A highly stereoselective and flexible strategy for the convergent synthesis of long-chain polydeoxypropionates: Application towards the synthesis of the glycolipid membrane components hydroxyphthioceranic and phthioceranic acid

Article abstract of DOI:10.1002/chem.201404034

A highly stereocontrolled and flexible access to biologically relevant polydeoxypropionates in optically pure form has been developed. Taking advantage of our previously established strategy for the asymmetric and stereo-divergent synthesis of trideoxypropionate building blocks, we have now been able to assemble large polydeoxypropio-nate chains with defined configuration in a highly convergent manner. Central steps of this approach include two Suzuki-Miyaura cross-coupling reactions with subsequent highly diastereoselective hydrogenations to join three advanced synthetic intermediates in excellent yield and with full stereochemical control. We have applied this strategy successfully towards the asymmetric synthesis of glycolipid membrane components phthioceranic acid and hydroxyphthioceranic acid, the latter of which was synthesized on a half-gram scale.

Full text of DOI:10.1002/chem.201404034

DOI: 10.1002/chem.201404034
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&
Natural Product Synthesis |Hot Paper|
A Highly Stereoselective and Flexible Strategy for the Convergent
Synthesis of Long-Chain Polydeoxypropionates: Application
towards the Synthesis of the Glycolipid Membrane Components
Hydroxyphthioceranic and Phthioceranic Acid
Matthias C. Pischl,[a] Christian F. Weise,[a] Stefan Haseloff,[a] Marc-Andrꢀ Mꢁller,[b]
Andreas Pfaltz,[b] and Christoph Schneider*[a]
Abstract: A highly stereocontrolled and flexible access to
biologically relevant polydeoxypropionates in optically pure
form has been developed. Taking advantage of our pre-
viously established strategy for the asymmetric and stereo-
divergent synthesis of trideoxypropionate building blocks,
we have now been able to assemble large polydeoxypropio-
nate chains with defined configuration in a highly conver-
gent manner. Central steps of this approach include two
Suzuki–Miyaura cross-coupling reactions with subsequent
highly diastereoselective hydrogenations to join three ad-
vanced synthetic intermediates in excellent yield and with
full stereochemical control. We have applied this strategy
successfully towards the asymmetric synthesis of glycolipid
membrane components phthioceranic acid and hydroxy-
phthioceranic acid, the latter of which was synthesized on
a half-gram scale.
lide,[8] as well as the long-chain aliphatic hydroxyphthioceranic
acid (Scheme 1).[9]
Introduction
Within the large natural product class known as polyketides,
the branched deoxypropionate subunit is a common structural
motif in various members produced by animals, plants, bacte-
ria, and fungi.[1] They are characterized by an alkyl chain substi-
tuted with methyl groups at every second carbon atom, differ-
ing from the related polypropionates by the lack of hydroxyl
groups at the other carbon atoms. The general biosynthetic
pathway to their assembly is characterized by type I fatty acid
synthases (FSS) of multi-cellular animals,[2] which are closely re-
lated to the modular type I polyketide synthases (PKS) located
in plants, fungi, and bacteria.[3] Therefore, the construction of
polyketides and fatty acids includes the same biosynthetic
transformations, differing in an additional dehydration/reduc-
tion sequence for the fatty acid motif to deoxygenate the ini-
tially formed propionate structure. The biological activities of
polydeoxypropionates are diverse and representative examples
of this product class include the pectinatone,[4] the phero-
mones vittatalactone[5] and 4,6,8,10,16,18-hexamethyldoco-
sane,[6] the cytotoxic natural products borrelidine[7] and dolicu-
In light of the multitude of biological activities associated
with deoxypropionates, substantial research efforts have been
undertaken to develop synthetic tools for their stereoselective
assembly. Almost all known asymmetric syntheses towards de-
oxypropionates are inspired by the principle of “biosynthesis”,
that is, building up the complete carbon chain with each itera-
tive chain elongation. Until today numerous efficient synthetic
strategies have been developed for their highly stereoselective
formation.[10] The most common method is the 1,4-conjugate
addition of a methyl nucleophile toward a reactive a,b-unsatu-
rated acid derivative. The configuration of this carbon–carbon
bond-forming event is controlled either by a chiral metal
catalyst (e.g., the Minnaard/Feringa approach),[11] through the
chirality of the substrate (e.g., the Hanessian and Breit ap-
proaches),[12] or by a covalently attached chiral auxiliary (e.g.,
the Oppolzer and Williams approaches).[13] The application of
chiral auxiliaries is also often employed in asymmetric (aza)-
enolate alkylation reactions as demonstrated by Enders, Evans,
Masamune, and Myers.[14] A zinc-catalyzed, stereospecific cross-
coupling reaction of lactate-derived triflates with Grignard re-
agents has been developed by Breit et al.[15] Another method
for the stereoselective synthesis of deoxypropionate subunits
employs allylic alkylation reactions of alkyl halides (the groups
of Breit and Spino).[16] A hydrogenation-based approach was
established by Burgess and Zhou on the basis of chiral IrꢀC,N-
catalyst, which converted prochiral, trisubstituted olefins into
methyl-branched alkyl chains with high levels of stereo-
control.[17] Negishi et al. developed the zirconium-catalyzed
asymmetric carboalumination (ZACA) reaction of styrene and
[a] Dr. M. C. Pischl, Dr. C. F. Weise, S. Haseloff, Prof. Dr. C. Schneider
Institute of Organic Chemistry, University of Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
Fax: (+49)341-9736599
E-mail: schneider@chemie.uni-leipzig.de
[b] Dr. M.-A. Mꢀller, Prof. Dr. A. Pfaltz
Institute of Organic Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404034.
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egy for the non-iterative synthe-
sis of trideoxypropionate build-
ing blocks in an optically pure
form. Starting from readily avail-
able chiral aldol products, the
trideoxypropionates were ob-
tained in good overall yields and
with excellent stereocontrol by
using only three synthetic steps:
A thermal oxy-Cope rearrange-
ment, an iridium-catalyzed hy-
drogenation, and an enolate
methylation.[21] Depending upon
the substrates and catalysts em-
ployed in this Scheme, all four
Scheme 1. Representative examples of deoxypropionate-containing natural products.
stereochemical
permutations
were easily accessible (syn/syn,
used it iteratively to access polydeoxypropionates.[18] Finally,
Ghosh took advantage of a cyclopropanation–fragmentation
protocol to access polydeoxypropionate motifs.[19]
syn/anti, anti/syn, and anti/anti). In addition, their differently
functionalized termini allow for flexible and selective modifica-
tions as we were able to demonstrate in the course of synthe-
ses of the pheromones (+)-vittatalactone and (+)-norvittatalac-
tone isolated from the striped cucumber beetle Acalymma vit-
tatatum.[21]
As a general characteristic feature, all these methods follow
a linear-iterative strategy: The new deoxypropionate subunits
are added to the growing alkyl chain one after another. How-
ever, for the conversion of the product of the previous cycle
into the substrate for the next cycle, additional transformations
have to be performed. This typically lowers the overall yield
and efficiency of the processes. The only exception in this re-
spect is a report by Micalizio et al. in 2012, who successfully
completed the asymmetric synthesis of smaller deoxy-
Inspection of the configuration within polydeoxypropionate-
based natural products reveals that the majority among them
carries an all-syn configuration along the carbon chain with all
of the branching methyl groups pointing in the same direc-
tion. This observation suggests that the syn,syn-configured ste-
reoisomer 5 constitutes the most versatile intermediate for
natural product synthesis and for a synthesis of the glycolipid
components hydroxyphthioceranic acid (9) and phthioceranic
acid (10) in particular. Thus, our first attention was devoted to
the large-scale synthesis of 5 (Scheme 2). The oxy-Cope rear-
rangement of benzoylated aldol product 1 was easily scaled
up even to 37 grams of substrate without any problems, which
gave the isolated product in 87% yield and as a single diaste-
reomer (vs. 95% in small-scale reactions). However, the hydro-
genation conditions had to be slightly adjusted: By using only
1.6–1.8 mol% of our previously optimized chiral iridium-Mes-
PHOX catalyst 4 and 85 bar hydrogen pressure in a 500 mL
autoclave with a special glass inlet, we were able to run the
hydrogenation on large scale. Thus, upon ensuing enolate
propionates through
a convergent alkyne/allylic alcohol
cross-coupling reaction with subsequent substrate-controlled
asymmetric hydrogenation.[5g] By using this methodology, the
pheromone (ꢀ)-vittatalactone produced by the striped
cucumber beetle was obtained in only five additional steps.
Recently, we reported the first highly convergent total
synthesis of the glycolipid components phthioceranic acid and
hydroxyphthioceranic acid.[20a,b] Subsequently, Aggarwal’s
group developed another convergent enantioselective synthe-
sis using a traceless lithiation–borylation–protodeboronation
strategy.[20c] Central to the success of our approach was the de-
velopment of a sequential and highly stereoselective Suzuki–
Miyaura cross-coupling–hydrogenation strategy to join three
advanced synthetic intermediates in excellent yield and with
full stereochemical control. We
now report the full details and
show that the flexibility associat-
ed with this strategy, which al-
lowed us to prepare the various
stereoisomeric products easily.
Results and Discussion
Large-scale synthesis of
trideoxypropionate 5
We have recently developed
Scheme 2. Large-scale synthesis of syn,syn-deoxypropionate 5. a) Toluene, 1858C, 5 h, 87%; b) Compound 4
a new and highly flexible strat- (1.8 mol%), CH2Cl2, H2, 85 bar, RT, 1 d, 99%; c) NaHMDS, MeI, THF, ꢀ788C, 3 h, 94%.
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methylation, we obtained 26 grams (80% overall yield) of the
desired syn,syn-trideoxypropionate 5.
this strategy might be implemented into a synthesis of larger
deoxypropionate chains. Being among the most challenging
target compounds we intended to approach the glycolipid
components phthioceranic acid (9) and hydroxyphthioceranic
acid (10), which have been shown to display significant biolog-
ical activity as immune-stimulating agents against Mycobacteri-
um tuberculosis (Scheme 4).
With sufficient quantities of trideoxypropionate 5 in our
hands, we turned our attention to a reliable conversion into
a broadly applicable synthetic intermediate for natural product
synthesis. Our first synthesis of the pheromone (+)-vittatalac-
tone, in which we had converted 5 into the corresponding hy-
droxy ester through base-cata-
lyzed transesterification, occa-
sionally suffered from partial epi-
merization at the carbon center
adjacent to the carbonyl group.
To avoid this detrimental side re-
action, which we expected to be
even more pronounced on
a
larger scale, we opted for
Scheme 4. Phthioceranic acid (9) and hydroxyphthioceranic acid (10).
a safer and more reliable alterna-
tive. Thus, applying a three-step
sequence comprising reductive
cleavage of the chiral auxiliary, protection of the liberated hy-
droxy group as either methoxymethyl (MOM)- or tert-butyldi-
methylsilyl (TBS) ethers, and mild hydrolysis of the benzoate
furnished 6 and 7, respectively, in excellent overall yields
(Scheme 3). Both products carried the free and readily manipu-
Inspection of their structure reveals that they each contain
seven deoxypropionate subunits and that compound 10 incor-
porates an additional propionate unit. For the assembly of
a long alkyl chain with seven branching methyl groups one of
the trideoxypropionates had to be converted into a tetradeoxy-
propionate before coupling of
the two would furnish the de-
sired heptadeoxypropionate. As
the most promising way for cou-
pling, we envisioned a strategy
that took advantage of a palladi-
um-catalyzed
Suzuki–Miyaura
cross coupling reaction of an
alkyl metal reagent and a vinyl
iodide followed by stereoselec-
tive hydrogenation of the result-
ing trisubstituted olefin. The
vinyl iodide in turn should easily
be available from a trideoxypro-
pionate aldehyde through alky-
nylation, hydrozirconation, and
iodination.
Scheme 3. Further conversion of 5 into the central trideoxypropionate intermediates 6–8. a) NaBH4, THF/H2O, 08C,
16 h, 94%; b) MOMCl, N,N-diisopropylethylamine (DIPEA), CH2Cl2, RT, 1 d, quant.; b) TBSCl, ImH, DMAP, CH2Cl2,
30 min, 08C, 99%; c) K2CO3, MeOH, RT–358C, 7 h–1 d, 93–98%; d) tBuNCO, TMSCl, CH2Cl2, RT, 1 h; quant.; e) K2CO3,
MeOH, RT, 1 d, 97%; f) TBDPSCl, ImH, CH2Cl2, RT, 1 h, quant.; g) Diisobutylaluminium hydride (DIBAL-H), THF, 08C,
3 h, 93%.
To put these plans into prac-
tice, we started from our central
lated alcohol moiety on the left side of the molecule. In addi-
tion, after reductive cleavage of the chiral auxiliary in 5, carba-
moylation with tBuNCO, cleavage of the benzoate moiety, sily-
lation with tert-butyl(chloro)diphenylsilane (TBDPSCl), and se-
lective cleavage of the carbamate group on the other end of
the molecule, we were able to prepare the pseudo-enantiomer
of 7 as well. This not only further expands the versatility of this
building block, but also opens more options for subsequent
coupling reactions.
trideoxypropionate intermediates 6–8 (Scheme 5). Iodination
of the two trideoxypropionates 7 and 8 produced the corre-
sponding pseudo-enantiomeric alkyl iodides 11 and 12 in
almost quantitative yields, which were intended to serve later
as the immediate precursors for the corresponding alkyl metal
reagents through halogen–metal exchange processes. As
second coupling partner vinyl iodides 15 and 17 were pre-
pared from 6 and 7 through a sequence comprising 2-iodoxy-
benzoic acid (IBX) oxidation, alkynylation with the Bestmann–
Ohira reagent,[22] methylation of the resulting terminal alkyne,
and finally, hydrozirconation/iodination with the Schwartz re-
agent. The final vinyl iodides were obtained in 75 (compound
15) and 71% (compound 17) overall yields as single regioisom-
ers (>50:1). It should be noted that increasing both the reac-
Total synthesis of phthioceranic acid (9)
At this stage, we wondered how we could merge two of the
building blocks 5 most economically and selectively and how
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MOM-protected alkene 18 were
performed accordingly with vari-
ous iridium catalysts.[26,27] Under
standard conditions all experi-
ments, however, resulted in
complex mixtures of products. In
our search for the origin of this
failure we came across studies
by the groups of Andersson and
Burgess on iridium-catalyzed hy-
drogenations, which showed
that IrꢀH species generated in
situ were typically so acidic that
enol ethers decomposed in the
course of the hydrogenations.[28]
These findings suggested that
the addition of finely powdered
NaHCO3 should buffer the solu-
tion effectively and prevent any
acid-catalyzed decomposition of
the MOM-protecting group both
Scheme 5. Synthesis of the coupling partners 15 and 17 for the Suzuki–Miyaura reaction. a) PPh3, I2, ImH, Et2O/
CH3CN, 08C, 1 h, 98%; b) PPh3, I2, ImH, Et2O/CH3CN, 08C, 30 min, 98%; c) IBX, DMSO/THF, RT, 2 h, 96%–quant.;
d) 1) Bestmann–Ohira reagent, NaOMe, THF/MeOH, ꢀ788C, 30 min; 2) then aldehyde, ꢀ788C to RT, 2 h, 88%;
e) 1) nBuLi, THF, ꢀ788C, 1 h; 2) MeI, DMPU, ꢀ788C to RT, 1 d, 97–98%; f) 1) Cp2ZrHCl, THF, RT, 1 d; 2) I2, THF, RT,
30 min, 86%; g) Tetra-n-butylammonium fluoride (TBAF), THF, RT, 4 h, 98%.
tion time and the amount of the Schwartz reagent had a bene-
ficial effect on the regioselectivity of the hydrozirconation,
presumably as a result of a reversible addition to the alkyne.[23]
With the requisite coupling partners for the critical Suzuki–
Miyaura cross-coupling reaction in our hands we felt that
conditions, which were originally developed by the groups of
Marshall and Lee for sp2–sp3 couplings and later employed by
Rychnovsky et al. in similar settings, were most promising for
our endeavor as well.[24] Thus, iodide 11 was first converted
into a reactive alkyl lithium-boranate complex through halo-
gen–metal exchange with tBuLi and subsequent reaction with
B-OMe-9-BBN (9-BBN=9-borabicyclo[3.3.1]nonane).[25] This re-
active alkyl metal compound was then treated with MOM-pro-
tected vinyl iodide 15 (1.3 equiv)
in the substrate and product. Gratifyingly, under the modified
conditions with added NaHCO3 we were able to isolate the hy-
drogenation product (8R)-21 in excellent yield and with 92:8-
diastereoselectivity (Scheme 6). More importantly, with the
quasi-enantiomeric catalyst (S)-20 the diastereomer (8S)-21
was obtained in 94% yield as a single diastereomer proving
the catalyst-controlled stereoselectivity in this reaction. The
use of NaHCO3 apparently had an effect on catalyst efficiency,
however, and we had to use 3 mol% of catalyst twice to drive
the hydrogenation to completion.
The difference in diastereoselectivity observed in the two re-
actions suggested a minor substrate influence and a matched
and mismatched scenario, which may be explained by consid-
in the presence of 5 mol%
[PdCl2(dppf)] (1,1’-bis(diphenyl-
phosphino)ferrocene) and K3PO4
in DMF at room temperature to
afford the trisubstituted olefin
18 in 92% yield under very mild
conditions (Scheme 6).
To establish the last stereo-
genic center in the carbon back-
bone of phthioceranic acid,
olefin 21 needed to be hydro-
genated with high stereoselec-
tivity. We had previously shown
that similar trisubstituted olefins
can be efficiently hydrogenated
with excellent enantioselectivity
with certain iridium–pyridine-
phosphinite catalysts and used
Scheme 6. First Suzuki–Miyaura cross-coupling of two trideoxypropionates. Determination of the diastereoselectiv-
ity of both diastereomers (8R)-21 and (8S)-21 after selective hydrogenation with the pyridyl-phosphinite complex
(R)-19 and (S)-20. a) 1) Compound 11, tBuLi, B-OMe-9-BBN, Et2O/THF, ꢀ788C to RT, 2,5 h; 2) then 15, aq. 3mK3PO4,
[PdCl2(dppf)]·CH2Cl2 (5 mol%), DMF, RT, 18 h, 92%; b) 2ꢃ3 mol% (R)-19, CH2Cl2, 60 bar, H2, NaHCO3, RT, 3 h+2 h,
this strategy in the asymmetric
synthesis of a-tocotrienyl ace-
tate.[26] Therefore, our first hydro-
genation experiments of the 91%; c) 2ꢃ3 mol% (S)-20, CH2Cl2, 60 bar, H2, NaHCO3, RT, 3 h+2 h, 94%.
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Miyaura cross-coupling–hydrogenation strategy is the
central element; however, we decided to assemble
the propionate-containing left fragment of 10 first.
Specifically, we intended to start from commercially
available palmitic acid as the long-chain C16-source,
which was to be converted through a number of
steps into the iodo-substituted allylic alcohol (R)-23
as the left fragment (Scheme 9), which in turn was
planned to be coupled to our first trideoxypropio-
nate building block 12 through a first cross-coupling
hydrogenation sequence. After some protecting
group manipulations, the coupling product should
Scheme 7. Proposed rationale for the diastereofacial selectivity of hydrogenation.
ering A(1.3)-strain effects on the preferred conforma-
tion of 18 (Scheme 7). In the lowest-energy confor-
mation of 18 the allylic CꢀH bond is oriented copla-
nar to the CꢀMe bond on the alkene with the allylic
Me group pointing to the front and the larger R2-sub-
stituent pointing to the back. For steric reasons, the
iridium-hydride addition to the olefin should now
occur from the front side over the smaller allylic sub-
stituent furnishing the anti-diastereomer (8S)-21 with
a diastereomeric ratio (d.r.) of >98:2 in a matched
situation. With the quasi-enantiomeric catalyst (R)-19
the opposite diastereomer (8R)-21 is formed prefer-
entially albeit in a slightly diminished selectivity of
92:8 d.r. in a mismatched scenario because the back-
side attack is somewhat retarded by the larger allylic
substituent.
Scheme 9. Design plan for the convergent assembly of hydroxyphthioceranic acid (10).
be further elongated to the complete carbon backbone of hy-
To complete the synthesis of phthioceranic acid (9) hepta-
deoxypropionate (8R)-21 was converted into tosylate 22 within
two chemical steps and the terminal C15-alkyl chain was intro-
duced through a copper-catalyzed cross-coupling with the
requisite Grignard reagent as the third building block. Finally,
MOM-deprotection and oxidation of the primary alcohol to the
acid[29] afforded phthioceranic acid (9) in 62% yield over the
three steps (Scheme 8).
droxyphthioceranic acid through a second cross-coupling hy-
drogenation sequence with vinyl iodide 17.
To put these plans into practice, we started from racemic
propargylic alcohol 25, which was conveniently obtained in
good yield through Grignard addition of ethynylmagnesium
bromide to palmitic aldehyde, further obtained by reduction–
oxidation reaction of commercially available palmitic acid (24).
For the sake of practicality and the production of large
amounts of material, we opted
for an enzymatic kinetic resolu-
tion strategy over alternative
enantioselective protocols. Thus,
Candida antarctica lipase B (CAL-
B)-catalyzed esterification of the
racemic mixture of 25 with vinyl
acetate yielded 54% of R-config-
ured, recovered alcohol (R)-25
with an enantiomeric excess (ee)
of 91%, and, upon hydrolysis,
40% of S-configured (S)-25 with
96% ee (Scheme 10). Both enan-
tiomers were separately convert-
ed into the homogenous, R-con-
Scheme 8. Total synthesis of the phthioceranic acid (9). a) TBAF, THF, RT, 4 h, 95%; b) TsCl, DMAP, CH2Cl2/pyridine
1:1, RT, 1 d, 92%; c) 8 mol% Li2CuCl4, C15H31MgBr, Et2O, RT, 1 d, 76%; d) cat. HCl, MeOH/DCE, 708C, 40 min, 96%;
e) RuCl3, NaIO4, CH3CN/CCl4/H2O, RT, 3 h, 85%.
Total synthesis of hydroxyphthioceranic acid (10)
figured para-nitrobenzoate (R)-26 through classical and Mitsu-
nobu esterifications, respectively, and the final product was
successfully recrystallized to>99% ee. Following this conven-
ient strategy we were able to convert 70% of racemic propar-
gylic alcohol 25 into enantiomerically pure para-nitrobenzoate
(R)-26 on large scale (10–20 gram batches). At the same time,
The design plan for the synthesis of hydroxyphthioceranic acid
(10) had to be carefully adjusted mainly to incorporate the ad-
ditional propionate unit. In principle, the same order of events
as shown previously in the phthioceranic acid synthesis was
planned here as well, in particular, the sequential Suzuki–
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With both enantiomers of al-
lylic alcohol (R)-23 and (S)-23, re-
spectively, in our hands we set
out to couple them with the
central trideoxypropionate build-
ing block 12 applying slightly
adjusted conditions compared
with the phthioceranic acid syn-
thesis. Thus, conversion of alkyl
iodide 12 into the corresponding
reactive
alkyl-lithium-boranate
complex with reduced amounts
of both tBuLi and B-OMe-9-BBN
and subsequently palladium-cat-
alyzed Suzuki–Miyaura reaction
with both enantiomers of vinyl
iodide 23 delivered olefins (9R)-
27 and (9S)-27, respectively, in
excellent yield in each case
(Scheme 11). It is noteworthy
(and saved substantial material)
that equimolar amounts of both
Scheme 10. Synthesis of the aliphatic chain containing building blocks (R)-23 and (S)-23 for the Suzuki–Miyaura
cross-coupling reactions. a) NaBH4, I2, THF, reflux, 1 h, 96%; b) IBX, DMSO/THF, RT, 1 d, 92%; c) ethynylmagnesium
bromide, THF, 08C, 30 min, 81%; d) 1) CAL-B, vinyl acetate, hexane, RT, 3 h; 2) acetyl-(S)-enantiomer, NaOH, MeOH/
H2O, reflux, 1 h, 54% of (R)-25 and 40% of (S)-25; e) p-NO2BzCl, pyridine, CH2Cl2, 08C, 1 h, 96%; f) p-NO2BzOH,
PPh3, DIAD, THF, 08C to RT, 4 h, 84%; g) Crystallization from hexane, 73%; h) NaOH, MeOH/H2O, reflux, 94%; i) 1)
MeLi, THF, ꢀ208C to RT; Cp2ZrHCl/ZnCl2, THF, 408C; 2) I2, THF, 08C, 70%.
this strategy provided us with a convenient access to the
enantiomeric product (S)-26.
starting materials were sufficient here to realize this elaborate
transformation successfully.
Upon hydrolysis of (R)-26 and (S)-26, a highly regioselective,
substrate-controlled hydrozirconation of the free propargylic
alcohols (R)-25 and (S)-25 was accomplished according to the
protocol of Ready et al.[31] With the assistance of a Cp2ZrHCl/
ZnCl2 complex (Cp2 =bis(cyclopentadienyl)) and subsequent io-
dination, the branched vinyl iodides (R)-23 and (S)-23 were ob-
tained in good yields and with >99% ee (branched/linear>
50:1).
The task ahead was now to hydrogenate the exo-methylene
group with high stereocontrol. Initially, we considered this sit-
uation to be an ideal scenario for acyclic stereocontrol through
A(1.2)-strain effects in which the methylene substituent R
would eclipse the allylic CꢀH bond in the lowest-energy con-
formation (Scheme 12). Precoordination of the catalyst to the
free hydroxyl group of allylic alcohol (9S)-27 was then expect-
ed to give rise to a transition state in which the hydrogenation
would now occur from the backside to furnish the anti-stereo-
Scheme 11. Flexible synthesis of the exo-methylens (9S)-28 and (9R)-28 and synthesis of all four diastereomers of 31. a) 1) Compound 12, tBuLi, Et2O, B-OMe-
9-BBN, THF, ꢀ788C to RT, 2 h; 2) then (R)-23 or (S)-23, aq. 3mK3PO4, 5 mol% [PdCl2(dppf)]·CH2Cl2, DMF, RT, 2 h, 79–82%; b) p-NO2BzCl, Pyr, CH2Cl2, 08C, 2 h,
89–97%; c) 10 mol% TBABr3, MeOH, RT, 4 h, 97%; d) Compound 29 (2 mol%), CH2Cl2, H2, 90 bar, RT, 1 d, 98%; e) Compound 30 (5 mol%, CH2Cl2, H2, 90 bar, RT,
3 h, 84%; f) TBSCl, ImH, DMAP, CH2Cl2, RT, 30 min, 98%; g) MeOH, K2CO3, reflux, 6 h, 94%; h) 1) PPh3, DIAD, p-NO2BzOH, THF, RT, 5 h; 2) 20 mol% TBABr3,
MeOH, RT, 4 h, 55%; i) PPh3, DIAD, p-NO2BzOH, THF, 08C, 1 h, 88%; j) Compound 29 (2 mol%), CH2Cl2, H2, 1 bar, RT, 1 d, 85%.
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range of chiral hydrogenation
catalysts that were expected to
override the inherent facial bias
of the substrate (for a full docu-
mentation see the Supporting
Information).
Eventually,
it
turned out that the Simple-
PHOX catalyst 30[36] hydrogenat-
ed the substrate (9R)-28 success-
fully to produce the desired anti-
isomer (8S,9R)-31 with 84% yield
and 98:2 anti/syn-diastereoselec-
tivity (Scheme 11). Unfortunately,
this scenario could not be ex-
Scheme 12. Expected products of the asymmetric hydrogenation of (9S)-27 and (9R)-28 with achiral metal-cata-
lysts: Top: Hydroxy-directed hydrogenation of the free alcohol (9S)-27; Bottom: Hydrogenation of the sterically
hindered derivative (9R)-28 to the Cram- and Felkin–Anh model.
isomer selectively. As consequence of the synthesis of hydrox-
yphthioceranic acid, we would have to start from the “wrong”
enantiomer of 23 to set the correct configuration at C(16) and
subsequently invert the allylic C(17)-configuration, for example,
through a Mitsunobu reaction. Alternatively, we envisioned
that a suitably O-protected substrate might be stereoselec-
tively hydrogenated in a Felkin–Anh-type transition state and
directly afford the desired syn diastereomer (8R, 9R)-31
(Scheme 12). The second option would obviously obviate the
need for subsequent inversion of the carbinol stereocenter.
Initial attempts using the free allylic alcohol and the catalyst
[Rh(nbd)(dppb)]+[BF4]ꢀ (nbd= norbornadiene; dppb=1,4-bis-
(diphenylphosphino)butane) in varying amounts ranging
between 1–20 mol%, however, were accompanied by a high
degree of isomerization to the ketone and surprisingly rather
low selectivities. Additional experiments with a range of other
transition-metal catalysts (e.g., [Rh(nbd)((R)-BINAP)][BF4],
[Rh(nbd)(dppb)][BArF], [Rh(nbd)((R)-BINAP)][BArF], [Rh(nbd)((S)-
tended to (9S)-28, which gave almost no selectivity in the hy-
drogenation. Instead, compound (8R,9S)-31 was conveniently
obtained from (8R,9R)-31 through a Mitsunobu inversion strat-
egy, which occurred with full inversion of the carbinol configu-
ration.
Assignment of the relative configuration of all four
diastereomers of 31 was subsequently carried out by the two-
dimensional NMR-spectroscopic method developed by Breit
et al. based upon conformational preferences of the deoxy-
propionate backbone (Scheme 13).[37]
The HSQC NMR-spectra of deoxypropionates (8R,9R)-31 and
(8R,9S)-31 showed two large chemical shift differences for the
signals of the 7-CH2 methylene protons with Dd=0.48 and
0.36 ppm, respectively, indicating a 6,8-syn-configuration each
for both compounds. Conversely, two small chemical shift dif-
ferences of Dd=0.12 ppm each were observed for the same
signals in the case of (8S,9R)-31 and (8S,9S)-31 suggesting
a 6,8-anti-configuration for both compounds. These results are
in perfect agreement with related data reported by Breit for
similar syn- and anti-configured deoxypropionates leaving no
doubt about the configuration of the new C8-stereogenic
center.
BINAP)][BArF];
BINAP=2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl); BArF =tetrakis(3,5-trifluoromethylphenyl)borate]) did
not improve upon these results.[33] Accordingly, we resorted to
the second option and converted both diastereomers (9R)-27
and (9S)-27 into the corresponding para-nitro benzoates (9R)-
28 and (9S)-28, respectively, which carry a free primary hydrox-
yl group. First, hydrogenation experiments of (9R)-28 instantly
In an attempt to broaden the scope of this hydrogenation
of exo-methylene groups, we briefly investigated substrates
similar to 28, which we employed in our hydroxyphthioceranic
acid synthesis (Table 1). It turned out that para-nitro benzoate
33a, which is structurally most reminiscent of 28, as well as
acetate 33b, were hydrogenated with very good syn diastereo-
selectivity by using catalyst 29 (entries 1 and 2, Table 1). The
corresponding benzoate 33c furnished the syn stereomer as
well albeit with diminished selectivity (entry 3, Table 1). The
two phenyl-substituted alkenes 33d and 33e, however, did
not give rise to significant stereoselectivity suggesting that the
Felkin–Anh transition state discussed in Scheme 12 could not
be accommodated so easily here due to the larger phenyl
group.
ꢀ
succeeded with the Crabtree catalyst (as its BArF salt) 32,[34]
which delivered the syn isomer (8R,9R)-31 in quantitative yield
and with 95:5-diastereoselectivity, suggesting that our transi-
tion state model shown above was working (Scheme 12). Fur-
ther investigation revealed that achiral catalysts consistently
gave rise to the syn-configuration with varying levels of diaste-
reoselectivity (see the Supporting Information). Eventually, the
iridium-complex ([Ir(cod)(SIMes)(Pyr)]+[PF6]ꢀ; cod=cycloocta-
1,5-diene) 29[35] carrying a NHC ligand instead of the PCy3
ligand proved to be the catalyst of choice for our substrates.
Thus, using only 2 mol% of catalyst 29, the product (8R,9R)-31
was obtained in almost quantitative yield and with 98:2 syn/
anti-diastereoselectivity. Likewise, epimeric (9S)-28 was
converted into (8S,9S)-31 in 85% yield and with 96:4 syn/anti
diastereoselectivity.
To proceed with the second Suzuki–Miyaura cross-coupling
reaction for the assembly of the complete carbon backbone of
hydroxyphthioceranic acid (10) the base-sensitive para-nitro-
benzoyl group within 31 was exchanged for the more robust
TBDPS group and the product was further converted into
iodide 35 (Scheme 14). Employing the same conditions, which
had proven successful above, the sp2–sp3 cross-coupling of
To also access the anti-configured para-nitro benzoates
(8S,9R)-31 and (8R,9S)-31 and make this approach as versatile
and flexible as possible, we extensively screened a broad
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Scheme 13. Determination of the relative configuration by using two-dimensional HSQC NMR spectroscopy. Comparison of the chemical shift difference (Dd)
of the methylene protons 7-CH2 of the propionates (8R,9R)-31, (8R,9S)-31, (8S,9R)-31, and (8S,9S)-31.
alkyl iodide 35 and vinyl iodide 17 also proceeded without any
problem, and delivered the product 36 in 85% yield as one
single stereoisomer. Once again, an excess of one of the sub-
strates was not necessary. The TBDPS protecting group in 36
was subsequently removed to avoid its partial cleavage in the
ensuing hydrogenation. In addition, the reaction could now be
performed without the use of NaHCO3, which had been shown
to reduce the reactivity of the catalyst in the synthesis of
phthioceranic acid (9). Thus, the iridium-catalyzed hydrogen-
ation of alkene 37 with only 2.5 mol% of catalyst (R)-19
delivered saturated alkane 38 in excellent yield and as a single
diastereomer as judged by 1H- and 13C NMR spectroscopy.
Oxidation of hydroxyphthioceranol (38) in a two-step process
consisting of a 2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO)
oxidation and a Pinnick oxidation completed the synthesis of
hydroxyphthioceranic acid (10) in 82% yield over the two
steps and produced almost a half-gram of material. Thus, the
natural product was produced in 23 steps along the longest
linear route and in an excellent 25% overall yield. The spectro-
scopic and analytical data accurately matched those reported
for the natural product.
To assign the relative configuration of hydrogenation
product 37 more rigorously we prepared the corresponding
TBDPS-protected C8-epimers (8S)-39 and (8R)-39 through hy-
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protons 7-CH2 and 9-CH2 within the double anti-configuration
in (8R)-39 was expected to give two small values Dd. Actually,
we even obtained three small values between Dd=0.20 and
0.25 ppm, presumably as a result of additional conformational
changes within the product. Notwithstanding this result, the
evidence strongly suggested a 6,8- and 8,10-anti-configuration
within (8R)-39. Additionally, in the 13C NMR spectrum of epi-
meric (8R)-39 with the unnatural 8-configuration, there is one
signal for a methyl substituent that is shifted significantly away
from all other methyl signals to lower frequencies at about d=
19 ppm, which indicated an opposite configuration of this 8’-
CH3 group (see the Supporting Information). All other signals
for methyl substituents both in (8S)-39 and (8R)-39, respective-
ly, appear very close together between d=21–22 ppm sug-
gesting an all-syn configuration between the other methyl
groups. Finally, this assignment of the relative configuration of
hydrogenation products (8S)-39 and (8R)-39 perfectly matches
the results of our enantioselec-
Table 1. Hydrogenation of some exo-methylene model substrates 33a–
e.[a]
Entry
Substrate
R1
R2
Cat.
Conv.
[%][d]
syn/anti[d]
1
2
3
4
5
33a
33b
33c
33d
33e
H13C6
H13C6
H13C6
Ph
p-NO2BzO
OAc
OBz
p-NO2BzO
OAc
29
29
29
32[b]
32[c]
99
99
99
91
99
92:8
92:8
84:16
56:44
64:36
Ph
[a] Reaction conditions: exo-methylene substrate 33 (1.0 equiv), catalyst
29 (5 mol%), CH2Cl2 (0.025m), H2, 90 bar, RT, 4 h. [b] Compound 32
1
(15 mol%). [c] Compound 32 (20 mol%). [d] Determined by H NMR spec-
troscopy.
tive hydrogenation of g-toco-
pheryl acetate.[26] As we have
been able to show that hydroge-
nation of 36 is purely a catalyst-
controlled event, a stereochemi-
cal influence exerted by the sub-
strate is highly unlikely.
Conclusion
We have developed a new and
highly convergent strategy for
the stereoselective and fully
flexible synthesis of long-chain
polydeoxypropionates.
Taking
advantage of our previously re-
ported trideoxypropionate syn-
thesis, which provides a general
access to all stereochemical per-
mutations, we have been able to
merge two of these fragments
through a Suzuki–Miyaura cross-
coupling reaction and subse-
quent iridium-catalyzed hydro-
genation to access heptadeoxy-
propionate building blocks with
Scheme 14. Completion of the total synthesis of hydroxyphthioceranic acid (10). a) TBSCl, ImH, DMAP, CH2Cl2, RT,
30 min, 98%; b) MeOH, K2CO3, reflux, 6 h, 94%; c) TBDPSOTf, 2,6-lutidine, CH2Cl2, 08C, 5 h, 98%; d) 30 mol%
TBABr3, MeOH/THF, RT, 3 h, 99%; e) PPh3, ImH, I2, Et2O/CH3CN, RT, 15 min, 99%; f) 1) Compound 35, tBuLi, Et2O, B-
OMe-9-BBN, THF, ꢀ788C to RT, 2 h; 2) then compound 17, aq. 3mK3PO4, 5 mol% [PdCl2(dppf)]·CH2Cl2, DMF, RT,
4 h, 85%; g) TBAF, THF, RT, 6 d, 94%; h) 2.5 mol% (R)-19, CH2Cl2, 60 bar, H2, 2.5 mol% (R)-19, RT, 1.5 d, 99%;
i) NaHCO3, KBr, NaOCl, 5 mol% TEMPO, CH2Cl2 08C, 50 min, 93%; j) tBuOH/H2O/isoprene, NaClO2, NaH2PO4, RT, 4 h,
88%.
excellent
stereocontrol.
By
adding a suitable third fragment,
we have completed the synthe-
sis of the glycolipid components
phthioceranic acid (9) and hy-
drogenation of 36 with enantiomeric iridium catalysts (R)-19
and (S)-19 and analyzed them by using NMR spectroscopy ac-
cording to the method of Breit et al. (Scheme 15).[37] Again,
a clear picture emerged with the stereoisomer (8S)-39 contain-
ing the natural configuration showing the expected chemical
shift difference of the methylene protons 5/7/9/11/13-CH2 with
large values ranging between Dd=0.37 and 0.45 ppm indicat-
ing an all-syn-deoxypropionate. On the contrary, the methylene
droxyphthioceranic acid (10), the latter of which was prepared
in an amount of almost half a gram, which documents the ap-
plicability of our approach. More importantly, we have shown
that this strategy is not limited to the synthesis of the two nat-
ural products, but is amenable to the synthesis of almost every
other diastereomer by modification of the cross-coupling and
hydrogenation conditions. Thus, we have been able to prepare
all stereoisomers of the propionate unit in 31 as well as the 8-
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Scheme 15. Asymmetric hydrogenation of 51 with the iridium-pyridyl-phosphinite complexes (R)-19 and (S)-19. Determination of the absolute configuration
by two-dimensional HSQC NMR-spectroscopy. Comparison of the chemical shift difference (Dd) of the methylene protons 5/7/9/11/13-CH2 of the propionates
(8S)-39 und (8R)-39. a) Compound (R)-19 (4ꢃ5 mol%), CH2Cl2, 90 bar, H2, 0.8 equiv NaHCO3, RT, 4ꢃ1 d, 91%; b) (S)-19 (15+10 mol%), CH2Cl2, 90 bar, H2,
1.5 equiv NaHCO3, RT, 2 d+1 d, 88%.
epimeric precursors (8S)-39 and (8R)-39 for the natural prod-
ucts by using the enantiomeric iridium catalyst. We therefore
believe that this strategy will be of great utility for the stereo-
selective and flexible synthesis of other long-chain deoxypropi-
onates as well.
polysiloxane). HPLC analyses were carried out on a Jasco MD-2010
plus instrument with chiral stationary phase column Chiracel OD-H
(250ꢃ4.6 mm) and Chiracel AD-H (250ꢃ4.6 mm) of Chiral Technol-
ogies Europe. Solvents were distilled from the indicated drying re-
agents: Dichlormethane (CaH2), tetrahydrofuran (Na, bezophe-
none), diethyl ether (Na, benzophenone), toluene (Na, benzophe-
none), n-hexane (Na), and acetonitrile (MgSO4, CaH2). Other sol-
vents were of technical grade and distilled from the indicated
drying reagents: Diethyl ether (KOH), methyl-tert-butyl ether (KOH),
ethyl acetate (CaCl2), n-hexane (KOH), and dichloromethane (CaH2).
Triethylamine, diisopropylamine and diisopropylethylamine were
directly distilled from CaH2 before use. Flash column chromatogra-
phy was performed using Merck silica gel 60 230–400 mesh
(0.040–0.063 mm). Abbreviations for solvents are used as follows:
Diethyl ether (Et2O), ethyl acetate (EtOAc), n-hexane (Hex), di-
chloromethane (CH2Cl2), methyl-tert-butylether (MTBE). Reactions
were monitored by thin-layer chromatography on precoated TLC
Silica gel 60 F254 plates (Merck), were visualized by UV and treated
with vanillin staining (5.0 g vanillin, 100 mL acetic acid, 50 mL
conc. sulfuric acid, 1 L methanol) solution. Hydrogenation
experiments were carried out in a Premex 50 mL MED 1234 at the
indicated reaction conditions.
Experimental Section
General methods
Unless otherwise stated, all reactions were carried out in dry sol-
vents under an argon atmosphere using standard vacuum line
1
techniques. H and 13C NMR spectra were recorded in CDCl3 solu-
tion using a Varian Gemini 300 spectrometer (300 MHz) and Bruker
Avance DRX 400 (400 MHz) and a Bruker Avance 700 (700 MHz).
Chemical shifts are reported in ppm and calibrated to residual
chloroform peaks (d=7.26 ppm, 1H, 77.16 ppm, 13C), multiplicities
are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p
(pentet), m (multiplet), and brs (broad singlet). Melting points
were determined uncorrected on a Boetius heating table. IR spec-
tra were obtained with an Avatar 360 FTIR of Thermo Nicolet and
a 4100 FTIR of Jasco. Optical rotations were measured using a Po-
larotronic polarimeter (V-630 UV/Vis of Jasco and DU-600 of Beck-
man). All ESI mass spectra were recorded on a Bruker Daltonics
Apex II FT-ICR and the EI mass spectra on a MAT 8230 of Finnigan
(70 eV). All GCMS mass spectra were recorded on an Agilent Tech-
nologies 6890N/5975B inert GC/MSD, with the capillary GC column
HP-5 ms (30 mꢃ0.25 mm x 0.25 mm, 5% diphenyl- 95% dimethyl-
Syntheses
Syntheses and characterizations of compounds 1–18, (8S)-21, 22,
(R)-23, (R)-25, (R)-26, (9R)-27, (9R)-28, (8R,9R)-31, and 35--38, as
well as the remaining spectral data of compounds (S)-23, have
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been reported in the Supporting Information of our previous
communication.[20b]
(30 mL), water (30 mL) and the directly filtrated into a seperatory
funnel. The mixture was extracted with Et2O (3ꢃ30 mL) and the
combined organic extracts were dried over Na2SO4. Removal of the
solvent under reduced pressure and purification by flash column
chromatography (Et2O/Hex 1:20) gave 2.73 g (11.4 mmol, 92%) pal-
mitic aldehyde as a clear and crystalline solid. Rf =0.66 (Hex/MTBE
10:1). 1H NMR (400 MHz, CDCl3, 268C): d=9.97–9.54 (m, 1H, 1-
Large scale synthesis of 5: Protected aldol product 1 (45.7 g,
105 mmol) was solved in a 250 mL screw cap round bottom flask
in 200 mL toluene (c=0.50m). The tube was sealed, placed into
a heating bath and the reaction mixture was stirred for 5 h
at1858C. After cooling to room temperature, the solvent was re-
moved and the viscous oil was treated with 400 mL of a 1:2 mix-
ture of Et2O/Hex. After slowly removal of a part of the solvent in
vacuum most product was appeared as a white powder in the
yellow solution. The solid was filtrated, washed with hexane, and
dried in vacuum to give 32.2 g (74.3 mmol, 71%) of beaming white
and clean rearrangement product 2. The mother liquor was treated
with 30 g of silica and dried in vacuum. Purification by flash
column chromatography (MTBE/Hex 1:2!1:1!2:1!MTBE) gave
additional 7.20 g (17 mmol, 16%) rearrangement product 2. A
250 mL special manufactured glass inlet for the autoclave (500 mL
inner volume) was filled with the combined rearrangement prod-
uct 2 (26.8 g, 61.7 mmol, 1.0 equiv), iridium catalyst 4 (1.82 g,
1.11 mmol, 0.018 equiv), and CH2Cl2 (200 mL; c=0.30m). The glass
inlet was placed into the hydrogenation autoclave that was sealed
and purged twice with 50 bar of hydrogen. The reaction mixture
was stirred at 85 bar hydrogenation pressure for one day. Removel
of the solvent under reduced pressure and purification by flash
column chromatography (EtOAc/Hex 1:4!1:2!1:1) gave 26.7 g
(61.1 mmol, 99%, d.r.=97/3) product 3 als colorless oil. A solution
3
CHO), 2.41 (dt, J=1.2, 7.3 Hz, 2H, 2-CH2), 1.85–1.46 (m, 2H, 3-CH2),
3
1.42–1.13 (m, 24H, 4–15-CH2), 0.87 ppm (t, J=6.7 Hz, 3H, 16-CH3);
13C NMR (101 MHz, CDCl3, 268C): d=203.0 (1-CHO), 44.05 (2-CH2),
32.06 (14-CH2), 29.83/29.81/29.80/29.77/29.72/29.56/29.49/29.31 (4–
13-CH2), 22.83 (3-CH2), 22.23 (15-CH2), 14.24 ppm (16-CH3); GCMS
+
C
(DB-50_S): tR =6.55 min, m/z=240.3 [M]
.
Propargylic alcohol 25: Ethynyl magnesium bromide (31 mL, 0.5m
in THF, 15.5 mmol, 1.05 equiv) was added to solution of palmitic al-
dehyde (3.54 g, 14.7 mmol, 1.0 equiv) in THF (70 mL; c=0.2m) at
08C and stirred for 30 min at this temperature. The reaction mix-
ture was treated with a saturated NH4Cl solution (30 mL) and was
extracted with MTBE (3ꢃ30 mL). The combined organic extracts
were dried over Na2SO4. Purification by flash column chromatogra-
phy (Hex/MTBE 40:1!30:1!20:1) gave 3.16 g (11.9 mmol, 81%) of
propargylic alcohol 25 as a colorless and crystalline solid. Enantio-
merically pure (S)-25 was obtained following the previously report-
ed procedure using CAL-B-induced kinetic resolution.[20] Hereby,
the racemic mixture (rac)-25 (10.9 g, 40.9 mmol) was transformed
into the propargylic alcohol (9S)-25 (6.63 g, 24.9 mmol, 61%,
>99% ee). [a]2D3 =ꢀ4.00 (c=1.00, CHCl3). The determination of the
enantiomeric excess of the free alcohol (S)-25 was performed after
conversion into the para-nitrobenzoic acid derivative.[20]
[a]2D3 =ꢀ18.0 (c=1.00, CHCl3, >99% ee); HPLC: Chiralcel OD-H
column, Hex/iPrOH=99:1, flow rate=0.5 mLminꢀ1; (R)-enantiomer
tR =17.5 min; (S)-enantiomer tR =18.9 min.
of 27.1 g (61.9 mmol, 1.0 equiv) hydrogenation product
3 in
250 mL THF (c=0.25m) was cooled to ꢀ788C. Sodium bis(trime-
thylsilyl)amide (NaHMDS; 33 mL, 65 mmol, 1.05 equiv, 2m in THF)
was added through a dropping funnel over a period of 15 min and
the solution was stirred for additional 45 min at this temperature.
MeI (7.00 mL, 111 mmol, 1.80 equiv) was added at ꢀ788C within
15 min and the reaction mixture was stirred additional three hours
at this temperature. The reaction was stopped by the addition of
half saturated NH4Cl solution (400 mL) at ꢀ788C and warmed to
room temperature. The aqueous phase was extracted with CH2Cl2
(5ꢃ100 mL). The combined organic extracts were dried over
Na2SO4. Purification by flash column chromatography (EtOAc/Hex
9:1!7:1!5:1!3:1) gave trideoxypropionate 5 (26.3 g, 58.3 mmol,
94%) as a colorless oil.
Internal vinyl iodide (S)-23: Propargyl alcohol (S)-25 (533 mg,
2.0 mmol, 1.0 equiv, 99% ee) was dissolved in THF (5 mL, c=
0.40m) and cooled to ꢀ408C. Then, methyllithium (1.25 mL, 1.6m
in THF, 2.0 mmol, 1.0 equiv) was added over a period of 10 min
and the reaction mixture was stirred for additional 30 min at room
temperature. Meanwhile, in a separate Schlenk flask, the Schwartz
reagent (1.03 g, 4.0 mmol, 2.0 equiv) was treated at 08C with a solu-
tion of ZnCl2 (12 mL, 1m in THF, 12 mmol, 6.0 equiv). After removal
of the ice bath, the lithium alkoxide-containing solution was con-
centrated under reduced pressure till half of its volume and then
transferred to the Cp2ZrHCl/ZnCl2 solution through a cannula, rins-
ing with 1.0 mL of THF. After stirring 1 h at room temperature, the
deep-grey suspension was treated with CH3CN (1.05 mL,
20.0 mmol, 10 equiv) and stirring was continued for 10 min. The
mixture was cooled to ꢀ508C, then treated with 1.01 g (4.0 mmol,
2.0 equiv) of iodine (dissolved in 4 mL THF) and allowed to reach
room temperature over 1 h. The excess of iodine was destroyed
with a sat. NaHSO3 solution (20 mL), then diluted with water
(20 mL) and extracted with MTBE (3ꢃ20 mL). The combined organ-
ic extracts were dried over anhydrous Na2SO4 and the residue was
brought onto 3.5 g of silica (60–200 mm). Flash column chromatog-
raphy (Hex/MTBE 30:1!20:1) gave 581 mg (1.47 mmol, 74%, inter-
nal/terminal> 50:1, >99% ee) of vinyl iodide (S)-23 as a colorless
solid. [a]2D3 = +10.0 (c=1.00, CHCl3); HPLC: Chiralcel OJ column,
Palmitol: NaBH4 (4.43 g, 117 mmol, 2.0 equiv) and 15.0 g
(58.8 mmol, 1.0 equiv) palmitic acid were placed in a 250 mL three
neck bottom flask with reflux condenser, dropping funnel, and gas
delivery pipe. The solvents were suspended in THF (90 mL) and
cooled to 08C. iodine (16.4 g, 254 mmol, 1.1 equiv; soluted in
30 mL abs. THF) was carefully added through a dropping funnel
over a period of two hours (H2›) followed by stirring under reflux
for 1 hour. The mixture was cooled to 08C and treated with 2 n
HCl (30 mL) and a saturated Na2S2O3 solution (30 mL). The mixture
was extracted with MTBE (3ꢃ50 mL). The combined organic ex-
tracts were washed with 3 n NaOH (100 mL) and the aqueous
phase was extracted with MTBE (3ꢃ50 mL). The combined organic
extracts were dried over MgSO4 and the solvent was removed
under reduced pressure. Purification by flash column chromatogra-
phy (Hex/EtOAc, 1:10) gave palmitol (13.6 g, 56.3 mmol, 96%) as
a clear and crystalline solid. Rf =0.68 (Hex/EtOAc 4/1). 1H NMR
2
3
(300 MHz, CDCl3, 268C): d=3.64 (dd, J=10.7 Hz, J=6.3 Hz, 2H, 1-
Hex/iPrOH=98:2,
flow
rate=0.5 mLminꢀ1
;
(S)-enantiomer
CH2), 1.67–1.43 (m, 2H, 2-CH2), 1.43–1.18 (m, 26H, 3–15-CH2),
0.88 ppm (t, J=6.7 Hz, 3H, 16-CH3).
tR =10.1 min; (R)-enantiomer tR =11.4 min.
3
Hydrogenation product (8S)-21: Alkene 18 (40 mg, 0.064 mmol,
1.0 equiv) was dissolved in CH2Cl2 (0.5 mL) in a 2 mL reaction vial.
Catalyst (S)-28 (3.1 mg (0.035 equiv)) followed by NaHCO3 (tip of
a spatula) were added and the vial was placed into the autoclave.
The reaction was stirred under hydrogen atmosphere (60 bar) for
Palmitic aldehyde: A solution of palmitol (3.00 g, 12.4 mmol,
1.0 equiv) in 60 mL of a 1:1 mixture of THF/DMSO (c=0.20m) was
treated with IBX (5.20 g, 18.6 mmol, 1.5 equiv) and stirred at room
temperature over night. The suspension was diluted with Et2O
Chem. Eur. J. 2014, 20, 17360 – 17374
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17370
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3 h. After that time GCMS indicated leftover starting material. Addi-
tional catalyst (0.03 equiv) was added and the reaction was stirred
for another 2 h under hydrogen atmosphere (60 bar) of hydrogen
pressure. The crude reaction mixture was subjected to a column
(Et2O/Hex 0:1!1:20) to give 37.5 mg (0.060 mmol, 94%) of alkane
(8S)-20 as a colorless liquid. GC-MS and 13C NMR spectroscopy indi-
cated that the ratio of epimers generated during the hydrogena-
tion was at least d.r.=98:2. Rf =0.30 (Et2O/Hex 1/20); [a]2D2 = +3.5
over anhydrous Na2SO4. Purification by flash column chromatogra-
phy (Hex/MTBE, 100:1) afforded 105 mg (0.152 mmol, 89%) of fully
protected (9S)-product as a slightly yellow, viscous oil. Rf =0.96
1
(Hex/MTBE, 9:1); [a]2D3 = +7.84 (c=1.02, CHCl3); H NMR (400 MHz,
CDCl3): d=8.31–8.28 (m, 2H, 2ꢃAr-CH), 8.25–8.21 (m, 2H, 2ꢃAr-
3
CH), 5.44 (t, J=6.3 Hz, 1H, 9-CH), 5.11 (s, 1H, 8’-CHH), 4.92 (s, 1H,
2
3
2
8’-CHH), 3.45 (dd, J=9.7 Hz, J=5.1 Hz, 1H, 1-CHH), 3.33 (dd, J=
9.7 Hz, 3J=6.5 Hz, 1H, 1-CHH), 2.18 (dd, 2J=14.0 Hz, 3J=3.5 Hz,
1H, 7-CHH), 1.88–1.55 (m, 6H, 2/4/6-CH, 7-CHH, 10-CH2), 1.44–1.17
(m, 28H, 11–23-CH2, 3/5-CHH), 1.06–0.77 (m, 23H, 3/5-CHH,
SiC(CH3)3), 2’/4’/6’/24-CH3), 0.03 ppm (s, 6H, 2ꢃSiCH3); 13C NMR
(101 MHz, CDCl3): d=164.0 (Ar-COO-), 150.7 (Ar-Cq), 146.0 (8-Cq),
136.2 (Ar-Cq), 130.8 (2ꢃAr-CH), 123.8 (2ꢃAr-CH), 112.4 (8’-CH2),
78.30 (9-CH), 68.16 (1-CH2), 45.61 (5-CH2), 41.25 (3-CH2), 40.26 (7-
CH2), 33.40 (2-CH), 32.08 (22-CH2), 29.84/29.82/29.82/29.78/29.72/
29.64/29.51 (10/12–21-CH2), 28.42 (6-CH), 27.80 (4-CH), 26.10
(SiC(CH3)3), 25.59 (11-CH2), 22.84 (23-CH2), 21.06 (4’-CH3), 20.43 (6’-
CH3), 18.49 (SiC(CH3)3), 18.09 (2’-CH3), 14.27 (24-CH3), ꢀ5.22 (2ꢃ
SiCH3); IR (film): u˜ =2953, 2925, 2854, 1727, 1608, 1531, 1462, 1378,
1348, 1272, 1114, 1101, 909. 873, 837, 776, 735, 719, 667, 647, 599,
488, 456 cmꢀ1; UV lmax (log e): 3.69 (260 nm, MeCN); HRMS (ESI):
m/z calcd for: C41H73NO5SiNa: 710.51522 [M+Na]+; found:
710.51480.
1
(c=1.80, CHCl3); H NMR (400 MHz, CDCl3, 268C): d=7.71–7.65 (m,
4H), 7.45–7.35 (m, 6H), 4.62 (mc, 2H), 3.52 (dd, J=9.8, 5.1 Hz, 1H),
3.46–3.39 (m, 2H), 3.36 (s, 3H), 3.27 (dd, J=9.3, 7.0 Hz, 1H), 1.89–
1.79 (m, 1H), 1.79–1.70 (m, 1H), 1.67–1.49 (m, 5H), 1.42–1.24 (m,
3H), 1.23–1.08 (m, 3H), 1.06 (s, 9H), 0.99–0.77 ppm (m, 27H);
13C NMR (100 MHz, CDCl3, 268C): d=135.8, 135.8, 134.3, 134.3,
129.6, 127.7, 96.74, 73.37, 68.97, 55.22, 46.33, 46.11, 45.68, 45.60,
41.92, 41.67, 33.28, 30.97, 27.62, 27.52, 27.50, 27.48, 27.06, 20.88,
20.83, 20.78, 20.71, 19.48, 19.12, 18.36, 18.23; IR (film): u˜ =3071,
3050, 2956, 2925, 1590, 1511, 1461, 1428, 1379, 1214, 1152, 1111,
1049, 971, 921, 824, 739, 702, 615, 505 cmꢀ1; HRMS (ESI): m/z calcd
for: C40H68O3SiNa: 647.48299 [M+Na]+; found: 647.48289.
Suzuki–Miyaura cross-coupling product (9S)-27: tBuLi (0.50 mL,
0.80 mmol, 2.1 equiv, 1.6m in pentane) was added slowly to a solu-
tion of alkyl iodide 20 (152 mg, 0.38 mmol, 1.0 equiv) in Et2O
(1.4 mL) at ꢀ788C. After 10 min stirring at ꢀ788C, the solution was
treated with B-OMe-9-BBN (0.89 mL, 0.89 mmol, 2.35 equiv, 1.0m in
Hex) and then with THF (1.4 mL). This emulsion was brought to
room temperature over a period of 2 h. In a separate flask, vinyl
iodide (S)-23 (150 mg, 0.38 mmol, 1.0 equiv) was dissolved in DMF
(2 mL) and K3PO4 (0.63 mL, 1.90 mmol, 5.0 equiv, 3m in water) and
mixed roughly. The mixture was added at room temperature to
the boronate solution with rinsing of 1 mL DMF. Finally, [PdCl2-
(dppf)]·CH2Cl2 (16 mg, 0.019 mmol, 0.05 equiv) was added and the
brown suspension was stirred for 2 h under exclusion of light. The
reaction mixture was diluted with MTBE (10 mL) and a sat. NaCl so-
lution (2 mL). The aqueous phase was extracted with MTBE (3ꢃ
10 mL) and the combined organic extracts were dried over anhy-
drous Na2SO4. Solvent was removed under reduced pressure and
the resulting crude product was purified by flash column chroma-
tography (MTBE/Hex 1:100) to give the coupling product (9S)-27
(161 mg, 0.30 mmol, 79%) as a colorless oil. Rf =0.50 (Hex/MTBE 9/
1); [a]2D3 =ꢀ1.74 (c=1.10, CHCl3); 1H NMR (300 MHz, CDCl3): d=
5.06 (s, 1H, 8’-CHH), 4.83 (s, 1H, 8’-CHH), 4.02 (brs, 1H, 9-CH), 3.46
(dd, 2J=9.7 Hz, 3J=5.0 Hz, 1H, 1-CHH), 3.34 (dd, 2J=9.7 Hz, 3J=
6.5 Hz, 1H, 1-CHH), 2.13 (dd, 2J=14.4 Hz, 3J=5.3 Hz, 1H, 7-CHH),
1.86–1.14 (m, 35H, -OH, 2/4/6-CH, 7-CHH, 3/5-CHH, 10–23-CH2),
0.99–0.75 (m, 23H, 3/5-CHH, SiC(CH3)3, 2’/4’/6’/24-CH3), 0.03ppm (s,
6H, 2ꢃSiCH3); 13C NMR (75 MHz, CDCl3): d=151.0 (8-Cq), 110.6 (8’-
CH2), 75.54 (9-CH), 68.12 (1-CH2), 45.57 (5-CH2), 41.15 (3-CH2), 39.97
(7-CH2), 35.75 (10-CH2), 33.26 (2-CH), 32.08 (22-CH2), 29.85/29.77/
29.52 (12–21-CH2), 28.89 (6-CH), 27.86 (4-CH), 26.11 (SiC(CH3)3),
25.88 (11-CH2), 22.84 (23-CH2), 21.24 (4’-CH3), 20.68 (6’-CH3), 18.50
(SiC(CH3)3), 18.21 (2’-CH3), 14.27 (24-CH3), ꢀ5.21 (2ꢃSiCH3); IR (film):
u˜ =3365, 2954, 2925, 2854, 2360, 1646, 1463, 1378, 1253, 1095,
1007, 902, 837, 814, 775, 666, 602, 454 cmꢀ1; HRMS (ESI): m/z calcd
for C34H70O2SiNa: 561.50403 [M+Na]+; found: 561.50373; GCMS
(DB-100L): tR =9.67 min, m/z=520.6 [MꢀH2O]+, 481.5 [MꢀtBu]+.
Mitsunobu protection of (9S)-27: A solution of the coupling prod-
uct (9S)-27 (2.35 g, 4.36 mmol, 1.0 equiv) in THF (22 mL, c=0.20m)
was treated at 08C with triphenyl phosphine (5.61 g, 21.4 mmol,
4.9 equiv), para-nitrobenzoic acid (3.21 g, 19.2 mmol, 4.4 equiv),
and Diisopropyl azodicarboxylate (DIAD; 4.20 mL, 21.4 mmol,
4.9 equiv). After stirring for 2 h at 08C, the orange solution was
treated with 20 mL water. The aqueous phase was extracted with
CH2Cl2 (3ꢃ20 mL) and the combined organic extracts were dried
over anhydrous Na2SO4. The solid residue was treated with hexane
and filtered through a 5 cm pipette of silica. Purification by flash
column chromatography (Hex/MTBE, 50:1) afforded fully protected
(9R)-product (2.63 g, 3.83 mmol, 88%) as a slightly yellow, viscous
oil. [a]2D0 =ꢀ7.00 (c=1.43, CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.32–8.26 (m, 2H, 2ꢃAr-CH), 8.24–8.18 (m, 2H, 2ꢃAr-CH), 5.45 (t,
3J=6.6 Hz, 1H, 9-CH), 5.16 (s, 1H, 8’-CHH), 4.96 (s, 1H, 8’-CHH),
3.44 (dd, 2J=9.7 Hz, 3J=5.0 Hz, 1H, 1-CHH), 3.32 (dd, 2J=9.7 Hz,
3J=6.5 Hz, 1H, 1-CHH), 2.19 (dd, 2J=13.8 Hz, 3J=4.1 Hz, 1H, 7-
CHH), 1.85–1.53 (m, 6H, 2/4/6-CH, 7-CHH, 10-CH2), 1.44–1.14 (m,
28H, 11–23-CH2, 3/5-CHH), 0.98–0.74 (m, 23H, 3/5-CHH, SiC(CH3)3,
2’/4’/6’/24-CH3), 0.02 ppm (s, 6H, 2ꢃSiCH3); 13C NMR (101 MHz,
CDCl3): d=164.1 (Ar-COO-), 150.6 (Ar-Cq), 145.8 (8-Cq), 136.2 (Ar-Cq),
130.8 (2ꢃAr-CH), 123.7 (2ꢃAr-CH), 113.9 (8’-CH2), 79.11 (9-CH),
68.11 (1-CH2), 45.58 (5-CH2), 41.01 (3-CH2), 40.18 (7-CH2), 33.20 (2-
CH), 32.07 (22-CH2), 29.83/29.81/29.77/29.71/29.63/29.50 (10/12–21-
CH2), 28.76 (6-CH), 27.79 (4-CH), 26.09 (SiC(CH3)3), 25.64 (11-CH2),
22.84 (23-CH2), 21.18 (4’-CH3), 20.41 (6’-CH3), 18.48 (SiC(CH3)3), 18.11
(2’-CH3), 14.26 (24-CH3), ꢀ5.23 ppm (2ꢃSiCH3).
Alcohol (9S)-28: Tetrabutylammonium tribromide (59.0 mg,
0.188 mmol, 0.1 equiv) was added to a solution of the fully protect-
ed (9S)-product (1.29 g, 1.88 mmol, 1.0 equiv) in MeOH (9.4 mL, c=
0.20m). After 4 h stirring at room temperature, TLC indicated full
conversion. The reaction mixture was quenched with a half sat.
NaHSO4 (20 mL) solution and all volatiles were removed under re-
duced pressure. The aqueous phase was extracted with EtOAc (3ꢃ
20 mL) and the combined organic extracts were dried over anhy-
drous Na2SO4. Flash column chromatography (Hex/MTBE, 30:1)
gave 1.04 g (1.82 mmol, 97%) of exo-methylene alcohol (9S)-28 as
a slighly yellow, viscous oil. Rf =0.21 (Hex/MTBE 9/1); [a]2D3 = +5.76
(c=1.21, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.33–8.26 (m, 2H,
Standard protection of (9S)-27:
A
solution of 92.0 mg
(0.171 mmol, 1.0 equiv) coupling product (9S)-27 in CH2Cl2 (0.7 mL,
c=0.25m) and pyridine (28 mL, 0.342 mmol, 2.0 equiv) was treated
at 08C with para-nitrobenzoyl chloride (48 mg, 0.257 mmol,
1.5 equiv). After stirring for 2 h at 08C, the solution was acidified
with 2n HCl to pH 1. The aqueous phase was extracted with
CH2Cl2 (3ꢃ10 mL) and the combined organic extracts were dried
3
2ꢃAr-CH), 8.26–8.19 (m, 2H, 2ꢃAr-CH), 5.44 (t, J=6.3 Hz, 1H, 9-
Chem. Eur. J. 2014, 20, 17360 – 17374
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17371
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
CH), 5.10 (s, 1H, 8’=CHH), 4.92 (s, 1H, 8’=CHH), 3.52 (mc, 1H, 1-
CHH), 3.38 (mc, 1H, 1-CHH), 2.17 (d, J=10.5 Hz, 1H, 7-CHH), 1.89–
3H, 2’-CH3), 0.98–0.78 (m, 5H, 3/5-CHH, 24-CH3), 0.85 (d, J=6.6 Hz,
3H, 4’-CH3), 0.81 (d, 3J=6.5 Hz, 3H, 6’-CH3); 13C NMR (101 MHz,
CDCl3): d=164.6 (Ar-COO-), 150.6 (Ar-Cq), 136.3 (Ar-Cq), 130.8 (2ꢃ
Ar-CH), 123.7 (2ꢃAr-CH), 80.39 (9-CH), 68.29 (1-CH2), 46.01 (5-CH2),
41.30 (3-CH2), 40.18 (7-CH2), 33.95 (8-CH), 33.21 (2-CH), 32.06 (22-
CH2), 31.42 (10-CH2), 29.82/29.80/29.76/29.71/29.67/29.64/29.50
(12–21-CH2), 27.61 (6-CH), 27.46 (4-CH), 25.88 (11-CH2), 22.83 (23-
CH2), 21.01 (6’-CH3), 20.31 (4’-CH3), 17.65 (2’-CH3), 14.49 (8’-CH3),
14.26 ppm (24-CH3); HPLC: Chiralcel AD-H column, Hept/iPrOH=
98:2, flow rate=1.0 mLminꢀ1; minor diastereomer tR =11.8 min;
major diastereomer tR =13.7 min.
2
1.52 (m, 6H, 2/4/6-CH, 7-CHH, 10-CH2), 1.46–1.19 (m, 28H, 11–23-
CH2, 3/5-CHH), 1.09–0.83 (m, 14H, 3/5-CHH, 2’/4’/6’/24-CH3);
13C NMR (75 MHz, CDCl3): d=164.1 (Ar-COO-), 150.6 (Ar-Cq), 146.1
(8-Cq), 136.1 (Ar-Cq), 130.8 (2ꢃAr-CH), 123.7 (2ꢃAr-CH), 112.4 (8’-
CH2), 78.19 (9-CH), 68.22 (1-CH2), 45.45 (5-CH2), 41.21 (3-CH2), 40.36
(7-CH2), 33.42 (2-CH), 33.22 (10-CH2), 32.07 (22-CH2), 29.81/29.79/
29.78/29.75/29.69/29.61/29.48 (12–21-CH2), 28.53 (6-CH), 27.83 (4-
CH), 25.57 (11-CH2), 22.81 (23-CH2), 21.09 (4’-CH3), 20.44 (6’-CH3),
17.72 (2’-CH3), 14.24 ppm (24-CH3); IR (film): u˜ =3376, 2952, 2924,
2853, 2360, 2341, 1726, 1650, 1608, 1530, 1461, 1409, 1380, 1348,
1320, 1274, 1168, 1116, 1102, 1080, 1037, 1015, 974, 903, 874, 838,
784, 719 cmꢀ1; UV lmax (log e): 9.01 (261.5 nm, CH3CN); HRMS (ESI):
m/z calcd for: C35H59NO5Na: 596.42857 [M+Na]+; found:
596.42837.
Diastereomer (8R,9S)-31: After TBS-protection and p-NO2Bz-depro-
tection of product (8R,9R)-31,[9b,20] the resulting alcohol (50.0 mg,
92 mmol, 1.0 equiv) was dissolved in THF (0.5 mL, c=0.20m) and
treated at 08C with triphenyl phosphine (119 mg, 0.45 mmol,
4.9 equiv), para-nitrobenzoic acid (68.0 mg, 0.45 mmol, 4.4 equiv),
and DIAD (0.89 mL, 0.41 mmol, 4.9 equiv). After stirring for 5 h at
08C the orange solution was treated with 15 mL water. The aque-
ous phase was extracted with MTBE (3ꢃ10 mL) and the combined
organic extracts were dried over anhydrous Na2SO4. The solid resi-
due was treated with hexane and filtered through a 5 cm pipette
of silica. Purification by flash column chromatography (Hex/MTBE,
50:1) afforded the protected deoxypropionate (44.0 mg, 63.8 mmol,
69%) of as a slightly yellow, viscous oil. The deoxypropionate was
dissolved in MeOH (0.3 mL, c=0.20m), treated with tetrabutylam-
monium tribromide (4.0 mg, 12.8 mmol, 0.2 equiv) and stirred for
4 h at room temperature. The reaction mixture was quenched with
a half sat. NaHSO4 (5 mL) solution and all volatiles were removed
under reduced pressure. The aqueous phase was extracted with
MTBE (3ꢃ10 mL) and the combined organic extracts were dried
over anhydrous Na2SO4. Flash column chromatography (Hex/MTBE,
10:1) gave (8R,9S)-31 (29.3 mg, 50.9 mmol, 80%) as a slighly yellow,
Catalyst screening: (see the Supporting Information, Table 1 in
Section II): A 2 mL glass inlet, equipped with a magnetic stirrer bar
was filled with the catalyst (0.871 mmol, 0.05 equiv) and 0.7 mL (c=
0.023m) of a stock solution of (9S)-28 or (9R)-28 (10 mg, 17.4
mmol, 1.0 equiv) in CH2Cl2. Four of the glass inlets were placed into
the autoclave, which was sealed and purged twice with 50 bar of
hydrogen. The reaction mixture was stirred under hydrogen atmos-
phere at room temperature with the given parameters (1 bar!
15 h, 90 bar!3 h). The solvent was removed under reduced pres-
sure and the residual solid was filtered over 4 cm of a silica pipette
with a 1:1-mixture of Hex/MTBE (6 mL) for HPLC analysis.
Synthesis of the diastereomers (8S,9R)-31, (8S,9S)-31 and
(8R,9S)-31: The hydrogenation experiments for the diastereomeric
pure products (8S,9R)-31 (the Supporting Information, Table 1:
entry 3) and (8S, 9S)-31 (the Supporting Information, Table 1:
entry 17) were repeated in a 34.8 mmol scale. The combined frac-
tions were purified with flash column chromatography (Hex/MTBE,
10:1) to complete the analytical data. Rf =0.21 (Hex/MTBE, 9:1); IR
(film): u˜ =3421, 2953, 2924, 2853, 1723, 1608, 1530, 1460, 1379,
1348, 1319, 1274, 1117, 1102, 1038, 1015, 874, 719 cmꢀ1; UV: lmax
(log e): 4.10 (261.5 nm, CH3CN); HRMS (ESI): m/z calcd for:
C35H61NO5Na: 598.44422 [M+Na]+; found: 598.44398.
viscous oil. [a]2D3 =ꢀ8.97 (c=1.45, CHCl3); H NMR (300 MHz, CDCl3):
1
d=8.29 (m, 2H, 2ꢃAr-CH), 8.20 (m, 2H, 2ꢃAr-CH), 5.17–5.05 (mc,
2
3
1H, 9-CH), 3.54 (dd, J=10.4 Hz, J=4.9 Hz, 1H, 1-CHH), 3.37 (dd,
2J=10.4 Hz, J=6.7 Hz, 1H, 1-CHH), 1.99 (mc, 1H, 8-CH), 1.78–1.49
3
(m, 5H, 2/4/6-CH, 10-CH2), 1.44–1.14 (m, 29H, 3/5/7-CHH, 11–23-
CH2), 1.04–0.81 ppm (m, 18H, 3/5/7-CHH, 2’/4’/6’/8’/24-CH3);
13C NMR (101 MHz, CDCl3): d=164.6 (Ar-COO-), 150.6 (Ar-Cq), 136.4
(Ar-Cq), 130.8 (2ꢃAr-CH), 123.7 (2ꢃAr-CH), 79.87 (9-CH), 68.16 (1-
CH2), 45.35 (5-CH2), 41.01 (3-CH2), 40.72 (7-CH2), 33.98 (8-CH), 33.26
(2-CH), 32.07 (22-CH2), 29.83/29.80/29.77/29.71/29.66/29.50/29.46
(10/12–21-CH2), 28.00/27.90 (4/6-CH), 26.05 (11-CH2), 22.84 (23-CH2),
21.33 (4’/6’-CH3), 17.92 (2’-CH3), 16.05 (8’-CH3), 14.26 ppm (24-CH3);
HPLC: Chiralcel AD-H column, Hept/iPrOH=98:2, flow rate=
1.0 mLminꢀ1; minor diastereomer tR =13.7 min; major diastereomer
tR =11.8 min.
Diastereomer (8S,9R)-31: Yield: 85%; [a]2D3 =ꢀ7.00 (c=1.75, CHCl3,
1
d.r.=98:2); H NMR (400 MHz, CDCl3): d=8.31–8.26 (m, 2H, 2ꢃAr-
2
CH), 8.22–8.17 (m, 2H, 2ꢃAr-CH), 5.16 (mc, 1H, 9-CH), 3.45 (dd, J=
10.4 Hz, 3J=5.1 Hz, 1H, 1-CHH), 3.32 (dd, 2J=10.4 Hz, 3J=6.6 Hz,
1H, 1-CHH), 1.99–1.87 (mc, 1H, 8-CH), 1.79–1.52 (m, 5H, 2/4/6-CH,
10-CH2), 1.37–1.17 (m, 29H, 3/5/7-CHH, 11–23-CH2), 1.14–1.05 (m,
3
3
1H, 7-CHH), 0.93 (d, J=6.7 Hz, 3H, 8’-CH3), 0.92 (d, J=6.7 Hz, 3H,
3
2’-CH3), 1.03–0.81 (m, 5H, 3/5-CHH, 24-CH3), 0.87 (d, J=6.5 Hz, 3H,
4’-CH3), 0.85 ppm (d, 3J=6.5 Hz, 3H, 6’-CH3); 13C NMR (101 MHz,
CDCl3): d=164.7 (Ar-COO-), 150.6 (Ar-Cq), 136.3 (Ar-Cq), 130.8 (2ꢃ
Ar-CH), 123.7 (2ꢃAr-CH), 80.68 (9-CH), 68.33 (1-CH2), 45.98 (5-CH2),
41.38 (3-CH2), 39.18 (7-CH2), 33.99 (8-CH), 33.24 (2-CH), 32.06 (22-
CH2), 30.43 (10-CH2), 29.82/29.80/29.76/29.71/29.66/29.64/29.49
(12–21-CH2), 27.68 (4-CH), 27.60 (6-CH), 25.88 (11-CH2), 22.83 (23-
CH2), 21.02 (6’-CH3), 20.31 (4’-CH3), 17.65 (2’-CH3), 15.48 (8’-CH3),
14.26 ppm (24-CH3); HPLC: Chiralcel OD-H column, Hept/iPrOH=
Hydrogenation product (8S)-39: In a 2 mL glass inlet, equipped
with a magnetic stirrer bar, were placed alcohol 36 (78.0 mg,
93.4 mmol, 1.0 equiv), sodium hydrogencarbonate (6.3 mg,
74.7 mmol, 0.8 equiv), and catalyst (R)-19 (7.1 mg, 46.7 mmol,
0.05 equiv) in CH2Cl2 (0.6 mL, c=0.10m). The glass inlet was placed
into the autoclave, which was sealed and purged twice with 50 bar
of hydrogen. The reaction mixture was stirred under hydrogen at-
mosphere (90 bar) at room temperature for 1 day. After that time
1H NMR spectroscopic analysis indicated leftover starting material.
This procedure was then repeated overall three times with the ad-
dition of 0.10 equiv catalyst for another 1 d under hydrogen at-
mosphere (90 bar). The solvent was removed under reduced pres-
sure and flash column chromatography (EtOAc/Hex 1:20) gave the
diastereomeric pure alkane (8S)-39 (70.8 mg, 70.5 mmol, 91%) as
a colorless oil. TLC: Rf =0.67 (Hex/Et2O, 1:1); [a]2D2 = +4.00 (c=1.75,
99.5/0.5, flow rate=0.5 mLminꢀ1
;
minor diastereomer tR =
56.6 min; major diastereomer tR =62.6 min.
Diastereomer (8S,9S)-31: Yield: 84%; [a]2D3 =ꢀ18.5 (c=1.50, CHCl3,
1
d.r.=96:4); H NMR (400 MHz, CDCl3): d=8.32–8.26 (m, 2H, 2ꢃAr-
2
CH), 8.23–8.18 (m, 2H, 2ꢃAr-CH), 5.08 (mc, 1H, 9-CH), 3.50 (dd, J=
10.4 Hz, 3J=5.1 Hz, 1H, 1-CHH), 3.36 (dd, 2J=10.4 Hz, 3J=6.7 Hz,
1H, 1-CHH), 1.95–1.85 (mc, 1H, 8-CH), 1.76–1.49 (m, 5H, H-2/4/6-
CH, 10-CH2), 1.35–1.21 (m, 27H, 3-CHH, 11–23-CH2), 1.21–1.02 (m,
3
3
1
3H, 3/5/7-CHH), 0.96 (d, J=6.7 Hz, 3H, 8’-CH3), 0.88 (d, J=6.9 Hz,
CHCl3); H NMR (300 MHz, CDCl3): d=7.74–7.65 (m, 4H, 4ꢃAr-CH),
Chem. Eur. J. 2014, 20, 17360 – 17374
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ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[1] S. Omura, H. Tanaka in Antibiotics: Chemistry, Biologie and Practice (Ed.:
S. Omura), Academic Press, New York, 1984, pp. 351–404.
[2] D. I. Chan, H. J. Vogel, Biochem. J. 2010, 430, 1–19.
[3] a) C. Khosla, Chem. Rev. 1997, 97, 2577–2590; b) L. Katz, Chem. Rev.
1997, 97, 2557–2576; c) D. H. Kwan, F. Schulz, Molecules 2011, 16,
6092–6115.
[4] Isolation: a) J. E. Biskupiak, C. M. Ireland, Tetrahedron Lett. 1983, 24,
3055–3058; Total synthesis: b) A. A. Birkbeck, D. Enders, Tetrahedron
Lett. 1998, 39, 7823–7826; c) Y. Galeyeva, S. Helbig, M. Morr, F. Sasse, M.
Nimtz, S. Laschat, A. Baro, Chem. Biodiversity 2006, 3, 935–941; d) G. Sa-
bitha, P. Gopal, J. S. Yadav, Tetrahedron: Asymmetry 2009, 20, 2205–
2210.
7.44–7.31 (m, 6H, 6ꢃAr-CH), 3.63–3.51 (m, 2H, 17-CH, 1-CHH),
3.42–3.33 (m, 1H, 1-CHH), 1.80–1.69 (mc, 1H, 2-CH), 1.04 (s, 9H,
SiC(CH3)3), 0.95 (d, J=6.7 Hz, 3H, 2’-CH3), 1.69–0.71 ppm (m, 74H,
-OH, 4/6/8/10/12/14/16-CH, 3/5/7/9/11/13/15/18–31-CH2, 4’/6’/8’/
10’/12’/14’/16’/32-CH3); 13C NMR (75 MHz, CDCl3): d=136.2 (2ꢃAr-
CH), 136.1 (2ꢃAr-CH), 135.5 (Ar-Cq), 134.6 (Ar-Cq), 129.5 (Ar-CH),
129.4 (Ar-CH), 127.5 (2ꢃAr-CH), 127.4 (2ꢃAr-CH), 76.91 (17-CH),
68.30 (1-CH2), 45.57/45.44/45.41/45.36/45.21 (5/7/9/11/13-CH2),
41.55 (15-CH2), 41.07 (3-CH2), 34.42 (16-CH), 34.36 (18-CH), 33.28 (2-
CH), 32.09 (30-CH2), 29.87/29.83/29.76/29.65/29.57/29.53 (20–29-
3
CH2),
27.99/27.89/27.84/27.79
(4/6/8/10/12/14-CH),
27.32
[5] Isolation: a) B. D. Morris, R. R. Smyth, S. P. Foster, M. P. Hoffmann, W. L.
Roelofs, S. Franke, W. Francke, J. Nat. Prod. 2005, 68, 26–30; Total syn-
theses: b) Y. Schmidt, B. Breit, Org. Lett. 2009, 11, 4767–4769; c) Y.
Schmidt, K. Lehr, U. Breuninger, G. Brand, T. Reiss, B. Breit, J. Org. Chem.
2010, 75, 4424–4433; d) see ref. 21; e) J. S. Yadav, E. Srinivas, C. K. S.
Kumar, K. A. G. A. Al, Synthesis 2012, 44, 628–634; f) P. S. Diez, G. C. Mi-
calizio, Angew. Chem. Int. Ed. 2012, 51, 5152–5156; Angew. Chem. 2012,
124, 5242–5246.
(SiC(CH3)3), 26.04 (19-CH2), 22.86 (31-CH2), 21.86/21.83/21.74/21.55/
21.38/21.24 (4’/6’/8’/10’/12’/14’-CH3), 19.76 (SiC(CH3)3), 17.91 (2’-
CH3), 14.78 (16’-CH3), 14.28 (32-CH3).IR (film): u˜ =3374, 2954, 2924,
2854, 2360, 2341, 1460, 1427, 1377, 1362, 1111, 1040, 822, 739, 702,
688, 611, 506, 488 cmꢀ1; UV lmax (log e): 4.29 (200.5 nm, CH3CN),
3.96 (218.5 nm, CH3CN), 2.86 (265.0 nm, CH3CN); HRMS (ESI): m/z
calcd for C56H100O2SiNa: 855.73848 [M+Na]+; found: 855.73856.
[6] Isolation: a) M. T. Fletcher, S. Chow, L. K. Lambert, O. P. Gallagher, B. W.
Cribb, P. G. Allsopp, C. J. Moore, W. Kitching, Org. Lett. 2003, 5, 5083–
5086; Total synthesis: b) C. Herber, B. Breit, Angew. Chem. Int. Ed. 2005,
44, 5267–5269; Angew. Chem. 2005, 117, 5401–5403; c) S. Chow, M. T.
Fletcher, L. K. Lambert, O. P. Gallagher, C. J. Moore, B. W. Cribb, P. G. All-
sopp, W. Kitching, J. Org. Chem. 2005, 70, 1808–1827; d) J. Zhou, Y.
Zhu, K. Burgess, Org. Lett. 2007, 9, 1391–1393; e) G. Zhu, B. Liang, E.-i.
Negishi, Org. Lett. 2008, 10, 1099–1101; f) N. B. Basar, H. Liu, D. Negi,
H. M. Sirat, G. A. Morris, E. J. Thomas, Org. Biomol. Chem. 2012, 10,
1743–1745.
[7] Isolation: M. Lumb, P. E. Macey, J. Spyvee, J. M. Whitmarsh, R. D. Wright,
Nature 1965, 206, 263–265.
[8] Isolation: H. Ishiwata, T. Nemoto, M. Ojika, K. Yamada, J. Org. Chem.
1994, 59, 4710–4711.
[9] Isolation: a) M. B. Goren, O. Brokl, B. C. Das, E. Lederer, Biochemistry
1971, 10, 72–81; Total synthesis: b) D. Geerdink, B. ter Horst, M. Lepore,
L. Mori, G. Puzo, A. K. H. Hirsch, M. Gilleron, G. De Libero, A. J. Minnaard,
Chem. Sci. 2013, 4, 709–716.
[10] a) S. Hanessian, S. Giroux, V. Mascitti, Synthesis 2006, 7, 1057–1076; B. t.
Horst, B. L. Feringa, A. J. Minnaard, Chem. Commun. 2010, 46, 2535–
2547.
Hydrogenation product (8R)-39: In a 2 mL glass inlet, equipped
with a magnetic stirrer bar, were placed alcohol 36 (49.0 mg,
60 mmol, 1.0 equiv), NaHCO3 (7.6 mg, 90 mmol, 1.5 equiv), and cata-
lyst (S)-19 (13.7 mg, 90 mmol, 0.15 equiv) in 0.5 mL CH2Cl2 (c=
0.10m). The glass inlet was placed into the autoclave, which was
sealed and purged twice with 50 bar of hydrogen. The reaction
mixture was stirred under hydrogen atmosphere (90 bar) at room
1
temperature for 1 day. After that time, H NMR spectroscopy indi-
cated leftover starting material. Another 0.10 equiv catalyst were
added and the reaction was stirred for another 1 day under a hy-
drogen atmosphere (90 bar). The solvent was removed under re-
duced pressure and flash column chromatography (EtOAc/Hex, 1:5)
gave 70.8 mg (70.5 mmol, 88%) of diastereomeric pure alkane (8R)-
39 as a colorless oil. [a]2D2 = +4.93 (c=1.80, CHCl3); 1H NMR
(700 MHz, CDCl3): d=7.71–7.66 (m, 4H, 4ꢃAr-CH), 7.44–7.33 (m,
2
3
6H, 6ꢃAr-CH), 3.61–3.56 (mc, 1H, 17-CH), 3.54 (dd, J=10.0 Hz, J=
4.8 Hz, 1H, 1-CHH), 3.38 (dd, 2J=10.0 Hz, 3J=7.1 Hz, 1H, 1-CHH),
1.73 (mc, 1H, 2-CH), 1.67–1.54 (m, 6H, 4/6/8/10/12/14-CH), 1.53–
1.44 (m, 2H, 16-CH, 15-CHH), 1.39 (mc, 1H, 18-CHH), 1.04 (s, 9H,
3
[11] R. D. Mazery, M. Pullez, F. Lopez, S. R. Harutyunyan, A. J. Minnaard, B. L.
Feringa, J. Am. Chem. Soc. 2005, 127, 9966–9967.
[12] a) B. Breit, P. Demel, Tetrahedron 2000, 56, 2833–2846; b) S. Hanessian,
Y. Yang, S. Giroux, V. Mascitti, J. Ma, F. Raeppel, J. Am. Chem. Soc. 2003,
125, 13784–13792.
[13] a) W. Oppolzer, R. Moretti, G. Bernardinelli, Tetrahedron Lett. 1986, 27,
4713–4716; b) D. R. Williams, W. S. Kissel, J. J. Li, R. J. Mullins, Tetrahe-
dron Lett. 2002, 43, 3723–3727.
SiC(CH3)3), 0.95 (d, J=6.7 Hz, 3H, 2’-CH3), 1.33–0.77 ppm (m, 63H,
18-CHH, 3/5/7/9/11/13/15/19–31-CH2, 4’/6’/8’/10’/12’/14’/16’/32-
CH3); 13C NMR (176 MHz, CDCl3): d=136.2 (2ꢃAr-CH), 136.1 (2ꢃAr-
CH), 135.5 (Ar-Cq), 134.5 (Ar-Cq), 129.5 (Ar-CH), 129.4 (Ar-CH), 127.5
(2ꢃAr-CH), 127.4 (2ꢃAr-CH), 76.75 (17-CH), 68.43 (1-CH2), 46.01/
45.81/45.69/45.52/45.25 (5/7/9/11/13-CH2), 41.56 (15-CH2), 41.46 (3-
CH2), 34.31 (18-CH), 34.28 (16-CH), 33.19 (2-CH), 32.09 (30-CH2),
[14] a) D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs, R. Zahler, J. Am. Chem.
Soc. 1990, 112, 5290–5313; b) A. Abiko, S. Masamune, Tetrahedron Lett.
1996, 37, 1081–1084; c) A. G. Myers, B. H. Yang, H. Chen, D. J. Kopecky,
Synlett 1997, 457–459.
[15] C. Studte, B. Breit, Angew. Chem. Int. Ed. 2008, 47, 5451–5455; Angew.
Chem. 2008, 120, 5531–5535.
29.87/29.83/29.76/29.65/29.59/29.57/29.54
(20–29-CH2),
27.68/
27.50/27.45/27.38 (4/6/8/10/12/14-CH), 27.30 (SiC(CH3)3), 26.03 (19-
CH2), 22.86 (31-CH2), 21.34/21.05/20.99/20.91/20.74 (4’/6’/10’/12’/
14’-CH3), 19.76 (SiC(CH3)3), 18.98 (8’-CH3), 17.70 (2’-CH3), 14.75 (16’-
CH3), 14.30 ppm (32-CH3).
[16] a) B. Breit, C. Herber, Angew. Chem. Int. Ed. 2004, 43, 3790–3792;
Angew. Chem. 2004, 116, 3878–3880; b) C. Spino, M. Allan, Can. J.
Chem. 2004, 82, 177–184.
Acknowledgements
[17] J. Zhou, K. Burgess, Angew. Chem. Int. Ed. 2007, 46, 1129–1131; Angew.
Chem. 2007, 119, 1147–1149.
[18] B. Liang, T. Novak, Z. Tan, E.-i. Negishi, J. Am. Chem. Soc. 2006, 128,
2770–2771.
This work was supported by the Deutsche Forschungsgemein-
schaft and the Studienstiftung des Deutschen Volkes (Ph.D.
fellowship to C.F.W.). We gratefully acknowledge generous
donations of chemicals from BASF, Evonik, and Chemetall
and cordially thank Johannes Diesel (University of Leipzig) for
the synthesis of precursors.
[19] A. K. Ghosh, C. Liu, Org. Lett. 2001, 3, 635–638.
[20] a) For the first linear synthesis of hydroxyphthiioceranic acid see
ref. [9b]; b) M. C. Pischl, C. F. Weise, M.-A. Mꢁller, A. Pfaltz, C. Schneider,
Angew. Chem. Int. Ed. 2013, 52, 8968–8972; Angew. Chem. 2013, 125,
9138–9142.c) R. Rasappan, V. K. Aggarwal, Nature Chem. 2014, 6, 810–
814.
[21] a) C. F. Weise, M. C. Pischl, A. Pfaltz, C. Schneider, Chem. Commun. 2011,
47, 3248–3250; b) C. F. Weise, M. C. Pischl, A. Pfaltz, C. Schneider, J. Org.
Chem. 2012, 77, 1477–1488.
Keywords: asymmetric
hydrogenation · natural products · stereoselectivity
synthesis
·
cross-coupling
·
Chem. Eur. J. 2014, 20, 17360 – 17374
www.chemeurj.org
17373
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[22] S. Mꢁller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521–522.
[23] D. W. Hart, T. F. Blackburn, J. Schwartz, J. Am. Chem. Soc. 1975, 97, 679–
680.
[29] B. ter Horst, B. L. Feringa, A. J. Minnaard, Org. Lett. 2007, 9, 3013–3015.
[30] C. Raminelli, J. V. Comasseto, L. H. Andrade, A. L. M. Porto, Tetrahedron:
Asymmetry 2004, 15, 3117–3122.
[24] a) J. A. Marshall, B. A. Johns, J. Org. Chem. 1998, 63, 7885–7892; b) Y.
Yuan, H. Men, C. Lee, J. Am. Chem. Soc. 2004, 126, 14720–14721.
[25] K. B. Bahnck, S. D. Rychnovsky, J. Am. Chem. Soc. 2008, 130, 13177–
13181.
[26] S. Bell, B. Wꢁstenberg, S. Kaiser, F. Menges, T. Netscher, A. Pfaltz, Science
2006, 311, 642–644.
[31] D. Zhang, J. M. Ready, J. Am. Chem. Soc. 2007, 129, 12088–12089.
[32] a) Procedure: J. M. Brown, P. A. Chaloner, A. G. Kent, B. A. Murrer, P. N.
Nicholson, D. Parker, P. J. Sidebottom, J. Organomet. Chem. 1981, 216,
263–276; b) Review article: J. M. Brown, Angew. Chem. Int. Ed. Engl.
1987, 26, 190–203; Angew. Chem. 1987, 99, 169–182.
[33] M. C. Pischl, Dissertation, University of Leipzig, 2013.
[27] a) S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. Int. Ed. 2006, 45, 5194–
5197; Angew. Chem. 2006, 118, 5318–5321; b) A. Wang, B. Wꢁstenberg,
A. Pfaltz, Angew. Chem. Int. Ed. 2008, 47, 2298–2300; Angew. Chem.
2008, 120, 2330–2332; c) G. G. Bianco, H. M. C. Ferraz, A. M. Costa, L. V.
Costa-Lotufo, C. Pessoa, M. O. de Moraes, M. G. Schrems, A. Pfaltz, L. F.
Silva, J. Org. Chem. 2009, 74, 2561–2566; d) T. Yoshinari, K. Ohmori,
M. G. Schrems, A. Pfaltz, K. Suzuki, Angew. Chem. Int. Ed. 2010, 49, 881–
885; Angew. Chem. 2010, 122, 893–897; e) H. J. Jessen, A. Schumacher,
F. Schmid, A. Pfaltz, K. Gademann, Org. Lett. 2011, 13, 4368–4370.
[28] a) P. Brandt, C. Hedberg, P. G. Andersson, Chem. Eur. J. 2003, 9, 339–
347; b) Y. Fan, X. Cui, K. Burgess, M. B. Hall, J. Am. Chem. Soc. 2004, 126,
16688–16689; c) Y. Zhu, Y. Fan, K. Burgess, J. Am. Chem. Soc. 2010, 132,
6249–6253.
[34] B. Wꢁstenberg, A. Pfaltz, Adv. Synth. Catal. 2008, 350, 174–178.
[35] a) H. M. Lee, T. Jiang, E. D. Stevens, S. P. Nolan, Organometallics 2001,
20, 1255–1258; b) L. D. Vazquez-Serrano, B. T. Owens, J. M. Buriak,
Chem. Commun. 2002, 2518–2519.
[36] M. G. Schrems, Dissertation, University of Basel, 2009.
[37] a) Y. Schmidt, B. Breit, Org. Lett. 2010, 12, 2218–2221; b) Y. Schmidt, K.
Lehr, L. Colas, B. Breit, Chem. Eur. J. 2012, 18, 7071–7081.
Received: June 19, 2014
Published online on October 28, 2014
Chem. Eur. J. 2014, 20, 17360 – 17374
www.chemeurj.org
17374
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim