Total synthesis of (+)-strongylin A, a rearranged sesquiterpenoid hydroquinone from a marine sponge

Article abstract of DOI:10.1002/ejoc.201300438

A biologically attractive and structurally unique marine natural product, (+)-strongylin A (1), was synthesized for the first time by starting from a known trans-decalone derivative (19 % overall yield in 11 steps). The synthetic method involved the following key steps: (i) stereocontrolled hydrogenation of an exo-olefinic decalin to install the C8 stereogenic centre present in the required decalin segment; (ii) coupling of the decalin segment with an aromatic moiety to assemble the desired carbon skeleton; and (iii) sequential BF ₃·Et₂O-induced dehydroxylation/rearrangement/ cyclization of a decalin tertiary alcohol to directly produce target compound 1. This total synthesis has established the absolute configuration of the natural product. (+)-Strongylin A has been synthesized for the first time by starting from (+)-5-methyl-Wieland-Miescher ketone (16 % overall yield in 14 steps). The characteristic tetracyclic core structure was constructed in a domino dehydroxylation/rearrangement/cyclization reaction. Copyright

Full text of DOI:10.1002/ejoc.201300438

Job/Unit: O30438
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Date: 13-06-13 12:17:11
Pages: 7
FULL PAPER
Natural Product Synthesis
(+)-Strongylin A has been synthesized for
the first time by starting from (+)-5-methyl-
Wieland–Miescher ketone (16% overall
yield in 14 steps). The characteristic tetra-
cyclic core structure was constructed in a
domino dehydroxylation/rearrangement/
cyclization reaction.
T. Kamishima, T. Kikuchi,
T. Katoh* .......................................... 1–7
Total Synthesis of (+)-Strongylin A, a Re-
arranged Sesquiterpenoid Hydroquinone
from a Marine Sponge
Keywords: Natural products / Total syn-
thesis / Terpenoids / Configuration deter-
mination / Cascade reactions /
Diastereoselectivity
0000, 0–0
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T. Kamishima, T. Kikuchi, T. Katoh
FULL PAPER
DOI: 10.1002/ejoc.201300438
Total Synthesis of (+)-Strongylin A, a Rearranged Sesquiterpenoid
Hydroquinone from a Marine Sponge
Takaaki Kamishima,[a] Takuya Kikuchi,[a] and Tadashi Katoh*[a]
Keywords: Natural products / Total synthesis / Terpenoids / Configuration determination / Cascade reactions /
Diastereoselectivity
A biologically attractive and structurally unique marine natu-
ral product, (+)-strongylin A (1), was synthesized for the first
time by starting from a known trans-decalone derivative
(19% overall yield in 11 steps). The synthetic method in-
volved the following key steps: (i) stereocontrolled hydrogen-
ation of an exo-olefinic decalin to install the C8 stereogenic
centre present in the required decalin segment; (ii) coupling
of the decalin segment with an aromatic moiety to assemble
the desired carbon skeleton; and (iii) sequential BF3·Et2O-
induced dehydroxylation/rearrangement/cyclization of
a
decalin tertiary alcohol to directly produce target compound
1. This total synthesis has established the absolute configura-
tion of the natural product.
scopic studies, including 2D NMR experiments,[3,4] but the
absolute configuration has not been assigned. This natural
product consists of a benzo[d]xanthene skeleton (ABCD
ring system) containing four contiguous asymmetric centres
and three quaternary carbon atoms, with the characteristic
feature of cis-fused AB and BC rings, an ether bond at the
bridgehead of the AB ring junction, and a mono-O-methyl-
ated hydroquinone moiety (D ring).[3,4] Closely related nat-
ural products with similar tetracyclic core structures have
been isolated. These include aureol (2) from the Caribbean
sponge Smenospogia aurea in 1980,[5] smenoqualone (3)
Introduction
Recently, a wide variety of natural products with unique
structural features and attractive biological activities have
been isolated from marine sponges.[1] Many of these natural
products have received considerable attention owing to their
potential for use as new therapeutic agents.[2] In most cases,
however, biological studies, including those focussing on
structure–activity relationships, have been severely restric-
ted, probably because of the scarcity of samples and/or the
structural diversity of the natural products derived from
marine sponges.[1,2] As a consequence, the development of
efficient and flexible methods for the synthesis of bioactive
marine natural products and their analogues is desirable
and worthwhile from the viewpoint of medicinal/pharma-
ceutical chemistry.
Strongylin A (1, Figure 1) was first isolated from the
Caribbean sponge Strongylophora hartmani by Wright et al.
in 1991,[3] and subsequently from the Bahamian sponge
Xestospongia wiedenmayeri by scientists from the Schering–
Plough Corporation (now Merck & Co., Inc.) in 1995.[4]
This marine natural product has been shown to have anti-
proliferative activity against P388 murine leukaemia cells
(IC50 = 13 μg/mL) and antiviral activity against the human
influenza A/PR/8/34 (H1N1) virus in vitro (IC50 = 6.5 μg/
mL).[3] The constitutional structure and relative stereo-
chemistry of 1 have been determined by extensive spectro-
[a] Laboratory of Synthetic and Medicinal Chemistry, Faculty of
Pharmaceutical Sciences, Tohoku Pharmaceutical University,
4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan
Fax: +81-22-727-0135
E-mail: katoh@tohoku-pharm.ac.jp
Homepage: http://www.tohoku-pharm.ac.jp/laboratory/
iyakugo/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300438.
Figure 1. Representative examples of sesquiterpenoid natural prod-
ucts having a tetracyclic benzo[d]xanthene skeleton (ABCD ring
system).
2
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Total Synthesis of (+)-Strongylin A
from the marine sponge Smenospongia sp. in 1992,[6] and the requisite cis-fused decalin ring junction (5 Ǟ [I Ǟ II Ǟ
stachyflin (4) from a culture broth of Stachybotrys sp. RF- III] Ǟ 1; Scheme 4). A second crucial step is the coupling
7260 in 1997.[7] Natural products 2 and 4 have also been reaction of an appropriately functionalized trans-decalin 7
shown to have remarkable biological properties, such as (accessible from the corresponding alcohol, i.e., 8) with
antiproliferative[5] and antiviral activities,[5,7] whereas the trioxy-substituted aryllithium compound 10 (accessible
biological activity of 3 has not been disclosed.
from known trioxybenzene derivative 9) to assemble the
Unique structural features coupled with attractive bio- carbon skeleton, represented by intermediate 6. Intermedi-
logical activities have made these natural products excep- ate 6 could be converted into intermediate 5, a precursor
tionally intriguing and timely targets for total synthesis. for the key cascade reaction, by deprotection and func-
There have been reports on the total synthesis of natural tional-group manipulation. Intermediate 8, in turn, was to
(+)-2,[8,9] unnatural (–)-2 and (–)-3,[10] and natural (+)-4.[11] be produced by stereoselective hydrogenation of exo-olefin
However, the total synthesis of 1 has not been reported to 11, which is accessible from known trans-decalone 12.[13]
date. An enantioselective approach to the tetracyclic core Starting material 12 is readily prepared from enantiomer-
structure of this family has been reported.[12] In this study, ically pure (+)-5-methyl-Wieland–Miescher ketone (13) in a
we describe the first total synthesis of naturally occurring three-step sequence according to the method reported by
(+)-1 in an enantiomerically pure form using a synthetic Smith et al.[13]
strategy developed in our laboratory.[8,11] This total synthe-
sis verified the absolute configuration of (+)-1, which is as
shown in Figure 1.
Synthesis of Decalin Segment 7
The synthesis of 7 from 12 (Ͼ 99% ee),[13] is shown in
Scheme 2. Initial attempts to realize the direct conversion
of 12 into 11 under conventional Wittig methylenation con-
ditions[14] were unsuccessful, probably because of the pres-
ence of the sensitive hydroxy group in 12. Therefore, we
decided to carry out the conversion of 12 into 11 in a step-
wise process. Thus, protection of the hydroxy group fol-
lowed by Wittig methylenation[14] of the resulting trieth-
ylsilyl (TES) ether (i.e., 14) and deprotection of the TES
group in the resulting exo-olefin (i.e., 15) provided the de-
sired exo-olefin (i.e., 11) in 69% yield over the three steps.
To form the C8 stereogenic centre, compound 11 was sub-
jected to hydroxy-group-directed hydrogenation by using
Crabtree’s catalyst {[Ir(COD)(PCy3)(py)]+[PF6]–; 2.5 mol-
%},[15] which resulted in the formation of 8 with complete
stereoselectivity and in almost quantitative yield (98%).
When the hydrogenation was carried out by using a conven-
tional Pd/C catalyst in methanol, an inseparable mixture of
stereoisomers (β-Me/α-Me, 2:1) was produced in a lower
yield (72%). Oxidation of 8 with tetra-n-propylammonium
perruthenate (TPAP)[16] then gave decalin segment 7 in 94%
yield.
Results and Discussion
Synthetic Plan
Our retrosynthetic analysis of (+)-strongylin A (1) is out-
lined in Scheme 1, and is based on our previous syntheses
of (+)-aureol (2)[8] and (+)-stachyflin (4).[11] A key element
of this approach is the acid-induced dehydroxylation/re-
arrangement/cyclization of tertiary alcohol 5 to directly
produce target molecule 1 in one step. We believed that this
cascade reaction would proceed stereoselectively to install
Scheme 2. Synthesis of decalin segment 7. (a) TESCl, imidazole,
CH2Cl2, room temp., 1 h; (b) Ph3PCH3+Br–, tBuOK, benzene, re-
flux, 1 h; (c) TBAF, THF, room temp., 1 h, 69% (3 steps); (d) H2
(1 atm), Crabtree’s catalyst (2.5 mol-%), CH2Cl2, room temp., 1 h,
98%; (e) TPAP, NMO, CH2Cl2/MeCN, 4 Å MS, room temp., 1 h,
94%. TES = triethylsilyl, TBAF = tetrabutylammonium fluoride,
Crabtree’s catalyst = [Ir(COD)(PCy3)(py)]+[PF6]– (COD = 1,5-cy-
clooctadiene, Cy = cyclohexyl, py = pyridine), TPAP = tetra-n-
propylammonium perruthenate, NMO = N-methylmorpholine N-
oxide, MS = molecular sieves.
Scheme 1. Retrosynthetic analysis of (+)-strongylin (1).
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T. Kamishima, T. Kikuchi, T. Katoh
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Synthesis of Intermediate 5
(Scheme 4). The desired cascade event was successfully
achieved by treating 5 with an excess of BF3·Et2O
(10 equiv.) in CH2Cl2 at –78 to 0 °C for 3 h, and 1 was
formed in high yield (84%) as a single stereoisomer. The
Having synthesized decalin segment 7, we approached
the synthesis of intermediate 5, a precursor of the key cas-
cade reaction (Scheme 3). The crucial coupling reaction of
sterically hindered decalin aldehyde 7 with an appropriately
functionalized aromatic portion such as 9 to construct the
desired carbon skeleton was investigated. Site-selective lithi-
ation at the C4 position in 9 was achieved by treatment with
tBuLi in THF at 0 °C for 30 min,[17] and the aryllithium
compound generated in situ (i.e., 10) was allowed to react
with 7 at 0 °C rising to room temperature over 1 h to give
the expected coupling product (i.e., 16) in excellent yield
(94%) as an inseparable mixture of epimeric alcohols (ca.
1
spectroscopic properties of 1 (IR, H and 13C NMR, and
MS) were identical to those of natural 1. The optical rota-
tion of synthetic 1 {[α]2D3 = +83.3 (c = 0.024, CH2Cl2)} was
in good agreement with that of natural 1 {ref.[3] [α]D20 = +72
(c = 0.023, CH2Cl2)}, which confirmed the absolute config-
uration of 1.
1
4:1, as assessed by 400 MHz H NMR spectroscopy). The
removal of the hydroxy group from 16 was achieved by the
Barton–McCombie procedure,[18] and the desired deoxy-
genated product (i.e., 6) was formed in 78% overall yield
via methyl xanthate 17. Exposure of 6 to concentrated hy-
drochloric acid in refluxing ethanol resulted in simulta-
neous deprotection of the acetonide and ethylene acetal
moieties to give the desired ketone (i.e., 18)[19] in 71% yield.
Finally, nucleophilic addition of a methyl anion to the carb-
onyl group in 18 was performed by using a Grignard rea-
gent [MeMgBr (5 equiv.), THF, 0 °C to room temp.], and
intermediate 5[19] was formed in 70% yield as an inseparable
mixture of epimeric alcohols (ca. 1.7:1, as estimated by
1
400 MHz H NMR spectroscopy).[20]
Scheme 4. Synthesis of (+)-strongylin A (1). (a) BF3·OEt2, CH2Cl2,
–78 to 0 °C, 3 h, 84%.
It is noteworthy that this cascade reaction proceeded
smoothly and cleanly in a completely stereocontrolled man-
ner. This can be rationalized by the mechanism shown in
Scheme 4. Thus, an initial coordination–activation between
the Lewis acid and the C4 tertiary hydroxy group in 5
causes the hydroxy group to leave, and results in the forma-
tion of a first intermediate carbocation I, which is trans-
formed into a second intermediate carbocation II by the
migration of the C5 methyl group to the C4 carbocation
centre. Intermediate II then undergoes a 1,2-hydride shift
from the C10 position to the C5 carbocation centre on the
α-face of the molecule to deliver a third intermediate carbo-
cation III. Finally, the C10 carbocation centre in this inter-
mediate is trapped by the C2Ј hydroxy group in the aro-
matic moiety to produce the desired cyclized product (i.e.,
1). We believe that this cascade sequence proceeds in a step-
wise manner under kinetically controlled conditions.
Scheme 3. Synthesis of advanced key intermediate 5. (a) 5-meth-
oxy-2,2-dimethylbenzo[d][1,3]dioxole (9), tBuLi, THF, 0 °C,
30 min; at 0 °C, add 7, 0 °C to room temp., 1 h, 94%; (b) NaN-
(SiMe3)2, CS2, MeI, THF, –78 to –65 °C, 3 h; (c) nBu3SnH, AIBN,
benzene, reflux, 5 h, 78% (2 steps); (d) HCl (12 m), EtOH, reflux,
5 h, 71%; (e) MeMgBr, THF, 0 °C to room temp., 1 h, 70%. AIBN
= 2,2Ј-azobis(isobutyronitrile).
Conclusions
We accomplished the first total synthesis of naturally oc-
curring (+)-strongylin A (1) in a highly efficient way start-
ing from the known trans-decalone 12, accessible from (+)-
5-methyl-Wieland–Miescher ketone (13; 19% overall yield
Synthesis of (+)-Strongylin A (1)
With key intermediate 5 in hand, we directed our atten- in 11 steps from 12; 16% overall yield in 14 steps from 13).
tion to the crucial acid-induced cascade dehydroxylation/ The key steps of the synthesis were (i) the highly stereoselec-
rearrangement/cyclization process to complete the synthesis tive hydrogenation of exo-olefinic decalin 11 to establish the
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Total Synthesis of (+)-Strongylin A
EtOAc/hexane (1:20; 100 mL). The resulting mixture was filtered
through a short pad of silica gel. The filtrate was concentrated in
vacuo to give {[(4aЈS,5ЈS,8aЈS)-5Ј,8aЈ-dimethyl-6Ј-methyleneocta-
hydro-2ЈH-spiro(1,3-dioxolane-2,1Ј-naphthalen-5Ј-yl)]methoxy}tri-
ethylsilane (15; 5.03 g, 13 mmol), which was used in the next reac-
tion without purification.
C8 stereogenic centre in the decalin segment (11 Ǟ 8,
Scheme 2); (ii) the coupling reaction of decalin segment 7
with aromatic portion 10 to construct the carbon skeleton
(7 + 10 Ǟ 16, Scheme 3); and (iii) the acid-induced cascade
dehydroxylation/rearrangement/cyclization
of
tertiary
alcohol 5 to stereoselectively construct the tetracyclic core
structure in one step, leading to target molecule 1. This to-
tal synthesis has verified the absolute configuration of 1.
Importantly, because of its generality and flexibility, this
synthesis has the potential to produce additional analogues
of 1 in enantiomerically pure form. Efforts to achieve this
are currently underway.
Tetrabutylammonium fluoride (TBAF; 1.0 m in THF; 42.3 mL,
42 mmol) was added dropwise to a stirred solution of 15 (5.03 g,
13 mmol) in THF (70 mL) at 0 °C, and stirring was continued at
room temperature for 1 h. The reaction was quenched with NH4Cl
(saturated aq.; 50 mL) at 0 °C, and the resulting mixture was ex-
tracted with EtOAc (2 ϫ 100 mL). The combined extracts were
washed with brine (2ϫ 50 mL), then dried with MgSO4. Concen-
tration of the solvent in vacuo gave a residue, which was purified
by column chromatography (hexane/EtOAc, 10:1 Ǟ 5:1 Ǟ 3:1) to
give 11 (2.60 g, 69% over three steps) as a white solid. Recrystalli-
zation from hexane/EtOAc gave colourless prisms. M.p. 84–86 °C.
Experimental Section
General Methods: All reactions involving air- and moisture-sensi-
tive reagents were carried out by using oven-dried glassware and
standard syringe/septum cap techniques. Routine monitoring of re-
actions was carried out by using glass-supported Merck silica gel
60 F254 TLC plates. Flash column chromatography was performed
on Kanto Chemical Silica Gel 60N (spherical, neutral 40–50 nm)
with the solvents indicated. All solvents and reagents were used as
supplied, with the following exceptions: tetrahydrofuran (THF) was
freshly distilled from Na metal/benzophenone under argon; benz-
ene and CH2Cl2 were distilled from calcium hydride under argon.
Optical rotations were measured with a JASCO DIP-370 automatic
digital polarimeter. Melting points were taken with a Yanaco MP-
3 micro melting point apparatus. 1H and 13C NMR spectra were
measured with a JEOL AL-400 (400 MHz) spectrometer. Chemical
shifts are expressed in ppm by using Me4Si (δ = 0 ppm) as internal
standard. The following abbreviations are used: singlet (s), doublet
(d), triplet (t), quartet (q), multiplet (m), and broad (br.). Infrared
(IR) spectroscopic measurements were carried out with a JASCO
FTIR-4100 spectrometer. Low- and high-resolution mass spectra
(HRMS) were measured with a JEOL JMS-DX 303/JMA-DA 5000
SYSTEM high-resolution mass spectrometer.
1
[α]2D2 = –6.2 (c = 1.07 in CHCl3). H NMR (400 MHz, CDCl3): δ
= 0.89 (s, 3 H), 1.14 (s, 3 H), 1.34–1.71 (m, 9 H), 1.93 (dd, J = 2.9,
12.2 Hz, 1 H), 2.16 (dt, J = 4.9, 14.1 Hz, 1 H), 2.32–2.39 (m, 1 H),
3.40 (d, J = 11.7 Hz, 1 H), 3.51 (d, J = 11.7 Hz, 1 H), 3.82–3.91
(m, 4 H), 4.72 (s, 1 H), 4.85 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.8, 19.5, 21.5, 22.8, 29.3, 30.2, 31.1, 42.0, 43.0, 44.5,
64.8, 65.2, 66.7, 106.6, 113.2, 153.5 ppm. IR (KBr): ν = 3445, 2982,
˜
2937, 1636, 1474, 1457, 1443, 1282, 1208, 1185, 1140, 1118, 1105,
1065, 1042, 1010, 985, 950, 927, 905, 892, 865, 747, 696, 651 cm–1.
C16H26O3 (266.19): calcd. C 72.14, H 9.84; found C 72.14, H 9.91.
[(4aЈS,5ЈR,6ЈS,8aЈS)-5Ј,6Ј,8aЈ-Trimethyloctahydro-2ЈH-spiro(1,3-di-
oxolane-2,1Ј-naphthalen-5Ј-yl)]methanol (8): [Ir(COD)(PCy3)(py)]+-
[PF6]– (Crabtree’s catalyst; 37.8 mg, 47 μmol) was added to a solu-
tion of 11 (502 mg, 1.9 mmol) in anhydrous CH2Cl2 (6.3 mL). The
mixture was degassed by ultrasonic means, and then it was stirred
under H2 (ballon) at room temperature for 1 h. The reaction mix-
ture was concentrated in vacuo to give a residue, which was purified
by column chromatography (hexane/EtOAc, 5:1) to give 8 (495 mg,
98%) as a colourless viscous liquid. [α]2D2 = –13.0 (c = 1.08 in
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.56 (s, 3 H), 0.81 (d, J
= 6.8 Hz, 3 H), 1.05 (s, 3 H), 1.21–1.70 (m, 12 H), 1.81 (dd, J =
2.4, 12.7 Hz, 1 H), 3.30 (d, J = 11.7 Hz, 1 H), 3.38 (d, J = 11.7 Hz,
1 H), 3.81–3.95 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.0, 15.9, 16.9, 20.4, 23.0, 26.7, 30.0, 30.4, 34.4, 40.5, 41.8, 43.4,
[(4aЈS,5ЈS,8aЈS)-5Ј,8aЈ-Dimethyl-6Ј-methyleneoctahydro-2ЈH-
spiro(1,3-dioxolane-2,1Ј-naphthalen-5Ј-yl)]methanol (11): Trieth-
ylsilyl chloride (2.83 mL, 17 mmol) was added dropwise to a stirred
solution of (4aЈR,5ЈR,8aЈS)-5Ј-hydroxymethyl-5Ј,8aЈ-dimethylhexa-
hydro-2ЈH-spiro[1,3-dioxolane-2,1Ј-naphthalen-6Ј(7ЈH)-one] (12;
3.79 g, 14 mmol) and imidazole (3.84 g, 56 mmol) in anhydrous
CH2Cl2 (47 mL) at 0 °C under argon, and the mixture was stirred
at room temperature for 1 h. The reaction was quenched with
NH4Cl (saturated aq.; 20 mL) at 0 °C, and the resulting mixture
was extracted with CHCl3 (2 ϫ 70 mL). The combined extracts
were washed with brine (2ϫ 50 mL), then dried with MgSO4. Con-
centration of the solvent in vacuo gave (4aЈR,5ЈR,8aЈS)-5Ј,8aЈ-di-
methyl-5Ј-[(triethylsilyloxy)methyl]hexahydro-2ЈH-spiro[1,3-dioxol-
ane-2,1Ј-naphthalen-6Ј(7ЈH)-one] (14; 5.51 g, 14 mmol), which was
used in the next reaction without purification.
64.8, 65.3, 65.9, 113.4 ppm. IR (neat): ν = 3418, 2870, 2360, 2340,
˜
1478, 1457, 1380, 1335, 1282, 1240, 1133, 1111, 1088, 950, 933,
908, 863, 752, 693 cm–1. HRMS (FAB): calcd. for C16H29O3 [M +
H]+ 269.2117; found 269.2121.
(4aЈS,5ЈR,6ЈS,8aЈS)-5Ј,6Ј,8aЈ-Trimethyloctahydro-2ЈH-spiro(1,3-di-
oxolane-2,1Ј-naphthalene-5Ј-carbaldehyde) (7): Tetra-n-propyl-
ammonium perruthenate (TPAP; 22 mg, 62 μmol) was added to a
stirred solution of 8 (330 mg, 1.2 mmol) in anhydrous CH2Cl2/
MeCN (5:1; 12 mL) containing N-methylmorpholine N-oxide
(NMO; 288 mg, 2.5 mmol) and molecular sieves (4 Å; 615 mg) at
room temperature. After 1 h, the reaction mixture was diluted with
CH2Cl2 (50 mL), and the molecular sieves were removed by fil-
tration through a short pad of Celite. Concentration of the filtrate
in vacuo gave a residue, which was purified by column chromatog-
raphy (hexane/EtOAc, 15:1) to give 7 (309 mg, 94%) as a colourless
oil. [α]2D5 = –11.3 (c = 0.87 in CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 0.67 (d, J = 6.8 Hz, 3 H), 0.89 (s, 3 H), 1.05 (s, 3 H), 1.27–1.70
(m, 11 H), 1.91 (dd, J = 2.9, 12.2 Hz, 1 H), 3.85–4.00 (m, 4 H),
9.16 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.9, 16.5,
16.6, 22.7, 23.3, 25.5, 29.8, 30.6, 34.5, 41.9, 42.3, 53.4, 64.9, 65.3,
A stirred suspension of tBuOK (15.8 g, 0.14 mol) and methyltri-
phenylphosphonium bromide (50.4 g, 0.14 mol) in anhydrous benz-
ene (300 mL) was heated at reflux under argon for 2 h. A solution
of 14 (5.51 g, 14 mmol) in anhydrous benzene (20 mL) was added
to the above the mixture at 0 °C. The resulting solution was heated
at reflux under argon for 1 h. After cooling, the reaction was
quenched with H2O (100 mL) at 0 °C, and the mixture was ex-
tracted with EtOAc (3 ϫ 200 mL). The combined extracts were
washed with brine (2ϫ 100 mL), then dried with MgSO4. Evapora-
tion of the solvent in vacuo gave a residue, which was diluted with
112.9, 206.7 ppm. IR (neat): ν = 2934, 2868, 2680, 2360, 2341,
˜
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1724, 1457, 1384, 1335, 1284, 1212, 1179, 1129, 1114, 1093, 1064,
1050, 1016, 985, 939, 898 cm–1. HRMS (EI): calcd. for C16H26O3
[M]+ 266.1882; found 266.1877.
(m, 11 H), 1.61 (s, 3 H), 1.66 (s, 3 H), 1.92 (d, J = 12.6 Hz, 1 H),
2.54 (d, J = 14.0 Hz, 1 H), 2.62 (d, J = 14.0 Hz, 1 H), 3.65–3.89
(m, 4 H), 3.70 (s, 3 H), 6.19 (d, J = 8.2 Hz, 1 H), 6.51 (d, J =
8.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.2, 17.3,
18.9, 22.4, 23.6, 26.2, 26.4, 28.4, 30.2, 31.3, 35.3, 38.4, 42.8, 44.4,
46.0, 56.1, 65.2, 65.6, 101.4, 105.2, 112.6, 114.1, 117.3, 141.3, 148.4,
(5-Methoxy-2,2-dimethylbenzo[d][1,3]dioxol-4-yl)[(4aЈS,5ЈR,6ЈS,8aЈS)-
5Ј,6Ј,8aЈ-trimethyloctahydro-2ЈH-spiro(1,3-dioxolane-2,1Ј-naphth-
alen-5Ј-yl)]methanol (16): tBuLi (1.5 m in pentane; 2.7 mL,
4.1 mmol) was added dropwise to a stirred solution of 5-methoxy-
2,2Ј-dimethylbenzo[d][1,3]dioxole (9; 739 mg, 4.1 mmol) in anhy-
drous THF (8.2 mL) at 0 °C under argon. After 30 min, a solution
of 7 (362 mg, 1.4 mmol) in anhydrous THF (6.8 mL) was added
dropwise to the above mixture at 0 °C, and the resulting solution
was stirred at room temperature for a further 1 h. The reaction
was quenched with NH4Cl (saturated aq.; 15 mL) at 0 °C, and the
resulting mixture was extracted with EtOAc (2ϫ 40 mL). The com-
bined extracts were washed with brine (2ϫ 20 mL), then dried with
MgSO4. Evaporation of the solvent in vacuo gave a residue, which
was purified by column chromatography (hexane/EtOAc, 20:1 Ǟ
6:1) to give 16 (ca. 4:1 diastereomeric mixture; 571 mg, 94%) as a
pale yellow amorphous solid. 1H NMR (400 MHz, CDCl3): δ =
0.58 (d, J = 6.3 Hz, 3/5 H), 0.77 (s, 3/5 H), 0.85 (s, 12/5 H), 0.95
(d, J = 6.8 Hz, 12/5 H), 1.06 (s, 12/5 H), 1.09 (s, 3/5 H), 1.12–1.68
154.6 ppm. IR (neat): ν = 2985, 2870, 2834, 2362, 2341, 1716, 1698,
˜
1684, 1635, 1558, 1540, 1520, 1507, 1462, 1437, 1382, 1337, 1212,
1179, 1162, 1104, 1046, 1024, 950, 936, 836, 799 cm–1. HRMS (EI):
calcd. for C26H38O5 [M]+ 430.2719; found 430.2712.
(4aS,5R,6S,8aS)-5-(2,3-Dihydroxy-6-methoxybenzyl)-5,6,8a-tri-
methyloctahydronaphthalen-1(2H)-one (18): HCl (12 m; 0.5 mL,
6.0 mmol) was added to a stirred solution of 17 (52.2 mg,
0.12 mmol) in EtOH (2.0 mL) at 0 °C. The reaction mixture was
heated at reflux for 5 h. After cooling, the reaction was quenched
with NaHCO3 (saturated aq.; 10 mL), and the resulting mixture
was extracted with EtOAc (3 ϫ 20 mL). The combined extracts
were washed with brine (2 ϫ 10 mL), then dried with MgSO4.
Evaporation of the solvent in vacuo gave a residue, which was puri-
fied by column chromatography (hexane/EtOAc, 4:1) to give 18
(33.4 mg, 71%) as a pale yellow amorphous solid. [α]2D4 = –33.8 (c
1
(m, 12 H), 1.63 (s, 3/5 H), 1.64 (s, 24/5 H), 1.69 (s, 3/5 H), 1.94– = 0.58 in CHCl3). H NMR (400 MHz, CDCl3): δ = 0.94 (s, 3 H),
2.05 (m, 8/5 H), 2.29–2.33 (m, 2/5 H), 3.75–3.96 (m, 4 H), 3.76 (s,
3/5 H), 3.77 (s, 12/5 H), 4.86 (d, J = 10.7 Hz, 4/5 H), 5.34 (s, 1/5
H), 6.20 (d, J = 8.3 Hz, 1/5 H), 6.22 (d, J = 8.8 Hz, 4/5 H), 6.53
(d, J = 8.3 Hz, 1/5 H), 6.54 (d, J = 8.3 Hz, 4/5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 12.5, 13.1, 16.6, 17.3, 18.1, 18.9, 21.8, 22.9,
23.2, 23.5, 25.8 (2 C), 25.9, 27.9, 29.0, 29.5, 29.9, 30.7, 30.9, 33.1,
35.5, 41.8, 42.3, 43.8, 44.5, 46.5, 46.7, 55.6 (2 C), 65.2, 65.3, 101.5,
101.7, 105.5, 113.5, 113.6, 117.8, 141.3, 141.4, 146.0, 152.9 ppm.
0.94 (d, J = 6.3 Hz, 3 H), 1.16 (s, 3 H), 1.22–1.73 (m, 8 H), 1.99–
2.04 (m, 1 H), 2.14–2.23 (m, 2 H), 2.59 (dt, J = 7.3, 13.7 Hz, 1 H),
2.65 (d, J = 14.1 Hz, 1 H), 2.71 (d, J = 13.7 Hz, 1 H), 3.68 (s, 3
H), 5.01 (br. s, 1 H), 5.57 (s, 1 H), 6.22 (d, J = 8.8 Hz, 1 H), 6.67
(d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.4,
18.4, 18.9, 22.5, 26.1, 27.5, 32.2, 34.3, 37.4, 37.6, 43.2, 49.5, 49.7,
55.2, 100.8, 112.7, 115.1, 136.7, 145.3, 153.8, 218.3 ppm. IR (neat):
ν = 2923, 2853, 1684, 1558, 1540, 1488, 1456, 1379, 1313, 1287,
˜
IR (neat): ν = 2933, 2359, 2340, 1715, 1698, 1682, 1651, 1557, 1539,
1254, 1160, 1128, 1082, 958, 940, 938, 842, 821 cm–1. HRMS (EI):
calcd. for C21H30O4 [M]+ 346.2122; found 346.2144.
˜
1506, 1456, 1385, 1252, 1214, 1129, 1078, 1060, 995, 979, 898,
790 cm–1. HRMS (FAB): calcd. for C26H39O6 [M + H]+ 447.2747;
found 447.2736.
3-{[(1R,2S,4aS,8aS)-5-Hydroxy-1,2,4a,5-tetramethyldecahydro-
naphthalen-1-yl]methyl}-4-methoxybenzene-1,2-diol (5): MeMgBr
(3.0 m in Et2O; 96 μL, 0.29 mmol) was added dropwise to a stirred
solution of 18 (20 mg, 58 μmol) in anhydrous THF (5.7 mL) at 0 °C
under argon, and stirring was continued at room temperature for
1 h. The reaction was quenched with HCl (1 m; 3 mL) at 0 °C, and
the resulting mixture was extracted with EtOAc (3ϫ 15 mL). The
(4aЈS,5ЈR,6ЈS,8aЈS)-5Ј-{(5-Methoxy-2,2-dimethylbenzo[d][1,3]di-
oxol-4-yl)methyl}-5Ј,6Ј,8aЈ-trimethyloctahydro-2ЈH-spiro(1,3-dioxol-
ane-2,1Ј-naphthalene) (6): NaN(SiMe3)2 (1.0 m in THF; 1.6 mL,
1.6 mmol) was added dropwise to a stirred solution of 16 (153 mg,
0.32 mmol) in anhydrous THF (3.2 mL) at –78 °C under argon.
After 30 min, CS2 (0.39 mL, 6.5 mmol) was added dropwise to the combined extracts were washed with NaHCO3 (saturated aq.; 2ϫ
mixture at –78 °C, and the resulting mixture was stirred at –65 °C
for 1 h. MeI (0.41 mL, 6.5 mmol) was added dropwise to the mix-
ture at –65 °C, and the resulting mixture was stirred at the same
temperature for a further 1 h. The reaction was quenched with
NH4Cl (saturated aq.; 10 mL), and the resulting mixture was ex-
tracted with EtOAc (3 ϫ 20 mL). The combined extracts were
10 mL) and brine (2ϫ 10 mL), then dried with MgSO4. Evapora-
tion of the solvent in vacuo gave a residue, which was purified by
column chromatography (hexane/EtOAc, 3:1 Ǟ 1:1) to give 5 (ca.
1:1.7 diastereomeric mixture; 14.7 mg, 70%) as a white amorphous
solid. H NMR (400 MHz, CDCl3): δ = 0.87 (s, 3 H), 0.88 (d, J =
3.4 Hz, 5.1/2.7 H), 0.93 (d, J = 6.3 Hz, 3/2.7 H), 0.98 (s, 5.1/2.7 H),
1
washed with brine (2ϫ 15 mL), then dried with MgSO4. Evapora- 1.04 (s, 5.1/2.7 H), 1.12 (s, 3/2.7 H), 1.16–1.91 (m, 13 H), 2.60–2.72
tion of the solvent in vacuo gave a residue, which was purified
by column chromatography (hexane/EtOAc, 10:1) to give methyl
xanthate 17 (142 mg, 0.26 mmol) as a yellow amorphous solid.
(m, 2 H), 3.70 (s, 3 H), 4.88 (s, 1/2.7 H), 5.3 (s, 1.7/2.7 H), 5.49 (s,
1/2.7 H), 5.58 (s, 1.7/2.7 H), 6.23–6.27 (m, 1 H), 6.64–6.69 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.1, 17.1 (2 C), 17.9,
18.5 (2 C), 22.5, 22.9, 23.2, 23.5, 23.6, 23.8, 28.0, 29.7, 31.3, 31.4,
34.8, 35.3, 37.2, 37.8, 38.1, 41.9, 42.2, 42.4, 55.3, 76.8, 100.9, 112.5,
nBu3SnH (0.36 mL, 1.3 mmol) and 2,2Ј-azobis(isobutyronitrile)
(AIBN; 22 mg, 0.13 mmol) were added successively to a stirred
solution of 17 (142 mg, 0.26 mmol) in anhydrous benzene (8.8 mL)
at room temperature. To degas the reaction mixture, it was frozen
by using liquid nitrogen, then the reaction vessel was placed under
vacuum for 30 min and then filled with dry argon. The mixture was
heated at reflux under argon for 5 h. After cooling, the reaction
mixture was concentrated in vacuo to give a residue, which was
purified by column chromatography (hexane/EtOAc, 1:0 Ǟ 15:1)
to give 6 (108 mg, 78% over 2 steps) as a colourless viscous liquid.
115.9, 137.2, 145.2, 153.8, 153.9 ppm. IR (neat): ν = 3545, 3445,
˜
2933, 2353, 2320, 1748, 1732, 1716, 1698, 1683, 1652, 1558, 1540,
1487, 1472, 1457, 1375, 1338, 1288, 1252, 1172, 1082, 997 cm–1.
HRMS (EI): calcd. for C22H34O4 [M]+ 362.2457; found 362.2458.
(4aS,7S,7aR,13aS)-9-Methoxy-4, 4,7,7a-tetramethyl-
1,2,3,4,4a,5,6,7,7a,8-decahydrobenzo[d]xanthen-12-ol [(+)-Strongy-
lin A] (1): BF3·OEt2 (51 μL, 0.39 mmol) was added to a stirred solu-
tion of 5 (14.2 mg, 39 μmol) in anhydrous CH2Cl2 (1.3 mL) at
–78 °C under argon, and the resulting mixture was gradually
warmed to 0 °C over 3 h. The reaction was quenched with NH4Cl
1
[α]2D1 = –5.0 (c = 1.64 in CHCl3). H NMR (400 MHz, CDCl3): δ
= 0.81 (s, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 1.04 (s, 3 H), 1.23–1.68
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30438
/KAP1
Date: 13-06-13 12:17:11
Pages: 7
Total Synthesis of (+)-Strongylin A
b) K. Minagawa, S. Kouzuki, J. Yoshimoto, Y. Kawamura, H.
(saturated aq.; 2 mL) at 0 °C, and the resulting mixture was ex-
tracted with CHCl3 (3ϫ 5 mL). The combined extracts were
washed with brine (2ϫ 3 mL), then dried with MgSO4. Evapora-
tion of the solvent in vacuo gave a residue, which was purified by
column chromatography (hexane/EtOAc, 20:1) to give 1 (11.3 mg,
84%) as a white amorphous solid. [α]2D3 = +83.3 (c = 0.024 in
Tani, T. Iwata, Y. Terui, H. Nakai, S. Yagi, N. Hattori, T. Fuji-
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171.
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Ishikawa, T. Katoh, Chem. Eur. J. 2008, 14, 829–837; b) A.
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1
CH2Cl2), {lit.[3] [α]2D0 = +72.0 (c = 0.023 in CH2Cl2)}. The H and
13C NMR, IR, and MS spectra (see below) were identical to those
of natural (+)-strongylin A. 1H NMR (400 MHz, [D6]benzene): δ
= 0.64 (s, 3 H), 0.82 (s, 3 H), 0.88 (d, J = 7.3 Hz, 3 H), 1.10 (s, 3
H), 1.19–1.40 (m, 7 H), 1.52–1.67 (m, 3 H), 1.80–1.90 (m, 2 H),
2.33 (d, J = 17.6 Hz, 1 H), 3.23 (d, J = 18.0 Hz, 1 H), 3.41 (s, 3
H), 5.12 (s, 1 H), 6.12 (d, J = 8.8 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 1
H) ppm. 13C NMR (100 MHz, [D6]benzene): δ = 17.3, 18.8, 20.3,
22.6, 27.9, 29.2, 29.4, 32.1, 32.8, 33.4, 33.9, 38.2, 39.8, 43.9, 54.9,
83.8, 100.8, 110.7, 111.4, 139.6, 139.7, 151.3 ppm. IR (neat): ν =
˜
3566, 2934, 2873, 1717, 1618, 1464, 1385, 1323, 1304, 1119, 1090,
1055, 1024, 1011, 978, 947, 887, 877, 851 cm–1. HRMS (EI): calcd.
for C22H32O4 [M]+ 344.2351; found 344.2357.
Supporting Information (see footnote on the first page of this arti-
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1
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This study was supported by a Grant-in-Aid for the Strategic Re-
search Foundation Program at Private Universities (2010–2014)
from the Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan (MEXT) and a Grant-in-Aid for Scientific Research
(C) (No. 24590017) from MEXT.
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[20] Attempted Wittig methylenation of ketone 18 [Ph3P+CH3Br–,
tBuOK or NaN(SiMe3)2, benzene or THF, 0 °C Ǟ reflux] was
unsuccessful, presumably due to the influence of the two hy-
droxy groups in the aromatic ring. Therefore, we looked at a
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carbocation I (cf. Scheme 4).
[7] a) T. Kamigauchi, T. Fujiwara, H. Tani, Y. Kawamura, I. Hor-
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Received: March 25, 2013
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7