Stereospecific Synthesis of Fluoroalkenes by Silver-Mediated Fluorination of Functionalized Alkenylstannanes

Article abstract of DOI:10.1002/chem.201605444

The known procedures for the conversion of alkenylstannanes into the corresponding fluoroalkenes suffer from largely variable yields and a limited compatibility with functional groups; most notably, protodestannation becomes a serious issue whenever protic sites are present in the substrate. Outlined in this paper is a convenient alternative with a much improved application profile, which is largely unperturbed by free alcohols and amides of all sorts. Key to success is the use of F-TEDA-PF₆in combination with non-hygroscopic and bench-stable silver phosphinate (AgOP(O)Ph₂) that acts as an essentially neutral, non-nucleophilic promotor and effective tin-scavenger at the same time. This new method opens many opportunities for late-stage fluorination of elaborate compounds far beyond the scope of the literature procedures, as witnessed by the preparation of a fluorinated macrolide antibiotic, a fluorinated prostaglandin derivative, and a set of fluorinated amino acid surrogates and peptide isosteres.

Full text of DOI:10.1002/chem.201605444

A Journal of
Accepted Article
Title: Stereospecific Synthesis of Fluoroalkenes by Silver-Mediated
Fluorination of Functionalized Alkenylstannanes
Authors: Alois Fürstner and Heiko Sommer
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10.1002/chem.201605444
Chemistry - A European Journal
Stereospecific Synthesis of Fluoroalkenes by Silver-Mediated Fluorination of
Functionalized Alkenylstannanes
Heiko Sommer and Alois Fürstner*
Dedicated to Prof. Masakatsu Shibasaki on the occasion of his 70th birthday
Abstract: The known procedures for the conversion of alkenylstannanes into the corresponding
fluoroalkenes suffer from largely variable yields and a limited compatibility with functional groups;
most notably, protodestannation becomes a serious issue whenever protic sites are present in the
substrate. Outlined in this paper is a convenient alternative with a much improved application profile,
which is largely unperturbed by free alcohols and amides of all sorts. Key to success is the use of F-
TEDA-PF6 in combination with non-hygroscopic and bench-stable silver phosphinate (AgOP(O)Ph2)
that acts as an essentially neutral, non-nucleophilic promotor and effective tin-scavenger at the same
time. This new method opens many opportunities for late-stage fluorination of elaborate compounds
far beyond the scope of the literature procedures, as witnessed by the preparation of a fluorinated
macrolide antibiotic, a fluorinated prostaglandin derivative, and a set of fluorinated amino acid
surrogates and peptide isosteres.
Our group has recently described a practical, mild and scalable method for the ruthenium catalyzed
trans-hydrostannation of internal alkynes.1,2 This stereochemically unorthodox transformation is
distinguished by high yields and an excellent compatibility with functional groups, including
substituents that would not persist under free radical conditions.1,2,3,4 Moreover, the addition process
is also highly regioselective when working with unsymmetrical acetylene derivatives such as A that
carry a protic group in vicinity to the reacting triple bond (Scheme 1): in this case, the tin moiety is
faithfully delivered to the C-atom proximal to the –XH (X = O, NR) group, provided that [Cp*RuCl]4 is
chosen as precatalyst. The massive steering effect originates from interligand hydrogen bonding
*
Dr. H. Sommer, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
E-Mail: fuerstner@kofo.mpg.de
** Supporting Information for this article is available on the WWW under ###################
1
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10.1002/chem.201605444
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between the protic substituent and the polarized [RuCl] unit, which imposes directionality onto the
ligand sphere of the loaded complex of type B.2
Scheme 1. Directed trans-hydrostannation/fluorination sequence; for X = N-PG, the resulting
fluoroalkenes capture the polarity and conformation of an s-trans amide bond and hence represent
valid peptide isosteres; PG = protecting group;  denotes a CMe unit
In order to harness the full potential of this remarkably selective transformation, it is necessary to
develop adequate downstream chemistry for the resulting alkenylstannanes C.5,6,7 In this context, we
became interested in converting them into the corresponding alkenyl fluorides D: strategic
placement of a fluorine atom adjacent to the hydroxyl substituent (X = O) is expected to result in
increased (metabolic) stability since the induced electron-withdrawal within the -framework
renders the allylic substituent less ionization-prone.8 Moreover, fluoroalkenes with a flanking amido
substituent (X = NR) are known to capture the polarization and conformation of an s-trans amide
bond and hence serve as non-scissile, lipophilic and conformationally locked peptide isosteres
(Scheme 1).9,10 Most synthetic approaches to compounds of type D start from one of the few readily
available small fluorinated building blocks and successively assemble the carbon framework from
there on.8-11 In conceptual terms, the proposed conversion of C into D is orthogonal in that the
formation of the (polyfunctionalized) skeleton precedes the introduction of the fluorine substituent.12
For this complementarity, the current method should be of interest for the life sciences at large.13,14
Surprisingly though, we had to learn that none of the literature methods that allow alkenyl tin
derivatives to be converted into the corresponding fluorides proved adequate for the projected case.
2
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Protocols relying on the use of elementary fluorine,15 acetyl hypofluoride16 or shock-sensitive
caesium fluoroxysulfate17 were neither deemed practical nor did the literature data look promising;18
likewise, XeF2 in combination with AgOTf is known to be low-yielding and unselective when applied
to alkenylstannanes containing unprotected –OH groups.19 Akin, the use of F-TEDA-BF4 (Selectfluor®)
or F-TEDA-PF6  with20,21 or without22,23 (stoichiometric or catalytic) AgOTf  engendered either
decomposition or substantial proto-destannation when applied to model substrate 1 (Table 1, entries
1-7), although F-TEDA-PF6/AgOTf is the reagent combination of choice for the (late stage) fluorination
of various aryltin derivatives.20 Since large amounts of alkene 3 are difficult to separate from the
desired fluoroalkene 2, its formation is a major complication in practical terms.
Scheme 2. Productive fluorodestannation mediated by AgX engenders lethal protodestannation
whenever the Bu3SnX primarily formed is prone to react with the protic substrate
We figured that the tin by-product formed in the transmetalation step might account for this
inadequate situation, at least to a large extent (Scheme 2). Although previous screening campaigns
had identified AgOTf as optimal promotor,19,20 the resulting R3SnOTf can react with compounds
containing an unprotected –OH group such as 1 to release detrimental TfOH; this off-cycle event
represents a potential suicide mechanism. The problem is all the more severe since early attempts to
quench incidental Bronsted acids in the mixture with the help of heterogeneous bases have been
reported to be of no avail; likewise, the use of excess 2,6-di-tert-butyl-4-methylpyridine in
combination with XeF2/AgOTf is known not to prevent protodestannation from occurring either.19
Entries 5 and 7 in Table 1 confirm these prior failures.
3
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Table 1. Optimization of the fluorodestannation of compound 1[a]
Entry
AgX (eq.)
---
F-TEDA-PF6 (eq.) Additive (eq.)
3 (%)[b]
---[c]
71
2 (%)[b]
---[c]
1
2
3
4
5
6
7
8
9
2.0
AgOTs (2)
AgOTf (2)
AgOTf (2)
AgOTf (0.1)
AgOTf (0.2)
AgOTf (0.2)
1.2
1.2[d]
29
48
52
1.2
35
65
1.5
1.2
1.2
NaHCO3 (2)
53
47
[Ph2P(O)O][Bu4N] (2)
[Ph2P(O)O][Bu4N] (2)/pyridine (0.2)[e] 67
59
41
33
AgOP(O)Ph2 (2) 1.2
AgOP(O)Ph2 (2) 2.0
29
71
<7%
>93 (78)[f,g]
[a] all reaction were carried out in acetone at ambient temperature; [b] ratio in the crude product, as determined
[c]
[d]
by NMR, upon full conversion of the substrate; complex mixture; using F-TEDA-BF4 instead of F-TEDA-PF6;
[e] 2,6-di-tert-butyl-4-methylpyridine; [f] slow addition of the stannane over 1 h; [g] isolated yield
Therefore we pursued a different strategy to remedy the problem, envisaging effective tin
scavenging rather than post-facto neutralization of any Bronsted acid released in situ. Aware of the
beneficial effect that certain phosphinate salts exert in exigent Stille reactions,24,25,26 we turned our
attention to this tin sequestering agent. Whereas addition of [Ph2P(O)O][Bu4N] to a mixture of F-
TEDA-PF6 (or F-TEDA-BF4) and AgOTf did not improve the outcome (entries 6, 7), replacement of
AgOTf by AgOP(O)Ph2 was rewarding. Specifically, addition of the alkenyltin derivative over the
course of 1 h to a pre-stirred and hence homogenized mixture of AgOP(O)Ph2 and F-TEDA-PF6 in
acetone furnished analytically pure fluoroalkene 2 in 78% yield on a 1 mmol scale (entry 9); under
these conditions, competing protodestannation was marginal ( 7% in the crude mixture, NMR).
AgOP(O)Ph2 is easy to prepare on multigram scale as a non-hygroscopic and bench-stable solid (see
the Supporting Information);27 since the resulting R3SnOP(O)Ph2 is poorly soluble and hence largely
removed upon filtration of the crude mixture through a pad of silica, product purification is
straightforward. These favorable attributes render the new procedure practical and robust.
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Figure 1. Model fluoroalkenes prepared by treatment of the corresponding alkenyltin derivatives
[a]
with F-TEDA-PF6 (2 eq.) and AgOP(O)Ph2 (1.2 eq.) in acetone at ambient temperature;
the
organotin substrate and the derived fluoroalkene were a 6:1 mixture of regioisomers; TBS = tert-
butyldimethylsilyl; Ts = p-toluenesulfonyl;
Figure 2. Structure of compound 14 in the solid state.
The scope of the new procedure is evident from the examples compiled in Figure 1. Protic sites in the
substrate are well tolerated: this includes primary, secondary and tertiary alcohols at allylic,
homoallylic and remote positions, as well as amides, carbamates, sulfonamides, and
phosphonamides (see below); competing protodestannation was no serious issue in any of the cases
investigated. Equally gratifying is the compatibility with functional groups such as aldehydes, esters,
enoates, nitriles, phthalimide and even silyl ethers. These common protecting groups are
5
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10.1002/chem.201605444
Chemistry - A European Journal
endangered by any recipe that comprises nucleophilic anions (most notably fluoride) or eventually
releases acids such as HOTf or HF; moreover, they are cleaved when F-TEDA-BF4 alone is used as [F+]
source.22 Likewise, the sensitive doubly allylic alcohol in 10 proved stable and the pre-existing alkene
passed uncompromised. Finally, compound 16 shows that the new procedure is not limited to
alkenylstannanes bearing an allylic –OH or NHR substituent but also works for “ordinary” substrates
of this type.
The stereospecific nature of the fluorination was conclusively demonstrated by X-ray diffraction of
compound 14 (Figure 2) and its stannylated precursor (see the Supporting Information), which are
both Z-configured.28 Another noteworthy feature of the structure of 14 in the solid state is the
hydrogen bond between the sulfonamide NH proton and the flanking fluoride (2.671 Å). This
interaction seems to impose a preferred conformation on the compound,29 which is particularly
relevant for the use of fluoroalkenes as peptide isosteres (see below).
Scheme 3. a) Bu3SnH, [Cp*RuCl2]n (5 mol%), CH2Cl2, 83%; b) Pd(PPh3)4 (5 mol%), [Ph2PO2][NBu4],
CuTC, MeI, DMF, 92%; c) F-TEDA-PF6, AgOP(O)Ph2, acetone, 84%
The significance of the new method is further illustrated by selected applications to natural product
chemistry. In a first foray, we prepared compound 20 as an analogue of the antibiotic 5,6-
dihydrocineromycin B (19), in which the C8 methyl branch of the natural product is formally replaced
by a stabilizing fluorine substituent.30 As shown in Scheme 3, the alkenyltin derivative 18 formed by
6
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hydroxyl-directed trans-hydrostannation of cycloalkyne 17 serves as common intermediate;5 17, in
turn is readily prepared by ring closing alkyne metathesis.31,32 Fluoroalkene 20 complements a series
of non-natural analogues of 5,6-dihydrocineromycin B (19) previously prepared in this laboratory;5,6
collectively, these compounds illustrate the versatility of the emerging trans-addition chemistry in
the context of diverted total synthesis.33 As expected, the late-stage fluorination proceeded well in
the presence of the two unprotected alcohols and the enoate subunit comprised in the macrocyclic
ring of stannane 18.
Scheme 4. a) TBSCl, imidazole, DMF; b) HOAc, aq. THF, 58% (over both steps); c) oxalyl chloride,
DMSO, Et3N, CH2Cl2, 60°C  RT; d) (MeO)2P(O)CHN2, KOtBu, THF, 78°C  RT, 66% (over both
steps); e) PhSC(O)C5H11, (dppf)PdCl2 (10 mol%), (2-furyl)3P (25 mol%), CuI, DMF/Et3N (5:1), 68%; f) 24,
BH3Me2S, THF, 30°C, 82% (dr > 20:1); g) Bu3SnH, [Cp*RuCl]4 (5 mol%), CH2Cl2, 62%; h) TBAF3H2O,
THF, 0°C  RT, 77%; i) F-TEDA-PF6, AgOP(O)Ph2, acetone, 67%; j) see ref.34; Cp* =
pentamethylcyclopentadienyl; dppf = 1,1′-ferrocenediyl-bis(diphenylphosphine); TBAF = tetra-n-
butylammonium fluoride
Next, we targeted compound 27 which is a known advanced building block for the synthesis of 14-
fluoro-prostaglandin F2 methyl ester (28); this analogue of natural PGE F2 exhibits pronounced
antifertility but reduced smooth-muscle activity.34,35 Commercial Corey lactone 21 served as
convenient point of departure,36 which was converted into ynoate 23 by routine operations. CBS-
reduction nicely set the (15S)-configuration (dr > 20:1),37 a critical determinant for PG-receptor
7
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affinity and specificity in mammals, and, in so doing, created the steering substituent for the
subsequent trans-hydrostannation. As expected, this reaction furnished compound 26 essentially as
a single isomer, which was desilylated prior to treatment with F-TEDA-PF6/AgOP(O)Ph2. Once again,
the reaction proceeded smoothly in the presence of two unprotected secondary alcohols, which
almost certainly preclude application of any other method for fluorodestannation known prior to this
work.
From the conceptual viewpoint, a brief comparison with the literature route is informative, which
used fluoroacetic acid as key building block for the preparation of 27.34 After conversion into a
suitable phosphonate reagent, incorporation into the prostaglandin framework relied on a Horner-
Emmons olefination that proved stereo-unselective and actually favored the undesired fluoroalkene
isomer to a large extent (64:10); for its elaboration into 27, the fluorine tag had to be carried through
seven linear operations. The new strategy shown in Scheme 4 is orthogonal in that it introduces the
fluorine substituent in the final step and avoids any selectivity issues by taking advantage of the
virtues of ruthenium catalyzed alkyne trans hydrometalation.12
Scheme 5. a) see the Supporting Information; b) Bu3SnH, [Cp*RuCl]4 (1 mol%), CH2Cl2; c) F-TEDA-PF6,
AgOP(O)Ph2, acetone; Cbz = benzyloxycarbonyl; Ns = 2-nitrophenylsulfonyl
The use of small fluorinated building blocks also dominates the preparation of -amino substituted
fluoroalkene derivatives as non-hydrolyzable, lipophilic and conformationally rigid peptide isosteres
for biochemical, biophysical and medicinal research.9,38 Therefore it seemed worthwhile to check if
8
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10.1002/chem.201605444
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the new methodology provides opportunities in this area too. For proof-of-concept, we prepared
several N-protected leucine- (32), valine- (33) and phenylalanine surrogates (34),39 as well as a more
elaborate tripeptide isostere (35) (Scheme 5). To this end, a series of secondary propargyl amines 29
was prepared by recourse to known methodology;40 it is emphasized that the hexynyl residue in
these model compounds was chosen only for practicality reasons. They were then either N-acylated
with one of the protecting groups commonly used in peptide chemistry or coupled to a small peptide
sequence (Z-Gly-Phe). The subsequent hydrostannations furnished the ,trans-adducts with high
selectivity, which shows that the protic amide (peptide), sulfonamide or phosphonamide groups are
adequate steering substituents for the chosen [Cp*RuCl]4 catalyst. The final introduction of the
fluorine substituent with the help of F-TEDA-PF6/AgOP(O)Ph2 also worked well; only in the case of 35
was the crude product no more than ca. 80% pure, whereas protodestannation was subordinate in
all other instances. In any event, this case study shows the ready availability of a library of valuable
synthons and peptide isosteres by late-stage fluorination, which none of the established methods
would be able to provide.12,41
Hence we conclude that the simple switch from AgOTf to AgOP(O)Ph2 upgrades the performance and
functional group compatibility of late-stage electrophilic fluorination of alkenyl tin derivatives to a
significant extent; for the first time, even protic sites are tolerated without risking protodestannation
to take over. When allied with powerful modern stannylation techniques such as the ruthenium
catalyzed trans-hydrostannation of internal alkynes, this new procedure enables functionalization of
elaborate and polyfunctionalized compounds, as illustrated by the preparation of a fluorinated
macrolide antibiotic, a fluorinated prostaglandin derivative and a set of fluorinated amino acid and
peptide isosteres. Further applications of this and related methodologies will be reported in due
course.
Acknowledgements. Generous financial support by the MPG is gratefully acknowledged. We thank
the Analytical Departments of our Institute for excellent support and Umicore AG & Co KG, Hanau,
for a generous gift of noble metal salts.
9
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For the Table of Contents
On (late) stage: A highly regioselective net trans-addition of HF across a triple bond is achieved by a
sequence of ruthenium-catalyzed trans-hydrostannation followed by fluorodestannation; the latter
reaction hinges on the use of silver phosphinate as non-nucleophilic tin scavenger, whereas other
promotors engender massive protodestannation if protic sites are present in the substrate.
Keywords: fluorination  peptide isosteres  silver  tin  trans-addition
10
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1
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Chemistry - A European Journal
21
The only application of F-TEDA-PF6/AgOTf to an alkenylstannane reported in the literature was
low yielding; this outcome was ascribed to the volatility of the product formed, cf. the
Supporting Information for ref. [20b].
22
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10.1002/chem.201605444
Chemistry - A European Journal
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