Stereoselective synthesis of benzylated prodelphinidins and their diastereomers with use of the mitsunobu reaction in the preparation of their gallocatechin precursors

Article abstract of DOI:10.1002/ejoc.201000053

The tetrabenzylated catechin 9 was prepared by benzylation of the commercially available pure (+)-catechin (3) and cou-pled with the commercially unavailable pentabenzylated (-)-gallocatechin 10, prepared in a one-step Mitsunobu-type cyclization of the triol 8. The highly stereoselective synthesis of benzylated prodelphinidins - catechin-(4α→8)-gallocate-chin (13), gallocatechin-(4α→8)-gallocatechin (14), and gallo-catechin- (4α→8)-catechin (15) - is reported for the first time. The ESI(+)-CID mass spectra of the coupling products were found to feature regioselective retro-Diels-Alder (RDA) reac-tions and unusual sequential losses of pairs of C₇H₇' radicals (182 u) from the Na⁺ adduct ions.

Full text of DOI:10.1002/ejoc.201000053

FULL PAPER
DOI: 10.1002/ejoc.201000053
Stereoselective Synthesis of Benzylated Prodelphinidins and Their
Diastereomers with Use of the Mitsunobu Reaction in the Preparation of Their
Gallocatechin Precursors
Karsten Krohn,*[a] Ishtiaq Ahmed,[a] Markus John,[b] Matthias C. Letzel,[c] and
Dietmar Kuck[c]
Dedicated to Prof. Gerhard Höfle on the occasion of his 70th birthday
Keywords: Natural products / Phytochemistry / Polyphenols / Flavanoids / C-C coupling
The tetrabenzylated catechin 9 was prepared by benzylation
of the commercially available pure (+)-catechin (3) and cou-
pled with the commercially unavailable pentabenzylated
(–)-gallocatechin 10, prepared in a one-step Mitsunobu-type
cyclization of the triol 8. The highly stereoselective synthesis
of benzylated prodelphinidins – catechin-(4αǞ8)-gallocate-
chin (13), gallocatechin-(4αǞ8)-gallocatechin (14), and gallo-
catechin-(4αǞ8)-catechin (15) – is reported for the first time.
The ESI(+)-CID mass spectra of the coupling products were
found to feature regioselective retro-Diels–Alder (RDA) reac-
tions and unusual sequential losses of pairs of C7H7 radicals
(182 u) from the Na+ adduct ions.
·
mintic,[9] antibacterial,[10] antiproliferative,[11] anti-HIV,[12]
and antioxidant properties.[13–16] Some members of the pro-
delphinidins have inhibitory effects on membrane type 1
matrix metalloproteinase (MT 1-MMP),[17] others against
glucose-mediated protein damage,[18] and some have trypsin
Introduction
Polyphenols are ingredients of agricultural products such
as wine, tea, fruit, vegetables, and herbal medicines and play
an important role due to their various biological func-
tions.[1] The specific interactions of polyphenolic com-
pounds with proteins have stimulated the search for new
drugs derived from them.[2] Among polyphenolic com-
pounds, flavonoids are considered to be particularly impor-
tant because many have shown antibacterial,[3] anticancer,[4]
antioxidant,[5] and antiviral[6] activities. The proanthocyani-
dins form an important subgroup of naturally occurring fla-
vanoids. They show particularly rich variation in hydroxy
substitution patterns, types of linkage between monomers,
and degrees of polymerization, including interflavanyl
bonds between the C4–C8 or C4–C6 positions of the flavan-
3-ol units.[7,8]
The prodelphinidins form a specific class of proanthocy-
anidins in which the main building blocks are (–)-gallocate-
chin (1, Figure 1) and (+)-epigallocatechin (2). They are
considered to be biologically particularly important poly-
phenolic secondary metabolites as a result of their anthel-
[a] Department of Chemistry, University of Paderborn,
Warburger Straße 100, 33098 Paderborn, Germany
Fax: +49-5251-603245
E-mail: k.krohn@uni-paderborn.de
[b] Macherey-Nagel GmbH & Co. KG,
Neumann-Neander-Straße 6–8, 52355 Düren, Germany
[c] Department of Chemistry, Bielefeld University,
Universitätsstraße 25, 33615 Bielefeld, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000053.
Figure 1. Structures of flavonoid monomers.
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Stereoselective Synthesis of Benzylated Prodelphinidins
inhibitory activity. Analysis of the structure/activity rela- ated with bloat prevention, especially in cattle that have
tionships suggests that the strength of inhibition is signifi- been fed a high-soluble-protein diet.[27] The prodelphinidin
cantly affected by the degree of polymerization, the number 6 and 7 (Figure 2) and higher condensation products have
of phenolic hydroxy groups, and the 2,3-stereochemistry of been found to occur in the bark of Quercus dentata,[28]
the constituent units.[19] The prodelphinidins are also used which serves as a source of tanning materials for the leather
as biochemical markers of HL60 cell differentiation[20] and industry in China. Prodelphinidin B3 (7) is one of the active
reference compounds in HPLC analysis of different food- principle found in leaves of Ribes nigrum, traditionally used
stuffs.[21] The proanthocyanidins (condensed tannins) have in Europe for the treatment of rheumatic diseases.[29] Beer
recently attracted considerable attention as antiviral, anti- is a beverage known to contain a wide variety of phenolic
bacterial, and antitumor agents.[22]
compounds, most of which originate from the raw materials
The polyphenolic proanthocyanidins are difficult to iso- of brewing: barley and hops. Stabilization of beer against
late from natural sources in pure form. The plant extracts clouding may be achieved by decreasing the simple flavanol
generally produce mixtures of closely related compounds, content, thereby limiting further flavanol polymerization
not easily separable even with modern chromatographic and complexation.[30] Prodelphinidin B3 (7) is present in
methods. Their synthesis is therefore still very important beer and (–)-gallocatechin (1), (+)-epigallocatechin (2), and
and a topic of current research both for structure confirm- prodelphinidin B3 (7) are constituents of red wine.[31]
ation and for obtaining larger amounts of the pure com-
pounds for biological testing.[7,8,23]
The main building blocks in the procyanidin class (also
named leucocyanidins; for general structure see Figure 1)
Results and Discussion
are (+)-catechin (3) and (–)-epicatechin (4), which are both
commercially available in enantiomerically pure form. (–)-
Synthesis
Gallocatechin (1) and (+)-epigallocatechin (2) are not com-
Couplings of monomeric flavans are usually performed
mercially available and so it is not surprising that no prodel- in Friedel–Crafts-type reactions (see Scheme 2). Electron-
phinidin synthesis based on the condensation of these two rich trioxygenated aromatics such as the benzylated cate-
building blocks has been reported. In a previous communi- chin 9 and gallocatechin 10 (Scheme 1) represent the nu-
cation we described the enantioselective synthesis of the cleophilic units, whereas their benzyloxylated counterparts
benzylated (–)-gallocatechin 10 (Scheme 1, below) by means 11 or 12, after activation with a Lewis acid, act as the elec-
of a Mitsunobu reaction.[24] We now report for the first time trophiles (see Scheme 2). The pentabenzylated (–)-gallocate-
on the highly stereoselective synthesis of benzylated prodel- chin 10 has already been prepared by our group[24] through
phinidins: catechin-(4αǞ8)-gallocatechin (13, Scheme 2, a one-step Mitsunobu-type cyclization of the triol 8[32]
below), gallocatechin-(4αǞ8)-catechin (14), and gallocate- (Scheme 1). The phenol 8 was treated with diethyl azodicar-
chin-(4αǞ8)-gallocatechin (15). These coupling products boxylate and triphenylphosphane in anhydrous tetra-
are present in food grains of barley and sorghum[25] and hydrofuran to afford the (–)-pentabenzylated gallocatechin
fresh leaves of Camellia sinensis[26] and impart a certain re- 10 with inversion of stereochemistry at C-2 and the ex-
sistance to feeding by birds. Their presence has been associ- pected 2,3-trans configuration. No loss of enantioselectivity
was observed[33] and the theoretically possible five-mem-
bered cyclization products could not be detected. The tetra-
benzylated catechin 9 was prepared in excess by the ben-
zylation of commercially available pure (+)-catechin (3)
with benzyl chloride and K2CO3 in DMF.[34] No formation
of a C-benzylated product was observed.
The electrophiles 11 and 12 were prepared from their
corresponding debenzyloxy compounds 9 and 10 by treat-
ment with DDQ for benzylic oxidation.[8] DDQ oxidation
at C-4 of the tetrabenzylated (+)-catechin 9 and the penta-
benzylated (–)-gallocatechin 10 was performed with benzyl
alcohol as the nucleophile and proceeded smoothly to give
the 4-O-benzyl derivatives 11 and 12 in 85 and 86% isolated
yields, respectively. The coupling reactions, starting only
from the two flavans 9 and 10 with two or three benzyloxy
groups rings on ring B, would thus theoretically give four
pairs of diastereoisomers. We restricted the synthesis to
those natural products prepared for the first time. Neither
the mixed coupling products with two and three benzyloxy
groups nor those with three benzyloxy groups on both ring
B and E (for ring letter see Scheme 2 and ref.[2,8]) have pre-
Figure 2. Structures of prodelphinidins and procyanidin.
viously been synthesized.
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FULL PAPER
Scheme 1. Synthesis of the nucleophilic units 9 and 10 and the electrophiles 11 and 12.
Scheme 2. TMSOTf-catalyzed condensations of 11/12 with 9/10 to afford the prodelphinidins 13–15.
In principle, diastereomers can be formed during the Lewis acid catalysts have been employed for the synthesis
coupling reaction. Procyanidin B3 and its diastereomers of proanthocyanidins in the literature; they include TiCl4
were prepared by the methods of Kawamoto and Vercaut- for epicatechin[37a] and the catechin coupling products[36]
eren in 1.5:1 and 2.0:1 ratios, respectively.[7] Synthetic stud- and SnCl4 and BF3·OEt2 for catechin “oligomers”.[1,35] An
ies of (–)-procyanidin B3 based on condensation between improved synthesis of procyanidin dimers with controlled
two substituted catechin units have been reported by Roux regio-and stereochemistry has recently been reported by the
et al.,[2] Kawamoto et al.,[35] and Vercauteren et al.,[36] but Fouquet group.[37b] The key step involves coupling between
the stereoselectivity of the intermolecular condensation has equimolar amounts of a tetraprotected monomer (the nu-
only been described in detail by Ubukata et al.[7] Many cleophilic partner) and a C4-activated, C8-protected mono-
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Stereoselective Synthesis of Benzylated Prodelphinidins
mer (the electrophilic partner) with TiCl4 as the Lewis cata- For (4α)-13 we observed rotational isomers in a 4:1 ratio.
lyst. However, we used larger amounts of the nucleophilic Rotamers were also observed for (4α)-14 and (4α)-15, in 2:1
partners (which can be recovered), in order to avoid the and 7:1 ratios, respectively (see Exp. Section).
need for protection steps and the formation of higher oligo-
mers.[37a] For the condensation we followed the procedure
of Saito et al.[23] with use of a solution of TMSOTf in
CH2Cl2 (0.5 ), because it has been reported that the
Mass Spectrometry
TMSOTf-catalyzed intermolecular condensation is very
The mass spectrometric characterization of the oligoben-
specific for the formation of the natural 3,4-trans isomers.
zyl ethers (4α)-13, (4α)-14, and (4α)-15 was achieved with
We first investigated the coupling reaction by starting the aid of NaBF4-assisted electrospray ionization (ESI+)
with the benzyl ether 11, prepared in fairly large amounts combined with collision-induced dissociation (CID) in an
from the enantiomerically pure (+)-catechin (3) by ben- ion trap. The sodium cation adducts formed particularly
zylation with benzyl chloride and K2CO3 in DMF, as the readily when sodium tetrafluoroborate was added to meth-
electrophile.[34] The penta-O-benzylated gallocatechin 10 anol/chloroform solutions of the samples; both the correct
served as the nucleophilic part. Treatment of 11 with accurate masses and the appropriate isotope patterns of the
TMSOTf generated an intermediate cation that was at- quasi-molecular [M + Na]+ ions were determined in each
tacked by the nucleophilic pentabenzyl ether 10 (Scheme 2) case by FT-ICR mass spectrometry.
to form a mixture of the diastereomeric coupling products
The collision-induced fragmentation of the [M + Na]+
(4α)-13 and (4β)-13 in 97% combined yield. However, the ions deserves special mention and is the subject of further
minor cis isomer (4β)-13 could not be isolated in pure form. investigation.[39] Unlike the protonated [M + H]+ quasi-mo-
1
Careful analysis of its H NMR spectrum (after chromato- lecular ions, which show rather complicated fragmentation
graphic enrichment) revealed a ratio of Ͼ50:1 in favor of behavior, the sodium-cationized oligobenzyl ethers decom-
the trans isomer (4α)-13. The 1H NMR spectrum of the pose through two very clear-cut fragmentation pathways:
minor isomer clearly showed the gross structure of (4β)-13, 1) apparently synchronous and repeated loss of two benzyl
but a clear assignment of all the signals of this complex units (182 u), which strongly predominates over the loss of
molecule was not possible.
single C7H7· residues, and 2) retro-Diels–Alder (RDA) frag-
Similarly, the TMSOTf-catalyzed condensation between mentation occurring with remarkable regioselectivity at the
the hexa-O-benzylated gallocatechin 12 (electrophilic unit) benzoannelated pyran ring. These processes were found to
and the penta-O-benzylated gallocatechin 10 (nucleophilic occur throughout with both the monomeric and the cou-
unit) proceeded smoothly to afford a mixture of (4α)-15 and pled oligobenzyl ethers, but we restrict the discussion here
(4β)-15 in 87% isolated yield in a Ͼ50:1 ratio. The prodel- largely to two coupling products – the isomeric oligobenzyl
phinidin derivative with three oxygen functions on both ethers (4α)-13 and (4α)-14 – that were found to be distin-
rings B and E[28,29] had thus been prepared for the first guishable by the RDA process.
time. For the synthesis of benzylated prodelphinidin B3
The ESI(+)-CID mass spectra of the [M + Na]+ ions
(14), the hexa-O-benzylated gallocatechin 12 was taken as of isomers (4α)-13 and (4α)-14 (m/z 1427, nominally) are
the electrophilic part and the tetra-O-benzylated catechin 9 illustrated in Figures 3 and 4. In both cases the dominant
as the nucleophile to afford the naturally occurring benzyl- fragmentation is the loss of 182 u, giving rise to ions at m/z
ated prodelphinidin B3 (14)[28,30] in 98% combined yield. 1245 and corresponding to the elimination either of molec-
·
Again the ratio was Ͼ50:1 and neither (4β)-14 nor (4β)-15 ular C14H14 or of two benzyl radicals (C7H7 ). The occur-
could be isolated in pure form.
rence of a minor peak at m/z 1336 in the spectrum of (4α)-
We also addressed the enantioselectivity of the coupling 13 points to the latter process (see below). Subsequent loss
products. In cases in which the benzylated commercially of another apparent C14H14 entity of 182 u from the [(M –
available enantiomerically pure catechin derivative 10 was 2 C7H7) + Na]+ ions leads in both cases to the fragment
involved, enantiomerically pure coupling products 13 and ions [(M – 4 C7H7) + Na]+ at m/z 1063. Even a third such
14 can reasonably be expected. However, although the en- process is observed in the case of (4α)-14; it may be specu-
antiomeric purities of the building blocks 10 and 12 were lated on whether the collisional activation was somewhat
checked by optical rotation, the absolute enantiomeric puri- more energetic than in the case of (4α)-13 or whether struc-
ties of these synthetic materials were not certain. All three tural factors are relevant here.[40] The overall sequence ob-
coupling products (4α)-13 to (4α)-15 were therefore care- served for the [(4α)-14 + Na]+ ions is shown in Scheme 3
fully checked by chiral HPLC under a large variety of sol- and a mechanism for the quasi-pairwise loss of two benzyl
vent systems and conditions (see Exp. Section). Under none radicals is depicted in Scheme 4 for the case of ions [(4α)-
of these sets of conditions could peaks indicating deviation 14 + Na]+. The origins of the different relative rates of the
of any of the coupling products from enantiomeric purity two subsequent C7H7· losses obviously lie in their quite dif-
be detected.
ferent energy requirements. The formation of the open-shell
Rotational isomers occurring with different ratios were fragments {[M – nC7H7]· + Na}+ {n = 1, 3, 5, m/z 1336,
observed in the NMR studies of all diastereomers in CDCl3 m/z 1154 and m/z 972 in the case of [(4α)-13 + Na]+ and
solutions, as has also been reported in the literature[7,8,23,38] [(4α)-14 + Na]+ ions} is energetically unfavorable and slow,
for such compounds possessing benzyl protecting groups. whereas the formation of the closed-shell sodiated quinone-
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K. Krohn, I. Ahmed, M. John, M. C. Letzel, D. Kuck
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Figure 3. ESI(+)-CID mass spectrum of the [M + Na]+ ions (m/z 1427) of the nonabenzyl ether (4α)-13. The inset shows the peak cluster
of the quasi-molecular ions (m/z 1427–1431); CID was carried out on this peak cluster (arrows).
Figure 4. ESI(+)-CID mass spectrum of the [M + Na]+ ions (m/z 1427) of the nonabenzyl ether (4α)-14.
Scheme 3. Fragmentation of [(4α)-14 + Na]+ ions through consecutive losses of C7H7 radicals.
·
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Stereoselective Synthesis of Benzylated Prodelphinidins
Scheme 4. Proposed mechanism for the fragmentation of [(4α)-13 + Na]+, [(4α)-14 + Na]+, and [(4α)-15 + Na]+ ions through consecutive
·
losses of C7H7 radicals. The starting site of the fragmentation is chosen arbitrarily; dashed lines indicate the backbone (X, X, Y) of the
molecule.
type ions {[M – 2nC7H7] + Na}+ (n = 1 and 2, m/z 1245
Whereas the consecutive losses of C14H14 (or pairs of
and m/z 1063, respectively) is favorable and relatively fast. C7H7) units appear to be characteristic for both isomeric
However, it remains unclear why the loss of six benzyl radi- [(4α)-13 + Na]+ and [(4α)-14 + Na]+ ions, an independent
cals from ions [(4α)-14 + Na]+, giving rise to the fragment fragmentation pathway that allows us to distinguish be-
ions m/z 881, is also very fast, in spite of the lack of a third tween the two isomers is open. In contrast to the [(4α)-13 +
ortho-benzyloxybenzene unit.
Na]+ ions, which expel 438 u corresponding to a C29H26O4
Scheme 5. Specific fragmentation of the isomeric [(4α)-13 + Na]+ and [(4α)-14 + Na]+ ions through regioselective retro-Diels–Alder
fragmentation. The insert illustrates a conceivably preferred coordination mode of the sodium cation.
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K. Krohn, I. Ahmed, M. John, M. C. Letzel, D. Kuck
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autosampler: ASI 100 (Dionex), column oven: STH 585 (Dionex).
molecule to give the characteristic fragment ions m/z 989,
the [(4α)-14 + Na]+ ions lose only 332 u, corresponding to
a C22H20O3 molecule. Undoubtedly, these fragmentations
can be traced to retro-Diels–Alder processes occurring in
the 3-hydroxychroman moieties. Ignoring possible tauto-
Mass Spectrometry: ESI mass spectra were recorded with an Es-
quire 3000 ion trap mass spectrometer (Bruker Daltonik GmbH,
Bremen, Germany) fitted with a standard nanoESI source. Samples
were introduced through self-made nanospray needles. Nitrogen,
merization steps, we assume that 3,4,5-tri(benzyloxy)-2-hy- generated by a Bruker nitrogen generator (NGM 11), was used as
a drying gas. Helium served as a cooling gas for the ion trap and
collision gas for MSn experiments. The spectra shown were re-
corded with the aid of Bruker Daltonik Esquire NT 5.2 Esquire
Control software by accumulation and averaging of several single
spectra. DataAnalysis 3.4 was used for spectra processing. Under
similar ESI conditions, accurate masses were measured by use of a
Fourier transform ion cyclotron resonance (FT-ICR) mass spec-
trometer APEX III (Bruker Daltonik GmbH, Bremen, Germany)
fitted with a 7.0 T, 160 mm bore superconducting magnet (Bruker
Analytik GmbH – Magnetics, Karlsruhe, Germany) and an infinity
droxystyrene is eliminated in the first case and 3,4-bis-
(benzyloxy)-2-hydroxystyrene in the second, as depicted in
Scheme 5.
One explanation for the occurrence of the regioselective
retro-Diels–Alder process may be a favorable coordination
mode of the sodium cation in the interior region of the
bis(hydroxychroman) unit (see insert in Scheme 5). Al-
though many other “tautomeric” [M + Na]+ adducts might
be formed prior to fragmentation, including species with
dominating cation–π interactions,[41,42] the coordination be- cell, and interfaced to an external nanoESI source. Scan accumu-
lation and Fourier transformation were performed with
XMASS NT (7.08) on a PC workstation; for further data pro-
cessing DataAnalysis 3.4 was used.
tween the 3-hydroxy and the 1ЈЈ-ether oxygen centers would
be expected to be most efficient to stabilize the adduct ions.
It appears reasonable to assume that in this “inner” adduct
the release of the hydroxystyrene fragment from the hy-
droxy-coordinated chroman moiety is prevented, leaving
2,3-trans-5,7,3Ј,4Ј-Tetrakis(benzyloxy)flavan-3-ol (9):
A stirred
solution of (+)-catechin (3, 3.00 g, 10.33 mmol), benzyl chloride
the retro-Diels–Alder fragmentation of the other hy- (6.62 g, 6.00 mL, 52.10 mmol), and K2CO3 (9.00 g, 65.1 mmol) in
DMF (30 mL) was heated for 4 h at 120–130 °C (monitored by
TLC). The mixture was poured into water (100 mL), and the re-
sulting solution was extracted with ethyl acetate (250 mL) and
dried with Na2SO4. Evaporation of the solvent gave a thick, brown
oil, which was subjected to column chromatography on silica gel
to provide pure (+)-3Ј,4Ј,5,7-tetra-O-benzylcatechin (9) as a white
solid in 80% yield (5.30 g, 8.15 mmol); m.p. 121–122 °C (ref.[34]
116 °C). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 2.68 (dd, J =
16.4, 8.6 Hz,1 H, 4-H-α), 3.14 (dd, J = 16.4, 5.5 Hz, 1 H, 4-H-β),
4.03 (m, 1 H, 3-H), 4.65 (d, J = 8.3 Hz, 1 H, 2-H), 5.01 (s, 2 H,
OCH2Ph), 5.05 (s, 2 H, OCH2Ph), 5.19 (s, 2 H, OCH2Ph), 5.20 (s,
2 H, OCH2Ph), 6.23 (d, J = 2.5 Hz, 1 H, 6-H), 6.29 (d, J = 2.5 Hz,
1 H, 8-H), 6.98 (d, J = 8.5 Hz, 1 H, 5Ј-H), 7.01 (dd, J = 8.5, 2.1 Hz,
1 H, 6Ј-H), 7.05 (d, J = 2.1 Hz, 1 H, 2Ј-H), 7.28–7.48 (m, 20 H,
Ar-H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 27.6 (C-4),
68.2 (C-3), 69.9 (OCH2Ph), 70.1 (OCH2Ph), 71.2 (OCH2Ph), 71.3
(OCH2Ph), 81.5 (C-2), 93.85 (C-6), 94.4 (C-8), 102.3 (C-4a), 113.9
(C-2Ј), 115.0 (C-5Ј), 120.6 (C-6Ј), 127.1, 127.2, 127.4, 127.5, 127.8,
127.8, 127.9, 128.4, 128.5, 128.5 (C-Ar), 130.9 (C-1Ј), 136.8, 136.9,
137.0, 137.1 (C-Ar) 149.1 (C-3Ј), 149.3 (C-4Ј), 155.2 (C-8a), 157.7
(C-5), 157.8 (C-7) ppm.
droxychroman unit as the only remaining pathway. Further
investigations to unravel the intriguing and characteristic
fragmentation behavior of sodium-cationized oligobenzyl
ethers under the conditions of ESI-CID mass spectrometry
are underway.[39,43,44]
Conclusions
In conclusion, the prodelphinidins[28,30] 13–15 with vary-
ing numbers of benzyloxy groups (two or three) on rings B
and E or with three benzyloxy groups on both rings have
been synthesized for the first time, through TMSOTf-cata-
lyzed intermolecular condensations. The mass spectromet-
ric characterization of these oligobenzyl ethers by ESI(+)
techniques revealed that the [M + Na]+ adduct ions un-
dergo unexpected sequential losses of pairs of benzyl radi-
cals as well as structure-specific, regioselective retro-Diels–
Alder (RDA) reactions.
2,3-trans-3,4-cis-4,5,7,3Ј,4Ј-Pentakis(benzyloxy)flavan-3-ol
(11):
DDQ (2 equiv., 140 mg, 0.61 mmol) was slowly added at 0 °C to a
solution of tetra-O-benzylcatechin (9, 500 mg, 0.78 mmol) and ben-
zyl alcohol (0.80 mL, 7.60 mmol) in CH2Cl2 (6 mL). After the sys-
tem had been stirred overnight at room temperature, excess 4-(di-
methylamino)pyridine (200 mg, 1.63 mmol) was added to the solu-
tion at 0 °C and the mixture was stirred for another 30 min. The
resulting mixture was filtered, and the filtrate was washed with
Experimental Section
General: TMSOTf-catalyzed intermolecular condensations were
performed under argon. TLC was performed on precoated TLC
plates (silica gel). Melting points were measured with a Gallen-
kamp apparatus and are not corrected. NMR spectra were re-
corded with a Bruker Avance 500 instrument at 500.13 MHz (1H)
and 125.76 MHz (13C). Chemical shifts (δ) for H and 13C NMR water (50 mL) and brine (20 mL) and dried with Na2SO4. After
1
spectra are reported in ppm downfield from TMS as an internal
standard. Upper case letters (A–F) designate the rings as shown in
Scheme 2. Optical rotations were measured at 25 °C with a Perkin–
Elmer Polarimeter 241. Mass spectra were recorded with a Finni-
gan MAT 8430 spectrometer in the electron impact mode at 70 eV
and with chemical ionization, and are reported as m/z values and
relative abundances. The infrared spectra were recorded with a Nic-
olet 510 P FT-IR spectrometer. The HPLC system used was: Sum-
filtration, the solvent was removed under reduced pressure and the
resulting residue was subjected to silica gel column chromatography
to give (2S,3S,4S)-4,5,7,3Ј,4Ј-pentabenzyloxyflavan-3-ol (11) as a
white solid in 86% yield (514 mg, 0.67 mmol); m.p. 127–128 °C
(ref.[8] 124–125 °C). [α]D = +53.7 (c = 0.48, CHCl3) [ref.[8] +56.4 (c
= 0.48, CHCl3)]. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 3.90 (dt,
J = 3.4, 9.7 Hz, 1 H, 3-H), 4.66 (d, J = 11.5 Hz, 1 H, OCH2Ph),
4.78 (d, J = 11.5 Hz, 1 H, OCH2Ph), 4.96 (d, J = 3.4 Hz, 1 H, 4-
mit (Dionex), pump: P 580 A (Dionex), detector: UVD 170S, H), 4.98 (d, J = 9.7 Hz, 1 H, 2-H), 5.00 (d, J = 9.7 Hz, 1 H,
2550
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2544–2554

Stereoselective Synthesis of Benzylated Prodelphinidins
OCH2Ph), 5.01 (d, J = 11.2 Hz, 1 H, OCH2Ph), 5.05 (d, J =
OCH2Ph), 6.22 (d, J = 2.2 Hz, 1 H, 8-H), 6.31 (d, J = 2.2 Hz, 1
11.2 Hz, 1 H, OCH2Ph), 5.13 (s, 4 H, OCH2Ph), 6.18 (d, J = H, 6-H), 6.84 (d, J = 2.1 Hz, 2 H, 2Ј,6Ј-H), 7.20–7.48 (m, 30 H,
2.2 Hz, 1 H, 8-H), 6.28 (d, J = 2.2 Hz, 1 H, 6-H), 6.94 (d, J = Ar-H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 68.9 (C-4),
8.3 Hz, 1 H, 5Ј-H), 6.99 (dd, J = 2.0, 8.3 Hz, 1 H, 6Ј-H), 7.07 (d,
70.5 (C-3), 70.63 (OCH2Ph), 70.66 (OCH2Ph), 71.1 (OCH2Ph),
J = 2.0 Hz, 1 H, 2Ј-H), 7.18–7.45 (m, 25 H, Ar-H) ppm. 13C NMR 71.3 (OCH2Ph), 72.5 (OCH2Ph), 75.2 (OCH2Ph), 77.2 (C-2), 93.5
(125 MHz, CDCl3, 25 °C): δ = 67.8 (C-4), 69.8 (OCH2Ph), 70.9 (C-6), 94.5 (C-8), 106.9 (C-2Ј), 107 (C-6Ј), 115.0 (C-5Ј), 127.5,
(OCH2Ph), 71.3 (C-3), 71.5 (OCH2Ph), 71.4 (OCH2Ph), 71.7
(OCH2Ph), 81.5 (C-2), 93.85 (C-6), 94.4 (C-8), 102.3 (C-4a), 113.9
127.5, 127.7, 127.8, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6,
128.6, 133.9, 136.3, 136.6, 137.1, 137.9, 138.9 (C-Ar), 138.9 (C-4Ј),
(C-2Ј), 115.0 (C-5Ј), 120.6 (C-6Ј), 127.1, 127.2, 127.4, 127.5, 127.8, 152.3 (C-5Ј), 156.2 (C-3Ј), 158.7 (C-5), 161.0 (C-7) ppm. MS (EI):
127.8, 127.9, 128.4, 128.5, 128.5 (C-Ar), 130.9 (C-1Ј), 136.8, 136.9,
m/z (%) = 862 (2) [M]+·, 846 (4), 754 (1), 663 (5), 614 (3), 523 (1),
137.0, 137.1 (C-Ar) 149.1 (C-3Ј), 149.3 (C-4Ј), 155.2 (C-8a), 157.7 505 (7), 396 (12), 361 (3), 265 (2), 193 (10), 181 (23), 108 (96), 91
(C-5), 157.8 (C-7) ppm. MS (EI, 70 eV): m/z (%) = 156 (44) [M]+·, (100), 44 (3). HRMS calcd. for C57H50O8 [M]+· 862.35057; found
756.1 (4), 648 (30), 620 (12), 557 (15), 529 (28), 332 (19), 256 (22), 862.35093.
211 (19), 181 (62), 108.1 (100).
Catechin-(4αǞ8)-Gallocatechin [(4α)-13]: 2,3-trans-5,7,3Ј,4Ј,5Ј-
2,3-trans-5,7,3Ј,4Ј,5Ј-Pentakis(benzyloxy)flavan-3-ol (10): Triphen-
ylphosphane (15 mg, 0.057 mmol) was added to a solution of triol
8 (30 mg, 0.038 mmol) in anhydrous THF (2 mL). The mixture was
stirred for 10 min and diethyl azodicarboxylate (0.01 mL,
0.057 mmol) was then added dropwise. After stirring for 2.5 h at
room temperature, the reaction mixture was diluted with ethyl ace-
tate (10 mL) and washed with water (10 mL) and brine (10 mL).
The organic phase was dried with MgSO4, filtered, and concen-
trated on a rotary evaporator to give a white residue. The obtained
residue was purified by silica gel column chromatography to afford
2,3-trans-5,7,3Ј,4Ј,5Ј-pentakis(benzyloxy)flavan-3-ol (10) as a white
solid in 71% yield (26 mg, 0.033 mmol); m.p. 116–118 °C.[24] [α]D
Pentakis(benzyloxy)flavan-3-ol (10, 150 mg, 0.198 mmol, 3 equiv.)
and 2,3-trans-3,4-cis-4,5,7,3Ј,4Ј-pentakis(benzyloxy)flavan-3-ol (11,
50 mg, 0.066 mmol) were dissolved in CH2Cl2 (20 mL) and
TMSOTf (0.5  solution in CH2Cl2, 0.2 mL) was added dropwise
at –78 °C. After stirring for 5 min at 0 °C, the reaction mixture
was quenched by addition of saturated aqueous sodium hydrogen
carbonate (1 mL). The aqueous solution was extracted with chloro-
form (15 mL) and the organic phase was washed with water
(10 mL) and brine (10 mL) and dried with Na2SO4. After filtration,
the organic phase was concentrated on a rotary evaporator. A mix-
ture of diastereomers was obtained in 97% yield and was purified
by preparative silica gel TLC (Macherey–Nagel, 1.0 mm, CH2Cl2/
EtOAc 100:0.5, 4 developments) to afford a thick, pale yellow oil.
[α]D = –86.66 (c = 0.35, CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C): 4:1 mixture of rotational isomers.
1
= –8.96 (c = 1.0, CHCl3), ref.[33] –7.21 (c = 1.0, CHCl3). H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.76 (br. s, 1 H, 3-OH), 2.75 (dd, J
= 16.5, 9.0 Hz, 1 H, 4-Ha), 3.15 (dd, J = 16.5, 6.0 Hz, 1 H, 4-Hb),
4.01 (ddd, J = 9.0, 8.1, 6.0 Hz, 1 H, 3-H), 4.65 (d, J = 8.1 Hz, 1
H, 2-H), 5.04 (s, 2 H, OCH2Ph), 5.07 (s, 2 H, OCH2Ph), 5.10 (s, 2
H, OCH2Ph), 5.11 (s, 2 H, OCH2Ph), 5.14 (s, 2 H, OCH2Ph), 6.29
(d, J = 2.4 Hz, 1 H, 8-H), 6.34 (d, J = 2.4 Hz, 1 H, 6-H), 6.78 (s,
2 H, 2Ј-H, 6Ј-H), 7.30–7.55 (m, 25 H, ArH) ppm. 13C NMR
Major Isomer: δ = 1.35–1.67 (m, 2 H, OH), 2.36 (dd, J = 9.3,
16.2 Hz, 1 H, 4F-H-β), 3.05 (dd, J = 5.2, 16.2 Hz, 1 H, 4F-H-α),
3.60 (d, J = 8.0 Hz, 1 H, 2F-H), 3.63–3.71 (m, 1 H, 3F-H), 4.26
(dd, J = 8.0, 9.8 Hz, 1 H, 3C-H), 4.50 (d, J = 9.8 Hz, 1 H, 4C-H),
4.55 (d, J = 10.7 Hz, 2 H, OCH2Ph), 4.67 (d, J = 8.8 Hz, 1 H, 2C-
H), 4.69–4.74 (m, 2 H, OCH2Ph), 4.79–4.83 (m, 2 H, OCH2Ph),
4.86–5.13 (m, 12 H, OCH2Ph), 6.10 (d, J = 2.2 Hz, 1 H, 6A-H),
6.18 (d, J = 2.2 Hz, 1 H, 8A-H), 6.23 (s, 1 H, 6D-H), 6.68 (dd, J
= 2.0, 8.7 Hz, 1 H, 6B-H), 6.84–6.94 (m, 7 H, Ar-H), 6.96–7.00 (m,
2 H, 2B-H, 6B-H), 7.11–7.15 (m, 2 H, 2E-H, 6E-H), 7.27–7.48 (m,
38 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 27.88
(4F-CH2), 37.14 (4C-CH), 68.50 (3F-CH-OH), 69.87 (OCH2Ph),
70.00 (OCH2Ph), 70.04 (OCH2Ph), 70.38 (OCH2Ph), 71.17
(OCH2Ph), 71.23 (OCH2Ph), 71.39 (OCH2Ph), 71.48 (OCH2Ph),
73.36 (3C-CH),75.24 (OCH2Ph), 80.62 (2C-CH), 82.19 (2F-CH),
91.51, 94.21, 94.96, 102.28, 106.54, 108.72, 112.03, 113.60, 114.88,
115.99, 121.30, 127.08 (ϫ2), 127.12, 127.23, 127.47, 127.51, 127.56,
127.62, 127.68, 127.75, 127.80, 127.87, 128.09, 128.15, 128.17,
128.27 (ϫ2), 128.32, 128.36, 128.38, 128.44, 128.46, 128.54, 128.59,
131.75, 134.19, 136.71, 136.97, 137.06, 137.13, 137.18, 137.29,
137.32, 137.70, 137.95, 138.44, 149.14, 149.32, 152.83, 153.59,
155.60, 158.02 ppm. MS [ESI(+), CHCl3/MeOH, NaBF4]: m/z (%)
= 1427.5 (96) [M + Na]+, 1428.5 (100) [(13C1)-M + Na]+, 1429.5
(44) [(13C2)-M + Na]+, 1430.6 (14) [(13C3)-M + Na]+, 1431.6 (4),
[(13C4)-M + Na]+. HRMS calcd. for C93H80O13Na 1427.54911;
found 1427.54905.
(50 MHz, CDCl3, 25 °C):
δ = 27.9 (C-4), 68.5 (C-3), 70.2
(OCH2Ph), 70.4 (OCH2Ph), 71.4 (OCH2Ph), 82.1 (C-2), 94.2 (C-
8), 94.6 (C-6), 102.6 (C-4a), 106.9 (C-2Ј, C-6Ј), 127.4, 127.8, 127.9,
128.0, 128.1, 128.2, 128.3, 128.5, 128.7, 128.8, 128.9, 129.0, 133.6,
137.1, 137.2, 138.0, 138.9 (Ar), 153.1 (C-4Ј), 153.3 (C-3Ј, C-5Ј),
155.4 (C-5), 158.0 (C-8a), 159.1 (C-7) ppm. IR (film): ν = 3550,
˜
3029, 1592, 1536, 1374, 1295, 1116, 773 cm–1. MS (EI): m/z (%) =
756 (1) [M]+·, 725 (1), 665 (3), 575 (1), 528 (1), 463 (1), 433 (4), 319
(10), 306 (7), 215 (2), 181 (25), 91 (100), 44 (8). HRMS calcd. for
C50H44O7 [M]+· 756.30872; found 756.30645.
2,3-trans-3,4-cis-4,5,7,3Ј,4Ј5Ј-Hexakis(benzyloxy)flavan-3-ol (12):
DDQ (2 equiv., 60 mg, 0.26 mmol) was slowly added at 0 °C to a
solution of tetra-O-benzylcatechin (10, 100 mg, 0.132 mmol) and
benzyl alcohol (0.10 mL, 0.96 mmol) in CH2Cl2 (5 mL). After the
system had been stirred overnight at room temperature, excess 4-
(dimethylamino)pyridine (40 mg, 0.32 mmol) was added at 0 °C
and the mixture was stirred for another 30 min. The resulting mix-
ture was filtered, and the filtrate was washed with water (50 mL)
and brine (20 mL) and dried with Na2SO4. After filtration the sol-
vent was removed under reduced pressure and the resulting residue
was subjected to silica gel column chromatography to give 2,3-
trans-3,4-cis-4,5,7,3Ј,4Ј5Ј-hexakis(benzyloxy)flavan-3-ol (12) as a
white foam in 85% yield (96 mg, 0.111 mmol); m.p. 121–123 °C.
Minor Isomer: δ = 1.35–1.67 (m, 0.50 H, OH), 2.64 (dd, J = 9.3,
[α]D = +53.25 (c = 0.4, CHCl3). 1H NMR (500 MHz, CDCl3, 16.2 Hz, 0.25 H, 4F-H-β), 3.23 (dd, J = 5.2, 16.2 Hz, 0.25 H, 4F-
25 °C): δ = 3.93 (m, 1 H, 3-H), 4.22 (d, J = 8.1 Hz, 1 H, 4-H), 4.68
H-α), 4.39 (d, J = 8.0 Hz, 0.25 H, 2F-H), 3.63–3.71 (m, 0.25 H,
(d, J = 11.4 Hz, 1 H, OCH2Ph), 4.77 (d, J = 11.4 Hz, 1 H, 3F-H), 4.15 (dd, J = 8.0, 9.8 Hz, 0.25 H, 3C-H), 4.53 (d, J = 9.8 Hz,
OCH2Ph), 4.94 (d, J = 3.4 Hz, 1 H, 4-H), 4.97 (d, J = 9.6 Hz, 1 0.25 H, 4C-H), 4.65–4.74 (m, 0.50 H, OCH2Ph), 4.77 (d, J =
H, 2-H), 5.00 (d, J = 11.5 Hz, 1 H, OCH2Ph), 5.01 (d, J = 11.2 Hz,
1 H, OCH2Ph), 5.05 (d, J = 11.2 Hz, 1 H, OCH2Ph), 5.13 (s, 4 H,
8.8 Hz, 0.25 H, 2C-H), 4.69–4.83 (m, 1.5 H, OCH2Ph), 4.85–5.14
(m, 3 H, OCH2Ph), 5.92 (d, J = 2.2 Hz, 0.25 H, 6A-H), 6.16 (d, J
Eur. J. Org. Chem. 2010, 2544–2554
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2551

K. Krohn, I. Ahmed, M. John, M. C. Letzel, D. Kuck
FULL PAPER
= 2.2 Hz, 0.25 H, 8A-H), 6.35 (s, 0.25 H, 6D-H), 6.99 (dd, J = 2.0,
0.50 H, 3C-H), 4.51 (d, J = 9.3 Hz, 0.50 H, 4C-H), 4.68–4.77 (m,
8.7 Hz, 0.25 H, 6B-H), 6.84–6.94 (m, 1.75 H, Ar-H), 7.10–7.23 (m, 1 H, OCH2Ph), 4.79 (d, J = 8.6 Hz, 0.50 H, 2C-H), 4.85–5.14 (m,
0.5 H, 2B-H, 6B-H), 7.27–7.47 (m, 10 H, Ar-H) ppm. 13C NMR 8 H, OCH2Ph), 6.05 (d, J = 2.4 Hz, 0.50 H, 6A-H), 6.09 (d, J =
(125 MHz, CDCl3, 25 °C): δ = 29.69 (4F-CH2), 37.19 (4C-CH), 2.4 Hz, 0.50 H, 8A-H), 6.35 (s, 0.50 H, 6D-H), 6.48 (dd, J = 1.9,
68.50 (3F-CH-OH), 70.00 (OCH2Ph), 70.15 (OCH2Ph), 70.42 8.2 Hz, 0.50 H, 6E-H), 6.56 (d, J = 1.9 Hz, 0.50 H, 6B-H), 7.12–
(OCH2Ph), 71.22 (OCH2Ph), 71.29 (OCH2Ph), 71.33 (OCH2Ph),
7.16 (m, 3.50 H, Ar-H), 7.27–7.47 (m, 20 H, Ar-H) ppm. 13C NMR
71.48 (OCH2Ph), 71.49 (OCH2Ph), 73.80 (3C-CH), 75.21 (125 MHz, CDCl3, 25 °C): δ = 33.55 (4F-CH2), 37.22 (4C-CH),
(OCH2Ph), 80.63 (2C-CH), 82.22 (2F-CH), 91.54, 94.17, 94.99, 68.56 (3F-CH-OH), 69.91 (OCH2Ph), 70.01 (OCH2Ph), 70.35
102.28, 106.58, 107.61, 108.71, 112.00, 113.59, 114.92, 115.97,
121.29, 127.12 (ϫ2), 127.23, 127.47, 127.51, 127.56, 127.62 (ϫ2),
127.68, 127.75, 127.80, 127.91, 128.09, 128.15, 128.17, 128.27 (ϫ3),
128.32, 128.36, 128.38, 128.44, 128.46, 128.54, 128.59, 131.79,
134.25, 136.68, 136.99, 137.07, 137.14, 137.20, 137.29, 137.32,
137.72, 137.99, 138.51, 149.17, 149.35, 152.82, 153.50, 155.66,
158.02 ppm.
(OCH2Ph), 71.06 (OCH2Ph), 71.20 (OCH2Ph), 71.30 (OCH2Ph),
71.34 (OCH2Ph), 71.69 (OCH2Ph), 73.37 (3C-CH), 77.58
(OCH2Ph), 80.68 (2C-CH), 82.35 (2F-CH), 91.93, 94.31, 94.95,
103.34, 107.21, 112.02, 113.96, 114.01, 114.93, 120.20, 120.65,
127.05, 127.10 (ϫ2), 127.13, 127.22 (ϫ3), 127.25, 127.26, 127.42,
127.46, 127.52, 127.54, 127.58, 127.69, 127.80, 127.83, 127.89,
127.91, 128.07, 128.09, 128.17, 128.18, 128.25, 128.33, 128.36,
128.38, 128.44, 128.49, 128.56, 128.60, 130.85, 131.65, 134.16,
136.68, 137.03, 137.11, 137.21, 137.28, 137.95 (ϫ2), 138.69, 148.99,
149.11, 152.81, 152.90, 153.99, 155.55 (ϫ2), 155.61, 156.68, 157.77,
158.07 ppm.
Gallocatechin-(4αǞ8)-catechin [(4α)-14]: 2,3-trans-5,7,3Ј,4Ј-Tet-
rakis(benzyloxy)flavan-3-ol (9, 90 mg, 0.139 mmol, 3 equiv.) and
2,3-trans-3,4-cis-5,7,3Ј,4Ј,5Ј-hexakis(benzyloxy)flavan-3-ol
(12,
40 mg, 0.046 mmol) were dissolved in CH2Cl2 (20 mL), and
TMSOTf (0.5  solution in CH2Cl2, 0.2 mL) was added dropwise
Gallocatechin-(4αǞ8)-gallocatechin [(4α)-15]: 2,3-trans-5,7,3Ј,4Ј,5Ј-
at –78 °C. After stirring for 5 min at 0 °C, the reaction mixture Pentakis(benzyloxy)flavan-3-ol (10, 105 mg, 0.139 mmol, 3 equiv.)
was quenched by addition of saturated sodium hydrogen carbonate
(1 mL). The aqueous solution was extracted with chloroform
(15 mL) and the organic phase was washed with water (10 mL) and
brine (10 mL) and dried with Na2SO4. After filtration of the or-
ganic phase it was concentrated on a rotary evaporator. A mixture
of diastereomers was obtained in 98% yield and purified by prepar-
ative silica gel TLC (Macherey–Nagel, 1.0 mm, CH2Cl2/EtOAc
100:0.5, 4 developments) as a thick, pale yellow oil. [α]D = –92.97
and 2,3-trans-3,4-cis-4,5,7,3Ј,4Ј,5Ј-hexakis(benzyloxy)flavan-3-ol
(12, 40 mg, 0.046 mmol) were dissolved in CH2Cl2 (20 mL).
TMSOTf (0.5  solution in CH2Cl2, 0.2 mL) was added dropwise
to this solution at –78 °C. After stirring for 5 min at 0 °C, the reac-
tion mixture was quenched by addition of saturated sodium hydro-
gen carbonate solution (1 mL). The aqueous solution was extracted
with chloroform (15 mL) and the organic phase was washed with
water (10 mL) and brine (10 mL) and dried with Na2SO4. After
(c = 0.32, CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C): 2:1 mixture filtration the organic phase was concentrated on a rotary evapora-
of rotational isomers.
tor. A mixture of diastereomers was obtained in 87% yield and
purified by preparative silica gel TLC (Macherey–Nagel, 1.0 mm,
CH2Cl2/EtOAc 100:0.5, 4 developments) as a thick, pale yellow oil.
[α]D = –83.75 (c = 0.26, CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C): 7:1 mixture of rotational isomers.
Major Isomer: δ = 1.28–1.61 (m, 2 H, OH), 2.39 (dd, J = 9.1,
16.2 Hz, 1 H, 4F-H-β), 3.03 (dd, J = 5.7, 16.2 Hz, 1 H, 4F-H-α),
3.61 (d, J = 8.5 Hz, 1 H, 2F-H), 3.63–3.75 (m, 1 H, 3F-H), 4.21
(dd, J = 8.6, 9.3 Hz, 1 H, 3C-H), 4.48 (d, J = 9.3 Hz, 1 H, 4C-H),
4.56 (d, J = 11.3 Hz, 2 H, OCH2Ph), 4.67 (d, J = 8.6 Hz, 1 H, 2C- Major Isomer: δ = 1.30–1.42 (m, 2 H, OH), 2.38 (dd, J = 9.2,
H), 4.68–4.75 (m, 2 H, OCH2Ph), 4.80–4.89 (m, 2 H, OCH2Ph), 16.2 Hz, 1 H, 4F-H-β), 3.03 (dd, J = 5.6, 16.2 Hz, 1 H, 4F-H-α),
4.90–5.16 (m, 12 H, OCH2Ph), 6.13 (d, J = 2.4 Hz, 1 H, 6A-H), 3.59 (d, J = 8.4 Hz, 1 H, 2F-H), 3.62–3.73 (m, 1 H, 3F-H), 4.21
6.18 (d, J = 2.4 Hz, 1 H, 8A-H), 6.25 (s, 1 H, 6D-H), 6.81 (dd, J (d, J = 9.0 Hz, 1 H, 4C-H), 4.53 (dd, J = 8.7, 9.0 Hz, 1 H, 3C-H),
= 1.9, 8.2 Hz, 1 H, 6E-H), 6.96 (d, J = 1.9 Hz, 1 H, 6B-H), 6.84–
6.94 (m, 7 H, Ar-H), 7.19–7.25 (m, 2 H, Ar-H), 7.25–7.47 (m, 38 4.77–4.86 (m, 3 H, OCH2Ph), 4.90–4.97 (m, 4 H, OCH2Ph), 4.99–
H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 31.22
5.13 (m, 8 H, OCH2Ph), 6.13 (d, J = 2.3 Hz, 1 H, 6A-H), 6.19 (d,
4.66–4.72 (m, 3 H, OCH2Ph), 4.73 (d, J = 8.7 Hz, 1 H, 2C-H),
(4F-CH2), 37.13 (4C-CH), 68.36 (3F-CH-OH), 69.88 (OCH2Ph), J = 2.3 Hz, 1 H, 8A-H), 6.25 (s, 1 H, 6D-H), 6.85–6.88 (m, 4 H, Ar-
69.93 (OCH2Ph), 70.16 (OCH2Ph), 70.94 (OCH2Ph), 71.03
(OCH2Ph), 71.17 (OCH2Ph), 71.25 (OCH2Ph), 71.68 (OCH2Ph),
73.26 (3C-CH), 77.57 (OCH2Ph), 80.67 (2C-CH), 82.08 (2F-CH),
H), 7.18–7.47 (m, 38 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3,
25 °C): δ = 32.17 (4F-CH2), 37.08 (4C-CH), 68.13 (3F-CH-OH),
69.71 (OCH2Ph), 70.03 (OCH2Ph), 70.17 (OCH2Ph), 70.37
91.55, 94.30, 94.95, 102.61, 106.93, 112.01, 113.94, 114.01, 114.37, (OCH2Ph), 71.09 (OCH2Ph), 71.37 (OCH2Ph), 71.87 (OCH2Ph),
114.92, 120.19, 120.65, 127.05 (ϫ2), 127.13 (ϫ3), 127.25, 127.42,
127.51, 127.58, 127.68, 127.80, 127.82, 127.89, 127.90, 128.07,
128.09, 128.17, 128.18, 128.25, 128.32, 128.36, 128.38, 128.43 (ϫ2),
128.49, 128.55, 128.60, 130.85, 131.55, 134.16, 136.68, 137.02,
137.11, 137.20, 137.28, 137.95 (ϫ2), 138.69, 148.99, 149.11, 152.81,
152.90, 153.98, 153.99, 155.55 (ϫ2), 155.60, 156.68, 157.61,
73.34 (3C-CH), 75.15 (OCH2Ph), 75.22 (OCH2Ph), 80.65 (2C-CH),
82.44 (2F-CH), 91.51, 94.34, 102.39, 103.05, 106.64, 107.06, 112.37,
113.73, 114.05, 114.57, 120.10, 120.65, 127.05, 127.11 (ϫ2), 127.45,
127.49, 127.68, 127.76, 127.81 (ϫ2), 127.82, 127.89, 127.93, 128.08
(ϫ3), 128.15, 128.18, 128.30, 128.35, 128.39, 128.45, 128.51, 128.55
(ϫ2), 128.60, 128.61, 130.95, 131.63, 134.23, 136.68, 136.69,
158.05 ppm. MS [ESI(+), CHCl3/MeOH, NaBF4]: m/z (%) = 136.95, 137.00, 137.11, 137.21, 137.28, 137.95 (ϫ2), 138.69, 148.99,
1427.5 (94) [M + Na]+, 1428.6 (100) [(13C1)-M + Na]+, 1429.6 (49) 152.60, 152.81, 152.98, 153.21, 153.47, 155.43 (ϫ2), 155.57, 156.10,
[(13C2)-M + Na]+, 1430.6 (16) [(13C3)-M + Na]+, 1431.6 (3) [(13C4)- 157.23, 158.09 ppm. MS [ESI(+), CHCl3/MeOH, NaBF4]: m/z (%)
M + Na]+. HRMS calcd. for C93H80O13Na 1427.54911; found
1427.54954.
= 1533.7 (68) [M + Na]+, 1534.6 (100) [(13C1)-M + Na]+, 1535.6
(50) [(13C2)-M + Na]+, 1536.6 (15) [(13C3)-M + Na]+, 1537.6 (5)
[(13C4)-M + Na]+. HRMS calcd. for C100H86O14Na 1533.59089;
found 1533.58914.
1
Minor Isomer: H NMR (500 MHz, CDCl3, 25 °C): δ = 1.35–1.70
(m, 1 H, OH), 2.64 (dd, J = 9.1, 16.2 Hz, 0.50 H, 4F-H-β), 3.17
(dd, J = 5.7, 16.2 Hz, 0.50 H, 4F-H-α), 3.63–3.75 (m, 0.50 H, 3F- Minor Isomer: H NMR (500 MHz, CDCl3, 25 °C): δ = 1.30–1.42
1
H), 4.18 (d, J = 8.5 Hz, 0.50 H, 2F-H), 4.46 (dd, J = 8.6, 9.3 Hz,
(m, 0.28 H, OH), 2.65 (dd, J = 9.2, 16.2 Hz, 0.14 H, 4F-H-β), 3.22
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Stereoselective Synthesis of Benzylated Prodelphinidins
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136.95, 137.03, 137.11, 137.21, 137.28, 137.95 (ϫ2), 138.69, 149.11,
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2553

K. Krohn, I. Ahmed, M. John, M. C. Letzel, D. Kuck
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Received: January 15, 2010
Published Online: March 23, 2010
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