Enantioselective Trost alkynylation with 2 E ,4 E -5-bromo-2,4-pentadienal

The synthetically useful aldehyde 2 E ,4 E -5-bromo-2,4-pentadienal was subjected to the enantioselective Trost alkynylation protocol, yielding highly functionalized propargylic secondary alcohols in an enantios-elective manner. In most cases, the isolated yields and enantiomeric excess of the products were modest to high, but several products were formed in both high yields and enantiomeric excess.


a b s t r a c t
The synthetically useful aldehyde 2E,4E-5-bromo-2,4-pentadienal was subjected to the enantioselective Trost alkynylation protocol, yielding highly functionalized propargylic secondary alcohols in an enantioselective manner.In most cases, the isolated yields and enantiomeric excess of the products were modest to high, but several products were formed in both high yields and enantiomeric excess.
Ó 2022 The Author(s).Published by Elsevier Ltd.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
The addition of alkyne nucleophiles to aldehydes or ketones is a classical and highly useful synthetic reaction [1] with several stereoselective methods reported.[2,3]Among these, the Trost asymmetric alkynylation reaction [4] is a very efficient and highly enantioselective method for preparing optically active secondary propargylic alcohols, that are convenient intermediates for drug synthesis and total synthesis of natural products.[5].
Hence, we became interested in investigating the Trost alkynylation reaction [4] with the ligand (S,S)-ProPhenol (3) using 1 and 2b, as well as other terminal alkynes.The results from these investigations are presented herein.
First, TMS-acetylene (2a), extensively applied in the Trost asymmetric alkynylation reaction, [4] was chosen in order to establish the preferred reaction conditions, Scheme 1.
For all experiments, one equivalent of aldehyde 1 and ligand 3 (10 mol%) were used, while the molar ratio of both alkyne 2a and the additive Me 2 Zn were altered.In all cases, toluene was the solvent and the reaction time was 24 h.The results are compiled in Table 1.
First, a slight excess of TMS-acetylene (2a) and Me 2 Zn was used, while aldehyde 1 was added as a solid in one portion.[13] Triphenylphosphine oxide (TPPO, 20 mol%) may improve both the enantioselectivity and yields.[14]The absolute configuration of 2a was established as R by using the Mosher ester analysis protocol reported by Hoye and co-workers.[15] The same conditions returned 4a in 42% isolated yield and an enantiomeric excess (ee) of 29% (entry 1).These conditions were attempted with a dropwise addition of 1 in toluene over 5 min, significantly improving the enantioselectivity (81% ee) (entry 2).This dramatic change of ee may be due to the reactivity and instability of aldehyde 1, making dropwise addition favorable.The yield, on the other hand, was disappointingly 36% and the methylated byproduct, (3E,5E)-6-bromohexa-3,5-dien-2-ol, was isolated in 9% yield (Supporting information).Therefore, molecular sieves was added in the next experiment, hopefully to improve the yield (entry 3).Surprisingly, these conditions gave both low yield (28%) and ee (30%).There were observed traces of additional byproducts, but no starting material at the end of the reaction time, indicating decomposition of aldehyde 1.The next experiment was performed without TPPO which improved the yield (50%), but the enantioselectivity was still unsatisfactory (entry 4).The addition of dry molecular sieves returned the S-enantiomer of 4a in 17% ee and 29% isolated yield (entry 5).Reducing the temperature to À20 °C did not alter the yield nor the enantioselectivity, comparing entries 4 and 6.Next both the amount of the alkyne 2a and Me 2 Zn were increased.This gave a slight improvement of the enantioselectivity and isolated yield of 4a (entry 7).Again, addition of molecular sieves lowered the enantioselectivity and the yield (entry 8).The presence of TPPO and molecular sieves (entry 9) gave both lower yield and enantioselectivity.The next experiment was performed without TPPO and molecular sieves, as well as allowing the reaction to reach ambient temperature (entry 10).These conditions gave similar yield and enantiomeric excess of 4a as entry 4. Lowering the temperature (entry 11) gave both higher yield and enantioselectivity.On the other hand, in the presence of 20 mol% TPPO at 4 °C and using a solution of 1 in the presence of three equivalents of both Me 2 Zn and 2a, the propargylic alcohol 4a was isolated in a satisfactory 72% yield and 88% ee (entry 12).The formation of byproducts were observed in all experiments.[13].
Twelve other alkynes (4b-4 m) were then investigated using the conditions established from entry 12 in Table 1, see Scheme 2.
For (3Z,6Z)-nona-3,6-dien-1-yne (2b), disappointingly low enantioselectivity (ee = 45%) and a low yield of 34% were observed for the product 4b (Scheme 2).However, the selectivity improved significantly (ee = 90%), but the yield was modest, when using 1heptyne (2c).The same ee-value was observed when phenylacetylene (2d) was applied, giving the product 4d in 67% yield.Similar results were observed when para-tert-butyl pheny-  a One equivalent of 1 and a reaction time of 24 h were used for all reactions; b TPPO: triphenylphosphine oxide; c average isolated yields from two parallel experiments; d determined by HPLC analysis using a chiral column and average results from two parallel experiments; e aldehyde 1 added as solid; f 5% g/mL (related to toluene) 4 Å molecular sieves added.lacetylene (2e) was reacted with 1, affording 4e in 64% yield and with ee = 85%.Notably, using electron donating para-metohoxy phenylacetylene (2f) afforded the product 4f with an ee-value of 12% and in 72% isolated yield.In the absence of TPPO, sometimes effective for alkynes without Lewis basic sites,[14b] gave ee = 50% of 4f in 87% yield.However, the selectivity was high when para-nitro phenylacetylene (2 g) was reacted, producing 4 g in 96% ee and in 63% yield.A higher yield (85%) was observed utilizing para-bromo phenylacetylene (2 h), while the selectivity was somewhat diminished in 4 h (92% ee).Similar results regarding both enantioselectivity and yield was observed when 2-thienyl acetylene (2i) was used (ee = 90%, 58%).When the 3-position contained a nitro-group and the 4-position a methoxy group, as in 2j, the corresponding propargylic alcohol 4j was obtained in a fairly high enantioselectivity and in good yield (79% ee, 87%).This stands in sharp contrast to using a methoxy-group in the para-position.
Finally, using para-and ortho-trifluoro phenyl acetylenes 2 k and 2 l, respectively, the reactions returned high enantioselectivity for both products 4 k and 4 l, 93 and 91 % ee, while the yield was 70 and 55%, respectively.Using meta-trifluoro phenyl acetylene (2 m) the selectivity was diminished for product 4 m (68% ee), Scheme 2. The method reported by Hoye and co-workers was again used enabling the identification of the absolute configuration to be R for all products 4b-4 m, [15] in accord with earlier results.[4,14].In summary, the highly functionalized and synthetically useful aldehyde 2E,4E-5-bromo-2,4-pentadienal (1) [9] was investigated in the enantioselective Trost alkynylation protocol.The enantiomeric excess of the products formed were determined to be in the range of 12-96% ee.However, the results using alkyne 2b, prepared over 4 steps and in 47 % yield from commercially available (Z)-hex-3-en-1-ol, [16] were unsatisfactory with respect to yields and enantiomeric excess.Hence, alternative approaches for making the biologically interesting [10,17] lipid mediator resolvin T3 are needed.

Declaration of Competing Interest
The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.
, https://doi.org/10.1016/j.tetlet.2022.1538790040-4039/Ó 2022 The Author(s).Published by Elsevier Ltd.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).⇑ Corresponding author.E-mail address: t.v.hansen@farmasi.uio.no(T.Vidar Hansen).Tetrahedron Letters 100 (2022) 153879 Contents lists available at ScienceDirect Tetrahedron Letters j o u r n a l h o m e p a g e : w w w .e l s e v i e r .c o m / l o c a t e / t e t l e t