ETAPAS DE LA METODOLOGIA DEL PROYECTO

3.4 Silylium ion-catalyzed Prins cyclization employing various R3Si–Nu (Et3Si–H,

Me3Si–allyl, and Me3Si–N3) as trapping nucleophiles

The trapping nucleophile (R3Si–Nu) scope of the silylium-catalyzed Prins-cyclization

was investigated; the best examples are listed in Table 3.1.xx Reaction of cinnamyl-amino aldehyde 3.3 with Et3Si–H resulted in the formation of pyrrolidine 3.5 in 77% yield as a

xx_{Other R}

3Si–Nu sources, including TMS–I, TMS–CN, and TMS–OAc, provided complex mixtures of

products by 1H and 13C NMR. NH2 OH NH OH Bs N Bs Ph O Bs = 4-bromobenzenesulfonyl CH2Cl2, 22 °C Bs—Cl, NEt3 (S)-phenylalaninol 1) K2CO3, acetone, 65 °C Ph N Bs O Ph 2) DMP DCM, 22 °C Ph Br Br 2) DMP DCM, 22 °C 3.2 3.3 75% yield 77% yield 3.4 92% yield Ph Ph Ph Ph 3.1

trityl BArF20 (10 mol %), Et3Si—H (12 mol %)

CH2Cl2, —78 °C, 1 h;

then acidic resin in 1:1 CH2Cl2/MeOH, 22 °C, 1 h N ArSO2 R OH Ar Nu N R O ArSO2 Ar + R3Si—Nu (2.50 eq.) * *

mixture of three diastereomers in 76:13:11 d.r. (entry 1). The reaction of 2-phenylallyl-amino aldehyde 3.4 with Et3Si–H resulted in piperidine 3.6 in 92% yield and 60:21:19 d.r. (entry 2).

Reaction of 3.4 with allyltrimethylsilane led to an 84% yield of piperidine 3.7, which

contains an all-carbon quaternary center (66:34 d.r., entry 3); from a mechanistic perspective, this transformation could be considered a vinylogous analog of the named Hosomi-Sakurai allylation.48b,53 When trimethylsilyl azide (Me3Si–N3) was employed as the trapping

nucleophile, alkyl azide 3.8 was obtained in 78% yield and 79:21 d.r. (entry 4). When chlorotrimethylsilane (Me3Si–Cl) was employed as the trapping nucleophile, no chloride-

trapped product was observed (<5%; 3.9, entry 5); Me3Si–Cl is apparently insufficiently

nucleophilic under these conditions, even upon warming to RT.xxi Fortuitously, the TiCl4-

promoted classic Prins cyclization (see 3.7.5.1) is complementary in that it produces the chloride-trapped piperidine 3.9 in 99% isolated yield and 85:9:6 d.r. favoring the vicinal cis- diastereomer (3JCH-CH = 5.9 Hz).

xxi_{The substrate is consumed; in the absence of a suitable trapping nucleophile, catalytic [Et}

3Si][B(C6F5)4]

Table 3.1. Scope of trapping nucleophiles.

3.5 Silylium ion-catalyzed Prins cyclization employing silyl enol ethers

With silyl enol ether trapping nucleophiles, various novel hetero(poly)cyclic piperidines (3.13-3.19) are accessible in fair to good yields and as single diastereomers (Table 3.2). These novel bridged tricyclic piperidine scaffolds contain two stereocenters, one of which is an all-carbon quaternary center. The initial intramolecular Prins

intermediate I; subsequent treatment of I with Brønsted acid (e.g. Dowex resin 50W-X8) catalyzes annulation (blue bond) and elimination to diastereomerically pure (>98:2 d.r.) tricyclic product. It is noteworthy that the annulation selects for a single diastereomer of trapped product; the yields likely reflect this.xxii

Entry 1 documents the effects of changing the ring size of the silyl enol ether; cyclopentanone-derived 3.13 is obtained in only trace amounts (13C NMR and HR-MS, see 3.7.4.2 and Figure 3.8 therein), presumably due to ring strain, while cyclohexanone- and cycloheptanone-derivatives 3.14 and 3.15 are obtained in 64% and 22% yields,

respectively. Alaninol-derivative 3.16 was obtained in 38% yield (entry 2) and the more hindered valinol-derivative was not obtainable under any conditions (not shown; see compound 3.40 in section 3.7.4.2). The presence of a conjugated aryl group on the silyl enol ether is also not well tolerated; see a-tetralone-derivative 3.17 (11% yield, entry 3).xxiii Aryl iodide 11, showcasing aryl substitution on the 2-phenylpropene fragment, undergoes cyclization and annulation to 3.18 in 24% yield (entry 4); such products could potentially be employed in cross-coupling reactions for further synthetic elaboration. Methyl-substituted 3.19, derived from the corresponding 2-methylpropenyl-substituted starting material 3.12, was obtained in 22% yield (entry 5).

xxii_{Analysis of crude pre- and post-annulation} 13_{C NMR suggests the reason for exclusively high d.r. but}

low yield is most likely due to double diastereo-differentiation during annulation of intermediate I; diastereomers with a trans-configuration of the C–O and C–Nu bonds decompose and/or are easily separated away from the cis-bridged products. We have not attempted to isolate or characterize the intermediate ketone diastereomers (I).

xxiii_{Reaction with the corresponding acyclic acetophenone-derived silyl enol ether yielded only trace}

Table 3.2. Silyl enol ethers as trapping nucleophiles.

3.5.1 Removal of aryl sulfonamide protecting groups and X-ray structure for 3.20

In light of the knowledge that deprotection of simple aryl sulfonamides (e.g. tosyl (Ts), brosyl (Bs)) often requires aggressive reagents,54 _{we endeavored to demonstrate}

removal under mild conditions. The 2-naphthalene sulfonamide-protected 3.20 was synthesized for this purpose (55%, see preparation of 3.20 in section 3.7.4.2 and Figure 3.16 therein for analytical data), and employing a modification of a previously reported reductive protocol,55 provided free amine 3.21 (91% yield, Scheme 3.6a; for

experimental details and analytical data, see section 3.7.4.4). It is also notable that the more potent Na-naphthalenide reductant was able to effect the Bs-deprotection of 3.14

(93% yield, see section 3.7.4.4). X-ray analysis of 3.20 (CSD-1548662; Scheme 3.6b, see also section 3.7.4.3) confirmed the relative stereochemistry of the C–O bond and amino R-group to be cis-(axial-equatorial), respectively, consistent with 3JCH-CH =

3 Hz.56