Total synthesis of (-)-brevenal: A streamlined strategy for practical synthesis of polycyclic ethers

Article abstract of DOI:10.1002/chem.201101437

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)₂-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by Suzuki-Miyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through Suzuki-Miyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.

Full text of DOI:10.1002/chem.201101437

DOI: 10.1002/chem.201101437
Total Synthesis of (ꢀ)-Brevenal: A Streamlined Strategy for Practical
Synthesis of Polycyclic Ethers
Makoto Ebine,[a, b] Haruhiko Fuwa,*[a] and Makoto Sasaki*[a]
Abstract: We describe a streamlined
strategy for the practical synthesis of
trans-fused polycyclic ethers and its ap-
plication to a concise total synthesis of
(ꢀ)-brevenal, a new pentacyclic poly-
ether natural product with intriguing
biological activities. The B-, D-, and E-
rings were constructed by TEMPO/
oxygen functionalities. The B- and E-
ring lactones were appropriately func-
tionalized by Suzuki–Miyaura coupling
of lactone-derived enol phosphates and
subsequent stereoselective hydrobora-
tion. The A-ring was formed by our
mixed thioacetalization methodology.
The AB- and DE-ring fragments were
assembled through Suzuki–Miyaura
coupling, and the C-ring was forged in
the same manner as that for the A-
ring. More than two grams of the
pentacyclic polyether core of (ꢀ)-bre-
venal have been synthesized by the
synthetic route developed in this study.
Keywords: cross-coupling · natural
products · oxacycles · oxidation ·
polyethers
PhIACHTUNGTRENNUNG(OAc)2-mediated oxidative lactoni-
zation of the corresponding 1,6-diols,
with minimal need for manipulation of
Introduction
in B exhibits potent neurotoxicity by acting as an agonist of
voltage-gated sodium channels (VGSCs) in excitable mem-
branes; brevetoxin B specifically binds to site 5 in a VGSC
and causes a shift of activation potential, induction of pro-
longed mean open times, and inhibition of channel inactiva-
tion.[7] The remarkably potent and specific binding ability of
brevetoxin B should be useful for better understanding of
the structure and functions of VGSCs at the molecular level.
Recently, Baden and co-workers identified the novel
pentacyclic ether brevenal (2) from a laboratory culture of
K. brevis.[8] The overall structure and relative stereochemis-
try of brevenal was originally proposed on the basis of ex-
tensive 2D NMR analysis. The complete stereostructure of
2, however, was eventually established through our total
synthesis, which resulted in the stereochemical reassignment
of the C26 stereogenic center.[9] It has been reported that
brevenal competitively inhibits the binding of tritiated di-
Secondary metabolites of marine organisms represent po-
tential collections of molecular probes useful for elucidation
of important biological functions as well as new lead com-
pounds with distinct biological modes of action in drug dis-
covery.[1] Marine polycyclic ether natural products, chiefly
produced by dinoflagellates, are a unique class of marine
metabolites, sharing a common ladder-shaped trans-fused
polycyclic ether structural motif and exhibiting a broad
range of biological activities with high potencies.[2] Among
the family of marine polycyclic ethers, brevetoxin B (1), iso-
lated from the Florida red-tide-forming dinoflagellate Kare-
nia brevis as a potent ichthyotoxic constituent, was the first
member to be structurally elucidated by spectroscopic and
X-ray crystallographic analyses.[3] Since then the isolation
and structure determination of natural congeners, including
brevetoxin A,[4] have been reported. The unprecedented
highly complex polycyclic ether structure of brevetoxin B
has served as a significant challenge to synthetic chemists
and as a source of inspiration for the development of new
synthetic methods and strategies.[5,6] Furthermore, brevetox-
AHCTUNGTRENNUNG
hydrobrevetoxin B ([3H]PbTx-3) to VGSCs in a dose-depen-
dent manner without showing neurotoxicity and acts as a
natural brevetoxin antagonist in vivo.[8,10] Moreover, Abra-
ham et al. have reported that brevenal significantly improves
tracheal mucus clearance ability in an animal model of
asthma, suggesting that brevenal might serve as a potential
drug candidate for treatment of cystic fibrosis.[11] More re-
cently, Mattei et al. have reported that brevenal is a potent
inhibitor of catecholamine secretion induced by ciguatoxin
(3) without affecting other secretagogue activities, such as
nicotine- or barium-induced secretion of catecholamine.[12]
Ciguatoxin is a secondary metabolite of the dinoflagellate
Gambierdiscus toxicus responsible for ciguatera seafood poi-
soning[13] and, like brevetoxin B, exhibits potent neurotoxici-
ty by binding to the VGSC receptor site 5.[14] Mattei et al.
suggested that brevenal and its derivatives could be poten-
tially useful for treatment of ciguatera.[12]
[a] Dr. M. Ebine, Prof. Dr. H. Fuwa, Prof. Dr. M. Sasaki
Graduate School of Life Sciences, Tohoku University
2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan)
Fax : (+81)022-217-6214
E-mail: hfuwa@bios.tohoku.ac.jp
[b] Dr. M. Ebine
Department of Chemistry, Graduate School of Sciences
Kyushu University, 6-10-1 Hakozaki, Higashi-ku
Fukuoka 812-8581 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101437.
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Chem. Eur. J. 2011, 17, 13754 – 13761

FULL PAPER
Because of its intriguing structure and promising biologi-
cal profile, brevenal represents an attractive synthetic target
for organic chemists.[15,16] In 2006 we reported the first total
synthesis of (ꢀ)-brevenal,[9b] based on our developed
Suzuki–Miyaura coupling/mixed-thioacetalization chemis-
try[17–19] as outlined in Scheme 1.
(50 steps from 2-deoxy-d-ribose, the longest linear se-
quence). Unfortunately, though, our first-generation synthe-
sis could afford only a milligram-scale quantity of synthetic
brevenal because of the lengthy linear sequences required
for the synthesis of the AB- and DE-ring fragments and the
low material throughput of the post-fragment coupling stage
of the total synthesis. To address these problems, here we
disclose a streamlined strategy for the practical synthesis of
polycyclic ethers and its successful implementation in a con-
cise total synthesis of (ꢀ)-brevenal.[20]
Results and Discussion
Synthetic plan: In designing the overall synthetic plan, we
paid particular attention to minimizing the number of ma-
nipulations of oxygen-containing functional groups and at-
tempted to formulate a streamlined strategy for the synthe-
sis of polycyclic ethers based on six- and seven-membered
rings (Scheme 2). TEMPO/PhIACHTNUGRTENUNG(OAc)2-mediated oxidative
lactonization of 1,5- and 1,6-diols has recently emerged as a
powerful means for producing six- and seven-membered lac-
tones, respectively.[21] Notably, this methodology does not re-
quire differentiation of primary and secondary hydroxy
groups: oxidation takes place exclusively at the less hin-
dered primary hydroxy group with concomitant lactoniza-
tion, thanks to the unique reactivity of TEMPO/PhI-
AHCTUNGTRENNUNG
(OAc)2.[22] The diol I would thus be directly transformed
into the lactone II. For the functionalization of the lactone
II, we thought it would be suitable to utilize Suzuki–
Miyaura coupling of the lactone-derived enol phosphate III
and hydroboration of the resultant endocyclic enol ether IV,
which should afford the cyclic ether V with simultaneous
generation of two stereogenic centers in a stereocontrolled
manner under substrate control. Significantly, only four
steps would be required for the construction of the cyclic
ether V from the simple diol I, and this sequence should
allow for a practical synthesis of small cyclic ether fragments
(e.g., VI and VII). Furthermore, as we had previously dem-
onstrated,[17–19] convergent assembly of small cyclic ether
Scheme 1. Outline of our first-generation total synthesis of (ꢀ)-brevenal.
Bn=benzyl, MPM=p-methoxyphenylmethyl, TBDPS=tert-butyldi-
ACHTUNGTRENNUNGphenylsilyl, TBS=tert-butyldimethylsilyl.
Assembly of the AB-ring enol phosphate 4 and the DE-
ring exocyclic enol ether 5, followed by construction of the
central C-ring through mixed thioacetalization, delivered
the pentacyclic ether 6, and a sequential installation of the
A- and E-ring side chains completed the total synthesis of 2
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H. Fuwa, M. Sasaki, and M. Ebine
Scheme 2. Streamlined strategy for practical synthesis of polycyclic
ethers; PG=protective group.
fragments by means of our Suzuki–Miyaura coupling/mixed-
thioacetalization chemistry should give access to larger poly-
cyclic ether arrays in a rapid and efficient manner (e.g., VI
+ VII ! VIII). Overall, a practical synthesis of polycyclic
ethers should be possible by exploitation of oxidative lacto-
nization, Suzuki–Miyaura coupling, and mixed thioacetaliza-
tion as key transformations.
Scheme 3. Synthesis plan for (ꢀ)-brevenal. MOM=methoxymethyl.
With the above considerations in mind, we planned a
second-generation total synthesis of (ꢀ)-brevenal as illus-
trated in Scheme 3. We envisioned the synthesis of the
pentacyclic polyether core 6 by our Suzuki–Miyaura cou-
pling/mixed-thioacetalization chemistry.[17] The assembly of
the AB-ring exocyclic enol ether 7 and the DE-ring enol
phosphate 8 through Suzuki–Miyaura coupling and subse-
quent construction of the C-ring by the mixed thioacetaliza-
tion methodology developed in our laboratory[18] should
thus deliver the pentacyclic ether 6 in a convergent fashion.
The AB-ring fragment 7 would be derived from the bicyclic
ether 9 through a series of functional group manipulations.
According to the general strategy formulated in Scheme 2,
the bicyclic ether 9 should be obtainable from the B-ring
enol phosphate 10 by means of Suzuki–Miyaura coupling
and subsequent formation of the A-ring by mixed thio-
tive lactonization, and this should in turn be synthesizable
from the E-ring enol phosphate 13 through Suzuki–Miyaura
coupling with an appropriate alkylborane. The E-ring
should be available from the 1,6-diol 14 by means of oxida-
tive lactonization.[23]
Accordingly, our synthetic plan for (ꢀ)-brevenal hinges
on 1) TEMPO/PhIACTHNUTRGNEUNG(OAc)2-mediated oxidative lactonization
for the construction of the B-, D-, and E-ring frameworks;
2) Suzuki–Miyaura coupling for the functionalization of the
B- and E-rings and the convergent union of the AB- and
DE-ring fragments; and 3) mixed thioacetalization for the
formation of the A- and C-rings. Notably, all of these syn-
thetic methodologies were developed in our laboratory.
Synthesis of the AB-ring fragment: The synthesis of the
AB-ring bicyclic ether 9 (Scheme 4) commenced with hydro-
genation of the known unsaturated ester 15, available in two
steps from 2-deoxy-d-ribose.[24,25] Subsequent reduction of
the derived ester with LiAlH4 and protection of the resul-
tant diol (MOMCl, iPr2NEt) gave the bis-MOM ether 16
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
We also planned to apply our general strategy to the syn-
thesis of the DE-ring fragment. The DE-ring enol phosphate
8 could thus be traced back to the 1,6-diol 12 through oxida-
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Total Synthesis of (ꢀ)-Brevenal
FULL PAPER
Scheme 4. Synthesis of the bicyclic ether 9. 9-BBN=9-borabicyclo
formamide, HMPA=hexamethylphosphoramide, KHMDS=potassium bis(trimethylsilyl)amide, mCPBA=m-chloroperoxybenzoic acid, MS=molecular
sieves, NMO=N-methylmorpholine N-oxide, NOE=nuclear Overhauser effect, TEMPO=2,2,6,6-tetramethylpiperidin-1-oxyl, Tf=trifluoromethane-
ACHTUNGTRENNUNGsulfonyl, TPAP=tetra-n-propylammonium perruthenate.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(94%, three steps). The benzylidene acetal was removed by
hydrogenolysis to provide the diol 17 (100%). Benzylation
of 17 provided the bis-benzyl ether 18 (98%), and this was
followed by cleavage of the MOM ethers under acidic con-
ditions to deliver the diol 11 (89%). Oxidative lactonization
(mCPBA, CH2Cl2, ꢀ788C; then excess Me3Al, 08C), which
furnished the AB-ring bicyclic ether 9 in 90% yield. The ste-
reochemistry of the C12 stereogenic center was unambigu-
ously confirmed by an NOE enhancement observed in 9.
The bicyclic framework of the AB-ring having been com-
pleted, our next challenge was functionalization of the B-
ring. To install the C14 hydroxy group, we envisioned a new
method that makes use of the intrinsic conformational bias
of seven-membered cyclic ethers, as summarized in
Scheme 5a. Because the secondary hydroxy group in the
oxepane A should be in a pseudoaxial orientation, transfor-
mation of the hydroxy group into a suitable leaving group
(X) should facilitate a regioselective E2 elimination through
the action of a base to provide the oxepene C. As a result of
the conformation of C, dihydroxylation of C should exclu-
sively occur from the sterically less hindered b face to afford
the diol D with the correct configuration at the C14 stereo-
genic center. To test this idea, the bicyclic ether 9 was elabo-
rated to the alcohol 26 in two steps involving debenzylation
and selective silylation of the resulting primary hydroxy
group (Scheme 5b). We examined several leaving groups for
regioselective elimination of the C15 secondary hydroxy
group and found that the corresponding mesylate[29] and
monochloromesylate[30] were not sufficiently reactive toward
base-mediated elimination, whereas the triflate 27 was very
unstable and readily decomposed during attempted isola-
tion. Eventually, a one-pot triflation/elimination protocol
(Tf2O, 2,6-lutidine, CH2Cl2, ꢀ788C; then DBU, room tem-
of 11 with a catalytic amount of TEMPO and PhIACTHNUGTRENUNG(OAc)2 as
a stoichiometric oxidant proceeded smoothly under non-
high-dilution conditions (CH2Cl2, 0.1m substrate concentra-
tion, room temperature) to afford the B-ring lactone 19[17b,c]
in 93% yield, securing a scalable access to this important
building block (>19 g in one batch).[26] Enolization of 19
with KHMDS in the presence of (PhO)2P(O)Cl gave the
enol phosphate 10 in 80% yield. Suzuki–Miyaura coupling
of 10 with the alkylborate 22, generated in situ from the
iodide 21 (derived from the alcohol 20[9]), was carried out in
the presence of [PdACHTUNRGTNEUNG(PPh3)4] as the catalyst and aqueous
Cs2CO3 as the base (DMF, 508C), which provided the endo-
cyclic enol ether 23 in 90% yield. Stereoselective hydro-
ACHTUNGTRENNUNGboration of 23 with thexylborane and oxidative workup gave
an alcohol as a single stereoisomer, which was oxidized with
TPAP/NMO[27] to deliver the ketone 24 in 85% yield (two
steps) as a single stereoisomer. The newly generated C11
stereogenic center was established by an NOE experiment
as shown. Removal of the MPM group and subsequent
mixed thioacetalization through the action of EtSH/Zn-
ACHTUNGTRENNUNG(OTf)2 afforded the O,S-acetal 25 in 96% yield (two steps).
The C12 axial methyl group was stereoselectively introduced
by a one-pot mCPBA oxidation/methylation procedure[9,28]
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H. Fuwa, M. Sasaki, and M. Ebine
Scheme 5. a) Elimination/dihydroxylation sequence for the stereoselective introduction of the C14 hydroxy group. b) Synthesis of the AB-ring fragment
7. DBU=diazabicyclo
ACHTUNGTRENNUNGsilyl.
ACHTUNGTRENNUNG[5.4.0]undec-7-ene, DCE=1,2-dichloroethane, MW=microwave, TBAF=tetra-n-butylammonium fluoride, TIPS=triisopropyl-
perature) was devised to address this problem, cleanly
trolled methylation of which with methylmagnesium chlo-
ride (Et2O, ꢀ788C)[36] afforded the tertiary alcohol 37 in
quantitative yield as a single stereoisomer, as judged by
1H NMR analysis (600 MHz). Protection of the resulting hy-
droxy group as its TBS ether gave the silyl ether 38 (97%).
Hydroboration of the terminal olefin in 38 with 9-BBN-H
gave the alcohol 39 after oxidative workup (99%). Cleavage
of the MPM ether with DDQ led quantitatively to the diol
giving the olefin 28 in 80% yield. As anticipated, dihydroxy-
lation of 28 with OsO4/NMO exclusively furnished the diol
29 (91%) as a single stereoisomer. We have thus successful-
ly introduced the C14 hydroxy group with complete stereo-
chemical control. The stereochemical outcome of the dihy-
droxylation was confirmed by an NOE experiment on the
corresponding acetonide derivative (see the Supporting In-
formation). Protection of the diol 29 with MOMCl/
iPr2NEt[31] under microwave irradiation conditions, followed
by selective cleavage of the TBDPS group under basic con-
ditions (KOH, MeOH/THF, 708C), gave the alcohol 30
(84%, two steps). Benzylation of 30 and subsequent desily-
lation with TBAF led to the alcohol 31 (97%, two steps),
which was transformed into the AB-ring exocyclic enol
ether 7 in 93% yield (two steps) by iodination under stan-
dard conditions and base treatment (KOtBu, THF, 08C).
14. Upon treatment of the diol 14 with TEMPO/PhIACHTUNGTRENNUNG(OAc)2
in CH2Cl2 (0.1m substrate concentration) at room tempera-
ture, oxidative lactonization took place smoothly to deliver
the seven-membered lactone 40, representing the E-ring, in
97% yield.
After conversion of the lactone 40 into the enol phos-
phate 13 (KHMDS, (PhO)2P(O)Cl, HMPA, THF, ꢀ788C),
Suzuki–Miyaura coupling with an alkylborane derived from
4-(4-methoxybenzyl)but-1-ene and 9-BBN-H was effected
under optimized conditions ([PdACHTUNGTRNEUNG(PPh3)4], aqueous Cs2CO3,
Synthesis of the DE-ring fragment: The synthesis of the
DE-ring enol phosphate 8 (Scheme 6) started from the
known epoxy alcohol 32,[32] readily prepared from butane-
1,4-diol in four steps. Regioselective ring-opening of the ep-
DMF, 508C) to afford the endocyclic enol ether 41 in 97%
yield for the two steps. Hydroboration of 41 with thexyl-
AHCTUNGTREGbNNNU orane proceeded in a highly stereoselective manner to pro-
vide the secondary alcohol 42 in 90% yield as a single ste-
reoisomer after alkaline peroxide workup; subsequent re-
moval of the MPM group with DDQ gave the diol 12
(93%). Oxidative lactonization of 12 with TEMPO/PhI-
oxide with Ti
diol 33 in 81% yield. Direct formation of the terminal ep-
oxide 34 from the 1,2-diol 33 was effected by Kishiꢁs proto-
ACHTUNGTRENNUNG
(OMPM)4 (toluene, 858C)[33] delivered the 1,2-
ACHTUNGTRENNUNG
col,[34] through treatment with N-(p-toluenesulfonyl)imida-
zole in the presence of NaH (THF, ꢀ788C to room tempera-
ture, 77%). Copper-catalyzed allylation of 34 regioselective-
ly opened the terminal epoxide to provide the secondary al-
cohol 35 in 95% yield. Oxidation of 35 with Dess–Martin
periodinane[35] gave the ketone 36 (97%), chelation-con-
ACHTUGNTRNE(UNNG OAc)2 (CH2Cl2, 0.1m substrate concentration, room tem-
perature) cleanly furnished the seven-membered lactone 43
(92%), the spectroscopic data and specific rotation value of
which matched those of the authentic material, which we
had previously prepared.[20] Finally, treatment of 43 with
KHMDS in the presence of (PhO)2P(O)Cl (HMPA, THF,
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Total Synthesis of (ꢀ)-Brevenal
FULL PAPER
Scheme 6. Synthesis of the DE-ring fragment 8. TsIm=N-(p-toluenesulfonyl)imidazole.
ꢀ788C) delivered the DE-ring enol phosphate 8 almost
steps). After protection of the hydroxy groups with
TBSOTf/Et3N to give the tris-silyl ether 47 (97%), the C19
axial methyl group was stereoselectively installed by the
one-pot mCPBA oxidation/methylation protocol, giving rise
to the pentacyclic ether 48 in 86% yield. The newly generat-
ed C19 stereogenic center was confirmed by an NOE ex-
periment. Debenzylation of 48 with LiDBB[39] (THF,
ꢀ788C) afforded the primary alcohol 6 in 94% yield, while
also successfully intercepting with our previous total synthe-
sis of (ꢀ)-brevenal.[9b] The spectroscopic data and specific
rotation value for 6 synthesized in this study were in full ac-
cordance with those of the authentic sample.[9b,20] It was sig-
nificant that we were able to synthesize the key intermedi-
ate 6 in quantities of over two grams, showcasing the feasi-
bility of our strategy for practical synthesis of polycyclic
ethers.
quantitatively.
Construction of the pentacyclic polyether core and comple-
tion of the total synthesis: The coupling of the AB-ring exo-
cyclic enol ether 7 and the DE-ring enol phosphate 8 was ef-
ficiently achieved through Suzuki–Miyaura chemistry
(Scheme 7). Hydroboration of 7 with 9-BBN-H generated
the corresponding alkylborane, which was treated in situ
with 8 under optimized conditions ([PdACHTNURTGNE(UNG PPh3)4], aqueous
Cs2CO3, DMF, 508C) to afford the endocyclic enol ether 44
in 93% yield as a single stereoisomer.[37] Stereoselective
hydroboration of 44 with BH3·SMe2 followed by oxidative
workup gave an inseparable 5:1 mixture of diastereomeric
secondary alcohols, which was oxidized with TPAP/NMO to
provide the ketone 45 in 80% yield (two steps) after remov-
al of the minor C18 epimer by flash chromatography on
silica gel. The C18 stereogenic center of 45 was confirmed
by an NOE experiment as shown.
Conclusion
At this stage it was necessary to remove the MOM ethers
for the formation of the C-ring. Treatment of 45 with aque-
ous HCl (6m) in THF/MeOH cleanly cleaved both the
MOM ethers and the silyl ethers to give an equilibrating
mixture of the corresponding tetraol-ketone and hemiacetal
almost quantitatively,[38] and this was converted into the
O,S-acetal 46 by mixed thioacetalization in 96% yield (two
We have described a newly designed streamlined strategy
for the practical synthesis of polycyclic ethers and its suc-
cessful application to a concise total synthesis of (ꢀ)-breve-
nal. TEMPO/PhIACTHNUTRGNEUNG(OAc)2-mediated oxidative lactonization of
1,6-diols enabled the efficient construction of the B-, D-,
and E-ring frameworks in their lactone forms with minimal
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H. Fuwa, M. Sasaki, and M. Ebine
Scheme 7. Synthesis of the pentacyclic polyether core 6 and completion of the total synthesis. DBB=4,4’-di-tert-butylbiphenyl.
transformations of oxygen functionalities. The B- and E-ring
lactones were suitably functionalized through Suzuki–
Miyaura coupling of lactone-derived enol phosphates and
subsequent stereoselective hydroboration. The A-ring was
constructed by our developed mixed thioacetalization meth-
odology. Finally, the AB- and DE-ring fragments were cou-
pled through Suzuki–Miyaura chemistry, and the C-ring was
constructed by mixed thioacetalization to complete the total
synthesis of (ꢀ)-brevenal. This synthesis took place in only
34 steps (longest linear sequence) from the commercially
available 2-deoxy-d-ribose, thus being much more efficient
than our previous synthesis (50 steps, longest linear se-
quence). Significantly, more than two grams of the pentacy-
clic ether core of (ꢀ)-brevenal have been synthesized by
these practical synthetic methodologies, thereby paving the
way to a variety of unnatural analogues of this promising
therapeutic lead compound. We believe that our strategy
should be generally applicable to the synthesis of marine
polycyclic ether natural products.
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Acknowledgements
We thank Y. Suga from our laboratory for his contribution to the early
stage of this work. This work was supported in part by Grant-in-Aids for
Challenging Exploratory Research (No. 21651090) and Scientific Re-
search (A) (No. 21241050) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan and from the Japan Soci-
ety for the Promotion of Sciences (JSPS). M.E. was a recipient of a pre-
doctoral fellowship from JSPS.
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Chem. Eur. J. 2011, 17, 13754 – 13761

Total Synthesis of (ꢀ)-Brevenal
FULL PAPER
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ty of SmI2 in THF (usually around 0.1m concentration) and care
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Received: May 11, 2011
Revised: August 8, 2011
Published online: November 3, 2011
[25] A referee has pointed out that d-ribose may serve as a good starting
material for the B-ring, because both the C14 and C15 hydroxy
Chem. Eur. J. 2011, 17, 13754 – 13761
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