A domino approach to the enantioselective total syntheses of blennolide C and gonytolide C

Article abstract of DOI:10.1002/chem.201402495

The first enantioselective total syntheses of the tetrahydroxanthenone (-)-blennolide C (ent-4) and related γ-lactonyl chromanone (-)-gonytolide C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2 -epi-gonytolide C 28.

Full text of DOI:10.1002/chem.201402495

DOI: 10.1002/chem.201402495
Full Paper
&
Natural Products
A Domino Approach to the Enantioselective Total Syntheses of
Blennolide C and Gonytolide C
Lutz F. Tietze,* Stefan Jackenkroll, Judith Hierold, Ling Ma, and Bernd Waldecker[a]
Dedicated to Professor Max Malacria on the occasion of his 65th birthday
Abstract: The first enantioselective total syntheses of the
tetrahydroxanthenone (ꢀ)-blennolide C (ent-4) and related
g-lactonyl chromanone (ꢀ)-gonytolide C (ent-3) are reported.
Key to the syntheses is an enantioselective domino-Wacker/
carbonylation/methoxylation reaction to set up the stereo-
centre at C-4a. Various chiral BOXAX ligands were investigat-
ed, including novel (S,S)-iBu-BOXAX, and allowed access to
chromane 8 in an excellent enantioselectivity of 99%. The
second stereocentre at C-4 was established employing a dia-
stereoselective Sharpless dihydroxylation. An extensive
survey of (DHQ)- and (DHQD)-based ligands enabled the
preparation of both the anti-isomer 14a and the syn-isomer
14b in very good to reasonable selectivities of 13.7:1 and
1:3.7, respectively. While 14a was further converted to ent-3
and ent-4, 14b was elaborated to syn-acid 25 and 2’-epi-go-
nytolide C 28.
1),[13] 4-dehydroxydiversonol[14] and the proposed structures of
paecilin A and B[15] by using an enantioselective domino-
Wacker/carbonylation/methoxylation reaction. This versatile
domino process[16] has also been applied to the synthesis of
chromanes, dioxins and oxazins.[17] Herein, we report its appli-
cation to the first enantioselective total syntheses of (ꢀ)-blen-
nolide C (ent-4), (ꢀ)-gonytolide C (ent-3), as well as some relat-
ed chromanones.
Introduction
The rapidly growing class of tetrahydroxanthenone natural
products has recently attracted increasing interest in the
chemical community, fuelled by their intriguing structural fea-
tures and varied biological profiles.[1] Among the most promi-
nent members are the dimeric rugulotrosins,[2] dicerandrols[3]
and secalonic acids,[4,5] which exhibit antimicrobial, antibiotic,
cytotoxic, antifungal, and antialgal activities. The
monomeric series includes diversonol (1)[6] and the
blennolides (Figure 1). Blennolide C (4), the structure
of which was originally assigned as b-diversonolic
ester, was isolated from the endophytic fungus Blen-
noria sp. by Krohn and co-workers.[7] In 2008, both
Brꢀse[8] and Nicolaou[9] reported biomimetic ap-
proaches to the racemic natural product; in 2011,
Porco utilized a “retrobiomimetic” process in the syn-
thesis of racemic blennolides and the related isomer-
ic gonytolide C (3).[10] Gonytolide C (3) was isolated in
2011 from the fungus Gonytrichum sp. by Kikuchi and
co-workers.[11] The chromanone with a tethered g-lac-
tone moiety is the monomeric unit of gonytolide A
(6), an innate immune promoter.
Our group has recently reported the syntheses of
enantiopure (ꢀ)-blennolide A,[12] (ꢀ)-diversonol (ent-
Figure 1. Tetrahydroxanthenones and related natural products.
[a] Prof. Dr. L. F. Tietze, S. Jackenkroll, Dr. J. Hierold, Dr. L. Ma, B. Waldecker
Institute of Organic and Biomolecular Chemistry
Georg-August-University Gçttingen
Results and Discussion
Retrosynthetic analysis reveals that both ent-4 and ent-3 can
be accessed from advanced intermediate 7 (Scheme 1). Chro-
manone 7 can be transformed into ent-4 by intramolecular
acylation and global deprotection, while a desilylating lactoni-
sation followed by demethylation would enable access to
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax: (+49)551-39-9476
E-mail: ltietze@gwdg.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402495.
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The conversion of 9 to chromane 8 was then in-
vestigated in the presence of a chiral BOXAX ligand,
catalytic amounts of palladium(II)-trifluoroacetate and
the reoxidant p-benzoquinone under an atmosphere
of carbon monoxide in methanol (Table 1). In line
with our syntheses of (ꢀ)-diversonol (ent-1)[13] and
(ꢀ)-blennolide A,[12] we initially utilized the (S,S)-Bn-
BOXAX ligand (i.e. 13, R=Bn) to induce enantioselec-
tivity. Chromane 8 was isolated in good yield (68%)
and very good enantioselectivity (93% ee) (Table 1,
entry 1). Steric tuning at the C-4 position of the
BOXAX-isoxazoline rings (cf. 13, Scheme 2) was re-
ported to affect both the catalytic activity and the
enantioselectivity.[18] Novel iBu-BOXAX ligand brought
about the domino process in a similar yield (68%)
and with excellent enantioselectivity (99% ee)
(Table 1, entry 2). iPr-BOXAX, the ligand of choice in
our synthesis of vitamin E,[19] gave an equally high
Scheme 1. Retrosynthetic analysis of (ꢀ)-blennolide C (ent-4) and (ꢀ)-gonytolide C (ent-
3).
ent-3. Synthesis of 7 may be achieved from 8 by C-4 hydroxyl-
ation (numbering as in 4), chain elongation and benzylic oxida-
tion. The efficient access of chromane 8 from phenolic precur-
sor 9, a key transformation in these total syntheses, was pro-
posed to proceed by the enantioselective domino-Wacker/car-
bonylation/methoxylation reaction central to our research pro-
gramme.
enantioselectivity (>99% ee) but a decreased yield of 62%
(entry 3). It seems that the increased bulk disturbs the coordi-
nation of the palladium–ligand complex to the alkene, thus
lowering the catalytic activity. Indeed using the bulky tBu-
BOXAX ligand, 8 was only isolated in a moderate yield of 7%
(entry 4). On the other hand, we assume that the improved
enantioselectivity in the transformation of 9 compared to sub-
strates lacking the benzyloxy group is due to a tighter enantio-
facial coordination of the catalyst to the double bond.
Reduction of 8 with LiAlH4 and subsequent elimination fol-
lowing the Grieco protocol[20] gave vinyl chromane 12 in 90%
yield over three steps. Direct conversion of a derivative of 9
containing an ethylidene instead of the methylidene group to
vinyl chromane 12 by an enantioselective Wacker oxidation
had been shown to proceed with low enantioselec-
tivity on related substrates and was therefore avoid-
ed.[12,13]
Our synthesis commenced with the preparation of domino-
precursor 9 from readily available orcinol (10). The six-step se-
quence required methylation, formylation, a Wittig-transforma-
tion to install the side chain, hydrogenation, a second Wittig-
transformation to incorporate the terminal alkene and chemo-
selective cleavage of one of the methyl ethers to afford 9 in
62% overall yield (Scheme 2).
For the introduction of the hydroxyl group at C-4
a Sharpless dihydroxylation[21] was used (Table 2).
Commercial AD-mix-a gave access to the desired
anti-isomer 14a, though the yield was only moderate
and the anti/syn ratio of 2.4:1 unsatisfactory (Table 2,
entry 1). Since the diastereoselectivity of this transfor-
mation was equally low in previous syntheses (diver-
sonol: 3.8:1, blennolide A: 2.4:1),[12,13] we decided to
survey other commercial dihydroquinine (DHQ) li-
gands for their ability to carry out the dihydroxyla-
tion. Phthalazine-based (DHQ)2-PHAL, the chiral
ligand present in the commercial mix, gave the ex-
pected low selectivity (1:8:1) albeit a higher yield
when compared with the premixed AD-mix-a (entry 2).
Use of pyrimidine-based (DHQ)2-Pyr and the monomer-
Scheme 2. Synthesis of vinyl chromane 12: a) Me2SO4, K2CO3, acetone, 608C, 24 h, 96%;
b) 1) nBuLi, TMEDA, Et2O, 0 to 458C, 3 h, 2) DMF, RT, 3 h, 92%; c) 1-(benzyloxy)-3-(triphe-
nylphosphoranylidene)propan-2-one, toluene, 1208C, 19.5 h, 89%; d) 1) H2 (1 atm.),
4 mol% PtO2, EtOAc, RT, 2 h, 2) IBX, CH3CN, 808C, 1 h, 91% (2 steps); e) Ph3PCH3Br, nBuLi,
THF, RT, 4 h, 93%; f) NaSEt, DMF, 1208C, 21 h, 87% (92% based on recovered starting ma-
terial (brsm)); g) see Table 1; h) LiAlH4, Et2O, 08C to RT, 2 h, 100%; i) nBu3P, o-NO2-
C6H4SeCN, THF, 08C, 4 h, j mCPBA, Na2HPO4·2H2O, CH2Cl2, ꢀ408C, 1 h, iPr2NH, ꢀ408C to
RT, 15 h, 90% (2 steps). IBX=2-iodoxybenzoic acid; TMEDA=N,N,N’,N’-tetramethylethyle-
nediamine.
ic “first generation” ligand DHQ-MEQ resulted in an in-
creased anti/syn ratio of 4.3:1 and 6.7:1, respectively
(entries 3–4). The best result was obtained by em-
ploying anthraquinone-based (DHQ)2-AQN,[22] which
gave 14a in 77% yield and an excellent selectivity of
13.7:1 (entry 5). The obtained diastereomers 14a and
14b were readily separable by preparative HPLC.
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intrinsic diastereofacial preference of the olefin substrate, thus
a lower diastereoselectivity seems plausible.
Table 1. Enantioselective domino-Wacker/carbonylation/methoxylation.
Diastereomer 14a, displaying the anti-configuration present
in the targeted natural products, was then silylated at both hy-
droxyl groups by using (tert-butyldimethylsilyl)trifluorometha-
nesulphonate (Scheme 3). Selective deprotection of the pri-
mary alcohol and subsequent oxidation with DMP provided al-
dehyde 15 in 78% yield (89% based on recovered starting ma-
terial (brsm)) over three steps. Chain elongation by Wittig–
Horner reaction with trimethyl phosphonoacetate gave the
corresponding a,b-unsaturated methyl ester as a mixture of E/
Z-isomers (4:1). Reduction of the double bond with concomi-
tant cleavage of the benzyl ether under hydrogenolytic condi-
tions yielded primary alcohol 16, which was converted to
methyl ester 17, by using a stepwise oxidation sequence. At
this stage, it was necessary to oxidize 16 at the benzylic chro-
mane position (C-9) without affecting the competing benzylic
methyl group (C-6, cf. numbering in 4, Figure 1). A related
direct oxidation in our total synthesis of (ꢀ)-diversonol was
plagued by low yields;[13] instead we applied a more suitable
and higher-yielding three-step procedure. Accordingly, chro-
mane 17 was dehydrogenated to the corresponding chromene
with 2,3-dichloro-5,6-dicyanobenzoquinone, which was hy-
droxylated in the presence of phenylsilane, oxygen and catalyt-
ic amounts of [Mn(dmp)3],[23] and further oxidized with per-
ruthenate and NMO[24] to afford chromanone 7 in 80% yield
over the three steps. At this junction, 7 was modified following
two different pathways, allowing access to both (ꢀ)-blennoli-
de C (ent-4) and (ꢀ)-gonytolide C (ent-3).
Entry
Ligand 13
Yield [%][a]
ee [%][b]
1
2
3
4
(S,S)-Bn-BOXAX
(S,S)-iBu-BOXAX
(S,S)-iPr-BOXAX
(S,S)-tBu-BOXAX
68
68
62
7
93
99
>99
[c]
–
[a] Isolated yield following flash column chromatography. [b] Determined
by HPLC (Chiracel IB, nHex/iPrOH 98:2, 234 nm). [c] Not determined.
Table 2. Diastereoselective dihydroxylation of 12.
Entry
Ligand
t [d]
Yield [%][a]
Ratio (14a/14b)[b]
[c]
1
2
3
4
5
6
7
8
–
4
2
2
2
3
3
2
2
2
2
3
2
64
82
90
84
77
94
80
90
90
89
93
88
2.4:1
1.8:1
4.3:1
6.7:1
13.7:1
1:1.7
1:2.2
1:1.9
1:1.5
1:3.1
1:3.0
1:3.7
(DHQ)2-PHAL
(DHQ)2-Pyr
DHQ-MEQ
For the total synthesis of (ꢀ)-blennolide C, 7 was treated
with trichlorotitanium isopropoxide and triethylamine in di-
chloromethane at 08C to give the tetrahydroxanthenone scaf-
fold in 84% yield (Scheme 4). Though we observed some epi-
merisation at C-4a (18a/18b 9.5:1), the diastereomers were
separable by standard column chromatography. Unfortunately
the subsequent silyl deprotection of 18a was again afflicted
by epimerisation. Thus, both the conditions we applied in the
total synthesis of diversonol (HF·py, 308C, 5 d)[13] and blennoli-
de A (HF·3Et3N, 508C, 6 d)[12] led to complete epimerisation,
while basic deprotection conditions using tetrabutylammoni-
um fluoride (TBAF) or tris(dimethylamino)sulfur trimethylsilyl
difluoride (TASF) resulted in decomposition of 18a. As the un-
desired syn-isomer is likely stabilised through intramolecular
hydrogen bonding, the presence of water was predicted to
suppress epimerisation. Indeed, treatment of 18a with aque-
ous fluorosilicic acid gave 19 in 56% yield and an anti/syn ratio
of 10.5:1. While it was possible to separate the epimers at this
stage by using reverse-phase HPLC (H2O/MeOH), we decided
to conduct the final step of the synthesis with the mixture.
Thus, treatment of 19 with BBr3 gave (ꢀ)-blennolide C (ent-4)
in a yield of 60%, alongside 6% of a syn-isomer. The ester
group of the syn-isomer was hydrolysed to the corresponding
acid under the reaction conditions (vide infra), allowing separa-
tion from ent-4 by HPLC. Reversing the order of silyl-/methyl-
deprotection was also investigated. When 18a was treated
with BBr3, phenol 20 was isolated in 86% with no observable
epimerisation. Desilylation with fluorosilicic acid then provided
(DHQ)2-AQN
[d]
–
(DHQD)2-PHAL
(DHQD)2-Pyr
DHQD-CLB
DHQD-MEQ
(DHQD)2-AQN
DHQD-PHN
9
10
11
12
[a] Isolated yield following flash column chromatography. [b] Separation of the
diastereomers by HPLC (IB column, nHex/iPrOH (96:4)). [c] Commercial AD-
mix-a used. [d] Commercial AD-mix-b used.
For an entry to the C-4 epimer of blennolide C, the mono-
meric unit of the rugulotrosins, we also investigated the selec-
tive preparation of syn-isomer 14b. Commercial AD-mix-b af-
forded the diol in an excellent yield of 94%; however, the se-
lectivity was poor (14a/14b 1:1.7) (Table 2, entry 6). Similar re-
sults were obtained by separate addition of the AD-mix com-
ponents as well as by replacing the (DHQD)2-PHAL ligand with
(DHQD)2-Pyr or monomeric ligand DHQD-CLB (entries 7–9).
DHQD-MEQ gave an increased diastereoselectivity of 1:3.0,
comparable with that observed for (DHQD)2-AQN (1:3.1) (en-
tries 10–11). The best result was obtained with the monocin-
chona alkaloid DHQD-PHN, which favoured the syn-isomer 14b
with a ratio of 1:3.7 (Table 2, entry 12). It should be noted that
for the synthesis of 14b, the chiral ligand has to override the
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sponding to the methyl ester moiety. Thus, instead of
the 4-epimer of blennolide C, acid 25 had been ob-
tained in a yield of 44%, presumably formed by b-
lactone intermediate 24.
To complete the total synthesis of gonytolide C,
chromanone 7 was treated with triethylamine trihy-
drofluoride in dioxane at 608C (Scheme 6). Cleavage
of the silyl ether and exclusive in situ formation of
the g- over the b-lactone furnished 26 in a very good
yield of 87%, which was then demethylated with
BBr3 to give rise to (ꢀ)-gonytolide C (ent-3). Again,
the spectroscopic data matched those reported for
natural 3. The optical rotation was determined to be
ꢀ28.5 (c=0.10 in CHCl3, 24.78C) relative to +25.1
(c=0.184, CHCl3) published by Kikuchi,[11] showing
that we have synthesized the enantiomer of the nat-
ural product. It should be noted that natural
(+)-blennolide C (4) and (+)-gonytolide C (3) are
readily accessible by completing our synthetic se-
quence with an (R,R)-BOXAX ligand.
Scheme 3. Synthesis of chromanone 7: a) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 2.5 h, 96%;
b) HF·py, THF/py (5:1), RT, 24 h, 85%, (97% brsm); c) DMP, CH2Cl2, 08C to RT, 2 h, 96%;
d) NaH, (MeO)2P(O)CH2CO2Me, THF, 08C, 30 min, then 15, THF, 08C to RT, 2 h; e) 10 mol%
Pd/C, H2 (4 bar), MeOH, 2d, 90% (2 steps); f) DMP, CH2Cl2, 08C to RT, 2 h, 92%; g) KOH, I2,
MeOH, 08C to RT, 9 h, 100%; h) DDQ, benzene, reflux, 3 h, 87%; i) 30 mol% [Mn(dpm)3],
PhSiH3, O2 (1 atm.), MeOH, 508C, 24 h; j) 20 mol% TPAP, NMO, CH2Cl2/CH3CN (3:1), 4 ꢃ
MS, 24 h, 92% (2 steps). DMP=Dess-Martin periodinane; NMO=N-methylmorpholine-N-
oxide; TPAP=tetrapropylammonium perruthenate.
Lastly, we converted chromanone 21 to 2’-epi-go-
nytolide 28, a diastereomer of 3. A desilylating lactonisation of
21 by using triethylamine trihydrofluoride yielded 27 in 84%,
which was then treated with BBr3 to give 28 in 86% yield.
Conclusion
We have achieved the first enantioselective total syntheses of
(ꢀ)-blennolide C (ent-4) and (ꢀ)-gonytolide C (ent-3). Key to
the syntheses was an enantioselective domino-Wacker/carbon-
ylation/methoxylation reaction to set up the stereocentre at C-
4a. Various chiral BOXAX ligands were investigated, including
novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in
an excellent enantioselectivity of 99%. The second stereocen-
tre, the hydroxyl group at C-4, was established employing
a diastereoselective Sharpless dihydroxylation. An extensive
survey of (DHQ)- and (DHQD)-based ligands enabled the prep-
aration of both anti- 14a and syn-isomer 14b in very good se-
lectivities of 13.8:1 and 1:3.7, respectively. While 14a was fur-
ther converted to ent-3 and ent-4, 14b was elaborated to syn-
acid 25 and 2’-epi-gonytolide C 28.
Scheme 4. Synthesis of (ꢀ)-blennolide C (ent-4): a) Ti(OiPr)Cl3, Et3N, CH2Cl2,
08C, 1 h, 59% of pure 18a plus 25% of a mixture of 18a/18b (2.2:1); b) aq.
H2SiF6, DMF, 508C, 6 d, 56% (anti/syn=10.5:1); c) BBr3, CH2Cl2, RT, 1 h, 60%;
d) BBr3, CH2Cl2, ꢀ78 to 08C, 4 h, 86%; e) aq. H2SiF6, DMF, 508C, 6 d, 50%.
(ꢀ)-blennolide C (ent-4) in 50% yield, alongside 17% of the syn
acid.
Experimental Section
All spectroscopic data are in complete agreement with the
published information of natural (+)-blennolide C (4). We have
prepared ent-4 with an optical rotation of ꢀ175.3 (c=0.20 in
CHCl3, 22.78C), which is slightly lower than the value of
+181.7 (c=0.06 in CHCl3, 258C) reported by Krohn.[7]
For an entry to the 4-epimer of blennolide C, syn-diol 14b
was converted to chromanone 21 by using the sequence es-
tablished for ent-4 (Scheme 5). Both the intramolecular acyla-
tion of 21 to 22 and the desilylation to afford 23 proceeded
smoothly without any epimerisation at C-4a. To our surprise,
the crude 1H NMR spectra of the product isolated after the
final methyl ether cleavage with BBr3 lacked the signal corre-
Experimental procedures and spectroscopic data of key in-
termediates 7, 8, 12, 14a, (S,S)-iBu-BOXAX ligand 13, (ꢀ)-
blennolide C (ent-4), 25, (ꢀ)-gonytolide C (ent-3) and 2’-epi-
gonytolide (28): The syntheses of all other new compounds in-
cluding the analytical data can be found in the Supporting In-
formation.
(ꢀ)-Gonytolide C (ent-3): BBr3 (0.44 mL, 1m in CH2Cl2, 440 mmol,
10.0 equiv) was added to a stirred solution of chromanyl lactone
26 (14.7 mg, 44.0 mmol, 1.00 equiv) in CH2Cl2 (2.2 mL) at ꢀ788C
and stirring was continued at ꢀ788C for 2 h. The reaction was
quenched by dropwise addition of sat. aq. NaHCO3 (10 mL) at
ꢀ788C, the aq. layer extracted with EtOAc (3ꢂ10 mL), and the
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(ꢀ)-Blennolide C (ent-4): A stirred solution of tetrahy-
droxanthenone 20 (28.4 mg, 65.4 mmol, 1.00 equiv) in
DMF (2.3 mL) was treated with H2SiF6 (0.84 mL, 23 wt.%
in H2O, 1.63 mmol, 25.0 equiv) at RT and stirring was con-
tinued at 508C for 3 d. Additional H2SiF6 (0.84 mL,
23 wt.% in H2O, 1.63 mmol, 25.0 equiv) was added at RT
and the mixture stirred at 508C for a further 3 d. The re-
action was quenched by addition of H2O (10.0 mL) at
08C, the aq. layer extracted with MTBE (3ꢂ5 mL) and the
combined organic phases were dried over Na2SO4. After
column chromatography on silica gel (CH2Cl2/MeOH
100:1!5:1), (ꢀ)-blennolide C (ent-4) was obtained
alongside ent-25 as a white solid (13.7 mg, 43.3 mmol,
66%, ent-4/ent-25=3:1). Purification by RP-HPLC (Jasco
Kromasil 100-C18, 4.6ꢂ250 mm, 5 mm, eluent: H2O (A)/
MeOH (B), gradient: 0–30 min: 50A/50B!0A/100B, 30–
Scheme 5. Attempted synthesis of the 4-epimer of blennolide (4) with observed deme-
thylation: a) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 2.5 h, 98%; b) HF·py, THF/py (5:1), RT, 30 h,
81% (89% brsm); c) DMP, CH2Cl2, 08C to RT, 2 h, 98%; d) NaH, (MeO)2P(O)CH2CO2Me, THF,
08C, 30 min, then aldehyde, THF, 08C to RT, 2 h; e) 10 mol% Pd/C, H2 (4 bar), AcOH,
MeOH, 80 h, 91% (2 steps); f) DMP, CH2Cl2, 08C to RT, 1.5 h, 93%; g) KOH, I2, MeOH, 08C
to RT, 6.5 h, 96%; h) DDQ, benzene, reflux, 3 h, 77%; i) 30 mol% [Mn(dpm)3], PhSiH3, O2
(1 atm.), MeOH, 508C, 30 h; j) 20 mol% TPAP, NMO, CH2Cl2/CH3CN (3:1), 4 ꢃ MS, RT, 24 h,
85% (2 steps); k) Ti(OiPr)Cl3, Et3N, CH2Cl2, 08C, 2 h, 73%; l) aq. H2SiF6, DMF, 508C, 6 d,
96%; m) BBr3, CH2Cl2, RT, 1 h, 44%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
40 min: 0A/100B!50A/B50, flow: 0.8 mLminꢀ1
, tR =
16.4 min) furnished (ꢀ)-blennolide C (ent-4) as a white
solid. [a]D =ꢀ175.3 (c=0.20 in CHCl3, 22.78C); 1H NMR
(600 MHz, CDCl3): d=1.93 (mc, 1H; 3-Ha), 2.12 (mc, 1H; 3-
Hb), 2.27 (s, 3H; 6-CH3), 2.36 (ddd, J=19.2, 6.9, 1.3 Hz,
1H; 2-Ha), 2.67 (s, 1H; 4-OH), 2.80 (ddd, J=18.8, 11.3,
7.0 Hz, 1H; 2-Hb), 3.67 (s, 3H; CO2CH3), 4.29 (s, 1H; 4-H),
6.32 (s, 1H; 5-H), 6.36 (s, 1H; 7-H), 11.25 (s, 1H; 8-OH),
14.02 ppm (s, 1H; 1-OH); 13C NMR (125 MHz, CDCl3): d=
22.5 (6-CH3), 23.1 (C-3), 24.3 (C-2), 53.4 (CO2CH3), 67.0 (C-
4), 83.8 (C-4a), 100.1 (C-9a), 104.9 (C-8a), 108.7 (C-5),
111.7 (C-7), 149.9 (C-6), 157.6 (C-10a), 161.9 (C-8), 171.2
(CO2CH3), 179.1 (C-1), 186.9 ppm (C-9); IR: n˜ =3484, 2922,
2852, 1740, 1613, 1571, 1456, 1416, 1363, 1298, 1256,
1239, 1206, 1149, 1111, 1078, 1051, 957, 879, 837, 819,
736, 568 cmꢀ1; UV (MeOH): lmax (lg e)=279 (3.4955),
333 nm (4.0719); MS (ESI): m/z (%): 663.2 (44) [2M+Na]+,
343.1 (100) [M+Na]+, 321.1 (36) [M+H]+; HRMS (ESI): m/
z: calcd for C16H16O7: 321.0969 [M+H]+; found: 321.0966.
Methyl (2S,1’R)-2-[1-(tert-butyldimethylsilyloxy)-4-me-
thoxy-4-oxobutyl]-5-methoxy-7-methyl-4-oxochroman-
2-carboxylate (7): A stirred solution of methyl (2S,1’R)-2-
[1-(tert-butyldimethylsilyloxy)-4-methoxy-4-oxobutyl]-5-
methoxy-7-methyl-2H-chromene-2-carboxylate (240 mg,
517 mmol, 1.00 equiv) in MeOH (12 mL) was treated with
[Mn(dpm)3] (32 mg, 51.7 mmol, 10 mol%) at RT and
oxygen was passed through the resulting mixture for
Scheme 6. Synthesis of (ꢀ)-gonytolide C (ent-3) and the diastereomeric 2’-epi-gonytoli-
de C (28): a) 3HF·Et3N, dioxane, 608C, 6 d, 87%; b) BBr3, CH2Cl2, ꢀ788C, 2 h, 77%;
c) 3HF·Et3N, dioxane, 608C, 6 d, 84%; d) BBr3, CH2Cl2, ꢀ788C, 2 h, 86%.
20 min. PhSiH3 (1.30 mL, 10.3 mmol, 20.0 equiv) was added by sy-
ringe pump (0.06 mLminꢀ1), while the reaction mixture was stirred
under an atmosphere of O2 (1 atm.) at 508C. Additional [Mn(dpm)3]
(32 mg, 51.7 mmol, 10 mol%) was added after 8 and 16 h. After stir-
ring at 508C for a further 8 h (overall 24 h), the reaction was
quenched by adsorption on silica gel. Evaporation of the solvent
and column chromatography on silica gel (n-hexane/EtOAc 10:1!
1:1) furnished two diastereomeric alcohols (157 mg, 325 mmol,
63%) and (83 mg, 172 mmol, 33%) as colourless oils. A solution of
the diastereomeric alcohols (157 mg, 325 mmol, 0.65 equiv) and
(83 mg, 172 mmol, 0.35 equiv) in CH2Cl2 (22.5 mL) and CH3CN
(7.5 mL) in the presence of 4 ꢃ molecular sieves (400 mg) was
treated with NMO (150 mg, 1.24 mmol, 2.50 equiv) at 08C and then
stirred at 08C for a further 5 min. TPAP (17.5 mg, 47.9 mmol,
10 mol%) was added at 08C and the resulting reaction mixture
stirred at RT for 12 h. Additional NMO (150 mg, 1.24 mmol,
2.50 equiv) and TPAP (17.5 mg, 47.9 mmol, 10 mol%) were added at
08C and the resulting reaction mixture stirred at RT for a further
12 h. After adsorption on silica gel, evaporation of the solvent and
column chromatography on silica gel (n-pentane/EtOAc 4:1!3:1)
combined organic phases were dried over Na2SO4. After column
chromatography on silica gel (n-pentane/EtOAc 2:1!1:2), (ꢀ)-go-
nytolide C (ent-3) was obtained as
a white solid (10.9 mg,
34.0 mmol, 77%). [a]D =ꢀ28.5 (c=0.10 in CHCl3, 24.78C); 1H NMR
(600 MHz, CDCl3): d=2.29 (s, 3H; 7-CH3), 2.41 (mc, 2H; 3’-H2), 2.57
(ddd, J=17.7, 10.2, 6.6 Hz, 1H; 4’-Ha), 2.69 (ddd, J=17.2, 9.9,
7.1 Hz, 1H; 4’-Hb), 2.93 (d, J=16.9 Hz, 1H; 3-Ha), 3.09 (d, J=
16.9 Hz, 1H; 3-Hb), 3.72 (s, 3H; CO2CH3), 4.84 (dd, J=8.0, 5.7 Hz,
1H; 2‘-H), 6.36 (s, 1H; 8-H), 6.38 (s, 1H; 6-H), 11.36 ppm (s, 1H; 5-
OH); 13C NMR (125 MHz, CDCl3): d=22.0 (C-3’), 22.6 (7-CH3), 27.6 (C-
4’), 39.4 (C-3), 53.6 (CO2CH3), 80.9 (C-2’), 84.0 (C-2), 105.6 (C-4a),
108.5 (C-8), 111.1 (C-6), 151.6 (C-7), 159.0 (C-8a), 161.8 (C-5), 169.0
(CO2CH3), 175.5 (C-5’), 193.0 ppm (C-4); IR: n˜ =2924, 2853, 1785,
1759, 1738, 1644, 1570, 1455, 1366, 1262, 1120, 1131, 1074, 1055,
1033, 935, 837, 800, 734, 702, 555 cmꢀ1; UV (CH3CN): lmax (lg e)=
277 (3.9702), 344 nm (3.3917); MS (ESI): m/z (%): 663.2 (50)
[2M+Na]+, 658.2 (10) [2M+NH4]+, 343.1 (85) [M+Na]+, 338.1 (29)
[M+NH4]+, 321.1 (100) [M+H]+; HRMS (ESI): m/z calcd for C16H16O7:
321.0969 [M+H]+; found: 321.0970.
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chromanone 7 (228 mg, 474 mmol, 95%, 92% over 2 steps) was ob-
tained as a colourless oil. [a]D =ꢀ71.3 (c=0.20 in CHCl3, 258C);
1H NMR (600 MHz, CDCl3): d=0.08 (s, 3H; Si(CH3)a), 0.14 (s, 3H;
Si(CH3)b), 0.85 (s, 9H; SiC(CH3)3), 1.66 (mc, 2H; 2’-H2), 2.30 (s, 3H; 7-
CH3), 2.36 (dt, J=16.2, 7.9 Hz, 1H; 3’-Ha), 2.52 (ddd, J=16.2, 7.6,
6.4 Hz, 1H; 3’-Hb), 2.96 (d, J=16.6 Hz, 1H; 3-Ha), 3.10 (d, J=
16.6 Hz, 1H; 3-Hb), 3.65 (s, 6H; 4’-OCH3, 2-CO2CH3), 3.85 (s, 3H; 5-
OCH3), 4.13 (dd, J=6.8, 5.3 Hz, 1H; ’-H), 6.30 (s, 1H; 8-H), 6.42 ppm
(s, 1H; 6-H); 13C NMR (125 MHz, CDCl3): d=ꢀ4.7, ꢀ3.7 (Si(CH3)a,
Si(CH3)b), 18.3 (SiC), 22.4 (7-CH3), 26.0 (SiC(CH3)3), 27.4 (C-2’), 30.3
(C-3’), 39.2 (C-3), 51.6 (4’-OCH3), 53.0 (2-CO2CH3), 56.1 (5-OCH3), 74.3
(C-1’), 87.2 (C-2), 105.8 (C-6), 108.6 (C-4a), 110.5 (C-8), 147.9 (C-7),
160.4, 160.8 (C-5, C-8a), 170.6 (2-CO2CH3), 173.3 (C-4’), 188.7 ppm
(C-4); IR: n˜ =2953, 2928, 2855, 1738, 1686, 1614, 1568, 1463, 1436,
treated with Na2HPO4·2H2O (3.59 g, 20.2 mmol, 5.00 equiv) and
meta-chloroperoxybenzoic acid (mCPBA) (2.48 g, 70%, 10.1 mmol,
2.50 equiv) at ꢀ408C and stirred at this temperature for 1 h. Diiso-
propylamine (2.82 mL, 20.2 mmol, 5.00 equiv) was added at ꢀ408C
and the reaction mixture warmed to RT within 15 h. The reaction
mixture was adsorbed on silica gel and the solvent removed under
reduced pressure. Column chromatography on silica gel (n-pen-
tane/EtOAc 100:0!90:10) furnished vinyl chromane 12 as a yellow
oil (1.18 g, 3.62 mmol, 90%). [a]D =ꢀ72.0 (c=0.50 in CHCl3,
23.78C); 1H NMR (600 MHz, CDCl3): d=1.91 (ddd, J=13.6, 6.1,
4.0 Hz, 1H; 3-Ha), 1.99 (ddd, J=13.6, 11.0, 5.6 Hz, 1H; 3-Hb), 2.28 (s,
3H; 7-CH3), 2.39 (ddd, J=17.1, 10.9, 6.2 Hz, 1H; 4-Ha), 2.68 (dt, J=
16.8, 4.8 Hz, 1H; 4-Hb), 3.52 (d, J=10.0 Hz, 1H; CHaOBn), 3.57 (d,
J=10.0 Hz, 1H; CHbOBn), 3.77 (s, 3H; 5-OCH3), 4.60 (d, J=12.3 Hz,
1H; OCHaPh), 4.63 (d, J=12.3 Hz, 1H; OCHbPh), 5.16 (dd, J=10.9,
1.4 Hz, 1H; 2’-Hcis), 5.25 (dd, J=17.3, 1.4 Hz, 1H; 2’-Htrans), 5.84 (dd,
J=17.3, 10.9 Hz, 1H; 1’-H), 6.22 (s, 1H; 8-H), 6.41 (s, 1H; 6-H), 7.27
(mc, 1H; Ph-Hp), 7.32 ppm (mc, 4H; Ph-Ho, Ph-Hm); 13C NMR
(125 MHz, CDCl3): d=16.0 (C-4), 21.6 (7-CH3), 26.6 (C-3), 55.3 (5-
OCH3), 73.6 (OCH2Ph), 75.5 (CH2OBn), 78.7 (C-2), 102.8 (C-8), 107.7
(C-4a), 110.0 (C-6), 116.1 (C-2’), 127.5 (Ph-Cp), 127.6, 128.3 (Ph-Co,
Ph-Cm), 136.9 (C-7), 137.9 (C-1’), 138.4 (Ph-Ci), 154.1, 157.4 ppm (C-5,
C-8a); IR: n˜ =2932, 2854, 1616, 1584, 1497, 1453, 1410, 1351, 1320,
1291, 1227, 1196, 1135, 1099, 1026, 991, 927, 812, 734, 696, 580,
550 cmꢀ1; UV (CH3CN): lmax (lg e)=207 (4.6903), 271 nm (2.9781);
MS (ESI): m/z (%): 671.3 (86) [2M+Na]+, 666.4 (56) [2M+NH4]+,
347.2 (48) [M+Na]+, 342.2 (13) [M+NH4]+, 325.2 (100) [M+H]+;
HRMS (ESI): m/z calcd for C21H24O3: 325.1798 [M+H]+; found:
325.1796.
1415, 1389, 1251, 1222, 1124, 1107, 1055, 993, 833, 777, 689 cmꢀ1
;
UV (CH3CN): lmax (lg e)=219 (4.2702), 268 (3.9879), 324 nm
(3.6228); MS (ESI): m/z (%): 983.4 (24) [2M+Na]+, 503.2 (49)
[M+Na]+, 481.2 (100) [M+H]+; HRMS (ESI): m/z calcd for
C24H36O8Si: 481.2252 [M+H]+; found: 481.2247.
Methyl (2S)-2-(2-benzyloxymethyl-5-methoxy-7-methylchroman-
2-yl)acetate (8): A solution of palladium(II)-trifluoroacetate (2.7 mg,
8.1 mmol, 5 mol%) and (S,S)-iBu-BOXAX 13 (16.2 mg, 32.1 mmol,
20 mol%) in MeOH (0.5 mL) was stirred at RT for 15 min before
being transferred to alkenylphenol 9 (50 mg, 160 mmol, 1.00 equiv)
by syringe (rinsing with 0.5 mL MeOH). p-Benzoquinone (71 mg,
640 mmol, 4.00 equiv) was added and the reaction stirred under an
atmosphere of CO (1 atm.) at RT for 24 h. The reaction mixture was
poured into 1n aq. HCl (10 mL) and the aq. layer was extracted
with MTBE (methyl tert-butyl ether) (3ꢂ5 mL). The combined or-
ganic phases were washed with 1n aq. NaOH (3ꢂ5 mL), dried over
Na2SO4 and evaporated in vacuo. Column chromatography on
silica gel (n-pentane/EtOAc 25:1!10:1) furnished methyl ester 8 as
a colourless oil that solidified under vacuum (40.5 mg, 109 mmol,
68%); analytical HPLC: Daicel Chirapak IB, 4.6ꢂ250 mm, eluent: n-
hexane/2-PrOH 98:2, flow: 0.8 mLminꢀ1, wavelength: 234 nm, tR =
11.0 min (ꢀ)-(R)-8, 0.7%, tR =14.2 min (+)-(S)-8, 99.3%, 99% ee.
[a]D = +0.9 (c=0.18 in CHCl3, 22.98C); 1H NMR (600 MHz, CDCl3):
d=2.01 (mc, 2H; 3-H2), 2.26 (s, 3H; 7-CH3), 2.58 (mc, 2H; 4-H2), 2.71
(d, J=15.0 Hz; 2’-Ha), 2.82 (d, J=14.4 Hz; 2’-Hb), 3.61 (s, 3H;
CO2CH3), 3.65 (d, J=3.0 Hz, 2H; CH2OBn), 3.78 (s, 3H; 5-OCH3), 4.53
(d, J=12.0 Hz; OCHaPh), 4.61 (d, J=12.0 Hz; OCHbPh), 6.23 (s, 1H;
8-H), 6.33 (s, 1H; 6-H), 7.25–7.34 ppm (m, 5H; 5ꢂ PhꢀH); 13C NMR
(125 MHz, CDCl3): d=15.8 (C-4), 21.6 (7-CH3), 26.2 (C-3), 39.3 (C-2’),
51.5 (CO2CH3), 55.4 (5-OCH3), 72.7 (CH2OBn), 73.6 (OCH2Ph), 76.27
(C-2), 103.1 (C-8), 107.2 (C-4a), 110.4 (C-6), 127.5, 127.6, 128.3 (Ph-
Co, Ph-Cm, PhꢀCp), 137.2 (C-7), 138.2 (PhꢀCi), 153.3, 157.5 (C-5, C-
8a), 170.8 ppm (C-1’); IR: n˜ =2923, 2360, 2885, 1728, 1579, 1316,
1223, 1094, 824, 750, 701 cmꢀ1; UV (CH3CN): lmax (lg e)=208
(4.7849), 272 (3.0529), 279 nm (3.0219); MS (ESI): m/z (%): 763.3
(75) [2M+Na]+, 393.2 (100) [M+Na]+; HRMS (ESI): m/z calcd for
C22H26O5: 393.1672 [M+Na]+; found: 393.1677.
(S)-2,2’-Bis-[(4S)-iso-butyl)-4,5-dihydrooxazol-2-yl]-1,1’-binaph-
thalene (13, R=iBu): A solution of (4’S)-2-(1-bromonaphthalen-2-
yl)-4-isobutyl-4,5-dihydrooxazole (2.00 g, 6.02 mmol, 1.00 equiv) in
pyridine (46 mL, distilled over calcium hydride) was treated with
activated copper powder (1.15 g, 18.1 mmol, 3.00 equiv) at RT and
the reaction mixture heated at reflux for 11 h. After cooling to RT,
the solvent was evaporated in vacuo, the residue taken up in
CH2Cl2 (100 mL) and filtered over Celite (rinsing with CH2Cl2). The
filtrate was washed with conc. NH3 solution (3ꢂ100 mL) until the
organic layer was colourless. The organic phase was dried over
Na2SO4 and evaporated in vacuo. Purification of the residue by
column chromatography on silica gel (n-pentane/EtOAc 100:1!
9:1) and HPLC (Jasco LiChrosorb, n-hexane/2-PrOH 99:1) furnished
the targeted (S,S)-iBu-BOXAX-ligand (0.73 g, 1.45 mmol, 48%). Al-
ternatively, the (S,S)-iBu-BOXAX-ligand can be purified by recrystal-
lization from 2-PrOH. Analytical HPLC: Jasco LiChrosorb Si60, 4.6ꢂ
250 mm, 5 mm, eluent: n-hexane/2-PrOH 99:1, flow: 0.8 mLminꢀ1
,
tR =7.0 min. Preparative HPLC: Jasco LiChrosorb Si60, 20ꢂ250 mm,
7 mm, eluent: n-hexane/2-PrOH 99:1, flow: 10 mLminꢀ1, wave-
length: 233 nm, tR =10.4 min. [a]D =ꢀ199.5 (c=0.48 in CHCl3);
1H NMR (600 MHz, CDCl3): d=0.70 (d, J=6.6 Hz, 6H; 2’’-CH3,a), 0.74
(d, J=6.6 Hz, 6H; 2’’-CH3,b), 0.82 (dt, J=13.3, 7.3 Hz, 2H; 1’’-Ha),
1.05 (dt, J=13.6, 6.9 Hz, 2H; 1’’-Hb), 1.33 (dp, J=13.4, 6.7 Hz, 2H;
2’’-H), 3.42 (t, J=7.7 Hz, 2H; 5’-Ha), 3.76 (dd, J=9.2, 8.0 Hz, 2H; 5’-
Hb), 3.89 (dq, J=9.2, 7.2 Hz, 2H; 4’-H), 7.22 (mc, 4H, 6-H; 7-H), 7.44
(ddd, J=8.0, 5.1, 2.8 Hz, 2H; 5-H), 7.88 (d, J=8.2 Hz, 2H; 8-H), 7.92
(d, J=8.6 Hz, 2H; 4-H), 8.03 ppm (d, J=8.7 Hz, 2H; 3-H); 13C NMR
(150 MHz, CDCl3): d=22.5, 22.6 (2’’-CH3,a, 2’’-CH3,b), 25.0 (C-2“), 45.0
(C-1”), 64.7 (C-4’), 72.8 (C-5’), 126.0 (C-8), 126.1, 126.3, 126.7, 127.0
(C-3, C-5, C-6, C-7), 127.5, 127.8 (C-4, C-8a), 132.9, 134.2 (C-2, C-4a),
137.8 (C-1), 163.7 ppm (C-2’); IR: n˜ =2953, 2916, 2891, 2866, 2360,
2341, 1656, 1505, 1468, 1379, 1364, 1296, 1243, 1233, 1103, 982,
951, 909, 854, 823, 753, 738, 569 cmꢀ1; UV (CH3CN): lmax (lg e)=228
(4.8388), 288 (4.1057), 336 (3.3266), 370 nm (2.5677); MS (ESI): m/z
(2S)-2-Benzyloxymethyl-5-methoxy-7-methyl-2-vinylchromane
(12): A solution of chromanyl alcohol 11 (1.38 g, 4.03 mmol,
1.00 equiv) in THF (50 mL) was treated with 2-nitrophenyl seleno-
cyanate (1.83 g, 8.06 mmol, 2.00 equiv) and nBu3P (2.00 mL,
7.70 mmol, 1.91 equiv) at 08C and stirred at 08C for 1.5 h. Addition-
al 2-nitrophenyl selenocyanate (458 mg, 2.02 mmol, 0.50 equiv)
and PnBu3 (0.50 mL, 1.93 mmol, 0.48 equiv) were added at 08C and
stirring was continued at 08C for 2.5 h. The reaction was quenched
by addition of sat. aq. NaHCO3 solution (180 mL) at 08C and the
aq. layer extracted with MTBE (5ꢂ50 mL). The combined organic
phases were dried over Na2SO4 and the solvent evaporated in
vacuo. A suspension of the crude product in CH2Cl2 (80 mL) was
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(%): 505.3 (100) [M+H]+; HRMS (ESI): m/z calcd for C34H36N2O2:
505.2850 [M+H]+; found: 505.2851.
phases were dried over Na2SO4. After column chromatography on
silica gel (n-pentane/EtOAc=2:1!1:3), 2’-epi-gonytolide C (28)
was obtained as a white solid (13.2 mg, 41.2 mmol, 86%). [a]D =
ꢀ32.4 (c=0.10 in CHCl3, 22.58C); 1H NMR (600 MHz, CDCl3): d=
2.28 (s, 3H; 7-CH3), 2.28–2.35 (m, 1H; 3’-Ha), 2.47 (mc, 1H; 3’-Hb),
2.55 (ddd, J=17.7, 10.5, 4.9 Hz, 1H; 4’-Ha), 2.79 (ddd, J=17.9, 10.2,
4.9 Hz, 1H; 4’-Hb), 3.04 (d, J=17.2 Hz, 1H; 3-Ha), 3.43 (d, J=
17.3 Hz, 1H; 3-Hb), 3.72 (s, 3H; CO2CH3), 4.75 (dd, J=8.5, 4.1 Hz,
1H; 2’-H), 6.34 (s, 1H; 8-H), 6.35 (s, 1H; 6-H), 11.39 ppm (s, 1H; 5-
OH); 13C NMR (125 MHz, CDCl3): d=21.7 (C-3’), 22.6 (7-CH), 27.8 (C-
4’), 40.3 (C-3), 53.7 (CO2CH3), 79.7 (C-2’), 84.6 (C-2), 105.5 (C-4a),
108.3 (C-8), 111.0 (C-6), 151.2 (C-7), 158.9 (C-8a), 161.7 (C-5), 169.1
(CO2CH3), 176.0 (C-5’), 194.0 ppm (C-4); IR: n˜ =3358, 2955, 1773,
1741, 1636, 1568, 1455, 1359, 1288, 1263, 1207, 1181, 1120, 1087,
1064, 1030, 837, 807, 743, 704 cmꢀ1; UV (MeOH): lmax (lg e)=224
(3.9672), 276 (3.8614), 343 nm (3.2846); MS (ESI): m/z (%): 663.2
(71) [2M+Na]+, 343.1 (67) [M+Na]+, 338.1 (25) [M+NH4]+, 321.1
(100) [M+H]+; HRMS (ESI): m/z calcd for C16H16O7: 343.0788
[M+Na]+; found: 343.0787.
(1’R,2R)-1-(2-Benzyloxymethyl-5-methoxy-7-methylchroman-2-
yl)ethane-1,2-diol (14a): A solution of vinyl chromane 12 (376 mg,
1.16 mmol, 1.00 equiv) in tBuOH/H2O (5.8/5.8 mL) was treated with
K2OsO4·2H2O (21.3 mg, 58 mmol, 5 mol%), (DHQ)2-AQN (143 mg,
159 mmol, 10 mol%), K3[Fe(CN)6] (2.29 g, 6.95 mmol, 6.00 equiv)
and K2CO3 (961 mg, 6.95 mmol, 6.00 equiv) at RT. After stirring for
3 d, the reaction was quenched by addition of sat. aq. NaHSO3 so-
lution (20 mL) at 08C and stirred at RT for an additional 30 min.
The aq. layer was extracted with EtOAc (3ꢂ10 mL), the combined
organic layers were dried over Na2SO4 and concentrated under re-
duced pressure. After column chromatography on silica gel (n-pen-
tane/EtOAc 5:1!1:1), a mixture of diastereomers was obtained as
a colourless oil (320 mg, 894 mmol, 77%, d.r.=13.7:1). The diaste-
reomeric alcohols 14a (anti) and 14b (syn) can be separated by
HPLC (Daicel Chiracel IB, 20ꢂ250 mm, n-hexane/2-PrOH 96:4,
7 mLminꢀ1, 210 nm): tR =14.7 min (14a), tR =19.7 min (14b); for
the analytical data of 14b, see the Supporting Information.
Compound 14a: [a]D = +2.8 (c=0.50 in CHCl3, 23.08C); 1H NMR
(600 MHz, CDCl3): d=2.00 (mc, 2H; 3-H2), 2.26 (s, 3H; 7-CH3), 2.47
(dt, J=16.8, 7.9 Hz, 1H; 4-Ha), 2.69 (dt, J=17.4, 5.7 Hz, 1H; 4-Hb),
2.74 (sbr, 1H; 2’-OH), 2.99 (d, J=6.8 Hz, 1H; 1’-OH), 3.57 (d, J=
10.0 Hz, 1H; CHaOBn), 3.64 (d, J=10.0 Hz, 1H; CHaOBn), 3.76–3.83
(m, 2H; 2’-H2), 3.78 (s, 3H; 5-OCH3), 3.85 (q, J=5.8 Hz, 1H; 1’-H),
4.47 (d, J=11.8 Hz, 1H; OCHaPh), 4.56 (d, J=11.8 Hz, 1H; OCHbPh),
6.24 (s, 1H; 8-H), 6.30 (s, 1H; 6-H), 7.27–7.34 ppm (m, 5H, 5ꢂPh-
H); 13C NMR (125 MHz, CDCl3): d=15.4 (C-4), 21.6 (7-CH3), 23.5 (C-
3), 55.4 (5-OCH3), 61.9 (C-2’), 70.2 (CH2OBn), 74.0 (OCH2Ph), 74.2 (C-
1’), 77.6 (C-2), 103.3 (C-8), 107.4 (C-4a), 110.0 (C-6), 127.7, 128.5 (Ph-
Co, Ph-Cm), 127.9 (Ph-Cp), 137.2, 137.3 (C-7, Ph-Ci), 153.1, 157.5 ppm
(C-5, C-8a); IR: n˜ =3399, 2924, 2855, 1618, 1584, 1497, 1453, 1413,
1352, 1291, 1223, 1139, 1098, 1073, 1026, 951, 814, 775, 736, 697,
576 cmꢀ1; UV (CH3CN): lmax (lg e)=208 (4.7425), 271 nm (3.0948);
MS (ESI): m/z (%): 739.4 (100) [2M+Na]+, 717.4 (6) [2M+H]+, 381.2
(32) [M+Na]+, 359.2 (48) [M+H]+; HRMS (ESI): m/z calcd for
C21H26O5: 359.1853 [M+H]+; found: 359.1852.
Acknowledgements
This work was supported by Deutsche Forschungsgemein-
schaft (DFG), Land Niedersachsen and Volkswagenstiftung. S.J.
thanks the CaSuS Program for a PhD scholarship and J.H.
thanks the Dorothea-Schlçzer Program for a postdoctoral
scholarship.
Keywords: dihydroxylation
products · tetrahydroxanthones · total synthesis
· domino reactions · natural
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Chem. Eur. J. 2014, 20, 1 – 9
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Received: March 6, 2014
Published online on && &&, 0000
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FULL PAPER
&
Natural Products
L. F. Tietze,* S. Jackenkroll, J. Hierold,
L. Ma, B. Waldecker
&& – &&
Highly efficient domino reactions: An
enantioselective PdII-catalyzed domino-
Wacker/carbonylation/methoxylation re-
action combined with a diastereoselec-
tive dihydroxylation reaction enables
the first total syntheses of both (ꢀ)-
blennolide C and (ꢀ)-gonytolide C with
ee values of 99% (see scheme). The
preparation of an epimeric acid deriva-
tive of blennolide C and 2’-epi-gonyto-
lide C are also reported.
A Domino Approach to the
Enantioselective Total Syntheses of
Blennolide C and Gonytolide C
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
9
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ