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Synthesis 2012(4): 579-584  
DOI: 10.1055/s-0031-1289671
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Synthesis of (4S,6S)-6-Hydroxy-4-undecanolide: A Pheromone of the Giant White Butterfly Idea leuconoe

Jhillu Singh Yadav*a,b, Poli Adi Narayana Reddya, Hissana Athera, Alleni Suman Kumara, Attaluri R. Prasada, Basi V. Subba Reddya, Ahmad Al Khazimb
a Pheromone Group, Natural product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax: +91(40)27160512; e-Mail: yadavpub@iict.res.in ;
b Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia

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Publication History

Received 11 October 2011
Publication Date:
16 January 2012 (online)

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Abstract

The stereoselective synthesis of (4S,6S)-6-hydroxy-4-undecanolide, a major pheromone component in the secretion of Idea leuconoe has been accomplished employing Prins cyclization to produce anti-1,3-diols and hydroboration/oxidation of terminal olefin to introduce primary alcohol as the key steps.

Key words

pheromones - Prins cyclization - Mitsunobu inversion - anti-1,3-diol - chemoselective oxidation of 1,4-diols

The males of the giant white butterfly Idea leuconoe possess hairpencils on the end of their abdomen, which release a mixture of compounds, namely, alkaloids, aromatics, terpenoids, hydrocarbons, and lactones, to act as courtship pheromones. [¹] The lactones, which are isolated from the hairpencil extract, are hydroxyalkanolides with two chiral centers. The lactone ring size differs from four- to six-membered and the chain lengths vary from C10 to C13. [²] Of these lactones, the major components of the hairpencil secretion are the g-lactones, 6-hydroxy-4-alkanolides 1a-c, which are accompanied by trace amounts of the respective β-lactones 2a (Figure  [¹] ). The first synthesis of a 6-hydroxy-4-alkanolide has been reported by Schulz et al. involving enantioselective hydrogenation of 4,6-diketo esters using a ruthenium-BINAP catalyst. [³]

Figure 1 Lactones 1a-c and 2a

In continuation of our research on the use of Prins cyclization in total synthesis of biologically active natural products, [4] we herein report an efficient approach for the synthesis of (4S,6S)-6-hydroxy-4-undecanolide (1b), a pheromone of the giant white butterfly Idea leuconoe.

In the retrosynthetic analysis (Scheme  [¹] ), we envisaged that the target molecule could be prepared from compound 7 via the reductive opening of iodomethyl-substituted tetrahydropyran ring followed by hydroboration/oxidation of the terminal olefin. The pyran derivative 7 could in turn be prepared via the Prins cyclization of a homoallylic­ alcohol 3 and hexanal. The chemoselective oxidation of 1,4-diol 11 using 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) and (diacetoxyiodo)benzene would give the γ-lactone 1b. In another strategy, 1,4-diol 11 could be alternatively prepared from compound 15 by ozonolytic oxidative cleavage of the olefin 15 followed by alkynylation of the resulting aldehyde and subsequent hydrogenation.

Scheme 1

The synthetic approach (route A, Scheme  [²] ) commenced from a chiral homoallylic alcohol 3, which was prepared via the copper-mediated regioselective opening of (S)-benzylglycidyl ether (obtained via the Jacobsen’s HKR methodology) [5] with vinylmagnesium bromide (formed in situ from vinyl bromide and Mg metal in THF) followed by debenzylation with sodium in liquid ammonia (overall yield for two steps 69%). Prins cyclization of the homoallylic alcohol 3 with n-hexanal in the presence of trifluoroacetic acid followed by hydrolysis of the resulting trifluoroacetate gave the trisubstituted tetrahydropyran 4 (52%). [6] The stereochemistry was assumed to be in accordance with the literature as it was well examined and established previously. [7] Moreover, the assumption was confirmed when compound 4 was elaborated to synthesize the target molecule 1b (overall yield 15%), which in all respects was identical with the reported data. [³] Tosyl­ation of the compound 4 with 1.2 equivalents of tosyl chloride in the presence of triethylamine in dichloromethane gave the corresponding primary tosylate 5 (95%). Protection of the secondary alcohol as a silyl ether in the presence of tert-butyldimethylsilyl chloride and imidazole in dichloromethane gave the compound 6 (97%). Treatment of tosylate 6 with sodium iodide in refluxing acetone gave the corresponding iodo derivative 7 (95%). Reductive opening of the iodo derivative 7 with activated zinc in refluxing ethanol furnished the compound 8 (92%). [8] The secondary alcohol of compound 8 was protected as its methoxymethyl ether 9 (98%) in the presence of N-diisopropylethylamine and methoxymethyl chloride in dichloromethane. Upon exposure of compound 9 to dicyclohexylborane and 30% hydrogen peroxide afforded the primary alcohol 10 (77%). [9] Subsequent removal of the silyl group from compound 10 using tetra-n-butylammonium fluoride in tetrahydrofuran furnished the 1,4-diol 11 (97%), which was readily converted into lactone 12 (87%) by chemoselective oxidation using TEMPO and (diacet­oxyiodo)benzene in dichloromethane. [¹0] Deprotection of methoxymethyl ether 12 using trifluoroacetic acid in dichloromethane (1:4) gave the final product 1b (97%), which in all respects was identical to the reported structure. [³]

Scheme 2 Route A. Reagents and conditions: (a) n-hexanal, TFA, CH2Cl2, 3 h; then K2CO3, MeOH, 25 ˚C, 0.5 h, 52%; (b) Et3N, TsCl, CH2Cl2, 0-25 ˚C, 3 h, 95%; (c) TBSCl, imidazole, DMAP, CH2Cl2, 0 to 25 ˚C, 3 h, 97%; (d) NaI, acetone, reflux, 24 h, 95%; (e) Zn, EtOH, reflux, 2 h, 92%; (f) MOMCl, DIPEA, DMAP, CH2Cl2, 0-25 ˚C, 3 h, 98%; (g) Cy2BH, THF, 30% H2O2, NaOH, 77%; (h) TBAF, THF, 0-25 ˚C, 4 h, 97%; (i) TEMPO, PhI(OAc)2, CH2Cl2, 25 ˚C, 4 h, 87%; (j) TFA, CH2Cl2 (1:4 ), 0-25 ˚C, 2 h, 97%.

The alternative synthetic approach (route B, Scheme  [³] ) commenced from 13, which was converted into 14 according to a reported procedure [¹¹] in three steps (overall yield 30%). Compound 14 was protected as its methoxymethyl ether gave 15 (98%). Ozonolytic oxidative cleavage of 15 gave the aldehyde 16 (85%), which was then treated with O-benzylpropargyl alcohol in the presence of n-butyllithium in tetrahydrofuran at -78 ˚C. The resulting propargylic alcohol was obtained as a mixture of syn-17a and anti-17b in a 1:1 ratio. To assign the stereo­chemistry, both the isomers were converted into the corresponding acetonides 18a and 18b in a three-step sequence. Upon exposure of both the isomers 17a/17b to 10% Pd/C in methanol resulted in the reduction of triple bond with concomitant removal of benzyl group to furnish the diols, which were then treated with aqueous 3 M hydrochloric acid in tetrahydrofuran to give the triols (structures not shown). Upon treatment of the triols with 2,2-DMP in acetone the acetonides 18a and 18b were obtained. The stereochemistry of the diastereomers could be established by ¹³C NMR analysis. In 18a, the two methyl groups resonate at δ = 19.8 and 30.5 ppm and quaternary carbon shows a peak at δ = 98.5 ppm representing the 1,3-syn orientation of two hydroxy groups. However, the two methyl groups and quaternary carbon resonate at δ = 24.7, 24.9, and 100.3 ppm, respectively, indicating the 1,3-anti-orientation of the two hydroxy groups in 18b. [¹²] The undesired isomer 17a was converted into 17b (overall yield 70%) under standard Mitsunobu condition. [¹³] Reduction of the triple bond with a concomitant debenzylation of compound 17b was achieved using Pd/C in methanol to give the key fragment 1,4-diol 11 (97%). The chemoselective oxidation of 1,4-diol 11 using TEMPO and (diacetoxyiodo)benzene in dichloromethane gave the lactone 12 (87%). [¹0] Deprotection of the methoxymethyl ether 12 using trifluoroacetic acid in dichloromethane (1:4) gave the final product 1b in 97% yield (overall yield 17%) (Scheme  [³] ), which in all respects was identical to the reported one. [³]

Scheme 3 Route B. Reagents and conditions: (a) MOMCl, DIPEA, DMAP, CH2Cl2, 0 ˚C to r.t., 3 h, 98%; (b) O3, TPP, CH2Cl2, -78 ˚C to r.t.; (c) BnOCH2C≡CH, n-BuLi, THF, -78 ˚C, 2 h, 85%; (d) DEAD, TPP, p-nitrobenzoic acid, THF, 0 ˚C to r.t., 88%; (e) Pd/C, MeOH, r.t., 4 h, 97%; (f) 1. aq 3 M HCl, THF, 0 ˚C to r.t., 4 h, 2. 2,2-DMP, acetone, PTSA, r.t., 2 h; (g) TEMPO, PhI(OAc)2, CH2Cl2, 25 ˚C, 4 h, 87%; (h) TFA-CH2Cl2 (1:4), 0- 25 ˚C, 2 h, 97%.

Using the above two synthetic approaches, optically active 1a and 1c should be accessed readily.

In summary, we have described a stereoselective formal total synthesis of (4S,6S)-6-hydroxy-4-undecanolide (1b) employing two alternative strategies. These methods would be very useful to generate a wide variety of five-membered-ring lactones.

All reactions were carried out under inert atmosphere. Solvents were dried and purified by conventional methods prior to use. The progress of the reaction was monitored by TLC using glass plates precoated with silica gel 60 F254 to a thickness of 0.5 mm (Merck). Column chromatography was performed on silica gel (60-120 mesh) and neutral alumina using Et2O, EtOAc, and hexanes as eluents. Optical rotation values were measured on PerkinElmer P241 polarimeter and JASCO DIP-360 digital polarimeter at 25 ˚C. IR spectra were recorded on PerkinElmer FT-IR spectrophotometer. ¹H and ¹³C NMR spectra were recorded on Varian Gemini 200 MHz, Bruker Avance 300 MHz, Varian Unity 400 MHz, or Varian Inova 500 MHz spectrometer using TMS as an internal standard in CDCl3. Mass spectra were recorded on Micromass VG-7070H for EI and VG Autospec M for FAB-MS.

(2 S ,4 R ,6 S )-2-(Hydroxymethyl)-6-pentyltetrahydro-2 H -pyran-4-ol (4)

TFA (48.34 mL) was added slowly to a solution of 3 (3 g, 29.40 mmol) and n-hexanal (8.82 g, 88.23 mmol) in anhyd CH2Cl2 (95 mL) at 25 ˚C under N2 atmosphere. The reaction mixture was stirred at r.t. for 3 h and then diluted with sat. aq NaHCO3 (150 mL). The pH was then adjusted to >7 by the addition of Et3N. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 70 mL) and the organic layers were combined and the solvent was removed under reduced pressure. The trifluoroacetate obtained in this reaction was directly used in the next step without purification. The residue was dissolved in MeOH (40 mL) and stirred with K2CO3 (6.0 g) for 0.5 h. The mixture was extracted with CH2Cl2 (3 × 30 mL) and the combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure. Purification of the crude by column chromatography on silica gel gave 4 (3.08 g, 52%) as a colorless gummy liquid; R f  = 0.3 (silica gel, 60% EtOAc in hexane); [α]D ²0 +2.4 (c 2.8, CHCl3).

IR (neat): 3380, 2930, 2859, 1722, 1651, 1458, 1373, 1025 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.7 Hz, 3 H), 1.05-1.64 (m, 10 H), 1.78-1.84 (m, 1 H), 1.88-1.94 (m, 1 H), 3.26-3.60 (m, 4 H), 3.73-3.81 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.4, 25.0, 31.6, 35.8, 36.7, 40.9, 65.6, 67.7, 75.2, 75.89.

HRMS (ESI): m/z calcd for C11H22O3 + Na: 225.1466; found: 225.1471.

[(2 S ,4 R ,6 S )-4-6-Pentyltetrahydro-2 H -pyran-2-yl]methyl 4-Methylbenzenesulfonate (5)

To stirred solution of diol 4 (2.5 g, 12.3 mmol) in anhyd CH2Cl2 (25 mL) was added Et3N (8.68 mL, 61.88 mmol) at 0 ˚C, and then TsCl (2.82 g, 14.8 mmol) was added over 2 h. The reaction mixture was allowed to warm to 25 ˚C and then allowed to stir for 3 h. The mixture was then treated with aq 1 M HCl (10 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with sat. aq NaHCO3 (15 mL), followed by H2O (15 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the crude product afforded tosylate 5 (4.18 g, 95%) as a gummy liquid; R f  = 0.6 (silica gel, 40% EtOAc in hexane); [α]D ²0 -3.0 (c 1.0, CHCl3).

IR (neat): 3410, 2930, 2860, 1598, 1454, 1360, 1176, 1097, 1030, 979, 816, 668 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.6 Hz, 3 H), 1.03-1.49, (m, 10 H), 1.87-1.93 (m, 2 H), 2.44 (s, 3 H), 3.18-3.26 (m, 1 H), 3.50-3.58 (m, 1 H), 3.71-3.82 (m, 1 H), 3.94-4.05 (m, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 21.5, 22.4, 24.9, 31.6, 35.6, 36.7, 40.5, 67.4, 72.0, 72.6, 75.7, 127.8, 129.6, 132.7, 132.7, 144.6.

HRMS (ESI): m/z calcd for C18H28O5S + Na: 379.1555; found: 379.156.

[(2 S ,4 R ,6 S )-4-( tert -Butyldimethylsilyloxy)-6-pentyltetrahydro-2 H -pyran-2yl]methyl 4-Methylbenzenesulfonate (6)

To a stirred solution of alcohol 5 (3.8 g, 10.67 mmol) in anhyd CH2Cl2 (30 mL) at 0 ˚C were added TBSCl (1.93 g, 12.8 mmol), DMAP (cat.), and imidazole (2.9 g, 42.6 mmol) successively, The mixture was stirred for 3 h at 25 ˚C, quenched with H2O (10 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine (10 mL) and dried (Na2SO4). Removal of the solvent followed by purification by column chromatography afforded the pure product 6 (4.86 g, 97%) as a colorless liquid; R f  = 0.7 (silica gel, 10% EtOAc in hexane); [α]D ²0 -1.6 (c 2.0, CHCl3).

IR (neat): 2931, 2857, 1598, 1463, 1364, 1254, 1178, 1122, 1079, 982, 837 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.03 (s, 6 H), 0.85-0.9 (m, 12 H), 1.06-1.45 (m, 10 H), 1.69-1.77 (m, 2 H), 2.43 (s, 3 H), 3.16-3.23 (m, 1 H), 3.48-3.56 (s, 1 H), 3.65-3.76 (m, 1 H), 3.92-4.02 (m, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = -4.5, 14.0, 18.0, 21.6, 22.5, 25.0, 25.7, 31.8, 35.7, 37.4, 41.2, 68.2, 72.2, 72.7, 75.8, 127.9, 129.7, 132.9, 144.6.

MS (ESI): m/z = 493 [M + Na].

tert -Butyl[(2 S ,4 R ,6 S )-2-(iodomethyl)-6-pentyltetrahydro-2 H -pyran-4-yloxy]dimethylsilane (7)

To a solution of 6 (3.8 g, 8.08 mmol) in acetone (70 mL) was added NaI (6.06 g, 40.43 mmol) and the mixture was heated to reflux for 24 h. After completion, the solvent was removed under reduced pressure. The residue was quenched with H2O (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by column chromatography gave 7 (3.27 g, 95%) as a colorless liquid; R f  = 0.8 (silica gel, 10% EtOAc in hexane); [α]D ²0 +10.8 (c 1.65, CHCl3).

IR (neat): 2930, 2856, 1465, 1378, 1254, 1148, 1125, 1076, 893, 839, 774 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 0.05 (s, 6 H), 0.88-0.93 (m, 12 H), 1.06-1.57 (m, 10 H), 1.66-1.74 (m, 1 H), 1.97-2.06 (m, 1 H), 3.08-3.16 (m, 2 H), 3.21-3.38 (m, 2 H), 3.63-3.81 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = -4.5, 9.0, 14.0, 18.0, 22.6, 25.2, 25.8, 31.7, 35.8, 41.3, 41.2, 68.5, 75.1, 75.9.

HRMS (ESI): m/z calcd for C17H35IO2Si + Na: 449.1348; found: 449.1365.

(4 S ,6 S )-4-( tert -Butyldimethylsilyloxy)undec-1-en-6-ol (8)

To a solution of iodide 7 (3.0 g, 7.04 mmol) in EtOH (90 mL) was added activated Zn dust (4.6 g, 70.36 mmol). The resulting mixture was stirred under reflux for 2 h and then cooled to 25 ˚C. Addition of solid NH4Cl (7.55 g) and Et2O (110 mL) followed by stirring for 5 min gave a gray suspension, which was filtered through Celite and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography gave 8 (1.94 g, 92%) as a colorless liquid; R f  = 0.5 (silica gel, 10% EtOAc in hexane); [α]D ²0 -0.7 (c 1.1, CHCl3).

IR (neat): 3379, 2931, 2858, 1641, 1465, 1254, 1073, 999, 913, 835 cm-¹.

¹H NMR (200 MHz, CDCl3): δ = 0.08 (s, 6 H), 0.83-0.97 (m, 12 H), 1.21-1.57 (m, 10 H), 2.33 (t, J = 7.3 Hz, 2 H), 2.82 (br, OH), 3.85-4.07 (m, 2 H), 4.97-5.09 (m, 2 H), 5.01-5.08 (m, 2 H), 5.61-5.82 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = -4.5, -4.8, 14.0, 17.9, 22.6, 25.2, 25.7, 31.8, 37.9, 41.0, 41.2, 68.1, 71.2, 117.3, 134.6.

HRMS (ESI): m/z calcd for C17H36O2Si + Na: 323.2382; found: 323.2389.

(5 S ,7 S )-7-Allyl-9,9,10,10-tetramethyl-5-pentyl-2,4,8-trioxa-9-silaundecane (9)

To a solution of alcohol 8 (1.8 g, 6 mmol) in anhyd CH2Cl2 (15 mL) at 0 ˚C were added successively DIPEA (3.10 mL, 17.95 mmol), DMAP (cat.), and MOMCl (0.96 g, 11.99 mmol). The mixture was stirred for 3 h at 25 ˚C, quenched with H2O (10 mL), and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the pure product 9 (2.02 g, 98%) as a colorless liquid; R f  = 0.7 (silica gel, 10% EtOAc in hexane); [α]D ²0 +19.0 (c 1.5, CHCl3).

IR (neat): 3076, 2953, 2930, 1640, 1466, 1379, 1253, 1150, 1044, 1001, 916, 834 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.06 (s, 6 H), 0.88-0.92 (m, 12 H), 1.25-1.63 (m, 10 H), 2.20-2.24 (t, J = 6.4 Hz, 2 H), 3.34 (s, 3 H), 3.55-3.63 (m, 1 H), 3.81-3.89 (m, 1 H), 4.59 (s, 2 H), 5.01-5.05 (m, 2 H), 5.71-5.85 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = -4.5, -4.0, 14.0, 18.0, 22.6, 24.7, 25.8, 31.9, 35.2, 42.3, 42.6, 55.4, 69.2, 75.7, 95.8, 116.9, 134.7.

HRMS (ESI): m/z calcd for C19H40O3Si + Na: 367.2644; found: 367.2631.

(4 S ,6 S )-4-( tert -Butyldimethylsilyloxy)-6-(methoxymethoxy)undecan-1-ol (10)

To a stirred solution of cyclohexene (2.64 mL, 26 mmol) in anhyd THF (2 mL) was added Me2S˙BH3 (1.22 mL, 13 mmol) at 0 ˚C. The mixture was stirred for 1 h at 0 ˚C, and then a solution of 9 (1.50 g, 4 mmol) in anhyd THF (15 mL) was added slowly over 10-15 min at 0 ˚C. The resulting solution was allowed to warm to 25 ˚C and then allowed to stir for 6 h. Upon completion, the mixture was quenched at 0 ˚C with EtOH (5 mL), and treated with 1 M aq NaOH (21.8 mL, 21.8 mmol) and 30% H2O2 (10 mL, 87 mmol). After stirring at r.t. for 1 h, the resulting mixture was quenched with 1 M aq Na2S2O3 (10 mL). The aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with 1 M aq Na2S2O3 (10 mL) followed by brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography to afford the alcohol 10 (1.21 g, 77%) as a colorless liquid; R f  = 0.3 (silica gel, 20% EtOAc in hexane); [α]D ²0 +15.8 (c 1.2, CHCl3).

IR (neat): 3417, 2931, 2858, 1466, 1380, 1253, 1212, 1150, 1041, 919, 835 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.07 (s, 6 H), 0.88-0.89 (m, 12 H), 1.29-1.88 (m, 15 H), 3.34 (s, 3 H), 3.53-3.61 (m, 3 H), 3.83-3.90 (m, 1 H), 4.59 (s, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = -4.6, -4.1, 13.9, 18.0, 22.5, 24.0, 24.5, 25.4, 25.8, 27.7, 31.9, 41.9, 55.4, 69.3, 70.2, 75.6, 95.6.

MS (ESI): m/z = 385 [M + Na].

(4 S ,6 S )-6-(Methoxymethoxy)undecan-1,4-diol (11)

To an ice cold solution of silyl ether 10 (0.75 g, 2.07 mmol) in anhyd THF (10 mL) was added TBAF (2.48 mL, M in THF, 2.48 mmol). After stirring for 15 min, the reaction mixture was brought to 25 ˚C and the stirring was continued for 4 h. The mixture was then cooled to 0 ˚C and quenched with sat. aq NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography to afford the alcohol 11 (0.49 mg, 97%) as a colorless gummy liquid; R f  = 0.2 (silica gel, 20% EtOAc in hexane); [α]D ²0 -17.1 (c 1.2, CHCl3).

IR (neat): 3413, 2931, 1639, 1456, 1377, 1214, 1148, 1097, 1036, 914 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 6.7 Hz, 3 H), 1.12-1.28 (m, 6 H), 1.43-1.71 (m, 8 H), 2.74 (br, OH), 3.35 (s, 3 H), 3.56-3.66 (m, 2 H), 3.70-3.91 (m, 2 H), 4.58-4.68 (m, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.4, 25.0, 29.2, 31.8, 34.5, 34.7, 41.2, 55.7, 62.7, 67.7, 76.1, 96.2.

HRMS (ESI): m/z calcd for C13H28O4 + Na: 271.1909; found: 271.1894.

(4 S )-4-(Methoxymethoxy)non-1-ene (15)

To a solution of alcohol 14 (5.0 g, 35.2 mmol) in anhyd CH2Cl2 (25 mL) at 0 ˚C were added successively DIPEA (12.13 mL, 70.4 mmol), DMAP (20 mg, cat.), and MOMCl (8.02 mL, 105.5 mmol). The mixture was stirred for 3 h at 25 ˚C, quenched with H2O (25 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography to afford the pure product 15 (6.35 g, 97%) as a colorless liquid; R f  = 0.8 (silica gel, 10% EtOAc in hexane); [α]D ²0 -17.8 (c 1.5, CHCl3).

IR (neat): 3367, 3019, 1215, 1096, 1038 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.7 Hz, 3 H), 1.26-1.47 (m, 8 H), 2.23-2.27 (m, 2 H), 3.33 (s, 3 H), 3.52-3.58 (m, 1 H), 4.57-4.63 (m, 2 H), 5.00-5.06 (m, 2 H), 5.72-5.83 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.5, 24.9, 31.8, 34.0, 38.8, 55.3, 76.7, 95.2, 116.8, 134.7.

MS (ESI): m/z = 209 [M + Na].

(3 S )-3-(Methoxymethoxy)octanal (16)

O3 was bubbled through a solution of 15 (4.5 g, 24.19 mmol) in CH2Cl2 (35 mL) at -78 ˚C until no unreacted starting material was observed on TLC (eluent: 10% EtOAc in hexanes). The reaction mixture was then purged with N2 to remove the excess O3 and cooled to 0 ˚C. Ph3P (7.6 g, 29.0 mmol) was added and the mixture was stirred for 2 h and concentrated in vacuo. After adding hexane (10 mL), the mixture was filtered through a Celite pad and the residue was washed with hexane (30 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the pure product 16 (3.64 g, 80%) as a colorless liquid; R f  = 0.6 (silica gel, 10% EtOAc in hexane); [α]D ²0 +20.1 (c 1.5, CHCl3).

IR (neat): 3019, 2932, 1724, 1215, 1036, 758 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.82 (t, J = 6.7 Hz, 3 H), 1.16-1.60 (m, 8 H), 2.50-2.56 (m, 2 H), 3.28 (s, 3 H), 3.97-4.06 (m, 1 H), 4.57-4.63 (m, 2 H), 9.73 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.5, 24.8, 31.7, 34.8, 48.7, 55.5, 73.1, 95.7, 201.4.

MS (ESI): m/z = 209 [M + Na].

(4 S ,6 S )-1-(Benzyloxy)-6-(methoxymethoxy)undec-2-yn-4-ol (17b)

A solution of n-BuLi in hexane (14.73 mL, 19.14 mmol, 1.3 M solution in hexane) was added to a solution (10 mL) of O-benzylpropargyl alcohol (2.79 g, 19.11 mmol) in THF at -78 ˚C under N2 atmosphere and the mixture was allowed to stir for 20 min. To this mixture, a solution of aldehyde 16 (3.0 g, 15.95 mmol) in anhyd THF (15 mL) was added. After stirring the mixture for 2 h at -78 ˚C, the reaction was quenched by sat. aq NH4Cl (15 mL), extracted with EtOAc (2 × 30 mL), and the combined organic layers were dried (Na2SO4). Evaporation of the solvent followed by purification on column chromatography afforded alcohols 17b (2.76 g 43%) and 17a (2.70 g, 42%). Unwanted 17a was converted into 17b by Mitsunobu inversion; 17b (total yield: 4.53 g, 70%) was obtained as a viscous liquid; R f  = 0.4 (SiO2, 30% EtOAc in hexane); [α]D ²0 +23.5 (c 0.9, CHCl3).

IR (neat): 3399, 3019, 2930, 1215, 1095, 757 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 6.7 Hz, 3 H), 1.26-1.30 (m, 6 H), 1.45-1.50 (m, 2 H), 1.79-1.84 (m, 2 H), 3.31 (s, 3 H), 3.36-3.41 (m, 1 H), 3.71-3.76 (m, 1 H), 4.14 (s, 2 H), 4.51 (s, 2 H), 4.55-4.63 (m, 2 H), 7.27 (m, 5 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.5, 24.4, 31.8, 34.3, 42.4, 53.5, 55.7, 57.3, 71.5, 76.0, 80.6, 87.3, 95.3, 127.7, 127.9, 128.3, 137.3.

MS (ESI): m/z = 357 [M + Na].

(4 S ,6 S )-6-(Methoxymethoxy)undecan-1,4-diol (11)

To a solution of 17b (2.0 g) in anhyd MeOH (15 mL) was added a catalytic amount of 10% Pd/C and the resulting mixture was stirred under H2 atmosphere at r.t. for 4 h. After completion, the catalyst was filtered and then washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to afford the alcohol 11 (1.44 g, 97%) as a colorless gummy liquid; R f  = 0.2 (silica gel, 20% EtOAc in hexane); [α]D ²0 -17.1 (c 1.2, CHCl3).

IR (neat): 3413, 2931, 1639, 1456, 1377, 1214, 1148, 1097, 1036, 914 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 6.7 Hz, 3 H), 1.12-1.28 (m, 6 H), 1.43-1.71 (m, 8 H), 2.74 (br, OH), 3.35 (s, 3 H), 3.56-3.66 (m, 2 H), 3.70-3.91 (m, 2 H), 4.58-4.68 (m, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.4, 25.0, 29.2, 31.8, 34.5, 34.7, 41.2, 55.7, 62.7, 67.7, 76.1, 96.2.

HRMS (ESI): m/z calcd for C13H28O4 + Na: 271.1909; found: 271.1894.

( S )-5-[( S )-2-(Methoxymethoxy)heptyl]dihydrofuran-2(3 H )-one (12)

To a stirred solution of diol 11 (0.23 g, 0.92 mmol) in anhyd CH2Cl2 (5 mL) were added sequentially PhI(OAc)2 (943 mg, 2.93 mmol) and TEMPO (33 mg, 0.21 mmol). After stirring the reaction mixture at 25 ˚C for 3.5 h, sat. aq Na2S2O3 (10 mL) was added, and the mixture was extracted with Et2O (2 × 10 mL). The combined organic extracts were washed with sat. aq NaHCO3 (10 mL) and brine (6 mL), and concentrated in vacuo. The residue was subjected to column chromatography to afford the lactone 12 (0.196 g, 87%) as a colorless liquid; R f  = 0.5 (silica gel, 40% EtOAc in hexane); [α]D ²0 +48.5 (c 1.9, CHCl3).

IR (neat): 2933, 1773, 1730, 1455, 1333, 1278, 1181, 1102, 1035, 918, 798, 737, 651 cm-¹.

¹H NMR (300 MHz CDCl3): δ = 0.90 (t, J = 6.7 Hz, 3 H), 1.30-1.61 (m, 8 H), 1.71-1.91 (m, 3 H), 2.28-2.39 (m, 1 H), 2.46-2.53 (m, 2 H), 3.35 (s, 3 H), 3.71-3.79 (m, 1 H), 4.57-4.71 (m, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.7, 22.3, 24.2, 28.3, 29.6, 31.7, 34.7, 41.1, 55.4, 74.6, 77.7, 95.8, 176.8.

MS (ESI): m/z = 245 [M + 1].

( S )-5-[( S )-2-Hydroxyheptyl]dihydrofuran-2(3 H )-one (1b)

To a solution of 12 (0.13 g, 0.53 mmol) in anhyd CH2Cl2 (0.92 mL) was added TFA (0.23 mL, 2.13 mmol) dropwise at 25 ˚C. After stirring the mixture at the same temperature for 2 h, it was quenched with sat. aq NaHCO3 (6 mL) and extracted with CH2Cl2 (2 × 6 mL). The combined organic extracts were washed with brine (6 mL) and concentrated in vacuo. The residue was purified by column chromatography to afford the pure alcohol 1b (0.103 g, 97%) as a colorless oil; R f  = 0.3 (silica gel, 40% EtOAc in hexane); [α]D ²0 +59.6 (c 1.2, Et2O).

IR (neat): 3445, 2929, 2859, 1767, 1460, 1420, 1359, 1185, 1036, 917, 766, 653 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 6.6 Hz, 3 H), 1.18-1.46 (m, 8 H), 1.69 (ddd, J = 3.5, 9.8, 14.3 Hz, 1 H), 1.78 (ddd, J = 2.8, 9.2 Hz, 1 H), 1.90 (ddt, J = 8.4, 9.4, 12.6 Hz, 1 H), 2.13 (br, OH), 2.25-2.36 (m, 1 H), 2.45-2.51 (m, 2 H), 3.76-3.85 (m, 1 H), 4.70-4.78 (m, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = 13.9, 22.5, 25.0, 28.4, 28.8, 31.6, 37.9, 43.1, 68.3, 78.1, 177.2.

HRMS (ESI): m/z calcd for C11H20O3 + Na: 223.1310; found: 223.1336.

Acknowledgment

P.A.N.R. and H.A. thank CSIR, New Delhi for the award of fellowships. The correspondence author acknowledges the partial support by King Saud University for Global Research Network for Organic Synthesis (GRNOS).

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Figure 1 Lactones 1a-c and 2a

Scheme 1

Scheme 2 Route A. Reagents and conditions: (a) n-hexanal, TFA, CH2Cl2, 3 h; then K2CO3, MeOH, 25 ˚C, 0.5 h, 52%; (b) Et3N, TsCl, CH2Cl2, 0-25 ˚C, 3 h, 95%; (c) TBSCl, imidazole, DMAP, CH2Cl2, 0 to 25 ˚C, 3 h, 97%; (d) NaI, acetone, reflux, 24 h, 95%; (e) Zn, EtOH, reflux, 2 h, 92%; (f) MOMCl, DIPEA, DMAP, CH2Cl2, 0-25 ˚C, 3 h, 98%; (g) Cy2BH, THF, 30% H2O2, NaOH, 77%; (h) TBAF, THF, 0-25 ˚C, 4 h, 97%; (i) TEMPO, PhI(OAc)2, CH2Cl2, 25 ˚C, 4 h, 87%; (j) TFA, CH2Cl2 (1:4 ), 0-25 ˚C, 2 h, 97%.

Scheme 3 Route B. Reagents and conditions: (a) MOMCl, DIPEA, DMAP, CH2Cl2, 0 ˚C to r.t., 3 h, 98%; (b) O3, TPP, CH2Cl2, -78 ˚C to r.t.; (c) BnOCH2C≡CH, n-BuLi, THF, -78 ˚C, 2 h, 85%; (d) DEAD, TPP, p-nitrobenzoic acid, THF, 0 ˚C to r.t., 88%; (e) Pd/C, MeOH, r.t., 4 h, 97%; (f) 1. aq 3 M HCl, THF, 0 ˚C to r.t., 4 h, 2. 2,2-DMP, acetone, PTSA, r.t., 2 h; (g) TEMPO, PhI(OAc)2, CH2Cl2, 25 ˚C, 4 h, 87%; (h) TFA-CH2Cl2 (1:4), 0- 25 ˚C, 2 h, 97%.