Site-Selective trans-Hydrostannation of 1,3- and 1,n-Diynes: Application to the Total Synthesis of Typhonosides E and F, and a Fluorinated Cerebroside Analogue

Article abstract of DOI:10.1002/chem.201801344

Propargyl alcohols are privileged substrates for stereochemically unorthodox trans-hydrostannation reactions catalyzed by [Cp*RuCl]₄ (Cp=pentamethylcyclopentadienyl), because an incipient hydrogen bond between the -OH group and the polarized [Ru-Cl] unit assists substrate binding. For this very reason, it is also possible to subject diyne derivatives carrying one -OH group to site-selective stannylation, even if the acetylene units are conjugated and hence, electronically coupled. An unusual temperature dependence was observed in that heating tends to improve site-selectivity, whereas per-stannylation is favored when the reaction is carried out in the cold. This counterintuitive trend can be rationalized based on spectroscopic data; additional support comes from the isolation of the unusual bimetallic complex 11. The bridging fulvene and enynyl ligands in 11 are thought to reflect an interligand redox isomerization process likely triggered by synchronous activation of the 1,3-diyne substrate by two metal centers. The preparative relevance of site-selective trans-hydrostannation is illustrated by the total synthesis of two members of the typhonoside series of glycolipids, which are endowed with neuroprotective properties. Moreover, the preparation of a fluoroalkene sphingosine analogue shows that the tin residue also serves as a versatile handle for late-stage modification of a bioactive target compound.

Full text of DOI:10.1002/chem.201801344

A Journal of
Accepted Article
Title: Site-selective trans-Hydrostannation of 1,3- and 1,n-Diynes.
Application to the Total Synthesis of Typhonosides E and F and a
Fluorinated Cerebroside Analogue
Authors: Alois Fürstner, Xiaobin Mo, Aurelien Letort, Dragos-Adrian
Rosca, and Kosuge Higashida
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To be cited as: Chem. Eur. J. 10.1002/chem.201801344
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Chemistry - A European Journal
10.1002/chem.201801344
Site-selective trans-Hydrostannation of 1,3- and 1,n-Diynes. Application to the Total
Synthesis of Typhonosides E and F and a Fluorinated Cerebroside Analogue
*
Xiaobin Mo, Aurélien Letort, Dragoş-Adrian Roşca, Kosuke Higashida, and Alois Fürstner
Abstract: Propargyl alcohols are privileged substrates for stereochemically unorthodox trans-
hydrostannation reactions catalyzed by [Cp*RuCl] , because an incipient hydrogen bond between the
4
–
OH group and the polarized [RuCl] unit assists substrate binding. For this very reason it is also
possible to subject diyne derivatives carrying one –OH group to site-selective stannylation, even if
the acetylene units are conjugated and hence electronically coupled. An unusual temperature
dependence was observed in that heating tends to improve site-selectivity, whereas per-stannylation
is favored when the reaction is carried out in the cold. This counterintuitive trend can be rationalized
on the basis of spectroscopic data; additional support comes from the isolation of the unusual
bimetallic complex 11. The bridging fulvene and enynyl ligands in 11 are thought to reflect an
interligand redox isomerization process likely triggered by synchronous activation of the 1,3-diyne
substrate by two metal centers. The preparative relevance of site-selective trans-hydrostannation is
illustrated by the total synthesis of two members of the typhonoside series of glycolipids, which are
endowed with neuroprotective properties. Moreover, the preparation of a fluoroalkene sphingosine
analogue shows that the tin residue also serves as a versatile handle for late-stage modification of a
bioactive target compound.
*
Dr. X. Mo, Dr. A. Letort, Dr. D.-A. Roşca, K. Higashida, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
4
5470 Mülheim/Ruhr (Germany)
Email: fuerstner@kofo.mpg.de
Supporting Information and the ORCID identification number(s) for the author(s) of this article can be
found under ##########
1
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Introduction
1,2
1,3,4,5
Our recent studies on ruthenium catalyzed trans-hydrogenation and trans-hydrometalation
reactions showed that internal alkynes of type A bearing a protic substituent at the propargylic
6,7,8,9
position are privileged substrates (Scheme 1).
Ample experimental and computational evidence
suggests that an incipient hydrogen bond between the –XH group (X = O, NR) and the polarized
6
,7,10
[
RuCl] entity of the catalyst favors substrate binding.
Moreover, this interligand interaction
imposes directionality on the loaded complex B and the ensuing transition state, which explains the
generally excellent levels of regio- and stereoselectivity in favor of the /trans-product C. Of the
different hydrometalation reactions investigated, trans-hydrostannation proved to be most receptive
6,7
to this effect. In any case, compounds of type C provide many opportunities for downstream
functionalization, as witnessed by a growing number of applications to target- and/or diversity-
8,11,12,13
oriented synthesis.
Scheme 1. Directed trans-hydrometalation of propargyl alcohol (or amine) derivatives and examples
for downstream diversification of the resulting products; in the Newman-type projection of the
loaded catalyst (B),  denotes the CMe groups of the Cp* ring; Cp* = pentamethylcyclopentadienyl;
DOS = diversity oriented synthesis
Yet another possibility to take advantage of the protic group concerns the site-selective
functionalization of substrates containing more than one triple bond. Proof-of-concept
2
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notwithstanding, our preliminary data had shown that the observed selectivities may not be ideal in
7
certain settings. We now report the results of a more systematic investigation that let us discover a
strong and  at first sight  perhaps counterintuitive temperature dependence. This effect allows the
outcome to be significantly improved in many cases and can be rationalized on the basis of
spectroscopic and crystallographic data. The preparative significance is illustrated by the total
syntheses of two isomeric cerebrosides and a non-natural fluorinated analogue thereof from a
common diyne derivative. This particular application capitalizes on the multitasking character of site-
selective trans-hydrostannation: it constitutes the crucial stereodetermining event and  at the same
time  places a R Sn- substituent onto the alkene product primarily formed, which can serve either as
3
a protecting or as an activating group for the double bond; as such, it enables “on-site” as well as
14
“
off-site” diversification of an elaborate compound at a late stage of the synthesis.
Results and Discussion
trans-Hydrostannation of 1,3-Diynes. Our investigation started with 1,3-diyne derivatives which
were deemed particularly challenging since their conjugated acetylene units are electronically
15,16
interdependent.
In fact, trans-hydrostannation of substrate 1 under standard conditions
furnished the expected /trans-product 2 as well as the distannylated compound 3 in almost equal
amounts as judged by NMR (Table 1). Although tert-propargylic alcohols engage particularly well in
6,7
hydrogen bonding with the [Cp*RuCl] catalyst and therefore exert a pronounced directing effect,
the peculiar steric and electronic features of 1 obviously render the second hydrostannation
competitive. When the reaction was performed at 40°C, an even less favorable product distribution
was obtained, with distannane 3 now being slightly major. To crosscheck this result, CH Cl was
2
2
17
replaced by 1,2-dichloroethane and the temperature raised to the boiling point. We were delighted
to find that these rather forcing conditions entailed a surprisingly selective mono-stannation, with
18
only traces of 3 being detectable by NMR. It is important to note that the mono-stannylated
product 2 was formed with basically unchanged selectivity even when a larger excess of Bu SnH was
3
used.
3
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[
a]
Table 1. Temperature dependence of the trans-hydrostannation of a 1,3-diyne.
[
b]
[b]
[b]
Entry
Solvent
T (°C)
+22
40
+80
2 (%)
51
44
3 (%)
49
56
other isomers (%)
traces
1
2
3
CH Cl2
2
CH Cl2
traces
2
[
c]
DCE
86
5
9
[
a]
[b]
The substrate was added over the course of 1 h to the reaction mixture; product distribution in
1
[c]
the crude material as determined by H NMR; structure not unambiguously confirmed; DCE = 1,2-
dichloroethane
Table 2. Site-selective trans-hydrostannation or one-pot trans-hydrostannation/protodestannation
[
a]
of 1,3-diynes.
[
b]
[c]
[b]
Entry
Product
Yield (%)
Enyne
Yield (%)
1
66
86
[
d]
2
3
42
89
76
4
64
82
85
[
e]
5
6
76
64
[
f]
7
81
[
a]
All reactions were performed in 1,2-dichloroethane at 80°C with [Cp*RuCl] (1.25 mol%) as the
4
[
b]
[c]
catalyst; yield of isolated product after flash chromatography; the crude product was treated
with CuOP(O)Ph in DMF at ambient temperature to entail protodestannation; NMR yield; 2.2.
mmol scale; the yield was 55% when the reaction was carried out at RT in CH Cl , cf. ref. 6,7
[d]
[e]
2
[
f]
2
2
4
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This inverse correlation between mono-hydrostannation and the reaction temperature proved to be
fairly general and the reaction also scaled well (Table 2). A set of 1,3-diynes could be trans-
hydrostannylated at the -bond flanking the propargylic alcohol substituent with good to excellent
levels of selectivity, independent of whether the alcohol substituent is primary, secondary or tertiary.
In all cases investigated, the selectivities and yields were (significantly) higher when the reaction was
performed in refluxing 1,2-dichloroethane than at (or below) ambient temperature. Comparison of
entries 1/2, 3/4 and 5/6 shows a consistent trend regarding the influence of the alkyl cap on the
unreacted alkyne (iPr versus nBu), in that a branched residue was beneficial for selectivity and yield.
The stannylated products do not need to be isolated: if desirable, the crude product can be treated
with, e. g., copper diphenylphosphinate in DMF which results in smooth proto-destannation; the
corresponding E-configured enynes were thus obtained in respectable yields over both steps.
19
Figure 1. Amount of complex formed upon addition of [Cp*RuCl] (1 equiv) to a solution of the
[
a]
respective alkyne in CD Cl , as judged by NMR; no binding at all observed at RT
2
2
The fact that the selective mono-stannation of the propargylic site is favored upon raising the
reaction temperature has its likely origin in the ability of the –OH group to engage in hydrogen
bonding with the polarized [RuCl] bond of the catalyst. This interligand interaction entails a
5
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
1
7
significant stabilization of the resulting complex;  2.8 kcalmol is a conservative estimate, but the
enthalpic gain might actually be substantially higher if a given substrate favors hydrogen bonding on
electronic and/or conformational grounds. The computational data are in excellent accord with NMR,
which showed that propargyl alcohols readily form adducts with [Cp*RuCl] at ambient conditions,
6,7
whereas binding of “ordinary” alkynes is significant only at low temperature; the examples
compiled in Figure 1 are representative. They also show that increased steric bulk further raises the
barrier for catalyst binding. If this trend applies to the conjugated -bonds of 1,3-diyne substrates
such as 1, it is reasonable to assume that the triple bond adjacent to the –OH will get preferentially
activated by the catalyst at ambient temperature or above. In fact, the cherry-red solution formed
1
9
upon addition of [Cp*RuCl]4 to 1 in CD Cl shows a markedly shifted –OH resonance ( = 5.20 ppm
2
2
H
in 4 versus 1.99 ppm in 1). We infer from our previous studies that this spectral feature indicates
6,7,10
strong hydrogen bonding to the chloride ligand on the metal.
Likewise, the complexation-
induced deshielding of the alkyne signals is more pronounced for the proximal than for the distal
20
triple bond (C1 = 73.9 ppm versus C3 = 47.2 ppm), in line with the notion that the propargylic
site binds to the metal, whereas the distal alkyne is primarily affected via conjugation.
Scheme 2. Preferential binding and activation of the propargylic triple bond of a 1,3-diyne at ambient
temperature; adduct formation is quantitative as judged by NMR
6
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Figure 2. Structure of complex 5 in the solid state; only the –OH protons engaged in interligand
hydrogen bonding to the chloride are shown; disorder of the isopropyl caps on the alkyne over two
positions is not shown for clarity
It was not possible to check if the putative complex 4 persists at elevated temperature. In the
4
absence of Bu SnH, facile [2+2] cycloaddition was observed to give the  -cyclobutadienyl complex 5.
3
The structure in the solid state (Figure 2) proved that only the alkyne proximal to the –OH group had
reacted and therefore must had been selectively activated by coordination to the ruthenium center.
It is also pointed out that 5 retains a hydrogen bonding array in the periphery; actually, the
interligand OHCl contacts (2.29(2) and 2.53(3) Å) are “short” and “strong” according to the
21
categories set forth in the literature.
The ability to foster distannation simply by lowering the temperature is also rewarding. Thus, slow
addition of Bu SnH (2.5 equiv.) to a solution of a 1,3-diyne substrate and [Cp*RuCl] (2.5 mol%) in
3
4
CH Cl at 40°C furnished the corresponding distannylated product as a mixture of regioisomers
2
2
(Table 3). While the trans-hydrostannation of the propargylic site was highly /trans-selective in all
cases by virtue of the directing effect exerted by the –OH group, the reaction at the distal triple bond
22
lacks such internal guidance; instead, steric factors seem to reign. The resulting isomers were
difficult to separate and the isolated yields tend to be modest because of inevitable loss of these
rather sensitive products during work up. That the reaction per se proceeds well, however, is evident
7
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from the fact that the yields of the corresponding diene products formed by protodestannation of
the crude material can be substantially higher than those of the bis-stannanes themselves.
Table 3. Exhaustive trans-hydrostannation or one-pot trans-hydrostannation/protodestannation of
[
a]
1
,3-diynes.
[
b]
[c]
[d]
[e]
[c]
Entry Product (, Isomer)
Yield (%)
,/,
Diene
Yield (%)
1
44
94/6
78
2
3
4
5
6
53
52
62
67
31
82/18
80/20
60/40
86/14
73/27
85
56
[
a]
All reactions were performed in CH Cl at 40°C with [Cp*RuCl] (2.5 mol%) and Bu SnH (2.5
2
2
4
3
[
b]
[c]
equiv.); only the ,-isomer is depicted, which was major in all cases but one; yield of the isomer
mixture after flash chromatography;
[
d]
[e]
isomer ratio (NMR) in the crude material;
the crude
product was treated with CuOP(O)Ph in DMF at ambient temperature to entail protodestannation
2
Control experiments indicated that the ease of distannation manifest in these examples likely mirrors
a rather involved process. Thus, attempted trans-hydrostannation of the already mono-stannylated
product 7 proved ineffective under conditions at which the parent 1,3-diyne 6 is readily consumed
(
Scheme 3); only when the time for addition of Bu SnH was massively prolonged could the
3
conversion be improved to still modest 78% (NMR). Therefore it seems unlikely that distannation
primarily proceeds in a stepwise manner, in which the propargylic triple bond reacts prior to the
distal alkyne; rather, we assume that it reflects  at least in part  a synchronistic activation of both
conjugated -systems.
8
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Scheme 3. Control experiments indicating that distannation does not necessarily proceed in a
stepwise manner; only the major ,-isomer of product 8 is shown, even though small amounts of
the ,-isomer are also formed; the reported yields refer to the isomer mixture
Scheme 4. Isolation of a bimetallic fulvene complex formed by formal interligand redox isomerization
9
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Figure 3. Structure of the bimetallic fulvene complex 11 in the solid state; only H-atoms relevant for
the discussion are shown for clarity
Although this notion deserves further investigation, it gains indirect support by the structure of the
bimetallic complex 11 (Scheme 4 and Figure 3). This highly unusual compound crystallized from a
solution of diyne 9 and [Cp*RuCl] (1 equiv.) in CD Cl at 60°C. It is of particular note that one of the
2
2
former Cp* rings has been transformed into a fulvene ligand that bridges the two ruthenium centers;
its very nature is evident from the alternating bond lengths within the ring and the notable
contraction of the exocyclic C15C16 bond (1.452(3) Å) compared to the four neighboring unaltered
methyl groups (e. g. C17C21 1.495(3) Å). Although we have to refrain from postulating how this
formal oxidation (and the concomitant reshuffling of the chlorides) might have taken place, a
“
hydride” must have been detached from the Cp* ring and been transferred to the former 1,3-diyne
unit to give the equally bridging “enynyl”-entity. Details apart, complex 11 is the outcome of a net
interligand redox isomerization and, as such, mirrors prototype reactivity of alkynes activated by
23,24
complexation to Cp*Ru fragments.
Moreover, it showcases the ability and propensity of two
[
Cp*RuCl] units to bind simultaneously to a (sterically unhindered) 1,3-diyne precursor at low
temperature; massive activation of the conjugated -system by the synergistic action of the two
metal fragments must have been the consequence.
trans-Hydrostannation of 1,n-Diynes. Application to the Total Synthesis of Neuroprotective
Cerebrosides. It is also possible to subject 1,n-diyne substrates (n > 3) to site-selective trans-
hydrostannation, the triple bonds of which are non-conjugated. As expected, it is the propargylic site
that reacts preferentially. As previously communicated, the selectivities are particularly high if the
7
remote alkyne is capped with a silyl group or if it is sterically hindered (Table 4).
If the setting is reversed in that binding of the catalyst to the propargylic triple bond is disfavored on
steric grounds, it is again advisable to perform the reaction at elevated temperatures. This aspect is
illustrated by the total synthesis of typhonoside E (12) and F (13), two cerebrosides isolated from the
rhizomes of Typhonium giganteum, which differ from each other only in the configuration of the
25,26
distal C8C9 double bond (Scheme 5).
The producing plant enjoys widespread use in traditional
Chinese medicine for the treatment of various ailments, including stroke and epilepsy. Therefore it is
relevant and noteworthy that these (and closely related) glycolipids were recently shown to exert
1
0
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potential neuroprotective activity in an assay monitoring glutamate-induced apoptosis of neural
PC12 cells; down-regulation of the concentration of cytosolic cytochrome c is supposed to be the
25,27
biochemical basis for this promising physiological effect.
As glutamate-induced toxicity is an
important inducer of neuronal death in various severe pathological conditions, further studies into
this family of natural products are warranted. Specifically, the EC50 values of 12 and 13 were similar

to that of Edaravone , a clinically approved drug compound used to foster recovery of stroke
25
patients as well as for the treatment of amyotrophic lateral sclerosis.
7
[a]
Table 4. Site-selective trans-hydrostannation of 1,n-diynes
[
b]
Entry
Substrate
Major product
Yield (%)
[
c]
1
2
87 (R = TBS)
[
c]
95 (R = TMS)
[
c]
3
4
5
86
90
55
[
d]
[
a]
All reactions were performed upon addition of Bu SnH (1.05-1.2 equiv.) to a solution of the
3
[
c]
substrate and [Cp*RuCl] (1-2 mol%) in CH Cl ; [b] pure compound after flash chromatography;
only traces of distannylated product were detected;
4
2
2
[
d]
yield of pure trans/-product after flash
chromatographic removal of the distannylated byproduct (15-20%)
We conceived that either compound could be made from the same diyne precursor E (Scheme 5).
Whereas exhaustive trans-hydrostannation/protodestannation opens entry into 13, the Bu Sn-group
3
introduced at C4 upon site-selective trans-hydrostannation of the propargylic entity might serve as
28,29
protecting group in the first place:
it ensures the integrity of the alkene it is bound to when the
distal -system is subjected to Lindlar hydrogenation; this sequence of events should allow the
isomeric target 12 to be reached. As an additional bonus, the alkenylstannane in D is a potential site
of late-stage diversification since the CSn bond is amenable to a variety of downstream
functionalizations other than protodestannation (compare Scheme 1). From a conceptual viewpoint,
1
1
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this strategy hence allows for “on site” (in the present case, that is C4) as well as “off-site” (that is
C8/C9) structural and/or functional modification of a relevant bioactive target compound. To
illustrate this point, we deliberately chose the sphingolipid arena, not least because nature produces
a vast number of these secondary metabolites differing in the degree of unsaturatation, the
configuration and the substitution of the double bonds embedded into lipidic tails of different chain
30,31
lengths.
The ability to prepare “libraries” of natural and non-natural compounds of this type in
pure form might ultimately lead to a better understanding of the subtle and still fairly opaque
structure/activity relationships; such knowledge is ever more desirable in view of the many favorable
physiological properties that biochemical and pharmacological studies into this class of compounds
32,33,34
continue to reveal.
The discovery of the neuroprotective activity of 12, 13 and their relatives
alluded to above is deemed representative.
Scheme 5. Structure and retrosynthetic analysis of typhonosides E and F
The actual synthesis of the typhonosides started with the C-alkylation of 4-pentyn-1-ol (14), which
35
was best achieved after temporary O-THP-protection (Scheme 6); although direct C-alkylation of
the dilithium salt formed from 14 and nBuLi (2 equiv.) is also possible, the reaction proved erratic
1
2
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because of the poor solubility of this salt in THF or THF/DMPU. A routine sequence of THP-cleavage,
36
37
Swern oxidation and Corey-Fuchs reaction furnished the desired diyne 16 without incident. When
carried out in the presence of DMPU (2 equiv), the addition of the derived lithium acetylide to Garner
38
aldehyde (22) was highly diastereoselective, providing the desired anti-configured propargyl
39,40
alcohol 17 with a dr > 20:1.
This favorable outcome is attributed to the affinity of DMPU to the
lithium cation, which prevents formation of a chelate of type G and hence ensures kinetic control via
a Felkin-Ahn transition state (F).
Scheme 6. a) 3,4-Dihydro-2H-pyran, TsOHH O (1 mol%), CH Cl , 93%; b) (i) nBuLi, THF, 78°C; (ii)
2
2
2
C H I, reflux; c) TsOHH O (2 mol%), MeOH, 93% (over both steps); d) (i) (COCl) , DMSO, CH Cl ,
9
19
2
2
2
2

78°C; (ii) Et N, 78°C  0°C, 69%; e) CBr , PPh , CH Cl ; f) nBuLi, THF, 78°C, 85% (over both steps);
3
4
3
2
2
g) (i) nBuLi, THF, 20°C; (ii) DMPU, then 22, 78°C  20°C, 77%; h) Bu SnH, [Cp*RuCl] (5 mol%),
3
4
CH Cl , 20°C, 80-84% (mixture of isomers); i) CuTC, Ph PO NBu , DMF, 85%; j) PhCOOH, DCC, DMAP,
2
2
2
2
4
1
3
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CH Cl , 86%; k) aq. HCl, EtOH, reflux; l) 23, Et N, THF, 66% (over both steps); m) 24, AgOTf, CH Cl , MS
2
2
3
2
2
4
Å, 20°C  0°C, 82%; n) NaOMe cat., MeOH/THF (1:1), 5°C, 83%; CuTC = copper thiophene-2-
carboxylate; DCC = dicyclohexylcarbodiimide; DMPU = N,N′-dimethylpropylene urea; MS = molecular
sieves; Ts = p-toluenesulfonyl; Tf = trifluorosulfonyl
In line with the results outlined above for conjugated 1,3-diynes, the exhaustive trans-
hydrostannation of the 1,5-diyne substructure in 17 was best carried out at low temperature to give
the distannylated product 18 in 80-84% yield as an inconsequential mixture of regioisomers at the
distal site. Subsequent protodestannation on treatment with CuTC/Ph PO NBu in DMF furnished the
2
2
4
expected E,E-configured diene as a single isomer within the limits of detection; its transformation
41
into typhonoside F (13) basically followed established methodology. Specifically, benzoylation of
the free alcohol preceded concomitant cleavage of the N-Boc and the isopropylidene group in 19
with HCl in EtOH; the resulting crude amine hydrochloride was acylated with the activated ester 23
(
for its preparation, see the Supporting Information). The resulting product 20 was subjected to a
AgOTf-mediated Koenigs-Knorr glycosidation with tetra-O-benzoyl--D-glucopyranosyl bromide (24)
42
at low temperature; global deprotection then furnished the target compound 13 in ca. 11% overall
yield over the 14 steps of the longest linear sequence. Suffice it to say that the analytical and
spectroscopic data of the synthetic samples were in excellent agreement with those of the natural
25
product as described by the isolation team.
Next, we explored the possibility to subject diyne 17 to a site-selective trans-hydrostannation, which
was expected to be challenging in this particular case: it is of note that the propargylic C4-C5 alkyne is
encumbered by the rigid isopropylidene acetal and the bulky N-Boc substituent in its vicinity,
whereas access of the catalyst to the “regular” alkyne at C8C9 is unhindered. Yet, the directing
effect exerted by the –OH substituent largely outweighed this a priori unfavorable situation (Scheme
7
). Although distannation could not be fully suppressed even in refluxing 1,2-dichloroethane, an
appreciable 50% (71% brsm) yield of 26 was obtained, provided the stannane was added slowly to
the mixture. To properly assess this result, it is emphasized that attempted intramolecular and hence
entropically favored trans-hydrosilylation failed completely under conditions previously
43,44
recommended in the literature.
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4
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Chemistry - A European Journal
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Scheme 7. a) Bu SnH, [Cp*RuCl] (1.3 mol%), 1,2-dichloroethane, reflux, 50% (71% brsm) + 18 (21%);
3
4
b) H , Pd/C, quinoline, MeOH, 91%; c) CuTC, Ph PO NBu , DMF, 91%; d) PhCOOH, DCC, DMAP, CH Cl ,
2
2
2
4
2
2
9
3%; e) aq. HCl, EtOH, reflux; f) 23, Et N, THF, 70% (over both steps); g) 24, AgOTf, CH Cl , MS 4 Å,
3
2
2

20°C  0°C, 80%; h) NaOMe cat., MeOH/THF (1:1), 5°C, 81%; i) Me (EtO)SiH, [Cp*Ru(MeCN) ]PF
2
3
6
(
1.3 mol%), CH Cl , 0°C  RT; j) HN(SiMe ) , tBuOK (20 mol%), THF
2
2
3 2
With ample material in hand, it was straightforward to complete the synthesis of typhonoside E (12).
To this end, 26 was subjected to hydrogenation over palladium on charcoal poisoned with quinoline,
which left the alkenylstannane entity intact. Subsequent protodestannation furnished the E,Z-
configured diene 27 as a single isomer according to NMR. Its transformation into 12 proceeded
uneventfully by following the route outlined above for isomer 13.
Scheme 8. a) AgOP(O)Ph , F-TEDA-PF , acetone, 50%
2
6
1
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10.1002/chem.201801344
To illustrate the versatility of the tin residue as a handle for late-stage modification, we targeted the
corresponding alkenyl fluoride 31 (Scheme 8). A number of fluorinated sphingolipids are known in
45
the literature, but we are aware of a single example in which the fluorine atom had been placed at
46
an olefinic site. Monolayers of this compound at an air/water interface showed higher stability than
monolayers of its non-fluorinated analogue; this observation might imply that the properties of
46
biological membranes can also be modulated by incorporation of fluorinated glycolipids. The
literature route had introduced the fluorine label in the very first step and carried it through the
46
entire sequence from there on. Our approach is conceptually different in that product 31 was
prepared by late-stage fluorination, wherein the tin atom of 25 was replaced with retention of the
double bond configuration on treatment with F-TEDA-PF in the presence of bench-stable silver
6
47
phosphinate (AgOP(O)Ph ); as previously shown by our group, the use of this essentially neutral and
2
non-nucleophilic promotor is essential for success, although competing protodestannation could not
be fully suppressed in this particular case, probably because access of the rather bulky fluorinating
47
agent to the congested metalated site in 25 is disfavored. In any case, formation of 31 adds an
important entry to the growing list of fluoroalkene derivatives of biological significance
(prostaglandins, macrolide antibiotics, fluorinated peptides and peptide isosteres) prepared by late-
47,11f,48
stage tin/fluorine exchange.
Conclusions
Conjugated as well as non-conjugated diyne derivatives are amenable to either exhaustive or site-
selective trans-hydrostannation as long as they carry an unprotected –OH substituent next to one of
their triple bonds. Interestingly, the site-selective process is favored in boiling 1,2-dichloroethane,
whereas low temperature is recommended for the concomitant stannylation of all alkynes present in
the substrate. This unusual temperature profile can be rationalized on the basis of spectroscopic and
crystallographic data; it proved instrumental for the total synthesis of two isomeric cerebrosides and
a fluorinated analogue thereof. In addition to providing valuable material for biological testing, this
particular application also showcases that trans-hydrostannation can gain a strategic function in
target-oriented synthesis beyond its role as a stereodetermining event. On the one hand, the R Sn-
3
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Chemistry - A European Journal
10.1002/chem.201801344
group can serve as a protecting group for the alkene it is placed upon, which in turn enables selective
off-site” derivatization of other -systems in a given compound; on the other hand does the rich
“
chemistry of the C-Sn bond open many opportunities for “on-site” functionalization and therefore
qualifies for diversity-oriented synthesis programs. What is true for trans-hydrostannation might very
well pertain to the growing portfolio of other alkyne trans-addition reactions too. Further studies
intending to corroborate this notion are underway in our laboratory.
Experimental Section
All experimental details can be found in the Supporting Information. The material includes
crystallographic abstracts, compound characterization data and copies of spectra of new compounds
Acknowledgements
Generous financial support by the Alexander-von-Humboldt Foundation (fellowship to D.-A. R.), JSPS
(research fellowship for young scientists to K. H.) and the MPG is gratefully acknowledged. We thank
Dr. F. Ungeheuer for preliminary results, Mrs. K. Radkowski for technical assistance, Mr. J. Rust and
Dr. R. Goddard for solving the X-ray structures, and all analytical departments of our Institute for
excellent support.
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Chemistry - A European Journal
10.1002/chem.201801344
For the Table of Contents
Counterintuitive: That the selectivity for site-selective mono-stannation increases at higher
temperature is non-obvious at first sight, but can be explained on the basis of spectroscopic,
computational and crystallographic data. This transformation gained a strategic role in the total
synthesis of two isomeric cerebroside derivatives and a non-natural fluoro-alkene analogue thereof.
Keywords: Alkynes  Cooperativity  Glycolipids  Natural Products  Organotin Compounds 
Ruthenium  trans-Hydrometalation
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Chemistry - A European Journal
10.1002/chem.201801344
1
The expression trans-hydrogenation (boration, silylation, germylation, stannation) of an alkyne
as used herein denotes a reaction in which the H and the E-unit (E = H, BR , SiR , GeR , SnR )
2
3
3
3
end up trans to each other. For the formalism of nomenclature, however, the resulting
products are correctly termed Z-configured for E = SiR , GeR , SnR but E-configured for E = H,
3
3
3
BR2.
2
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Chemistry - A European Journal
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7
8
As expected, site-selectivity is lost upon silylation or acetylation of the –OH group.
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1
19
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0
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Chemistry - A European Journal
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22
A comparison of entries 3 and 4 is instructive: the bulkier iso-propyl cap favors the isomer in
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3
tin residue preferentially at the more distal site. Whereas this pattern is counterintuitive on
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