Diastereoselective synthesis of cis-2,6-disubstituted dihydropyrane derivatives through a competitive silyl-prins cyclization versus alternative reaction pathways

Ci a ion: Peña, L.F.; López, E.; Sánchez-González, Á.; Ba be o, A. Dias e eoselec i e Syn hesis o cis-2,6-Disubs i u ed Dihyd opy ane De i a i es h ough a Compe i i e Silyl-P ins Cycliza ion e sus Al e na i e Reac ion Pa hways. Molecules 2023,28, 3080. h ps://doi.o g/10.3390/ molecules28073080 Academic Edi o : F ancesca Ma ini Recei ed: 20 Feb ua y 2023 Re ised: 20 Ma ch 2023 Accep ed: 27 Ma ch 2023 Published: 30 Ma ch 2023 Copy igh : © 2023 by he au ho s. Licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion (CC BY) license (h ps:// c ea i ecommons.o g/licenses/by/ 4.0/). molecules A icle Dias e eoselec i e Syn hesis o cis-2,6-Disubs i u ed Dihyd opy ane De i a i es h ough a Compe i i e Silyl-P ins Cycliza ion e sus Al e na i e Reac ion Pa hways Lau a F. Peña 1, Enol López 1,Ángel Sánchez-González 1,2 and Asunción Ba be o 1,* 1 Depa men o O ganic Chemis y, Campus Miguel Delibes, Uni e si y o Valladolid, 47011 Valladolid, Spain 2BioISI-Biosys ems and In eg a i e Sciences Ins i u e, Depa amen o de Química e Bioquímica, Faculdade de Ciências, Uni e sidade de Lisboa, Campo G ande, 1749-016 Lisboa, Po ugal *Co espondence: asuncion.ba be [email p o ec ed] Abs ac : A con enien egioselec i e syn hesis o allyl- and inylsilyl alcohols, om a common p e- cu so , was desc ibed, by selec ing he app op ia e eac ion condi ions. Allyl- and inylsilyl alcohols we e es ed in silyl-P ins cycliza ions o he p epa a ion o disubs i u ed oxygena ed he e ocycles in a one-po sequen ial eac ion. The me hodology was sensi i e o he s uc u e o he s a ing alkenylsi- lyl alcohol and eac ion condi ions, wi h compe i i e pa hways obse ed (pa icula ly o allylsilyl alcohols), such as Pe e son elimina ion and oxonia-Cope eac ions. Howe e , he use o inylsilyl alcohols allowed he p epa a ion o di e en ly disubs i u ed cis-2,6-dihyd opy ans in mode a e o good yields. Compu a ional s udies suppo he p oposed mechanism. Keywo ds: P ins cycliza ion; he e ocycles; oxacycles 1. In oduc ion He e ocyclic compounds a e some o he mos common chemical s uc u es ound in na u e. Among hem, unc ionalized oxygen he e ocycles ha e a ac ed he a en ion o sci- en is s, due o hei p esence in a wide numbe o biologically ac i e na u al p oduc s [1,2] . T emendous e o s ha e been made o de elop syn he ic me hodologies which can con- ibu e o he cons uc ion o hese co es. Pa icula ly, in amolecula P ins cycliza ion has been es ablished as a powe ul ool in o ganic syn hesis, o he cons uc ion o i e- o eigh -membe ed oxacycles, se ing as key in e media es o he o al syn hesis o a a ie y o na u al p oduc s [ 3 ]. This me hodology in ol es he eac ion o an alkenol wi h an aldehyde, in he p esence o a B øns ed o Lewis acid. The gene al accep ed mechanism in- ol es he gene a ion o an ini ial oxoca benium ion in e media e, which can subsequen ly e ol e h ough an endo-dig cycliza ion. Then, he co esponding cyclic ca boca ion can be apped wi h a nucleophile, p esen in he eac ion medium. High s e eoselec i i ies a e usually ob ained, due o he equa o ial disposi ion o subs i uen s in chai like ansi ion s a es (TS). Due o he impo ance o hese ypes o oxacycles in d ug disco e y, new chemical modi ica ions ha e been s udied in ecen decades, o e ine and imp o e hei syn hesis. The so-called silyl-P ins cycliza ion, in ol es he pa icipa ion o elec on- ich alkenes, such as allyl- o inylsilanes, and shows be e selec i i y owa ds he o ma ion o sin- gle p oduc s, due o he s abiliza ion o he ca boca ion β o silicon [ 4 – 6 ]. Al hough his me hodology has been epo ed o some allylsilyl [ 7 – 10 ] and inylsinyl alcohols [11–15] , mo e e o s a e equi ed o inc ease he eac ion scope and acili a e he access o no el 2,6-disubs i u ed dihyd opy ane de i a i es. Based on ou expe ience in silyl-P ins cycliza- ions [ 16 – 18 ], in his wo k we in es iga e he access o ei he allyl- o inylsilyl homoallylic alcohols om a common allyl(dime hyl)phenylsilane, and he possibili ies o pa icipa ion o he esul ing subs a es in silyl-P ins cycliza ions (Scheme 1). Conside ing p e iously Molecules 2023,28, 3080. h ps://doi.o g/10.3390/molecules28073080 h ps://www.mdpi.com/jou nal/molecules Molecules 2023,28, 3080 2 o 14 epo ed me hodologies, as well as ou model subs a e, we an icipa e some challenges ha mus be o e come: (a) Selec i e me hodologies a e needed o ob ain exclusi ely allyl- o inyl silylalcohols om a common allylsilane p ecu so (condi ions Aand B, Scheme 1). (b) Al e na i e eac ion pa hways may in e e e in he silyl-P ins cycliza ion eac ion ou come [ 19 ], gene a ing complex mix u es due o he o ma ion o highly eac i e in e media es. Molecules 2023, 28, x FOR PEER REVIEW 2 o 14 P ins cycliza ions [16–18], in his wo k we in es iga e he access o ei he allyl- o i- nylsilyl homoallylic alcohols om a common allyl(dime hyl)phenylsilane, and he pos- sibili ies o pa icipa ion o he esul ing subs a es in silyl-P ins cycliza ions (Scheme 1). Conside ing p e iously epo ed me hodologies, as well as ou model subs a e, we an- icipa e some challenges ha mus be o e come: (a) Selec i e me hodologies a e needed o ob ain exclusi ely allyl- o inyl silylalcohols om a common allylsilane p ecu so (condi ions A and B, Scheme 1). (b) Al e na i e eac ion pa hways may in e e e in he silyl-P ins cycliza ion eac ion ou come [19], gene a ing complex mix u es due o he o ma ion o highly eac i e in e media es. Scheme 1. Regioselec i e o ma ion o allyl- and inyl alcohols and subsequen P ins cycliza ion. Ou i s goal, is he egioselec i e syn hesis o new allyl- and E- inylsilyl homoal- lylic alcohols, om a common allylsilane 1. Once hese eac ion condi ions ha e been op- imized, a emp s o achie e silyl-P ins cycliza ion om bo h de i a i es a e e alua ed, in o de o compa e he selec i i y and he scope o bo h con e gen p ocesses. In addi- ion, we s udy (bo h by compu a ional and expe imen al me hods) he challenge o a- o ing silyl-P ins cycliza ion o e al e na i e eac ion pa hways. 2. Resul s 2.1. Syn hesis o Allyl- and Vinylsilyl Alcohols We s a ed ou in es iga ions syn hesizing allyl(diphenyl)silane 1. This subs a e was p epa ed wi h he in si u o ma ion o an o ganozinc eagen om allyl b omide, which was subsequen ly added o a solu ion o chlo o(dime hyl)phenylsilane in THF a 0 °C (Sec ion 3.2.2) [20]. The desi ed de i a i e 1 was ob ained in a 95% yield and could be used wi hou any u he pu i ica ion. Wi h 1 in hand, we ocused ou a en ion on he egioselec i e syn hesis o allyl- and inylsilyl alcohols 2 and 3. The acidic cha ac e o he p o ons α o he silicon a om, could be used o gene a e an α-silylca banion, ha was in equilib ium wi h a γ-silylca banion. Then, subsequen addi ion o an aldehyde unde con olled condi ions exclusi ely gene a ed he desi ed de i a i es (2 o 3). Allylsilyl alcohols 2 we e ob ained when he inco po a ion o he elec ophile oc- cu ed hough he α-posi ion. Thus, he eac ion o 1 wi h n-BuLi, in he p esence o N- e ame hyle hylendiamine (TMEDA), gene a ed an in e media e silylca banion I. Ti(OiP )4 was subsequen ly added as an auxilia y eagen , o block he γ-posi ion and p omo e he selec i e addi ion h ough he α-posi ion (Scheme 2). In his manne , a i- ous homoallylic alcohols 2 we e selec i ely p epa ed in mode a e yields, by addi ion o ei he alkyl- o a ylaldehyde coupling pa ne s (2a–c, 35–55%). The eac ion akes places wi h o al dias e eoselec i i y, ob aining exclusi ely an i p oduc s [21]. Scheme 1. Regioselec i e o ma ion o allyl- and inyl alcohols and subsequen P ins cycliza ion. Ou i s goal, is he egioselec i e syn hesis o new allyl- and E- inylsilyl homoallylic alcohols, om a common allylsilane 1 . Once hese eac ion condi ions ha e been op imized, a emp s o achie e silyl-P ins cycliza ion om bo h de i a i es a e e alua ed, in o de o compa e he selec i i y and he scope o bo h con e gen p ocesses. In addi ion, we s udy (bo h by compu a ional and expe imen al me hods) he challenge o a o ing silyl-P ins cycliza ion o e al e na i e eac ion pa hways. 2. Resul s 2.1. Syn hesis o Allyl- and Vinylsilyl Alcohols We s a ed ou in es iga ions syn hesizing allyl(diphenyl)silane 1 . This subs a e was p epa ed wi h he in si u o ma ion o an o ganozinc eagen om allyl b omide, which was subsequen ly added o a solu ion o chlo o(dime hyl)phenylsilane in THF a 0 ◦ C (Sec ion 3.2.2) [ 20 ]. The desi ed de i a i e 1 was ob ained in a 95% yield and could be used wi hou any u he pu i ica ion. Wi h 1 in hand, we ocused ou a en ion on he egioselec i e syn hesis o allyl- and inylsilyl alcohols 2 and 3 . The acidic cha ac e o he p o ons α o he silicon a om, could be used o gene a e an α -silylca banion, ha was in equilib ium wi h a γ -silylca banion. Then, subsequen addi ion o an aldehyde unde con olled condi ions exclusi ely gene a ed he desi ed de i a i es (2o 3). Allylsilyl alcohols 2 we e ob ained when he inco po a ion o he elec ophile oc- cu ed hough he α -posi ion. Thus, he eac ion o 1 wi h n-BuLi, in he p esence o N- e ame hyle hylendiamine (TMEDA), gene a ed an in e media e silylca banion I . Ti(O i P ) 4 was subsequen ly added as an auxilia y eagen , o block he γ -posi ion and p omo e he selec i e addi ion h ough he α -posi ion (Scheme 2). In his manne , a ious homoal- lylic alcohols 2 we e selec i ely p epa ed in mode a e yields, by addi ion o ei he alkyl- o a ylaldehyde coupling pa ne s ( 2a–c , 35–55%). The eac ion akes places wi h o al dias e eoselec i i y, ob aining exclusi ely an i p oduc s [21]. Molecules 2023, 28, x FOR PEER REVIEW 3 o 14 Scheme 2. Regioselec i e syn hesis o allylsilyl alcohols 2. Fo una ely, in he absence o he auxilia y eagen Ti(OiP )4, he in e media e silyl- ca banion I, eac s wi h aldehydes h ough he desi ed γ-posi ion, which is he leas hinde ed one, p o iding he egioisome ic inylsilyl alcohols 3. Rep esen a i e examples we e ob ained wi h bo h alkyl- and a yl aldehydes, in mode a e yields (Scheme 3). Wi h hese al e na i e p o ocols we we e able o p epa e a se ies o compounds 2 and 3, eady o be used in silyl-P ins cycliza ion eac ions. Scheme 3. Regioselec i e syn hesis o inylsilyl alcohols 3. 2.2. S udy o he Silyl-P ins Cycliza ion wi h Allylsilyl Alcohols 2 Wi h a ious allylsilyl alcohols 2 in hand, we sc eened a se ies o eac ion condi- ions, o achie e he desi ed silyl-P ins cycliza ion. We s a ed ou in es iga ions wi h de i a i e 2a (R1 = Me), which was ea ed wi h a ious Lewis acids (1.2 equi .) a di e en eac ion empe a u es (Table 1, en ies 1–4). Un o una ely, we did no obse e he o ma ion o he desi ed oxacycle 4, ob aining complex mix u es, and iden i ying p oduc 3 a low empe a u e (Table 1, en y 1). The o ma ion o inylsilyl alcohol 3, would imply a compe i i e oxonia-Cope eac ion o in- e media e II, ins ead o he desi ed cycliza ion s ep (Scheme 4). To minimize side- eac ions, we decided o use less eac i e aldehydes, such as (E)-3-phenylp op-2-enal (Table 1, en y 5). Howe e , 1H-NMR analysis o he eac ion c ude, showed a complex mix u e, in which un eac ed aldehyde was obse ed, bu nei he he s a ing ma e ial no oxonia-Cope p oduc s could be iden i ied. This esul sugges s he possibili y o an al e na i e eac ion pa hway om 2, such as a Pe e son elimina ion, which would p o- ide a ola ile 1,3-pen adiene, p obably los in he o a apo sys em (Scheme 4). To u - he s udy he occu ence o his compe i i e eac ion, we se up he eac ion wi h allylsi- lyl alcohols 2b (R1 = CH2Ph) and 2c (R1 = Ph) (Table 1, en ies 6–9). G a i yingly, a de ailed analysis o he eac ion mix u e now showed he p esence o cyclic p oduc s (4a o 4i), oge he wi h 3a (Table 1, en ies 6 and 7), which sugges ed an ini ial oxonia-Cope eac- ion, ollowed by subsequen cycliza ion. In o de o y o o e come seconda y eac- ions, we u ned ou a en ion o he use o ime hylsilyl es e de i a i es as s a ing ma e ials (Table 1, en ies 10–12) [22]. Un o una ely, no eac ion, o complex mix u es, was obse ed (Table 1, en ies 10 and 11), al hough an in e es ing new p oduc 5 was iden i ied and cha ac e ized (Table 1, en y 12). The o ma ion o his ca bocycle can be explained h ough a Diels–Alde eac ion o he 1,3-diene p oduced in he Pe e son elim- ina ion and he co esponding aldehyde ((E)-3-phenylp op-2-enal), which co obo a es he p e iously p oposed Pe e son elimina ion pa hway (Scheme 4). Scheme 2. Regioselec i e syn hesis o allylsilyl alcohols 2. Molecules 2023,28, 3080 3 o 14 Fo una ely, in he absence o he auxilia y eagen Ti(O i P ) 4 , he in e media e silylca - banion I , eac s wi h aldehydes h ough he desi ed γ -posi ion, which is he leas hinde ed one, p o iding he egioisome ic inylsilyl alcohols 3 . Rep esen a i e examples we e ob- ained wi h bo h alkyl- and a yl aldehydes, in mode a e yields (Scheme 3). Wi h hese al e na i e p o ocols we we e able o p epa e a se ies o compounds 2 and 3 , eady o be used in silyl-P ins cycliza ion eac ions. Molecules 2023, 28, x FOR PEER REVIEW 3 o 14 Scheme 2. Regioselec i e syn hesis o allylsilyl alcohols 2. Fo una ely, in he absence o he auxilia y eagen Ti(OiP )4, he in e media e silyl- ca banion I, eac s wi h aldehydes h ough he desi ed γ-posi ion, which is he leas hinde ed one, p o iding he egioisome ic inylsilyl alcohols 3. Rep esen a i e examples we e ob ained wi h bo h alkyl- and a yl aldehydes, in mode a e yields (Scheme 3). Wi h hese al e na i e p o ocols we we e able o p epa e a se ies o compounds 2 and 3, eady o be used in silyl-P ins cycliza ion eac ions. Scheme 3. Regioselec i e syn hesis o inylsilyl alcohols 3. 2.2. S udy o he Silyl-P ins Cycliza ion wi h Allylsilyl Alcohols 2 Wi h a ious allylsilyl alcohols 2 in hand, we sc eened a se ies o eac ion condi- ions, o achie e he desi ed silyl-P ins cycliza ion. We s a ed ou in es iga ions wi h de i a i e 2a (R1 = Me), which was ea ed wi h a ious Lewis acids (1.2 equi .) a di e en eac ion empe a u es (Table 1, en ies 1–4). Un o una ely, we did no obse e he o ma ion o he desi ed oxacycle 4, ob aining complex mix u es, and iden i ying p oduc 3 a low empe a u e (Table 1, en y 1). The o ma ion o inylsilyl alcohol 3, would imply a compe i i e oxonia-Cope eac ion o in- e media e II, ins ead o he desi ed cycliza ion s ep (Scheme 4). To minimize side- eac ions, we decided o use less eac i e aldehydes, such as (E)-3-phenylp op-2-enal (Table 1, en y 5). Howe e , 1H-NMR analysis o he eac ion c ude, showed a complex mix u e, in which un eac ed aldehyde was obse ed, bu nei he he s a ing ma e ial no oxonia-Cope p oduc s could be iden i ied. This esul sugges s he possibili y o an al e na i e eac ion pa hway om 2, such as a Pe e son elimina ion, which would p o- ide a ola ile 1,3-pen adiene, p obably los in he o a apo sys em (Scheme 4). To u - he s udy he occu ence o his compe i i e eac ion, we se up he eac ion wi h allylsi- lyl alcohols 2b (R1 = CH2Ph) and 2c (R1 = Ph) (Table 1, en ies 6–9). G a i yingly, a de ailed analysis o he eac ion mix u e now showed he p esence o cyclic p oduc s (4a o 4i), oge he wi h 3a (Table 1, en ies 6 and 7), which sugges ed an ini ial oxonia-Cope eac- ion, ollowed by subsequen cycliza ion. In o de o y o o e come seconda y eac- ions, we u ned ou a en ion o he use o ime hylsilyl es e de i a i es as s a ing ma e ials (Table 1, en ies 10–12) [22]. Un o una ely, no eac ion, o complex mix u es, was obse ed (Table 1, en ies 10 and 11), al hough an in e es ing new p oduc 5 was iden i ied and cha ac e ized (Table 1, en y 12). The o ma ion o his ca bocycle can be explained h ough a Diels–Alde eac ion o he 1,3-diene p oduced in he Pe e son elim- ina ion and he co esponding aldehyde ((E)-3-phenylp op-2-enal), which co obo a es he p e iously p oposed Pe e son elimina ion pa hway (Scheme 4). Scheme 3. Regioselec i e syn hesis o inylsilyl alcohols 3. 2.2. S udy o he Silyl-P ins Cycliza ion wi h Allylsilyl Alcohols 2 Wi h a ious allylsilyl alcohols 2 in hand, we sc eened a se ies o eac ion condi ions, o achie e he desi ed silyl-P ins cycliza ion. We s a ed ou in es iga ions wi h de i a i e 2a (R 1 = Me), which was ea ed wi h a ious Lewis acids (1.2 equi .) a di e en eac ion empe a u es (Table 1, en ies 1–4). Un o una ely, we did no obse e he o ma ion o he desi ed oxacycle 4 , ob aining complex mix u es, and iden i ying p oduc 3 a low empe a u e (Table 1, en y 1). The o ma ion o inylsilyl alcohol 3 , would imply a compe i i e oxonia-Cope eac ion o in e media e II , ins ead o he desi ed cycliza ion s ep (Scheme 4). To minimize side- eac ions, we decided o use less eac i e aldehydes, such as (E)-3-phenylp op-2-enal (Table 1, en y 5). Howe e , 1 H-NMR analysis o he eac ion c ude, showed a complex mix u e, in which un eac ed aldehyde was obse ed, bu nei he he s a ing ma e ial no oxonia-Cope p oduc s could be iden i ied. This esul sugges s he possibili y o an al e na i e eac ion pa hway om 2 , such as a Pe e son elimina ion, which would p o ide a ola ile 1,3-pen adiene, p obably los in he o a apo sys em (Scheme 4). To u he s udy he occu ence o his compe i i e eac ion, we se up he eac ion wi h allylsilyl alcohols 2b (R 1 = CH 2 Ph) and 2c (R 1 = Ph) (Table 1, en ies 6–9). G a i yingly, a de ailed analysis o he eac ion mix u e now showed he p esence o cyclic p oduc s ( 4a o 4i ), oge he wi h 3a (Table 1, en ies 6 and 7), which sugges ed an ini ial oxonia-Cope eac ion, ollowed by subsequen cycliza ion. In o de o y o o e come seconda y eac ions, we u ned ou a en ion o he use o ime hylsilyl es e de i a i es as s a ing ma e ials (Table 1, en ies 10–12) [ 22 ]. Un o una ely, no eac ion, o complex mix u es, was obse ed (Table 1, en ies 10 and 11), al hough an in e es ing new p oduc 5 was iden i ied and cha ac e ized (Table 1, en y 12). The o ma ion o his ca bocycle can be explained h ough a Diels–Alde eac ion o he 1,3-diene p oduced in he Pe e son elimina ion and he co esponding aldehyde ((E)- 3-phenylp op-2-enal), which co obo a es he p e iously p oposed Pe e son elimina ion pa hway (Scheme 4). Molecules 2023,28, 3080 4 o 14 Table 1. Sc eening o he eac ion condi ions. Molecules 2023, 28, x FOR PEER REVIEW 4 o 14 Table 1. Sc eening o he eac ion condi ions. En y R1 R2 R3 LA (1 equi .) T (°C) NMR Analysis (Isola - ed Yield) 1 CH3 CH2CH2Ph H TMSOT −78 3 2 CH3 CH2CH2Ph H TMSOT 0 Complex mix u e 3 a CH3 CH2CH2Ph H TMSOT −78 Complex mix u e 4 CH3 CH2CH2Ph H BF3·OE 2 −78 Complex mix u e 5 CH3 CH=CHPh H TMSOT −20 Aldehyde 6 a CH2Ph CH3 H TMSOT −78 3a + 4a 7 a CH2Ph CH2Ph H TMSOT −78 4i 8 a Ph CH3 H TMSOT −78 Complex mix u e 9 Ph CH2CH2Ph H TMSOT −78 Complex mix u e 10 CH3 CH=CHPh TMS TMSOT −78 2a 11 CH3 CH=CHPh TMS BF3·OE 2 −78 Complex mix u e 12 CH3 CH=CHPh TMS BF3·OE 2 0 5 (29%) a Wi h 3 equi . o aldehyde ins ead o 1.2 equi . Scheme 4. Reac ion pa hways om allylsilyl alcohols 2. As shown be o e, he eac ion o di e en allylsilyl alcohols wi h aldehydes, in he p esence o Lewis acids, u ned ou o be e y challenging, due o he di e en beha io o he implica ed subs a es, as well as he a ie y o compe i i e eac ion pa hways. Howe e , we we e able o iden i y and isola e key p oduc s o a be e unde s anding o he implica ed in e media es, ha will help in he de elopmen o u u e silyl-P ins cy- cliza ions. Nex , and conside ing p e ious da a, we ocused ou a en ion on he s udy o he silyl-P ins cycliza ion o inylsilyl alcohols 3. 2.3. Silyl-P ins Cycliza ion S udy o Vinylsilyl Alcohols 3 Fi s o all, we sc eened di e en condi ions and Lewis acids, in o de o ind he op imized condi ions o he cycliza ion, using as a key model de i a i e 3a. As shown in Table 2, complex mix u es we e ob ained a 0 °C when BF3·OE 2 o TMSCl we e used as Lewis acids (Table 2, en ies 1–4). G a i yingly, a cis-2,6-disubs i u ed dihyd opy ane de i a i e 4a was ob ained when 1 equi . o TMSOT was used a −78 °C (Table 2, en ies 5–7). Analysis o he eac ion c ude, showed e y good dias e eoselec i i y o cis-4a (cis: ans, 90:10), which was isola ed in a 48% yield (Table 2, en y 6). Inc easing he En y R1R2R3LA (1 equi .) T (◦C) NMR Analysis (Isola ed Yield) 1 CH3CH2CH2Ph H TMSOT −78 3 2 CH3CH2CH2Ph H TMSOT 0 Complex mix u e 3aCH3CH2CH2Ph H TMSOT −78 Complex mix u e 4 CH3CH2CH2Ph H BF3·OE 2−78 Complex mix u e 5 CH3CH=CHPh H TMSOT −20 Aldehyde 6aCH2Ph CH3H TMSOT −78 3a +4a 7aCH2Ph CH2Ph H TMSOT −78 4i 8aPh CH3H TMSOT −78 Complex mix u e 9 Ph CH2CH2Ph H TMSOT −78 Complex mix u e 10 CH3CH=CHPh TMS TMSOT −78 2a 11 CH3CH=CHPh TMS BF3·OE 2−78 Complex mix u e 12 CH3CH=CHPh TMS BF3·OE 205(29%) aWi h 3 equi . o aldehyde ins ead o 1.2 equi . Molecules 2023, 28, x FOR PEER REVIEW 4 o 14 Table 1. Sc eening o he eac ion condi ions. En y R1 R2 R3 LA (1 equi .) T (°C) NMR Analysis (Isola - ed Yield) 1 CH3 CH2CH2Ph H TMSOT −78 3 2 CH3 CH2CH2Ph H TMSOT 0 Complex mix u e 3 a CH3 CH2CH2Ph H TMSOT −78 Complex mix u e 4 CH3 CH2CH2Ph H BF3·OE 2 −78 Complex mix u e 5 CH3 CH=CHPh H TMSOT −20 Aldehyde 6 a CH2Ph CH3 H TMSOT −78 3a + 4a 7 a CH2Ph CH2Ph H TMSOT −78 4i 8 a Ph CH3 H TMSOT −78 Complex mix u e 9 Ph CH2CH2Ph H TMSOT −78 Complex mix u e 10 CH3 CH=CHPh TMS TMSOT −78 2a 11 CH3 CH=CHPh TMS BF3·OE 2 −78 Complex mix u e 12 CH3 CH=CHPh TMS BF3·OE 2 0 5 (29%) a Wi h 3 equi . o aldehyde ins ead o 1.2 equi . Scheme 4. Reac ion pa hways om allylsilyl alcohols 2. As shown be o e, he eac ion o di e en allylsilyl alcohols wi h aldehydes, in he p esence o Lewis acids, u ned ou o be e y challenging, due o he di e en beha io o he implica ed subs a es, as well as he a ie y o compe i i e eac ion pa hways. Howe e , we we e able o iden i y and isola e key p oduc s o a be e unde s anding o he implica ed in e media es, ha will help in he de elopmen o u u e silyl-P ins cy- cliza ions. Nex , and conside ing p e ious da a, we ocused ou a en ion on he s udy o he silyl-P ins cycliza ion o inylsilyl alcohols 3. 2.3. Silyl-P ins Cycliza ion S udy o Vinylsilyl Alcohols 3 Fi s o all, we sc eened di e en condi ions and Lewis acids, in o de o ind he op imized condi ions o he cycliza ion, using as a key model de i a i e 3a. As shown in Table 2, complex mix u es we e ob ained a 0 °C when BF3·OE 2 o TMSCl we e used as Lewis acids (Table 2, en ies 1–4). G a i yingly, a cis-2,6-disubs i u ed dihyd opy ane de i a i e 4a was ob ained when 1 equi . o TMSOT was used a −78 °C (Table 2, en ies 5–7). Analysis o he eac ion c ude, showed e y good dias e eoselec i i y o cis-4a (cis: ans, 90:10), which was isola ed in a 48% yield (Table 2, en y 6). Inc easing he Scheme 4. Reac ion pa hways om allylsilyl alcohols 2. As shown be o e, he eac ion o di e en allylsilyl alcohols wi h aldehydes, in he p esence o Lewis acids, u ned ou o be e y challenging, due o he di e en beha io o he implica ed subs a es, as well as he a ie y o compe i i e eac ion pa hways. Howe e , we we e able o iden i y and isola e key p oduc s o a be e unde s anding o he implica ed in e media es, ha will help in he de elopmen o u u e silyl-P ins cycliza ions. Nex , and conside ing p e ious da a, we ocused ou a en ion on he s udy o he silyl-P ins cycliza ion o inylsilyl alcohols 3. 2.3. Silyl-P ins Cycliza ion S udy o Vinylsilyl Alcohols 3 Fi s o all, we sc eened di e en condi ions and Lewis acids, in o de o ind he op imized condi ions o he cycliza ion, using as a key model de i a i e 3a . As shown in Table 2, complex mix u es we e ob ained a 0 ◦ C when BF 3· OE 2 o TMSCl we e used as Lewis acids (Table 2, en ies 1–4). G a i yingly, a cis-2,6-disubs i u ed dihyd opy ane de i a i e 4a was ob ained when 1 equi . o TMSOT was used a − 78 ◦ C (Table 2, en ies 5–7) . Analysis o he eac ion c ude, showed e y good dias e eoselec i i y o Molecules 2023,28, 3080 5 o 14 cis- 4a (cis: ans, 90:10), which was isola ed in a 48% yield (Table 2, en y 6). Inc easing he equi alen s o he aldehyde, o educing he amoun o he Lewis acid, p o ided lowe yields (Table 2, en ies 5 and 7). Table 2. Sc eening o he eac ion condi ions. Molecules 2023, 28, x FOR PEER REVIEW 5 o 14 equi alen s o he aldehyde, o educing he amoun o he Lewis acid, p o ided lowe yields (Table 2, en ies 5 and 7). Table 2. Sc eening o he eac ion condi ions. En y LA (equi .) Tempe a u e (°C) Isola ed Yield 1 a BF3·OE 2 (1.0) 0 Complex mix u e 2 BF3·OE 2 (1.2) 0 Complex mix u e 3 BF3·OE 2 (0.5) 0 Complex mix u e 4 TMSCl (1.5) 0 o b n 5 a TMSOT (1.0) −78 35% 6 TMSOT (1.0) −78 48% 7 TMSOT (0.5) −78 25% a Wi h 3 equi . o aldehyde. b Room empe a u e. Ha ing de e mined he op imal condi ions, we s udied he eac ion scope o o he inylsilyl alcohols and aldehydes (Scheme 5). As shown, he eac ion o (E)- inylsilyl al- cohols bea ing an alkylic R1 g oup, wi h alkylic aldehydes, p o ides, in mode a e o good yields, he desi ed disubs i u ed dihyd opy ans (4a–4g). In e es ingly, al hough he eac ion o allylsilyl alcohols 2 wi h aldehydes ailed o gi e he desi ed oxacycles (Table 2), we now we e able o ci cum en his di icul y by choosing he app op ia e subs i u- en s in he inylsilyl alcohols and he aldehyde ( o ins ance, dihyd opy an 4b could be ob ained using he homologa ed aldehyde pa ne ). I was also possible o ins all a phe- nyle hylene g oup in he dihyd opy ane wi h good dias e eoselec i i y (d > 95:5), wi h he p epa a ion o compound 4 (79% yield). Howe e , he p esence o a hyd oxy g oup in he a oma ic ing o he aldehyde (when he co esponding 3-(p- hyd oxyphenyl)p opionaldehyde was used) signi ican ly a ec ed he yield o he eac- ion (4g, 43%). O he in e es ing unc ional g oups, such as an isop opyles e , could also be ins alled success ully (4h, 46% yield). An in e es ing aspec o his eac ion, is he ex- cellen dias e eoselec i i y obse ed in mos cases o he o ma ion o he cis-2,6- disubs i u ed dihyd opy an. On he o he hand, less eac i e a oma ic o inylic alde- hydes p oduced complex mix u es, in which i was possible o isola e symme ic e a- hyd opy ans, wi h iden ical subs i uen s a ached a he 2,6-posi ions (4i, 37% yield). This is in acco dance wi h ou p e ious esul s on he eac ion wi h inylsilyl alcohols, in which an al e na i e sigma opic [3,3] oxonia-Cope ansposi ion pa hway was mo e a o ed. Simila ly, inylsilyl alcohols wi h an a yl R1 g oup, p o ided complex eac ion mix u es. En y LA (equi .) Tempe a u e (◦C) Isola ed Yield 1aBF3·OE 2(1.0) 0 Complex mix u e 2 BF3·OE 2(1.2) 0 Complex mix u e 3 BF3·OE 2(0.5) 0 Complex mix u e 4 TMSCl (1.5) 0 o bn 5aTMSOT (1.0) −78 35% 6 TMSOT (1.0) −78 48% 7 TMSOT (0.5) −78 25% aWi h 3 equi . o aldehyde. bRoom empe a u e. Ha ing de e mined he op imal condi ions, we s udied he eac ion scope o o he inylsilyl alcohols and aldehydes (Scheme 5). As shown, he eac ion o (E)- inylsilyl alcohols bea ing an alkylic R 1 g oup, wi h alkylic aldehydes, p o ides, in mode a e o good yields, he desi ed disubs i u ed dihyd opy ans ( 4a–4g ). In e es ingly, al hough he eac ion o allylsilyl alcohols 2 wi h aldehydes ailed o gi e he desi ed oxacycles (Table 2), we now we e able o ci cum en his di icul y by choosing he app op ia e subs i uen s in he inylsilyl alcohols and he aldehyde ( o ins ance, dihyd opy an 4b could be ob ained using he homologa ed aldehyde pa ne ). I was also possible o ins all a phenyle hylene g oup in he dihyd opy ane wi h good dias e eoselec i i y (d > 95:5), wi h he p epa a ion o compound 4 (79% yield). Howe e , he p esence o a hyd oxy g oup in he a oma ic ing o he aldehyde (when he co esponding 3-(p-hyd oxyphenyl)p opionaldehyde was used) signi ican ly a ec ed he yield o he eac ion ( 4g , 43%). O he in e es ing unc ional g oups, such as an isop opyles e , could also be ins alled success ully ( 4h , 46% yield). An in e es ing aspec o his eac ion, is he excellen dias e eoselec i i y obse ed in mos cases o he o ma ion o he cis-2,6-disubs i u ed dihyd opy an. On he o he hand, less eac i e a oma ic o inylic aldehydes p oduced complex mix u es, in which i was possible o isola e symme ic e ahyd opy ans, wi h iden ical subs i uen s a ached a he 2,6-posi ions ( 4i , 37% yield). This is in acco dance wi h ou p e ious esul s on he eac ion wi h inylsilyl alcohols, in which an al e na i e sigma opic [ 3 , 3 ] oxonia-Cope ansposi ion pa hway was mo e a o ed. Simila ly, inylsilyl alcohols wi h an a yl R 1 g oup, p o ided complex eac ion mix u es. Molecules 2023,28, 3080 6 o 14 Molecules 2023, 28, x FOR PEER REVIEW 6 o 14 Scheme 5. Reac ion scope o he silyl-P ins cycliza ion. 2.4. Reac ion Mechanism S udy The eac ion o allylsilyl alcohols u ned ou o be mo e challenging han he co e- sponding one wi h E- inylsilyl alcohols. Ve y likely, his is due o he concu ence o mo e a o ed al e na i e pa hways, such as oxonia-Cope ansposi ion and Pe e son elimina ion. In he case o E- inylsilyl alcohols, cis-dihyd opy ane de i a i es we e se- lec i ely ob ained h ough a silyl-P ins cycliza ion eac ion. A plausible mechanism o his eac ion would s a wi h he eac ion o E- inylsilyl alcohol 3 wi h he aldehyde, in he p esence o a Lewis acid, o gene a e an oxoca benium ion III (Scheme 6). Then, a 6- endo-dig cycliza ion would ake place, o a o d in e media e IV (s abilized by he silicon a om), ollowed by a subsequen desilyla ion eac ion, o a o d inal p oduc 4 [23]. This p ocess can be conside ed a andem eac ion, in which TMSOT p omo es he o ma ion o in e media e III and he elimina ion s ep. The s e eocon ol can be explained h ough he p e e en ial pseudoequa o ial con o ma ion o subs i uen s R1 and R2 in he ansi- ion s a e, o achie e minimal epulsion. Scheme 6. Mechanism p oposal o he silyl-P ins cycliza ion. In o de o gain insigh in o he eac ion mechanism and he high s e eoselec i i y obse ed, a compu a ional s udy o he silyl-P ins cycliza ion has been pe o med a a undamen al le el. In his wo k, he Ams e dam Densi y Func ional 2017.01 (ADF) [24,25] so wa e package was used o pe o m DFT calcula ions. The geome ies we e ully op imized wi hou symme y cons ain s, using he combina ion o he g adien Scheme 5. Reac ion scope o he silyl-P ins cycliza ion. 2.4. Reac ion Mechanism S udy The eac ion o allylsilyl alcohols u ned ou o be mo e challenging han he co e- sponding one wi h E- inylsilyl alcohols. Ve y likely, his is due o he concu ence o mo e a o ed al e na i e pa hways, such as oxonia-Cope ansposi ion and Pe e son elimina ion. In he case o E- inylsilyl alcohols, cis-dihyd opy ane de i a i es we e selec i ely ob ained h ough a silyl-P ins cycliza ion eac ion. A plausible mechanism o his eac ion would s a wi h he eac ion o E- inylsilyl alcohol 3 wi h he aldehyde, in he p esence o a Lewis acid, o gene a e an oxoca benium ion III (Scheme 6). Then, a 6-endo-dig cycliza- ion would ake place, o a o d in e media e IV (s abilized by he silicon a om), ollowed by a subsequen desilyla ion eac ion, o a o d inal p oduc 4 [ 23 ]. This p ocess can be conside ed a andem eac ion, in which TMSOT p omo es he o ma ion o in e media e III and he elimina ion s ep. The s e eocon ol can be explained h ough he p e e en ial pseudoequa o ial con o ma ion o subs i uen s R 1 and R 2 in he ansi ion s a e, o achie e minimal epulsion. Molecules 2023, 28, x FOR PEER REVIEW 6 o 14 Scheme 5. Reac ion scope o he silyl-P ins cycliza ion. 2.4. Reac ion Mechanism S udy The eac ion o allylsilyl alcohols u ned ou o be mo e challenging han he co e- sponding one wi h E- inylsilyl alcohols. Ve y likely, his is due o he concu ence o mo e a o ed al e na i e pa hways, such as oxonia-Cope ansposi ion and Pe e son elimina ion. In he case o E- inylsilyl alcohols, cis-dihyd opy ane de i a i es we e se- lec i ely ob ained h ough a silyl-P ins cycliza ion eac ion. A plausible mechanism o his eac ion would s a wi h he eac ion o E- inylsilyl alcohol 3 wi h he aldehyde, in he p esence o a Lewis acid, o gene a e an oxoca benium ion III (Scheme 6). Then, a 6- endo-dig cycliza ion would ake place, o a o d in e media e IV (s abilized by he silicon a om), ollowed by a subsequen desilyla ion eac ion, o a o d inal p oduc 4 [23]. This p ocess can be conside ed a andem eac ion, in which TMSOT p omo es he o ma ion o in e media e III and he elimina ion s ep. The s e eocon ol can be explained h ough he p e e en ial pseudoequa o ial con o ma ion o subs i uen s R1 and R2 in he ansi- ion s a e, o achie e minimal epulsion. Scheme 6. Mechanism p oposal o he silyl-P ins cycliza ion. In o de o gain insigh in o he eac ion mechanism and he high s e eoselec i i y obse ed, a compu a ional s udy o he silyl-P ins cycliza ion has been pe o med a a undamen al le el. In his wo k, he Ams e dam Densi y Func ional 2017.01 (ADF) [24,25] so wa e package was used o pe o m DFT calcula ions. The geome ies we e ully op imized wi hou symme y cons ain s, using he combina ion o he g adien Scheme 6. Mechanism p oposal o he silyl-P ins cycliza ion. Molecules 2023,28, 3080 7 o 14 In o de o gain insigh in o he eac ion mechanism and he high s e eoselec i i y obse ed, a compu a ional s udy o he silyl-P ins cycliza ion has been pe o med a a undamen al le el. In his wo k, he Ams e dam Densi y Func ional 2017.01 (ADF) [ 24 , 25 ] so wa e package was used o pe o m DFT calcula ions. The geome ies we e ully op i- mized wi hou symme y cons ain s, using he combina ion o he g adien co ec ions o he Becke exchange unc ional and Pe dew co ela ion unc ional, which use he Vosko– Wilk–Nusai exchange-co ela ion po en ial epo ed by Becke (1998) and Pe dew (1986) (BP86-D3) [ 26 – 28 ], in combina ion wi h he la es e sion o G imme dispe sion co ec- ion [ 29 ]. T iple- ζ Sla e - ype o bi als (STO), we e used o desc ibe he alence shells. The sol a ion en i onmen was ea ed wi h he Conduc o -like Sc eening Model (COSMO) [ 30 ], conside ing dichlo ome hane ( E = 8.9) in o de o ep oduce he expe imen al condi ions pe o med in ou lab. Analy ical equencies we e compu ed, o cha ac e ize he s a iona y poin s and calcula e he ee ene gies (s anda d s a e T = 298.15 K, p= 1 a m). The ansi ion s a e was ollowed a e a ac ional displacemen o he imagina y ib a ional mode, o de e mine he eac ion pa h o eac an (s) and p oduc (s). Molecula ende ings we e made wi h Chemc a [31]. In Figu e 1, he eac ion p o ile o he 6-endo silyl-P ins cycliza ion owa ds dihyd opy- an 4a is shown. In his s udy, only he app oxima ion be ween he wo ca bon a oms ha yields a chai con o ma ion o he oxygena ed he e ocycle is desc ibed, since no ansi ion s a e has been ound o a boa con o ma ion. The esul s ob ained, indica e ha he eac ion shows a e y low ene gy p o ile, wi h an ene gy ba ie o he ansi ion s a e o 2.7 kcal/mol. In such a ansi ion s a e, he dis ance be ween he C a oms which will be bonded in he cycliza ion s ep, co esponds o 1.95 Å. Following he imagina y ib a ional mode o cyclic in e media e IV ( e ahyd opy anyl ca boca ion), he minimum p esen s a Gibbs ee ene gy alue o 1.6 kcal/mol, which co esponds o an ene gy di e ence wi h he ansi ion s a e o only 1.1 kcal/mol. This low ene gy p o ile is consis en wi h he expe imen al esul s conce ning he e e sibili y o he silyl-P ins cycliza ion, which could ollow o he compe i i e pa hways. Fu he mo e, we ca ied ou compu a ional s udies o he Risome (C a om ha holds he me hyl g oup); geome ies o he eac an s and p oduc s we e ully op imized. The ob ained esul s, show ha o he Risome , whe e he me hyl is in axial a angemen , bo h ∆ H and ∆ G ene gies p esen highe alues in compa ison wi h he Sisome (see Suppo ing In o ma ion, Figu e S1). In addi ion, o he Risome , he o a ional eedom allowed by he sigma bonds p io o cycliza ion could lead o ano he con o ma ion, whe e he bulky g oups (me hyl and benzyl) a e placed in equa o ial a angemen , which explains he p e e en ial o ma ion o cis-2,6-disubs i u ed de i a i es 4(see Suppo ing In o ma ion, Scheme S1). Molecules 2023,28, 3080 8 o 14 Molecules 2023, 28, x FOR PEER REVIEW 8 o 14 Figu e 1. Reac ion scheme o silyl-P ins cycliza ion. Gibbs ee ene gies a e p o ided in kcal·mol−1, and dis ances in angs oms (Å ). 3. Ma e ials and Me hods 3.1. Gene al Rema ks Unless o he wise no ed, expe imen s we e ca ied ou wi h d y sol en s unde a ni- ogen a mosphe e. Dichlo ome hane was d ied wi h p eac i a ed molecula sie es. Flash column ch oma og aphy was pe o med using Silica Gel 60 (230–400 mesh ASTM). Thin-laye ch oma og aphy (TLC) was pe o med using an aluminum backed pla e, p e- coa ed wi h silica gel (0.20 mm, silica gel 60), wi h a luo escen indica o (254 nm) om Mache ey. NMR spec a we e eco ded a he nuclea magne ic esonance se ice o he Labo a o y o Ins umen al Techniques (L.T.I., www.labo a o io ecnicasins umen ales.es), Uni e si y o Valladolid, a Va ian 400 MHz (1H, 399.85 MHz; 13C, 100.61 MHz) and Va ian 500 MHz (1H, 500.12 MHz; 13C, 100.61 MHz), wi h he spec ome e s a oom empe a u e (25 °C). Chemical shi s (δ) we e e- po ed in pa s pe million (ppm), ela i e o he esidual sol en peaks eco ded, ounded o he nea es 0.01 o 1H-NMR and 0.1 o 13C-NMR ( e e ence: CDCl3 [1H: 7.26, 13C: 77.2]). Spin–spin coupling cons an s (J) in 1H-NMR we e gi en in Hz, o he nea es 0.1 Hz, and peak mul iplici y was indica ed as ollows s (single ), d (double ), ( iple ), q (qua e ), m (mul iple ), and b (b oad). 13C-NMR we e eco ded wi h comple e p o on decoupling. Ca bon ypes, s uc u e assignmen s and a ibu ion o peaks we e de e - mined om wo-dimensional co ela ion expe imen s (HSQC, COSY, and HMBC). Rela- i e s e eochemis y was assigned based on he 2D-NOE expe imen s. High- esolu ion mass spec a (HRMS) we e measu ed a he mass spec ome y se ice o he Labo a o y o Ins umen al Techniques, Uni e si y o Valladolid, on a UPLC-MS sys em (UPLC: Wa- e s ACQUITY H-class UPLC; MS: B uke Maxis Impac ) by elec osp ay ioniza ion (ESI posi i e and nega i e). Figu e 1. Reac ion scheme o silyl-P ins cycliza ion. Gibbs ee ene gies a e p o ided in kcal · mol −1 , and dis ances in angs oms (Å). 3. Ma e ials and Me hods 3.1. Gene al Rema ks Unless o he wise no ed, expe imen s we e ca ied ou wi h d y sol en s unde a ni ogen a mosphe e. Dichlo ome hane was d ied wi h p eac i a ed molecula sie es. Flash column ch oma og aphy was pe o med using Silica Gel 60 (230–400 mesh ASTM). Thin-laye ch oma og aphy (TLC) was pe o med using an aluminum backed pla e, p e- coa ed wi h silica gel (0.20 mm, silica gel 60), wi h a luo escen indica o (254 nm) om Mache ey. NMR spec a we e eco ded a he nuclea magne ic esonance se ice o he Labo a o y o Ins umen al Techniques (L.T.I., www.labo a o io ecnicasins umen ales.es), Uni e si y o Valladolid, a Va ian 400 MHz ( 1 H, 399.85 MHz; 13 C, 100.61 MHz) and Va ian 500 MHz ( 1 H, 500.12 MHz; 13 C, 100.61 MHz), wi h he spec ome e s a oom empe a u e (25 ◦ C). Chemical shi s ( δ ) we e epo ed in pa s pe million (ppm), ela i e o he esidual sol en peaks eco ded, ounded o he nea es 0.01 o 1 H-NMR and 0.1 o 13 C-NMR ( e e ence: CDCl 3 [ 1 H: 7.26, 13 C: 77.2]). Spin–spin coupling cons an s (J) in 1 H-NMR we e gi en in Hz, o he nea es 0.1 Hz, and peak mul iplici y was indica ed as ollows s (single ), d (double ), ( iple ), q (qua e ), m (mul iple ), and b (b oad). 13 C-NMR we e eco ded wi h comple e p o on decoupling. Ca bon ypes, s uc u e assignmen s and a ibu ion o peaks we e de e mined om wo-dimensional co ela ion expe imen s (HSQC, COSY, and HMBC). Rela i e s e eochemis y was assigned based on he 2D-NOE expe imen s. High- esolu ion mass spec a (HRMS) we e measu ed a he mass spec ome y se ice o he Labo a o y o Ins umen al Techniques, Uni e si y o Valladolid, on a UPLC-MS sys em (UPLC: Wa e s ACQUITY H-class UPLC; MS: B uke Maxis Impac ) by elec osp ay ioniza ion (ESI posi i e and nega i e). Molecules 2023,28, 3080 9 o 14 3.2. Syn hesis o Allyl(diphenyl)silane 1 A solu ion o 2.99 g (45 mmol, 1.5 equi .) o zinc, in 25 mL THF (1.2 M), was cooled o 0 ◦ C unde a ni ogen a mosphe e. Then, allyl b omide (45 mmol, 1.5 equi .) was added, and a e i e minu es unde igo ous s i ing, 5.03 mL o phenyldime hylchlo osilane (30 mmol, 1.0 equi .) was added d opwise. When he s a ing ma e ials had been consumed, i was hyd olyzed wi h 20 mL o NH 4 Cl sa . The phases we e hen sepa a ed, ex ac ing he aqueous phase h ee imes wi h die hyl e he . The o ganic phases we e combined, washed wi h NaCl sa ., and d ied o e anhyd ous Na 2 SO 4 . The sol en was hen e apo a ed unde educed p essu e. The c ude mix u e was analyzed by NMR and hen pu i ied by column ch oma og aphy in silica gel, using hexane, p o iding allylsilane 1 in quan i a i e yield. This ( 1 ) was ob ained as a colo less oil in 95% chemical yield (5.02 g om 30 mmol o PhMe 2 SiCl). 1 H-NMR (500 MHz, CDCl 3 ) δ 7.52–7.47 (m, 2H, A -H), 7.36–7.32 (m, 3H, A -H), 5.83–5.71 (m, 1H, HC=), 4.87 (d, J ans = 17.0 Hz, 1H, =CHH), 4.83 (d, J cis = 10.4 Hz, 1H, = CHH), 1.74 (d, J= 8.0 Hz, 2H, CH2), 0.27 (s, 6H, (CH3)2- Si). 3.3. Syn hesis o Allylsilyl Alcohols 2 A solu ion o 1.5 g (8.5 mmol, 1.0 eq.) o allylsilane 1 , in 15 mL THF (0.57 M), was cooled o 0 ◦ C (unde ni ogen). Nex , 6.4 mL n-BuLi (10.2 mmol, 1.1 eq.) and 2.1 mL TMEDA (14.0 mmol, 1.65 eq.) we e added d opwise. The mix u e was s i ed a his empe a u e o 2 h. Then, he eac ion as cooled down o − 78 ◦ C and 2.52 mL Ti( i OP ) 4 (8.5 mmol, 1.0 eq.) was added. A e 1 h, he co esponding aldehyde (10.2 mmol, 1.2 eq.) was added d opwise o he solu ion. When he s a ing ma e ials had been consumed (con ol by TCL), i was hyd olyzed wi h 15 mL o NH 4 Cl sa . The phases we e hen sepa a ed, ex ac ing he aqueous phase h ee imes wi h die hyl e he . The o ganic phases we e combined, washed wi h NaCl sa ., and d ied o e anhyd ous Na 2 SO 4 . The sol en was hen e apo a ed unde educed p essu e. The c ude mix u e was analyzed by NMR and hen pu i ied by column ch oma og aphy in silica gel, using a mix u es o hexane-e hyl ace a e (10:1), yielding allylsilyl alcohols 2. 3-(dime hyl(phenyl)silyl)pen -4-en-2-ol ( 2a ) was ob ained ollowing he gene al p oce- du e 3.3, as a yellow oil, in 55% chemical yield (3.028 g om 22.7 mmol o 1 ). 1 H-NMR (500 MHz, CDCl 3 ) δ 7.56–7.49 (m, 2H, A -H), 7.39–7.32 (m, 3H, A -H), 5.81 (d , J= 17.2, 10.4 Hz, 1H, HC=), 5.09 (dd, J= 10.4, 1.7 Hz, 1H, =CHH), 4.96 (ddd, J= 17.2, 2.0, 0.7 Hz, 1H, =CHH), 4.00–3.87 (m, 1H, HC-OH), 1.85 (dd, J= 10.4, 6.0 Hz, 1H, HC), 1.52 (b s, 1H, OH), 1.11 (d, J= 6.3 Hz, 3H, CH 3 ), 0.35 (s, 3H, Si-CH 3 ), 0.32 (s, 3H, Si-CH 3 ). 13 C-NMR (101 MHz, CDCl 3 ) δ 138.0 (C), 135.9 (HC=), 134.1 (CH), 129.2 (CH), 127.9 (CH), 116.1 (=CH 2 ), 67.6 (HC-OH), 44.7 (CH), 23.6 (CH3), −3.0 (Si-CH3), −3.8 (Si-CH3). 3-(dime hyl(phenyl)silyl)-1-phenylpen -4-en-2-ol ( 2b ) was ob ained ollowing he gene al p ocedu e 3.3, as a yellow oil, in 33% chemical yield (826 mg om 8.5 mmol o 1 ). 1 H-NMR (500 MHz, CDCl 3 ) δ 7.56–7.49 (m, 2H, A -H), 7.37–7.31 (m, 3H, A -H), 7.29–7.24 (m, 3H, A -H), 7.23–7.17 (m, 1H, A -H), 7.12–7.08 (m, 2H, A -H), 5.97 (d , J= 17.1, 10.5 Hz, 1H, HC=), 5.11 (dd, J= 10.4, 2.1 Hz, 1H =CHH), 4.92 (ddd, J= 17.1, 2.1, 0.5 Hz, 1H, =CHH), 4.01–3.90 (m, 1H, HC-OH), 2.70–2.65 (m, 2H, Ph-CH 2 ), 1.96 (dd, J= 10.4, 3.5 Hz, 1H, CH), 1.45 (dd, J= 3.5, 1.1 Hz, 1H, OH), 0.36 (s, 3H, Si-CH 3 ), 0.32 (s, 3H, Si-CH 3 ). 13 C-NMR (101 MHz, CDCl 3 ) δ 139.1 (C), 138.0 (C), 135.1 (HC=), 134.2 (CH), 129.4 (CH), 129.2 (CH), 128.6 (CH), 127.9 (CH), 126.4 (CH), 115.7 (=CH 2 ), 72.6 (HC-OH), 44.0 (CH 2 ), 41.6 (CH), − 3.4 (Si-CH3), −3.8 (Si-CH3). 2-(dime hyl(phenyl)silyl)-1-phenylbu -3-en-1-ol ( 2c ) was ob ained ollowing he gene al p ocedu e 3.3, as a yellow oil, in 49% chemical yield (1.18 g om 8.5 mmol o 1 ). 1 H-NMR (500 MHz, CDCl 3 ) δ 7.48–7.42 (m, 2H, A -H), 7.37–7.31 (m, 3H, A -H), 7.29–7.25 (m, 2H, A -H), 7.24–7.20 (m, 3H, A -H), 5.88 (d , J= 17.2, 10.4 Hz, 1H, HC=), 5.05 (dd, J= 10.4, 1.8 Hz, 1H, =CHH), 4.90 (dd, J= 17.2, 1.8 Hz, 1H, =CHH), 4.75 (dd, J= 6.9, 2.7 Hz, 1H, HC-OH), 2.26 (dd, J= 10.4, 6.9 Hz, 1H, HC), 2.03 (d, J= 2.7 Hz, 1H, OH), 0.19 (s, 3H, Si-CH 3 ), 0.08 (s, 3H, Si-CH 3 ). 13 C-NMR (101 MHz, CDCl 3 ) δ 143.8 (C), 137.5 (C), 135.8