Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers

Tetrahedron Letters xxx (xxxx) xxx

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Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers William P. Gallagher ⇑, Gregory L. Beutner, Tyler J. Wadzinski, Prashant P. Deshpande Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, United States

a r t i c l e

i n f o

Article history: Received 27 January 2020 Revised 13 February 2020 Accepted 16 February 2020 Available online xxxx Keywords: Vinyl ethers Acetal opening TMSOTf Nucleosides

a b s t r a c t During efforts to employ a Claisen rearrangement in the synthesis of a complex nucleoside, a highly functionalized, protected vinyl ether was required as a key intermediate. The optimal route to this vinyl ether was found to be a remarkably selective ring opening of a cyclic acetal with TMSOTf and NEt3. In this paper we describe factors affecting the selectivity of this vinyl ether synthesis as well as the scope of the reaction for preparation of highly functionalized nucleoside vinyl ethers. Ó 2020 Published by Elsevier Ltd.

Introduction The preparation of complex, highly-functionalized vinyl ethers remains a significant synthetic challenge despite continuing research in the area. A diverse array of conditions exist for this transformation, but most are harsh or use sensitive transition metal catalysts, and few have wide substrate scope [1]. This can pose a significant challenge when a retrosynthesis reveals a Claisen rearrangement disconnection en route to a natural product or pharmaceutical target [2]. Choosing conditions for installation of the vinyl ether in the presence of the other functional groups in the molecule can severely limit the choices and pose a major hurdle in implementing the proposed route. Although the Claisen rearrangement has been used in complex molecule synthesis [3], some gaps still remain in accessing the intermediates required to employ this powerful transformation. During recent efforts to prepare the nucleoside reverse transcriptase inhibitor (NRTI) 40 -Ed4T, retrosynthetic analysis revealed an alternative Claisen rearrangement (Scheme 1) [4]. Leveraging the pool of chiral starting materials derived stereogenic center at C2 of 5-methyl uridine 4 [5], a [3,3]-sigmatropic rearrangement would allow for installation of the challenging C4 quaternary stereocenter present in the final product [6]. This route could provide an efficient and selective method for preparation of ()-1 without relying on chiral catalysts or kinetic resolution, as demonstrated ⇑ Corresponding author. E-mail address: [email protected] (W.P. Gallagher).

in other routes to the target compound ()-1 [7]. The main challenge for execution of this strategy then became the preparation of the vinyl ether ()-3 with minimal protecting group exchanges. In this report we describe efforts towards the selective synthesis of vinyl ether ()-3. Several procedures were evaluated but, in the end, cleavage of cyclic acetal 5a gave the best yields and demonstrated surprising levels of selectivity (Scheme 2). We provide details on factors affecting selectivity as well as the scope of the reaction. Starting from the readily available and inexpensive 5-methyl uridine (+)-4, several routes were evaluated to access the desired vinyl ether intermediate ()-6a. The first and most direct route involved formation of a cyclic silane between the C3 and C5 hydroxyl groups to provide the C2 alcohol ()-7 (Scheme 3). Attempts to employ a Lewis acid catalyzed vinyl ether exchange proved unsuccessful. Mild Lewis acids like Hg(II), Au(I) and Pd(II) salts failed to promote transfer from ethyl vinyl ether (EVE) to alcohol ()-7 [8]. The failure of these methods was ascribed to interference from the strongly Lewis basic nucleoside carbonyls, which could compete with the weakly basic vinyl ether for binding to the metal center. In contrast, the two step procedure described by Dujardin [9] involving a Brønsted acid catalyzed vinyl ether exchange did prove successful in giving access to ()-8. Alcohol ()-7 was treated with ethyl vinyl ether (EVE) and PPTS in DCM and, after holding the resulting mixture at 20 °C for 12 h, the mixed acetal 9 was obtained. Subsequent treatment with TMSOTf/NEt3 then led to formation of the desired C2 vinyl ether ()-8 in 90% yield. Despite the success of this method, it would require additional steps due to the

https://doi.org/10.1016/j.tetlet.2020.151750 0040-4039/Ó 2020 Published by Elsevier Ltd.

Please cite this article as: W. P. Gallagher, G. L. Beutner, T. J. Wadzinski et al., Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151750

2

W.P. Gallagher et al. / Tetrahedron Letters xxx (xxxx) xxx

HO

4

O

1

O

O

PGO

O N

N

NH

NH O

O 3 2 4'-Ed4T

O (-)-2 Claisen Rearrangement

O

N

HO

OH

O

PGO

O

HO

O

N

NH

NH

O

O

O

(-)-3

(+)-4

Scheme 1. Proposed Retrosynthesis of 1.

O O

NH

NH O OR O

N

TMSOTf (10 equiv) NEt3 (13 equiv)

N

O

O

O

RO

O

5a Ph

O

O

O

RO

HO (-)-6a 19:1 C2/C3 selectivity 94 % yield

DCE (8 mL/g) 55oC, 16h

O

carbon-oxygen bond cleavage. This strategy might then provide direct access to the desired vinyl ether ()-6 (Scheme 4). The acetal 5a could easily be accessed by treating 5-methyluridine (+)-4 with H2SO4 (10 mol%) and acetaldehyde (1.5 equiv) in acetonitrile (Scheme 5, eq 1). After holding the solution at 20 °C for 18 h, a slurry formed and a simple filtration allowed for isolation of the 2,3-acetal 11a in 97% yield as a mixture of diastereomers. Subsequent protection of the C5 hydroxyl as the biphenyl ester allowed for straightforward isolation of compound 5a in good yield and purity (eq 2). The biphenyl ester was chosen as a C5 protecting group to facilitate isolation of the desired product via crystallization. To investigate the key ring opening of acetal 5a, we utilized Dujardin’s conditions, but found no reaction (Table 1, entry 1). Rather it was found that increasing the charge of the TMSOTf and amine gave increasing levels of conversion. Addition of 10 equivalents of TMSOTf allowed for >98% conversion and with 20:1 selectivity, favoring the desired 2-isomer ()-6a. We found that triethylamine had to remain in excess relative to TMSOTf (1.3:1 ratio) in order to prevent decomposition of the vinyl ether ()-6a over the long reaction time. Careful monitoring showed a slight decrease in the C2:C3 selectivity over the course of the reaction (Table 1, entry 5). Upon reaction completion, the mixture was

N HO

O N

3 O

Scheme 2. Selective Opening of Acetal 5a.

(-)-6 2-isomer +

O

RO

2 O

NH O

O O

RO

t-Bu t-Bu

O Si O

O Metal O O Catalyst t-Bu Si N NH X O t-Bu EVE O OH

EVE, PPTS DCM 20 °C, 12 h

O t-Bu t-Bu

O

O Si

N O O

O

O

O

NH O

OH

NH

(-)-10 3-isomer

O

(-)-8

(-)-7

N

5

O N

O

O

=R

NH

Scheme 4. 2,3-Acetal Opening to provide access vinyl ethers 6.

TMSOTf TEA, 40 °C 18 h

NH

H2SO4 (6 mol %) acetaldehyde NH (excess) O

O

HO

EtO 9 Scheme 3. Two-step rote to Vinyl Ether ()-8.

N

O

HO

O OH

HO

N

O

NH O

O

MeCN 20 °C, 18 h

(+)-4

need for a protecting group exchange at C3 and C5 prior to elimination of the C3 alcohol to form the desired [3,3]-rearrangement substrate ()-3. An alternative approach to the desired vinyl ether was inspired by the work of Hoye and others who demonstrated the selective silylation/ring opening of a 1,2-acetal to afford an allyl vinyl ether [10]. This strategy was particularly attractive since it would avoid the use transition metal catalysis. Use of excess silylating agent would overcome unproductive binding of the reagent to the numerous Lewis basic sites in 5a, allowing for binding of the silyl cation to the acetal oxygen and facilitating the desired

O

(1)

O 11a

Ph

97% yield

11a +

pyridine (1.3 equiv)

O Cl

Ph

MeCN 50oC, 2h

O

O

O O

N

NH

(2)

O O

95% yield

O 5a

Scheme 5. Preparation of Acetal 5a.

Please cite this article as: W. P. Gallagher, G. L. Beutner, T. J. Wadzinski et al., Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151750

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W.P. Gallagher et al. / Tetrahedron Letters xxx (xxxx) xxx Table 1 Screening of TMSOTf/NEt3 Loading for Opening of 5a.

entry

TMSOTf (equiv)

NEt3 (equiv)

conv. (%, 16 h)

yield (%)

6a:10a (6 h, HPLC)

6a:10a (16 h, HPLC)

1 2 3 4 5

3 4 6 8 10

3.9 5.2 7.8 10.4 13

0 1.4 56 96 98

ND ND ND ND 94

ND ND ND ND 21:1

ND 3:1 15:1 18:1 20:1

0.25 0.2

Response (AU)

0.15 0.1 0.05 0 0.0 -0.05

1.0

2.0

3.0

4.0

5.0

TMSOTf (equivlanets)

TMSOTf (1393 cm-1) intermediate #1 (1666 cm-1)

6.0

7.0

8.0

intermediate #2 (1554 cm-1) 6a (1696 cm-1)

Fig. 1. In situ IR Study of the Silylation of ()-6a with TMSOTf.

cooled to 20 °C and quenched [11] with aqueous NH4OAc to cleave the intermediate silyl ether at C3 and afford [12] the desired vinyl ether ()-6a in 94% yield. The need for a large excess of TMSOTf is attributed to the competitive binding of the TMSOTf to other Lewis basic sites on 5a/()-6a. This phenomena was examined by monitoring the reaction of TMSOTf/NEt3 with ()-6a by in situ IR to gain a better understanding of the reaction stoichiometry. After dissolving ()-6a in DCE with NEt3 (10 equiv) [13], TMSOTf (8.0 equiv)

was slowly added via syringe pump over 2 h and the signal derived from TMSOTf (1393 cm1) was monitored (Fig. 1) [14]. During the slow addition process a number of intermediates could be observed, but only after addition of 3 equivalents of TMSOTf, did any appreciable amount of free TMSOTf appear. This helps explain why such a large excess of TMSOTf is required to obtain high conversions. The first three equivalents likely bind in an unproductive manner to the carbonyl groups of the nucleoside, consistent with evidence for double silylation observed previously [15]. The need for 7 additional equivalents of TMSOTf to drive the reaction likely represents the unfavorable equilibrium for silylation of the relatively hindered C3 acetal oxygen. A brief investigation of solvent effects showed that less polar solvents led to higher levels of selectivity for ()-6a (Table 2). In all cases, the same minor loss in selectivity over the course of the reaction was observed, although it was less significant in more

Table 3 Silyl Triflate Screening on Acetal Opening of 5a. entry

Silyl triflate

time (h)

conv (%, HPLC)

6a:10a

1 2 3 4 5

TMSOTf TMSONf TESOTf TESOTf TBSOTf

16 14 16 40 16

98 100 11 39 0

20:1 25:1 >99:1 58:1 ND

Table 2 Solvent Screening on Acetal Opening of 5a. entry

1 3 4 5 6 7 8 9 10 12 13

solvent

sulfolane CF3Ph toluene DCE CPME IPAc 2-MeTHF DME THF DMAc tAmOH

conv (%, HPLC)

6a:10a

6h

23 h

6h

23 h

95 90 90 89 61 5 9 4 3 1 0

99 98 99 97 85 17 14 5 3 0 0

6 20 9 19 4 ND ND ND ND ND ND

6 17 8 17 4 ND ND ND ND ND ND

Please cite this article as: W. P. Gallagher, G. L. Beutner, T. J. Wadzinski et al., Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151750

W.P. Gallagher et al. / Tetrahedron Letters xxx (xxxx) xxx

HPLC AY (%)

4

100 90 80 70 60 50 40 30 20 10 0

6a

0

5

10

Time (h)

10a

15

5a

20

25

6a:10a rao (HPLC)

Fig. 2. Quantitative Monitoring of the Reaction Kinetics of Acetal Opening of 5a.

29 27 25 23 21 19 17 15 13 11 0

2

4

6 Time (h)

0 eq. HNEt3OTf

8

10

2 eq. HNEt3OTf

Fig. 3. Effect of Et3NHOTf (12) on 6a:10a Selectivity.

polar solvents like sulfolane and cyclopentyl methyl ether (CPME, compare entries 1 and 6 to entries 3–5). Additional optimization around the silyl triflate showed that TMSOTf was optimal (Table 3). Reaction rate dropped off rapidly as the steric bulk of the silane was increased. TESOTf did show a noticeable increase in selectivity,

but the slow rate of the reaction made this an impractical choice for further optimization. A screen of alternative Lewis acids and amine bases did not yield any significant or practical improvements over the TMSOTf/NEt3 system. In an effort to improve the selectivity of the reaction and arrive at an optimal process, we sought to understand the observed erosion in selectivity over the long reaction times (see Table 1, entry 5). Quantitative HPLC analysis demonstrated that this change was not due to selective decomposition of the desired vinyl ether ()-6a (Fig. 2). In fact, re-subjection of ()-6a to the reaction conditions showed no decomposition of ()-6a nor equilibration between the two vinyl ethers ()-6a and ()-10a. Having observed that more polar solvents gave lower selectivities, we wondered if the triethylammonium triflate 12 formed during the reaction could be leading to this change. Spiking 12 into the reaction led to a dramatic loss in selectivity, confirming this hypothesis and showing that the slight loss in selectivity is inherent to the required reaction conditions (Fig. 3). With optimal conditions in hand, the key Claisen rearrangement of ()-6a was examined (Scheme 6). An iododination/elimination sequence from ()-6a allowed for ready access to ()-3a [16]. Heating the vinyl ether ()-3a in benzonitrile provided clean formation of the desired product ()-2a [17]. This sequence was eventually used to demonstrate a viable route to multi-gram quantities of the target molecule 1. Having found a highly selective method for formation of the vinyl ether, we examined the effect of the C5-protecting group on the reaction. We hoped to demonstrate the scope of the process but also gain information about what factors give rise to this unexpectedly high selectivity for the C2 vinyl ether. One hypothesis for the high selectivity in the ring opening was that the group at C5 may act as a directing group, delivering the silyl cation to the ethereal oxygen at C3. Therefore, systematic variation in the donor ability of this group may provide insights into the process. Switching to a simple benzoate led to nearly identical levels of selectivity compared to the biphenyl (Table 4, entries 1 and 2). Altering the electronics of the ester, by installation of a strong donor or acceptor group at the para position of the phenyl ring, showed little change in selectivity compared to the parent compound 5a (entries 3 + 4). Moving away from esters at C5 led to more dramatic effects. While a C5 carbamate showed moderate levels of selectivity, the

Ph

O

1. I2/PPh3 imidazole O THF, 60 °C 4h NH

N

O

O

2. DABCO (3.0 equiv) PhCH3, 90 °C 2h

O HO

O

(-)-6a

O O

N

NH

RO

(1)

O O (-)-3a 72 % yield over 2 steps O

O O

N

NH

PhCN 190 °C

O

N

(2)

RO

O O O

(-)-3a

NH

RO O (-)-2a 85% yield

Scheme 6. Approach to the Claisen rearrangement of ()-3a.

Please cite this article as: W. P. Gallagher, G. L. Beutner, T. J. Wadzinski et al., Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151750

W.P. Gallagher et al. / Tetrahedron Letters xxx (xxxx) xxx Table 4 Scope and Selectivity of the Acetal Opening.

entry

R

yield (%)

6:10

1 2 3 4 5 6 7

p-PhC6H4-CO2- (5a) PhCO2- (5b) p-MeOC6H4CO2- (5c) p-CF3C6H4CO2- (5d) PhNHCO2- (5e) PhCH2O- (5f) Cl- (5g)

94 85 91 89 88 91 87

20:1 15:1 >99:1 20:1 7:1 1:4 2:1

complete removal of a C5 carbonyl led to low or reversed levels of selectivity (entries 5–7). Taken together, analysis of the data did not clearly support the hypothesis that the C5 group had any directing effect. The reversal in selectivity observed on going from the benzoate to the benzyl ether seemed to support this idea (compare entries 2 + 6), but contradictory results obtained with other poorly coordinating groups (e.g chloride, entry 7) suggested a more complex interaction was at play. In conclusion, we have indentified a remarkably selective opening of an acetal protected nucleoside alowing access to the corresponding vinyl ethers. The challenges of installing a vinyl ether in a highly complex molecule bearing a diversity of functional groups was overcome by using an excess of TMSOTf/NEt3, a reagent combination which could saturate unproductive binding sites and allow the desired reaction to proceed in high yields. This set the stage for a [3,3]-sigmatropic rearrangement to install a quaternary center at C4 of the resulting nucleoside. Although we were unable to clearly identify the factors controlling this remarkable selectivity, we were able to explore the substrate scope and demonstrate the robustness of the process. We hope that this method will be complimentary to numerous other methods of vinyl ether installation and will enable the use of Claisen rearrangements in the synthesis of other complex, highly functionalized structures. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tetlet.2020.151750. References

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Please cite this article as: W. P. Gallagher, G. L. Beutner, T. J. Wadzinski et al., Selective opening of nucleoside derived acetals to form highly functionalized vinyl ethers, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151750