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Total Synthesis and Determination of Absolute Configuration of

Cryptorigidifoliol G
Utkal Mani Choudhury, Kishor L. Mendhekar, Ajit C. Kunwar, and Debendra K. Mohapatra*
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ABSTRACT: The first asymmetric total synthesis of (1S,5R,7S)-

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cryptorigidifoliol G and (1S,5R,7R)-cryptorigidifoliol G of the

proposed natural product was achieved. The key steps in the
synthesis involved Keck−Maruoka allylation, our own developed
protocol for the construction of the trans-2,6-disubstituted
dihydropyran, iodolactonization, cross-metathesis, Prins cycliza-
tion, and cis-Wittig olefination reaction. A comparison of the NMR as well as analytical data and thorough analysis of the 2D NMR
suggested that the absolute stereochemistry of the proposed natural product is (1S,5R,7S)-cryptorigidifoliol G.

■ INTRODUCTION
The plant genus Cryptocarya is disseminated throughout the
world’s tropic, subtropic, and clement regions.1,2 The class of
Cryptocarya-derived mono-cyclic-5,6-dihydro-α-pyrones as
well as bicyclic tetrahydropyrones exhibits antimycobacterial,2b
anti-parasitic,2b antitumor,2e and anticancer activities.1,2c,d,f,g
Among the bicyclic tetrahydro-α-pyrones, some of them have
been used in traditional medicine for treating arthritis,
headache, and hepatitis infections.2h Due to their interesting
chemical framework and promising biological profiles, these
compounds have attracted much attention from the chemical
synthesis community over the past decade.3,4 Cryptorigidifo-
liols F−K are aliphatic polyketide lactones bearing a bicyclic
tetrahydropyrone moiety, isolated from the root wood of
Cryptocarya rigidifolia (Lauraceae) in 2015 by Kingston et al.
(Figure 1).2h Cryptorigidifoliol G shows antimalarial activity
(IC50 > 10 μM) against the Dd2 of Plasmodium falciparum and
antiproliferative activity (IC50 > 10 μM) against A2780 human
ovarian cancer cells.1h Structurally, cryptorigidifoliol G (1)
contains a bicyclic tetrahydropyrone moiety comprising three
stereogenic centers at C1, C5, and C7 and attached to an
aliphatic side chain at C7 having Z olefin in between C8′ and Figure 1. Structure of cryptorigidifoliol G and other bicyclic lactone-
containing natural products.
C9′ (Figure 1). The relative stereochemistry at C1 and C5
positions was assigned by the interpretation of electronic
circular dichroism spectroscopic data, and further, the Wittig salt 10 prepared from 1-bromododecane. The aldehyde
geometry of the olefin was assigned as cis by two-dimensional 9 could be obtained by cross-metathesis reaction between
(2D) nuclear magnetic resonance (NMR) data. However, the compound 11 and 6-hepten-1-ol (12) followed by oxidation.
absolute configuration at the C7 position is not assigned due to The bicyclic lactone 11 was planned to be prepared through
the strained nature of the bicyclic compound. Owing to its
interesting biological activities and to assign the absolute
configuration, herein, we report the first total synthesis of Received: October 5, 2022
(1S,5R,7S)- and (1S,5R,7R)-cryptorigidifoliol G.
The retrosynthetic approach to (1S,5R,7S)-cryptorigidifoliol
G (1) is illustrated in Scheme 1. Our initial strategy called for
the introduction of a Z-alkene side chain as the end game
following a cis-Wittig olefination with aldehyde 9 and the

© XXXX American Chemical Society https://doi.org/10.1021/acs.joc.2c02398

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Scheme 1. Retrosynthetic Plan Scheme 2. Synthesis of Bicyclic Lactone Fragment 11

iodolactonization of acid 13. The acid 13 could be synthesized was subjected to hydrogenation by using Pd/C under an H2
from a known intermediate 14, which in turn could be atmosphere in ethanol to furnish compound 22 in 93% yield
synthesized following our earlier developed protocol starting (Scheme 3).15 Alcohol 22 was oxidized under TEMPO/BAIB
from 15, which was planned to synthesize from 1,3-propane
diol (16). Scheme 3. Total Synthesis of (1S,5R,7S)-Cryptorigidifoliol
G (1)
■ RESULTS AND DISCUSSION
The synthesis of bicyclic lactone precursor 11 began with 1,3-
propane diol (16); selective protection of the hydroxyl group
of 16 as its PMB ether with PMB alcohol in the presence of the
catalytic amount of amberlyst-155 under refluxing CH2Cl2
followed by oxidation under PCC6 conditions afforded the
corresponding aldehyde which was used for the next reaction
without further characterization. The resulting aldehyde was
treated with allyltributyltin in the presence of Ti(iPrO)4 and
(R)-BINOL in CH2Cl2 at −20 °C to furnish the homoallyl
alcohol 18 [ee 98% by high-performance liquid chromatog-
raphy (HPLC)] in 66% yield over two steps (Scheme 1).7 The
cross-metathesis between homoallylic alcohol 18 and acrolein
was carried out in the presence of Hoveyda−Grubbs’ catalyst8
to afford the δ-hydroxy-α,β-unsaturated aldehyde 15 in 80%
yield. Treatment of 15 with 10 mol % molecular iodine and
allyl-TMS gave 2,6-trans-disubstituted-3,4-dihydropyran 14 (dr
= 99:1) in 90% yield.9a Oxidative removal of the PMB group in
14 using DDQ10 in CH2Cl2/H2O (9:1) afforded primary conditions to afford the corresponding aldehyde in 85%
alcohol followed by oxidation with TEMPO/BAIB11 in yield.11 The resulting aldehyde 9 was purified by a flash
aqueous CH3CN (1:2), which furnished the carboxylic acid column and immediately subjected to the next reaction
13 in 90% yield. Iodolactonization of 13 with molecular without characterization. Aldehyde 9 was subjected to Wittig
iodine12 and NaHCO3 in acetonitrile was performed to obtain olefination reaction (LHMDS, PPh3+C12H25Br− (10), tetrahy-
the bicyclic iodolactone 20 in 89% yield with excellent drofuran (THF), 0 °C)16 to afford the proposed structure of
diastereoselectivity (dr 98:2, analyzed by HPLC). Deiodina- one of the isomers, (1S,5R,7S)-cryptorigidifoliol G (1) in 76%
tion of 20 was achieved smoothly under Barton−McCombie yield.
conditions13 with Bu3SnH and a catalytic amount of AIBN in After successfully synthesizing one of the isomers, we
refluxing toluene which furnished compound 11 in 96% yield compared the data with the natural product data. Notably, the
1
(Scheme 2). H NMR and 13C NMR data of the synthetic one closely
After enough quantity of compound 11 was in hand, a cross- matched the data reported for the natural product except for
metathesis reaction with 6-hepten-1-ol (12) was carried out one peak in the 13C NMR data (see Table S1). The magnitude
using Grubbs’ second-generation catalyst14 (11/12 = 1:1.5) to of specific rotation of the synthetic isomer 1 (1S,5R,7S)-
obtain the alcohol compound 21 in 82% yield. Compound 21 cryptorigidifoliol G {[α]21
D −3.8 (c 0.6, MeOH)} matched with

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2h
the natural product {[α]21D −4.0 (c 0.5, MeOH)}. Even corresponding homoallyl alcohol 25 in 80% yield (over two
though the spectral and analytical data matched closely with steps) with an enantiomeric ratio of 95:5 (determined by
the natural product, it was decided to synthesize the other NMR of its Mosher’s ester).19 Even though the synthesis of
isomer of (1S,5R,7R)-cryptorigidifoliol G (2) for the aldehyde 26 was cited in Scheme 2, we followed a more
confirmation of absolute configuration at the C7 position. practical and simple protocol to obtain the neat product.20b
A new route was designed that would introduce the side Having both the coupling partners 25 and 26 in hand, the
chain at the beginning and bicyclic ring to be formed at the crucial Prins cyclization was carried out with TFA in CH2Cl2
end of the synthesis as the incorporation of the Z-olefin side followed by hydrolysis with K2CO3 in methanol to obtain diol
chain in the end game was troubleshooting in our initial compound 24 in 42% yield after two steps (Scheme 5).21 Even
strategy. The retrosynthetic analysis shown in Scheme 4 though direct selective oxidation under TEMPO/BAIB11
conditions furnished (1S,5R,7R)-cryptorigidifoliol G (2), the
Scheme 4. Retrosynthetic Analysis of (1S,5R,7R)- yield was not satisfactory. To circumvent the problem, the diol
Cryptorigidifoliol G (2) compound 24 was protected with TBSCl in the presence of
imidazole to obtain compound 31 in 82% yield.22
Selective deprotection of the silyl group in 31 with PPTS in
CH2Cl2/MeOH at 0 °C provided primary alcohol compound
32 in 86% yield.23 Alcohol compound 32 was oxidized with
TEMPO and BAIB in CH3CN/H2O to furnish acid 33 in 83%
yield.10 Removal of the TBS group by using TBAF24 in THF
followed by an intramolecular lactonization under Yamaguchi
conditions25 completed the synthesis of (1S,5R,7R)-cryptor-
igidifoliol G (2) (Scheme 5). The 1H and 13C NMR data as
well as the specific rotation values of the synthesized isomer 2
(1S,5R,7R)-cryptorigidifoliol G {[α]21 D + 12.7 (c 0.4, MeOH);
Lit.2h [α]21
D −4.0 (c 0.5, MeOH)} showed significant deviation
from the natural product data, which suggests that the absolute
stereochemistry of the proposed natural product is (1S,5R,7S)-
cryptorigidifoliol G (1). Further, the assignment for some of
the protons (where overlap was moderate) was carried out
with the help of various 2D NMR experiments. The NOESY
experiments were specifically useful for confirming the
structure of compound 2. The presence of NOE correlation
between H7−H9 (flagpole interaction) confirmed the boat
conformation of the six-membered ring (with long-chain
substituent) as well as fixed the configuration of C7 as “R”
(Figure S1). Further confirmation of the configuration of 2 was
obtained from its precursor, which showed the NOE
correlation peaks H2/H4, H2/H6, and H4/H6, implying a
revealed that the (1S,5R,7R)-cryptorigidifoliol G (2) could be chair conformation of the six-membered ring and axial
obtained from acid 23 under Yamaguchi lactonization reaction disposition of protons H2, H4, and H6 (Figure S2). For
conditions. Intermediate 23 could be achieved from diol 24 illustrious purposes, minimum energy structures were obtained
upon oxidation. Synthesis of compound 24 was planned where the long substituents are replaced with the ethyl group
through TFA-mediated Prins cyclization. Compound 25 could (Figure S1).
be synthesized from compound 27 following deprotection,
oxidation, and Keck asymmetric allylation. Compound 27
would be obtained from commercially available 1,9-nonane
■ CONCLUSIONS
In summary, we have achieved the first asymmetric total
diol (28). synthesis of (1S,5R,7S)-cryptorigidifoliol G (1) and
With the general synthetic plan in our hand, 1,9-nonane diol (1S,5R,7R)-cryptorigidifoliol G (2) of the proposed natural
(28) is protected as its benzyl ether using benzyl bromide and product. The key steps in both the synthesis involved Keck−
NaH in THF to obtain compound 29.17 Oxidation of the Maruoka allylation, our own developed protocol for the
alcohol group in 29 under IBX18 conditions gave its construction of the trans-2,6-disubstituted dihydropyran,
corresponding aldehyde, which was taken for the next reaction iodolactonization, cross-metathesis, Prins cyclization, and cis-
without any further characterization. The aldehyde was Wittig olefination reaction. A comparison of the spectral as
subjected to cis-Wittig olefination by using ylide obtained well as analytical data suggests that the absolute stereo-
from 10 in the presence of LHMDS in THF at −78 °C to chemistry of the proposed natural product is (1S,5R,7S)-
afford exclusively Z-isomer 27 in 61% yield (over two steps).16 cryptorigidifoliol G (1).
Oxidative removal of benzyl ether in compound 27 with DDQ
in C2H4Cl2/H2O (9:1) at 50 °C furnished 30 in 89% yield.10
Treatment of alcohol 30 with IBX in THF/dimethyl sulfoxide
■ EXPERIMENTAL SECTION
General Information. All air and/or moisture sensitive reactions
(DMSO) furnished corresponding aldehyde, which was passed were carried out in anhydrous solvents under an inert atmosphere in
through a small bed of silica gel followed by Keck allylation flame-dried glassware. All commercially available starting materials
using allyltributyltin in the presence of (S)-BINOL and and reagents were used as received without further purification.
Ti(OiPr)4 in CH2Cl2 at −20 °C, which provided the Anhydrous solvents were distilled prior to use: THF from Na and

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Scheme 5. Total Synthesis of (1S,5R,7R)-Cryptorigidifoliol G (2)

benzophenone; CH2Cl2, DMF from CaH2; MeOH from Mg cake. For slowly added and allowed to stir for 1 h at ambient temperature. After
reactions that require heating, an oil bath was used as the heating completion of the reaction (as indicated by TLC), filtered through a
source. Reactions were monitored by thin-layer chromatography celite pad, the filtrate was dried over anhydrous Na2SO4 and
(TLC) on silica gel GF254 (0.25 mm). Column chromatography was concentrated under reduced pressure. The obtained crude product
carried out by using silica gel (60−120 mesh). Specific optical was passed through a small plug of silica gel to afford the
rotations [α]D were given in 10−1 deg cm2 g−1 and were measured corresponding aldehyde (2.52 g, 79%) as a pale-yellow colored liquid
using Anton Paar MCP 200 digital polarimeter at 20 °C. Infrared was immediately used for the next step.
spectra were recorded in CHCl3 and reported in wave number To a stirred solution of TiC14 (0.28 mL, 2.6 mmol), in CH2C12 (5
(cm−1). The diastereomeric ratio was analyzed by Shimadzu LC− mL) and Ti(i-PrO)4 (1.2 mL, 3.9 mmol) were added at 0 °C under
mass spectrometry (MS)-8040 instrument. High-resolution mass argon atmosphere. The solution was allowed to rise to room
spectrometry (HRMS) spectra were recorded by using Waters Q- temperature. After 1 h, silver oxide (0.60 g, 2.61 mmol) was added
TOF mass spectrometer. 1H and 13C NMR chemical shifts were and the reaction mixture was stirred for 6 h under the exclusion of
reported in ppm downfield from tetramethylsilane relative to the direct light. The reaction mixture was diluted with CH2C12 (20 mL)
CDCl3, 7.26 ppm for 1H NMR, and 77.00 ppm for 13C NMR, and treated with (R)-binaphthol (1.11 g, 3.92 mmol) at room
respectively, and coupling constants (J) were reported in hertz (Hz). temperature for 2 h to furnish chiral bis-(R)-Ti(IV) oxide. The in situ
Structural assignments were made with additional information from generated bis-(R)-Ti(IV) oxide in CH2Cl2 (40 mL) was cooled to
gCOSY, gHSQC, and gHMBC experiments. The following −20 °C and treated sequentially with the aldehyde (2.51 g, 12.93
abbreviations were used to designate signal multiplicity: s = singlet, mmol) and allyltributyltin (4.01 mL, 11.05 mmol) at same
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. temperature. The reaction mixture was stirred to the same
3-((4-Methoxybenzyl)oxy)propan-1-ol (17). Propane-1,3-diol temperature for 24 h. The reaction mixture was quenched with
(16) (4.0 g, 52.63 mmol), 4-methoxybenzyl alcohol (5.8 g, 42.11 saturated NaHCO3 (50 mL) solution and extracted with ethyl acetate
mmol), and amberlyst-15 (0.58 g, 4.21 mmol) were dissolved in (3 × 50 mL). The combined organic layers were dried over Na2SO4,
anhydrous CH2Cl2 (40 mL) and refluxed to 45 °C for 12 h. After filtered, and concentrated under reduced pressure. Flash chromatog-
completion of the reaction (monitored by TLC) filtered through a raphy of the residue over silica gel (ethyl acetate/hexane = 1:19)
celite pad, the filtrate was dried over anhydrous Na2SO4 and afforded homoallylic alcohol 18 (2.55 g, 84%). [α]20 D + 3.9 (c 1.0,
concentrated under reduced pressure. The crude product was purified CHCl3); IR (CHCl3) νmax: 3453, 2926, 2859, 1616, 1517, 1457, 1253,
by column chromatography over silica gel (ethyl acetate/hexane = 1097, 1035, 826 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J =
3:7) to give the desired product 17 (7.8 g, 76%); IR (CHCl3) νmax: 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.89−5.77 (m, 1H), 5.13−5.06
3467, 2929, 2852, 1637, 1501, 1442, 1096, 1009, 825 cm−1; 1H NMR (m, 2H), 4.45 (s, 2H), 3.88−3.83 (m, 1H), 3.80 (s, 3H), 3.72−3.66
(400 MHz, CDCl3): δ 7.27−7.23 (m, 2H), 6.88 (d, J = 8.7 Hz, 2H), (m, 1H), 3.65−3.58 (m, 1H), 2.90 (d, J = 2.7 Hz, 1H), 2.28−2.20 (m,
4.45 (s, 2H), 3.80 (s, 3H), 3.76 (t, J = 5.7 Hz, 2H), 3.63 (t, J = 5.8 Hz, 2H), 1.78−1.72 (m, 2H)ppm; 13C{1H} NMR (125 MHz, CDCl3): δ
2H), 2.42 (s, 1H), 1.85 (dt, J = 11.5, 5.8 Hz, 2H) ppm; 13C{1H} 159.2, 134.8, 129.9, 129.3, 117.4, 113.8, 72.9, 70.4, 68.6, 55.2, 41.9,
NMR (100 MHz, CDCl3): δ 159.2, 130.1, 129.2, 113.8, 72.9, 68.9, 35.8 ppm; HRMS (ESI-TOF) m/z: [M + Na] + calcd for
61.8, 55.2, 32.0 ppm. C14H20O3Na, 259.1310; found, 259.1307.
(R)-1-((4-Methoxybenzyl)oxy)hex-5-en-3-ol (18). To a stirred (R,E)-5-Hydroxy-7-((4-methoxybenzyl)oxy)hept-2-enal (15).
solution of alcohol 17 (3.23 g, 16.47 mmol) in anhydrous CH2Cl2 (38 To a stirred solution of allyl alcohol 18 (2.5 g, 10.59 mmol) in
mL), celite (0.33 g) was added at room temperature. The reaction CH2Cl2 (4 mL), were sequentially added acrolein (1.1 mL, 15.79
mixture was cooled to 0 °C, and PCC (5.33 g, 24.71 mmol) was mmol) and Hoveyda−Grubbs second generation catalyst (332 mg, 5

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mol %) at room temperature; Argon gas was purged through it for 10 20 mL). The combined organic layer was washed with brine (30 mL),
min and allowed to stir at room temperature for 2 h. After completion dried over anhydrous Na2SO4, and evaporated under reduced
of the reaction (monitored by TLC), the solvent was evaporated pressure. The crude product was purified by silica gel column
under reduced pressure and the resulting crude product was purified chromatography (ethyl acetate/hexane = 1:3) to afford the acid 13
by silica gel column chromatography (ethyl acetate/hexane = 1:3) to (409 mg, 90%) as a viscous liquid. [α]20 D + 99.9 (c 0.8, CHCl3); IR
afford δ-hydroxy α,β-unsaturated aldehyde 15 (2.24 g, 80% yield) as a (CHCl3) νmax: 3364, 3032, 2932, 1712, 1647, 1271, 1071, 910, 763
colorless liquid. [α]20
D + 14.8 (c 1.2, CHCl3); IR (CHCl3) νmax: 3444, cm−1; 1H NMR (500 MHz, CDCl3): δ 5.91−5.69 (m, 3H), 5.19−
2931, 2862, 1683, 1513, 1362, 1247, 1090, 1029, 823 cm−1; 1H NMR 5.00 (m, 2H), 4.26 (br s, 1H), 4.23−4.16 (m, 1H), 2.62 (dd, J = 15.4,
(500 MHz, CDCl3): δ 9.50 (d, J = 7.9 Hz, 1H), 7.27−7.21 (m, 2H), 8.3 Hz, 1H), 2.54 (dd, J = 15.4, 4.8 Hz, 1H), 2.48−2.39 (t, J = 14.5
6.96−6.91 (m, 1H), 6.90−6.86 (m, 2H), 6.21−6.12 (m, 1H), 4.45 (s, Hz, 1H), 2.33−2.24 (m, 1H), 2.17−2.07 (m, 1H), 2.05−1.96 (m,
2H), 4.02 (br d, J = 3.7 Hz, 1H), 3.80 (s, 3H), 3.74−3.69 (m, 1H), 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 176.8, 134.5, 128.9,
3.67−3.61 (m, 1H), 3.39 (br s, 1H), 2.52−2.47 (m, 2H), 1.83−1.72 123.4, 117.2, 72.5, 64.8, 40.2, 38.6, 29.8 ppm; HRMS (ESI-TOF) m/
(m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 193.9, 159.3, z: [M + Na]+ calcd for C10H14O3Na, 205.0841; found, 205.0843.
154.9, 134.6, 129.6, 129.3, 113.8, 73.0, 70.2, 68.5, 55.2, 40.4, 36.0 (1R,5R,7S,8R)-7-Allyl-8-iodo-2, 6-dioxabicyclo[3.3.1]nonan-
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H20O4Na, 3-one (20). To a stirred solution of acid 13 (300 mg, 1.65 mmol) in
287.1254; found, 287.1250. MeCN (15 mL) were sequentially added NaHCO3 (414 mg, 4.95
(2R,6S)-6-Allyl-2-(2-((4-methoxybenzyl)oxy)ethyl)-3,6-dihy- mmol) and I2 (503 mg, 1.98 mmol) at −20 °C. After stirring for 2 h,
dro-2H-pyran (14). To a stirred solution of δ-hydroxy α,β- the mixture was allowed to warm to room temperature and stirred for
unsaturated aldehyde 15 (2.0 g, 7.58 mmol) in THF (20 mL) were 10 h. After completion of the reaction (monitored by TLC), it was
sequentially added allyltrimethylsilane (1.8 mL, 11.36 mmol) and quenched with saturated aqueous Na2S2O3 solution (20 mL) and
iodine (0.29 g, 1.14 mmol) at 0 °C. The reaction mixture was allowed diluted with ethyl acetate (25 mL). The organic layer was separated,
to stir at room temperature for 1 h. After completion of the reaction and the aqueous layer was extracted with ethyl acetate (2 × 25 mL).
(monitored by TLC), it was quenched with aqueous saturated The combined organic layers were dried over anhydrous Na2SO4 and
Na2S2O3 solution (20 mL) and diluted with ethyl acetate (30 mL). evaporated under reduced pressure. The crude product was purified
The organic layer was separated, and the aqueous layer was extracted by silica gel column chromatography (ethyl acetate/hexane = 1:19) to
with ethyl acetate (2 × 50 mL). The combined organic layers were obtain the bicyclic lactone 20 (452 mg, 89%) as a yellow liquid. [α]20 D
dried over anhydrous Na2SO4 and concentrated under reduced −39.3 (c 0.7, CHCl3); IR (CHCl3) νmax: 3081, 2969, 1740, 1345,
−1 1
pressure. The crude product was purified by column chromatography 1257, 1159, 1070, 810 cm ; H NMR (400 MHz, CDCl3): δ 5.79−
over silica gel (ethyl acetate/hexane = 1:9) to obtain the cyclized 5.61 (m, 1H), 5.24 (d, J = 17.1 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H),
product 14 (1.96 g, 90%) as a colorless liquid. [α]20 D + 38.7 (c 0.7, 5.00 (s, 1H), 4.33 (s, 2H), 3.07−2.90 (m, 2H), 2.88−2.72 (m, 2H),
CHCl3); IR (CHCl3) νmax: 3032, 2916, 1640, 1612, 1586, 1513, 1436, 2.51−2.36 (m, 1H), 2.30−2.12 (m, 1H), 1.88 (d, J = 14.3 Hz, 1H)
1361, 1248, 1178, 1088, 1036, 823, 709 cm−1; 1H NMR (400 MHz, ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 168.6, 131.9, 118.9, 77.1,
CDCl3): δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.91− 66.2, 66.0, 42.4, 36.6, 34.0, 25.2 ppm; HRMS (ESI-TOF) m/z: [M +
5.78 (m, 2H), 5.73−5.67 (m, 1H), 5.12−5.03 (m, 2H), 4.43 (s, 2H), Na]+ calcd for C10H13O3INa, 330.9802; found, 330.9807.
4.22−4.15 (m, 1H), 3.91−3.83 (m, 1H), 3.79 (s, 3H), 3.63−3.51 (m, (1S,5R,7S)-7-Allyl-2, 6-dioxabicyclo[3.3.1]nonan-3-one (11).
2H), 2.44−2.35 (m, 1H), 2.27−2.19 (m, 1H), 2.02−1.91 (m, 2H), To a stirred solution of iodo-lactone 20 (401 mg, 1.30 mmol) in
1.82−1.75 (m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ toluene (20 mL) were added catalytic amount of AIBN (21 mg, 0.13
159.0, 135.1, 130.5, 129.2, 129.1, 124.3, 116.6, 113.7, 72.6, 72.3, 66.5, mmol) followed by n-tributyltin hydride (1.05 mL, 3.90 mmol) and
64.7, 55.1, 38.7, 35.5, 30.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ refluxed by using an oil bath for 30 min. After completion of the
calcd for C18H24O3Na, 311.1623; found, 311.1616. reaction (monitored by TLC), toluene was removed under reduced
2-((2R,6S)-6-Allyl-3,6-dihydro-2H-pyran-2-yl)ethanol (19). pressure. The crude product was purified by silica gel column
To a stirred solution of compound 14 (1.5 g, 5.21 mmol) in chromatography (ethyl acetate/hexane = 3:7) to give compound 11
CH2Cl2 (27 mL) and water (3 mL) was added DDQ (1.77 g, 7.81 (226 mg, 96%) as a colorless liquid. [α]20 D −19.1 (c 0.6, CHCl3); IR
mmol) at room temperature and allowed to stir for 2 h at the same (CHCl3) νmax: 2951, 2860, 1734, 1218, 1076, 780 cm−1; 1H NMR
temperature. After completion of the reaction (indicated by TLC), it (400 MHz, CDCl3): δ 5.86−5.70 (m, 1H), 5.16−5.05 (m, 2H),
was quenched with saturated NaHCO3 (30 mL) solution. After 4.94−4.87 (m, 1H), 4.38 (d, J = 3.4 Hz, 1H), 3.88−3.79 (m, 1H),
stirring for 3 h, the organic layer was separated and the aqueous layer 2.96−2.83 (m, 1H), 2.78 (dd, J = 19.2, 5.2 Hz, 1H), 2.35−2.21 (m,
was extracted with CH2Cl2 (3 × 50 mL). The combined organic layer 2H), 2.09−1.97 (m, 2H), 1.97−1.88 (m, 1H), 1.65−1.53 (m, 1H)
was washed with brine (2 × 60 mL), dried over anhydrous Na2SO4, ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 169.7, 133.5, 117.7, 72.9,
and evaporated under reduced pressure. The crude product was 65.9, 65.3, 40.0, 36.4, 36.3, 29.6 ppm; HRMS (ESI-TOF) m/z: [M +
purified by silica gel column chromatography (ethyl acetate/hexane = Na]+ calcd for C10H14O3Na, 205.0841; found, 205.0840.
3:17) to afford the desired primary alcohol 19 (0.82 g, 94%) as a pale- (1S,5R,7S)-7-((E)-8-Hydroxyoct-2-en-1-yl)-2,6-dioxabicyclo-
yellow color liquid. [α]20D + 71.0 (c 0.6, CHCl3); IR (CHCl3) νmax: [3.3.1]nonan-3-one (21). To a stirred solution of bicyclic
3437, 2933, 1718, 1266, 1077, 769 cm−1; 1H NMR (400 MHz, compound 11 (150 mg, 0.82 mmol) in CH2Cl2 (2 mL) were
CDCl3): δ 5.97−5.78 (m, 2H), 5.78−5.62 (m, 1H), 5.23−5.04 (m, sequentially added 6-hepten-1-ol (12) (188 mg, 1.24 mmol) and
2H), 4.35−4.20 (m, 1H), 3.97−3.87 (m, 1H), 3.78 (s, 2H), 2.70 (s, Grubbs second generation catalyst (34 mg, 5% mol) at room
1H), 2.44 (dd, J = 19.1, 11.6 Hz, 1H), 2.35−2.25 (m, 1H), 2.09−1.92 temperature, and Argon gas was purged through it for 10 min. The
(m, 2H), 1.84−1.69 (m, 2H) ppm; 13C{1H} NMR (100 MHz, reaction mixture was allowed to stir at room temperature for 4 h. After
CDCl3): δ 134.9, 128.7, 124.1, 117.1, 72.3, 67.5, 60.9, 38.6, 37.4, 30.6 completion of the reaction (monitored by TLC), the solvent was
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C10H16O2Na, evaporated under reduced pressure, and the resulting crude product
191.1043; found, 191.1035. was purified by silica gel column chromatography (ethyl acetate/
2-((2R,6S)-6-Allyl-3,6-dihydro-2H-pyran-2-yl) Acetic Acid hexane = 2:3) to yield 21 (180 mg, 82%) as a brown liquid. [α]20 D
(13). To a stirred solution of alcohol 19 (420 mg, 2.5 mmol) in a −20.5 (c 0.4, CHCl3); IR (CHCl3) νmax: 3440, 3150, 2928, 2857,
mixture of CH3CN/H2O (2:1, 15 mL) were added PhI(OAc)2 (1.89 1731, 1351, 1263, 1077, 803 cm−1; 1H NMR (400 MHz, CDCl3): δ
g, 5.86 mmol) and TEMPO (70 mg, 0.45 mmol) at room 5.56−5.42 (m, 1H), 5.42−5.30 (m, 1H), 4.94−4.85 (m, 1H), 4.37 (br
temperature. The reaction mixture was allowed to stir at the same s, 1H), 3.82−3.72 (m, 1H), 3.64 (t, J = 6.6 Hz, 2H), 2.89 (d, J = 19.2
temperature for 3 h. After completion of the reaction (monitored by Hz, 1H), 2.77 (dd, J = 19.2, 5.2 Hz, 1H), 2.34−2.11 (m, 2H), 2.08−
TLC), it was quenched with saturated aqueous Na2S2O3 solution (15 1.97 (m, 4H), 1.95−1.88 (m, 1H), 1.65 (br s, 1H), 1.60−1.51 (m,
mL) and diluted with ethyl acetate (20 mL). The organic layer was 3H), 1.41−1.32 (m, 4H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
separated, and the aqueous layer was extracted with ethyl acetate (2 × 169.9, 133.7, 124.8, 73.1, 65.9, 65.8, 62.9, 38.9, 36.5, 36.4, 32.6, 32.5,

E https://doi.org/10.1021/acs.joc.2c02398
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The Journal of Organic Chemistry pubs.acs.org/joc Article

29.7, 29.0, 25.2 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for to room temperature and stirred for 12 h. The reaction was quenched
C15H25O4, 269.1752; found, 269.1764. with saturated aqueous ammonium chloride solution (30 mL) at 0 °C
(1S,5R,7S)-7-(9-Hydroxynonyl)-2,6-dioxabicyclo[3.3.1]- and diluted with ethyl acetate (50 mL). The layers were separated,
nonan-3-one (22). To a stirred solution of compound 21 (21 mg, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL).
0.08 mmol) in EtOH (3 mL) was added 10% palladium on carbon (4 The combined organic extracts were washed with brine (70 mL),
mg). The reaction mixture was stirred under H2 atmosphere for 3 h. dried over Na2SO4, and concentrated under reduced pressure
After completion of the reaction (monitored by TLC), Pd/C was followed by purification using silica gel column chromatography
filtered through a small pad of celite, and the filtrate was concentrated (ethyl acetate/hexane = 1:19), which provided 9-(benzyloxy)-nonan-
under reduced pressure. The crude residue was purified by silica gel 1-ol (29) (7.25 g, 93%) as a colorless liquid. IR (neat) νmax: 3392,
column chromatography (ethyl acetate/hexane = 2:3) to afford 2932, 2860, 1461, 1280, 1111, 745, 607 cm−1; 1H NMR (500 MHz,
primary alcohol 22 (20 mg, 93%) as a colorless liquid. [α]20 D −11.7 (c CDCl3): δ 7.34 (d, J = 4.5 Hz, 4H), 7.31−7.24 (m, 1H), 4.50 (s, 2H),
0.4, CHCl3); IR (CHCl3) νmax: 3406, 2934, 2860, 1735, 1351, 1215, 3.62 (t, J = 6.7 Hz, 2H), 3.46 (t, J = 6.7 Hz, 2H), 1.59 (ddd, J = 22.7,
1079, 920, 769 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.92−4.86 (m, 14.0, 7.0 Hz, 5H), 1.38−1.29 (m, 9H) ppm; 13C{1H} NMR (100
1H), 4.39−4.33 (m, 1H), 3.77−3.69 (m, 1H), 3.64 (t, J = 6.6 Hz, MHz, CDCl3): δ 138.6, 128.3, 127.6, 127.4, 72.8, 70.5, 63.0, 32.7,
2H), 2.92−2.83 (m, 1H), 2.77 (dd, J = 19.2, 5.2 Hz, 1H), 2.07−1.97 29.7, 29.5, 29.4, 29.3, 26.1, 25.7 ppm; HRMS (ESI-TOF) m/z: [M +
(m, 2H), 1.96−1.88 (m, 1H), 1.63 (br s, 1H), 1.60−1.50 (m, 4H), H]+ calcd for C16H27O2, 251.2011; found, 251.2004.
1.48−1.28 (m, 10H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ (Z)-((Henicos-9-en-1-yloxy)methyl)benzene (27). A solution
169.9, 73.2, 65.8, 65.6, 63.0, 36.9, 36.5, 35.8, 32.8, 29.8, 29.39, 29.35, of IBX (4.16 g, 14.89 mmol) in anhydrous DMSO (15 mL) was
29.2, 25.7, 25.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for stirred at room temperature for 30 min, and then, a solution of 29
C15H26O4Na, 293.1729; found, 293.1737. (2.5 g, 9.92 mmol) in THF (30 mL) was added. The resulting mixture
N-Dodecyltriphenylphosphonium Bromide (10). To a sol- was allowed to stir at room temperature for 3 h. The reaction mixture
ution of 1-bromododeccane (10.0 g, 43.0 mmol) in toluene (100 mL) was filtered and diluted with H2O (50 mL) and extracted with tert-
was added Ph3P (12.0 g, 47.0 mmol). The reaction mixture was butyl methyl ether (3 × 70 mL). The combined organic layers were
refluxed by using an oil bath for 7 days. The resulting reaction mixture washed with brine (70 mL), dried (anhydrous Na2SO4), and
was cooled to room temperature, and the toluene solvent was evaporated to give the corresponding aldehyde (2.06 g) as a colorless
removed under reduced pressure. The crude reaction mixture was liquid, which was used for the next reaction.
washed with distilled hexane (150 mL) followed by filtration to The n-dodecyltriphenylphosphonium bromide (10) (13.81 g, 27.1
furnish a white solid compound 10 (20.0 g, 94%) as phosphonium mmol) in THF (30 mL) was stirred at room temperature under a
salt. nitrogen atmosphere until it was dissolved completely. To this
(1S,5R,7S)-7-((Z)-Pentadec-3-en-1-yl)-2,6-dioxabicyclo- solution was slowly added LiHMDS (1.0 M in THF, 20.12 mL, 20.12
[3.3.1]nonan-3-one (1). To a stirred solution of alcohol 22 (7 mg, mmol) at −78 °C, and the resulting solution was warmed to 0 °C.
0.026 mmol) in CH2Cl2 (2 mL), TEMPO (40 mg, 0.003 mmol) and After 1 h, the reaction mixture was cooled again to −78 °C, and
BAIB (10 mg, 0.03 mmol) were added to 0 °C and allow to stir to aldehyde (2.0 g, 7.89 mmol) was added slowly. The mixture was
room temperature for 1 h. After completion of the reaction (indicated stirred at the same temperature for 4 h. After complete consumption
by TLC), it was quenched with saturated Na2S2O3 and NaHCO3 of the starting material (monitored by TLC), the reaction was
solution (5 mL) and diluted with CH2Cl2 (5 mL). The organic layer quenched with saturated NH4Cl (50 mL) and warmed to room
was separated, and the aqueous layer was extracted with CH2Cl2 (2 × temperature. The organic layer was separated, and the aqueous layer
5 mL). The combined organic layer was washed with brine (10 mL), was extracted with ethyl acetate (3 × 70 mL). The combined organic
dried over anhydrous Na2SO4, and evaporated under reduced layers were washed with brine (100 mL), dried over anhydrous
pressure. The obtained crude aldehyde 9 (6 mg) was used for the Na2SO4, and concentrated. Purification by silica gel column
next step. chromatography (ethyl acetate/hexane = 1:99) afforded 27 (2.51 g,
To a suspension of n-dodecyltriphenylphosphonium bromide (10) 61% over two steps) as a colorless liquid. IR (neat) νmax: 2930, 2859,
(23 mg, 0.046 mmol) in anhydrous THF (2 mL) was added a 1683, 1462, 1113, 740 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.34 (d,
solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 0.05 mL, J = 4.5 Hz, 4H), 7.31−7.25 (m, 1H), 5.42−5.30 (m, 2H), 4.50 (s,
0.05 mmol) at 0 °C, and the mixture was stirred at room temperature 2H), 3.47 (d, J = 6.7 Hz, 2H), 2.01 (dd, J = 12.3, 6.6 Hz, 4H), 1.66−
for 1 h. A solution of aldehyde 9 (6 mg, 0.022 mmol) in THF (1 mL) 1.57 (m, 3H), 1.37−1.25 (m, 27H), 0.88 (t, J = 6.9 Hz, 3H) ppm;
13
was added to the ylide at 0 °C, and the resulting mixture was stirred at C{1H} NMR (125 MHz, CDCl3): δ 138.7, 129.9, 129.8, 128.3,
ambient temperature for 1 h; saturated aqueous NH4Cl (2 mL) was 127.6, 127.4, 72.8, 70.5, 31.9, 29.8, 29.68, 29.65, 29.6, 29.49, 29.46,
added to the mixture and extracted with ethyl acetate (3 × 3 mL). 29.34, 29.32, 29.25, 27.2, 26.2, 22.7, 14.1 ppm; HRMS (APCI-TOF)
The combined organic layer was washed with brine (5 mL), dried m/z: [M + NH4]+ calcd for C28H52ON, 418.4043; found, 418.4034.
over anhydrous Na2SO4, and concentrated under reduced pressure. (Z)-Henicos-9-en-1-ol (30). DDQ (6.93 g, 30.56 mmol) was
The crude product was purified by silica gel column chromatography added in one portion to a stirred solution of compound 27 (1.58 g,
(ethyl acetate/hexane = 1:9) to obtain 1 (7 mg, 65% over two steps) 3.82 mmol) in C2H4Cl2/H2O (9:1) (50 mL) at 50 °C. The reaction
as a colorless liquid. [α]21
D −3.8 (c 0.6, MeOH); IR (CHCl3) νmax: mixture was allowed to stir for 2 h at the same temperature. After the
3080, 2951, 2860, 1733, 1650, 1353, 1256, 1209, 1070, 798 cm−1; 1H complete conversion of the starting material (monitored by TLC), the
NMR (400 MHz, CDCl3): δ 5.41−5.28 (m, 2H), 4.94−4.84 (m, 1H), reaction was quenched with saturated aqueous NaHCO3 solution (30
4.40−4.35 (br s, 1H), 3.78−3.69 (m, 1H), 2.91−2.83 (br d, J = 19.2 mL) and diluted with CH2Cl2 (75 mL). The organic layer was
Hz, 1H), 2.77 (dd, J = 19.2, 5.2 Hz, 1H), 2.07−1.97 (m, 5H), 1.95− separated, and the aqueous layer was extracted with CH2Cl2 (2 × 75
1.89 (m, 1H), 1.59−1.50 (m, 6H), 1.48−1.38 (m, 2H), 1.35−1.22 mL). The combined organic layers were dried over anhydrous
(m, 24H), 0.88 (t, J = 6.9 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, Na2SO4 and concentrated under reduced pressure. The crude product
CDCl3): δ 169.9, 130.0, 129.8, 73.2, 65.8, 65.7, 37.0, 36.5, 35.9, 31.9, was purified by silica gel column chromatography (ethyl acetate/
29.9, 29.8, 29.73, 29.68, 29.64, 29.61, 29.58, 29.56, 29.5, 29.4, 29.35, hexane = 2:3) to afford the alcohol compound 30 (1.1 g, 89%) as a
29.3, 27.20, 27.18, 25.2, 22.7, 14.1 ppm; HRMS (ESI-TOF) m/z: [M colorless liquid. IR (neat) νmax: 3671, 2929, 2860, 1464, 758, 608
+ H]+ calcd for C27H49O3, 421.3682; found, 421.3698. cm−1; 1H NMR (400 MHz, CDCl3): δ 5.40−5.32 (m, 2H), 3.64 (t, J
9-(Benzyloxy)-nonan-1-ol (29). A flask was charged with sodium = 6.6 Hz, 2H), 2.01 (dd, J = 12.0, 6.2 Hz, 4H), 1.62−1.53 (m, 2H),
hydride (washed with anhydrous hexane and dried under reduced 1.36−1.25 (m, 28H), 0.89 (t, J = 6.7 Hz, 3H) ppm; 13C{1H} NMR
pressure) (1.5 g, 37.5 mmol), and anhydrous THF (20 mL) was (100 MHz, CDCl3): δ 129.9, 129.8, 63.1, 32.8, 31.9, 29.8, 29.74,
added slowly. The solution was cooled to 0 °C, and nonane-1,9-diol 29.68, 29.6, 29.56, 29.5, 29.4, 29.35, 29.3, 29.2, 27.2, 27.19, 25.7, 22.7,
(28) (5.0 g, 31.25 mmol) in was added dropwise followed by benzyl 14.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H43O,
bromide (3.75 mL, 31.25 mmol). The reaction mixture was warmed 311.3313; found, 311.3302.

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(R,Z)-Tetracosa-1,12-dien-4-ol (25). A solution of IBX (1.14 g, 1090, 840, 777 cm−1; 1H NMR (400 MHz, CDCl3): δ 5.40−5.24 (m,
4.10 mmol) in anhydrous DMSO (4 mL) was stirred for 20 min at 2H), 3.80−3.72 (m, 2H), 3.69 (m, 1H), 3.41 (m, 1H), 3.20 (m, 1H),
room temperature, and then, a solution of 30 (0.88 g, 2.73 mmol) in 2.07−1.92 (m, 4H), 1.82−1.75 (m, 2H), 1.73−1.61 (m, 2H), 1.44−
THF (10 mL) was added. The resulting mixture was allowed to stir at 1.36 (m, 2H), 1.33−1.27 (m, 28H), 1.21−1.15 (m, 2H), 0.91−0.85
room temperature for 3 h. The reaction mixture was filtered and (m, 21H), 0.06 (s, 6H), 0.05 (d, J = 0.8 Hz, 6H) ppm; 13C{1H} NMR
diluted with H2O (20 mL) and extracted with tert-butylmethyl ether (100 MHz, CDCl3): δ 130.1, 130.0, 75.7, 72.1, 69.2, 59.6, 42.13,
(3 × 40 mL). The combined organic layers were washed with brine 42.05, 39.3, 36.4, 32.1, 29.9, 29.8, 29.73, 29.70, 29.52, 29.49, 29.45,
(50 mL), dried (anhydrous Na2SO4), and evaporated under reduced 27.4, 26.2, 26.0, 22.9, 18.5, 18.3, 14.3, −4.4, −5.15, −5.20 ppm.
pressure to afford the corresponding aldehyde (0.75 g, 86%) as a HRMS (ESI-TOF) m/z [M + H]+: calcd for C39H81O3Si2, 653.5718;
colorless liquid, which was used as such for the next reaction. found, 653.5706.
To a stirred solution of TiC14 (0.038 mL, 0.34 mmol) in CH2C12 2-((2S,4S,6R)-4-((tert-Butyldimethylsilyl)oxy)-6-((Z)-icos-8-
(2 mL) was added Ti(iPrO)4 (0.21 mL, 0.70 mmol) at 0 °C under en-1-yl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (32). To a stirred
argon atmosphere. The solution was allowed to stir at room solution of compound 31 (61 mg, 0.094 mmol) in CH2Cl2/MeOH
temperature for 1 h. Silver oxide (0.107 g, 0.46 mmol) was added (4:1) (10 mL) was added PPTS (3 mg, 0.010 mmol) at 0 °C under
to it, and the reaction mixture was stirred for 6 h under the exclusion N2 atmosphere and allowed to stir for 2 h. After completion of the
of direct light. The reaction mixture was diluted with CH2C12 (5 mL) reaction (monitored by TLC), the solvent was removed under
and treated with (S)-binaphthol (0.20 g, 0.70 mmol) at room reduced pressure. The crude reaction mixture was quenched with
temperature for 2 h to furnish chiral bis-(S)−Ti(IV) oxide. The in situ water (5 mL) and diluted with CH2Cl2 (15 mL). The organic layer
generated bis-(S)−Ti(IV) oxide in CH2Cl2 (8 mL) was cooled to was separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
−10 °C and treated sequentially with the aldehyde (0.75 g, 2.3 mmol) 10 mL). The combined organic layer was dried over anhydrous
and allyltributyltin (0.88 mL, 2.83 mmol) at the same temperature Na2SO4 and evaporated to dryness under reduced pressure. The crude
and stirred for 24 h. The reaction mixture was quenched with product was purified by silica gel column chromatography (ethyl
saturated aqueous NaHCO3 solution (10 mL) and extracted with acetate/hexane = 1:9) to afford compound 32 (43 mg, 86%) as a
ethyl acetate (3 × 20 mL). The combined organic layers were dried colorless liquid. [α]20
D + 8.50 (c 1.2, CHCl3). IR (neat) νmax: 3125,
over Na2SO4, filtered, and concentrated under reduced pressure. 2932, 2360, 1214, 1095, 764 cm−1; 1H NMR (400 MHz, CDCl3): δ
Column chromatography of the residue over silica gel (ethyl acetate/ 5.43−5.23 (m, 2H), 3.80−3.76 (m, 3H), 3.54 (m, 1H), 3.31 (m, 1H),
hexane = 1:20) afforded homoallylic alcohol 25 (0.79 g, 80% yield 2.09−1.90 (m, 4H), 1.84−1.65 (m, 4H), 1.37−1.34 (m, 2H), 1.33−
over two steps). [α]20 D + 3.30 (c 1.0, CHCl3); IR (neat) νmax: 3588,
1.23 (m, 28H), 1.19 (m, 1H), 0.91−0.86 (m, 15H), 0.06 (s, 6H);
13
2930, 2859, 2356, 1562, 927, 758, 600 cm−1; 1H NMR (400 MHz, C{1H} NMR (100 MHz, CDCl3): δ 129.9, 129.8, 76.4, 76.1, 68.6,
CDCl3): δ 5.91−5.76 (m, 1H), 5.40−5.29 (m, 2H), 5.19−5.10 (m, 61.7, 41.7, 41.5, 37.6, 36.0, 31.9, 29.77, 29.75, 29.7, 29.6, 29.44, 29.35,
2H), 3.64 (m, 1H), 2.36−2.27 (m, 1H), 2.18−2.09 (m, 1H), 2.01 (m, 29.3, 27.2, 25.8, 25.7, 22.7, 18.1, 14.3, 14.1, 13.5, −4.53; HRMS (ESI-
4H), 1.50−1.42 (m, 3H), 1.36−1.26 (m, 27H), 0.88 (t, J = 6.8 Hz, TOF) m/z: [M + H]+ calcd for C33H67O3Si, 539.4854; found,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 134.9, 129.9 129.8, 539.4842.
118.1, 70.7, 41.9, 36.8, 31.9, 29.8, 29.68, 29.65, 29.57, 29.55, 29.5, 2-((2R,4S,6R)-4-((tert-Butyldimethylsilyl)oxy)-6-((Z)-icos-8-
29.4, 29.3, 29.2, 27.2, 25.7, 22.7, 14.1 ppm; HRMS (ESI-TOF) m/z: en-1-yl)tetrahydro-2H-pyran-2-yl)acetic Acid (33). To a stirred
[M − H]− calcd for C24H45O, 349.3464; found, 349.3460. solution of alcohol 32 (35 mg, 0.064 mmol) in a mixture of CH3CN/
(2S,4S,6R)-2-(2-Hydroxyethyl)-6-((Z)-icos-8-en-1-yl)-tetrahy- H2O (2:1, 1.5 mL) were added PhI(OAc)2 (30 mg, 0.096 mmol) and
dro-2H-pyran-4-ol (24). Trifluoroacetic acid (0.15 mL, 20.54 TEMPO (19 mg, 0.012 mmol) at room temperature. The reaction
mmol) was added slowly to a solution of alcohol 25 (0.23 g, 0.79 mixture was allowed to stir at the same temperature for 3 h. After the
mmol) and aldehyde 26 (0.46 g, 2.37 mmol) in CH2Cl2 (10 mL) at complete conversion of the starting material (monitored by TLC), it
room temperature under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous Na2S2O3 solution (5 mL) and
was stirred for 4 h, and then, saturated aqueous NaHCO3 solution (10 diluted with ethyl acetate (10 mL). The organic layer was separated,
mL) was added and the pH was adjusted to >7 by the addition of and the aqueous layer was extracted with ethyl acetate (3 × 10 mL).
triethylamine. The layers were then separated, the aqueous layer was The combined organic layer was washed with brine (10 mL), dried
extracted with CH2Cl2 (3 × 20 mL), and the organic layers were over anhydrous Na2SO4, and evaporated under reduced pressure. The
combined, dried, and removed under reduced pressure. The crude crude product was purified by silica gel column chromatography
residue was dissolved in methanol (5 mL) and stirred with potassium (ethyl acetate/hexane = 1:3) to afford the acid 33 (30 mg, 83%) as a
carbonate (0.188 g, 1.37 mmol) for 1 h. After removing MeOH under viscous liquid. [α]20D + 21.20 (c 1.0, CHCl3); IR (neat) νmax: 2933,
reduced pressure, water (5 mL) was added, and the mixture was 2859, 1465, 1256, 1093, 843, 777, 602 cm−1; 1H NMR (400 MHz,
extracted with dichloromethane (3 × 20 mL). The combined organic CDCl3): δ 5.38−5.25 (m, 2H), 3.82−3.70 (m, 2H), 3.39 (m, 1H),
layer was dried (anhydrous Na2SO4), and the solvent was removed 2.56 (dd, J = 7.3, 6.3 Hz, 2H), 2.05−1.95 (m, 4H), 1.84 (m, 2H),
under reduced pressure. Column chromatography (ethyl acetate/ 1.58−1.56 (m, 2H), 1.47−1.39 (m, 2H), 1.32−1.24 (m, 28H), 0.92−
hexane = 1:1) afforded product 24 (0.14 g, 42% yield) as a colorless 0.81 (m, 12H), 0.06 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ
liquid. [α]20
D + 2.40 (c 1.0, CHCl3). IR (neat) νmax: 3780, 3663, 2930, 172.5, 130.0, 129.8, 76.6, 71.9, 68.1, 41.3, 41.0, 40.5, 35.8, 32.0, 29.81,
2859, 2359, 1524, 604 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd 29.77, 29.72, 29.69, 29.6, 29.53, 29.45, 29.39, 29.36, 29.3, 27.3, 25.8,
for C27H53O3, 425.3989; found, 425.3980. 25.5, 22.7, 18.1, 14.2, −4.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd
tert-Butyl(2-((2S,4S,6R)-4-((tert-butyl-dimethylsilyl)oxy)-6- for C33H65O4Si, 553.4646; found, 553.4634.
((Z)-icos-8-en-1-yl)tetrahydro-2H-pyran-2-yl)ethoxy)- 2-((2R,4S,6R)-4-Hydroxy-6-((Z)-icos-8-en-1-yl)tetrahydro-
dimethylsilane (31). To a stirred solution of compound 24 (81 mg, 2H-pyran-2-yl)acetic Acid (23). To a stirred solution of compound
0.19 mmol) in CH2Cl2 (10 mL) was added imidazole (53 mg, 0.77 33 (0.015 g, 0.027 mmol) in THF (1.0 mL) was added TBAF (1.0 M,
mmol) followed by TBSCl (85 mg, 0.58 mmol) at 0 °C under N2 0.27 mL, 0.27 mmol) at 0 °C. The reaction mixture was allowed to
atmosphere and allowed to stir for 2 h. After completion of the stir at room temperature for 2 h. After the complete conversion of the
reaction (monitored by TLC), it was quenched with water (10 mL) starting material (monitored by TLC), the reaction was quenched
and diluted with CH2Cl2 (15 mL). The organic layer was separated, with H2O (5 mL) and diluted with ethyl acetate (10 mL). The
and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layer was separated, and the aqueous layer was extracted with
combined organic layer was dried over anhydrous Na2SO4 and ethyl acetate (2 × 10 mL). The combined organic layers were dried
evaporated to dryness under reduced pressure. The crude product was over anhydrous Na2SO4 and concentrated under reduced pressure.
purified by silica gel column chromatography (ethyl acetate/hexane = The crude product was purified by silica gel column chromatography
1:19) to afford compound 31 (102 mg, 82%) as a colorless liquid. (ethyl acetate/hexane = 2:3) to afford compound 23 (10 mg, 85%) as
[α]20
D + 11.30 (c 1.0, CHCl3); IR (neat) νmax: 2931, 2857, 2361, 1255, a colorless liquid. [α]20
D + 15.1 (c 1.0, CHCl3); IR (neat) νmax: 3314,

G https://doi.org/10.1021/acs.joc.2c02398
J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry pubs.acs.org/joc Article

2925, 2855, 1718, 1459, 1149, 1076, 630 cm−1; 1H NMR (500 MHz, 500007, India; Academy of Scientific and Innovative
CDCl3): δ 5.40−5.26 (m, 2H), 3.91−3.81 (m, 1H), 3.81−3.73 (m, Research (AcSIR), Ghaziabad 201002, India
1H), 3.38 (m, 1H), 2.63 (dd, J = 15.8, 8.1 Hz, 1H), 2.54 (dd, J = 15.8,
4.7 Hz, 1H), 2.04−1.99 (m, 4H), 1.67−1.54 (m, 2H), 1.50−1.39 (m, Complete contact information is available at:
2H), 1.34−1.23 (m, 28H), 1.22−1.15 (m, 2H), 0.88 (t, J = 6.9 Hz, https://pubs.acs.org/10.1021/acs.joc.2c02398
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.5, 130.0, 129.8, 76.3,
71.8, 67.7, 40.8, 40.6, 35.8, 32.0, 29.81, 29.78, 29.73, 29.69, 29.6, Notes
29.51, 29.48, 29.39, 29.36, 29.3, 27.2, 25.5, 22.7, 14.2; HRMS (ESI- The authors declare no competing financial interest.
TOF) m/z: [M + H]+ calcd for C27H51O4, 439.3781; found,
439.3773.
(1S,5R,7R)-7-((Z)-Icos-8-en-1-yl)-2,6-dioxabicyclo[3.3.1]-
nonan-3-one (2). To a solution of compound 23 (6.0 mg, 0.014
■ ACKNOWLEDGMENTS
This manuscript is dedicated to Dr. Mukund K. Gurjar, CSO,
mmol) in THF (1 mL) were added Et3N (0.02 mL, 0.084 mmol) and Emcure Pharmaceuticals Pvt., Ltd., on the occasion of his 70th
2,4,6-trichlorobenzoyl chloride (0.009 mL, 0.054 mmol) at 0 °C birthday. The authors gratefully acknowledge the financial
under argon atmosphere, and stirring was continued for 4 h at room
support received from the Department of Science and
temperature. The reaction mixture was then diluted with toluene (2.0
mL). The mixture was then added dropwise (ca. 2 h) into a solution Technology-Science and Engineering Research Board (DST-
of DMAP (0.051 g, 0.42 mmol) in toluene (5 mL) at 100 °C by using SERB), New Delhi, India, through grant no. EMR/2017/
an oil bath and allowed to stir overnight. The reaction was then 002298. The authors thank the director, CSIR-IICT, for his
cooled to room temperature and washed successively with 0.5 M HCl constant support and for providing excellent research facilities
solution (2 mL), saturated aqueous NaHCO3 solution (3 mL), and (manuscript communication number IICT/Pubs/2022/351).
then brine (2 mL). The organic layer was dried over Na2SO4, filtered, U.M.C. and K.L.M. thank UGC, New Delhi, India, for financial
concentrated under reduced pressure, and then purified by flash assistance in the form of fellowships.
chromatography (ethyl acetate/hexane = 1:9) to afford 2 (4.7 mg,
82%) as a colorless liquid. [α]21 D + 12.7 (c 0.4, MeOH); IR (neat)
νmax: 2925, 2855, 1734, 1215, 1075, 751, 669 cm−1; 1H NMR (500
MHz, CDCl3): δ 5.39−5.25 (m, 2H), 4.91 (m, 1H), 4.43 (m, 1H),
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