A Stereoconvergent Tsuji–Trost Reaction in the Synthesis of Cyclohexenyl Nucleosides

Article abstract of DOI:10.1002/chem.201905367

A highly regio- and stereoselective route to d- and l-cyclohexenyl nucleosides has been devised, using the Tsuji–Trost reaction as the key step. Contrarily to the widely accepted mechanism (involving a net retention of configuration), the reaction proceeded in a highly stereoconvergent manner, providing cis nucleosides regardless of the relative configuration of the starting materials. DFT calculations confirmed the experimental data while suggesting the origin of the stereochemical reaction outcome.

Full text of DOI:10.1002/chem.201905367

A Journal of
Accepted Article
Title: A Stereoconvergent Tsuji-Trost Reaction in the Synthesis of
Cyclohexenyl Nucleosides
Authors: Anna Esposito, Concetta di Giovanni, Maria De Fenza,
Giovanni Talarico, Marco Chino, Giovanni Palumbo, Daniele
D'Alonzo, and Annalisa Guaragna
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To be cited as: Chem. Eur. J. 10.1002/chem.201905367
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A Stereoconvergent Tsuji-Trost Reaction in the Synthesis of
Cyclohexenyl Nucleosides
Anna Esposito,[a] Concetta di Giovanni,[a] Maria De Fenza,[a] Giovanni Talarico,[a] Marco Chino,[a]
Giovanni Palumbo,[a] Annalisa Guaragna*[a] and Daniele D’Alonzo*[a]
[a]
A. Esposito, C. di Giovanni, Dr. M. De Fenza, Prof. G. Talarico, Dr. M. Chino, Prof. G. Palumbo, Dr. A. Guaragna, Dr. D. D’Alonzo
Department of Chemical Sciences
Università degli Studi di Napoli Federico II
via Cintia, 80126 Napoli (Italy
E-mail: annalisa.guaragna@unina.it (A.G.), daniele.dalonzo@unina.it (D.D.).
Supporting information for this article is given via a link at the end of the document.
Abstract: A highly regio- and stereoselective route to D- and L-
cyclohexenyl nucleosides has been devised, using the Tsuji-Trost
reaction as the key step. Contrarily to the widely accepted mechanism
(involving a net retention of configuration), the reaction proceeded in
analysis of biological properties of enantiomeric compounds13
took us to explore the antiviral properties of novel cyclohexenyl
nucleosides 5 and ent-5 (Figure 1c).14 Compared to 4 and ent-4,
the formal removal of the sec-OH function at C5'-position was
conceived to provide antiviral agents acting as chain
terminators.15
a
highly stereoconvergent manner, providing cis nucleosides
regardless the relative configuration of the starting materials. DFT
calculations confirmed the experimental data while suggesting the
origin of the stereochemical reaction outcome.
The palladium-catalyzed allylic substitution reaction (also
known as the Tsuji-Trost reaction, Figure 1a) represents one of
the most powerful methodologies enabling the stereoselective
installation of C–X (X = C, O, N, S, etc.) bonds.1-4 Given the high
degree of efficiency and versatility, over the last four decades this
reaction has been at the core of a huge variety of synthetic
investigations, aimed at performing the total synthesis of bioactive
molecules including natural products,2,3 nucleosides and their
analogues.4 In the area of de novo approaches to biologically
important carbocyclic nucleosides, the Tsuji-Trost reaction
currently stands as the most popular method for the direct
introduction of a heterocyclic base into a carbocyclic core,5 as
exemplified by the synthetic approaches leading to the anti-HIV
drugs Abacavir and Carbovir4 (Figure 1b). As extensively
reported,4,5 the reaction relies on the treatment of allylic esters or
carbonates 1 with a Pd(0)-based catalyst, with formation of a (3-
cyclopentenyl)palladium(II) complex 2 (Figure 1a). The last one
then undergoes nucleophilic attack by a nucleobase to the less
hindered carbon atom, to release nucleoside 3. Since the process
involves a double inversion of configuration, both in the formation
of the 3-complex and in the subsequent substitution stage, the
reaction overall proceeds with retention of configuration, providing
cis nucleosides from cis esters/carbonates5-7 (Figure 1a).
Exploiting the synthetic utility of the Tsuji-Trost reaction, its
use in the preparation of cyclohexenyl nucleosides (Figure 1c) is
herein explored. Cyclohexenyl nucleosides represent promising
antiviral agents;5a their pharmacological potential results from the
ability by the cyclohexene ring to act as an efficient bioisostere8
of deoxyribose, enabling cyclohexenyl nucleosides to resemble
structure and properties of natural nucleosides while interfering
with the life cycles of various DNA viruses.9 In previous studies,
both “D” and “L”-cyclohexenyl nucleoside enantiomers10 4 and ent-
4 were found to exhibit in vitro anti-HHV (Human Herpes Virus)
activity comparable to those of the antiviral drugs currently on the
market.11 Along this line, our interest into the synthesis12 and the
Figure 1. a) The Tsuji-Trost reaction as a tool for the synthesis of carbocyclic
nucleosides. b) Anti-HIV drugs Abacavir and Carbovir. c) D- and
L-cyclohexenyl nucleosides.
The synthesis of 5 and ent-5 was based on the Tsuji-Trost
reaction of methyl carbonates 10 and ent-10, in turn obtained from
cyclohexanone (6) as depicted in Scheme 1.
The enantioselective synthesis of 8, involving the
organocatalyzed hydroxymethylation of 6 (L-proline/CH2O), the
protection of the resulting alcohol (7a: BnOC(NH)CCl3/TfOH; 7b:
TBDPSCl/imidazole; 7c: BzCl/Py) and the subsequent Saegusa
dehydrogenation of ketones 7a-b [LDA/TMSCl, then Pd(OAc)2]
was performed as already described.13d Alternatively to the two-
steps dehydrogenation reaction, the direct conversion of ketones
7a-c into cyclohexenones 8a-c with 2-iodoxybenzoic acid (IBX)16
revealed to hold a greater synthetic potential (for details see ESI,
Table S1). In this case, we found that, while the reaction provided
a mixture of unsaturated ketones 8 and 9 (e.g., 8a:9a up to 3:1;
entries 1-3 Table S1), the addition of 1 eq benzoic acid (BzOH)
significantly improved the reaction regioselectivity toward the
desired 8 (e.g., 8c:9c > 20:1; 69% yield; entries 5-6 Table S1).17
1
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allylic alcohol [MeOC(O)Cl/TMEDA] yielded trans-10a as the
main product13d (86%; cis:trans = 1:10). Conversely, reduction
with DIBAL-H (from 8a-b) or NaBH4/CeCl3 (from 8c) and
subsequent protection gave a 1:1 mixture of cis- and trans-10a-c
(69-93%). The same synthetic path described in Scheme 1, using
D-proline as chiral catalyst in the first step, allowed the preparation
of carbonates ent-10 (e.g. ent-10b; see ESI, Scheme S2).
The Tsuji-Trost reaction was then considered (Table 1). At a
glance, the Pd(0)-catalyzed substitution reaction of 10a-c
appeared a simple repetition, on a six-membered system, of the
work on the synthesis of bioactive cyclopentenyl nucleosides,6
since the extra-methylene group was not expected to influence
the reaction outcome. Accordingly, among the two carbonates
cis- and trans-10, only the cis isomer was at first considered of
synthetic utility. Treatment of cis-10a with 6-chloropurine (11),
.
Pd2(dba)3 CHCl3 (0.1 eq ) and PPh3 (1.0 eq) in a 1:1 THF/DMSO
mixture provided, after 1h at rt, the expected nucleoside cis-14a
(entry 1), whose relative configuration was assessed by 1H NMR
analysis (J1’-6’a = 2 Hz; J1’-6’b = 4 Hz), along with its N7
regioisomer18 (N9:N7 = 2:1). Surprisingly, when the same reaction
was carried out starting from trans-10a, the formation of cis-14a
was again observed (entry 2), while only traces of the
corresponding trans nucleoside were detected19 (cis:trans > 10:1).
Scheme 1. Synthesis of carbonates 10a-c and ent-10b
Optically active cyclohexenones 8a-c were then converted
into the corresponding carbonates 10a-c (Scheme 1). Ketone
reduction with LiAlH4 (from 8a) and protection of the resulting
Table 1. Pd-catalyzed allylic substitution reaction of carbonates cis- and trans-10a-d
Entry
Carbonate
cis-10a
Nucleobase
Nucleoside
14a
t(h)
1
Yielda (%)
90 (60)b
83 (66)b
76 (65)b
69 (55)b
76 (57)b
82 (68)b
97 (73)b
98 (70)b
83 (69)b
78b
cis:trans
>20:1
>10:1
>20:1
>20:1
>10:1
>20:1
>20:1
>10:1
>20:1
>20:1
N9:N7
2:1
1
2
11
11
11
11
11
11
12
12
12
13
trans-10a
cis/trans-10b
cis-10c
14a
1
4:1
3
14b
20
1
6:1
4
14c
4:1
5
trans-10cc
cis/trans-10dc
cis-10a
14c
2
3:1
6
14d
2
5:1
7
15a
1
3:1
8
trans-10a
cis/trans-10b
trans-10a
15a
1
2.5:1
5:1
9
15b
20
1
10
16a
>95:5
General reaction conditions (unless otherwise stated): nucleobase, 1.0 eq; Pd2(dba)3, 0.1 eq (corresponding to 0.2 eq of Pd(0)
active catalyst); PPh3, 1.0 eq.
[a] Sum of regioisomeric N9 and N7 nucleosides. [b] Sum of cis and trans N9 nucleosides. [c] Reaction performed with 0.5 eq of
Pd2(dba)3, corresponding to 1 eq of Pd(0) active catalyst.
2
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Similar results were also obtained replacing 11 with 2-amino-6-
chloropurine (12), leading to cis-15a (entries 7 and 8), or with N6-
bis-Boc-adenine (13), leading to 16a (entry 10). As expected, in
the latter case a much higher stereo- and regioselectivity was
found (cis:trans > 20:1; N9:N7 = 95:5). When the inseparable
mixture of TBDPS ethers cis/trans-10b was used as the starting
material, a similar stereochemical outcome for the reaction was
observed, providing cis-14b and cis-15b (from 11 and 12
respectively, entries 3 and 9) as the sole N9 stereoisomers, albeit
with different conversion rates (from trans-10b: 20h; from cis-10b:
1h).20 Eventually, in the reaction of Bz ester 10c with 11, the cis
isomer exhibited the same reactivity profile as the previous
substrates (entry 4), while trans-10c was recovered unreacted
from the reaction mixture. In this case, a complete conversion to
cis nucleoside could be observed only when a stoichiometric
amount of Pd2(dba)3 was added (entry 5). Bis-methyl
carbonates21 cis and trans-10d also exhibited the same reactivity
as 10c (entry 6, see ESI for details).
To the best of our knowledge, no precedent examples of
stereoconvergent Tsuji-Trost reaction from sterically unhindered
substrates have ever been described in literature.22,23 Beyond its
singularity, this result holds an apparent synthetic relevance (no
stereoselective processes for the synthesis of the substrates of
the Tsuji-Trost reaction are required). In addition, our data
suggest a reconsideration of the reaction mechanism. As widely
reported,1,5 the treatment of cis-10 with Pd(PPh3)4 is expected to
provide the (3-cyclohexenyl)palladium(II) complex trans-17
(Scheme 2a), leading to cis-14 after nucleobase attack. To
explain the stereoconvergent outcome herein observed, we
hypothesize that, even though trans-10 could be similarly
converted into the 3-complex cis-17, the latter, rather than giving
nucleoside trans-14, was isomerized to trans-17 by the well-
known Pd-catalyzed π-inversion,24 thus providing nucleoside cis-
14 (Scheme 2b).
Scheme 2. Stereoconvergent Tsuji-Trost reaction of cis- and trans-10: a
mechanistic hypothesis
In line with previous reports,1a the formation of 3 complexes cis-
and trans-17 was found to represent, in both cases, the rate-
limiting step (Figure 2). Indeed, the conversion of 2 complexes
cis- and trans-18a (deriving from cis- and trans-10a) into the
corresponding 3 complexes involved comparable energy barriers
(cis-18a → trans-17a, 13.7 kcal/mol; trans-18a → cis-17a, 15.5
kcal/mol, see ESI). In addition, the conversion of cis-17 into its
trans-isomer by the Pd-catalyzed π-inversion required a low
activation energy (6.1 kcal/mol; via TSinv). Based on this fast
equilibrium, the conversion of cis- and trans-10a into cis-19a
appears to be favored by both kinetic and thermodynamic factors.
On one hand, the SN2’ substitution of trans-17a leading to cis-19a
(via TS2) is associated to an activation energy of 7.1 kcal/mol,
whereas a higher value (12.0 kcal/mol) is necessary to convert
cis-17a into trans-19a (via TS2’). On the other hand, the formation
of cis-19a was favored by the thermodynamics (ΔGT = -4.7
kcal/mol), which is against the transformation cis-17a → trans-
19a (ΔGT = +1.0 kcal/mol; Figure 2).
The origin of the reaction stereoselectivity was explored by
DFT calculations, which were performed using the Bn-containing
carbonate 10a as model substrate. The calculated free energy
profile for the Pd-catalyzed reaction of cis- and trans-10a is shown
in Figure 2 (see ESI for full details).
Figure 2. Free energies for the Tsuji-Trost reaction of cis- and trans-10a.
The results of Table 1 also suggest that the nature of the
protective group at C7 position influence the reactivity of trans-10
in the Tsuji-Trost reaction. In the presence of ether groups (e.g.
in 10a-b), the relative reaction rates of trans isomers depend on
3
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the steric hindrance of the protective group (the bulkier TBDPS
group affecting the reactivity of trans-10b, compared to the faster
reaction with Bn-protected trans-10a). Conversely, the peculiar
reactivity of trans-10c-d bearing carbonyl-containing protective
groups suggest the occurrence of other than steric effects. In this
case, a plausible hypothesis involves catalyst sequestration by
the reaction product. This is suggested by the following
observations: a) opposite to trans-10a-b, in the case of trans-10c-
d a complete conversion of PPh3 into the corresponding oxide
was detected;25 b) the reaction did not proceed in the presence of
the formed nucleoside. This side process would remove the
catalyst from the reaction medium, thereby requiring the use of
stoichiometric amounts (1.0 eq) of Pd(PPh3)4 to bring the reaction
to completion.
a relatively fast Pd-mediated isomerization of η3-complexes cis
and trans-17. We are currently working to widen the synthetic
potential of the reaction beyond cyclohexene-based substrates 10
and ent-10, to define scope and limitations of this methodology in
asymmetric catalysis and more generally to demonstrate the
importance of these results in the synthesis of bioactive molecules.
Cyclohexenyl nucleosides 5A, 5G and the corresponding ent-5A
and ent-5G are currently undergoing biological evaluation to
explore their antiviral potential against a variety of DNA viruses.
Acknowledgements
The authors wish to thank Prof. E. Bedini for his assistance with
NMR experiments.
Finally, protected nucleosides 14a-16a were converted into
nucleosides 5A and 5G (A: adenine; G: guanine) (Scheme 3). De-
26
O-benzylation was at first considered: while use of BCl3 was
Keywords: Tsuji-Trost reaction • carbocyclic nucleosides •
stereoconvergent reaction • density functional calculations •
antiviral agents
ineffective, treatment of 14a and 15a with BBr3 provided, already
at -78°C, 20 (78% yield) and 21 (88% yield) respectively.
Displacement of chlorine atom of 20 with a free amino group
(NH3/MeOH) led to deoxyadenosine analogue 5A (92% yield),
while alkaline hydrolysis (NaOH) of 21 provided nucleoside 5G in
75% yield. Similarly, nucleoside 5A was also obtained from 16a
by treatment with trifluoroacetic acid (TFA) to remove N-Boc
groups (84% yield), followed by de-O-benzylation of 22. A similar
reaction path (see ESI, Scheme S4), conducted on ent-14b and
ent-15b, led to the corresponding enantiomeric nucleosides ent-
5A and ent-5G.
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Scheme 3. Synthesis of cyclohexenyl nucleosides 5 and ent-5
In summary, a highly regio- and stereoselective route to
cyclohexenyl nucleosides has been finely tuned. Herein, an
unprecedented example of stereoconvergent Tsuji-Trost reaction
has been documented, enabling the conversion of carbonates 10
into cis-configured nucleosides 14-16 with high selectivity
(cis:trans up to > 20:1), regardless the relative configuration of the
starting materials. DFT calculations revealed the origin of the
stereoconvergent reaction, pointing out the kinetic and
thermodynamic factors in the SN2’ substitution step combined with
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4
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[17] While addition of organic acids is reported to improve the reaction rate
(see ref. 16), the acid-mediated improvement of regioselectivity of this
reaction is unprecedented. A preliminary hypothesis is based on the
formation of a bulky IBX-BzOH adduct acting as the enolizing agent (see
ESI for details).
[18] N9/N7 assignment was assessed by 1H NMR analysis (see ref. 7a)
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5
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Entry for the Table of Contents
All roads lead to cis: contrarily to its well-established reaction mechanism, the Tsuji-Trost reaction of cyclohexene-based substrates
proceeds under highly stereoconvergent conditions, leading to cis-nucleosides regardless the relative configuration of the starting
materials. Experimental data and DFT calculations enabled to shed light on the origin of the unprecedented stereochemical outcome
of the reaction.
6
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