Total synthesis of the postulated structure of fulicineroside

Article abstract of DOI:10.1002/chem.201204545

A total synthesis of the proposed structures of fulicineroside and its aglycone fulicinerine is reported. The tetrasubstituted dibenzofuran substructure was accessible either through a Pd-mediated ortho-metalation or by an Ir-catalyzed meta-borylation. The synthesis of the β,β,α- linked trisaccharide consisting of D-olivose, L-rhodinose, and L-rhamnose was challenged by the unprecedented β-linked rhodinose. A Pd-catalyzed β-selective glycosylation of a 4-epi-rhodinose and a subsequent Mitsunobu inversion provided selectively the β-linked L-rhodinose-L-rhamnose disaccharide. Comparison with the reported data for the natural product and the aglycone suggests a misassignment of the structure of the natural product. Natural product reassignment: Total synthesis of the proposed structures for fulicineroside and its aglycone fulicinerine has been achieved (see figure). Key issues were the tetrasubstituted dibenzofuran and the trisaccharide with its β-linkage between L-rhodinose and L-rhamnose. A comparison with the reported data for the natural product and the aglycone suggests a misassignment of the structure of the natural product. Copyright

Full text of DOI:10.1002/chem.201204545

FULL PAPER
DOI: 10.1002/chem.201204545
Total Synthesis of the Postulated Structure of Fulicineroside
Ruben Bartholomꢀus, Fabian Dommershausen, Markus Thiele, Narayan S. Karanjule,
Klaus Harms, and Ulrich Koert*[a]
Abstract: A total synthesis of the pro-
posed structures of fulicineroside and
its aglycone fulicinerine is reported.
The tetrasubstituted dibenzofuran sub-
structure was accessible either through
a Pd-mediated ortho-metalation or by
an Ir-catalyzed meta-borylation. The
synthesis of the b,b,a-linked trisacchar-
ide consisting of d-olivose, l-rhodinose,
and l-rhamnose was challenged by the
unprecedented b-linked rhodinose. A
Pd-catalyzed b-selective glycosylation
of a 4-epi-rhodinose and a subsequent
Mitsunobu inversion provided selec-
tively the b-linked l-rhodinose-l-rham-
nose disaccharide. Comparison with
the reported data for the natural prod-
uct and the aglycone suggests a misas-
signment of the structure of the natural
product.
Keywords: dibenzofuran
·
fulici-
neroside · glycosylation · natural
products · total synthesis
Introduction
The natural product (+)-fulicineroside was first isolated in
2005 from the slime mold Fuligo cinerea collected in the
Czech republic.[1] Slime molds belong to the animal branch
of taxonomy because they engulf their food, in contrast to
fungi, which digest their food by enzyme exudation and re-
absorption. Fulicineroside shows moderate inhibitory activi-
ty towards Staphylococcus aureus and Bacillus subtilis,
whereas the significant growth inhibition of crown gall
tumors suggests in vivo antitumor activity. Based on UV, IR,
MS, 1D, and 2D NMR spectroscopic data and chemical deg-
ˇ
radation structure 1 was proposed by Rezanka et al. for fuli-
cineroside. Structure 2 was proposed for the aglycone fulici-
nerine. Fulicineroside (1) consists of a dibenzofuran core
with one side chain at C6 and a shorter side chain at C2.
The C6 side chain contains an (E,E)-diene (C1’–C4’), a syn-
epoxy alcohol (C7’–C9’) and two additional stereocenters
(C5’, C10’). A trisaccharide is attached to C13 of the shorter
side chain. The trisaccharide consists of b,b,a-linked d-oli-
vose, l-rhodinose, and l-rhamnose. In natural products the
presence of a b-linked l-rhodinose is unprecedented.
The structure of fulicineroside (1, Figure 1) contains sev-
eral new structural features that make it an attractive syn-
thetic target. Here we report the synthesis of the proposed
structures for the aglycone fulicinerine (2) and the glycosy-
Figure 1. Postulated structures of fulicineroside (1) and fulicinerine (2).
lated natural product fulicineroside (1) and a comparison of
the spectroscopic data with the reported data for the natural
product.
Results and Discussion
[a] R. Bartholomꢀus, F. Dommershausen, Dr. M. Thiele, N. S. Karanjule,
Dr. K. Harms, Prof. Dr. U. Koert
Fachbereich Chemie
Retrosynthesis of fulicinerine: Our synthetic strategy for fu-
licineroside (1) was based on a final-stage glycosylation for
the introduction of the trisaccharide. This way the synthesis
of the aglycone fulicinerine (2) and the trisaccharide part
could be addressed in parallel.
Philipps-Universitꢀt Marburg
Hans-Meerwein-Strasse
35043 Marburg (Germany)
Fax : (+49)6421-2825677
For fulicinerine (2)
a
retrosynthetic consideration
E-mail: koert@chemie.uni-marburg.de
(Scheme 1) led to a sulfone fragment 3 (C4’–C12’) and an al-
dehyde fragment 4 (dibenzofuran part). A Julia–Kocienski
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204545.
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thioether 9 selectively. Oxidation of the thioether by hydro-
gen peroxide/ammonium molybdate[2] gave the correspond-
ing hydroxysulfone, which was subjected to another thiol-
Mitsunobu reaction to obtain the thioether sulfone 10. A
Julia–Kocienski olefination of the sulfone 10 with the alde-
hyde 7 resulted in the formation of the alkene 11 (E/Z=
95:5). After molybdate-catalyzed oxidation of the thioether
to the sulfone, the desired building block 3 was obtained
(Scheme 2).
Different routes to substituted dibenzofurans have been
developed in the context of total syntheses of natural prod-
ucts.[5] For the unprecedented fulicinerine substructure 12,
two routes were taken into closer consideration (Scheme 3).
Scheme 1. Retrosynthesis of the aglycone fulicinerine (2). PT=1-Phenyl-
tetrazol-5-yl; THP=tetrahydropyranyl; TBS=tert-butyldimethylsilyl.
olefination[2] was scheduled as the concluding step for the
aglycone synthesis. The di-tert-butylsilene group[3] was
chosen for the protection of the dibenzofurandiol.
Synthesis of the aglycone fulicinerine (2): The stereoselec-
tive synthesis of sulfone fragment 3 (C4’–C12’) started with
aldehyde 5 (Scheme 2). Brownꢂs asymmetric crotylboration
Scheme 3. Two alternative routes to the dibenzofuran part of fulicinerine.
DG=Directing group.
ꢀ
A C C bond formation initiated by an ortho-directed metal-
ation[6] for the furan ring closure could be the key step in a
route starting from a diaryl ether 13. A second route could
use the biaryl compound 15 as a key intermediate. A meta-
selective borylation would lead to the arylboronic acid 14
and introduce an attachment point for the C6 side chain. A
ꢀ
subsequent C O bond formation could close the furan ring
to deliver 12. Both routes were investigated in the context
of the present study.
The construction of the dibenzofuran by an ortho-directed
Scheme 2. Synthesis of sulfone 3: a) (E)-butene, nBuLi, KOtBu, (+)-b-
(IPC)2BCl, THF, ꢀ788C; b) TBSOTf, 2,6-lutidine, CH2Cl2, RT; c) H2,
1 atm, Pd(OH)2/C, EtOH, RT; d) Dess–Martin periodinane, CH2Cl2, RT;
e) PTSH, PPh3, DIAD, THF, RT; f) (NH4)6Mo7O24·4H2O, H2O2, EtOH,
RT; g) NaHMDS, 7, THF, ꢀ788C. DIAD=Diisopropyl azodicarboxylate.
ꢀ
C H activation is shown in Scheme 4. Ullman-type cou-
pling[7] of 1-bromo-3,5-dimethoxybenzene (16) with resorcin
(17) provided the corresponding biarylether phenol, which
ꢀ
was converted into the dimethyl carbamate 18. Fagnouꢂs C
H activation conditions[8] were suitable for the Pd-mediated
[9]
ꢀ
C H activation dibenzofuran ring closure. The reaction
(enantiomeric excess (ee)=94%, diastereomeric ratio
(d.r.)=95:5) gave a homoallylic alcohol and a subsequent
TBS-protection led to the silyl ether 6.[4] Hydrogenolytic
cleavage of the benzyl ether produced a primary alcohol,
which was oxidized by using Dess–Martin conditions to the
aldehyde 7 (Scheme 2).
Stereocenter C5’ was introduced through the diol 8. The
two primary alcohol groups in 8 could be differentiated
through a thiol-Mitsunobu reaction to produce the mono-
times were significantly shortened and the best yields were
obtained when AgOAc was used instead of ambient air as a
stoichiometric oxidant. The desired ortho-product 19 and
the regioisomeric para-product 20 were formed in a 3:2
ratio and could easily be separated by chromatography. The
directing effect of the carbamate group, which has to over-
ride substantial steric hindrance, becomes clear when the
result is compared with our initial experiments using a me-
thoxy group instead of a carbamate. In this case, the unde-
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Total Synthesis of Fulicineroside
FULL PAPER
the tetrasubstituted dibenzofuran 24 was obtained
(Scheme 5).
The following attachment of the C6 side chain required a
differentiation between the methoxy group positions at C1,
C6, and C8 (Scheme 6). A selective deprotection of the C1/
Scheme 4. Synthesis of dibenzofuran 19: a) CuI, Cs2CO3, N,N-dimethyl-
glycine, DMF, 1358C; b) Me2NCOCl, K2CO3, MeCN, 608C; c) Pd
AgOAc, PivOH, 1308C.
ACHTUNGERTN(NUNG OAc)2,
sired regioisomer was formed as the main product (ortho/
para=1:5).
The carbamate group could not only be used for the con-
struction of the dibenzofuran but also for the introduction
of the C2 side chain (Scheme 5). An anionic Fries rearrange-
ment through directed ortho-lithiation converted the carba-
mate 19 into the corresponding C2-carboxamide.[10] Subse-
quent methylation of the resulting phenol gave 21. The in-
corporation of the carbon atom of the directing group into
the scaffold of the natural product is a noteworthy advant-
age of this reaction sequence. The following reduction of
the amide 21 with Schwartzꢂs reagent gave the aldehyde
22.[11] An X-ray structure of 22 proved the correct substitu-
tion pattern at the dibenzofuran.[51] The C2 side chain was
completed by the addition of the Grignard reagent 23[12] and
reductive removal of the resulting benzylic alcohol
(Scheme 5). After THP protection of the primary alcohol
Scheme 6. Synthesis of aldehyde 4: a) LiSEt, DMF, 1008C; b) (tBu)2Si-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
DDQ=2,3-Dichloro-5,6-dicyano-1,4-benzoquinone; PMB=p-methoxy-
phenyl; Py=pyridine.
C8 methyl ethers of 24 was possible by treatment with lithi-
um thioethanolate at 1008C in DMF. A chelation-type com-
plexation of the lithium cation and release of the steric
strain can be accounted for the observed selectivity. After
introduction of the di-tert-butylsilene group[3] the dibenzo-
furan 25 was obtained. Initial attempts to cleave the remain-
ing C6 methyl ether with lithium thioethanolate resulted in
substantial loss of the di-tert-butylsilene protecting group.
This was overcome by the application of lithium thio-tert-bu-
tanolate as a more selective reagent. The corresponding
phenol was converted into the aryl triflate 26. A Stille cou-
Scheme 5. Attachment of the C2 side chain and X-ray structure of 22:
a) LDA, THF, ꢀ788C!RT; Me2SO4, KOH, Bu4NBr; b) [ZrCl(Cp)2(H)];
c) 23, THF, ꢀ608C; d) H2/PdC, MeOH, TFA; e) DHP, PPTS, CH2Cl2.
Cp=Cyclopentadienyl; DHP=dihydropyran.
pling with a [PdACTHNUGTRNEUNG(dba)2]/AsPh3 (dba=dibenzylideneacetone)
catalyst with the alkenyl stannane 27 (for preparation see
Scheme 7) gave the completely substituted dibenzofuran 28.
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U. Koert et al.
um-catalyzed borylation of a benzofuran 36 results in an
attack at the neighboring position to the dibenzofuran
oxygen atom, which is not appropriate to the present strat-
egy. In contrast, the borylation at the stage of a biaryl 37
should lead to the desired regioisomer. Therefore the intro-
duction of the C6 side chain was scheduled prior to the di-
benzofuran ring closure.
The borylation route for the tetrasubstituted dibenzofuran
started with resorcin dimethyl ether (38) (Scheme 8). ortho-
Directed lithiation and a CuI-catalyzed reaction with 5-iodo-
Scheme 7. Synthesis of the building blocks 27, 32, and 35: a) nBuLi,
(Bu3Sn)2, CuCN, MeOH, THF, ꢀ788C!RT; b) Br2, Na2CO3, CH2Cl2,
08C; c) PMBOC(NH)CCl3, CSA, CH2Cl2; d) [RuACHTUNGRTNEUNG(C6H6)Cl{(S)-binap}]Cl,
H2, C6H6/EtOH, 508C, 100 bar; e) HBr 33% in AcOH, RT; f) EtOH,
DCC, DMAP, CH2Cl2. DCC=N,N’-Dicyclohexylcarbodiimide; DMAP=
4-dimethylaminopyridine.
The oxidative deprotection of the PMB ether led directly to
the desired aldehyde 4 in 92% yield.
The syntheses of the three side chain building blocks 27,
32, and 35 used for the fulicinerine aglycone are summarized
in Scheme 7. A stannylcupration of butinol 29 provided the
(E)-alkenyl stannane 30.[13] para-Methoxybenzyl ether
(PMB) protection of 30 led to compound 27. Treatment of
the stannane 30 with bromine resulted in the formation of
the (E)-bromoalkene 31. After PMB-protection the ether 32
was obtained.[14,15] The stereoselective synthesis of the C2
side chain bromide 35 used an asymmetric hydrogenation of
the alkene 33 (Scheme 7). By using [Ru{(S)-binap}-
A
(binap=2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl) as a catalyst, the lactone 34 was obtained with
86% ee. A subsequent ring opening of the lactone provided
the bromide building block 35.[16]
The second route for the tetrasubstituted dibenzofuran
consisted of a meta-selective borylation to install the C6 side
Scheme 8. Synthesis of the dibenzofuran 45 through meta-selective bory-
lation: a) n-BuLi, CuI, Et2O; 2-iodo-1,3-dimethoxybenzene, Py; b) NBS,
ꢀ
chain. The iridium-catalyzed C H borylation of aromatics
CH3CN; c) Zn, [Pd
THF/H2O; f) Ac2O, Py ; g) B2Pin2, [Ir
858C; h) KHF2, THF/H2O; i) TMSCl, H2O; [Pd
H2O, 70 8C; j) LiOH, THF/H2O; k) DCC, DMAP, CH2Cl2; l) perfluoro-1-
(OAc)2,
2ACHUTNGTRNENUG(dba)3], PACTHNUGTRENNNUG
and heteroaromatics has evolved into a valuable synthetic
tool over recent years.[17,18] The regioselective arene boryla-
tion reaction has been used as a key step in natural product
synthesis.[19] One task of interest for the fulicineroside proj-
ect was the optimal timing[20] for the borylation step
(Figure 2). Earlier experiments[21] had shown that the iridi-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
butane-sulfonyl fluoride, DIEA, DMAP, CH2Cl2, ꢀ208C; m) Pd
ACHTUNGTRENNUNG
2-(di-tert-butylphosphino)biphenyl, K3PO4, toluene, 1008C. DIEA=N,N-
Diisopropylethylamine; DMA=dimethylacetamide.
resorcin dimethyl ether led to the biphenyl 39.[22] Monobro-
mination of 39 and subsequent Negishi coupling of the re-
sulting bromide with the organozinc compound prepared
from 35 gave the pentasubstituted biphenyl 40. Huoꢂs proce-
dure (Zn, I2, DMA) was used for the preparation of the or-
ganozinc compound.[23] The Negishi coupling worked well
Figure 2. Ir-directed borylation of a benzofuran 36 and a biphenyl 37.
(o-Tol)3 at ambient temperature.[24]
with [Pd2ACTHNGUTREN(NUG dba)3] and PCAHTUNGTRENNUNG
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Total Synthesis of Fulicineroside
FULL PAPER
After cleavage of all four methyl ethers in 40 with borontri-
bromide, and following hydrolysis of the ethyl ester, the acid
41 was obtained. Treatment of the tetrahydroxy acid with
acetic anhydride resulted in the formation of the seven-
membered lactone, addition of pyridine led to the acetyla-
tion of the phenyl groups, and the corresponding triacetate
could be isolated. The latter could be subjected to a boryla-
(Scheme 9). After selective TBS deprotection, the resulting
allylic alcohol was subjected to a Sharpless epoxidation. The
Sharpless system (diethyl tartrate (DET), TiACTHNURGTNEUNG(OiPr)4) favours
the erythro product strongly.[28] By using (ꢀ)-DET, the eryth-
ro product 48 was obtained with 9:1 selectivity (matched
case). To get access to the threo product, the mismatched
case using (+)-DET was investigated. This time a 1:1 mix-
ture of both diastereomers 47 and 48 was formed, which
could be separated by HPLC. Epoxidation using [VO-
(Bpin)2}[17b] (cod=1,5-cycloocta-
tion {[IrACHTUNGTRENNUNG(cod)OMe]2/dtbpy/ACHUTNGTRENNUGN
diene, 4,4-dtbpy=di-tert-butyl bipyridine, Bpin=bis(pinaco-
lato)diborane) with complete meta selectivity in very good
yield. The boronic ester was converted into the potassium
trifluoroborate 42, which could be purified easily by crystal-
lization.[25] For the following Suzuki coupling, the trifluoro-
borate 42 was converted into the more reactive aryl boronic
acid first.[26] Pd-catalyzed coupling with the alkenyl bromide
32 then led to alkenyl-substituted biphenyl 43.
Whereas the introduction of the C6 side chain through
borylation/Suzuki reaction had worked fine, the following
ring closure of the dibenzofuran ring was more cumbersome.
Alkaline hydrolysis of all four ester groups in 43 and subse-
quent lactone reformation by DCC coupling led to the trihy-
droxylactone 44. Treatment of the latter with one equivalent
of perfluoro-1-butanesulfonyl fluoride gave a mononona-
flate, which was subjected to an intramolecular Hartwig–
Buchwald reaction[27] to yield only 25% of the desired di-
benzofuran 45. At this point, the low yield for the dibenzo-
furan ring closure disfavored the borylation route clearly
AHCTUNGTERG(NNUN acac)2] (acac=acetylacetone) resulted in a 6:1 ratio with
the erythro product as a main product. The final TBAF-
mediated deprotection of the di-tert-butylsilene group pro-
duced the postulated structure of fulicinerine (2) and its
epoxy diastereomer 49.
Synthesis of the trisaccharide: Structure 50 was proposed for
the trisaccharide part of fulicineroside (Figure 3).[1] The b-
glycosidic linkage between l-rhodinose and l-rhamnose is
unprecedented in natural products. For comparison reasons
the corresponding trisaccharide 51 with the a-glycosidic
linkage was also chosen as a synthetic target. The synthesis
of the trisaccharide part of fulicineroside required the prep-
ꢀ
against the C H activation route. Therefore the synthesis of
the aglycone fulicinerine (2) was continued with the alde-
ꢀ
hyde 4, which was reached efficiently on the C H activation
route as described earlier. The final part of the aglycone
synthesis started with a Julia–Kocienski olefination of the
sulfone 3 with the aldehyde 4 to produce the triene 46
Figure 3. Structures of trisaccharides 50 and 51.
Scheme 9. Synthesis of fulicinerine (2) and the epoxy-stereoisomer 49: a) LiHMDS, 3, THF, ꢀ788C; b) HF (aq), MeCN; c) tBuOOH, (+)-DET, Ti-
(OiPr)4, 3 ꢃ molecular sieves, CH2Cl2, ꢀ208C; d) TBAF, THF. (+)-DET=(+)-Diethyl-l-tartrate; LiHMDS=lithium hexamethyl disilazide; TBAF=tet-
rabutylammonium fluoride.
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U. Koert et al.
aration of three monosaccharide building blocks (d-olivose,
l-rhodinose, and l-rhamnose) in an adequately protected
form and ready for glycosylation. Their syntheses are sum-
marized in Scheme 10.
NMR spectroscopic data or a hithero unknown biosynthetic
pathway.[39] One way for a b-glycosidation of 2-deoxy sugars
is the use of a glycal as a starting material and the tempora-
ry introduction of an auxiliary directing group at C2.[40,41]
For the present task, a phenylthioether was chosen due to
the known predictability for the trans attack at the episulfo-
nium ion intermediate.[42] Rhodinal 58 was treated with phe-
nylsulfenyl chloride to generate the glycosyl chloride 62
[43]
(Scheme 11). Upon addition of AgOTf/SnCl2 and the gly-
Scheme 10. Synthesis of monosaccharide building blocks: a) PMBCl,
NaH, Bu4NI, DMF; b) 80% HOAc; c) Ac2O, Py; d) DDQ; e) triphos-
gene; f) MeOH, Et3N; g) BzOH, DIAD, PPh3; h) LAH, dioxane, 1008C,
i) TBSCl; j) Cl3CCN, NaH, ꢀ208C. LAH=lithium aluminium hydride.
Scheme 11. Synthesis of a-disaccharide 63 with X-ray structure of 64 and
synthesis of a-disaccharide 67: a) PhSCl, CH2Cl2; b) 54, AgOTf, SnCl2;
c) TBAF; d) PPTS; e) K2CO3, MeOH; f) BzCl, Py. PPTS=Pyridinium p-
toluenesulfonate.
Benzyl
2,3-O-isopropylidene-a-l-rhamnopyranoside
(52)[29] was blocked at position 4 with a PMB group and a
subsequent acetonide cleavage gave the diol 53.[30] Acetate
protection of position 2 and 3 and oxidative PMB deprotec-
tion delivered the rhamnose derivative 54 suitable for a 4-
glycosylation. Compound 53 could also be converted into
the cyclic carbonate 55. The allylic acetate 56 is available by
a Ferrier rearrangement of 3,4-diacetoxy rhamnal.[31] Metha-
nolysis of the acetate followed by a Mitsunobu reaction
gave the benzoate 57.[32] The latter was converted into the 4-
OTBS-protected glycal 58. The epimeric glycal 59 was pre-
pared according to ref. [33]. The olivose building block was
synthesized by starting from d-glucal, which was trans-
formed into the hemiacetal 60 according to Roush[34] and
subsequently into the corresponding trichloroacetimidate 61.
Within the assembly of the trisaccharides 50 and 51 we fo-
cused our attention on the formation of the l-rhodinose-l-
rhamnose disaccharide first and scheduled the d-olivose at-
tachment for later. The known examples for l-rhodinose in
natural products have an a-glycosidic linkage (landomy-
cosyl donor 54, the disaccharide 63 was obtained. After
TBS-deprotection to 64, an X-ray structure[51] gave a some-
how unexpected result. The glycosylation (62+54!63) was
a-selective and the cis product was obtained. Probably the
glycosylation had behaved more SN2-like and not through
the opening of an episulfonium ion. A more straightforward
route to the a-glycosylated disaccharide used the acid-cata-
lyzed addition of the rhamnose derivative 55 to the rhodinal
58. Disaccharide 65 was obtained with >95:5 a-selectivity.
Exchange of the carbonate to benzoate protecting groups
gave compound 66. After TBS-deprotection the a-linked
rhodinose/rhamnose dissaccharide 67 was available.
At this point it became clear that a direct b-attack at the
rhodinose building block was not possible. The steric shield-
ing of the b-side by both b-substituents at C4 and C5 domi-
nated the stereochemical outcome of the glycosylation.
Better chances for a b-attack could be given if the bulky 4-
TBSO group would be a instead of b. So the b-selective gly-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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Total Synthesis of Fulicineroside
FULL PAPER
cosylation was investigated with this type of glycosyl accept-
or (Scheme 12). A Pd-catalyzed allylic substitution[44] of the
allylic acetate 59 and the glycosyl donor 54 gave the disac-
Scheme 13. Mechanism of the Pd-catalyzed glycosylation.
Scheme 12. Synthesis of b-disaccharide 73: a) Et2Zn, PdACTHUNTGRNE(NUG OAc)2, DTBBP;
b) TBAF; c) ClCH2COOH, DIAD, PPh3; d) Et3N, MeOH; e) TsNHNH2,
NaOAc. DTBBP=Di-tert-butylbiphenyl.
charide 68 with >95:5 b-selectivity. The activation of alco-
hol 54 as zinc alcoholate 69 led to an (O3!O4) acetyl mi-
gration to form the alcoholate 70, which gave rise to the ob-
served rhamnose glycosylation in position 3. TBS-deprotec-
tion of 68 gave the alcohol 71. A Mitsunobu inversion of the
secondary alcohol produced the allylic alcohol 72 with the
desired relative configuration in the rhodinose part. After
diimide reduction[45] the alcohol 73 was obtained.
Scheme 14. Synthesis of b-disaccharide 80: a) Compound 59, Et2Zn,
Pd(OAc)2, DTBBP; b) TBAF; c) ClCH2COOH, DIAD, PPh3; d) Et3N,
MeOH; e) TsNHNH2, NaOAc, f) K2CO3, MeOH; g) BzCl, Py.
AHCTUNGTRENNUNG
The stereochemical outcome of the Pd-catalyzed allylic
substitution (59+54!63) in a mechanistic context is illus-
trated in Scheme 13.[44] For the bulky DTBBP ligand a net
retention mechanism is operative (I!III).[46] Paths A–D
exist for the formation of the a-anomer IV and these paths
may become competitive when the less bulky ligand
74 selectively. The presence of the carbonate interfered with
the attempted subsequent diimide reduction (75!76). Thus
the carbonate 74 was methanolyzed to the diol 77. After
benzoylation and TBS cleavage (77!78) the Mitsunobu in-
version to 79 and the subsequent diimide reduction to 80
proceeded smoothly.
PACHTUNGTRENNUNG
(OMe)3 is used.[47] The Zn2+ ion plays a dual role by acti-
vating both the glycosyl acceptor and the leaving group of
the donor.[48]
The undesired (O3!O4) acyl migration observed during
the formation of 68 was avoided by the use of a carbonate
instead of the bisacetate (Scheme 14). Pd-catalyzed glycosy-
lation of 59 with the carbonate 55 produced the b-glycoside
With the rhodinose–rhamnose disaccharides (b-linked 80,
a-linked 67) in hand, the synthesis of the complete trisac-
charide was addressed next. The b-l-rhodinose-1,4-a-l-
rhamnose disaccharide 80 could be glycosylated with the d-
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U. Koert et al.
olivose trichloroacetimidate 61 to obtain the trisaccharide
81 with a 6:1 b/a-selectivity (Scheme 15).[49] Transformation
of the tosylate into the corresponding iodide and subsequent
Scheme 16. Synthesis of b,a-trisaccharide 86: a) TMSOTf, Et2O/CH2Cl2,
ꢀ788C; b) LiI, THF; c) Ra-Ni, EtOH; d) Cl3CCN, NaH.
the a-anomer 88 in 61% yield. No b-anomer was detected
in this glycosylation step.
Scheme 15. Synthesis of b,b-trisaccharide 83: a) TMSOTf, Et2O/CH2Cl2,
ꢀ788C; b) LiI, THF; c) Ra-Ni, EtOH; d) Cl3CCN, NaH.
Final removal of the protecting groups was attempted ini-
tially by methanolysis of the esters prior to desilyation due
to the sensitive character of the unprotected dibenzofuran.
But it proved difficult to cleave the acetate, which was steri-
cally hindered by the neighboring TBS group. Eventually,
treatment with TBAF in THF followed by K2CO3 in MeOH
and purification on reversed-phase silica gel afforded the
target compound 1 with its b,b,a-trisaccharide in 61% yield.
The glycosylation of 87 with the b,a,a-trisaccharide 86 gave
the protected b,a,a-fulicineroside 89 in 35% yield.
treatment with Ra-Ni resulted in the simultaneous removal
of the thioether, the iodine, and the benzyl ether to give tri-
saccharide 82. After conversion of compound 82 into the tri-
chloroacetimidate 83, a properly protected trisaccharide
building block suitable for the final aglycone glycosylation
was obtained.
The a-l-rhodinose-1,4-a-l-rhamnose disaccharide 67 was
glycosylated with the d-olivose trichloroacetimidate 61 to
deliver the trisaccharide 84 with
a
6:1 b/a-selectivity
Discussion of NMR spectroscopic data for the aglycone fuli-
cinerine (2) and the natural product fulicineroside (1): With
the completed structures of fulicinerine (2) and its epoxy di-
(Scheme 16). After conversion of the tosylate into the corre-
sponding iodide, treatment with Ra-Ni resulted in the simul-
taneous removal of the thioether, the iodine substituent, and
the benzyl ether to give trisaccharide 85. Transformation
into the trichloroacetimidate 86 gave a trisaccharide suitable
for the aglycone glycosylation.
astereomer 49 in hand, a detailed comparison of our NMR
[1]
ˇ
spectroscopic data with those published by Rezanka was
accomplished.
1
In the H NMR spectra of 2 the most significant devia-
To complete the synthesis of fulicineroside (1), initial at-
tempts were undertaken to directly glycosylate the protected
aglycone 47 with trichloroacetimidate 83. At low tempera-
tures (ꢀ788C) the activated trisaccharide was expected to
tions were observed for H-13 (Dd(synth/lit)=ꢀ0.94/
ꢀ0.88 ppm) and H-13’ (Dd= +0.43 ppm, see Figure 4). Fur-
thermore, major differences occurred in the region of the
epoxy alcohol at H-7’ (Dd= +0.33 ppm) and H-9’ (Dd=
ꢀ0.25 ppm). 13C NMR spectroscopic analysis revealed the
strongest discrepancies at C-13 (Dd=ꢀ6.3 ppm) and the
quaternary dibenzofuran carbon atoms C-5a (Dd= +
12.5 ppm) and C-6 (Dd= +11.6 ppm). The data of the
epoxy diastereomer 49 did not fit closer to the literature
data but showed even slightly higher deviations. Our analy-
sis suggests a misassignment of the aglycone structure.
ꢀ
react with the primary alcohol (C13 OH) selectively. Un-
fortunately, a hardly separable mixture of mono- and bisgly-
cosylated products was formed. This led to the conclusion
ꢀ
that a protection for the secondary alcohol (C9’ OH) prior
to the glycosylation was inevitable. Triethylsilyl (TES) pro-
tection of 47 with subsequent monodeprotection employing
AcOH in THF/H2O led to compound 87 (Scheme 17). Sub-
sequent glycosylation with trichloroacetimidate 83 afforded
In the NMR spectroscopic analysis of the glycosylated
natural product an emphasis was set on the postulated un-
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Total Synthesis of Fulicineroside
FULL PAPER
common b-linked l-rhodinose (Figure 5). Signals for the
rhodinosyl-H-1’’’ of the b-linked products 1 (d=4.45 ppm)
and 88 (d=4.53 ppm) were consistent with data of Kirsch-
Figure 5. NMR spectroscopic data comparison between synthetic and nat-
ural fulicineroside (1).
ning[50] for a synthetic b-linked rhodinose (d=4.45 ppm) but
ˇ
differed from Rezankaꢂs value (d=4.78 ppm). The latter
value matched better with the data for the a-rhodinose com-
pound 89 (d=4.89 ppm) and Kirschningꢂs data (d=
4.93 ppm for an a-rhodinose). The 13C-shift of C-1’’’ in 1
ˇ
(d=104.2 ppm) in comparison with Rezankaꢂs shift (d=
Scheme 17. Synthesis of fulicineroside (1): a) TESOTf, lutidine, CH2Cl2,
08C; b) AcOH, H2O, THF; c) 83, TMSOTf, CH2Cl2, ꢀ788C; d) TBAF,
THF; K2CO3, MeOH, e) TMSOTf, CH2Cl2, ꢀ788C.
96.9 ppm) agrees with the b/a-correlation in Kirschningꢂs
values (b: d=101.1, a: 95.6 ppm). Analysis of the coupling
constants also supports the presence of an a-linked rhodi-
nose instead of the postulated b-linkage in fulicineroside.
1
The H NMR spectroscopic data of 1 showed additional de-
viations at rhamnosyl-H-4’’ (Dd=ꢀ0.89 ppm) and olivosyl-
H-4’’’’ (d=ꢀ1.50 ppm, see Figure 4). At the same positions
the 13C-signals were significantly aberrant (Dd= +11.9 and
+3.5 ppm, respectively). This analysis also suggests a misas-
signment of the trisaccharide part of natural product struc-
ture.
Details for the comparison of the NMR spectroscopic
data are given in the Supporting Information. Unfortunately,
no original analytical data could be provided for comparison
ˇ
by Dr. Rezanka even on repeated request.
Conclusion
The efficient stereoselective syntheses for the proposed
structures of fulicineroside and its aglycone fulicinerine
have been achieved. The aglycone epoxy-epimer and the a-
Figure 4. NMR spectroscopic data comparison between synthetic and nat-
ural fulicinerine (2).
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U. Koert et al.
(s), 606 (w), 436 cmꢀ1 (m); HRMS (ESI): m/z calcd for C51H80O6Si2Na:
867.5386 [M+Na]+; found: 867.5396.
linked rhodinose–rhamnose structure could also be synthe-
sized for comparison. Key features of the aglycone synthesis
were two separate routes to the pentasubstitututed dibenzo-
furan, either through a Pd-mediated ortho-functionalization
or an Ir-catalyzed meta-directed borylation. The C6 side
chain could be attached by a Julia–Kocienski olefination. A
stereoselective synthesis of the trisaccharide part was chal-
lenged by the b-linkage between l-rhodinose and l-rham-
nose. This problem could be solved by a Pd-mediated b-gly-
cosylation of a 4-epi-rhodinose and a subsequent Mitsunobu
inversion. Comparison of the reported data for fulicinero-
side and fulicinerine suggests a misassignment of the natural
product structure and the aglycone structure. NMR spectro-
sopic analysis supports the presence of an a-linked rhodi-
nose instead of the postulated b-linkage.
(5’R,7’S,8’S,9’R,10’R,12R)-(1’E,3’E,7’E)-1,8-Bis(tert-butylsiloxy)-9’,13-di-
hydroxy-7’,8’-epoxy-2-(12-methylbutyl-6-(1’,5’,10’-trimethyl-1’,3’-dienyldo-
decanyl))-dibenzofuran
(47)
and
(5’R,7’R,8’R,9’R,10’R,12R)-
(1’E,3’E,7’E)-1,8-bis(tert-butylsiloxy)-9’,13-dihydroxy-7’,8’-epoxy-2-(12-
methylbutyl-6-(1’,5’,10’-trimethyl-1’,3’-dienyldodecanyl))dibenzofuran
(48): A 50 mL polyethylene tube was used to dissolve THP ether 46
(299 mg, 0.35 mmol) in CHCl3 (6 mL). HF (aq) (15 mL, 15.0 mmol, 1.0m
in MeCN) was added. Further MeCN (8 mL) was added until the solu-
tion became clear. The reaction mixture was stirred for 4–6 h at RT. Par-
tial isomerization or/and elimination of the allylic alcohol was observed
when the reaction was stirred for longer periods. After complete conver-
sion of the starting material, the mixture was slowly poured on cold sat.
NaHCO3 (30 mL). When the gas evolution had stopped the mixture was
extracted with CHCl3 (3ꢄ50 mL) and the combined organic fractions
were dried over anhydrous Na2SO4. Silica gel (1.5 g) was added and all
volatiles were removed under reduced pressure. Silica gel flash chroma-
tography (30 g, CHCl3/n-pentane/Et2O 5:4:1—pure CHCl3) delivered the
corresponding diol as a colorless foam (188 mg, 0.29 mmol, 83%). TLC:
Rf =0.22 (n-pentane/Et2O 1:1); [a] (c=1.23 in CHCl3, 208C): [a]D = +32,
[a]578 = +34, [a]546 = +40, [a]436 = +95; 1H NMR (300 MHz, CDCl3): d=
7.21 (pdd, J=5.1, 1.2 Hz, 1H, H-5), 7.17 (d, J=8.3 Hz, 1H, H-3), 7.05 (d,
J=8.3 Hz, 1H, H-4), 6.98 (pdd, J=10.7, 1.1 Hz, 1H, H-7), 6.54 (d, J=
10.8 Hz, 1H, H-2’), 6.42 (dd, J=14.2, 11.3 Hz, 1H, H-3’), 5.79 (dd, J=
14.7, 7.7 Hz, 1H, H-4’), 5.68–5.57 (m, 1H, H-7’), 5.49 (dd, J=15.4,
7.2 Hz, 1H, H-8’), 3.98–3.85 (m, 1H, H-9’), 3.60 (dd, J=10.4, 5.4 Hz, 1H,
H-13), 3.48 (dd, J=10.5, 6.4 Hz, 1H, H-13), 2.87 (ddd, J=13.2, 10.6,
5.4 Hz, 1H, H-10), 2.77–2.64 (m, 1H, H-10), 2.43–2.33 (m, 1H, H-5’),
2.21 (s, 3H, H-13’), 2.19–2.04 (m, 2H, H-6’), 1.83–1.75 (m, 1H, H-11),
1.79–1.71 (m, 1H, H-12), 1.60–1.45 (m, 3H, H-11’, H-11, H-12), 1.39 (brs,
Experimental Section
General: General experimental conditions and all detailed experimental
procedures for Schemes 2, 4–8, 10–12, and 14–16 are given in the Sup-
porting Information. The following section focuses on the experimental
procedures of Schemes 9 and 17.
(5’R,9’R,10’R,12R)-(1’E,3’E,7’E)-1,8-Bis(tert-butylsiloxy)-9’-(tert-butyldi-
methylsiloxy)-2-(12-methylbutyl-13-tetrahydropyranyloxy)-6-(1’,5’,10’-tri-
methyl-1’,3’,7’-trienyldodecanyl)dibenzofuran (46): Sulfone
3 (717 mg,
2H, OH), 1.17–1.10 (m, 1H, H-11’), 1.11 (s, 18H, SiACTHNURGTNEUNG(tBu)2), 1.08 (d, J=
1.46 mmol) was dissolved in THF (30 mL) and cooled to ꢀ788C.
LiHMDS (1.36 mL, 1.0m in THF) was then added. The clear yellow solu-
tion was stirred for 10 min. Aldehyde 4 (562 mg, 0.97 mmol) was dis-
solved in THF (6 mL) and added to the reaction mixture at ꢀ788C. Sub-
sequently the reaction was stirred at ꢀ788C for 20 min. After complete
conversion of the starting material, sat. NH4Cl (2 mL) and silica gel (3 g)
were added and all volatiles were removed under reduced pressure. Silica
gel flash chromatography (40 g, n-pentane/Et2O 60:1–40:1–19:1–9:1) de-
livered triene 46 as a pale-yellow gum (813 mg, 0.96 mmol, 99%, E/Z:
21:1). Sulfone 3 (190 mg, 0.39 mmol) was recovered. TLC: Rf =0.26 (n-
6.8 Hz, 3H, H-14’), 1.04 (d, J=6.6 Hz, 3H, H-14), 0.91 (t, J=6.0 Hz, 3H,
H-12’), 0.87 ppm (d, J=6.8 Hz, 3H, H-15’); 13C NMR (75 MHz, CDCl3):
d=157.0 (C-5a), 155.2 (C-4a), 150.2 (C-8), 148.0 (C-1), 144.1 (C-6), 141.4
(C-4’), 134.0 (C-1’), 132.8 (C-8’), 130.9 (C-7’), 128.5 (C-3), 128.0 (C-2’),
125.7 (C-3’), 124.9 (C-10), 114.4 (C-9b), 113.3 (C-9a), 109.5 (C-7), 104.1
(C-4), 101.7 (C-5), 76.9 (C-9’), 68.4 (C-13), 40.6 (C-10’), 40.0 (C-6’), 37.4
(C-5’), 36.1 (C-12), 34.5 (C-11), 27.6 (C-10), 27.2 (Si
ACHTUNGRTEN(NUGN tBu)3), 25.4 (C-11’),
21.4 (Si(tBu)3), 20.2 (C-14’), 16.7 (C-14), 16.4 (C-13’), 14.6 (C-15’),
AHCTUNGTRENNUNG
11.6 ppm (C-12’); IR (film): n˜ =3347 (br, w), 2959 (m), 2932 (m), 2860
(m), 1599 (m), 1583 (m), 1501 (m), 1470 (m), 1410 (s), 1334 (m), 1271
(m), 1242 (m), 1072 (s), 1035 (s), 965 (s), 911 (w), 864 (s), 827 (s), 795 (s),
755 (s), 659 (s), 605 (m), 435 cmꢀ1 (m); HRMS (ESI): m/z calcd for
C40H58O5SiNa: 669.3946 [M+Na]+; found: 669.3953.
pentane/Et2O 40:1); [a] (c=0.90 in CHCl3, 198C): [a]D = +20.3, [a]578
=
+21.8, [a]546 = +25.7, [a]436 = +59.0; 1H NMR (300 MHz, CDCl3): d=
7.20 (dd, J=6.8, 1.2 Hz, 1H, H-5), 7.18/1.17 (d, J=8.3 Hz, 1H, H-3), 7.04
(d, J=8.3 Hz, 1H, H-4), 6.98 (d, J=9.0, 1.2 Hz, 1H, H-7), 6.54 (d, J=
10.9 Hz, 1H, H-2’), 6.42 (dd, J=14.6, 10.9 Hz, 1H, H-3’), 5.80 (dd, J=
14.6, 7.7 Hz, 1H, H-4’), 5.56–5.36 (m, 2H, H-7’, H-8’), 4.58 (ps, 1H,
THP), 3.86 (pt, J=6.0 Hz, 1H, H-9’), 3.88–3.80 (m, 1H, THP), 3.69 (dd,
J=9.4, 5.8 Hz, 0.5H, H-13), 3.59 (dd, J=9.3, 6.9 Hz, 0.5H, H-13), 3.53–
3.45 (m, 1H, THP), 3.30 (dd, J=9.4, 5.7 Hz, 0.5H, H-13), 3.21 (dd, J=
9.4, 6.3 Hz, 0.5H, H-13), 2.93–2.80 (m, 1H, H-10), 2.77–2.65 (m, 1H, H-
10), 2.43–2.30 (m, 1H, H-5’), 2.21 (s, 3H, H-13’), 2.16–2.07 (m, 2H, H-6’),
1.92–1.82 (m, 1H, H-12), 1.87–1.75 (m, 1H, H-11), 1.58–1.47 (m, 1H, H-
11), 1.90–1.44 (m, 6H, THP), 1.54–1.44 (m, 1H, H-11’), 1.46–1.38 (m,
Sharpless epoxidation: Molecular sieves (3 ꢃ, 100 mg) were dried by
heating under high vacuum in a 50 mL Schlenk flask. CH2Cl2 (5 mL) was
added and the suspension was cooled to ꢀ208C. Ti
ACHTUNGTERN(NGNU OiPr)4 (0.135m in
CH2Cl2, 1.14 mL, 0.15 mmol) was added followed by immediate addition
of l-(+)-DET (0.175m in CH2Cl2, 1.06 mL, 0.19 mmol). The mixture was
stirred at ꢀ208C for 10 min and then tBuOOH (0.165m in CH2Cl2,
1.22 mL, 0.20 mmol) was added. The allylic alcohol (100 mg, 0.15 mmol,
dissolved in 3 mL CH2Cl2) was added after further 5 min at ꢀ208C. The
reaction mixture was stirred at ꢀ208C for 16 h. Subsequently the reaction
was stopped by addition of sat. Na2S2O3 (6 mL). The mixture was extract-
ed with CHCl3 (3ꢄ30 mL). The combined organic extracts were dried
over anhydrous Na2SO4 and filtered. The solvents were removed under
reduced pressure. To saponify the ethyl tartrate the remaining oil was dis-
solved in THF (20 mL) and NaOH (3.0m, 1 mL) was added. The mixture
was stirred for 4 h and then extracted with CHCl3 (3ꢄ20 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4 and filtered
through a short plug of silica gel. The solvent was removed under re-
duced pressure. Separation by HPLC (0.5% MeOH in CHCl3) gave
epoxy alcohol 47 (28 mg, 0.042 mmol, 28%) as a colorless foam. Earlier
fractions delivered the diastereomeric epoxy alcohol 48 (39 mg,
0.059 mmol, 39%, 70% purity) also as a colorless foam. Analytically
pure material of 48 was obtained by Sharpless epoxidation by using d-
(ꢀ)-DET under similar conditions (d.r.=9:1) followed by HPLC purifica-
tion.
1H, H-10’), 1.10–1.06 (m, 1H, H-11’), 1.10 (s, 18H, SiACTHNUGTRENUNG(tBu)2), 1.06 (d, J=
8.3 Hz, 3H, H-14’), 1.05 (d, J=8.3 Hz, 3H, H-14), 0.88 (s, 9H, TBS), 0.88
(d, J=7.6 Hz, 3H, H-12’), 0.82 (d, J=6.7 Hz, 3H, H-15’), 0.03 (s, 3H,
TBS), 0.01 ppm (s, 3H, TBS); 13C NMR (75 MHz, CDCl3): d=157.0 (C-
5a), 155.3 (C-4a), 150.2 (C-8), 148.0 (C-1), 144.2 (C-6), 141.7 (C-4’), 133.8
(C-1’), 133.3 (C-8’), 129.3 (C-7’), 128.5 (C-3), 128.2 (C-2’), 125.6 (C-3’),
125.2/125.1 (C-2), 114.4 (C-9b), 113.3 (C-9a), 109.5 (C-7), 104.1 (C-4),
101.7 (C-5), 99.2/98.9 (THP), 77.4 (C-9’), 73.2/73.1 (C-13), 62.23/62.18
(THP), 41.7 (C-10’), 40.1 (C-6’), 37.7 (C-5’), 35.2/35.1 (C-11), 33.9/33.8
(C-12), 30.8 (THP), 27.8 (C-10), 27.2 (Si
ACHTUNGERTN(NUNG tBu)2), 26.1 (TBS), 25.7 (THP),
25.3 (C-11’), 21.5 (Si(tBu)2), 20.3 (C-14’), 19.69/19.65 (THP), 18.4 (TBS),
ACHTUNGTRENNUNG
17.34/17.30 (C-14), 16.4 (C-13’), 14.6 (C-15’), 11.9 (C-12’), ꢀ3.9 (TBS),
ꢀ4.7 ppm (TBS); IR (film): n˜ =2955 (m), 2932 (m), 2858 (m), 1600 (m),
1471 (m), 1419 (m), 1410 (m), 1337 (m), 1248 (m), 1120 (w), 1073 (s),
1033 (s), 966 (m), 911 (w), 865 (m), 829 (s), 796 (s), 774 (s), 757 (s), 659
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Total Synthesis of Fulicineroside
FULL PAPER
Compound 47: TLC: Rf =0.15 (CHCl3); [a]: (c=1.40 in CHCl3, 238C):
[a]D = +28, [a]578 = +30, [a]546 = +36, [a]436 = +89; 1H NMR (500 MHz,
CDCl3): 7.20 (d, J=1.3 Hz, 1H, H-5), 7.17 (d, J=8.3 Hz, 1H, H-3), 7.05
(d, J=8.3 Hz, 1H, H-4), 7.00 (d, J=1.3 Hz, 1H, H-7), 6.55 (dd, J=10.9,
1.0 Hz, 1H, H-2’), 6.48 (ddd, J=14.7, 10.9, 1.0 Hz, 1H, H-3’), 5.83 (dd,
J=14.7, 7.8 Hz, 1H, H-4’), 3.59 (dd, J=10.5, 5.5 Hz, 1H, H-13), 3.48 (dd,
J=10.5, 6.6 Hz, 1H, H-13), 3.26 (pt, J=5.8 Hz, 1H, H-9’), 2.99–2.94 (m,
1H, H-7’), 2.89–2.82 (m, 1H, H-10), 2.81 (dd, J=5.2, 2.3 Hz, 1H, H-8’),
2.72 (ddd, J=13.4, 10.7, 5.6 Hz, 1H, H-10), 2.58–2.50 (m, 1H, H-5’), 2.21
(s, 3H, H-13’), 1.98 (brs, 1H, OH), 1.82–1.72 (m, 1H, H-11), 1.78–1.69
(m, 1H, H-12), 1.70–1.53 (m, 3H, H-6’, H-10’), 1.68–1.60 (m, 1H, H-11’),
1.55–1.45 (m, 1H, H-11), 1.26 (s, 1H, OH), 1.28–1.18 (m, 1H, H-11’),
Reversed-phase silica gel chromatography (silica gel 100, C18, 3 g, MeCN/
H2O 1:1–2:1) afforded fulicinerine (2) as a pale-brown foam (17 mg,
0.033 mmol, 86%). TLC: Rf =0.28 (RP, MeCN/H2O 2:1); [a] (c=0.85 in
CHCl3, 218C): [a]D = +23, [a]578 = +25, [a]546 = +29; 1H NMR
(600 MHz, CDCl3): d=7.12 (s, 1H, H-5), 7.11 (d, J=8.3 Hz, 1H, H-3),
7.02 (d, J=8.2 Hz, 1H, H-4), 6.90 (s, 1H, H-7), 6.51 (d, J=11.0 Hz, 1H,
H-2’), 6.45 (dd, J=14.4, 11.0 Hz, 1H, H-3’), 5.77 (dd, J=14.6, 7.7 Hz,
1H, H-4’), 3.86 (dd, J=10.1, 4.2 Hz, 1H, H-13), 3.64 (dd, J=9.9, 8.2 Hz,
1H, H-13), 3.27 (pt, J=5.8 Hz, 1H, H-9’), 2.99–2.92 (m, 2H, H-7’, H-10),
2.81 (dd, J=5.2, 2.2 Hz, 1H, H-8’), 2.74 (ddd, J=13.7, 8.1, 4.9 Hz, 1H,
H-10), 2.56–2.50 (m, 1H, H-5’), 2.17 (s, 3H, H-13’), 1.84–1.77 (m, 1H, H-
12), 1.80–1.68 (m, 2H, H-11), 1.70–1.57 (m, 3H, H-10’, H-6’), 1.68–1.60
(m, 1H, H-11’), 1.26–1.20 (m, 1H, H-11’), 1.14 (d, J=6.8 Hz, 3H, H-14’),
0.97 (d, J=6.7 Hz, 3H, H-15’), 0.93 (t, J=7.3 Hz, 3H, H-12’), 0.89 ppm
(d, J=6.7 Hz, 3H, H-14); 13C NMR (126 MHz, CDCl3): d=157.5 (C-5a),
155.7 (C-4a), 150.0 (C-8), 147.1 (C-1), 144.0 (C-6), 140.4 (C-4’), 134.6 (C-
1’), 128.8 (C-3), 127.6 (C-2’), 126.0 (C-3’), 121.9 (C-2), 112.8 (C-9b), 110.9
(C-9a), 106.5 (C-7), 104.1 (C-4), 100.7 (C-5), 75.0 (C-9’), 69.5 (C-13), 60.5
(C-8’), 55.9 (C-7’), 39.2 (C-6’, C-10’), 36.8 (C-11), 35.2 (C-5’), 33.0 (C-12),
27.2 (C-10), 25.1 (C-11’), 20.7 (C-14’), 18.0 (C-14), 16.4 (C-13’), 14.8 (C-
15’), 11.4 ppm (C-12’); IR (film): n˜ =3335 (br, w), 2961 (s), 2927 (s), 2875
(m), 1607 (m), 1554 (s), 1431 (m), 1383 (m), 1319 (m), 1269 (m), 1236
(m), 1154 (w), 1055 (m), 1022 (s), 967 (w), 908 (m), 838 (w), 795 (w), 733
(s), 649 cmꢀ1 (m); HRMS (ESI): m/z calcd for C32H41O6: 521.2909
[MꢀH]ꢀ; found: 521.2915.
1.15 (d, J=6.7 Hz, 3H, H-14’), 1.10 (s, 18H, SiACTHNUTRGENUG(N tBu)2), 1.04 (d, J=6.6 Hz,
3H, H-14), 0.97 (d, J=6.8 Hz, 3H, H-15’), 0.93 ppm (t, J=7.3 Hz, 3H,
H-12’); 13C NMR (126 MHz, CDCl3): d=157.0 (C-5a), 155.3 (C-4a), 150.2
(C-8), 148.0 (C-1), 144.0 (C-6), 140.6 (C-4’), 134.5 (C-6), 128.5 (C-3),
127.8 (C-2’), 126.0 (C-3’), 124.9 (C-2), 114.4 (C-9b), 113.4 (C-9a), 109.5
(C-7), 104.1 (C-4), 101.7 (C-5), 74.9 (C-9’), 68.4 (C-13), 60.5 (C-8’), 55.8
(C-7’), 39.2/39.1 (C-6’, C-10’), 36.1 (C-12), 35.2 (C-5’), 34.5 (C-11), 27.7
(C-10), 27.19/27.18 (SiACHTUNGTRENNUNG(tBu)2), 25.1 (C-11’), 21.45/21.44 (SiCAHTUNGTERN(NUGN tBu)2), 20.7
(C-14’), 16.8 (C-14), 16.4 (C-13’), 14.8 (C-15’), 11.4 ppm (C-12’); IR:
(film): n˜ =3414 (br, w), 2961 (m), 2932 (m), 2860 (m), 1600 (m), 1584
(m), 1502 (m), 1470 (m), 1410 (s), 1334 (m), 1271 (m), 1242 (m), 1073 (s),
1035 (s), 940 (s), 912 (m), 864 (s), 828 (s), 795 (s), 755 (s), 659 (s), 606
(m), 436 cmꢀ1 (m); HRMS (ESI): m/z calcd for C40H58O6SiNa: 685.3895
[M+Na]+; found: 685.3889.
7’,8’-epi-Fulicinerine (49): Epoxy alcohol 48 (32 mg, 0.048 mmol) was dis-
solved in CHCl3 (5 mL) under argon atmosphere. TBAF was added
(1.0m in THF, 0.97 mL, 0.97 mmol) and the mixture was stirred at RT for
1 h. After complete conversion of the starting material the reaction mix-
ture was poured into NH4Cl (1.0m, 20 mL) and stirred for 10 min until
the yellow color almost disappeared. The combined organic fractions
from extraction with CHCl3 (3ꢄ15 mL) were dried over anhydrous
Na2SO4 and filtered. All volatiles were removed under reduced pressure.
To remove the tetrabutylammonium salts the residue was dissolved in
Et2O/H2O 1:1 (30 mL) and extracted with NH4Cl (1.0m, 5ꢄ10 mL). The
organic phase was dried over anhydrous Na2SO4 and filtered. After re-
moval of the solvent under reduced pressure a brown oil was obtained.
Reversed-phase silica gel chromatography (silica gel 100, C18, 3 g, MeCN/
H2O 1:1–2:1) afforded epi-fulicinerine (49) as a pale-brown foam (15 mg,
0.029 mmol, 60%). TLC: Rf =0.29 (RP, MeCN/H2O 2:1); [a] (c=0.80 in
CHCl3, 258C): [a]D = +47, [a]578 = +50, [a]546 = +59; 1H NMR
(500 MHz, CDCl3): d=7.12 (d, J=1.3 Hz, 1H, H-5), 7.11 (d, J=9.1 Hz,
1H, H-3), 7.02 (d, J=8.2 Hz, 1H, H-4), 6.88 (d, J=1.1 Hz, 1H, H-7),
6.48 (m, 2H, H-2’, H-3’), 5.70 (dd, J=13.9, 8.3 Hz, 1H, H-4’), 3.83 (dd,
J=10.3, 4.2 Hz, 1H, H-13), 3.63 (dd, J=10.1, 7.7 Hz, 1H, H-13), 3.61
(dd, J=5.7, 3.0 Hz, 1H, H-9’), 3.08–3.03 (m, 1H, H-7’), 2.94 (dt, J=14.1,
8.2 Hz, 1H, H-10), 2.84 (dd, J=3.4, 2.5 Hz, 1H, H-8’), 2.73 (ddd, J=13.1,
8.1, 4.6 Hz, 1H, H-10), 2.59–2.49 (m, 1H, H-5’), 2.17 (s, 3H, H-13’), 1.85–
1.76 (m, 1H, H-12), 1.82–1.65 (m, 2H, H-11), 1.71–1.55 (m, 3H, H-6’, H-
10’), 1.66–1.56 (m, 1H, H-11’), 1.27–1.18 (m, 1H, H-11’), 1.13 (d, J=
6.8 Hz, 3H, H-14’), 0.95 (d, J=6.8 Hz, 3H, H-15’), 0.90 (d, J=6.5 Hz,
3H, H-14), 0.89 ppm (t, J=6.4 Hz, 3H, H-12’); 13C NMR (126 MHz,
CDCl3): d=157.5 (C-5a), 155.7 (C-4a), 149.8 (C-8), 147.1 (C-1), 143.9 (C-
6), 140.3 (C-4’), 134.7 (C-1’), 128.8 (C-3), 127.5 (C-2’), 126.4 (C-3’), 121.9
(C-2), 112.7 (C-9b), 111.0 (C-9a), 106.4 (C-7), 104.0 (C-4), 100.8 (C-5),
72.5 (C-9’), 69.4 (C-13), 60.0 (C-8’), 54.2 (C-7’), 39.4 (C-6’), 38.6 (C-10’),
36.5 (C-11), 35.8 (C-5’), 33.1 (C-12), 27.2 (C-10), 25.2 (C-11’), 21.4 (C-
14’), 17.9 (C-14), 16.4 (C-13’), 14.7 (C-15’), 11.4 ppm (C-12’); IR (film):
n˜ =3331 (br, w), 2960 (s), 2926 (s), 2874 (m), 1607 (m), 1510 (w), 1453
(m), 1431 (m), 1382 (m), 1319 (m), 1265 (m), 1236 (m), 1155 (w), 1055
(m), 1022 (s), 967 (m), 898 (w), 840 (m), 793 (m), 756 (s), 652 cmꢀ1 (m);
HRMS (ESI): m/z calcd for C32H41O6: 521.2909 [MꢀH]ꢀ; found:
521.2904.
Compound 48: TLC: Rf =0.19 (CHCl3); [a] (c=0.90 in CHCl3, 228C):
[a]D = +42, [a]578 = +44, [a]546 = +52, [a]436 = +118; H NMR (500 MHz,
1
CDCl3): 7.20 (d, J=1.3 Hz, 1H, H-5), 7.17 (d, J=8.3 Hz, 1H, H-3), 7.05
(d, J=8.2 Hz, 1H, H-4), 7.00 (d, J=1.3 Hz, 1H, H-7), 6.54 (dd, J=11.1,
1.3 Hz, 1H, H-2’), 6.50 (dd, J=12.5, 10.9, 0.9 Hz, 1H, H-3’), 5.77 (dd, J=
13.2, 8.1 Hz, 1H, H-4’), 3.62 (dd, J=5.7, 2.9 Hz, 1H, H-9’), 3.59 (dd, J=
10.5, 5.5 Hz, 1H, H-13), 3.48 (dd, J=10.5, 6.6 Hz, 1H, H-13), 3.06 (ddd,
J=7.1, 5.0, 2.3 Hz, 1H, H-7’), 2.90–2.83 (m, 1H, H-10), 2.84 (dd, J=3.3,
2.5 Hz, 1H, H-8’), 2.72 (ddd, J=13.4, 10.8, 5.6 Hz, 1H, H-10), 2.61–2.52
(m, 1H, H-5’), 2.22 (s, 3H, H-13’), 1.83–1.76 (m, 1H, H-11), 1.78–1.71 (m,
1H, H-12), 1.69–1.55 (m, 3H, H-6’, H-10’), 1.65–1.58 (m, 1H, H-11’),
1.55–1.46 (m, 1H, H-11), 1.26–1.19 (m, 1H, H-11’), 1.15 (d, J=6.8 Hz,
3H, H-14’), 1.11 (s, 18H, SiACHTNUGTRNEUNG(tBu)2), 1.04 (d, J=6.7 Hz, 3H, H-14), 0.96
(d, J=6.9 Hz, 3H, H-15’), 0.91 ppm (t, J=7.4 Hz, 3H, H-12’); 13C NMR
(75 MHz, CDCl3): d=157.0 (C-5a), 155.3 (C-4a), 150.2 (C-8), 148.0 (C-1),
144.0 (C-6), 140.4 (C-4’), 134.7 (C-1’), 128.5 (C-3), 127.7 (C-2’), 126.4 (C-
3’), 124.9 (C-2), 114.4 (C-9b), 113.4 (C-9a), 109.6 (C-7), 104.1 (C-4), 101.7
(C-5), 72.4 (C-9’), 68.4 (C-13), 59.9 (C-8’), 53.9 (C-7’), 39.4 (C-6’), 38.6
(C-10’), 36.1 (C-12), 35.7 (C-5’), 34.5 (C-11), 27.7 (C-10), 27.2 (Si
ACHTUNGRTEN(NUNG tBu)2),
25.2 (C-11’), 21.44 (Si(tBu)2), 21.36 (C-14’), 16.8 (C-14), 16.5 (C-13’), 14.7
ACHTUNGTRENNUNG
(C-15’), 11.4 ppm (C-12’); IR (film): n˜ =3409 (br, w), 2961 (m), 2933 (m),
2861 (m), 1600 (m), 1502 (m), 1470 (m), 1410 (s), 1335 (m), 1272 (m),
1242 (m), 1073 (s), 1035 (s), 910 (s), 865 (s), 828 (s), 796 (s), 733 (s), 660
(s), 606 (m), 437 cmꢀ1 (m); HRMS (ESI): m/z calcd for C40H58O6SiNa:
685.3895 [M+Na]+; found: 685.3886.
Fulicinerine (2): Epoxy alcohol 47 (25 mg, 0.038 mmol) was dissolved in
CHCl3 (3 mL) under an argon atmosphere. TBAF was added (1.0m,
0.26 mL, 0.26 mmol) and the mixture was stirred at RT for 2 h. A second
portion of TBAF (0.26 mL, 0.26 mmol) was added and the reaction was
stirred for 1 h. Subsequently
a third portion of TBAF was added
(0.26 mL, 0.26 mmol). After 1 h, the conversion of the starting material
was complete. The bisphenol 2 was found to be unstable on standard
silica gel. Therefore the reaction monitoring by TLC analysis showed de-
creasing starting material and an increasing base line spot (n-pentane/
Et2O, 1:1). After complete conversion of the starting material the reac-
tion mixture was poured into NH4Cl (1.0m, 20 mL) and stirred for 10 min
until the yellow color almost disappeared. The combined organic frac-
tions from extraction with CHCl3 (3ꢄ15 mL) were dried over anhydrous
Na2SO4 and filtered. All volatiles were removed under reduced pressure.
To remove the tetrabutylammonium salts the residue was dissolved in
Et2O/H2O 1:1 (30 mL) and extracted with NH4Cl (1.0m, 5ꢄ10 mL). The
organic phase was dried over anhydrous Na2SO4 and filtered. After re-
moval of the solvent under reduced pressure a brown oil was obtained.
(5’R,7’S,8’S,9’R,10’R,12R)-(1’E,3’E,7’E)-1,8-Bis(tert-butylsilyloxy)-9’-trie-
thylsilyloxy-13-hydroxy-7’,8’-epoxy-2-(12-methylbutyl-6-(1’,5’,10’-trimeth-
yl-1’,3’-dienyldodecanyl))dibenzofuran (87): Epoxy alcohol 47 (33 mg,
0.050 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 08C. 2,6-Luti-
dine (35 mL, 0.30 mmol) was added before addition of TESOTf (45 mL,
0.20 mmol) and the reaction mixture was stirred at RT for 2 h. The reac-
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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U. Koert et al.
tion was quenched by addition of sat. NaHCO3 (5 mL) and the mixture
was extracted with Et2O (3ꢄ15 mL). The combined organic layers were
extracted with H2O (3ꢄ15 mL), dried with anhydrous Na2SO4 and fil-
tered. The solvent was removed under reduced pressure and after silica
gel chromatography (10 g, n-pentane/Et2O 100:1–50:1) double TES-pro-
tected product was obtained as a colorless oil (32 mg, 0.036 mmol, 73%).
TLC: Rf =0.37 (n-pentane/Et2O 50:1); [a] (c=1.60 in CHCl3, 208C):
ꢀ788C for 1 h. The reaction was quenched by addition of NEt3 (0.05 mL)
at ꢀ788C. The cooling bath was removed and the temperature was al-
lowed to rise to RT. Water (5 mL) was added and the mixture was ex-
tracted with CHCl3 (3ꢄ10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and filtered. The solvent was removed under re-
duced pressure. Silica gel chromatography (5 g, n-pentane/Et2O 9:1–4:1–
2:1) afforded the glycosylation product 88 (12.2 mg, 7.97 mmol, 61%) as
an amorphous colorless solid. TLC: Rf =0.57 (n-pentane/Et2O 2:1); [a]
1
[a]D = +42, [a]578 = +44, [a]546 = +52, [a]436 = +122; H NMR (300 MHz,
CDCl3): d=7.20 (d, J=1.1 Hz, 1H, H-5), 7.17 (d, J=8.3 Hz, 1H, H-3),
7.05 (d, J=8.3 Hz, 1H, H-4), 7.00 (d, J=1.0 Hz, 1H, H-7), 6.55 (d, J=
10.8 Hz, 1H, H-2ꢂ), 6.47 (dd, J=14.1, 11.1 Hz, 1H, H-3’), 5.81 (dd, J=
14.2, 7.8 Hz, 1H, H-4ꢂ), 3.55 (dd, J=9.8, 5.5 Hz, 1H, H-13), 3.41 (dd, J=
9.7, 6.7 Hz, 1H, H-13), 3.10 (dd, J=7.0, 5.3 Hz, 1H, H-9’), 2.91–2.77 (m,
2H, H-10, H-7), 2.77–2.65 (m, 1H, H-10), 2.74 (dd, J=7.1, 2.2 Hz, 1H,
H-8’), 2.61–2.46 (m, 1H, H-5’), 2.21 (s, 3H, H-13’), 1.84–1.64 (m, 3H, H-
12, H-11, H-6’), 1.58–1.40 (m, 4H, H-11, H-6’, H-10’, H-11’), 1.25–1.18
(c=0.55 in CHCl3, 188C): [a]D = +39, [a]578 = +41, [a]546 = +49, [a]436
=
+105; 1H NMR (500 MHz, CDCl3): d=8.03 (dd, J=8.3, 1.2 Hz, 2H,
OBz), 7.97 (dd, J=8.2, 1.2 Hz, 2H, OBz), 7.61–7.57 (m, 1H, OBz), 7.48–
7.43 (m, 3H, OBz), 7.30 (t, J=7.8 Hz, 2H, OBz), 7.21 (d, J=8.3 Hz, 1H,
H-3), 7.19 (d, J=1.1 Hz, 1H, H-5), 7.07 (d, J=8.3 Hz, 1H, H-4), 6.99 (d,
J=1.2 Hz, 1H, H-7), 6.54 (d, J=10.8 Hz, 1H, H-2’), 6.47 (ddd, J=14.7,
10.9, 0.7 Hz, 1H, H-3’), 5.81 (dd, J=14.7, 7.8 Hz, 1H, H-4’), 5.69 (dd, J=
9.4, 3.5 Hz, 1H, H-3’’), 5.60 (dd, J=3.5, 1.7 Hz, 1H, H-2’’), 4.88 (d, J=
1.6 Hz, 1H, H-1’’), 4.56 (pt, J=9.2 Hz, 1H, H-4’’’’), 4.53 (dd, J=9.4,
1.8 Hz, 1H, H-1’’’), 4.30 (dd, J=9.8, 1.8 Hz, 1H, H-1’’’’), 4.01 (dq, J=
12.1, 6.0 Hz, 1H, H-5’’), 3.94 (pt, J=9.5 Hz, 1H, H-4’’), 3.63 (ddd, J=
11.6, 8.8, 5.3 Hz, 1H, H-3’’’’), 3.54 (dd, J=9.1, 7.5 Hz, 1H, H-13), 3.43
(dd, J=9.3, 5.2 Hz, 1H, H-13), 3.25–3.14 (m, 3H, H-5’’’’, H-4’’’, H-5’’’),
3.10 (dd, J=7.0, 5.3 Hz, 1H, H-9’), 2.91–2.79 (m, 2H, H-10, H-7’), 2.77–
2.70 (m, 2H, H-10, H-8’), 2.57–2.49 (m, 1H, H-5’), 2.21 (s, 3H, H-13’),
2.13–2.07 (m, 1H, H-3’’’), 2.04 (s, 3H, OAc), 2.02 (ddd, J=13.1, 5.3,
1.7 Hz, 1H, H-2’’’’), 1.95–1.86 (m, 1H, H-12), 1.82–1.73 (m, 2H, H-11, H-
2’’), 1.72–1.68 (m, 1H, H-6’), 1.68–1.64 (m, 1H, H-2’’’’), 1.61–1.46 (m, 6H,
H-11’, H-10’, H-6’, H-11, H-2’’’, H-3’’’), 1.40 (d, J=6.1 Hz, 3H, H-6’’),
1.23–1.19 (m, 1H, H-11’), 1.15 (d, J=6.7 Hz, 3H, H-14’), 1.13–1.10 (m,
(m, 1H, H-11’), 1.15 (d, J=6.7 Hz, 3H, H-14’), 1.10 (s, 18H, Si
1.02–0.89 (m, 27H, H-12’, H-15’, H-14, 2ꢄSi(CH2CH3)3), 0.68–0.54 ppm
(m, 12H, 2ꢄSi
(CH2CH3)3); 13C NMR: (75 MHz, CDCl3): d=157.0 (C-
ACHTUNGRTEN(NUNG tBu)2),
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
5a), 155.2 (C-4a), 150.3 (C-8), 148.0 (C-1), 144.0 (C-6), 140.9 (C-4’), 134.5
(C-1’), 128.5 (C-3), 127.8 (C-2’), 126.0 (C-3’), 125.3 (C-2), 114.4 (C-9b),
113.4 (C-9a), 109.5 (C-7), 104.1 (C-4), 101.7 (C-5), 78.2 (C-9’), 68.4 (C-
13), 61.5 (C-8’), 55.3 (C-7’), 40.3 (C-10’), 39.4 (C-6’), 36.3 (C-11), 35.0 (C-
5’), 34.7 (C-12), 27.7 (C-10), 27.2 (Si
(tBu)2), 20.8 (C-14’), 17.0 (C-14), 16.4 (C-13’), 15.2 (C-15’), 11.9 (C-12’),
7.1/7.0 (Si(CH2CH3)3), 5.2/4.6 ppm (Si(CH2CH3)3); IR (film): n˜ =2955
ACHTUNGTRNE(NUNG tBu)2), 25.2 (C-11’), 21.5/21.4 (Si-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(m), 2875 (m), 1600 (m), 1585 (m), 1503 (m), 1469 (m), 1411 (m), 1336
(m), 1271 (m), 1241 (m), 1074 (s), 1037 (m), 1012 (m), 965 (m), 913 (m),
866 (m), 828 (s), 796 (s), 742 (s), 728 (s), 660 (m), 607 (w), 437 cmꢀ1 (w);
HRMS (ESI): m/z calcd for C52H87O6Si3: 891.5805 [M+H]+; found:
891.5800.
21H, SiACTHUNGRTENUNG(tBu)2, H-6’’’’), 1.09 (d, J=6.7 Hz, 3H, H-14), 0.96 (t, J=8.0 Hz,
9H, TES), 0.96–0.89 (m, 6H, H-15’, H-12’), 0.84 (s, 9H, TBS), 0.77 (d,
J=6.3 Hz, 3H, H-6’’’), 0.68–0.58 (m, 6H, TES), 0.04 (s, 3H, TBS),
0.01 ppm (s, 3H, TBS); 13C NMR (101 MHz, CDCl3): d=170.0 (OAc),
165.7 (OBz), 165.2 (OBz), 157.0 (C-5a), 155.3 (C-4a), 150.3 (C-8), 148.0
(C-1), 143.9 (C-6), 140.8 (C-4’), 134.5 (C-1’), 133.3 (OBz), 132.7 (OBz),
130.7 (OBz), 130.2 (OBz), 130.0 (4ꢄOBz), 128.7 (C-3), 128.6 (2ꢄOBz),
128.1 (2ꢄOBz), 127.8 (C-2’), 126.0 (C-3’), 124.9 (C-2), 114.4 (C-9b), 113.5
(C-9a), 109.5 (C-7), 104.2 (C-4), 102.9 (C-1’’’), 101.7 (C-5), 101.4 (C-1’’’’),
97.7 (C-1ꢂꢂ), 78.3 (C-4’’), 78.2 (C-9’), 77.5 (C-4’’’’), 74.5 (C-4’’’), 73.7 (C-
5’’’), 73.5 (C-13), 71.5 (C-2’’), 71.1 (C-3’’), 70.2 (C-3’’’’), 69.9 (C-5’’’’), 67.6
(C-5’’), 61.5 (C-8’), 55.3 (C-7ꢂ), 40.5 (C-2’’’’), 40.3 (C-10’), 39.4 (C-6’), 35.0
(C-5’), 34.8 (C-11), 33.5 (C-12), 29.4 (C-3’’’), 27.6 (C-10), 27.23/27.22 (Si-
Mono TES-deprotection: The double TES-protected compound (32 mg,
0.036 mmol) was dissolved in THF (5 mL) and HOAc/THF/H2O (3:1:1,
5 mL) was added. The reaction mixture was stirred at RT for 2.5 h. The
reaction was diluted with H2O and adjusted to pH 8 by addition of sat.
NaHCO3. The mixture was extracted with CHCl3 (3ꢄ15 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and filtered. The
solvent was removed under reduced pressure. Silica gel chromatography
(10 g, n-pentane/Et2O 9:1–4:1–2:1) afforded alcohol 87 as a colorless
gum (23 mg, 0.030 mmol, 82%). TLC: Rf =0.35 (n-pentane/Et2O 2:1); [a]
(c=1.15 in CHCl3, 208C): [a]D = +44, [a]578 = +47, [a]546 = +56, [a]436
=
1
ACHUTNGREN(NUG tBu)2), 26.6 (C-2’’’), 25.7 (TBS), 25.2 (C-11ꢂ), 21.48/21.47 (SiCAHTUNGTERN(NUGN tBu)2), 21.3
+130; H NMR (500 MHz, CDCl3): d=7.20 (d, J=1.3 Hz, 1H, H-5), 7.17
(d, J=8.3 Hz, 1H, H-3), 7.05 (d, J=8.2 Hz, 1H, H-4), 7.00 (d, J=1.3 Hz,
1H, H-7), 6.54 (dd, J=10.9, 1.0 Hz, 1H, H-2’), 6.47 (dd, J=14.7, 10.9,
1.0 Hz, 1H, H-3’), 5.82 (dd, J=14.7, 7.8 Hz, 1H, H-4’), 3.59 (dd, J=10.5,
5.5 Hz, 1H, H-13), 3.49 (dd, J=10.5, 6.6 Hz, 1H, H-13), 3.10 (dd, J=7.1,
5.3 Hz, 1H, H-9’), 2.91–2.79 (m, 2H, H-10, H-7’), 2.76–2.68 (m, 2H, H-
10, H-8’), 2.58–2.48 (m, 1H, H-5’), 2.21 (s, 3H, H-13’), 1.85–1.66 (m, 3H,
H-12, H-11, H-6’), 1.62–1.46 (m, 5H, H-11, H-6’, H-10’, H-11’, OH), 1.25–
1.18 (m, 1H, H-11’), 1.15 (d, J=6.8 Hz, 3H, H-14’), 1.11 (s, 18H, Si-
(OAc), 20.8 (C-14ꢂ), 18.3 (C-6’’), 18.0 (TBS), 17.9 (C-6’’’’), 17.5 (C-14),
16.8 (C-6’’’), 16.4 (C-13’), 15.2 (C-15’), 11.9 (C-12ꢂ), 7.1 (TES), 5.2 (TES),
ꢀ4.3 (TBS), ꢀ4.7 ppm (TBS); IR (film): n˜ =2958 (m), 2934 (m), 2875
(m), 2860 (m), 1728 (s), 1602 (m), 1585 (w), 1502 (w), 1452 (m), 1411
(m), 1369 (m), 1318 (m), 1275 (s), 1262 (s), 1242 (s), 1109 (s), 1070 (s),
1055 (s), 1021 (m), 982 (w), 964 (w), 912 (m), 866 (m), 837 (m), 797 (w),
777 (w), 755 (w), 711 (m), 661 (m), 605 (w), 437 cmꢀ1 (w); HRMS (ESI):
m/z calcd for C86H126O18Si3Na [M+Na]+: 1553.8144; found: 1553.8112.
ACHTUNGTRENNUNG
Fulicineroside (1): Glycosylation product 88 (11.5 mg, 7.5 mmol) was dis-
solved in THF (4 mL). TBAF (1.0m in THF, 0.43 mL, 0.43 mmol) was
added through a syringe at RT. The reaction mixture immediately turned
yellow and was stirred at RT for 2 h. After complete desilylation (Rf =
0.61, CH2Cl2/MeOH 9:1) the reaction was stopped by the addition of sat.
NH4Cl (3 mL) and water (3 mL). ESI and NMR spectroscopic analysis
indicated complete cleavage of the acetate occurred along with desilyla-
tion by TBAF. The benzoate residues were also partially cleaved during
the treatment with TBAF (Rf =0.55 and 0.45, CH2Cl2/MeOH 9:1). Et2O
(12 mL) was added and the resulting mixture was extracted with NH4Cl
(1.0m, 5ꢄ5 mL). The organic layer was separated and dried over anhy-
drous Na2SO4 and filtered. The solvent was removed under reduced pres-
sure. The crude product was dissolved in MeOH/Et2O 4:1 (5 mL) under
an argon atmosphere. K2CO3 (25 mg, 0.18 mmol) was added and the mix-
ture was stirred for 2.5 h at RT. After complete benzoate cleavage,
NH4Cl (1.0m, 6 mL) was added and the mixture was extracted with
CHCl3 (5ꢄ6 mL). The combined organic layers were dried with Na2SO4
and filtered. The solvent was removed under reduced pressure. Re-
versed-phase silica gel chromatography (Silica gel 90, C18, 3.5 g, MeCN/
G
ACHTUNGTRENNUNG
CDCl3): d=157.0 (C-5a), 155.3 (C-4a), 150.2 (C-8), 148.0 (C-1), 144.0 (C-
6), 140.9 (C-4’), 134.4 (C-1’), 128.5 (C-3), 127.9 (C-2’), 126.0 (C-3’), 124.9
(C-2), 114.4 (C-9b), 113.4 (C-9a), 109.5 (C-7), 104.1 (C-4), 101.7 (C-5),
78.2 (C-9’), 68.5 (C-13), 61.5 (C-8’), 55.3 (C-7’), 40.3 (C-10’), 39.4 (C-6’),
36.1 (C-11), 35.0 (C-5’), 34.5 (C-12), 27.7 (C-10), 27.2 (Si
11’), 21.5/21.4 (Si(tBu)2), 20.8 (C-14’), 16.8 (C-14), 16.4 (C-13’), 15.2 (C-
15’), 11.9 (C-12’), 7.1 (Si(CH2CH3)3), 5.2 ppm (Si(CH2CH3)3); IR: (film):
n˜ =3358 (bw), 2958 (s), 2934 (s), 2875 (s), 1600 (m), 1585 (m), 1502 (m),
1470 (m), 1411 (m), 1336 (m), 1272 (m), 1242 (m), 1074 (s), 1036 (m),
1012 (m), 965 (m), 913 (m), 866 (s), 829 (s), 797 (s), 744 (m), 661 (m),
607 (m), 438 cmꢀ1 (w); HRMS (ESI): m/z calcd for C46H73O6Si2: 777.4940
[M+H]+; found: 777.4958.
ACHTUNGTREN(UNNG tBu)2), 25.2 (C-
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
Protected fulicineroside (88): Activated molecular sieves (3 ꢃ, 100 mg)
were suspended in CH2Cl2 (2 mL). Alcohol 87 (10.2 mg, 13.1 mmol) and
trisaccharide 83 were added and the mixture was stirred for 15 min at
RT. Then it was cooled to ꢀ788C and TMSOTf (0.055m in CH2Cl2,
6.0 mL, 0.33 mmol) was added dropwise. The mixture was stirred at
&
12
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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Total Synthesis of Fulicineroside
FULL PAPER
H2O 1:2–1:1–1.5:1–2:1–3:1) afforded fulicineroside (1, 4.2 mg, 4.6 mmol,
61%) as an amorphous colorless solid. TLC: Rf =0.45 (CH2Cl2/MeOH
9:1); [a] (c=0.20, MeOH, 198C): [a]D = +8.5, [a]578 = +9.5, [a]546 = +13,
TES), 0.04, 0.01 ppm (s, 6H, SiACTHGNUTERNNUG
(CH3)2.; 13C NMR (125 MHz, CDCl3): d=
170.0 (Cq OAc), 166.0 (2ꢄCO Bz), 157.0 (C-5a), 155.2 (C-4a), 150.2 (C-
8), 148.0 (C-1), 143.9 (C-6), 140.8 (C-4’), 137.4 (Bz), 134.5 (C-1’), 133.7
(2ꢄCq Bz), 129.9 (2ꢄBz), 129.5 (Bz), 129.1 (Bz), 128.7 (2ꢄBz), 128.6 (C-
3), 128.2 (2ꢄBz), 127.8 (C-2’), 126.6 (2ꢄBz), 126.0 (C-3’), 124.9 (C-2),
114.3 (C-9b), 113.4 (C-9a), 109.5 (C-7), 104.0 C-4), 101.6 (C-5), 101.3 (C-
1’’’’), 99.1 (C-1’’’), 97.9 (C-1’’), 78.2 (C-9’), 77.4 (C-4’’’’), 76.4 (C-2’’), 76.0
(C-4’’’), 75.9 (C-4’’), 73.8 (C-3’’), 71.7 (C-5’’), 70.2 (C-3’’’’), 70.0 (C-5’’’’),
69.0 (C-13), 67.0 (C-5’’’), 61.5 (C-8’), 55.3 (C-7’), 40.7 (C-2’’’’), 40.3 (C-
10’), 39.4 (C-6’), 35.0 (C-5’), 34.7 (C-11), 33.6 (C-12), 27.6 (C 10), (2ꢄ27.1
1
[a]436 = +48; H NMR (600 MHz, CDCl3): d=8.69 (s, 1H, 1-OH), 8.36 (s,
1H, 8-OH), 7.13 (d, J=1.2 Hz, 1H, H-5), 7.12 (d, J=8.3 Hz, 1H, H-3),
6.97 (d, J=8.2 Hz, 1H, H-4), 6.90 (d, J=1.1 Hz, 1H, H-7), 6.49–6.43 (m,
2H, H-2’, H-3’), 5.79 (dd, J=14.0, 8.0 Hz, 1H, H-4’), 4.97 (s, 1H, 2ꢂꢂ-
OH), 4.84 (d, J=0.9 Hz, 1H, H-1’’), 4.51 (dd, J=9.7, 1.5 Hz, 1H, H-1’’’’),
4.45 (dd, J=9.9, 1.5 Hz, 1H, H-1’’’), 4.07 (d, J=1.9 Hz, 1H, H-2’’), 3.96
(dd, J=9.1, 3.5 Hz, 1H, H-3’’), 3.95–3.92 (m, 1H, H-5’’), 3.74 (dd, J=9.6,
4.8 Hz, 1H, H-13), 3.70 (q, J=6.3 Hz, 1H, H-5’’’), 3.55 (ddd, J=11.8, 8.7,
5.1 Hz, 1H, H-3’’’’), 3.45 (s, 1H, H-4’’’), 3.39 (t, J=9.3 Hz, 1H, H-4’’),
3.28 (dd, J=9.6, 6.0 Hz, 1H, H-13), 3.24 (dd, J=5.5, 5.0 Hz, 1H, H-9’),
3.22 (dd, J=8.2, 5.3 Hz, 1H, H-5’’’’), 3.06 (t, J=8.9 Hz, 1H, H-4’’’’), 2.96
(ddd, J=7.4, 3.9, 2.4 Hz, 1H, H-7’), 2.91 (s, 1H, OH), 2.83–2.78 (m, 1H,
H-10), 2.80 (dd, J=5.5, 2.4 Hz, 1H, H-8’), 2.65 (ddd, J=13.3, 10.6,
6.3 Hz, 1H, H-10), 2.56–2.50 (m, 1H, H-5’), 2.26 (ddd, J=11.9, 4.6,
1.4 Hz, 1H, H-2’’’’), 2.24–2.20 (m, 1H, H-3’’’), 2.18 (s, 3H, H-13’), 1.94–
1.87 (m, 2H, H-11, H-2’’’), 1.81–1.76 (m, 2H, H-6’, H-12), 1.74–1.59 (m,
5H, H-11’, H-10’, H-2’’’, H-3’’’, H-2’’’’), 1.48 (ddd, J=14.3, 8.6, 7.6 Hz,
1H, H-6’), 1.43–1.37 (m, 1H, H-11), 1.30 (d, J=6.4 Hz, 3H, H-6’’’), 1.28
(d, J=6.2 Hz, 3H, H-6’’), 1.24 (d, J=6.1 Hz, 3H, H-6’’’’), 1.23–1.20 (m,
1H, H-11’), 1.13 (d, J=6.8 Hz, 3H, H-14’), 0.96 (d, J=7.0 Hz, 3H, H-14),
0.95 (d, J=7.0 Hz, 3H, H-15’), 0.92 ppm (t, J=7.3 Hz, 3H, H-12’); three
OH signals could not be identified unambiguously. 13C NMR (101 MHz,
CDCl3): d=157.4 (C-5a), 155.8 (C-4a), 148.6 (C-8), 148.1 (C-1), 143.8 (C-
6), 140.5 (C-4’), 134.8 (C-1’), 128.9 (C-3), 127.9 (C-2’), 126.0 (C-3’), 122.6
(C-2), 111.7 (C-9b), 111.5 (C-9a), 106.6 (C-7), 104.2 (C-1’’’), 102.8 (C-4),
101.9 (C-5), 101.2 (C-1’’’’), 99.9 (C-1’’), 85.1 (C-4’’), 77.3 (covered by sol-
vent signal) (C-4’’’’), 75.1 (C-9’), 74.5 (C-5’’’), 74.3 (C-4’’’), 72.8 (C-13),
72.0 (C-5’’’’), 71.9 (C-3’’’’), 70.6 (C-2’’), 69.9 (C-3’’), 66.4 (C-5’’), 60.4 (C-
8’), 56.7 (C-7’), 39.3 (C-6’), 39.2 (C-2’’’’), 39.1 (C-10’), 36.1 (C-5’), 34.9 (C-
11), 33.3 (C-12), 28.8 (C-3’’’), 28.0 (C-10), 26.1 (C-2’’’), 25.2 (C-11’), 21.2
(C-14’), 17.93 (C-14), 17.91 (C-6’’’’), 17.6 (C-6’’), 17.2 (C-6’’’), 16.7 (C-13’),
14.8 (C-15’), 11.4 ppm (C-12’); IR (film): n˜ =3347 (br, m), 2964 (w), 2928
(w), 2875 (w), 1614 (w), 1510 (m), 1450 (m), 1380 (w), 1315 (w), 1269
(w), 1235 (w), 1165 (w), 1132 (m), 1055 (s), 1011 (s), 981 (m), 951 (w),
905 (s), 837 (w), 795 (w), 728 (s), 647 (m), 595 (w), 548 cmꢀ1 (w); HRMS
(ESI): m/z calcd for C50H72O15Na: 935.4763 [M+Na]+; found: 935.4765.
SitBu2), 25.7 (SiC
21.3 (SitBu2), 21.3 (OAc), 20.8 (C-14’), 18.9 (Cq SiC
17.8 (C-6’’’’), 17.3 (C-6’’’), 17.2 (C-14), 16.4 (C-13’), 15.2 (C-15’), 11.9 (C-
(CH3)2); IR (film): n˜ =2958
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
12’), 7.1 (TES), 5.2 (TES), ꢀ4.4, ꢀ4.8 ppm (Si
ACHTUNGTRENNUNG
(m), 2932 (m), 2874 (m), 2859 (m), 1748 (m), 1726 (m), 1412 (w), 1271
(s), 1240 (m), 1106 (s), 1071 (s), 1056 (s), 1018 (s), 966 (w), 866 (w), 840
(w), 713 cmꢀ1 (w); HRMS (ESI): m/z calcd for C86H126O18Si3Na:
1553.8144 [M+Na]+; found: 1553.8123.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft (KO 1349/13-
1) and the Humboldt foundation (fellowship to N. S. Karanjule) is grate-
fully acknowledged.
ˇ
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Protected b,a,a-fulicineroside (89): Activated molecular sieves (3 ꢃ,
100 mg) were suspended in CH2Cl2 (2.5 mL). The trisaccharide 86
(22 mg, 24 mmol) and the aglycone 87 (19 mg, 24 mmol) were added and
the reaction mixture was cooled to ꢀ788C. TMSOTf (0.055m in CH2Cl2
(25 mL, 1.4 mmol) was added dropwise and the reaction was stirred at
ꢀ788C for 1 h. NEt3 (50 mL) was added, the reaction was warmed to RT
and filtered through Celite. To remove the NEt3, the mixture was co-
evaporated with toluene (3ꢄ2 mL). The remaining oil was purified by
chromatography on silica (8 g silica gel, n-pentane/MTBE, 20:1–1:1) to
give the protected b,a,a-fulicineroside (89) (13 mg, 8.5 mmol, 35%) as a
colorless oil. Rf =0.50 (n-hexane/MTBE 2:1); [a] (c=0.64 in CHCl3,
198C): [a]D = +24.2, [a]578 = +14.8, [a]546 = +17.3, [a]436 = +37.5;
1H NMR (500 MHz, CDCl3): d=8.06–8.02 (m, 2H, Bz), 7.66–7.61 (m,
2H, Bz), 7.59–7.54 (m, 1H, Bz), 7.45–7.40 (m, 2H, Bz), 7.38–7.33 (m,
3H, Bz), 7.18 (d, J=1.2 Hz, 1H, H-5), 7.05 (d, J=8.3 Hz, 1H, H-3), 6.99
(d, J=8.2 Hz, 1H, H-4), 6.97 (d, J=1.2 Hz, 1H, H-7), 6.53 (d, J=
10.8 Hz, 1H, H-2’), 6.46 (ddd, J=14.6, 10.9, 0.8 Hz, 1H, H-3’), 5.81 (dd,
J=14.6, 7.8 Hz, 1H, H-4’), 5.61 (d, J=3.2 Hz, 1H, H-2’’), 5.36 (dd, J=
9.5, 4.0 Hz, 1H, H-3’’), 5.11 (br s, 1H, H-1’’’), 4.89 (pt, J=3.7 Hz, 1H, H-
1’’), 4.56 (pt, J=9.3 Hz, 1H, H-4’’’’), 4.42 (dd, J=9.8, 1.8 Hz, 1H, H-1’’’’),
3.94–3.86 (m, 2H, H-4’’, H-5’’’), 3.68 (ddd, J=11.5, 8.8, 5.3 Hz, 1H, H-
3’’’’), 3.61 (dq, J=8.3, 6.2 Hz, 1H, H-5’’), 3.43 (br s, 1H, H-4’’’), 3.31–3.22
(m, 2H, H-5’’’’, H-13), 3.10 (dd, J=7.0, 5.3 Hz, 1H, H-9’), 2.82 (dt, J=
5.6, 2.2 Hz, 1H, H-7’), 2.73 (dd, J=7.1, 2.3 Hz, 1H, H-8’), 2.73–2.64 (m,
1H, H-10), 2.61–2.48 (m, 2H, H-10, H-5’), 2.20 (s, 3H, H-13’), 2.14 (ddd,
J=12.8, 5.2, 1.8 Hz, 1H, H-2’’’’), 2.04 (s, 3H, OAc), 1.87–1.61 (m, 5H, H-
2’’’, H-2’’’’, H-12, H-11), 1.45–1.35 (m, 1H, H-11), 1.28–1.25 (m, 4H, H-
3’’’, H-11’), 1.14 (d, J=6.7 Hz, 3H, H-14’), 1.11 (d, J=6.1 Hz, 3H, H-6’’’),
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AHCTUNGTRENNUNG
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: February 20, 2013
Published online: && &&, 2013
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14
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www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Total Synthesis of Fulicineroside
FULL PAPER
Natural product reassignment: Total
synthesis of the proposed structures
for fulicineroside and its aglycone fuli-
cinerine has been achieved (see
figure). Key issues were the tetrasub-
stituted dibenzofuran and the trisac-
charide with its b-linkage between l-
rhodinose and l-rhamnose. A compari-
son with the reported data for the nat-
ural product and the aglycone suggests
a misassignment of the structure of the
natural product.
Organic Synthesis
R. Bartholomꢀus, F. Dommershausen,
M. Thiele, N. S. Karanjule, K. Harms,
U. Koert* ...................... &&&& — &&&&
Total Synthesis of the Postulated
Structure of Fulicineroside
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
15
&
ÞÞ
These are not the final page numbers!