Synthesis of 8-desmethoxy psymberin: A putative biosynthetic intermediate towards the marine polyketide psymberin

Article abstract of DOI:10.1002/chem.201203149

The synthesis of a putative biosynthetic precursor of psymberin including a formal synthesis of the natural product is described. The key step towards the densely functionalized tetrahydropyran core was an enantioselective catalytic Mukaiyama aldol reacti

Full text of DOI:10.1002/chem.201203149

DOI: 10.1002/chem.201203149
Synthesis of 8-Desmethoxy PsymACTHNUGRTENUNGberin: A Putative Biosynthetic Intermediate
Towards the Marine Polyketide PsymACTHNUTRGNEUGbN erin
Max Bielitza and Jçrg Pietruszka*[a]
Abstract: The synthesis of a putative
biosynthetic precursor of psymberin in-
lowed by ozonolysis led to a rapid as-
sembly of the tetrahydropyran ring.
This flexible approach also allows the
synthesis of similar fragments of other
complex molecules such as bryostatins
and pederins. The syn-selective cou-
pling between the tetrahydropyran and
the aromatic aldehyde was achieved
using a boron-mediated aldol reaction
which was followed by further transfor-
mations to complete the synthesis of
the precursor as well as the formal syn-
thesis of the natural product.
AHCTUNGTRENNUNG
cluding a formal synthesis of the natu-
ral product is described. The key step
towards the densely functionalized tet-
rahydropyran core was an enantioselec-
tive catalytic Mukaiyama aldol reaction
using a titanium(IV)–BINOL catalyst
system. syn-Selective reduction fol-
Keywords: biosynthesis · cytotoxin ·
formal synthesis · Mukaiyama aldol ·
natural product
Introduction
liams.[6a] Interestingly, it is believed that psym
ACHUTGTNRENNUG ACHUTTGNRENbNUGN erin (1) is not
produced by the sponges themselves, but by symbiotic bac-
PsymACHTUNGTRENNUNGberin (1) (Psammocinia, symbiont, pederin), also
teria.[7]
known as irciniastatin A (1), is a marine cytotoxin which dis-
plays high potency. It belongs to the pederins, a group of 36
natural products which may be of either terrestrial or
marine origin.[1] Since its independent isolation in 2004 from
two genera of sponges by Crews[2] (Psammocinia) and
PsymACTHNGUTERNbUNG erin analogues were prepared and tested for their
biological activities revealing new potent structures.[4e,f,8] In
particular, pedastatin (2), a hybrid which combines frag-
ments from psymACTHNUTRGNEUNGberin (1) and pederin (3), turned out to be
very potent against colon cell line HCT116. Furthermore,
molecular conformational and hydrogen-bonding models of
Pettit[3] (Ircinia ramose), the synthesis of psym
ACTHNUGRTENUNGberin (1) has
created enormous attention. There are several total synthe-
ses,[4] a formal synthesis[5] and partial syntheses[6] reported so
far. Such interest is due to the unique structural motifs for
example, the dihydroisocoumarin unit (DHIC), the N,O-
hemiaminal structure and the densely functionalized tetra-
hydropyran (THP) core, its selective antitumor activity and
its paucity in nature.
It was initially tested for 60 human cell lines and displays
excellent efficacy (LC50 <2.5ꢀ10ꢀ9 m) especially against
some melanoma, breast and colon cancer cell lines. In con-
trast, leucemia cell lines are relatively immun (LC50 >2.5ꢀ
10ꢀ5 m). The cytotoxic activity of the Psammocinia extracts
has already been known since 1990, but could not be attrib-
uted to a substance until Crews[2] suggested a structure
which possessed such a high cytotoxicity and was proven
and further characterized by De Brabander[4a] and Wil-
complexes between psymACHTUNGETRNbUNG erin-related structures [pederin
(3), mycalamide A—not shown] and ribosomes have assisted
to comprehend the functions of defined structural motifs of
the molecules.[4f]
The Piel group has shed light on most of the steps of the
biosynthesis of psymACTHNUTRGNEUNG
berin (1), but a few are still unknown.[7]
Of particular interest is the order of introduction of the hy-
droxyl group in 5- and the methoxy group in 8-position (see
structure 4, Figure 1) during the biosynthetic pathway, re-
spectively. It is assumed that 8-desmethoxy psymACTHNUTRGENUGbN erin (5) is
possibly that penultimate intermediate. Therefore, we decid-
ed to synthesize the putative biosynthetic precursor to help
evaluate these last steps. It should be noted that intermedi-
ate 5 is already a highly cytotoxic compound which is more
readily accessible and presumably more stable, albeit not as
potent as psymACTHNUTRGNEUNG
berin (1) itself.[4i] Herein, we present our dif-
ferent approaches towards the construction of the THP
core, which also allows for synthesizing similar THP units
from other natural products, for example, pederin (3) or
bryostatin 1 (6), the aromatic unit and the following reaction
sequences that enabled us to synthesize 8-desmethoxy psym-
[a] Dipl.-Chem. M. Bielitza, Prof. Dr. J. Pietruszka
Institut fꢁr Bioorganische Chemie
der Universitꢂt Dꢁsseldorf im Forschungszentrum Jꢁlich
Stetternicher Forst, 52426 Jꢁlich (Germany)
Fax : (+49)2461-616196
N
ACHTUNGTRENNbUNG erin (1),
E-mail: j.pietruszka@fz-juelich.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203149: contains experimen-
tal details for all other compounds.
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FULL PAPER
allow for a possible synthetic pathway towards the THP-
core 7. Psym
ACHTUNGTRENbNUNG eric acid (9) should be synthesized from psym-
AHCTUNGTREGbNNNU eric acid methylester (14), which had previously been syn-
thesized within our group via chemical and chemoenzymatic
transformations[6g,h] and which was readily available. Alde-
hyde 8 could be disconnected to commercially available
phloroglucinol-carboxylic acid monohydrate (15) as starting
material.
Figure 1. Structures of psym
methoxy psymberin (5), bryostatin 1 (6), and a segment 4 from the bio-
synthesis of psymberin (1).
ACHTUNGTRENbNUNG erin (1), pedastatin (2), pederin (3), 8-des-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Results and Discussion
Scheme 1. Retrosynthetic analysis.
Retrosynthetic plan: Our strategy is based on a general ap-
proach to synthesize intermediates that lead to the synthesis
of 8-desmethoxy psymACTHNUGRTENUNGberin (5) and related molecules by
Synthesis of the THP core: Our synthesis of the THP-unit
7a (Scheme 2) started off by preparing silylenol ether 16.[11]
As described before,[9] it was synthesized in four steps from
isobutyraldehyde in multigram quantities. The enoate func-
tionality displayed a masked aldehyde and was also chosen
because of polarity reasons of the desired aldol product.
Thereby, chromatographic separation from the BINOL
ligand was readily possible. For the electrophilic component
of the aldol reaction, our first choice was commercially
available ethyl glyoxalate (17). Having prepared the racemic
reference materials using LDA for enolate formation, we
implemented our initially established results.[9] The titani-
chemical transformations and also allows us to apply our
knowledge of enzymatic transformations in future. For the
construction of the THP-moiety 3 we wanted to apply our
initial results[9] with sterically demanding ketones in enantio-
selective Mukaiyama aldol reactions.[10]
Therefore, we disconnected the molecule into three units
similar to the De Brabander group:[4a] the THP-core 7, the
highly-substituted aromatic system 8 and psym
(Scheme 1). A late stage coupling of amine 10 and psym-
beric acid (9) should establish the amide group. Amine 10
ACHTUNGTRENbNUNG eric acid (9)
ACHTUNGTRENNUNG
should arise from alcohol 11 and the latter from a diastereo-
selective aldol coupling reaction between THP-unit 7 and al-
dehyde 8 followed by further transformations. As men-
tioned above an enantioselective Mukaiyama aldol reaction
should set the first stereogenic center to give b-hydroxy
ACHTUNGTRENuNGNU m(IV)–BINOL 18 system that proved to be superior to the
one using the unsubstituted BINOL 19, provided the aldol
product 12a in excellent enantioselectivity (ee 98%) and
yield (84%). The next steps should be a diastereoselective
syn-reduction.[12] But as previously shown, the linear product
20 could not be obtained in a pure fashion because of cycli-
zation to the corresponding lactone 21. Continuation on that
ꢀ
ketone 12. Therefore, we envisioned that the C C discon-
nection between C6 and C7 would lead to ketone 13 and
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J. Pietruszka and M. Bielitza
be purchased or prepared by double benzyl protection of
(Z)-but-2-ene-1,4-diol followed by dihydroxylation with sub-
sequent oxidative cleavage.[13] We made use of our initial re-
sults and directly applied the titanium(IV)–BINOL 19 cata-
lyst system to our substrates. To our delight, the simple, un-
substituted BINOL ligand 19 proved to give already satisfy-
ing results.
The aldol product 12b was always obtained with high
enantiomeric excess (ꢁ95% ee), but yields relied heavily on
the temperature. At lower temperatures (ꢀ408C, Table 1,
entry 4) the conversion was low yielding only 44%, at room
temperature (entry 1) the yield was also only 45%, because
of increased side product formation of which one turned out
to be the Evans–Tishchenko[14] product 27. Therefore, the
reaction was run at 08C as a compromise between reactivity
and selectivity to give the product in 65% yield and an ee of
ꢁ97% (entry 2). We based our assumptions that the (S)-
BINOL ligand should lead to the desired (S)-aldol product
on our results and those of Keck[15] and Mikami.[16] Unfortu-
nately, the configuration could not be assigned at that stage,
because Mosher ester preparation was obviously not possi-
ble due to the formation of elimination products.
Scheme 2. First enantioselective approach towards the THP unit.
strategy would not have led to the intended coupling part-
ner. However, the lactone is a known, potential intermedi-
ate towards psymACHTUNGTRENNUNG
berin (5).[6i]
Thus, cyclization to THP 22 was performed by
ozonolysis first (Scheme 3). After spontaneous cyc-
lization and acetylation with acetic anhydride, THP
23 could be obtained as a 5.5:1 diastereomeric mix-
ture in 81% yield over two steps. The next step
turned out to be more difficult than anticipated.
The reduction of ketones 22 and 23 (available by al-
lylation of 22) to the secondary alcohols 24 and 25
was performed with different reagents, but the use
of sodium borohydride led only to traces of the un-
desired diastereomer. The relative configuration of
23 could not be resolved until the reduction step
and this finding showed that the allylation reaction
had furnished the undesired 2,6-cis isomer. The use
Table 1. Enantioselective Mukaiyama aldol reactions.
Entry
Conditions[a]
Catalyst [20 mol%]
Yield [%][b]
ee [%][c]
1
2
3
4
RT, Et2O, 4 ꢄ MS
Ti
Ti
Ti
Ti
N
45
65
59
44
ꢁ95
ꢁ97
ꢁ97
97
08C, Et2O, 4 ꢄ MS
ꢀ158C, Et2O, 4 ꢄ MS
ꢀ408C, Et2O, 4 ꢄ MS
[a] 0.50 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC.
of L-selectride caused a considerable formation of side
products and proved to be unhelpful.
Aldol 12b was reduced under Prasad conditions[12] using
diethylmethoxyborane and sodium borohydride to yield diol
28 in high yield (90%) and diastereoselectivity (d.r. 94:6)
(Scheme 4). Its Mosher ester[17] 29 and dimethyl acetal[18] 30
were prepared proving the expected S configuration at C7
and the syn-relation of both hydroxyl groups at C5 and C7
(Scheme 4, for more details see Supporting Information).
Ozonolysis and double acetylation of diol 28 followed by
Due to the dead ends of the first two attempts we pursued
a different route. For this purpose we switched from ethyl
glyoxalate (17) to 2-(benzyloxy) acetaldehyde (26) as the
electrophile in the aldol reaction to avoid cyclization to the
corresponding five-membered ring. The latter could either
diaACHTNUTGRNEUNG
stereoselective allylation[19] using allyltrimethylsilane and
BF3·OEt2 furnished smoothly THP-core 31 in 60% yield
over three steps. NOESY correlations confirmed the relative
configuration. This unit displays a useful building block for
other members of the pederin family. Alkene 31 was trans-
formed to aldehyde 32 by dihydroxylation and oxidative
cleavage. The nucleophilic addition of diethylzinc under the
conditions reported by Kobayashi[20] afforded an alcohol
that was submitted to Dess–Martin oxidation[21] to provide
ketone 33 in 78% yield over two steps.
Scheme 3. Different synthetic attempts towards the THP unit.
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8-Desmethoxy PsymACHTUNGTRENNUNGberin
FULL PAPER
Scheme 5. Construction of the aromatic unit.
throughout the sequence, then to cleave them all at once at
the end. First, we converted resorcin 39 into its bisacetate 40
followed by ozonolysis to obtain aldehyde 41 in 71% yield
over two steps.
Fragment coupling: Then we focused on the boron mediated
aldol reaction (Scheme 6).[26] In analogy to the De Braband-
er protocol,[4a] boron enolate derived from ketone 33 and di-
chlorophenyl borane reacted with aldehyde 41 at ꢀ788C to
give aldol 42 with good selectivity albeit modest conversion.
Furthermore, separation of the two diastereomers and by-
products was not possible by column chromatography. We
thought that switching to a more stable protective group
(acetate to benzoate, 39!43, 44) could solve the problem of
the low conversion. Unfortunately, that was not the case and
separation of the diastereomers of 45 could still not be
achieved. We revised the protective group strategy and
chose the TBS group for the protection of both phenolic hy-
droxy groups. Reaction of resorcin 39 with TBSOTf/2,6-luti-
dine provided the fully protected aromatic compound 46 in
80% yield which was subjected to ozonolysis as realized
before. But it turned out that oxidative double bond cleav-
age caused the considerable formation of by-products and
therefore could not be used. Presumably, TBS protection in-
creased the electron density in such a way that the aromatic
system could be oxidized. Instead we performed an oxida-
tive cleavage to generate the aldehyde which was done by
one-pot dihydroxylation with potassium osmate and diol
cleavage with sodium periodate[27] to obtain aldehyde 47 in
Scheme 4. Synthesis of THP-core 33 from aldol 12b.
Synthesis of the DHIC unit: The synthesis of aryl fragment
8 began with phloroglucinol carboxylic acid monohydrate
(15) as an inexpensive starting material (Scheme 5). Per-
ACHTUNGTRENNUNGmethACHTUNGTRENNUNGylACHTUNGTRENNUNGation and regioselective deprotection of one methoxy
group furnished phenol 34 in 83% yield over two steps.[22] It
was formylated under Vilsmeier–Haack conditions[23] and re-
duced with hydrogen and Pd/C to install the methyl group
in 3-position.[24]
In the following reaction sequence a protocol from Huang
et al.[4b] was applied: formation of triflate 35 provided us
with a suitable substrate for cross-coupling reactions. Under
Stille conditions allyl product 36 was available in 84% yield.
A Suzuki reaction using [PdACHTUNGTRENUNG(dppf)Cl2]CH2Cl2 as catalyst and
allylboronic acid pinacol ester led to similar results (80%
yield), but the reaction time could be decreased to 8 h.[25]
The deprotection of the two methoxy groups of 36 proved
to be difficult due to side product formation (37 and 38,
Scheme 5) and phenol 39 could only be obtained in satisfy-
ing yield of 58% after work-up optimisation.
Next, we had to decide upon the protecting group strat-
egy. Our plan was to keep one kind of protecting group
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J. Pietruszka and M. Bielitza
diol 49 in good yield (84%) and high diastereoselectivity
(d.r.>15:1). Its all-syn configuration was proven by Rych-
novskyꢅs acetonide method (conversion to its dimethyl
acetal 49a; see Supporting Information for detailed NMR
data). The DHIC moiety was installed in the next step by
cyclization under acidic conditions with camphor sulfonic
acid (CSA) (99%) giving an alcohol (!50a) which was
TBS protected (TBSOTf, 2,6-lutidine) in 89% yield
A
Formal synthesis: To assure the configurational assignments
proposed before and to complete the formal synthesis of
psymACTHNUGTRENUNGberin (1) we could also synthesize the N7–C27 fragment
51 (Scheme 8). For the conversion of the alcohol functionali-
Scheme 6. Syntheses of different aromatic aldehydes and their coupling
reactions to THP 33.
80% yield. Then we turned our attention to the coupling re-
action according to our previous attempts. This time aldol
48 was obtained in good yield (63%) and good stereoselec-
tivity (d.r. >12:1). Furthermore, the diastereomers could be
separated by column chromatography.
Scheme 8. Completion of the formal synthesis. tris(dimethylamino)sulfo-
nium difluorotrimethylsilylsilicate (TASF).
The following steps were performed as planned at the be-
ginning (Scheme 7). The syn-reduction with sodium borohy-
dride in the presence of diethylmethoxyborane furnished
ty to the corresponding primary amide, benzyl ether 50b
had to be deprotected using Pearlmanꢅs catalyst.[28] This
transformation was performed in 99% yield. Alcohol 52 was
oxidized in a two-step sequence using Dess–Martin and Pin-
nick[29] conditions. Amide formation proved to be difficult
due to the lability of the phenolic TBS groups towards any
nucleophiles. The reaction of the acid with ammonium
acetate under peptide coupling conditions[30] [O-(Benzotri-
azol-1-yl)-N,N,N,N-tetramethyluronium
tetrafluoroborate
(TBTU), Huenigꢅs base] followed by treatment with
TBSOTf afforded the desired fragment 53 in 47% yield
over three steps. To complete the formal synthesis the pro-
tective groups were switched from TBS to acetate to give
peracetylated amide 51 in 86% over two steps. The analyti-
cal data were all in full agreement with those reported pre-
viously.[4a,5]
Final steps towards the title compound: With alcohol 52 in
Scheme 7. Fragment coupling and the synthesis of DHIC 50b.
hand and the configuration unambiguously confirmed, a
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8-Desmethoxy PsymACHTUNGTRENNUNGberin
FULL PAPER
one-step conversion to azide 54 was initially intended em-
ploying Mitsunobu conditions[31] [diethyl azadicarboxylate
(DEAD), PPh3, diphenylphosphoryl azide (DPPA)], but no
conversion was observed. The use of DPPA and 1,8-
diazabicycloACHTUNGTRENNUNG
[5.4.0]undec-7-ene (DBU)[32] was also not suc-
cessful. Thus, we turned to a two-step procedure, first gener-
ating a good leaving group followed by a subsequent dis-
placement by a nucleophile (Scheme 9). The conversion of
Scheme 11. Amide formation between 60 and 57 followed by global de-
protection yielded 8-desmethoxy psymACTHNURGTNEbUNG erin (5).
(TASF)[36] followed by acetate hydrolysis to yield 8-des-
methoxy psym
berin (5)[4f] in 35% over four steps.
A
R
ACHTUNGTRENNUNG
Conclusion
Scheme 9. Synthesis of azide 54 starting from alcohol 52.
In summary, 8-desmethoxy psym
thetic precursor of psymberin (1), could be successfully syn-
thesized in 25 steps (longest linear sequence) and was sub-
mitted for further testing. 8-Desmethoxy psymberin (5)
might cast light on the final steps of the biosynthesis of
psymberin (1). Additionally, our strategy enabled us to
verify all stereochemical assignments by completing
formal synthesis of the natural product in 24 steps. The frag-
ments 31 and 47 were accessible from simple starting mate-
rials. The application of a highly enantioselective aldol reac-
tion paved the way for a rapid assembly of the highly func-
tionalized THP-core 33. Our flexible reaction sequence also
displays a possible approach to similar tetrahydropyran
units of other natural products such as pederin. The synthe-
sis of aldehyde 47 describes a further development towards
this coupling unit. The work being presented lays the foun-
dation for the synthesis of related molecules and will be
considered for further developments.
ACHTUNGTNERbNUNG erin (5), a putative biosyn-
AHCTUNGTRENNUNG
alcohol 52 to the corresponding triflate worked, but the
product hydrolyzed during work-up. Next, we tried to intro-
duce a mesylate under standard conditions. Having success-
fully obtained 55 in 94% yield (with minor impurities of
mesyl chloride), two different azide reagents were tested.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
a
[33]
The use of NaN3 only caused deprotection of TBS groups
[34]
while (Bu4N)N3 provided the azide along with cleavage of
both TBS groups on the aromatic system (!56). Deprotec-
tion could not be avoided, but the protective groups could
be reintroduced under standard conditions yielding azide 54
in 37% yield over two steps.
The synthesis was continued generating the acid chloride
of psymACHTUNGTRENNUNGberic acid 57 in three steps from psymACHUTNGTRENNbGUN eric acid
methyl ester[6h] (14) (Scheme 10). TBS protection (!58, hy-
drolysis with aqueous LiOH (!59) and the use of Ghosezꢅs
reagent[35] furnished acid chloride 57 in 52% yield (over
3 steps). Simultaneouly, azide 54 was hydrogenated to amine
60 and coupled to acid chloride 57 (Scheme 11). The slightly
impure coupling product 61 was directly deprotected in a
two-step sequence. All TBS groups were cleaved using tris-
Experimental Section
A
difluorotrimethylsilylsilicate
Chemicals being used were purchased from the companies Sigma–Al-
drich/Fluka, TCI International, Alpha Aesar and VWR International/
Merck. Pure solvents were either purchased or distilled prior to use. Ab-
solute solvents were either taken from
a drying machine (MBraun
(model MB SPS-800) (THF, Et2O, CH2Cl2, toluene), distilled using
common methods (MeOH, NEt3, DIPEA) (according to W. L. F. Armar-
ego, C. L. L. Chai, Purification of Laboratory Chemicals, Vol. 5, Butter-
worth-Heinemann, Burlington, 2003) or purchased (DMF, pyridine, 2,6-
lutidine). Evaporation of solvents was performed on Buechi rotary evap-
orators (heating bath temperature: 30–408C) and on high vacuum pumps.
Usually, reactions were conducted under N2-atmosphere in Schlenk flasks
or tubes, which were previously heated at 1208C overnight. NMR spectra
were recorded on a Bruker–Avance/Drx 600 instrument (1H at 600 MHz;
13C at 151 MHz). Chemical shifts (d) are reported relative to chloroform
(1H: 7.26 ppm; 13C: 77.00 ppm) or acetonitrile (1H: 1.94 ppm; 13C:
Scheme 10. Preparation of psymACTHUNTGRNEUNGberic acid chloride 57.
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8305

J. Pietruszka and M. Bielitza
118.69 ppm). The multiplicities are reported with the following abbrevia-
tions: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, mc =
centered multiplet, brs=broad singlet). Higher order chemical shifts and
J values are not corrected. Where it was necessary DEPT 135, COSY,
HSQC, HMBC and NOESY spectra were recorded for structure elucida-
tion. Structures 30, 49a, 50a, 50b, 51–56, 61 and 5 were not numbered ac-
cording to IUPAC. Instead, the DHIC-unit was given highest priority due
to ease of comparison of NMR data. Diasteromeric ratios were deter-
2’’), 78.8 (C-3), 110.6 (arom. C), 110.7 (C-7), 118.7, 141.2, 156.9, 158.3
(arom. C), 163.5 (C-1), 170.3 ppm (OC(O)CH3); IR (film) n˜ =2955, 2930,
2858, 2098, 1726, 1593, 1569, 1472, 1413, 1351, 1247, 1200, 1167, 1069,
1033, 1006, 938, 837, 808, 779, 674 cmꢀ1; HRMS (ESI+): m/z calcd for
C42H75N3O8Si3: 834.4935; found: 834.4938 [M+H+].
AHCTUNGTERG(NNUN 2S,3S)-2-(Tert-butyldimethylsilyloxy)-3-methoxy-5-methylhex-5-enoyl
chloride (57): 1-Chloro-N,N-2-trimethyl-1-propenylamine (411) (9 mL,
69 mmol) was added to a stirred solution of acid 59 (9.8 mg, 34 mmol) in
CH2Cl2 (0.25 mL) at 08C. The reaction mixture was stirred for 10 min
and then warmed to room temperature: After 3 h the solvent was evapo-
rated and the residue dried under high vacuum. 1H NMR (600 MHz,
1
mined by H NMR or HPLC. Infrared spectra were recorded using a Per-
kinElmer SpectrumOne IR-spectrometer. Silica gel 60m (0.040–
0.063 mm, 230–400 mesh) from Macherey–Nagel was used for flash-
column chromatography. Eluents are stated for each substance in the ex-
perimental section. Thin layer chromatography (TLC) was conducted on
POLYGRAM SIL G/UV254 plates with fluorescence indicator. Detec-
tion was either by UV absorption or treatment with ceric ammonium mo-
lybdate solution followed by heating. HPLC measurements were per-
formed on a chiral stationary phase using a Dionex machine with analyti-
cal column (Chiralpak IC) from Daicel. Substances were detected by UV
at wavelengths of 205, 225 and 254 nm, respectively. Optical rotations
were determined using a PerkinElmer (type 341) polarimeter. Mass spec-
tra were either measured using GC-MS (instrument: Thermo Elektron
MAT 95, ionization by EI (70 eV), column: HP-5 ms (30 mꢀ250 mmꢀ
0.25 mm) from Agilent) or MS (instrument: Finnigan MAT LC-Q, ioniza-
tion by ESI). High-resolution mass (HRMS) spectra were measured by
the Biospec group of the Research Center Juelich. Measurements were
recorded on a LTQ-FT Ultra machine from Thermo Fisher. Samples
were dissolved in MeOH and ionized by ESI. Melting points were deter-
mined using a Buechi instrument (type: melting point B-540). Elemental
analyses were either measured at the central analytical department
(ZCH) of the Research Center Juelich or at the institute for Organic
Chemistry of the University of Stuttgart.
CDCl3): d=0.10 (s, 3H, Si-CH3), 0.11 (s, 3H, Si-CH3), 0.93 (s, 9H, Si-C-
3
N
4-Ha), 2.31 (dd, 2J4b,4a =14.7 Hz, 3J4b,3 =8.0 Hz,1H, 4-Hb), 3.42 (s, 3H, 3-
OCH3), 3.74 (ddd, 3J3,4b =8.1 Hz, 3J3,4a =4.5 Hz, 3J3,2 =4.2 Hz, 1H, 3-H),
4.47 (d, 3J2,3 =4.1 Hz, 1H, 2-H), 4.81–4.83 (m, 1H, 6-Ha), 4.84–4.86 ppm
(m, 1H, 6-Hb); 13C NMR (151 MHz, CDCl3): d=ꢀ5.2 (Si-CH3), ꢀ5.1 (Si-
CH3), 18.1 (Si-CACHTUNGTRENN(GU CH3)3), 22.8 (5-CH3), 25.5 (Si-CCAHTUNGTRNE(NUGN CH3)3), 38.4 (C-4), 58.4
(3-OCH3), 73.6 (C-3), 81.4 (C-2), 113.6 (C-6), 141.6 (C-5), 175.2 ppm (C-
1).
AHCTUNGTERG(NNUN 2R,4R,6S)-2-((2S,3S)-3-((R)-6,8-Bis(tert-butyldimethylsilyloxy)-5-
methyl-1-oxoiso-chroman-3-yl)-2-(tert-butyldimethylsilyloxy)butyl)-6-
(((2S,3S)-2-(tert-butyl-dimethylsilyloxy)-3-methoxy-5-methylhex-5-enami-
do)methyl)-3,3-dimethyltetra-hydro-2H-pyran-4-yl acetate (61): Pd(OH)2
(0.7 mg) was added to a stirred solution of azide 48 (2.5 mg, 3.0 mmol) in
THF (0.50 mL) and the suspension was hydrogenated for 4 h. It was fil-
tered over celite and the solvent was removed in vacuo. Meanwhile, acid
chloride 57 was prepared from its acid 59 (4.00 mg, 14 mmol). Acid chlor-
ide 57 was placed in a flask, diluted with CH2Cl2 (0.30 mL) and charged
with Huenigꢅs base (6.00 mL). The resulting solution was cooled to 08C
and the a solution of the crude amine in CH2Cl2 (0.20 mL) was added
dropwise. The reaction mixture was stirred for 2 h and then warmed to
room temperature and stirred for 1 h. It was diluted with CH2Cl2 and
quenched by the addition of aqueous NaHCO3. The layers were separat-
ed and the aqueous layer was extracted with CH2Cl2 (3ꢀ). The combined
organic layer was washed with saturated aqueous NaHCO3 (1ꢀ), brine
(1ꢀ) and dried over MgSO4. The solvents were evaporated and the prod-
uct was obtained as a colorless solid (1.1 mg) after column chromatogra-
phy (petrol ether/ethyl acetate 80:20) with impurities. Rf (petroleum
Details for all other compounds can be found in the Supporting Informa-
tion.
ACHTUNGTRENNUNG(2R,4R,6S)-6-(Azidomethyl)-2-((2S,3S)-3-((R)-6,8-bis(tert-butyldimethyl-
silyloxy)-5-methyl-1-oxoisochroman-3-yl)-2-(tert-butyldimethylsilyloxy)-
butyl)-3,3-dimethyl-tetrahydro-2H-pyran-4-yl acetate (54): Azide 56
(10.0 mg, 16.5 mmol) was dissolved in CH2Cl2 (1.00 mL). The solution was
cooled to ꢀ158C and was then treated with 2,6-lutidine (19.0 mL,
165 mmol) and TBSOTf (19.0 mL, 82.5 mmol) and warmed to room tem-
perature overnight. Further 2,6-lutidine (25.0 mL, 215 mmol) and TBSOTf
(25.0 mL, 87.0 mmol)were added to complete conversion. After 3 h the re-
action mixture was quenched by adding saturated aqueous NaHCO3. The
layers were separated and the aqueous layer was extracted with CH2Cl2
(3ꢀ). The organic layers were combined and washed with brine. The
crude product was purified by column chromatography (petrol ether/
ethyl acetate 80:20) to yield azide 54 (10.0 mg, 12.0 mmol, 73%). Rf (pe-
troleum ether/ethyl acetate 70:60)=0.78; [a]2D0 = +45.5 cm3 gꢀ1 dmꢀ1 (c=
1.0, CHCl3); 1H NMR (600 MHz, CDCl3): d=0.03 (s, 3H, Si-CH3), 0.11
(s, 3H, Si-CH3), 0.22 (s, 3H, Si-CH3), 0.24 (s, 3H, Si-CH3), 0.24 (s, 3H,
1
ether/ethyl acetate 70:60)=0.76; H NMR (600 MHz, CDCl3): d=0.02 (s,
3H, Si-CH3), 0.07 (s, 3H, Si-CH3), 0.09 (s, 3H, Si-CH3), 0.13 (s, 3H, Si-
CH3), 0.22 (s, 3H, Si-CH3), 0.23 (s, 3H, Si-CH3), 0.24 (s, 6H, Si-CH3),
0.89 (s, 9H, Si-C
ACHTUGTNRENGUN(CH3)3), 0.92 (s, 9H, Si-CACTHUNGTRENNUNG
G
CH3b), 1.10 (d, 3J16-CH3,16 =6.8 Hz, 3H, 16-CH3), 1.70 (s, 3H, 2-CH3), 1.71
(m, 2H), 1.82 (m, 1H), 1.98 (m, 1H), 2.07 (m, 1H), 2.07 (s, 3H,
OCOCH3), 2.08 (s, 3H, 20-CH3), 2.25 (dd, JH,H =14.4 Hz, JH,H =8.3 Hz,
1H), 2.63 (dd, 2JH,H =16.4 Hz, 3JH,H =12.3 Hz, 1H, 18-Ha), 3.03 (dd,
3
2JH,H =16.2 Hz, JH,H =2.2 Hz, 1H, 18-Hb), 3.10 (ddd, JH,H =14.6 Hz, JH,H
=
Si-CH3), 0.24 (s, 3H, Si-CH3), 0.83 (s, 9H, Si-C
ACHTUNGTRENNUNG
7.2 Hz, JH,H =4.9 Hz, 1H), 3.20 (ddd, JH,H =13.3 Hz, JH,H =6.8 Hz, 5.1 Hz,
1H), 3.37 (s, 3H, 4-OCH3), 3.45 (dd, JH,H =11.5 Hz, JH,H =2.4 Hz, 1H),
CH3a), 1.01 (s, 9H, Si-C(CH3)3), 1.02 (s, 9H, Si-CCAHTUNGTRENNUNG
G
CH3b), 1.10 (d, 3J1’,2’ =6.7 Hz, 3H, 1’-H), 1.69 (ddd, 2J5’’ax,5’’eq =13.9 Hz,
3J5’’ax,4’’ =6.7 Hz, 3J5’’ax,6’’ =4.4 Hz, 1H, 5’’-Hax), 1.73 (ddd, 2J4’a,4’b =14.6 Hz,
3J4’a,3’ =9.8 Hz, 3J4’a,2’’ =2.0 Hz, 1H, 4’-Ha), 1.80 (ddd, 2J5’’eq,5’’ax =13.9 Hz,
3J5’’eq,6’’ =7.5 Hz, 3J5’’eq,4’’ =3.9 Hz, 1H, 5’’-Heq), 1.98–2.04 (m, 1H, 2’-H),
3
3
3.61–3.69 (m, 4H), 3.89 (m, 1H), 4.23 (ddd, JH,H =10.3 Hz, JH,H =7.6 Hz,
3JH,H =2.2 Hz, 1H, 15-H), 4.37 (d, J5,4 =1.9 Hz, 1H, 5-H), 4.72 (m, 1H, 1-
3
Ha), 4.75 (m, 1H, 1-Hb), 4.86 (dd, 3J11,10ax =5.8 Hz, 3J11,10eq =3.7 Hz, 1H,
11-H), 6.31 ppm (s, 1H, 22-H); 13C NMR (151 MHz, CDCl3): d=ꢀ5.4,
ꢀ4.8, ꢀ4.5, ꢀ4.4, ꢀ4.4, ꢀ4.3, ꢀ4.2, ꢀ3.6, 8.9, 11.8, 14.1, 18.0, 18.2, 18.3,
18.6, 21.2, 22.6, 22.7, 25.7, 25.8, 25.9, 25.9, 25.9, 27.1, 28.6, 31.9, 34.8, 37.4,
40.2, 45.8, 57.8, 64.9, 69.2, 74.2, 74.3, 78.1, 78.7, 110.6, 110.7, 112.5, 141.0,
142.4, 150.0, 150.5, 156.9, 158.4, 171.8, 171.9 ppm; IR (film) n˜ =2952,
2827, 2856, 1735, 1679, 1593, 1570, 1472, 1350, 1360, 1249, 1168, 1067,
2.07 (s, 3H, OCOCH3), 2.08 (s, 3H, 5-CH3), 2.07–2.15 (m, 1H, 4’-Hb),
2
2.68 (dd, 2J4a,4b =16.3 Hz, 3J4a,3 =12.0 Hz, 1H, 4-Ha), 3.05 (dd, J4b,4a
=
3
16.3 Hz, 3J4b,3 =2.4 Hz, 1H, 4-Hb), 3.28 (dd, 2J1’’’a,1’’’b =12.9 Hz, J1’’’a,6
=
3.9 Hz, 1H, 1’’’-Ha), 3.41 (dd, 2J1’’’b,1’’’a =12.9 Hz, 3J1’’’b,6 =8.6 Hz, 1H, 1’’’-
Hb), 3.43 (dd, 3J2’’,4’b =12.9 Hz, 3J2’’,4’a =1.8 Hz, 1H, 2’’-H), 3.97–4.03 (mc,
1H, 6’’-H), 4.19 (ddd, 3J3’,4’a =9.7 Hz, 3JH,H =3.8 Hz, 3JH,H =3.2 Hz, 1H, 3’-
H), 4.25 (ddd, 3J3,4a =11.9 Hz, 3J3,2’ =7.9 Hz, 3J3,4b =2.4 Hz, 1H, 3-H), 4.79
(dd, 3J4’’,5’’ax =6.7 Hz, 3J4’’,5’’eq =3.9 Hz, 1H, 4-H), 6.31 ppm (s, 1H, 7-H);
13C NMR (151 MHz, CDCl3): d=ꢀ4.9 (Si-CH3), ꢀ4.4 (Si-CH3), ꢀ4.4 (Si-
CH3), ꢀ4.3 (Si-CH3), ꢀ4.2 (Si-CH3), ꢀ3.5 (Si-CH3), 8.7 (C-1’), 11.6 (5-
862, 839, 780 cmꢀ1
1078.6681; found: 1078.6676 [M+H+].
8-Desmethoxy psymberin (5): Amide 61 (1.1 mg) was dissolved in DMF
; HRMS (ESI+): m/z calcd for C56H103NO11Si4:
AHCTUNGTRENNUNG
(0.10 mL) and placed in a 2 mL Eppendorf vial. The solution was charged
with TASF (5.2 mg, 19 mmol) at room temperature and placed in an oil
bath at 508C. The reaction mixture was stirred overnight, quenched with
aqueous NH4Cl and stirred for 5 min. It was diluted with ethyl acetate
and H2O. The layers were separated and the aqueous layer was extracted
CH3), 14.1 (3’’-CH3a), 18.0 (Si-C
(CH3)3), 21.2 (OC(O)CH3), 25.2 (3’’-CH3b), 25.7 (Si-C
(CH3)3), 26.0 (Si-C(CH3)3), 29.1 (C-5’’), 29.8 (C-4), 32.5 (C-4’), 36.5 (C-
3’’), 39.9 (C-2’), 53.6 (C-1’’’), 66.9 (C-6’’), 68.9 (C-3’), 74.2 (C-4’’), 75.7 (C-
ACHTUGTNRNENUG(CH3)3), 18.3 (Si-CACTHUNGTRENNNUG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
8306
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 8300 – 8308

8-Desmethoxy PsymACHTUNGTRENNUNGberin
FULL PAPER
with ethyl acetate (5ꢀ). The combined organic layer was washed with
brine (1ꢀ) and dried over MgSO4. Column chromatography (petrol
ether/ethyl acetate 30:70 ! CH2Cl2/MeOH 95:5) yielded the desilylated
amide (0.7 mg), which was taken up in THF (0.20 mL) and treated with
aqueous LiOH (1.50 mL, 0.5m) at 08C. After 10 min the solution was al-
lowed to warm to room temperature overnight. It was quenched by the
addition of saturated aqueous NH4Cl and then diluted with ethyl acetate
and H2O. The layers were separated. The aqueous layer was extracted
with ethyl acetate (3ꢀ). The organic layers were combined and dried
over MgSO4. The crude was purified by column chromatography (n-pen-
tane/ethyl acetate 10:90 ! 0:100) to yield amide 5 (0.6 mg, 1.04 mmol,
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35% over 4 steps) as a colourless solid. Rf (ethyl acetate)=0.08; [a]D20
=
+50.0 cm3 gꢀ1 dmꢀ1 (c=0.06, MeOH) (lit. [4f]: [a]2D0 = +34.8 (c=0.27,
1
MeOH); H NMR (600 MHz, CH3OD): d=0.89 (s, 3H, 12-CH3a), 0.97 (s,
3H, 12-CH3b), 1.11 (d, 3J16-CH3,16 =7.0 Hz, 1H, 16-CH3), 1.57–1.63 (m,
1H), 1.71 (s, 3H, 2-CH3), 1.68–1.74 (m, 2H), 1.84 (ddd, JH,H =18.1, 11.5,
6.7 Hz, 1H), 1.91–1.96 (m, 1H), 2.01–2.06 (m, 1H), 2.10 (s, 3H, 20-CH3),
2.26 (dd, JH,H =14.4, 9.2 Hz, 1H), 2.90 (dd, JH,H =16.4, 12.0 Hz, 1H), 3.12
(dd, JH,H =13.9, 4.7 Hz, 1H), 3.14 (dd, JH,H =15.4, 2.9 Hz, 1H), 3.24 (s,
3H, 4-OCH3), 3.55 (dd, JH,H =9.7, 2.4 Hz, 1H), 3.58 (dd, JH,H =11.2,
4.7 Hz, 1H), 3.66 (ddd, JH,H =9.4, 3.2 Hz, JH,H =3.2 Hz, 1H), 3.85 (dd,
J
H,H =13.9, 9.9 Hz, 1H), 4.00–4.04 (m, 1H), 4.07–4.13 (m, 1H), 4.30 (d,
3J5,4 =2.9 Hz, 1H, 5-H), 4.50 (ddd, JH,H =12.1, 5.9, 3.0 Hz, 1H), 4.69–4.71
(m, 1H, 1-Ha), 4.72–4.75 (m, 1H, 1-Hb), 6.25 ppm (s, 1H, 22-H);
13C NMR (151 MHz, CD3OD): d=8.9, 10.5, 13.1, 22.7, 23.5, 29.3, 30.9,
33.2, 38.3, 40.4, 40.4, 42.8, 57.1, 71.4, 72.1, 72.4, 72.6, 78.2, 82.2, 101.4,
112.8, 115.7, 141.3, 143.9, 164.4, 164.8, 172.8, 175.1 ppm; IR (film): n˜ =
3357, 2922, 1659, 1631, 1467, 1262, 1100 cmꢀ1; HRMS (ESI+): m/z calcd
for C30H45NO10: calcd 580.3116; found: 580.3114 [M+H+].
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Acknowledgements
We gratefully acknowledge the Fonds der Chemischen Industrie (scholar-
ship to M.B.), the Deutsche Forschungsgemeinschaft, the Ministry of In-
novation, Science, and Research of the German federal state of North
Rhine-Westphalia, the Heinrich-Heine-Universitꢂt Dꢁsseldorf and the
Forschungszentrum Jꢁlich GmbH for their generous support of our proj-
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Received: September 5, 2012
Published online: April 19, 2013
8308
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