A formal total synthesis of dysiherbaine and neodysiherbaine A

Article abstract of DOI:10.1002/ejoc.201200439

A domino olefin metathesis reaction of 1-alkyl-3-(allyloxy)-7-oxabicyclo[2. 2.1]hept-5-enes 7 produced the fused bis(oxacyclic) structure for dysiherbaine and neodysiherbaine A (i.e., 6b) with the complete control of the relative stereochemistry at the quaternary carbon center and the ring junction of the dysiherbaine core skeleton. A formal total synthesis of dysiherbaine and neodysiherbaine A was achieved from 6b. A domino ring-opening/ring-closing olefin metathesis reaction of 7 produced the core structure of dysiherbaine and neodysiherbaine A with complete control of the relative stereochemistry. The stereoselective functionalization of 6b produced 5, the known intermediate for the total synthesis of dysiherbaine and neodysiherbaine A.

Full text of DOI:10.1002/ejoc.201200439

Job/Unit: O20439
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Date: 19-06-12 15:09:29
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201200439
A Formal Total Synthesis of Dysiherbaine and Neodysiherbaine A
Hee-Yoon Lee,*[a] Sang-Shin Lee,[a] Hoon Seok Kim,[a] and Kang Mun Lee[a]
Keywords: Total synthesis / Natural products / Oxygen heterocycles / Cycloaddition / Domino reactions / Chiral resolution
A domino olefin metathesis reaction of 1-alkyl-3-(allyloxy)-
7-oxabicyclo[2.2.1]hept-5-enes 7 produced the fused bis-
(oxacyclic) structure for dysiherbaine and neodysiherbaine A
(i.e., 6b) with the complete control of the relative stereochem-
istry at the quaternary carbon center and the ring junction of
the dysiherbaine core skeleton. A formal total synthesis of
dysiherbaine and neodysiherbaine A was achieved from 6b.
eral reports for the total syntheses of dysiherbaine,[7] neody-
siherbaine A,[8] and their unnatural analogues.[9] The main
challenge of the total syntheses for these compounds was
the stereoselective construction of the core structure of the
natural products along with control of the relative stereo-
chemistry at C-4, C-6, and C-7. Most of the reported total
syntheses carried out the preparation of the fused bis-
(oxacyclic) system by starting from the existing tetra-
hydropyran ring system. The stereochemistry at C-4 was in-
troduced directly either during the formation of the tetra-
hydrofuran ring or during the quaternization of the C-4
center of the core ring system, occurring with low stereose-
lectivity in most cases. We became interested in the stereose-
lective synthesis of the core structure of the dysiherbaines,
that is, compound 5 which is a common intermediate in the
total syntheses of DH and DHA. The advanced intermedi-
ate 5 could be prepared from 6. The protected diol of 5
could be introduced stereoselectively from the correspond-
ing olefin, and the ester group of 5 could be prepared
through the oxidative cleavage of the corresponding C–C
double bond. Intermediate 6, possessing two olefins, could
readily be obtained through the tandem ring-opening/
Introduction
The activity-guided screening of the marine sponge Dysi-
dea herbacea for seizurogenic activity led to the isolation of
dysiherbaine (DH) and neodysiherbaine A (NDH).[1] DH
and NDH, along with kainic acid and domoic acid, belong
to a class of compounds called excitatory amino acids
(EAAs, Figure 1).[2] These compounds are agonists of iono-
tropic glutamate receptors (iGluRs) that play central roles
in excitatory neurotransmission in the mammalian central
nervous system (CNS) and are implicated in various neuro-
logical diseases.[3] Also, DH and NDH are selective agonists
for GluK1,[4] which is associated with pain pathways and
epilepsy,[5] and their activity relationship guides the devel-
opment of drugs for the treatment of epilepsy, stroke, and
neuropathic pain.[6]
ring-closing metathesis of oxabicyclo[2.2.1]heptene
7
(Scheme 1).[10]
Figure 1. Structures of dysiherbaines, kainic acid, and domoic acid.
The unique structural features and interesting biological
activities of the dysiherbaines have attracted the attention
of the synthetic chemistry community. There have been sev-
[a] Department of Chemistry, KAIST,
Daejeon, Korea 305-701
E-mail: leehy@kaist.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200439.
Scheme 1. Retrosynthetic analysis of dysiherbaines.
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H.-Y. Lee, S.-S. Lee, H. S. Kim, K. M. Lee
FULL PAPER
The bicyclic structure of 7 could be prepared from substi- Diels–Alder product that was then converted by meth-
tuted furan 8 through a Diels–Alder reaction[11] which anolysis into dimethyl acetal 10, though the overall effi-
could introduce the relative stereochemistry selectively at C- ciency was lower than the corresponding series of reactions
4, C-6, and C-7 either directly through a Diels–Alder reac- with 2-methylfuran.[13] In addition to the low efficiency, the
tion with an oxygenated dienophile or through functional hydrolysis product of 10 was unstable to various decarbox-
group manipulations of a Diels–Alder adduct from a dieno- ylation reaction conditions[14] which prevented the synthesis
phile with an activating group. The ring-opening/ring-clos- of 11. To circumvent the decarboxylation problem, the ester
ing metathesis reaction would transform the relative stereo- group was substituted with a reductively removable sulfonyl
chemistry of 7 into the relative stereochemistry of 6. The group.[15] However, the Diels–Alder reaction of 12 with 8
olefin metathesis reaction could proceed in a domino fash- produced two regioisomeric products with low selectivity.[16]
ion[9c] to introduce another functional group to the terminal At last, the Diels–Alder reaction of symmetric dienophile
olefin of 6a. This would differentiate the two double bonds 14 was explored.[17] When bis(phenylsulfonyl)ethylene was
of 6 for their selective manipulation in subsequent steps. used as the dienophile, the Diels–Alder reaction stereoselec-
The domino metathesis strategy to construct the core struc- tively produced the Diels–Alder adduct. Regio- and stereo-
ture of the dysiherbaines appeared quite feasible, as a sim- selective alkoxide displacement of the exo-sulfonyl group
ilar strategy has been used in the preparation of structural produced 15 as the sole product with the introduction of
analogues of the core skeleton of the dysiherbaines.[9c,10b]
an oxygen atom at the C-6 position.[18] Reductive removal
of the sulfonyl group of 15[19] and the inversion of the
stereochemistry at C-6 would furnish the desired intermedi-
ate 7 for use in the metathesis reaction. Prior to these trans-
formations, we resolved the two enantiomers of 15 by form-
ing its ester from a chiral carboxylic acid. As there were
two available alcohol functional groups in 15 for the attach-
ment of the chiral auxiliary, the PMB (p-methoxybenzyl)
protecting group was oxidatively removed to give the free
alcohol 16, which was then resolved through the prepara-
tion of (+)-O-acetyl-l-mandelates 18a and 18b (Scheme 3).
Results and Discussion
At the outset of the total synthesis, compound 7 with its
moderate complexity prepared through a Diels–Alder reac-
tion of a substituted furan turned out not to be a straight-
forward task. The Diels–Alder reaction with 2-alkyl-substi-
tuted furans require electron-poor dienophiles for good re-
activity.[12] Thus, the oxygen functionality at the C-6 posi-
tion of 7 had to be introduced by converting the electron-
withdrawing group installed by the dienophile in the Diels–
Alder reaction into a hydroxy group. Taking into account
the reactivity with substituted furans and the introduction
of the oxygen functionality at C-6, bromopropiolate, bro-
moacetylenyl sulfone, and bis(phenylsulfonyl)ethylene were
explored for the Diels–Alder reaction and the ensuing func-
tional group transformations (Scheme 2).
Scheme 3. Preparation of enantiomerically pure 7.
Scheme 2. Diels–Alder reaction of a silyl ether of furfuryl alcohol.
Gratifyingly, 18a was recrystallized to form a crystalline
material suitable for X-ray crystal structure analysis. The
The Diels–Alder reaction of methyl bromopropiolate (9) absolute stereochemistry of 18a clearly indicated that 18b
with TBS-protected (tert-butyldimethylsilyl-protected) fur- was the correct isomer for the total synthesis of the dysiher-
furyl alcohol (8) regioselectively produced the anticipated baines (Figure 2).[20]
2
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A Formal Total Synthesis of Dysiherbaine and Neodysiherbaine A
Figure 2. ORTEP diagram of X-ray crystal structure of 18a.
The chiral auxiliary was removed from the separated iso-
mer 18b using LiOH to produce the enantiomerically pure
alcohol 16Ј. Under these reaction conditions, the hydrolysis
reaction did not compete with the possible base-promoted
dehydration reaction[21] previously reported by Rick-
born.[18] At this stage, the reductive removal of the sulfone
using Na(Hg) produced alcohol 19 without the possible
complication of an elimination reaction. Inversion of the
stereochemistry at C-6 in 19 through an oxidation–re-
duction sequence stereoselectively produced 20. Preparation
of the allylic ether of 20 furnished precursor 7 for use in the
key tandem ring-opening/ring-closing metathesis reaction.
The tandem ring-opening/ring-closing metathesis (ROM/
RCM) reaction of 7 using the Grubbs II catalyst unevent-
fully produced 6a with the correct relative stereochemistry
for the core skeleton of dysiherbaine. Although the two ole-
fins in 6a could have different reactivities towards oxidative
functionalization reactions, to further differentiate them, 6b
was stereoselectively prepared through a domino metathesis
reaction of 7 with vinyl acetate using Hoveyda–Grubbs II
catalyst. The enol acetate group was expected to provide a
distinct electronic environment for selective functionaliza-
tion reactions (Scheme 4).
Scheme 4. Rearrangement of bicyclic structure through tandem
metathesis.
Table 1. Selective epoxidation of 6a.
Entry
R
Reagents
21[a]
22[a]
1
2
3
TBS
TBS
TBS
m-CPBA[b]/CH2Cl2, 0 °C
Oxone/acetone, NaHCO3
TFA,[b] DCC,[b] DMAP,[b]
H2O2/CH2Cl2
–
–
12%
7%
–
37%[c]
[e]
4
5
6
TBS
H
TFAA,[b] H2O2, NaHCO3/
37%[c]
–
[d]
CH2Cl2
Ti(OiPr)4, (–)-DET,[b] TBHP[b]
CH2Cl2
/
–
–
H
VO(acac)2, TBHP/PhH
–
–
Initially, we envisioned that the two olefins in 6a should
be readily distinguishable by electrophilic reagents, as the
olefin of the pyran ring has a higher electron density than
the terminal olefin, which is also sterically hindered by the
adjacent quaternary center. However, we were unable to
find an oxidative reaction, among the ones tested, that
showed good selectivity along with efficiency (Table 1,
Scheme 5).
[a] Isolated yield. [b] m-CPBA = meta-chloroperoxybenzoic acid,
TFA = trifluoroacetic acid, DCC = N,NЈ-dicyclohexylcarbodi-
imide, DMAP = 4-(dimethylamino)pyridine, TFAA = trifluoro-
acetic anhydride, DET = diethyl tartrate, and TBHP = tert-butyl
hydroperoxide. [c] 2:1 mixture of diastereomers. [d] 50% H2O2 was
used. [e] Bis(epoxide) 23 was obtained in 39% yield.
When 6a was oxidized by m-CPBA, the anticipated selec-
tivity was observed, but in low yield. The oxidation reaction
was so sluggish that the starting material could not be com-
pletely consumed without the decomposition of the prod-
uct. The dimethyldioxirane oxidation of 6a proceeded with
similar reactivity and selectivity. To our surprise, when we
tested the more reactive peroxytrifluoroacetic acid gener-
ated in situ from trifluoroacetic acid and hydrogen perox-
ide,[22] a reversal in the selectivity was observed (Table 1,
Entry 3). The higher concentration of hydrogen peroxide
with trifluoroacetic anhydride[23] produced 21 and the bis- Scheme 5. Selective dihydroxylation of 6a.
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H.-Y. Lee, S.-S. Lee, H. S. Kim, K. M. Lee
FULL PAPER
(epoxide) in equal amounts (Table 1, Entry 4). A Sharpless converted into enol ether 30. As the direct ozonolysis of the
epoxidation reaction aiming for the selective epoxidation of enol ether of 30 to the corresponding methyl ester 5 pro-
the homoallylic alcohol did not produce any epoxide prod- ceeded with moderate efficiency,[25] 30 was subjected to the
ucts (Table 1, Entries 5 and 6).[24]
classical ozonolysis conditions to produce aldehyde 31.
Oxidation with OsO4 also gave a similar result as in Then, aldehyde 31 was oxidized by using a Pinnick oxi-
Table 1, Entry 4 to produce a mixture of diol 24 and tetraol dation[26] to afford the carboxylic acid, and the final esterifi-
25, whereas other oxidative reagents (PhSeX, KMnO4, cation step produced 5, that is, Sasaki’s intermediate[8b]
ozonolysis) only led to the decomposition of 6a. As the leading to both dysiherbaine and neodysiherbaine A.
selectivity and reactivity in the functionalization of 6a
turned out to be a difficult task, the domino metathesis
product 6b was explored for selective functionalization.
Contrary to our expectations, the seemingly electron-rich
vinyl acetate moiety of 6b could not be selectively oxidized
Conclusions
In summary, a formal total synthesis of dysiherbaine and
neodysiherbaine A was achieved through a Diels–Alder and
domino metathesis reaction sequence to construct the dy-
siherbaine core structure with complete stereocontrol. The
current synthesis offers an opportunity for the facile synthe-
sis of the dysiherbaine natural products and their analogues
for pharmacological study.
by ozonolysis, epoxidation, or dihydroxylation which only
led to the decomposition of 6b. As the bis(allylic) nature of
the two olefins of 6b appeared to be detrimental to oxidat-
ive reaction conditions, the vinyl acetate of 6b was hy-
drolyzed to aldehyde 26. As anticipated, the functional
group transformations of 26 proceeded smoothly to com-
plete the formal total synthesis of the dysiherbaines
(Scheme 6).
Experimental Section
General Information: The NMR spectroscopic data were obtained
with a Bruker DPX400 spectrometer (400 MHz for 1H NMR,
100 MHz for 13C NMR) or a Bruker AM300 spectrometer
1
(300 MHz for H NMR, 75 MHz for 13C NMR), and the spectra
were measured in CDCl3. The chemical shifts were recorded in ppm
relative to the internal standard CDCl3, and the coupling constants
were reported in Hz. The high resolution mass spectra were re-
corded with VG Autospec Ultima and JMS-700 spectrometers. X-
ray crystallography data were collected with a Bruker Apex II-CCD
area detector diffractometer. The detailed crystallographic data and
select bond lengths and angles are given in the Supporting Infor-
mation. All of the reactions were carried out in oven-dried glass-
ware under a N2 atmosphere. All of the solvents were distilled from
the indicated drying reagents directly before using them [Et2O and
THF (Na, benzophenone); CH2Cl2 (P2O5); and MeCN, 1,4-diox-
ane, and dimethylformamide (CaH2)]. The normal workup in-
cluded extraction, drying with MgSO4, and evaporation of the vol-
atile materials in vacuo. Purification by column chromatography
was performed using Merck (Darmstadt, Germany) silica gel 60
(230–400 mesh).
tert-Butyl{[(1S,2S,3R,4R)-3-(4-methoxybenzyloxy)-2-(phenylsulf-
onyl)-7-oxabicyclo[2.2.1]hept-5-en-1-yl]methoxy}dimethylsilane (15):
To a stirred solution of trans-1,2-bis(phenylsulfonyl)ethylene
(1.96 g, 6.36 mmol) in CH2Cl2 (196 mL) was added the TBS-pro-
tected furfuryl alcohol (4.04 g, 19.04 mmol). The reaction mixture
was stirred at room temperature for 5 d and then concentrated. The
residue was purified by column chromatography on silica (CH2Cl2/
EtOAc/n-hexane, 1:2) to give a white, solid product (2.75 g, 83.4%)
1H NMR (300 MHz, CDCl3): δ = 0.06 (s, 6 H), 0.89 (s, 9 H), 3.86
(d, J = 4.4 Hz, 1 H), 4.10 (dd, 1 H), 4.41 (d, 1 H), 4.52 (d, J =
4.4 Hz, 1 H), 5.34 (s, 1 H), 6.62 (s, 2 H), 7.46 (m, 4 H), 7.62 (m, 2
H), 7.66 (m, 2 H), 7.84 (d, 2 H) ppm. HRMS: calcd. for
C25H32O6S2SiNa 543.1307; found 543.1311. To a stirred solution
of sodium (198 mg, 8.61 mmol) in THF (20 mL) was added p-
methoxybenzyl alcohol (1.05 mL) at room temperature, and the
Scheme 6. Completion of the formal total synthesis.
The aldehyde moiety of 26 was not protected during the
functional group manipulations, but instead was reduced to
the corresponding alcohol 27, as the dihydroxylation and
acetonide formation proceeded more efficiently with 27
than 26. The dihydroxylation reaction stereoselectively in-
troduced from the β-face of the molecule two hydroxy
groups to the pyran ring, and the diol was protected as
acetonide 28. At this point, the primary alcohol was oxid-
ized back to the aldehyde to give 29 which was then further mixture was stirred for 1.2 h. The Diels–Alder product (896.38 mg,
4
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A Formal Total Synthesis of Dysiherbaine and Neodysiherbaine A
1.72 mmol) in THF (10 mL) was added through a cannula, and the
reaction mixture was stirred at room temperature for 2.5 h. The
reaction mixture was filtered, and the filtrate was diluted with water
(30 mL) and then extracted with EtOAc (30 mL). The combined
organic layers were washed with brine (10 mL), dried with magne-
sium sulfate, and concentrated. The residue was purified by flash
column chromatography (EtOAc/n-hexane, 1:3) to give 15
(818.28 mg, 92 %) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 0.06 (s, 6 H), 0.89 (s, 9 H), 3.81 (s, 3 H), 3.84 (d, J =
2.6 Hz, 1 H), 4.12 (d, 2 H), 4.16 (d, J = 2.6 Hz, 1 H), 4.87 (d, J =
1.6 Hz, 1 H), 6.48 (m, 2 H), 6.82 (d, 2 H), 7.05 (d, 2 H), 7.53
(m, 2 H), 7.65 (d, 1 H), 7.88 (m, 2 H) ppm. HRMS: calcd. for
C27H36O6SSiNa 539.1900; found 539.1909.
HRMS: calcd. for C29H36O8SSiNa 595.1798; found for 595.1793.
[α]2D6 = +47.4 (c = 0.34, CHCl3).
(1R,3S,4S)-4-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(phenylsulf-
onyl)-7-oxabicyclo[2.2.1]hept-5-en-2-ol (16Ј): To a stirred solution of
ester compound 18b (928.2 mg, 1.62 mmol) in THF (16 mL) was
added lithium hydroxide monohydrate (339.4 mg, 8.09 mmol), and
the solution was stirred at room temperature for 18 h. The reaction
mixture was then diluted with ice water (50 mL)/EtOAc (20 mL),
and the resulting solution was extracted with EtOAc (3ϫ10 mL).
The combined organic layers were washed with brine (10 mL),
dried with MgSO4, and concentrated. The residue was purified by
flash column chromatography (n-hexane/EtOAc, 3:1) to give 16Ј
(530.4 mg, 82.7%) as a colorless oil. 1H NMR (400 MHz, CDCl3):
δ = 7.89–7.88 (m, 2 H), 7.69–7.59 (m, 1 H), 7.60–7.50 (m, 2 H),
6.52 (dd, J = 5.8, 1.9 Hz, 1 H), 6.45 (d, J = 5.9 Hz, 1 H), 4.76 (d,
J = 1.9 Hz, 1 H), 4.40 (d, J = 2.3 Hz, 1 H), 4.21–4.01 (m, 2 H),
3.64 (d, J = 2.4 Hz, 1 H), 0.85 (s, 7 H), 0.04 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 140.6, 135.7, 135.2, 133.7, 129.3,
127.8, 91.9, 85.9, 70.2, 61.0, 25.8, 18.3, –5.4 (d, J = 3.7 Hz) ppm.
HRMS: calcd. for C19H28O5SSiNa 419.1324; found 419.1324.
[α]2D7 = –16.3 (c = 0.78, CHCl3).
rac-(1R,2R,3S,4S)-4-[(tert-Butyldimethylsilyloxy)methyl]-3-(phen-
ylsulfonyl)-7-oxabicyclo[2.2.1]hept-5-en-2-ol (16): To a stirred solu-
tion of 15 (818.28 mg, 1.58 mmol) in a mixture of CH2Cl2 (15 mL)/
water (1 mL) was added DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, 539.2 mg, 2.38 mmol) at ice bath temperature. The
reaction mixture was stirred at room temperature for 3.5 h. The
reaction mixture was diluted with a mixture of water (10 mL)/satu-
rated sodium hydrogen carbonate solution (10 mL), and the re-
sulting mixture was extracted with CH2Cl2 (2ϫ5 mL). The com-
bined organic layers were washed with a saturated solution of so-
dium hydrogen carbonate (10 mL) and then brine (10 mL), dried
with magnesium sulfate, and concentrated. The residue was puri-
fied by flash column chromatography (EtOAc/n-hexane, 1:2) to give
(1R,4S)-4-{[(tert-Butyldimethylsilyl)oxy]methyl}-7-oxabicyclo-
[2.2.1]hept-5-en-2-ol, (19): To a stirred solution of alcohol 16Ј
(498.0 mg, 1.26 mmol) in methyl alcohol (15 mL) was added
NaH2PO4 monohydrate (866.6 mg, 6.28 mmol) at ice bath tempera-
ture. To the reaction was added 5% sodium amalgam (1.74 g), and
the mixture was stirred at room temperature for 1.5 h. The reaction
mixture was filtered through Celite, and the filtrate was concen-
trated. The residue was purified by flash column chromatography
(n-hexane/EtOAc, 2:1) to give 19 (238.4 mg, 74%) as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 6.31 (d, J = 4.5 Hz, 1 H),
6.25 (dd, J = 4.5, 1.5 Hz, 1 H), 4.70 (d, J = 1.5 Hz, 1 H), 4.00 (s,
2 H), 3.98 (d, J = 1.5 Hz, 1 H), 1.85 (dd, J = 9.3, 4.8 Hz, 1 H),
1.32 (dd, J = 9.3, 1.5 Hz, 1 H), 0.88 (s, 9 H), 0.08 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 139.7, 133.3, 89.5, 85.8, 73.0,
63.1, 38.6, 25.9, 18.39, –5.4 ppm. [α]2D7 = +17.5 (c = 0.47, CHCl3).
1
16 (468.5 mg, 74.6%). H NMR (300 MHz, CDCl3): δ = 0.04 (s, 6
H), 0.84 (s, 9 H), 3.63 (d, J = 2.3 Hz, 1 H), 4.03 (d, 1 H), 4.16 (d,
1 H), 4.40 (d, J = 2.3 Hz, 1 H), 4.76 (d, J = 1.9 Hz, 1 H), 6.44 (d,
J = 5.8 Hz, 1 H), 6.51 (dd, J = 1.9 Hz, 1 H), 7.55 (t, 2 H), 7.62 (t,
1 H), 7.88 (d, 2 H) ppm.
(2S)-(1R,3S,4S)-4-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(phen-
ylsulfonyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl 2-Acetoxy-2-phenyl-
acetate (18b): To a solution of alcohol 16 (1.57 g, 3.95 mmol),
DMAP (2.41 g, 19.77 mmol), and (S)-2-acetoxy-2-phenylacetic
acid (921 mg, 4.743 mmol) in CH2Cl2 (15 mL) was added DIC
(N,NЈ-diisopropylcarbodiimide, 1.84 mL, 11.86 mmol), and the re-
action mixture was stirred at room temperature for 3 h. The reac-
tion mixture was diluted with ice water (50 mL), and the resulting
mixture was extracted with CH2Cl2 (3ϫ20 mL). The combined or-
ganic layers were washed with brine (10 mL), dried with MgSO4,
and concentrated. The residue was purified by flash column
chromatography (n-hexane/EtOAc/CH2Cl2, 10:1:2) to give the de-
sired product 18b (980.3 mg, 43.2%) as a colorless oil and dia-
(1R,2R,4S)-4-{[(tert-Butyldimethylsilyl)oxy]methyl}-7-oxabicyclo-
[2.2.1]hept-5-en-2-ol (20): To a stirred solution of alcohol 19
(232.3 mg, 0.91 mmol) in CH2Cl2 (10 mL) was added DMP (Dess–
Martin periodinane, 576.4 mg, 1.36 mmol) at ice bath temperature,
and the resulting mixture was stirred at room temperature for 12 h.
The reaction mixture was then diluted with a saturated sodium
hydrogen carbonate solution (20 mL), and the resulting solution
was extracted with CH2Cl2 (3ϫ10 mL). The combined organic lay-
stereomer 18a (961.7 mg, 42.4%) as a white solid. Data for 18b: 1H ers were washed with brine (20 mL), dried with MgSO4, and con-
NMR (400 MHz, CDCl3): δ = 7.80 (m, 2 H), 7.55 (m, 1 H), 7.42 centrated. The concentrated residue was diluted with EtOAc/n-hex-
(m, 2 H), 7.24 (m, 5 H), 6.54 (d, J = 5.7 Hz, 1 H), 6.51 (d, J =
1.8 Hz, 1 H), 5.63 (s, 1 H), 5.32 (d, J = 2.6 Hz, 1 H), 4.64 (d, J =
1.8 Hz, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 4.11 (d, J = 12.0 Hz, 1
H), 3.87 (d, J = 2.5 Hz, 1 H), 2.09 (s, 3 H), 0.87 (s, 9 H), 0.08 (d,
J = 17.0 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.0,
168.2, 140.3, 136.9, 134.9, 133.7, 132.9, 129.3, 129.2, 128.8, 127.7,
127.2, 92.3, 83.4, 78.7, 74.4, 66.9, 60.9, 25.8, 20.5, 18.3, –5.4 ppm.
HRMS: calcd. for C29H36O8SSiNa 595.1798; found for 595.1793.
ane (1:1 solution, 15 mL), and the mixture was filtered through
silica gel to give the ketone product (210.9 mg, 91.5%) as an oil.
1H NMR (400 MHz, CDCl3): δ = 6.58 (d, J = 5.8 Hz, 1 H), 6.47
(ddd, J = 5.7, 2.0, 0.8 Hz, 1 H), 4.60 (d, J = 2.0 Hz, 1 H), 4.07 (s,
2 H), 2.23 (dd, J = 15.8, 0.8 Hz, 1 H), 1.92 (d, J = 15.7 Hz, 1 H),
0.89 (s, 8 H), 0.09 (s, 7 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 208.1, 142.4, 131.6, 90.8, 83.7, 62.9, 35.5, 25.8, 18.3, –5.4 ppm.
HRMS: calcd. for C13H22O3SiNa 277.1236; found 277.1240. To a
stirred solution of the ketone (190.1 mg, 0.75 mmol), methyl
1
[α]2D5 = –4.0 (c = 0.51, CHCl3). Data for 18a: H NMR (400 MHz,
CDCl3): δ = 7.44 (m, 2 H), 7.30 (m, 1 H), 7.23 (m, 5 H), 7.15 (m, alcohol (1 mL), and CH2Cl2 (6 mL) was added sodium borohydride
2 H), 6.54 (m, 2 H), 5.72 (s, 1 H), 5.34 (d, J = 2.8 Hz, 1 H), 4.88
(d, J = 1.6 Hz, 1 H), 4.37 (d, J = 12 Hz, 1 H), 4.11 (d, J = 12 Hz,
1 H), 3.72 (d, J = 2.4 Hz, 1 H), 2.08 (s, 3 H), 0.85 (s, 9 H), 0.42 (d,
J = 13 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1,
168.0, 140.1, 136.9, 135.0, 133.6, 132.9, 129.2, 129.0, 128.8, 127.5,
127.4, 92.3, 83.8, 78.5, 74.2, 66.8, 60.8, 25.8, 20.5, 18.2, –5.4 ppm.
(42.7 mg, 1.13 mmol) at ice bath temperature. The reaction mixture
was stirred at ice bath temperature for 3 h. The mixture was then
diluted with CH2Cl2 (5 mL)/water (5 mL), and the resulting solu-
tion was extracted with CH2Cl2 (3ϫ5 mL). The combined organic
layers were washed with brine (5 mL), dried with MgSO4, and con-
centrated. The residue oil 20 was used in the next step without
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O20439
/KAP1
Date: 19-06-12 15:09:29
Pages: 9
H.-Y. Lee, S.-S. Lee, H. S. Kim, K. M. Lee
FULL PAPER
further purification. 1H NMR (400 MHz, CDCl3): δ = 6.54 (d, J
of diene 6a, (229.0 mg, 0.77 mmol) in CH2Cl2 (10 mL) were added
= 4.2 Hz, 1 H), 6.37 (dd, J = 4.2, 1.2 Hz, 1 H), 4.85 (dd, J = 3.3, sodium hydrogen carbonate (324.4 mg, 3.87 mmol) and hydrogen
1.2 Hz, 1 H), 4.5 (m, 1 H), 3.93 (s, 2 H), 2.15 (dd, J = 9, 6.3 Hz, 1
H), 1.01 (dd, J = 9, 1.8 Hz, 1 H), 0.88 (s, 9 H), 0.60 (s, 6 H) ppm.
peroxide (50% solution, 2 mL) at –15 °C. Trifluoroacetic anhydride
(0.22 mL, 1.55 mmol) was added to the reaction mixture, and the
13C NMR (100 MHz, CDCl3): δ = 139.3, 132.3, 91.1, 80.1, 70.8, resulting mixture was stirred in an ice bath for 1.5 h. The reaction
63.3, 38.1, 25.9, 18.4, –5.4 ppm. HRMS: calcd. for C13H24O3SiNa
mixture was diluted with a mixture of saturated sodium hydrogen
carbonate (10 mL)/CH2Cl2 (5 mL), and the resulting solution was
extracted with CH2Cl2 (2ϫ5 mL). The combined organic layers
were washed with brine (5 mL), dried with MgSO4, and concen-
trated. The residue was purified by flash column chromatography
(n-hexane/EtOAc, 5:1) to give epoxide 21 (58.4 mg, 24.2%), its dia-
stereomer (30.8 mg, 12.7%), and a bis(epoxide) (99.63 mg, 39.3%).
279.1392; found 279.1387. [α]2D3 = +62.5 (c = 0.33, CHCl3).
{[(1S,3R,4R)-3-(Allyloxy)-7-oxabicyclo[2.2.1]hept-5-en-1-yl]-
methoxy}(tert-butyl)dimethylsilane (7): To a stirred solution of so-
dium hydride (72 mg, 1.797 mmol) in DMF (dimethylformamide,
2 mL) was added dropwise endo alcohol 20, (153.58 mg,
0.599 mmol) in DMF (4 mL) at ice bath temperature over 10 min.
The reaction mixture was stirred at ice bath temperature for 0.5 h.
Allyl bromide (0.156 mL, 1.797 mmol) was then added over 5 min,
and the reaction mixture was stirred at ice bath temperature for
3 h. The mixture was then quenched with ice water (20 mL), and
the resulting solution was extracted with ethyl acetate (2ϫ5 mL).
The combined organic layers were washed with water (2ϫ5 mL)
and brine (5 mL), dried with MgSO4, and then concentrated. The
residue was purified by flash column chromatography on silica (n-
hexane/EtOAc, 20:1) to give 7 (137.27 mg, 77%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 6.34 (d, J = 4.5 Hz, 1 H), 6.31
(dd, J = 4.5, 1.2 Hz, 1 H), 5.81 (m, 1 H), 5.15 (m, 2 H), 4.93 (dd,
J = 3.3, 1.2 Hz, 1 H), 4.21 (m, 1 H), 3.94 (m, 4 H), 2.04, J = (dd,
J = 8.7, 6 Hz, 1 H), 1.12 (dd, J = 9, 1.8 Hz, 1 H), 0.89 (s, 9 H),
0.06 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.6, 134.6,
132.8, 117.3, 90.8, 79.0, 77.8, 71.2, 63.4, 34.9, 25.9, 18.4, –5.4 ppm.
HRMS: calcd. for C16H28O3SiNa 319.1705; found 319.1702. [α]2D3
= +69.0 (c = 0.50, CHCl3).
1
Data for 21: H NMR (400 MHz, CDCl3): δ = 6.00 (m, 2 H), 4.14
(m, 2 H), 4.01 (m, 2 H), 3.60 (d, J = 10.3 Hz, 1 H), 3.57 (d, J =
10.4 Hz, 1 H), 3.12 (dd, J = 4.2, 2.8 Hz, 1 H), 2.88 (dd, J = 5.0,
2.8 Hz, 1 H), 2.68 (dd, J = 4.9 Hz, J = 4.3 Hz, 1 H), 2.30 (dd, J =
14.6, 6.1 Hz, 1 H), 1.83 (d, J = 14.6 Hz, 1 H), 0.88 (s, 9 H), 0.05
(s, 6 H) ppm. Data for diastereomer of epoxide 21: 1H NMR
(300 MHz, CDCl3): δ = 6.02 (m, 2 H), 4.14 (m, 2 H), 4.04 (m, 2
H), 3.68 (m, 2 H), 3.06 (dd, J = 4.0, 2.8 Hz, 1 H), 2.82 (dd, J =
5.6, 2.7 Hz, 1 H), 2.73 (dd, J = 5.5, 4.1 Hz, 1 H), 2.52 (dd, J =
14.2, 5.8 Hz, 1 H), 2.01 (dd, J = 14.2 Hz, 1 H), 0.89 (s, 9 H), 0.09
1
(s, 6 H) ppm. Data for bis(epoxide): H NMR (400 MHz, CDCl3):
δ = 4.19 (t, J = 4.4 Hz, 1 H), 4.08 (d, J = 14.2 Hz, 1 H), 3.77 (m,
1 H), 3.65 (d, J = 10.4 Hz, 1 H), 3.60 (d, J = 13.2 Hz, 1 H), 3.50
(d, J = 10.5 Hz, 1 H), 3.44 (m, 1 H), 3.18 (dd, J = 4.1, 2.7 Hz, 1
H), 2.87 (dd, J = 4.9, 2.8 Hz, 1 H), 2.71 (t, J = 4.6 Hz, 1 H), 2.28
(dd, J = 14.6, 6.8 Hz, 1 H), 1.76 (d, J = 14.9 Hz, 1 H), 0.87 (s, 9
H), 0.05 (s, 6 H) ppm. HRMS: calcd. for C16H28O5SiNa 351.1604;
found 351.1608.
tert-Butyldimethyl{[(2R)-2-vinyl-3,3a,5,7a-tetrahydro-2H-furo-
[3,2-b]pyran-2-yl]methoxy}silane (6a): To a stirred solution of 7
(271.8 mg, 0.92 mmol) in CH2Cl2 (75 mL) was added Grubbs sec-
ond generation catalyst (38.9 mg, 0.05 mmol) at room temperature.
The reaction solution was heated to reflux for 1.5 h. The reaction
mixture was then cooled to room temperature and concentrated in
vacuo. The residue was purified by flash column chromatography
2-((2R,3aR,7aR)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3,3a,5,7a-
tetrahydro-2H-furo[3,2-b]pyran-2-yl)acetaldehyde (26): To a solu-
tion of vinyl acetate 6b (163.8 mg, 0.46 mmol) in methyl alcohol
(20 mL) was added potassium carbonate (63.8 mg, 0.46 mmol), and
the reaction mixture was stirred at –10 °C for 50 min. The reaction
mixture was then diluted with saturated ammonium chloride solu-
tion (100 mL)/EtOAc (50 mL)/water (20 mL), and the solution was
extracted with EtOAc (2ϫ10 mL). The combined organic layers
were washed with water (2ϫ20 mL) and brine (50 mL), dried with
MgSO4, and concentrated to give 26 (142.1 mg, 94.2%) as a color-
less oil. 1H NMR (400 MHz, CDCl3): δ = 9.78 (t, J = 2.6 Hz, 1
H), 6.07–5.94 (m, 2 H), 4.21–3.95 (m, 4 H), 3.53 (d, J = 0.8 Hz, 2
H), 2.75–2.56 (m, 2 H), 2.33 (dd, J = 14.3, 5.9 Hz, 1 H), 2.05–1.93
(m, 1 H), 0.86 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 202.7, 130.9, 122.7, 83.5, 77.0, 76.7, 73.3, 68.8, 64.2,
51.2, 40.1, 25.8, 18.2, –5.5 ppm. HRMS: calcd. for C16H28O4SiNa
335.1655; found 335.1659. [α]2D3 = –59.8 (c = 0.07, CHCl3).
1
on silica gel to give 6a (229.0 mg, 84.3%) as a pale yellow oil. H
NMR (400 MHz, CDCl3): δ = 6.02–5.92 (m, 3 H), 5.23 (dd, J =
13.4, 1.5 Hz, 2 H), 5.05 (dd, J = 11, 1.5 Hz, 2 H), 4.20 (m, 1 H),
4.11 (dd, J = 3.2 Hz, 1 H), 4.06 (m, 1 H), 3.99 (m, 1 H), 3.57 (d, J
= 10.3 Hz, 1 H), 3.47 (d, J = 10.3 Hz, 1 H), 2.55 (dd, J = 14.0,
6.0 Hz, 1 H), 1.96 (d, J = 14 Hz, 1 H), 0.88 (s, 9 H), 0.046 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.1, 130.3, 123.4,
113.5, 85.5, 77.4, 73.7, 68.9, 64.0, 39.7, 25.9, 18.3, –5.5 ppm.
2-((2R,3aR,7aR)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3,3a,5,7a-
tetrahydro-2H-furo[3,2-b]pyran-2-yl)vinyl Acetate (6b): To a stirred
solution of allyl ether 7, (130.2 mg, 0.44 mmol) in benzene (44 mL)
were added vinyl acetate (378 mg, 4.39 mmol) and the Hoveyda–
Grubbs second generation catalyst (22 mg, 0.04 mmol). The reac-
tion mixture was stirred at 60 °C for 4 h. The reaction mixture was
concentrated, and the residue was purified by flash column
chromatography (n-hexane/EtOAc, 10:1) to give the trans product
(132.2 mg, 84.9 %) and a mixture of the trans and cis products
2-((2S,3aR,7aR)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3,3a,5,7a-
tetrahydro-2H-furo[3,2-b]pyran-2-yl)ethanol (27): To a stirred solu-
tion of aldehyde 26 (12.1 mg, 0.037 mmol) in CH2Cl2 (1 mL)/
methyl alcohol (0.1 mL) was added sodium borohydride (3.2 mg,
0.085 mmol), and the reaction was stirred at room temperature for
1 h. The reaction mixture was quenched with water (1 mL), and
the resulting solution was extracted with CH2Cl2 (3ϫ1 mL). The
combined organic layers were washed with brine (2 mL), dried with
MgSO4, and concentrated. The concentrated residue (11.0 mg,
1
(16.4 mg, 10.5%). H NMR (300 MHz, CDCl3): δ = 7.24 (d, J =
12.5 Hz, 1 H), 6.00 (m, 2 H), 5.55 (d, J = 12.5 Hz, 1 H), 3.95 (m,
4 H), 3.57 (d, J = 10.2 Hz, 1 H), 3.46 (d, J = 10.2 Hz, 1 H), 2.51
(dd, J = 13.8, 5.8 Hz, 1 H), 2.06 (s, 3 H), 1.95 (d, J = 13.7 Hz, 1 H),
0.87 (s, 9 H), 0.045 (s, 6 H) ppm. HRMS: calcd. for C18H30O5SiNa
377.1760; found 377.1750. [α]2D7 = –38.7 (c = 0.31, CHCl3).
1
90.5%) was used next step without further purification. H NMR
(400 MHz, CDCl3): δ = 6.01 (tdd, J = 7.1, 3.6, 2.1 Hz, 2 H), 4.25–
3.97 (m, 4 H), 3.79 (dddd, J = 9.7, 7.8, 5.5, 2.7 Hz, 1 H), 3.58–3.40
(m, 3 H), 2.42 (dd, J = 14.5, 6.2 Hz, 1 H), 2.05 (d, J = 14.5 Hz, 1
H), 1.86–1.69 (m, 2 H), 0.87 (s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 130.9, 122.6, 85.6, 77.5, 73.5, 69.7, 64.3,
tert-Butyldimethyl({(2S)-2-[(R)-oxiran-2-yl]-3,3a,5,7a-tetrahydro-
2H-furo[3,2-b]pyran-2-yl}methoxy)silane (21): To a stirred solution
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20439
/KAP1
Date: 19-06-12 15:09:29
Pages: 9
A Formal Total Synthesis of Dysiherbaine and Neodysiherbaine A
58.9, 39.1, 38.4, 25.9, 18.2, –5.5 ppm. HRMS: calcd. for C16H30O4- (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.7, 108.7, 82.6,
SiNa 337.1811; found 337.1813.
78.0, 76.3, 72.3, 68.8, 68.3, 65.8, 51.0, 39.8, 28.1, 25.9, 18.3,
–5.5 ppm. [α]2D7 = –28.4 (c = 0.15, CHCl3).
2-((3aS,5aR,7S,8aS,8bS)-7-{[(tert-Butyldimethylsilyl)oxy]methyl}-
2,2-dimethylhexahydro-3aH-[1,3]dioxolo[4,5-d]furo[3,2-b]pyran-
7-yl)ethanol (28): To a solution of alkene 27 (105.9 mg, 0.32 mmol)
in a mixture of acetone (25 mL)/water (5 mL) were added NMO
(N-methylmorpholine-N-oxide, 75.5 mg, 0.64 mmol) and osmium
tetroxide solution (2.5 wt.-% solution in tert-butyl alcohol,
4.04 mL, 0.3224 mmol), and the solution was stirred at room tem-
perature for 16 h. The reaction mixture was quenched with sodium
hydrosulfite (16% solution, 10 mL) and then diluted with water
(10 mL). The solution was extracted with ethyl acetate (3ϫ10 mL).
The combined organic layers were washed with water (5 mL) and
brine (5 mL), dried with MgSO4, and concentrated. The residue
was purified by flash column chromatography (ethyl acetate) to
give a white, solid product (76.6 mg, 66%). 1H NMR (400 MHz,
CDCl3): δ = 4.21–4.08 (m, 2 H), 4.04–3.96 (m, 1 H), 3.85 (s, 1 H),
3.71–3.58 (m, 3 H), 3.55–3.42 (m, 3 H), 2.84 (d, J = 5.9 Hz, 1 H),
2.62 (d, J = 2.0 Hz, 1 H), 2.18 (dd, J = 14.3, 5.2 Hz, 1 H), 2.02–
1.87 (m, 2 H), 1.81–1.70 (m, 1 H), 0.87 (s, 9 H), 0.04 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 84.7, 81.6, 75.5, 68.8, 67.0, 64.7,
64.2, 59.0, 39.0, 38.3, 25.9, 18.3, –5.5 ppm. HRMS calcd. for
C16H32O6SiNa 371.1866; found 371.1861. To a stirred solution of
the triol compound (75 mg, 0.21 mmol) in CH2Cl2 (10 mL) were
added PPTS (pyridinium para-toluenesulfonate, 2.6 mg,
0.01 mmol) and 2-methoxypropene (39.6 μL, 0.41 mmol), and the
mixture was stirred at room temperature for 19 h. The reaction was
quenched with a saturated ammonium chloride solution (10 mL),
and the mixture was extracted with CH2Cl2 (3ϫ5 mL). The com-
bined organic layers were washed with saturated sodium hydrogen
carbonate solution (5 mL) and brine (5 mL), dried with MgSO4,
and concentrated. The residue was purified by flash column
chromatography (n-hexane/EtOAc, 3:1) to give 28 (76.6 mg, 92%)
tert-Butyl{[(E)-2-((3aS,5aR,7R,8aS,8bS)-7-{[(tert-butyldimethyl-
silyl)oxy]methyl}-2,2-dimethylhexahydro-3aH-[1,3]dioxolo[4,5-
d]furo[3,2-b]pyran-7-yl)vinyl]oxy}dimethylsilane (30): To a stirred
solution of aldehyde 29 (0.18 mmol), synthesized above, in CH2Cl2
(13 mL) were added DBU (1,8-diazabicyclo[5.4.0]undec-7-ene,
0.80 mL, 5.37 mmol) and tert-butyldimethylsilyl chloride (539 mg,
3.58 mmol). The reaction solution was stirred at room temperature
for 7 h, and then it was concentrated. The residue was purified by
flash column chromatography (n-hexane/EtOAc, 10:1) to give 30
(67.9 mg, 75.8% for 2 steps) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 6.47 (d, J = 11.9 Hz, 1 H), 5.05 (d, J = 12.0 Hz, 1 H),
4.42 (dd, J = 5.7, 1.7 Hz, 1 H), 4.21–4.08 (m, 3 H), 3.74 (dd, J =
11.5, 5.5 Hz, 1 H), 3.53 (d, J = 10.4 Hz, 1 H), 3.39 (d, J = 10.4 Hz,
1 H), 3.15 (dd, J = 11.5, 8.8 Hz, 1 H), 2.48 (dd, J = 13.8, 5.5 Hz,
1 H), 1.88 (d, J = 13.8 Hz, 1 H), 1.45 (s, 3 H), 1.34 (s, 3 H), 0.88
(d, J = 5.9 Hz, 18 H), 0.10 (s, 6 H), 0.04 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.8, 113.7, 108.5, 83.0, 78.1, 77.0, 72.4,
69.4, 65.0, 27.9, 26.0–25.5 (m), 18.3, –5.1 to –5.4 (m), –5.5 ppm.
(3aS,5aR,7S,8aS,8bS)-7-{[(tert-Butyldimethylsilyl)oxy]methyl}-
2,2-dimethylhexahydro-3aH-[1,3]dioxolo[4,5-d]furo[3,2-b]pyran-
7-carbaldehyde (31): To a stirred solution of silyl enol ether 30
(3.3 mg, 0.01 mmol) in CH2Cl2 (1 mL) was added sodium hydrogen
carbonate (11.1 mg, 0.14 mmol), and the solution was cooled to
–78 °C. Into the reaction solution was bubbled ozone for 20 s. The
reaction mixture was stirred at that temperature for 1 min, and then
argon gas was bubbled through the mixture. To this was added
triphenylphosphane (8.7 mg, 0.03 mmol), and the mixture was
stirred at –78 °C for 30 min and then room temperature for 1 h.
The reaction mixture was diluted with water (2 mL), and the re-
sulting solution was extracted with CH2Cl2 (3ϫ2 mL). The com-
bined organic layers were purified by flash column chromatography
(n-hexane/EtOAc, 5:1) to give 31 (2.0 mg, 80%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 9.58 (s, 1 H), 4.52 (dd, J = 5.2,
1.5 Hz, 1 H), 4.29–4.18 (m, 2 H), 4.08–4.02 (m, 1 H), 3.83–3.71 (m,
2 H), 3.61 (d, J = 10.9 Hz, 1 H), 3.10 (dd, J = 11.4, 10.5 Hz, 1 H),
2.27 (dd, J = 13.7, 3.8 Hz, 1 H), 2.15 (d, J = 13.8 Hz, 1 H), 1.45
(s, 3 H), 1.37 (s, 3 H), 0.86 (s, 9 H), 0.03 (m, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 204.4, 108.9, 89.5, 79.4, 75.1, 72.3, 68.5,
65.7, 64.8, 38.0, 28.2, 26.1, 25.8, 18.3, –5.5 ppm.
1
as a colorless oil. H NMR (400 MHz, CDCl3): δ = 4.41–4.35 (m,
1 H), 4.24 (dt, J = 10.2, 5.8 Hz, 1 H), 4.18–4.04 (m, 2 H), 3.86–
3.75 (m, 2 H), 3.68 (d, J = 12.6 Hz, 1 H), 3.54–3.40 (m, 2 H), 3.29
(s, 1 H), 3.12 (dd, J = 11.4, 10.2 Hz, 1 H), 2.28 (dd, J = 14.5,
5.7 Hz, 1 H), 2.11–2.00 (m, 1 H), 1.88 (ddd, J = 14.8, 8.8, 3.6 Hz,
1 H), 1.73 (ddd, J = 14.8, 5.9, 3.0 Hz, 1 H), 1.44 (s, 3 H), 1.34 (s,
3 H), 0.87 (s, 7 H), 0.05 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 108.7, 84.1, 78.1, 76.7, 72.3, 68.8, 65.7, 58.9, 39.0,
38.6, 28.1, 25.9, 18.3, –5.5 ppm. HRMS: calcd. for C19H36O6SiNa
411.2179; found 411.2177.
2-((3aS,5aR,7R,8aS,8bS)-7-{[(tert-Butyldimethylsilyl)oxy]methyl}-
2,2-dimethylhexahydro-3aH-[1,3]dioxolo[4,5-d]furo[3,2-b]pyran-
7-yl)acetaldehyde (29): To a stirred solution of oxalyl chloride
(30.3 μL, 0.36 mmol) in CH2Cl2 (20 mL) was added DMSO (di-
methyl sulfoxide, 38.1 μL, 0.54 mmol) at –78 °C, and the reaction
mixture was stirred for 30 min. A solution of alcohol 28 (72 mg,
(3aS,5aR,7S,8aS,8bS)-Methyl 7-{[(tert-Butyldimethylsilyl)-
oxy]methyl}-2,2-dimethylhexahydro-3aH-[1,3]dioxolo[4,5-d]furo-
[3,2-b]pyran-7-carboxylate (5): To a stirred solution of aldehyde 31
(3.7 mg, 0.01 mmol) in a mixture of tert-butyl alcohol (1 mL)/water
(0.2 mL) were added NaH2PO4 monohydrate (3.9 mg, 0.03 mmol),
90 % 2-methyl-2-butene (6.7 μL, 0.06 mmol), and 80 % sodium
0.18 mmol) in CH2Cl2 (10 mL) was added over 10 min, and the chlorite (4.3 mg, 0.04 mmol). The reaction solution was stirred at
mixture was stirred for an additional 45 min. To the reaction mix-
ture was added triethylamine (99.7 μL, 0.7156 mmol), and the reac-
tion was stirred at –78 °C for 30 min and then at room temperature
for 2 h. The mixture was diluted with water (20 mL), and the re-
sulting solution was extracted with CH2Cl2 (3ϫ10 mL). The com-
bined organic layers were washed with brine (10 mL), dried with
MgSO4, and concentrated. The residue was used in the next step
without further purification. 1H NMR (400 MHz, CDCl3): δ = 9.75
(t, J = 2.6 Hz, 1 H), 4.42–4.34 (m, 1 H), 4.19 (dt, J = 10.2, 5.8 Hz,
1 H), 4.13–4.04 (m, 2 H), 3.77 (dd, J = 11.3, 6.1 Hz, 1 H), 3.58–
3.47 (m, 2 H), 3.16–3.02 (m, 1 H), 2.72 (dd, J = 15.7, 2.4 Hz, 1 H),
2.60 (dd, J = 15.7, 2.8 Hz, 1 H), 2.20 (dd, J = 14.3, 5.2 Hz, 1 H),
room temperature for 4 h, and to this was added trimethylsilyldia-
zomethane (95 μL, 0.19 mmol). The mixture was stirred for 6 h and
then was diluted with water (2 mL). The resulting solution was ex-
tracted with EtOAc (3ϫ2 mL). The combined organic layers were
washed with brine (2 mL), dried with MgSO4, and concentrated.
The residue was purified by flash column chromatography (n-hex-
ane/EtOAc, 5:1) to give 5 (3.43 mg, 90%) as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 4.57–4.51 (m, 1 H), 4.29–4.16 (m, 2
H), 4.10–4.03 (m, 1 H), 3.82 (d, J = 10.5 Hz, 1 H), 3.78–3.63 (m,
5 H), 3.07 (dd, J = 11.3, 10.1 Hz, 1 H), 2.44 (d, J = 13.7 Hz, 1 H),
2.30 (dd, J = 13.8, 4.2 Hz, 1 H), 1.44 (s, 3 H), 1.35 (s, 3 H), 0.86
(s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
2.04–1.95 (m, 1 H), 1.45 (s, 3 H) 1.34 (s, 3 H), 0.87 (s, 9 H), 0.04 173.2, 108.6, 86.7, 79.1, 75.0, 72.6, 68.7, 66.6, 65.2, 52.2, 38.8, 28.1,
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O20439
/KAP1
Date: 19-06-12 15:09:29
Pages: 9
H.-Y. Lee, S.-S. Lee, H. S. Kim, K. M. Lee
FULL PAPER
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G. T. Swanson, K. Shimamoto, R. Sasaki, Eur. J. Org. Chem.
2009, 5531–5548.
26.0, 25.8, 18.3, –5.5 ppm. HRMS: calcd. for C19H34O7SiNa
425.1971; found 425.1974. [α]2D5.8 = –9.7 (c = 0.17).
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR of the intermediates and X-ray crystallo-
graphic data of 18a.
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Acknowledgments
This work was supported by a 2008 basic research grant from the
Korea Advanced Institute of Science & Technology (KAIST) and
a 2009 post-URP grant (to H. S. K.)
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Received: April 5, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 19-06-12 15:09:29
Pages: 9
A Formal Total Synthesis of Dysiherbaine and Neodysiherbaine A
Natural Product Synthesis
H.-Y. Lee,* S.-S. Lee, H. S. Kim,
K. M. Lee ......................................... 1–9
A Formal Total Synthesis of Dysiherbaine
and Neodysiherbaine A
Keywords: Total synthesis / Natural prod-
ucts / Oxygen heterocycles / Cycloaddition /
Domino reactions / Chiral resolution
A domino ring-opening/ring-closing olefin
metathesis reaction of 7 produced the core
structure of dysiherbaine and neodysiher-
baine A with complete control of the rela-
tive stereochemistry. The stereoselective
functionalization of 6b produced 5, the
known intermediate for the total synthesis
of dysiherbaine and neodysiherbaine A.
Eur. J. Org. Chem. 0000, 0–0
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