molecules Article Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes Diego M. Monzón 1,2, Juan Manuel Betancort 2,†, Tomás Martín 2,3, Miguel Ángel Ramírez 1,2,Víctor S. Martín 1,2,* and David Díaz Díaz 1,2,4,* 1 Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain; [email protected] (D.M.M.); [email protected] (M.Á.R.) 2 Instituto de Bio-Orgánica Antonio González, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain; [email protected] (J.M.B.); [email protected] (T.M.) 3 Instituto de Productos Naturales y Agrobiología, CSIC, Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain 4 Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany * Correspondence: [email protected] (V.S.M.); [email protected] (D.D.D.) † Current address: Rakuten Medical, Inc., 11080 Roselle St., San Diego, CA 92121, USA. Abstract: Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co2(CO)8, and treatment with BF3·Et2O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the Citation: Monzón, D.M.; Betancort, formation of cyclooctynes exclusively with (R) configuration, in good agreement with theoretical J.M.; Martín, T.; Ramírez, M.Á.; predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the Martín, V.S.; Díaz Díaz, D. presence of azides yielding substituted triazoles. Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes. Molecules Keywords: Nicholas reaction; cyclooctyne; propargylic carbocation; cyclization; oxacycle; ring strain 2021, 26, 1629. https://doi.org/ 10.3390/molecules26061629 Academic Editor: Narciso M. Garrido 1. Introduction Organometallic complexes have found extensive use in organic chemistry due to the Received: 1 March 2021 unique properties they impart on the coordinated organic ligands. A notable transforma- Accepted: 13 March 2021 tion that showcases this altered reactivity is the Nicholas reaction [1–6]. It involves the Published: 15 March 2021 reaction of dicobalt hexacarbonyl-stabilized propargylic carbocations with nucleophiles. The remarkable stability of these carbocations arises from delocalization of the cationic Publisher’s Note: MDPI stays neutral charge onto the metallic complex. The mild conditions used to form the acetylenic cobalt with regard to jurisdictional claims in complexes, coupled with the versatility of the highly functionalized reaction products published maps and institutional affil- obtained upon demetallation, has rendered this reaction a useful tool for the synthesis of iations. diverse and complex molecules [7–11]. An extensive list of nucleophiles has been employed in this transformation, from carbon-based entities such as ketones and enol silanes, to nitrogen nucleophiles such as amines and sulfonamides, or oxygen centered species such as alcohols [12,13] or epox- Copyright: © 2021 by the authors. ides [14,15]. In the case where the nucleophile is connected to the alkyne via a suitable chain, Licensee MDPI, Basel, Switzerland. the Nicholas reaction will result in intramolecular attack and formation of a ring [12,13]. This article is an open access article This process is favored by the altered geometry of the complexed triple bond that reduces distributed under the terms and ring strain. Of particular interest are cyclooctynes, the smallest stable cyclic alkynes. Their conditions of the Creative Commons inherent strain has been exploited in organic synthesis and bioorthogonal chemistry for the Attribution (CC BY) license (https:// development of novel cycloaddition reactions and labeling agents [16–18]. Introduction creativecommons.org/licenses/by/ of heteroatoms in their structure has subtle effects on the reactivity and stability of the 4.0/). Molecules 2021, 26, 1629. https://doi.org/10.3390/molecules26061629 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 13 inherent strain has been exploited in organic synthesis and bioorthogonal chemistry for the development of novel cycloaddition reactions and labeling agents [16–18]. Introduc- tion of heteroatoms in their structure has subtle effects on the reactivity and stability of the resulting rings [19]. Herein, we describe the synthesis of 1-oxa-3-cyclooctyne deriva- tives by making use of an intramolecular Nicholas reaction. The use of this reaction has Molecules 2021, 26, 1629 been also reported to obtain other strained cycloalkynes such as cyclononynes [20].2 of 12 2. Results and Discussion resultingOur ringssynthetic [19]. design Herein, towards we describe the preparation the synthesis of of strained 1-oxa-3-cyclooctyne 1-oxa-3-cyclooctynes derivatives via bythe making Nicholas use reaction of an intramolecular was based on the Nicholas use of reaction.(1R,3S)-camphoric The use of acid this as reaction starting has material been also(Scheme reported 1), a tolow obtain-cost natural other strained product cycloalkynes that is commercially such as cyclononynes available in both [20]. enantiomeric forms. Apart from the cyclopentane ring, the structure of the desired cyclooctynes is char- 2.acterized Results by and the Discussion presence of two quaternary centers at α- and β-positions of the triple bond,Our thus synthetic providing design a sterically towards demanding the preparation environment of strained around 1-oxa-3-cyclooctynes it. via the NicholasIn this way, reaction we wasfirst based envisioned on the the use preparation of (1R,3S)-camphoric of the corresponding acid as starting propargylic material (Schemealcohols1 ),as a in low-costtermediate natural products product, which that iscould commercially be obtained available from (+) in both-(1R,3 enantiomericS)-camphoric forms.acid. The Apart camphoric from the acid cyclopentane not only provides ring, the a cyclic structure structure of the to desiredcontribute cyclooctynes to the preor- is characterizedganization of bythe the system presence prior of to two cyclization, quaternary but centersit also enables at α- and theβ -positionspresence of of the the oxygen triple bond,heteroatom, thus providing which would a sterically act as demandingthe nucleophile environment during formation around it. of the oxacycle. H H H OH OH H O H COOH R R R COOH (CO) Co 6 2 OH OH 1-oxa-3-cyclooctyne propargylic (+)-(1R,3S)-camphoric alcohol acid SchemeScheme 1.1.Retrosynthetic Retrosynthetic analysisanalysis ofof thethe cyclooctynescyclooctynes envisionedenvisioned in in this this work. work. InTherefore this way,, t wehe first first objective envisioned was the to preparation form a suitable of the precursor corresponding of the propargylic alco-alco- holshol, asfrom intermediate which we products,could introduce which different could be R obtained substituents. from (+)-(1For thisR,3 Spurpose,)-camphoric we began acid. Thewith camphoric the reduction acid notof only(+)-(1 providesR,3S)-camphoric a cyclic structure acid using to contributeborane complexes to the preorganization to obtain the ofcorresponding the system prior diol to 2 cyclization, (Scheme 2 but). In it alsothis enablesstep, the the best presence result of was the oxygen obtained heteroatom, with the whichBH3·SM woulde2 complex act as thein THF nucleophile, affording during the desired formation diol of 2 the in oxacycle.96% yield. Subsequently, the differentTherefore, steric demand the first of objective both alcohols was to in form2, dictated a suitable by the precursor presence of the chiral propargylic methyl alcohol,group, made from it which possible we to could perform introduce the selective different protection R substituents. of the most For accessible this purpose, hydroxyl we begangroup withas its the t-butyldiphenylsilyl reduction of (+)-(1 etherR,3S)-camphoric at 0 °C in 1 h, acid affording using borane product complexes 3 in excellent to obtain yield the(95%). corresponding diol 2 (Scheme2). In this step, the best result was obtained with the BH3·SMe2 complex in THF, affording the desired diol 2 in 96% yield. Subsequently, the different steric demand of both alcohols in 2, dictated by the presence of the chiral methyl Molecules 2021, 26, x FOR PEER REVIEW 3 of 13 group, made it possible to perform the selective protection of the most accessible hydroxyl group as its t-butyldiphenylsilyl ether at 0 ◦C in 1 h, affording product 3 in excellent yield (95%). 1. SO ·Py, DCM H H TBDPSCl H 3 H BH3·Me2S OH imidazole OTBDPS Et N, DMSO OTBDPS i) n-BuLi, THF COOH 3 Br COOH THF DCM, 0 ºC 2. CBr4, PPh3 ii) RCHO Br OH OH DCM (+)-(1R,3S)-camphoric 4 (91%) acid 2 (96%) 3 (95%) H H H H OTBDPS TBAF 1. Co2(CO)8, DCM OH O NMO O H R R R THF 2. BF3·Et2O DCM R DCM, −20 ºC OH OH Co2(CO)6 5, R = n-hexyl, 78% 10, R = n-hexyl, 90% 15, R = n-hexyl 1, R = n-hexyl, 64% (from 10) 6, R = H, 81% 11, R = H, 99% 16, R = H 20, R = H, n.d. 7, R = Me, 84% 12, R = Me, 92% 17, R = Me 21, R = Me, 58% (from 12) 8, R = Ph, 70% 13, R = Ph, 86% 18, R = Ph 22, R = Ph, 31% (from 13) 9, R = 3-butenyl, 66% 14, R = 3-butenyl, 76% 19, R = 3-butenyl 23, R = 3-butenyl, 57% (from 14) SchemeScheme 2. Synthetic2. Synthetic route route forfor the preparation preparation of ofstrained strained cyclooctynes cyclooctynes (1, 20 (213,)20 starting−23) startingfrom commercially from commercially available (+) available- (+)-(1(1R,3S))-camphoric-camphoric acid acid.