94 (3H,
d, J ) 7.0 Hz), 0.95 (3H, d, J ) 7.0 Hz), 1.60-1.76 (1H, m), 1.82
(1H, m), 1.90 (3H, s), 2.19 (3H, d, J ) 1.0 Hz), 2.21-2.40 (5H,
m), 2.57 (1H, dd, J ) 5.0, 17.0 Hz), 2.80-3.06 (1H, m), 3.08-3.16
(1H, m), 3.32 (1H, dd, J ) 17.0, 5.5 Hz), 3.49 (1H, d, J ) 14.0
Hz), 3.82 (1H, d, J ) 14.0 Hz), 3.82 (3H, s), 4.86-5.08 (2H, m),
5.70-5.86 (1H, m), 5.74 (1H, br s), 6.17 (1H, s), 6.19 (1H, br s),
7.09 (1H, s); 13C NMR (75 MHz, CDCl3) δ 18.5, 19.6, 20.0, 24.0,
25.1, 26.5, 26.8, 28.0, 31.4, 31.7, 34.0, 40.8, 44.1, 52.7, 60.8, 115.6,
124.1, 125.6, 137.3, 140.0, 144.7, 160.5, 169.3, 191.6, 200.9; MS
(EI) m/z 478 (M+); HRMS (EI) m/z calcd for C26H38O4S2 (M+)
478.2212, found 478.2186.
and a saturated aqueous solution of NH4Cl (0.1 mL) was added.
The mixture was diluted with water (2.0 mL), and the aqueous layer
was extracted with EtOAc (2.0 mL × 3). The extracts were washed
with brine (2.0 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified with silica-gel column
chromatography (3.7 g, 2:1 hexane:EtOAc including 1% Et3N) to
afford 23 (26.5 mg, 56%) as a colorless solid: Rf ) 0.68 (1:1 hexane:
EtOAc); [R]D26 -2.70 (c 1.56, CHCl3); IR (KBr, cm-1) 2960, 2930,
Ketone 4O. To a solution of 4SS (3.7 mg, 0.00773 mmol) in
t-BuOH (0.129 mL) were added a 1.0 M pH 5.6 phosphate buffer
(0.129 mL), 2-methyl-2-butene (0.0082 mL, 0.0773 mmol), and
NaClO2 (4.9 mg, 0.0467 mmol). After 2 h at rt, water (1.0 mL)
was added, and the mixture was extracted with EtOAc (1.0 mL ×
3). The extracts were washed with brine (1.0 mL), dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified with silica-gel column chromatography (1.0 g, 4:1 hexane:
EtOAc) to afford 4O (2.1 mg, 70%) as a yellow syrup: Rf ) 0.50
(3:1 hexane:EtOAc); [R]D24 +40.5 (c 0.44, CHCl3); IR (neat, cm-1
)
FIGURE 4. Solution conformations of 2 and 64 in toluene-d8 at
50 °C.
2959, 2925, 1720, 1675, 1625, 1435, 1370, 1270, 1210, 1080, 995,
1
915, 855; H NMR (300 MHz, CDCl3) δ 0.88 (3H, d), 1.02 (3H,
d, J ) 7.0 Hz), 1.84 (3H, br s), 2.16 (3H, d, J ) 1.5 Hz), 2.12-2.30
(5H, m), 2.65 (1H, dd, J ) 3.0, 17.0 Hz), 3.12 (1H, ddd, J ) 3.0,
5.0, 10.0 Hz), 3.23 (1H, dd, J ) 10.0, 17.0 Hz), 3.76 (3H, s), 4.22
(1H, d, J ) 17.5 Hz), 4.28 (1H, d, J ) 17.5 Hz), 4.99 (1H, br d,
J ) 11.0 Hz), 5.02 (1H, br d, J ) 17.5 Hz), 5.72-5.86 (1H, m),
5.74 (1H, br s), 5.99 (1H, s), 6.18 (1H, br s), 7.24 (1H, s); 13C
NMR (75 MHz, CDCl3) δ 17.8, 18.7, 20.0, 21.3, 29.1, 31.7, 34.9,
40.8, 41.7, 52.2, 52.6, 115.6, 124.8, 125.1, 137.0, 137.3, 144.4,
161.6, 167.7, 190.9, 200.3, 209.0; MS (EI) m/z 388 (M+); HRMS
(EI) m/z calcd for C23H32O5 (M+) 388.2250, found 388.2271.
Methyl Sarcoate (2). A solution of 4O (22.3 mg, 0.0573 mmol)
in dry toluene (57.3 mL) was degassed with Ar, and to this was
added Grubbs second-generation catalyst 29 (48.7 mg, 0.0573
mmol). The resulting purple solution was again degassed with Ar
and warmed to 100 °C. After 0.5 h at 100 °C, the reaction mixture
was cooled to rt, and the solvent was removed under reduced
FIGURE 5. Transition states of the Diels-Alder reaction between 2
and 64.
J. Org. Chem. Vol. 74, No. 1, 2009 241

Ichige et al.
pressure. The residue was purified with silica-gel column chroma-
tography (6.0 g, 3:1 hexane:EtOAc) to afford methyl sarcoate (2)
(8.8 mg, 43%) as a yellow syrup: Rf ) 0.27 (3:1 hexane:EtOAc);
[R]D29 +175.8 (c 0.40, CHCl3); IR (neat, cm-1) 2960, 2930, 2870,
1715, 1660, 1605, 1435, 1390, 1375, 1360, 1310, 1260, 1165, 1145,
1090, 1070, 980; 1H NMR (300 MHz, CDCl3) δ 0.94 (3H, d, J )
7.0 Hz), 1.03 (3H, d, J ) 7.0 Hz), 1.73 (3H, s), 2.10-2.24 (1H,
m), 2.17 (1H, dd, J ) 3.0, 13.0 Hz), 2.17 (3H, s), 2.30-2.52 (3H,
m), 2.54-2.70 (1H, m), 2.84 (1H, ddd, J ) 3.0, 6.0, 10.0 Hz),
2.99 (1H, d, J ) 18.0 Hz), 3.33 (1H, dd, J ) 10.0, 13.0 Hz), 3.67
(1H, d, J ) 18.0 Hz), 3.74 (3H, s), 6.10 (1H, s), 6.31 (1H, br d, J
) 10.0 Hz), 7.19 (1H, s); 13C NMR (75 MHz, CDCl3) δ 11.6, 18.6,
19.6, 21.0, 26.1, 30.2, 35.1, 39.8, 43.7, 52.5, 56.9, 124.7, 129.1,
139.3, 142.2, 142.3, 160.5, 166.7, 193.3, 202.3, 208.9; MS (EI)
m/z 478 (M+); CD (EtOH) λmax 255 (∆ꢀ +20.6), 225 (∆ꢀ -6.4)
nm; HRMS (EI) m/z calcd for C21H28O5 (M+) 360.1937, found
360.1930.
configuration of 39b was determined by the modified Mosher ester
analysis in Scheme 13.
Dihydropyran 58. To a -78 °C solution of 57 (343 mg, 0.487
mmol) in dry MeOH (9.7 mL) was added BF3 ·OEt2 (0.184 mL,
1.46 mmol), and the resulting solution was warmed to 0 °C during
a period of 2 h. After 1 h at 0 °C, a saturated aqueous solution of
NaHCO3 (3 mL) and water (6 mL) were added. This was extracted
with 1:1 hexane:EtOAc (9 mL × 3), and the extracts were washed
with brine (9 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified with silica-gel column
chromatography (11.6 g, 1:2 hexane:EtOAc) to afford 58 (224 mg,
27
97%) as a colorless syrup: Rf ) 0.20 (1:1 hexane:EtOAc); [R]D
+16.7 (c 1.21, CHCl3); IR (neat, cm-1) 3420, 2935, 2860, 1735,
1610, 1515, 1455, 1440, 1375, 1300, 1250, 1175, 1070, 1040, 930,
820; 1H NMR (300 MHz, CDCl3) δ 1.28 (3H, s), 1.58-1.78 (2H,
m), 1.63 (3H, br s), 1.66 (3H, br s), 1.69 (3H, br s), 1.92-2.48
(6H, m), 3.63 (1H, dd, J ) 10.5, 2.5 Hz), 3.67 (1H, dd, J ) 11.0,
3.5 Hz), 3.80 (3H, s), 3.92-4.06 (5H, m), 4.44 (2H, s), 5.43 (1H,
br t, J ) 6.5 Hz), 5.47-5.64 (2H, m), 6.88 (2H, d, J ) 8.5 Hz),
7.27 (2H, d, J ) 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ 14.2,
16.7, 19.6, 20.0, 25.1, 29.5, 29.8, 36.6, 55.4, 66.5, 68.7, 71.0, 72.0,
74.9, 75.3, 77.1, 113.9, 119.7, 121.5, 122.5, 129.6, 130.6, 135.1,
138.2, 139.9, 159.3; MS (EI) m/z 456 (M - H2O+); HRMS (EI)
m/z calcd for C28H40O5 (M - H2O+) 456.2876, found 456.2855.
Diels-Alder adducts 71 and 72. A solution of 2 (3.8 mg, 0.0105
mmol) and 64 (3.7 mg, 0.0103 mmol) in dry toluene (0.105 mL)
was heated at 100 °C for 1.5 days under an Ar atmosphere. The
resulting solution was cooled to rt, and the solvent was removed
under reduced pressure. The residue was purified with preparative
TLC on silica gel (2:1 hexane:EtOAc) to afford Diels-Alder
adducts 71 (22%, 1.6 mg) and 72 (27%, 2.0 mg) along with the
recovered starting materials 2 (1.5 mg, 39%) and 64 (1.1 mg, 30%).
71: Rf ) 0.54 (2:1 hexane:EtOAc); [R]D26 +73.5 (c 0.39, CHCl3);
IR (neat, cm-1) 2960, 2930, 2855, 1735, 1715, 1655, 1610, 1460,
1370, 1260, 1105, 1055, 1020, 895, 855, 805; 1H NMR (300 MHz,
CDCl3) δ 0.80 (3H, d, J ) 7.0 Hz), 0.98 (3H, d, J ) 7.0 Hz), 1.29
(3H, s), 1.42 (3H, s), 1.46 (3H, s), 1.64 (3H, br s), 1.73 (3H, s),
1.76 (3H, br s), 1.80 (3H, s), 2.08 (3H, s), 2.17 (1H, d, J ) 19.0
Hz), 1.53-2.70 (16H, m), 2.86 (1H, dd, J ) 18.0, 8.5 Hz), 3.27
(1H, d, J ) 19.0 Hz), 3.46-3.55 (1H, m), 3.47 (1H, dd, J ) 13.5,
5.5 Hz), 3.56 (3H, s), 3.68 (1H, dd, J ) 10.0, 3.5 Hz), 3.88 (1H,
d, J ) 9.0 Hz), 3.90 (1H, d, J ) 8.5 Hz), 4.07 (1H, d, J ) 9.5 Hz),
4.64 (1H, d, J ) 12.0 Hz), 5.59 (1H, m), 6.02 (1H, s), 6.24 (1H,
br d, J ) 8.0 Hz); 13C NMR (75 MHz, CDCl3) δ 11.9, 17.5, 18.5,
19.9, 20.5, 20.6, 20.9, 21.2, 25.5, 26.3, 29.8, 29.9, 30.3, 31.8, 32.4,
33.1, 33.6, 39.1, 39.8, 41.2, 46.8, 47.7, 48.3, 51.4, 56.2, 68.3, 79.4,
84.3, 85.2, 108.7, 120.6, 125.7, 126.8, 126.9, 127.0, 134.3, 137.9,
140.3, 141.4, 158.3, 173.6, 202.6, 203.6, 210.4; MS (EI) m/z 718
(M+); HRMS (EI) m/z calcd for C44H62O8 (M+) 718.4444, found
718.4430. 72: Rf ) 0.67 (2:1 hexane:EtOAc); [R]D27 +45.7 (c 0.50,
CHCl3); IR (neat, cm-1) 2985, 2935, 2855, 1735, 1715, 1655, 1620,
Allyl Alcohol 39a. To a -78 °C solution of 44 (11.8 g, 28.3
mmol) in dry THF (141 mL) was added a 1.57 M hexane solution
of n-BuLi (21.6 mL, 34.0 mmol). The resulting solution was
allowed to warm to 0 °C over 1 h, and then a saturated aqueous
solution of NH4Cl (30 mL) and water (200 mL) were added. The
mixture was extracted with EtOAc (200 mL × 3), and the extracts
were washed with brine (200 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified with
silica-gel column chromatography (329 g, 1.5:1 hexane:EtOAc) to
afford 39a (8.06 g, 98%) as a colorless syrup. Compound 39a could
be synthesized directly from 43 according to the following
procedure.38 To a solution of 43 (1.91 g, 6.23 mmol) in 5:3 ether:
CH3CN (12.5 mL) were added dry pyridine (2.02 mL, 24.9 mmol)
and PPh3 (4.90 g, 18.7 mmol). After the mixture had cooled to 0
°C, I2 (2.37 g, 9.35 mmol) was added, and the reaction mixture
was stirred at 0 °C for 2 h. Water (0.112 mL, 6.23 mmol) was
added, and the mixture was stirred at rt for 12 h. A saturated
aqueous solution of Na2S2O3 (6.0 mL), a saturated aqueous solution
of NaHCO3 (6.0 mL), and water (20 mL) were added, and the
mixture was extracted with EtOAc (30 mL × 3). The extracts were
washed with brine (20 mL), dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified with silica-gel
column chromatography (91 g, 4:1 hexane:EtOAc) to afford 39a
(1.47 mg, 81%) as a colorless oil. For the kinetic resolution of 39a,
to a mixture of D-(-)-DIPT (89.7 mg, 0.383 mmol) and MS4A
powder (1.85 g) in dry CH2Cl2 (10.6 mL) was added (i-PrO)4Ti
(0.0949 mL, 0.319 mmol) at -20 °C. The reaction mixture was
stirred at -20 °C for 0.5 h, and then a 3.89 M CH2Cl2 solution of
TBHP (0.410 mL, 1.60 mmol) was added. After 0.5 h at -20 °C,
a solution of 39a (927 mg, 3.19 mmol) in dry CH2Cl2 (5.3 mL)
was added, and this mixture was stirred at -20 °C for 1 h. Water
(3 mL) and a 30% aqueous solution of NaOH saturated with NaCl
(3 mL) were added, and this mixture was stirred at rt for 0.5 h.
This mixture was extracted with CHCl3 (10 mL × 3), and the
extracts were washed with brine (10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified with
silica-gel column chromatography (46 g, 4:1 hexane:EtOAc) to
afford 39b (815 mg, 88%) as a colorless oil: Rf ) 0.27 (2:1 hexane:
EtOAc); [R]D26 -7.54 (c 2.16, CHCl3); IR (neat, cm-1) 3430, 2940,
2860, 1615, 1585, 1515, 1440, 1370, 1300, 1250, 1175, 1110, 1070,
1
1440, 1370, 1140, 1105, 1055, 1020, 855; H NMR (300 MHz,
CDCl3) δ 0.78 (3H, d, J ) 6.5 Hz), 1.03 (3H, d, J ) 6.5 Hz), 1.31
(3H, s), 1.44 (3H, s), 1.47 (3H, s), 1.63 (3H, br s), 1.72 (3H, br s),
1.79 (6H, br s), 1.94 (3H, s), 1.50-2.52 (13H, m), 2.35 (1H, dd, J
) 14.0, 10.0 Hz), 2.61 (1H, d, J ) 14.0 Hz), 2.52-2.75 (2H, m),
2.83 (1H, d, J ) 18.0 Hz), 2.91 (1H, d, J ) 18.0 Hz), 3.20 (1H, br
d, J ) 11.0 Hz), 3.36 (1H, dd, J ) 13.5, 7.0 Hz), 3.53 (3H, s),
3.54 (1H, dd, J ) 11.0, 3.0 Hz), 3.64 (1H, dd, J ) 10.0, 3.5 Hz),
3.87 (1H, d, J ) 10.0 Hz), 4.08 (1H, br d, J ) 9.5 Hz), 4.74 (1H,
d, J ) 11.0 Hz), 5.59 (1H, m), 6.60 (1H, dd, J ) 10.5, 5.0 Hz),
6.65 (1H, s); 13C NMR (75 MHz, CDCl3) δ 11.5, 18.0, 19.6, 20.5,
20.6, 21.2, 21.4, 25.4, 26.1, 27.3, 29.7, 30.1, 30.7, 31.7, 31.96,
32.02, 32.4, 34.0, 39.4, 44.6, 46.3, 47.4, 49.3, 51.2, 55.7, 68.5, 79.2,
84.2, 84.4, 109.4, 120.5, 126.1, 126.9, 127.1, 127.5, 134.3, 137.1,
140.9, 143.9, 156.7, 174.5, 201.6, 203.5, 210.1; MS (EI) m/z 718
(M+); HRMS (EI) m/z calcd for C44H62O8 (M+) 718.4444, found
718.4447. Results of the NOE experiments are in Figure 3.
1
1040, 900, 820, 760; H NMR (300 MHz, CDCl3) δ 1.60-1.76
(2H, m), 1.65 (3H, br s), 1.72 (3H, br s), 1.95-2.20 (2H, m), 3.80
(3H, s), 3.96-4.09 (1H, m), 3.99 (2H, d, J ) 7.0 Hz), 4.43 (2H,
s), 4.84 (1H, br s), 4.94 (1H, br s), 5.42 (1H, tq, J ) 7.0, 1.0 Hz),
6.87 (2H, d, J ) 9.0 Hz), 7.27 (2H, d, J ) 9.0 Hz); 13C NMR (75
MHz, CDCl3) δ 16.7, 17.7, 33.0, 35.6, 55.4, 66.4, 71.9, 75.7, 111.3,
113.8, 121.3, 129.5, 130.7, 140.1, 147.5, 159.2; MS (EI) m/z 290
(M+); HRMS (EI) m/z calcd for C18H26O3 (M+) 290.1882, found
290.1874. Enantiomeric excess was determined to be >98% by
comparing the 1H NMR of (S)-MTPA and (R)-MTPA esters of 39b,
which were easily synthesized using the procedure described in
the preparation of 19a (Supporting Information). The absolute
242 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of Methyl Sarcophytoate
Methyl Sarcophytoate (1). A solution of 71 (2.1 mg, 0.00292
mmol) in an 80% aqueous solution of AcOH (0.30 mL) was heated
at 50 °C for 3 h. After cooling to rt, the solvents were removed
under reduced pressure, and the residue was purified with prepara-
tive TLC on silica gel (1:1 hexane:EtOAc) to afford 1 (1.0 mg,
Acknowledgment. We thank Takenori Kusumi at The
University of Tokushima for providing spectral copies of natural
methyl sarcoate and methyl sarcophytoate and for his generous
discussion. We are grateful to Yoshiko Koyama at the Hiyoshi
Medicinal Chemistry Research Institute for the measurement
of 500 MHz NMR spectra. We thank Satoshi Kamimura,
Kazuya Mayumi, Yasuyuki Sakamoto, Shingo Terashita, and
Eriko Ohteki for their early contributions to this work. This
research was partially supported by the Grant-in-Aid for the
21st Century COE program “KEIO Life Conjugate Chemistry”
(T.I.) and for Scientific Research on Priority Areas 17035076
and 18032067 (M.N.) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (MEXT).
26
50%) as a colorless syrup: Rf ) 0.24 (2:1 hexane:EtOAc); [R]D
+152.2 (c 0.10, CHCl3); IR (neat, cm-1) 3520, 2925, 2855, 1730,
1710, 1665, 1610, 1435, 1370, 1275, 1100, 1075, 1055, 1020, 965,
940; 1H NMR (300 MHz, CDCl3) δ 0.82 (3H, d, J ) 7.0 Hz), 0.98
(3H, d, J ) 7.2 Hz), 1.31 (3H, s), 1.64 (3H, br s), 1.70 (3H, br s),
1.73 (3H, s), 1.83 (3H, d, J ) 1.5 Hz), 1.96 (1H, d, J ) 18.8 Hz),
2.09 (3H, d, J ) 1.0 Hz), 1.60-2.25 (8H, m), 2.25-2.70 (8H, m),
2.97 (1H, dd, J ) 18.0, 7.5 Hz), 3.19 (1H, d, J ) 11.0 Hz), 3.28
(1H, d, J ) 18.8 Hz), 3.44 (1H, dd, J ) 14.0, 6.0 Hz), 3.57 (3H,
s), 3.56-3.63 (1H, m), 3.65 (1H, dd, J ) 10.2, 3.2 Hz), 3.98 (1H,
d, J ) 7.5 Hz), 4.01 (1H, d, J ) 10.0 Hz), 4.69 (1H, d, J ) 11.0
Hz), 5.58 (1H, m), 6.05 (1H, s), 6.25 (1H, dd, J ) 8.6, 4.0 Hz);
13C NMR (75 MHz, CDCl3) δ 11.9, 17.7, 18.9, 19.6, 20.1, 20.3,
20.6, 20.9, 24.8, 25.6, 30.4, 31.3, 32.8, 33.3, 39.0, 39.9, 40.8, 46.9,
47.4, 48.6, 51.5, 56.2, 68.4, 70.8, 75.5, 79.6, 120.5, 124.2, 125.8,
126.8, 129.3, 134.5, 138.2, 140.8, 141.4, 159.4, 173.2, 203.3, 203.4,
210.5; MS (EI) m/z 678 (M+); HRMS (EI) m/z calcd for C41H58O8
(M+) 678.4131, found 678.4112.
Supporting Information Available: Experimental proce-
dures for compounds 6-8, 13-22, 24-28, 33-37, 42-57,
1
59-61, and 73 and copies of the H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802249K
J. Org. Chem. Vol. 74, No. 1, 2009 243