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Synthesis 2010(6): 1014-1022  
DOI: 10.1055/s-0029-1218639
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Hydrazinium Carbazate-H2O2: An Ideal Combination for Diimide Reduction of Base-Sensitive Unsaturated Peroxides [¹]

Chandan Singh*, Ajit Shankar Singh, Niraj Krishna Naikade, Ved Prakash Verma, Mohammad Hassam, Nitin Gupta, Shilpi Pandey
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Fax: +91(522)2623405; e-Mail: chandancdri@yahoo.com;

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Publication History

Received 9 September 2009
Publication Date:
08 January 2010 (online)

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Abstract

The utility of a hydrazinium carbazate (N2H3COON2H5) and H2O2 combination for the double bond reduction of base-sensitive unsaturated 1,2,4-trioxanes, 1,2,4-trioxepanes, and their precursors β- and γ-hydroxyhydroperoxides is presented. The method is superior to the conventional diimide reduction using N2H4˙H2O-H2O2 and catalytic hydrogenation.

Key words

diimide reduction - hydrazinium carbazate - hydrogen peroxide - β-/γ-hydroxyhydroperoxides - 1,2,4-trioxanes

Artemisinin, a naturally occurring 1,2,4-trioxane from Artemisia­ annua and its semi-synthetic derivatives such as artemether and arteether (Figure  [¹] ) are currently the drugs of choice for the treatment of malaria caused by Plasmodium falciparum. [²]

Figure 1 Artemisinin and its semi-synthetic derivatives

As a part of an endeavor to develop synthetic substitutes for artemisinin and its derivatives, we have earlier reported photooxygenation routes for the preparation of 1,2,4-trioxanes [³] [4] and 1,2,4-trioxepanes [5] [6] (Scheme  [¹] ).

Scheme 1 Synthesis of 1,2,4-trioxanes (n = 1) and 1,2,4-triox­epanes (n = 2) via photooxygenation of allylic and homoallylic alcohols

Several of the 6-arylvinyl-1,2,4-trioxanes prepared by this method have shown promising antimalarial activity. [7] We have also shown that these trioxanes undergo a facile fragmentation under basic conditions to furnish α,β-unsaturated keto alcohols, which react with various amines and thiols to give Michael adducts (Scheme  [²] ). Based on these results we have earlier suggested that this facile formation of α,β-unsaturated keto systems under basic conditions and their equally facile reaction with amines and thiols might have relevance to the mechanism of action of these trioxanes as antimalarials. [8] This suggestion naturally makes the double bond the key group for the activity of this group of 1,2,4-trioxanes and calls for the preparation and antimalarial assessment of the corresponding saturated 1,2,4-trioxanes.

Scheme 2 Base mediated fragmentation of 1,2,4-trioxanes into α,β-unsaturated keto alcohols and their entrapment by amines and thiols

In our efforts to achieve this objective, we have discovered hydrazinium carbazate/hydrogen peroxide (N2H3COON2H5-H2O2) as a new combination for the diimide reduction of these base-sensitive 1,2,4-trioxanes and 1,2,4-trioxepanes and their precursors, β- and γ-hydroxyhydroperoxides. In the present study, we demonstrate the superiority of this new diimide reduction method over the conventional diimide reduction using N2H4˙H2O-H2O2 [9] [¹0] and catalytic hydrogenation. [¹¹] Towards this end, we first attempted catalytic hydrogenation of trioxane 1a with hydrogen over platinum(IV) oxide at room temperature and atmospheric pressure, which furnished only diol 2 and ketone 3 in 64 and 89% yield, respectively, and no trace of the corresponding saturated trioxane was isolated [¹²] (Scheme  [³] ).

Scheme 3 Catalytic hydrogenation of unsaturated 1,2,4-trioxane 1a

Further we attempted diimide reduction using a N2H4˙H2O-H2O2 combination (Method A). Thus, the reaction of trioxane 1a with N2H4˙H2O-30% H2O2 in a 1:1 mixture of THF-EtOH was complete within three days and furnished the corresponding saturated trioxanes 4a (less polar) and 5a (more polar) as a diastereomeric mixture in 44% yield and in a ratio of 2:3. Reduction of the trioxanes 1b-e under similar conditions furnished a mixture of the corresponding saturated trioxanes 4b-e (less polar) and 5b-e (more polar) in 36-58% yields. Similar reduction of the trioxepanes 6a-c furnished a mixture of the corresponding saturated trioxepanes 7a-c (less polar) and 8a-c (more polar) in 53-57% yields (Scheme  [4] , Table  [¹] ).

Table 1 Comparative Yields of Diimide Reduction of 1,2,4-Trioxanes 1a-e and 1,2,4-Trioxepanes 6a-c a
Unsaturated peroxide Method Time (d) Products Yield (%)b
1a A
B 		 3
 9 		4a + 5a4a + 5a 44
97
1b A
B 		 2
14 		4b + 5b4b + 5b 36
95
1c A
B 		 2
10 		4c + 5c4c + 5c 36
92
1d A
B 		 2
12 		4d + 5d4d + 5d 37
89
1e A
B 		 4
16 		4e + 5e4e + 5e 58
91
6a A
B 		 2
 6 		7a + 8a7a + 8a 57
79
6b A
B 		 2
 6 		7b + 8b7b + 8b 55
70
6c A
B 		 3
 8 		7c + 8c7c + 8c 53
76
a Method A: N2H4˙H2O-30% H2O2; Method B: N2H3COON2H5-30% H2O2.
b The ratio of the two diastereomers 4:5 and 7:8 is around 2:3 as seen by ¹H NMR spectra of the crude mixtures of the diastereomers.

We believed that the poor yields in diimide reduction of trioxanes 1a-e, were due to the high basicity of N2H4˙H2O, which can lead to a fragmentation of the trioxane moiety by a mechanism similar to that shown in Scheme  [²] . On the other hand, hydrazine hydrate is known to react with CO2 to form hydrazinium carbazate (N2H3COON2H5), a 2:1 adduct of hydrazine and CO2. [¹³] [¹4] A comparison of the pH values of aqueous solutions of N2H4˙H2O and N2H3COON2H5, prepared in our laboratory, showed that the latter was much less basic and therefore more suitable for our work. [¹5] In fact, the reaction of trioxane 1a with N2H3COON2H5-30% H2O2 (method B) took more time to complete, but gave a mixture of the corresponding saturated trioxanes 4a and 5a in a 2:3 ratio in 97% yield. Similarly, reduction of the trioxanes 1b-e under these conditions furnished the corresponding saturated trioxanes 4b-e and 5b-e in 89-95% yields. A similar reduction of the trioxepanes 6a-c furnished the corresponding saturated trioxepanes 7a-c and 8a-c in 70-79% yields (Scheme  [4] , Table  [¹] ). The diastereomers were separated by column chromatography and characterized individually. [¹6]

The lower basicity of N2H3COON2H5 as compared with N2H4 could be the main reason for the sluggishness of this reaction. The oxidation of N2H4 to N2H2, the actual reducing species, is known to be influenced by the pH of the reaction; at pH <8 it is very slow. [¹7]

Scheme 4 Reduction of unsaturated 1,2,4-trioxanes 1a-e and 1,2,4-trioxepanes 6a-c by N2H4˙H2O-30% H2O2 (method A) and N2H3COON2H5-30% H2O2 (method B)

The difference in diimide reduction using N2H4˙H2O-H2O2 and N2H3COON2H5-H2O2 was found to be even more dramatic in the reduction of unsaturated β- and γ-hydroxyhydroperoxides. The diimide reduction of β-hydroxyhydroperoxide 9 with N2H3COON2H5-H2O2 furnished the saturated β-hydroxyhydroperoxide 10 as an inseparable mixture of diastereomers in 50% yield together with saturated diol 11 in 17% yield, also as an inseparable mixture of diastereomers. Similarly, the reduction of β-hydroxyhydroperoxide 13 under these conditions furnished saturated β-hydroxyhydroperoxide 14 and diol 15 in 51 and 28% yield, respectively. Analogous reduction of unsaturated γ-hydroxyhydroperoxides 17 and 21 with N2H3COON2H5-H2O2 furnished the corresponding saturated hydroperoxides 18 and 22 in 62 and 63% yield, respectively; no corresponding diols were obtained in this case (Scheme  [5] , Table  [²] ).

Scheme 5  Reduction of β-hydroxyhydroperoxides 9 and 13 and γ-hydroxyhydroperoxides 17 and 21 by N2H3COON2H5-30% H2O2

Table 2 Yield of Diimide Reduction of Unsaturated Hydroperoxides with N2H3COON2H5-30% H2O2
Unsaturated
hydroperoxide 		Time (d) Product Yield (%)
 9 4 10 50
13 4 14 51
17 3.5 18 62
21 3.5 22 63

Reduction of β-hydroxyhydroperoxides 9 and 13 and γ-hydroxyhydroperoxides 17 and 21 by the conventional method using N2H4˙H2O-H2O2 provided only the corresponding saturated diols. Also, the catalytic reduction of hydroperoxide 9 furnished only diol 11 in 97% yield and no trace of the corresponding saturated hydroperoxide was isolated. To the best of our knowledge, this is the first report on the reduction of the unsaturated hydroxyhydroperoxides to the saturated hydroxyhydroperoxides.

The saturated hydroxyhydroperoxides 10, 14, 18, and 22 were reduced with NaBH4 to furnish saturated diols 11, 15, 19, and 23, which on acetylation furnished the corresponding diacetates 12, 16, 20, and 24, respectively, as inseparable­ mixtures of diastereomers. [¹8]

The comparative superiority of N2H3COON2H5-H2O2 over N2H4˙H2O-H2O2 was also evident in the double bond reduction of ascaridole (25). While the reaction of ascaridole (25) with N2H4˙H2O-H2O2 furnished dihydroascaridole (26) in only 25% yield, [¹9] the reaction with N2H3COON2H5-H2O2 furnished the same compound in 72% yield (Scheme  [6] ).

Scheme 6 Reduction of ascaridole (25) to dihydroascaridole (26) by N2H4 ˙H2O-30% H2O2 (method A) and N2H3COON2H5-30% H2O2 (method B)

Since the objective of these studies was to figure out the role of the double bond in the biological activity of the trioxanes, we evaluated some of these saturated trioxanes for antimalarial activity. Several of the saturated trioxanes, particularly the less polar isomers, were found to be several fold more active than the parent unsaturated trioxanes. The details of the biological activity of the saturated trioxanes will be disclosed elsewhere.

In conclusion, we have discovered N2H3COON2H5-H2O2 as a new combination for the double bond reduction of base-sensitive arylvinyl-1,2,4-trioxanes/trioxepanes and their precursors β-/γ-hydroxyhydroperoxides. [²0] This new method is superior to the conventional diimide reduction with N2H4˙H2O-H2O2 and catalytic hydrogenation. While there are several precedents in the literature on the double bond reduction of unsaturated peroxides, to the best of our knowledge, this is the first report on the preparation of saturated hydroxyhydroperoxides from unsaturated hy­droxy­hydroperoxides.

 

All glass apparatus were oven dried prior to use. Melting points were recorded in open capillaries and are uncorrected. Compounds were characterized by IR, ¹H, ¹³C, ¹H-¹H COSY (correlation spectroscopy), HSQC (heteronuclear single quantum coherence spectra), HMBC (heteronuclear multiple bond correlation spectra), ESI-MS (electron spray ionization mass spectra), FAB-MS (fast atom bombardment mass spectra), EI-HRMS (electron impact high-resolution mass spectra), and elemental analysis (C, H). ¹H and ¹³C NMR spectra were obtained using CDCl3 as a solvent. TMS (δ 0.00 ppm) served as an internal standard in ¹H NMR and CDCl3 (δ 77.0 ppm) in ¹³C NMR. Chemical shifts are reported in parts per million. Column chromatography was performed over silica gel (particle size: 60-120 mesh), or flash silica gel (particle size: 230-400 mesh).

Catalytic Hydrogenation of Trioxane 1a

A solution of 6-arylvinyl-1,2,4-trioxane 1a (0.200 g, 0.64 mmol) in EtOAc (15 mL) was hydrogenated in the presence of Adam’s catalyst (PtO2, 0.003 g) using a Parr shaker assembly at r.t. and atmospheric pressure for 1.5 h. The reaction mixture was filtered over Celite, concentrated under vacuum, and the crude product was purified by column chromatography over silica gel to furnish the saturated diol 2 (0.060 g, 64%) as a colorless oil together with 2-adamantanone (3; 0.080 g, 89%) as a white solid.

3-Phenylbutane-1,2-diol (2)

Oil.

FT-IR (neat): 1057, 1593, 2923, 3403 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.36-7.17 (m, 5 H), 3.79-3.75 (br m, 1 H), 3.58-3.35 (br m, 1 H), 2.88 and 2.81 (2 quint, J = 7.2 Hz,1 H), 2.13-2.03 (br m, 4 H), 1.35 and 1.27 (2 d, J = 7.0, 7.1 Hz, 3 H ).

¹³C NMR (75 MHz, CDCl3): δ = 142.4 (C), 141.8 (C), 127.5 (CH), 127.3 (CH), 126.7 (CH), 126.3 (CH), 125.6 (CH), 125.4 (CH), 76.2 (CH), 75.0 (CH), 63.30 (CH2), 63.27 (CH2), 41.7 (CH), 41.5 (CH), 16.5 (CH3), 16.1 (CH3).

ESI-MS: m/z = 167 [M + H+].

EI-HRMS: m/z calcd for C10H14O2 [M+]: 166.0994; found: 166.0990.

2-Adamantanone (3)

White solid; mp 256-259 ˚C.

FT-IR (KBr): 1717, 2920 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 2.53 (br s, 2 H), 2.12-1.95 (m, 12 H).

¹³C NMR (75 MHz, CDCl3): δ = 217.7 (C), 46.7 (3 × CH2), 38.9 (3 × CH), 36.0 (CH), 27.2 (2 × CH2).

FAB-MS: m/z = 151 [M + H+].

Hydrazinium Carbazate Solution

A slow stream of CO2 gas was bubbled through ice cooled hydrazine hydrate (N2H4˙H2O, 103 g, 2.06 mol) till the weight of reaction mixture became constant (150 g, which corresponded to a 2:1 adduct of N2H4˙H2O and CO2). A small amount (1 g) of this highly viscous material (density = 1.45 g/mL) was dissolved in H2O (100 mL) for the measurement of pH, which was found to be 7.51, while the pH value of 1% aq N2H4˙H2O was found to be 9.79.

Diimide Reduction of 1,2,4-Trioxanes/Trioxepanes, β-/γ-Hydroxyhydroperoxides and Ascaridole Using Hydrazine Hydrate and 30% H 2 O 2 ; Typical Procedure for the Reduction of 1,2,4-Trioxane 1a (Method A)

To a stirred and ice cooled solution of trioxane 1a (1.00 g, 3.205 mmol) and N2H4˙H2O (3.2 mL, 20 equiv) in a 1:1 mixture of EtOH-THF (50 mL) was added 30% H2O2 (10.89 mL, 30 equiv) dropwise over 30 min and the reaction mixture was allowed to stir at r.t. for 3 d. The mixture was concentrated under vacuum, diluted with H2O (20 mL) and extracted with Et2O (2 × 50 mL). The combined organic extracts were washed successively with aq 10% HCl (10 mL), H2O (10 mL), and with sat. aq NaHCO3 (10 mL), dried (Na2SO4), and concentrated under vacuum. The crude product was purified by column chromatography over silica gel to furnish saturated trioxanes 4a and 5a (0.440 g, 44%) as a mixture of diastereomers in approximately 2:3 ratio, which on flash chromatography furnished the pure isomers 4a (less polar, oil) and 5a (more polar, white solid, mp 84-85 ˚C).

Diimide Reduction of 1,2,4-Trioxanes/Trioxepanes, β-/γ-Hydroxyhydroperoxides and Ascaridole Using Hydrazinium Carbazate and 30% H 2 O 2 ; Typical Procedure for the Reduction of 1,2,4-Trioxane 1a (Method B)

To a stirred and ice cooled solution of trioxane 1a (3.00 g, 9.62 mmol) and hydrazinium carbazate (9.55 mL, 10 equiv) in a mixture of EtOH-THF (1:1; 150 mL) was added 30% H2O2 (32.69 mL, 30 equiv) dropwise over 30 min and the reaction mixture was allowed to stir at r.t. for 9 d. The mixture was worked up and the crude product was chromatographed as above to furnish a mixture of 4a and 5a (2.92 g, 97%). No significant difference in yield and reaction time was observed when 1a was reacted with a large excess of N2H3COON2H5-H2O2.

Trioxane 4a

Oil.

FT-IR (neat): 763, 1025, 1117, 1223, 1602, 2914 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.35-7.18 (m, 5 H), 4.35 (dt, J = 9.6, 2.6 Hz, 1 H), 3.62 (dd, J = 11.8, 9.6 Hz, 1 H), 3.34 (dd, J = 11.8, 2.6 Hz, 1 H), 2.81 (s, 1 H), 2.76 (quint, J = 6.9 Hz, 1 H), 2.06-1.59 (m, 13 H), 1.39 (d, J = 6.9 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 142.0 (C), 128.9 (2 × CH), 127.8 (2 × CH), 127.3 (CH), 104.5 (C), 83.3 (CH), 61.2 (CH2), 41.0 (CH), 37.4 (CH2), 35.7 (CH), 33.7 (2 × CH2), 33.5 (CH2), 33.2 (CH2), 30.1 (CH), 27.4 (2 × CH), 18.6 (CH3).

FAB-MS: m/z = 315 [M + H+].

Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C, 76.10; H, 8.40.

Trioxane 5a

White solid; mp 84-85 ˚C.

FT-IR (KBr): 759, 1029, 1086, 1113, 1219, 1604, 2914 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.36-7.23 (m, 5 H), 4.35 (ddd, J = 9.6, 7.6, 3.4 Hz, 1 H), 3.83 (dd, J = 11.6, 9.6 Hz,1 H), 3.77 (dd, J = 11.6, 3.4 Hz, 1 H), 2.87 (quint, J = 7.2 Hz, 1 H), 2.77 (s, 1 H), 2.08-1.55 (m, 13 H), 1.29 (d, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 142.5 (C), 128.7 (2 × CH), 127.8 (2 × CH), 126.9 (CH), 104.60 (C), 82.6 (CH), 60.9 (CH2), 40.7 (CH), 37.4 (CH2), 36.1 (CH), 33.7 (CH2), 33.6 (CH2), 33.3 (CH2), 33.2 (CH2), 29.7 (CH), 27.33 (CH), 27.29 (CH), 17.5 (CH3).

FAB-MS: m/z = 315 [M + H+].

Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C, 76.37; H, 7.96.

Trioxane 4b

White solid; mp 92-94 ˚C.

FT-IR (KBr): 768, 1091, 1112, 1217, 1655, 29117 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.29 (d, J = 8.4 Hz, 2 H), 7.13 (d, J = 8.4 Hz, 2 H), 4.28 (dt, J = 9.1, 2.3 Hz, 1 H), 3.59 (dd, J = 11.7, 9.4 Hz, 1 H), 3.36 (dd, J = 11.8, 2.5 Hz, 1 H), 2.83-2.77 (m, 2 H), 2.03-1.60 (m, 13 H), 1.36 (d, J = 6.9 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 140.6 (C), 133.0 (C), 129.14 (2 × CH), 129.08 (2 × CH), 104.6 (C), 83.0 (CH), 60.9 (CH2), 40.3 (CH), 37.4 (CH2), 35.5 (CH), 33.6 (2 × CH2), 33.4 (CH2), 33.2 (CH2), 30.2 (CH), 27.3 (2 × CH), 18.5 (CH3).

FAB-MS: m/z = 349 [M + H+].

Anal. Calcd for C20H25ClO3: C, 68.86; H, 7.22. Found: C, 68.69; H, 6.99.

Trioxane 5b

White solid; mp 114-115 ˚C.

FT-IR (KBr): 772, 1089, 1113, 1220, 1636, 2918 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.29 (d, J = 8.3 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 2 H), 4.41 (br ddd, 1 H), 3.80-3.78 (m, 2 H), 2.84 (quint, J = 7.2 Hz, 1 H), 2.71 (s, 1 H), 2.06-1.55 (m, 13 H), 1.26 (d, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 141.1 (C), 132.7 (C), 129.2 (2 × CH), 128.8 (2 × CH), 104.7 (C), 82.5 (CH), 60.9 (CH2), 40.2 (CH), 37.4 (CH2), 35.9 (CH), 33.7 (CH), 33.6 (CH2), 33.4 (CH2), 33.2 (CH2), 29.9 (CH), 27.4 (CH), 27.3 (CH), 17.7 (CH3).

FAB-MS: m/z = 349 [M + H+].

Anal. Calcd for C20H25ClO3: C, 68.86; H, 7.22. Found: C, 68.78; H, 6.88.

Trioxane 4c

Oil.

FT-IR (neat): 772, 1111, 1653, 2925 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.16-6.96 (m, 4 H), 4.26 (dt, J = 9.3, 2.6 Hz, 1 H), 3.58 (dd, J = 11.8, 9.3 Hz, 1 H), 3.32 (dd, J = 11.8, 2.6 Hz, 1 H), 2.78 (br quint, 1 H), 2.75 (s, 1 H), 2.02-1.57 (m, 13 H), 1.35 (d, J = 6.9 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 162.0 (C, d, J C,F = 244 Hz), 137.8 (C), 129.2 (2 × CH, d, J C,F = 7.5 Hz), 115.8 (2 × CH, d, J C,F  = 21 Hz), 104.6 (C), 83.2 (CH), 61.0 (CH2), 40.2 (CH), 37.4 (CH2), 35.6 (CH), 33.7 (2 × CH2), 33.5 (CH2), 33.2 (CH2), 30.2 (CH), 27.4 (2 × CH), 18.6 (CH3).

FAB-MS: m/z = 333 [M + H+].

EI-HRMS: m/z calcd for C20H25FO3 [M+]: 332.1788; found: 332.1786.

Trioxane 5c

White solid; mp 80-81 ˚C.

FT-IR (KBr): 767, 1113, 1637, 2923 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.22-6.98 (m, 4 H), 4.41 (br ddd, 1 H), 3.85-3.75 (m, 2 H), 2.86 (quint, J = 7.2 Hz, 1 H), 2.73 (s, 1 H), 2.07-1.55 (m, 13 H), 1.26 (d, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 161.8 (C, d, J C,F = 242 Hz), 138.2 (C, d, J C,F = 3 Hz), 129.2 (2 × CH, d, J C,F = 7.5 Hz), 115.4 (2 × CH, d, J C,F = 21 Hz), 104.64 (C), 82.5 (CH), 60.9 (CH2), 40.0 (CH), 37.4 (CH2), 36.0 (CH), 33.6 (CH2), 33.5 (CH2), 33.3 (CH2), 33.2 (CH2), 29.8 (CH), 27.30 (CH), 27.26 (CH), 17.7 (CH3).

FAB-MS: m/z = 333 [M + H+].

EI-HRMS: m/z calcd for C20H25FO3 [M+]: 332.1788; found: 332.1781.

8-(1-Phenylethyl)-6,7,10-trioxaspiro[4.5]decane (4d)

Oil.

FT-IR (neat): 760, 1063, 1118, 1604, 2970 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.33-7.16 (m, 5 H), 4.34 (dt, J = 9.0, 2.9 Hz, 1 H), 3.52 (dd, J = 11.8, 9.0 Hz, 1 H), 3.41 (dd, J = 11.8, 2.9 Hz, 1 H), 2.80 (quint, J = 6.9 Hz, 1 H), 2.37-2.32 (m, 1 H), 1.85-1.63 (m, 7 H), 1.36 (d, J = 6.9 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 142.0 (C), 128.9 (2 × CH), 127.8 (2 × CH), 127.2 (CH), 114.4 (C), 83.2 (CH), 63.9 (CH2), 40.7 (CH), 36.6 (CH2), 33.4 (CH2), 24.7 (CH2), 23.6 (CH2), 18.4 (CH3).

FAB-MS: m/z = 249 [M + H+].

EI-HRMS: m/z calcd for C15H20O3 [M+]: 248.14125; found: 248.13959.

Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C 72.32; H, 7.95.

8-(1-Phenylethyl)-6,7,10-trioxaspiro[4.5]decane (5d)

Oil.

FT-IR (neat): 701, 1031, 1110, 1603, 2966 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.33-7.20 (m, 5 H), 4.48 (ddd, J = 9.8, 7.6, 2.8 Hz, 1 H), 3.82 (dd, J = 11.5, 2.8 Hz, 1 H), 3.69 (dd, J = 11.5, 9.8 Hz, 1 H), 2.86 (quint, J = 7.2 Hz, 1 H), 2.34-2.29 (m, 1 H), 1.78-1.60 (m, 7 H), 1.27 (d, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 142.2 (C), 128.5 (2 × CH), 127.8 (2 × CH), 126.8 (CH), 114.4 (C), 82.5 (CH), 63.6 (CH2), 40.5 (CH), 36.9 (CH2), 33.0 (CH2), 24.7 (CH2), 23.5 (CH2), 17.4 (CH3).

FAB-MS: m/z = 249 [M + H+].

EI-HRMS: m/z calcd for C15H20O3 [M+]: 248.1413; found: 248.1413.

Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.90; H, 8.50.

3-(1-Phenylethyl)-1,2,5-trioxaspiro[5.5]undecane (4e)

Oil.

FT-IR (neat): 764, 1023, 1097, 1602, 2935 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.33-7.16 (m, 5 H), 4.30 (dt, J = 9.2, 2.1 Hz, 1 H), 3.62 (dd, J = 11.8, 9.2 Hz, 1 H), 3.33 (dd, J = 11.8, 2.1 Hz, 1 H), 2.80 (br quint, 1 H), 2.13-2.07 (m, 1 H), 1.91-1.84 (m, 1 H), 1.64-1.44 (m, 8 H), 1.37 (d, J = 6.7 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 142.0 (C), 128.9 (2 × CH), 127.8 (2 × CH), 127.3 (CH), 102.5 (C), 83.3 (CH), 61.6 (CH2), 40.9 (CH), 34.2 (CH2), 29.7 (CH2), 25.7 (CH2), 22.5 (CH2), 22.47 (CH2), 18.5 (CH3).

FAB-MS: m/z = 263 [M + H+].

EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found: 262.1569.

Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.35; H, 8.50.

3-(1-Phenylethyl)-1,2,5-trioxaspiro[5.5]undecane (5e)

Oil.

FT-IR (neat): 765, 1030, 1091, 1602, 2940 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.32-7.20 (m, 5 H), 4.44 (ddd, J = 9.9, 7.8, 3.2 Hz, 1 H), 3.82 (dd, J = 11.7, 9.9 Hz, 1 H), 3.73 (dd, J = 11.7, 3.2 Hz, 1 H), 2.86 (quint, J = 7.3 Hz, 1 H), 2.11-2.03 (m, 1 H), 1.87-1.79 (m, 1 H), 1.61-1.38 (m, 8 H), 1.27 (d, J = 7.3 Hz, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 142.3 (C), 128.7 (2 × CH), 127.9 (2 × CH), 126.9 (CH), 102.6 (C), 82.7 (CH), 61.4 (CH2), 40.7 (CH), 34.6 (CH2), 29.4 (CH2), 25.7 (CH2), 22.5 (CH2), 22.4 (CH2), 17.5 (CH3).

FAB-MS: m/z = 263 [M + H+].

EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found: 262.1534.

Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.10; H, 8.70.

8-(1-Phenylethyl)-6,7,11-trioxaspiro[4.6]undecane (7a)

Oil.

FT-IR (neat): 1023, 1100, 1607, 2920 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.33-7.16 (m, 5 H), 4.22 (dt, J = 9.7, 3.8 Hz, 1 H), 3.80 (dt, J = 12.0, 1.2 Hz, 1 H), 3.67 (td, J = 12.2, 3.7 Hz, 1 H), 2.75 (quint, J = 6.9 Hz, 1 H), 2.15-1.47 (m, 10 H), 1.37 (d, J = 6.8 Hz, 3 H).

¹³C NMR (50 MHz, CDCl3): δ = 144.5 (C), 128.9 (2 × CH), 128.1 (2 × CH), 126.9 (CH), 118.3 (C), 88.8 (CH), 62.5 (CH2), 43.9 (CH), 36.8 (CH2), 36.5 (CH2), 34.9 (CH2), 24.4 (2 × CH2), 19.3 (CH3).

ESI-MS: m/z = 263 [M + H+], 285 [M + Na+].

EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found: 262.1583.

8-(1-Phenylethyl)-6,7,11-trioxaspiro[4.6]undecane (8a)

Oil.

FT-IR (neat): 1020, 1150, 1615, 2925 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.33-7.20 (m, 5 H), 4.40-4.29 (m, 1 H), 3.87-3.72 (m, 2 H), 2.93 (quint, J = 7.2 Hz, 1 H), 2.14-1.57 (m, 10 H), 1.29 (d, J = 7.2 Hz, 3 H).

¹³C NMR (50 MHz, CDCl3): δ = 143.7 (C), 128.7 (2 × CH), 128.4 (2 × CH), 126.9 (CH), 118.2 (C), 88.0 (CH), 62.3 (CH2), 43.4 (CH), 36.5 (CH2), 35.2 (CH2), 35.0 (CH2), 24.4 (2 × CH2), 18.1 (CH3).

ESI-MS: m/z = 269 [M + Li+], 285 [M + Na+], 301 [M + K+].

EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found: 262.1593.

8-(1-Biphenyl-4-ylethyl)-6,7,11-trioxaspiro[4.6]undecane (7b)

White solid; mp 76-79 ˚C.

FT-IR (KBr): 1041, 1158, 1605, 2945 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.59-7.23 (m, 9 H), 4.26 (dt, J = 9.6, 3.8 Hz, 1 H), 3.82 (dt, J = 12.2, 1.8 Hz, 1 H), 3.69 (td, J = 12.2, 3.7 Hz, 1 H), 2.81 (quint, J = 6.9 Hz, 1 H), 2.16-1.47 (m, 10 H), 1.41 (d, J = 6.9 Hz, 3 H).

¹³C NMR (50 MHz, CDCl3): δ = 143.5 (C), 141.2 (C), 139.9 (C), 129.2 (2 × CH), 128.5 (2 × CH), 127.7 (CH), 127.6 (2 × CH), 127.4 (2 × CH), 118.3 (C), 88.7 (CH), 62.4 (CH2), 43.5 (CH), 36.8 (CH2), 36.5 (CH2), 34.9 (CH2), 24.4 (2 × CH2), 19.2 (CH3).

ESI-MS: m/z = 339 [M + H+].

EI-HRMS: m/z calcd for C22H26O3 [M+]: 338.1882; found: 338.1834.

8-(1-Biphenyl-4-ylethyl)-6,7,11-trioxaspiro[4.6]undecane (8b)

White solid; mp 100-104 ˚C.

FT-IR (KBr): 1036, 1163, 1609, 2950 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.60-7.26 (m, 9 H), 4.37 (ddd, J = 10.5, 6.8, 4.1 Hz, 1 H), 3.89 (dt, J = 11.9, 1.9 Hz, 1 H), 3.77 (td, J = 12.1, 3.8 Hz, 1 H), 2.92 (quint, J = 7.2 Hz, 1 H), 2.15-1.65 (m, 10 H), 1.32 (d, J = 7.2 Hz, 3 H).

¹³C NMR (50 MHz, CDCl3): δ = 142.9 (C), 141.5 (C), 139.7 (C), 129.1 (2 × CH), 128.7 (2 × CH), 127.5 (5 × CH), 118.2 (C), 88.0 (CH), 62.3 (CH2), 43.0 (CH), 36.4 (CH2), 35.3 (CH2), 34.9 (CH2), 24.4 (2 × CH2), 18.2 (CH3).

ESI-MS: m/z = 339 [M + H+], 377 [M + K]+.

EI-HRMS: m/z calcd for C22H26O3 [M+]: 338.1882; found: 338.1886.

9-(1-Biphenyl-4-ylethyl)-7,8,12-trioxaspiro[5.6]dodecane (7c)

White solid; mp 70-73 ˚C.

FT-IR (KBr): 1010, 1153, 1611, 2930 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.60-7.22 (m, 9 H), 4.22 (dt, J = 12.3, 3.5 Hz, 1 H), 3.87 (t, J = 11.4 Hz, 1 H), 3.68-3.62 (m, 1 H), 2.80 (br m, 1 H), 1.81-1.56 (m, 12 H), 1.40 (d, J = 6.8 Hz, 3 H).

¹³C NMR (50 MHz, CDCl3): δ = 143.5 (C), 141.3 (C), 139.9 (C), 129.2 (2 × CH), 128.5 (2 × CH), 127.7 (CH), 127.6 (2 × CH), 127.4 (2 × CH), 106.8 (C), 88.5 (CH), 60.5 (CH2), 43.4 (CH), 36.9 (CH2), 34.4 (CH2), 32.0 (CH2), 25.9 (CH2), 23.4 (CH2), 23.2 (CH2), 19.1 (CH3).

ESI-MS: m/z = 353 [M + H+], 371 [M + NH4 +].

EI-HRMS: m/z calcd for C23H28O3 [M+]: 352.2039; found: 352.2036.

9-(1-Biphenyl-4-ylethyl)-7,8,12-trioxaspiro[5.6]dodecane (8c)

White solid; mp 76-80 ˚C.

FT-IR (KBr): 1008, 1150, 1615, 2935 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.60-7.24 (m, 9 H), 4.32 (ddd, J = 10.9, 10.2, 3.5 Hz, 1 H), 3.93 (dt, J = 12.0, 0.9 Hz, 1 H), 3.70 (td, J = 12.3, 3.3 Hz, 1 H), 2.99 (quint, J = 7.2 Hz, 1 H), 1.86-1.39 (m, 12 H), 1.33 (d, J = 7.2 Hz, 3 H).

¹³C NMR (50 MHz, CDCl3): δ = 142.7 (C), 141.4 (C), 139.7 (C), 129.1 (2 × CH), 128.8 (2 × CH), 128.5 (CH), 127.4 (4 × CH), 106.8 (C), 87.9 (CH), 60.6 (CH2), 42.9 (CH), 35.1 (CH2), 34.6 (CH2), 31.8 (CH2), 25.9 (CH2), 23.5 (CH2), 23.1 (CH2), 17.8 (CH3).

ESI-MS: m/z = 353 [M + H+].

EI-HRMS: m/z calcd for C23H28O3 [M+]: 352.2039; found: 352.2052.

2-Hydroperoxy-3-naphthalen-2-ylbutan-1-ol (10)

Oil.

FT-IR (neat): 750, 820, 1063, 1599, 2928, 3405 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 9.72 (br m, 1 H, OOH), 7.77-7.21 (m, 7 H), 4.15-4.02 (m, 1 H), 3.74 (dd, J = 12.3, 2.3 Hz) and 3.50 (dd, J = 12.2, 2.9 Hz, 1 H total), 3.66 (dd, J = 12.3, 6.2 Hz) and 3.42 (dd, J = 12.2, 6.4 Hz, 1 H total), 3.09 (br quint, J = 7.2 Hz) and 2.20 (quint, J = 7.2 Hz, 1 H total), 1.40 (d, J = 7.0 Hz) and 1.28 (d, J = 7.2 Hz, 3 H total).

¹³C NMR (75 MHz, CDCl3): δ = 140.0 (C), 139.4 (C), 133.7 (C), 132.8 (C), 132.7 (C), 128.7 (CH), 128.4 (CH), 127.9 (CH), 127.83 (CH), 127.78 (CH), 126.6 (CH), 126.5 (CH), 126.4 (CH), 126.14 (CH), 126.11 (CH), 125.9 (CH), 125.7 (CH), 83.2 (CH), 82.6 (CH), 61.2 (CH2), 61.0 (CH2), 41.04 (CH), 40.98 (CH), 18.8 (CH3), 17.8 (CH3).

ESI-MS: m/z = 255 [M + Na+].

3-(4-Fluorophenyl)-2-hydroperoxybutan-1-ol (14)

Oil.

FT-IR (neat): 841, 1045, 1603, 2932, 3405 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 9.73 (br m, 1 H, OOH), 7.22-6.98 (m, 4 H), 4.05 and 3.96 (2 m, 1 H), 3.89 (dd, J = 12.3, 2.6 Hz) and 3.56 (dd, J = 12.2, 2.8 Hz, 1 H total), 3.70 (dd, J = 12.3, 6.6 Hz) and 3.44 (dd, J = 12.2, 6.6 Hz, 1 H total), 3.09 (quint, J = 7.2 Hz) and 3.03 (quint, J = 7.0 Hz, 1 H total), 1.34 (d, J = 7.0 Hz) and 1.25 (d, J = 7.2 Hz, 3 H total).

¹³C NMR (75 MHz, CDCl3): δ = 162.0 (d, C, J C,F = 244 Hz), 161.9 (d, C, J C,F = 243 Hz), 138.0 (d, C, J C,F = 3.0 Hz), 137.7 (d, C, J C,F = 3.0 Hz), 129.3 (d, CH, J C,F = 7.5 Hz), 129.2 (d, CH, J C,F = 7.5 Hz), 115.8 (d, CH, J C,F = 22 Hz), 115.4 (d, CH, J C,F = 21 Hz), 83.2 (CH), 82.7 (CH), 61.44 (CH2), 61.37 (CH2), 40.05 (CH), 39.99 (CH), 18.5 (CH3), 17.7 (CH3).

ESI-MS: m/z = 223 [M + Na+].

3-Hydroperoxy-4-phenylpentan-1-ol (18)

Oil.

FT-IR (neat): 836, 1038, 1601, 2926, 3396 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 10.49 (br m, 1 H, OOH), 7.39-7.15 (m, 5 H), 4.16-3.54 (m, 3 H), 3.27 (quint, J = 6.7 Hz) and 3.08 (quint, J = 7.4 Hz, 1 H total), 1.79-1.49 (m, 2 H), 1.35 (d, J = 6.9 Hz) and 1.27 (d, J = 6.9 Hz, 3 H total).

¹³C NMR (50 MHz, CDCl3): δ = 144.2 (C), 143.6 (C), 128.9 (CH), 128.8 (CH), 128.4 (CH), 128.3 (CH), 126.9 (CH), 126.8 (CH), 88.8 (CH), 88.7 (CH), 60.6 (CH2), 42.9 (CH), 41.9 (CH), 33.2 (CH2), 31.9 (CH2), 18.7 (CH3), 15.8 (CH3).

ESI-MS: m/z = 197 [M + H+].

4-Biphenyl-4-yl-3-hydroperoxypentan-1-ol (22)

Oil.

FT-IR (neat): 821, 1042, 1600, 2949, 3401 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.59-7.23 (m, 9 H), 4.27-4.01 (m, 1 H), 3.88-3.64 (m, 2 H), 3.34-3.05 (m, 2 H), 1.82-1.62 (m, 2 H), 1.41 (d, J = 7.0 Hz) and 1.33 (d, J = 7.2 Hz, 3 H total).

¹³C NMR (50 MHz, CDCl3): δ = 143.3 (C), 142.7 (C), 141.3 (C), 139.7 (C), 129.2 (CH), 128.8 (CH), 128.7 (CH), 127.5 (CH), 127.4 (CH), 89.3 (CH), 89.1 (CH), 61.0 (CH2), 42.7 (CH), 42.0 (CH), 33.2 (CH2), 32.4 (CH2), 30.1 (CH2), 29.8 (CH2), 18.7 (CH3), 16.5 (CH3).

ESI-MS: m/z = 273 [M + H+].

1-Isopropyl-4-methyl-2,3-dioxabicyclo[2,2,2]octane (Dihydro­ascaridole, 26)

Oil.

FT-IR (neat): 1039, 1116, 2965 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 1.97-1.81 (br m, 4 H), 1.75-1.63 (br m, 5 H), 1.11 (s, 3 H), 0.87 (d, J = 7.1 Hz, 6 H).

¹³C NMR (75 MHz, CDCl3): δ = 79.1 (C), 74.4 (C), 34.4 (CH), 30.8 (2 × CH2), 26.1 (2 × CH2), 24.1 (CH3), 16.9 (2 × CH3).

ESI-MS: m/z = 171 [M + H+].

EI-HRMS: m/z calcd for C10H18O2 [M+]: 170.1307; found: 170.1284.

Borohydride Reduction of Saturated β-Hydroxyhydroperoxides and γ-Hydroxyhydroperoxides; Typical Procedure for the Reduction of Saturated β-Hydroxyhydroperoxide 10

To a stirred and ice cooled solution of β-hydroxyhydroperoxide 10 (0.100 g, 0.431 mmol) in MeOH (5 mL), was added NaBH4 (0.033 g, 2 equiv) and the reaction mixture was allowed to stir for 5 min. The mixture was quenched with glacial AcOH (0.5 mL), concentrated under vacuum, diluted with H2O (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (5 mL), concentrated, and the crude product was purified by column chromatography over silica gel to furnish the saturated diol 11 (0.090 g, 97%) as a colorless oil.

Hydroperoxides 14, 18, and 22 were also reduced by the same procedure to furnish diols 15, 19, and 23 as inseparable diastereomeric mixtures in 87, 81, and 85% yields, respectively.

Catalytic Hydrogenation of β-Hydroxyhydroperoxide 9

A solution of β-hydroxyhydroperoxide 9 (0.200 g, 0.869 mmol) in EtOAc (15 mL) was hydrogenated in the presence of Adam’s catalyst (PtO2, 0.003 g) using a Parr shaker assembly at r.t. and pressure for 1 h. The reaction mixture was filtered over Celite, concentrated, and the crude product was purified by column chromatography over silica gel to furnish the saturated diol 11 (96%) as a colorless oil.

3-Naphthalen-2-ylbutane-1,2-diol (11)

Oil.

FT-IR (neat): 751, 1068, 1109, 1623, 2929, 3282 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.67-7.28 (m, 7 H), 3.81 (dt, J = 7.4, 2.6, 1 H), 3.73 (dd, J = 11.4, 2.8 Hz) and 3.39 (dd, J = 11.3, 2.9 Hz, 1 H total), 3.49 (dd, J = 11.4, 7.2 Hz) and 3.29 (dd, J = 11.3, 7.5 Hz, 1 H total), 2.98 (quint, J = 7.0 Hz) and 2.89 (quint, J = 7.0 Hz, 1 H total), 3.02-2.84 (br m, 2 H, 2 OH), 1.41 (d, J = 7.0 Hz) and 1.32 (d, J = 7.0 Hz, 3 H total).

¹³C NMR (75 MHz, CDCl3): δ = 140.9 (C), 133.7 (C), 133.6 (C), 132.6 (C), 132.5 (C), 128.4 (CH), 128.3 (CH), 127.79 (H), 127.76 (CH), 126.8 (CH), 126.30 (CH), 126.27 (CH), 126.21 (CH), 126.17 (CH), 125.7 (CH), 125.6 (CH), 76.7 (CH), 76.3 (CH), 65.2 (CH2), 64.8 (CH2), 43.1 (CH), 43.0 (CH), 18.0 (CH3), 17.7 (CH3).

ESI-MS: m/z = 239 [M + Na+].

EI-HRMS: m/z calcd for C14H16O2 [M+]: 216.1150; found: 216.1148.

3-(4-Fluorophenyl)butane-1,2-diol (15)

Oil.

FT-IR (neat): 1035, 1066, 1605, 2929, 3322 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.21-6.95 (m, 4 H), 3.72-3.64 (m, 2 H), 3.45 (dd, J = 11.8, 7.7 ) and 3.27 (dd, J = 11.1, 7.6 Hz, 1 H total), 2.82 (quint, J = 7.0 Hz) and 2.75 (quint, J = 7.1 Hz, 1 H total), 2.86-2.70 (br m, 2 H, 2 OH), 1.30 (d, J = 7.0 Hz) and 1.24 (d, J = 7.1 Hz, 3 H total).

¹³C NMR (75 MHz, CDCl3): δ = 161.9 (C, d, J C,F = 243 Hz) 161.8 (C, d, J C,F = 244 Hz), 139.6 (C, d, J C,F = 3.0 Hz), 139.0 (C, d, J C,F = 3.0 Hz), 129.6 (CH, d, J C,F = 8.0 Hz), 129.1 (d, CH, J C,F = 7.5 Hz), 115.5 (d, CH, J C,F = 21 Hz), 76.8 (CH), 76.4 (CH), 65.1 (CH2), 64.8 (CH2), 42.3 (CH), 42.2 (CH), 18.2 (CH3), 17.7 (CH3).

ESI-MS: m/z = 185 [M + H+].

4-Phenylpentane-1,3-diol (19)

Oil.

¹H NMR (200 MHz, CDCl3): δ = 7.35-7.17 (m, 5 H), 3.94-3.70 (m, 3 H), 2.84-2.70 (m, 3 H), 1.70-1.51 (m, 2 H), 1.32 (d, J = 7.1 Hz) and 1.26 (d, J = 7.0 Hz, 3 H total).

¹³C NMR (50 MHz, CDCl3): δ = 146.4 (C), 129.0 (CH), 128.9 (CH), 128.7 (CH), 128.5 (CH), 128.2 (CH), 127.2 (CH), 126.9 (CH), 125.3 (CH), 124.9 (CH), 76.8 (CH), 65.4 (CH2), 46.9 (CH), 46.7 (CH), 36.4 (CH2), 35.9 (CH2), 17.9 (CH3), 16.8 (CH3).

ESI-MS: m/z = 198.4 [M + NH4 +].

4-Biphenyl-4-ylpentane-1,3-diol (23)

Oil.

¹H NMR (200 MHz, CDCl3): δ = 7.65-7.30 (m, 9 H), 4.02-3.78 (m, 3 H), 2.91-2.85 (m, 1 H), 1.89-1.64 (m, 3 H), 1.39 (d, J = 7.0 Hz) and 1.36 (d, J = 7.0 Hz, 3 H total).

¹³C NMR (50 MHz, CDCl3): δ = 143.7 (C), 142.7 (C), 141.2 (C), 140.1 (C), 139.8 (C), 129.2 (CH), 128.9 (CH), 128.7 (CH), 127.6 (CH), 127.4 (CH), 77.0 (CH), 76.8 (CH), 62.3 (CH2), 62.0 (CH2), 46.6 (CH), 46.4 (CH), 36.4 (CH2), 35.9 (CH2), 17.9 (CH3), 16.9 (CH3).

ESI-MS: m/z = 257.2 [M + H+].

Acetylation of Saturated Diols; Typical Procedure

To a stirred solution of diol 11 (0.100 g, 0.463 mmol) in CH2Cl2 (5 mL) were added Ac2O (0.23 mL, 5 equiv), Et3N (0.23 mL, 5 equiv), and a catalytic amount of DMAP (2 mg) in succession and the reaction mixture was allowed to stir for 2 h. The mixture was concentrated under vacuum and the crude product was purified by column chromatography over silica gel to furnish the diacetate 12 (0.125 g, 91%) as an oil.

Saturated diols 15, 19 and 23 were also acetylated by the same procedure to furnish corresponding diacetates 16, 20 and 24 as inseparable diastereomeric mixtures in 93, 91, and 89% yields, respectively.

Acetic Acid 1-Acetoxymethyl-2-naphthalen-2-ylpropyl Ester (12)

Oil.

FT-IR (neat): 1047, 1650, 1744, 2971 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.85-7.38 (m, 7 H), 5.44-5.37 (m, 1 H), 4.32 (dd, J = 12.0, 3.0 Hz) and 4.17 (dd, J = 12.0, 2.8 Hz, 1 H total), 4.08 (dd, J = 12.0, 7.1 Hz) and 3.85 (dd, J = 12.0, 6.6 Hz, 1 H total), 2.15 (s) and 2.06 (s, 3 H total), 3.30 (br quint, J = 7.1 Hz) and 3.22 (quint, J = 7.1 Hz, 1 H total), 1.42 (merged d) and 1.40 (d, J = 7.1 Hz, 3 H total), 2.03 (s) and 1.95 (s, 3 H total).

¹³C NMR (75 MHz, CDCl3): δ = 170.9 (C), 170.82 (C), 170.78 (C), 170.5 (C), 139.8 (C), 139.6 (C), 133.8 (C), 133.6 (C), 132.8 (C), 132.6 (C), 132.7 (C), 128.7 (CH), 128.2 (CH), 127.9 (CH), 127.8 (CH), 127.8 (CH), 126.7 (CH), 126.5 (CH), 126.4 (CH), 126.2 (CH), 125.9 (CH), 125.8 (CH), 75.4 (CH), 74.9 (CH), 64.3 (CH2), 64.1 (CH2), 41.4 (CH), 41.1 (CH), 21.2 (CH3), 21.0 (CH3), 20.9 (CH3), 20.9 (CH3), 18.2 (CH3), 17.5 (CH3).

FAB-MS: m/z = 301 [M + H+].

EI-HRMS: m/z calcd for C18H20O4 [M+]: 300.1362; found: 300.1360.

Anal. Calcd for C18H20O4: C, 71.98; H, 6.71. Found: C, 72.25; H, 6.50.

Acetic Acid 1-Acetoxymethyl-2-(4-fluorophenyl)propyl Ester (16)

Oil.

FT-IR (neat): 1049, 1604, 1743, 2973 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.22-6.95 (m, 4 H), 5.27-5.20 (m, 1 H), 4.23 (dd, J = 12.0, 3.3 Hz) and 4.13 (dd, J = 12.0, 2.9 Hz, 1 H total), 4.00 (dd, J = 12.0, 6.8 Hz) and 3.78 (dd, J = 12.0, 6.5 Hz, 1 H total), 3.08 (quint, J = 7.1 Hz) and 3.04 (quint, J = 6.8 Hz, 1 H total), 2.01 (s) and 1.94 (s, 3 H total), 2.09 (s) and 2.04 (s, 3 H total), 1.30 (d, J = 7.1 Hz) and 1.28 (d, J = 6.8 Hz, 3 H total).

¹³C NMR (75 MHz, CDCl3): δ = 170.8 (C), 170.7 (C), 170.65 (C), 170.4 (C), 162.0 (d, C, J C,F = 244 Hz), 161.9 (d, C, J C,F = 243 Hz), 138.0 (d, C, J C,F = 3.0 Hz), 137.8 (d, C, J C,F = 3.0 Hz), 129.5 (d, CH, J C,F = 8.0 Hz), 129.2 (d, CH, J C,F = 8.0 Hz), 115.7 (d, CH, J C,F = 22 Hz), 115.3 (d, CH, J C,F = 21 Hz), 75.3 (CH), 74.8 (CH), 63.9 (CH2), 63.9 (CH2), 40.4 (CH), 40.2 (CH), 21.1 (CH3), 20.9 (CH3), 17.9 (CH3), 17.6 (CH3).

ESI-MS: m/z = 286 [M + NH4 +].

Acetic Acid 1-(2-Acetoxyethyl)-2-phenylpropyl Ester (20)

Oil.

FT-IR (neat): 1741 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.64-7.21 (m, 5 H), 4.10-3.95 (m, 3 H), 3.00-2.97 (m, 1 H), 2.31-2.16 (m, 2 H), 2.07 (s) and 1.95 (s, 3 H total), 2.00 (s) and 1.88 (s, 3 H total), 1.30-1.25 (m, 3 H).

ESI-MS: m/z = 282.4 [M + NH4 +].

Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 67.82; H, 7.29.

Acetic Acid 1-(2-Acetoxyethyl)-2-biphenyl-4-ylpropyl Ester (24)

Oil.

FT-IR (neat): 1741 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 7.62-7.23 (m, 9 H), 5.29-5.23 (m, 1 H), 4.10-4.02 (m, 2 H), 3.08 (quint, J = 7.1 Hz) and 3.00 (quint, J = 7.1 Hz, 1 H total), 2.12 (s) and 2.03 (s, 3 H total), 2.04 (s) and 2.01 (s, 3 H total), 1.67-1.52 (m, 2 H), 1.36-1.31 (m, 3 H).

ESI-MS: m/z = 358.4 [M + NH4 +].

EI-HRMS: m/z calcd for C21H24O4: 340.1675; found: 340.1678.

Acknowledgment

A.S.S., N.K.N., V.P.V., M.H., N.G., and S.P. are thankful to Council for Scientific and Industrial Research (CSIR), New Delhi and University Grant Commission (UGC) for the award of Senior Research Fellowships. We thank SAIF, Lucknow for providing spectral and analytical data.

1

CDRI communication number: 7233.

12

The progress of the reaction was monitored by TLC of the samples drawn at regular time intervals of 15 min. At no stage of the reaction was the required saturated trioxane observed.

15

The pH values of 1% aqueous solutions of N2H4˙H2O and N2H3COON2H5 at 25 ˚C (glass electrode) were found to be 9.79 and 7.51, respectively.

16

The stereochemistry assigned to the diastereomers is only relative and is based upon coupling constants and NOESY experiments.

18

Due to intramolecular hydrogen bonding in diols 11, 15, 19, and 23, ¹H NMR spectra of these compounds show complex multiplicity pattern. Conversion of these diols into the corresponding diacetates, on the other hand, provides clear multiplicity pattern in ¹H NMR spectra.

19

Diimide reduction of ascaridole using dipotassium azodicarboxylate is known to furnish dihydroascaridole in ∼40% yield: see reference 10a.

20

In our hands all these peroxides have behaved well, but the usual precautions for handling of peroxides are recommended.

1

CDRI communication number: 7233.

12

The progress of the reaction was monitored by TLC of the samples drawn at regular time intervals of 15 min. At no stage of the reaction was the required saturated trioxane observed.

15

The pH values of 1% aqueous solutions of N2H4˙H2O and N2H3COON2H5 at 25 ˚C (glass electrode) were found to be 9.79 and 7.51, respectively.

16

The stereochemistry assigned to the diastereomers is only relative and is based upon coupling constants and NOESY experiments.

18

Due to intramolecular hydrogen bonding in diols 11, 15, 19, and 23, ¹H NMR spectra of these compounds show complex multiplicity pattern. Conversion of these diols into the corresponding diacetates, on the other hand, provides clear multiplicity pattern in ¹H NMR spectra.

19

Diimide reduction of ascaridole using dipotassium azodicarboxylate is known to furnish dihydroascaridole in ∼40% yield: see reference 10a.

20

In our hands all these peroxides have behaved well, but the usual precautions for handling of peroxides are recommended.

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Figure 1 Artemisinin and its semi-synthetic derivatives

Scheme 1 Synthesis of 1,2,4-trioxanes (n = 1) and 1,2,4-triox­epanes (n = 2) via photooxygenation of allylic and homoallylic alcohols

Scheme 2 Base mediated fragmentation of 1,2,4-trioxanes into α,β-unsaturated keto alcohols and their entrapment by amines and thiols

Scheme 3 Catalytic hydrogenation of unsaturated 1,2,4-trioxane 1a

Scheme 4 Reduction of unsaturated 1,2,4-trioxanes 1a-e and 1,2,4-trioxepanes 6a-c by N2H4˙H2O-30% H2O2 (method A) and N2H3COON2H5-30% H2O2 (method B)

Scheme 5  Reduction of β-hydroxyhydroperoxides 9 and 13 and γ-hydroxyhydroperoxides 17 and 21 by N2H3COON2H5-30% H2O2

Scheme 6 Reduction of ascaridole (25) to dihydroascaridole (26) by N2H4 ˙H2O-30% H2O2 (method A) and N2H3COON2H5-30% H2O2 (method B)