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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 July 2.
Published in final edited form as:
PMCID: PMC2755244

Stereoselective Synthesis of Syn,Syn- and Syn,Anti-1,3,5-Triols via Intramolecular Hydrosilylation of Substituted Pent-3-en-1,5-diols


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A stereoselective method for synthesis of syn,syn- and syn,anti-1,3,5-triols based on a double allylboration-intramolecular hydrosilylation sequence has been developed. 1,3-Syn stereocontrol is achieved in the intramolecular hydrosilylation of mono-protected (Z)-1,5-syn-diols and (E)-1,5-anti-diols with 87:13 to 95:5 and 86:14 to 88:12 diastereomeric ratios, respectively, by using 0.5 mol % of Karstedt’s catalyst in toluene.

The 1,3,5-triol motif is a common subunit of many biologically active natural products.1,2 Consequently, the stereoselective synthesis of these units has attracted much interest.1,3 During the course of our efforts toward the synthesis of polyketide natural products, we became interested in exploring the intramolecular hydrosilylation of substituted pent-3(Z)-en-1,5-syn- (1) and (E)-1,5-anti-diol monoethers, 1 and 5, respectively, which are prepared using our double allylboration methodology,4 as a strategy for synthesis of syn,syn- and syn,anti-1,3,5-triols 4 and 6, respectively (Scheme 1).

Scheme 1
Intramolecular Hydrosilylation of Homoallylic Alcohols 1 and 5

Intramolecular hydrosilylation of acyclic homoallylic alcohols followed by oxidative cleavage of the resultant carbon-silicon bond presents a mild and efficient way to construct 1,3-diols.5-7 Several publications by the Tamao group described the regio- and stereocontrolled synthesis of 1,3-diols from allylic and homoallylic alcohols.5,6a However, 1,3-stereochemical control was not observed in hydrosilylation reactions of acyclic (E)- and (Z)- disubstituted homoallylic alcohols by using Speier’s catalyst (H2PtCl6•6H2O).5,8 Further investigations of the intramolecular hydrosilylation of homoallylic alcohols have not been reported. We report herein our studies of this reaction, using homoallylic alcohols 1 and 5 as the substrates, which demonstrate that syn,syn-diols 4 and syn,anti-diols 6 are obtained with 87-95% and 84-88% diastereoselectivity, respectively, by using 0.5 mol % of Karstedt’s catalyst9 in toluene.

Syntheses of 1,5-diol derivatives 1 and 5 were accomplished as summarized in Scheme 2. Sequential treatment of two aldehydes with γ-borylallylboranes 7 or 9 provided (Z)-1,5-syn-diols 8 and (E)-1,5-anti-diols 10, respectively, with excellent diastereo- and enantioselectivity.4 Treatment of 1,5-diols 8 and 10 with 1.1 equiv of TES-Cl or TBS-Cl, imidazole, and catalytic DMAP in CH2Cl2-DMF furnished the targeted mono-silyl ethers 1 and 5 with good chemoselectivity and yield (see Supporting Information for details).10

Scheme 2
Synthesis of Mono-protected 1,5-Diols 1 and 5

We used homoallylic alcohol 11 to screen catalysts and reaction conditions for the intramolecular hydrosilylation reaction. We elected to use Speier’s catalyst8 (PtCl6•6H2O), Karstedt’s catalyst9 (14, platinum(0)-1,3-divinyl-1,1,3,3-tetramethyl-disiloxane) and Pt(PPh3)4,11 due to their commercial availibility and known utility as catalysts for hydrosilylation reactions. Hence, a mixture of homoallylic alcohol 11 and (HMe2Si)2NH (2 equiv) was stirred at room temperature overnight to ensure silylation of the hydroxy group. The excess disilazane was removed under vacuum, then the silane intermediate was subjected to a range of hydrosilylation conditions as summarized in Table 1.

Table 1
Optimization of Conditions for Intramolecular Hydrosilylation of (Z)-1,5-syn-Diol Monosilyl Ether 11
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The results indicated that hydrosilylation of 11 using 0.5 mol % of Karstedt’s catalyst (14) in toluene proceeded to completion very smoothly at 0 °C in 3 h (entry 3). On the other hand, elevated temperatures and longer reaction times were needed for complete hydrosilyaltion using Speier’s catalyst (0.5 mol %, 60 °C, 12 h, entry 1) and Pt(PPh3)4 (5 mol %, 110 °C, 5 h, entry 2). More importantly, use of Karstedt’s catalyst (14) led to superior 1,3-syn diastereoselectivity (93 : 7), compared to the selectivity obtained by using Speier’s catalyst (85 : 15 d.r.) and Pt(PPh3)4 (72 : 18 d.r.). The stereochemistry of of siloxane 12 was assigned as discussed subsequently. The overall reaction diastereoselectivity was best in toluene and hexanes among the solvents that we examined (entries 3-5).

Intermediate 12 was oxidized to 1,3-syn diol 15 by treatment with 30% H2O2 (20 equiv) and KHCO3 (5 equiv) in THF-MeOH (Scheme 3).12 The overall yield of 15 was 85% for this three-step sequence starting from 11.

Scheme 3
Synthesis of syn-1,3-Diol 15 and Proposal for Origin of 1,3-syn-Stereocontrol

The stereochemistry of 15 was assigned by conversion to acetonide 16 (Scheme 3). 13C NMR analysis of 16 according to Rychnovsky’s method13 established the syn- 1,3-cis acetonide stereochemistry. This also confirmed the 1,3-syn-stereochemistry of hydrosilylation product 12, since the oxidative cleavage of the C-Si bond is known to proceed with retention of configuration.12

Tamao has suggested that the Pt-catalyzed intramolecular hydrosilylation reaction preceeds through an oxidative addition-hydrometalation-reductive elimination sequence.14 We speculate that the origin of 1,3-syn-stereocontrol could derive from a chair-like transition state 17 for the 6-exo-hydrometalation step with the olefin in a pseudo-equatorial position (Scheme 3). Intermediate 18 could then undergo reductive elimination to provide the five-membered syn-cyclic siloxane 3.

Having developed suitable conditions for intramolecular hydrosilylation of 11, we explored the scope of this sequence with additional substrates as summarized in Table 2. The (Z)-1,5-syn-diol monosilyl ethers 19, 21, 23 and 25 were converted into the corresponding syn,syn- 1,3,5-triol monoethers 20, 22, 24 and 26, respectively, in 72-78% yield with 87 : 13 to 95 : 5 diastereoselectivity. This procedure worked well for the sterically demanding substrate 23 (Table 2, entry 3). Moreover, from a practical standpoint, this reaction can be performed essentially as a one-pot operation without purification of the silyl ether and cyclic siloxane intermediates.

Table 2
Intramolecular Hydrosilylation of (Z)-1,5-syn-Diol Monosilyl Ethers 19, 21, 23 and 25
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We next turned our attention to the synthesis of the syn,anti triol unit 6 from mono-protected (E)-1,5-anti- diols 5. Optimization of the hydrosilylation conditions was conducted using (E)-homoallylic alcohol 27. Therefore, as summarized in Table 3, alcohol 27 was silylated with (HMe2Si)2NH and then subjected to various hydrosilylation catalysts and conditions to form the syn hydrosilylation product 28 as a major diastereomer. Again, use of 0.5 mol % Karstedt’s catalyst 14 (Table 3, entry 3) in toluene (0 °C, 2 h, then room temperature, 2 h) provided the best reaction diastereoselectivity (syn:anti = 85:15). Attempts to improve the diastereoselectivity by conducting the reaction in other solvents (entries 4, 5), at lower temperatures (entry 6; only trace amounts of 28 were observed after 12 h at -40 °C), or with other catalysts (entries 1, 2) were unsuccessful.

Table 3
Optimization of Intramolecular Hydrosilylation of (E)-1,5-anti-Diol Monosilyl Ether 27
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Further investigation of the scope of the hydrosilylation of (E)-1,5-anti-diol monoethers was performed as summarized in Table 4. The intramolecular hydrosilylations of 30, 32 and 34 in Table 4 proceeded with 84:16 to 88:12 diastereoselectivity favoring the formation of the indicated 1,3-syn diols 31, 33 and 35 (which were obtained in 72-82% yield for the three-step sequence). It is also worth noting that, as demonstrated by substrate 34 (Table 4, entry 4), the intramolecular hydrosilylation occur on the proximal internal olefin, leaving the distal trisubstitute olefin intact without any olefin isomerization or intermolecular hydrosilylation products being observed.

Table 4
Intramolecular Hydrosilylation of Mono-protected (E)-1,5-anti-Diols
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We also investigated the effect of greater steric bulk in the silane unit in an attempt to improve the diastereoselectivity of the intramolecular hydrosilylation process. Accordingly, substrates 36, 37 and 38 were synthesized and subjected to hydrosilyaltion conditions as summarized in Table 5. The diphenylsilane 37 (Table 5, entry 2) underwent hydrosilylation but required 12 h at room temperature for complete conversion; subsequent oxidation of the intermediate siloxane gave triol 31 in good yield. However, the reaction diasteroselectivity (84 : 16) was not improved as compared to the analogous reaction of dimethylsilane 36 (Table 5, entry 1). On the other hand, diisopropylsilane 38 failed to undergo the intramolecular hyrosilylation, presumely due to steric hindrance. When 38 was heated at 110 °C in toluene for 12 h in the presence of Karstedt’s catalyst, an unidentified by-product began to form.

Table 5
Effect of Silane Substituents on the Intramolecular Hydrosilylation Reaction
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In summary, we have developed a mild, stereoselective procedure for synthesis of syn,syn and syn,anti-1,3,5-triol derivatives based on the intramolecular hydrosilylation of 1,5-diol monoethers 1 and 5. By using 0.5 mol % Karstedt’s catalyst 14 in toluene, 87:13 to 95:5 syn- diasteroselectivity was achieved for the intramolecular hydrosilylation of (Z)-1,5-syn-diol monoethers 1. Similarly, 84:16 to 88:12 syn diasteroselectivity was achieved for the analogous intramolecular hydrosilylation of (E)-1,5-anti-diol monoethers 5. In all cases, the syn- 1,3-diol derivatives were obtained in 72-85% yields for the simple three-step silyl ether formation-hydrosilylation-oxidative cleavage sequence. Applications of this method in natural products synthesis will be reported in due course.

Supplementary Material




We acknowledge the NIH (GM038436 and GM027682) for support of this research.


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