Asymmetric synthesis of (+)-tanikolide and the β-methyl-substituted analogues of (+)-tanikolide and (-)-malyngolide

Article abstract of DOI:10.1002/ejoc.201101190

The δ-lactone-containing natural product (+)-tanikolide, a brine shrimp toxin and antifungal compound, was synthesized in nine steps with an overall yield of 26.4 % by employing Sharpless asymmetric epoxidation and ZrCl₄-catalyzed intramolecula

Full text of DOI:10.1002/ejoc.201101190

FULL PAPER
DOI: 10.1002/ejoc.201101190
Asymmetric Synthesis of (+)-Tanikolide and the β-Methyl-Substituted
Analogues of (+)-Tanikolide and (–)-Malyngolide
Robert Doran,[a] Lesley Duggan,[a] Surrendra Singh,[a,b] Colm D. Duffy,[a] and
Patrick J. Guiry*[a]
Keywords: Asymmetric synthesis / Zirconium / Lactones / Natural products
The δ-lactone-containing natural product (+)-tanikolide, a
brine shrimp toxin and antifungal compound, was synthe-
sized in nine steps with an overall yield of 26.4% by em-
lyzed intramolecular acetalization as the key steps. The
novel β-methyl-substituted analogues of (+)-tanikolide and
(–)-malyngolide have also been prepared by using the same
ploying Sharpless asymmetric epoxidation and ZrCl4-cata- asymmetric synthetic approach.
dihydroxylation of enamides have also been investigated.[8]
Introduction
The asymmetric synthesis of (–)-malyngolide was first re-
ported by Mukaiyama.[9] Since then, a variety of ap-
proaches have been employed, including chiral auxiliary,[10]
chiral pool,[11] other asymmetric syntheses,[12] and catalytic
asymmetric syntheses[13] (Figure 1).
(+)-Tanikolide (1) was isolated from the marine blue-
green algae cyanobacterium Lyngbya majuscula collected
from Tanikeli Island, Madagascar.[1] Tanikolide exhibits
strong toxicity against brine shrimp (LD50 = 3.6 μgmL–1)
and snail (LD50 = 9.0 μgmL–1) and antifungal activity
against C. albicans. The marine antibiotic (–)-malyngolide
(2), isolated from the shallow water variety of Lyngbya Ma-
juscula, has a similar structure to that of (+)-tanikolide,
with three key differences, as it contains (a) the opposite
stereoconfiguration of the quaternary carbon center; (b) an
n-nonyl instead of an n-undecyl aliphatic chain, and (c) a
C2 methyl group. (–)-Malyngolide displays antimicrobial
activity against Mycobacterium smegmatis, Staphylococcus,
Pseudomonas, and Streptococcus pyogenes[2] but, despite its
structural similarity to 1, (–)-malyngolide (2) shows no ac-
tivity against C. albicans.[1]
Figure 1. Structures of (+)-tanikolide and (–)-malyngolide.
We have recently discovered the ZrCl4-catalyzed forma-
tion of δ-lactones through a deprotection/cyclization/oxi-
dation sequence.[14] We subsequently exploited this in an
asymmetric synthesis of both enantiomers of a mosquito
attractant pheromone.[15] We have also reported further ap-
plications of this methodology in a microwave-assisted,
asymmetric synthesis of substituted tetrahydropyrans,
which were useful synthons for an asymmetric synthesis of
(+)-exo- and (+)-endo-brevicomin,[16] and for a short and
efficient synthesis of (–)-frontalin and (–)-exo-isobrevico-
min.[17]
The (+)-tanikolide and (–)-malyngolide δ-lactone struc-
tures appeared to us as attractive target molecules to which
we could apply our methodology, and herein we report a
concise asymmetric synthesis of (+)-tanikolide. In addition,
we wished to synthesize a set of analogues of (+)-tanikolide
and (–)-malyngolide containing a methyl substituent at the
C3 carbon. The purpose of these analogues was to investi-
gate the effect of this structural change on the biological
activity. Therefore, we also report the preparation of (+)-
tanikolide analogues 3 and 4 and (–)-malyngolide analogues
5 and 6, with 3/5 and 4/6 related as pairs of enantiomers
(Figure 2).
A number of different strategies have been employed in
previous syntheses of (+)-tanikolide,[3] including Sharpless
asymmetric
epoxidation/dihydroxylation
of
allylic
alcohols,[4] the use of the enantiopure starting materials d-
erythrulose[5a] and d-erythrose,[5b] stereospecific C–H inser-
tion of dichlorocarbene with a chiral secondary alcohol,[5c]
asymmetric α-alkylation of a β-keto ester and subsequent
Bayer–Villiger oxidation,[5d] α-metalation of ketones, and
ring-closing metathesis.[4b,5a,6] Domino reactions of epoxy
alcohols with hypervalent iodine reagents[7] and asymmetric
[a] Centre for Synthesis and Chemical Biology,
School of Chemistry and Chemical Biology,
University College Dublin,
Belfield, Dublin 4, Ireland
Fax: +353-1-716-2501
E-mail: patrick.guiry@ucd.ie
[b] Department of Chemistry, University of Dehli,
Dehli 110007, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101190.
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R. Doran, L. Duggan, S. Singh, C. D. Duffy, P. J. Guiry
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aqueous formaldehyde and K2CO3. The ester 15 was re-
duced to primary alcohol 16 by DIBAL at –30 °C in 96%
yield. The Sharpless asymmetric epoxidation of allylic
alcohol 16 was carried out at –25 °C by using Ti(OiPr)4,
(+)-diisopropyltartrate, and cumene hydroperoxide for 36 h
to afford epoxide 10 in 90% yield and with 95%ee. The
ring-opening of (–)-epoxide 10 was carried with the Grig-
nard derivative of 2-bromoethyl-1,3-dioxane (17), transmet-
alated with CuI (10 mol-%) at –35 °C, to form diol 8 in 90%
yield.[18] Diol 8 was then subjected to our deprotection/cy-
clization protocol and was therefore treated with methanol
in the presence of a catalytic amount of ZrCl4 (10 mol-%)
under microwave irradiation at 50 °C for 5 min at 150 W.
Unfortunately, we did not obtain the desired acetal 7a but
instead obtained bicyclic compound 18 in 90% yield.
As a result, we protected the primary hydroxy group of
(–)-epoxide 10 as a benzyl ether (Scheme 3) according to
a literature procedure.[4c] Benzyl-protected epoxide 11 was
treated with the Grignard reagent of 2-bromoethyl-1,3-di-
oxane (17) as before to afford tertiary alcohol 9 in 85%
yield. This was then treated with methanol in the presence
of ZrCl4 (10 mol-%) at 50 °C for 5 min under microwave
irradiation at 150 W to give the desired cyclization product,
(R)-6-methoxytetrahydropyran (7b), in 85% yield with a
diastereomeric ratio of 2:1. Subsequent conversion into δ-
lactone 19 by using BF3·OEt2 and m-CPBA proceeded in
83% yield.[19] The hydrogenolysis of benzyl ether 19 was
carried out with Pd(OH)2/C (10 wt.-%) at 20 bar hydrogen
pressure for 24 h to give the natural product (+)-tanikolide
(1) in 90% yield. Thus, the enantioselective total synthesis
of (+)-tankolide (1) has been accomplished in nine steps in
26.4% overall yield.
Figure 2. Structures of (+)-tanikolide and (–)-malyngolide ana-
logues.
The retrosynthesis of (+)-tanikolide (1) (Scheme 1) shows
our proposal that it could be synthesized from the Lewis
acid catalyzed oxidation of 6-methoxytetrahydropyran (7a),
which in turn could be obtained by ZrCl4-catalyzed intra-
molecular acetalization of tertiary alcohol 8 as the key step.
Alcohol 8 could be synthesized by the ring opening of epox-
ide 10 with the Grignard derivative of 2-bromoethyl-1,3-
dioxane (17).
Scheme 1. Retrosynthetic analysis of (+)-tanikolide (1).
Following the successful synthesis of (+)-tanikolide we
decided to apply our synthetic approach to the synthesis of
Results and Discussion
The first step towards epoxide 10 began with the synthe- the C3-methyl-substituted analogues of (+)-tanikolide, 3
sis of monoalkylated phosphonate intermediate 13 in 75% and 4. In order to construct these analogues we first had
yield from phosphonate 12, and we also isolated dialkylated to synthesize methyl-substituted Grignard precursor 22 by
phosphonate 14 in 20% yield as a byproduct (Scheme 2).[4c] dioxane protection of crotonaldehyde (20) and subsequent
The terminal alkene 15 was prepared in 90% yield by in situ bromination, as reported in our earlier studies
Horner–Wadsworth–Emmons reaction of 13 with 35% (Scheme 4).[14]
Scheme 2.
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Asymmetric Synthesis of (+)-Tanikolide
Scheme 3. Synthesis of (+)-tanikolide (1).
Scheme 4.
The benzyl-protected epoxide 11, used in our (+)-tanikol-
ide synthesis, was ring opened with Grignard reagent 23
derived from 2-(2-bromopropyl)-1,3-dioxane (22) at –35 °C
by using CuI (10 mol-%) and gave tertiary alcohol 24 in
64% yield (Scheme 5). Compound 24 then underwent suc-
cessful acetalization with methanol in the presence of ZrCl4
(10 mol-%) at 50 °C for 3 min under microwave irradiation
at 100 W to give desired methyl-substituted cyclic acetal 25
in 81% yield.
Scheme 5.
The diastereomers of compound 25 were successfully
separated by column chromatography to yield acetals 26
and 27, epimeric at the methoxy group (Scheme 6). Dia-
stereomer 26 was oxidized to its corresponding δ-lactone 28
by using BF3·OEt2 and m-CPBA in a yield of 82%. The
hydrogenolysis of the benzyl group of 28 was carried out as
before with Pd(OH)2/C (10 wt.-%) at 20 bar hydrogen for
24 h to give (3S,5R)-3-methyltanikolide (3) in quantitative
Scheme 6.
Following the successful completion of 3-methyltanikol-
yield. Diastereomer 27 was also converted into δ-lactone ide analogues 3 and 4, we decided to attempt the synthesis
(3R,5R)-3-methyltanikolide (4) by using the same synthetic of their enantiomers, (–)-malyngolide analogues 5 and 6,
sequence.
which retain the n-undecyl chain present in (+)-tanikolide.
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FULL PAPER
The synthetic scheme proposed was identical to that used (Scheme 7). Following successful formation of epoxide 30
for the synthesis of 3 and 4, except for the employment in 79% yield and subsequent benzyl ether protection in
of the opposite configuration of the tartrate ligand in the 87% yield, we formed protected epoxide 31 in 95%ee. Sub-
Sharpless asymmetric epoxidation of allylic alcohol 16 sequent Grignard ring opening of epoxide 31 was carried
Scheme 7.
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Asymmetric Synthesis of (+)-Tanikolide
out as before. At this stage, we decided to attempt to sepa- the β-methyl-substituted analogues of (+)-tanikolide (1)
rate the ring-opened product into its diastereomers. This and the marine antibiotic (–)-malyngolide (2). In the future
was to allow for the separation, as was achieved in the syn- we will evaluate the biological activity of these analogues
thesis of 3 and 4, of two proposed epimeric products and the results of these studies will be reported in due
formed after the ZrCl4-catalyzed acetalization. Otherwise, course.
the more difficult separation of four diastereomeric prod-
ucts would have to be investigated, as in the synthesis of 3
and 4. Following successful separation of diastereomers 33
and 34, the synthesis was concluded with successful lacton-
ization of the mixture of 35/36 and hydrogenolysis to yield
(3R,5S)-3-methyltanikolide (5). Similarly, lactonization of
the mixture of 37/38 and deprotection yielded (3S,5S)-3-
methyltanikolide (6).
Extensive NOE experiments were carried out on tanikol-
ide analogues 3 and 4 and the set of malyngolide analogues
Experimental Section
General Information: All reagents were obtained from commercial
sources and used without further purification. Anhydrous tetra-
hydrofuran and dichloromethane were obtained from a PureSolv-
300–3-MD dry solvent dispenser. All other anhydrous solvents
were obtained from commercial sources and used as received. In
vacuo refers to the evaporation of solvent under reduced pressure
with a Büchi rotary evaporator with an integrated vacuum pump.
Thin-layer chromatography (TLC) were performed on Merck DC-
Alufolien plates precoated with silica gel 60 F254. Flash column
5 and 6 to confirm the relative stereochemistry of each (Fig-
ure 3). In the case of analogues 3 and 5, irradiation of the
proton signals at δ = 2.24 ppm (C3) led to a positive re- chromatography was carried out by using Merck Kiesegel 60 F254
(230–400 mesh) or ZEOCHEM ZEOprep 60 (40–63 microns).
High-resolution mass spectra were measured with a Waters/Micro-
mass liquid chromatography time-of-flight (LCT) mass spectrome-
ter with leucine enkephalin as an internal lock mass. 1H NMR and
13C NMR spectra were recorded with Varian NMR System 300,
400, 500, and 600 MHz spectrometers at the following operating
frequencies: 1H NMR 300, 400, 500, and 600 MHz, respectively,
and 13C NMR at 75, 101, 126, and 151 MHz, respectively. Chemi-
cal shifts (δ) are given in parts per million (ppm) downfield from
tetramethylsilane by using the NMR solvent as an internal refer-
ence. The reference values used for deuterated chloroform (CDCl3)
were 7.26 and 77.00 ppm for 1H and 13C NMR spectra, respec-
tively. Infrared spectra were recorded with a Varian 3100 FTIR
spectrometer. Optical rotation values were measured with a Perkin–
Elmer 343 polarimeter.
sponse from the signal corresponding to the methoxymethyl
protons centered at δ = 3.62 ppm, indicating that the C3
methine proton is on the same side as the methoxymethyl
protons, in both cases. Similarly, irradiation of the meth-
oxymethyl proton signal at δ = 3.62 ppm led to enhance-
ment of the C3 methine proton at δ = 2.24 ppm.
Microwave Irradiation Experiments: All microwave experiments
were performed by using a CEM Discover Synthesizer possessing
a single-mode microwave cavity producing controlled irradiation
at 2.45 GHz. Experiments were carried out in standard microwave
process Pyrex vials (capacity 10 mL) by using the high-absorbance
level. Reaction time reflects irradiation times at the set reaction
temperature (fixed hold times).
Figure 3. Confirmation of relative stereochemistry by NOE experi-
ments.
Ethyl 2-(Diethoxyphosphoryl)tridecanoate (13): NaH (60% in min-
eral oil, 2.2 g, 55 mmol) was placed in a dry 250-mL two-necked,
round-bottomed flask containing a magnetic stirring bar under an
inert atmosphere and washed with anhydrous hexanes (2ϫ10 mL)
For analogues 3 and 5, with the opposite relative stereo-
chemistry to that of analogues 4 and 6, irradiation of the and dried under high vacuum. Dry THF (150 mL) was added to
the reaction flask and ethyl-2-(diethoxyphosphoryl) acetate (12;
11.4 g, 50 mmol) in dry THF (20 mL) was added dropwise over
20 min to the reaction mixture with H2 gas being evolved. 1-
Bromoundecane (5.6 mL, 25 mmol) was added dropwise to the re-
action mixture, and the reaction mixture was heated at reflux for
24 h. The reaction mixture was quenched with H2O (50 mL), and
the aqueous layer was extracted with Et2O (2ϫ100 mL). The com-
bined organic layers were washed with H2O (50 mL) and brine
(50 mL) and dried with anhydrous Na2SO4. The solvent was re-
moved in vacuo, and the crude product was purified by silica gel
column chromatography (pentane/ethyl acetate, 5:1) to yield 13 as
a colorless oil (7.09 g, 75%) and dialkylated phosphonate 14 in
C3 methine proton at δ = 2.08 ppm showed no response
to the methoxymethyl protons at δ = 3.45 and 3.68 ppm,
respectively. However, a small positive interaction was ob-
served for one of the protons α to the quaternary center on
the n-undecyl chain.
Conclusions
In summary, we have described a concise asymmetric
synthesis of the marine antifungal agent (+)-tanikolide (1)
by utilizing ZrCl4-catalyzed deprotection/cyclization as the
key transformation in the synthesis. Further use of this
strategy, developed within our group, was employed in the
20% yield. R = 0.36 (pentane/ethyl acetate, 3:1). IR (neat): ν =
˜
f
3489, 2926, 2361, 1736, 1467, 1257, 1027 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 4.30–4.08 (m, 6 H), 2.92 (ddd, J = 22.5,
asymmetric synthesis of all four possible stereoisomers of 11.1, 3.8 Hz, 1 H), 2.07–1.90 (m, 1 H), 1.81 (m, 1 H), 1.47–1.17
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R. Doran, L. Duggan, S. Singh, C. D. Duffy, P. J. Guiry
(m, 27 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, for 3 h at room temperature. The reaction mixture was filtered
FULL PAPER
CDCl3): δ = 169.3, 169.2, 62.6, 62.5, 61.2, 46.5, 45.2, 31.8, 29.5,
29.3, 29.0, 28.4, 28.3, 26.9, 22.6, 16.4, 16.3, 14.1, 14.0 ppm. HRMS
(ESI): calcd. for C19H39O5P [M]+ 378.2547; found 378.2535.
through a pad of Celite and concentrated in vacuo. The epoxide
was purified by column chromatography (pentane/ethyl acetate,
9.5:0.5 Ǟ 8.5:0.15) to yield epoxide 10 as a colorless oil (1.02 g,
90%, 95%ee). The ee value was calculated by HPLC (Agilent 1200,
Ethyl 2-Methylenetridecanoate (15): Phosphate ester 13 (7.482 g,
19.77 mmol) was placed in a 250-mL round-bottomed flask and
deionized water (55 mL) was added along with potassium carbon-
ate (5.464 g, 39.54 mmol) followed by aqueous formaldehyde
(5.93 mL, 79.07 mmol). The reaction mixture was stirred at 80 °C
for 48 h. A further addition of aqueous formaldehyde (5.93 mL,
79.07 mmol) and potassium carbonate (5.464 g) was made to drive
the reaction to completion, as judged by 1H NMR spectroscopic
analysis. The reaction was extracted with diethyl ether
(2ϫ150 mL), and the combined organic layers were washed with
H2O (75 mL) and brine (75 mL) and dried with anhydrous Na2SO4.
Excess solvent was removed in vacuo, and the crude product was
purified by silica gel column chromatography (pentane/ethyl acet-
Chiracel OJ-H, heptane/ethanol
0.5 mLmin) analysis of benzyl-protected epoxide 11. Rf = 0.67
(pentane/ethyl acetate, 4:1). IR (neat): ν = 3424, 2925, 2854, 1467,
= 99.9:0.01, flow rate =
˜
1048 cm–1. [α]20 = –11.4 (c = 1.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 3.76 (dd, J = 12.3, 4.5 Hz, 1 H), 3.61 (dd, J = 12.3,
8.4 Hz, 1 H), 2.86 (d, J = 4.7 Hz, 1 H), 2.65 (d, J = 4.7 Hz, 1 H),
1.97 (br. s, 1 H), 1.81–1.70 (m, 1 H), 1.56–1.41 (m, 1 H), 1.38–1.22
(m, J = 16.8 Hz, 18 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 62.8 (-CH2OH), 59.9 (C), 49.8 (-CH2O),
31.9 (2 C, -CH2), 29.7 (-CH2), 29.6 (2 C, -CH2), 29.5 (2 C, -CH2),
29.3 (-CH2), 24.6 (-CH2), 22.7 (-CH2), 14.1 (-CH3) ppm. HRMS
(ESI): calcd. for C14H29O2 [M + H]+ 229.2168; found 229.2174.
ate, 9:1) to yield 15 as a colorless oil (4.550 g, 90%). Rf = 0.87 (R)-2-[3-(1,3-Dioxan-2-yl)propyl]tridecane-1,2-diol (8): Diol 8 was
(pentane/ethyl acetate, 4:1). IR (neat): ν = 2925, 2854, 1455, 1102,
synthesized according to a published procedure[18] in 90% yield.
˜
1
1054 cm–1. H NMR (400 MHz, CDCl3): δ = 6.12 (d, J = 1.5 Hz, [α]20 = –1.7 (c = 1.1, CH3Cl). 1H NMR (400 MHz, CDCl3): δ =
1 H), 5.50 (d, J = 1.5 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 2.29 (dd, 4.54 (t, J = 5.0 Hz, 1 H), 4.10 (dd, J = 11.5, 4.8 Hz, 2 H), 3.75 (t,
J = 11.2, 4.1 Hz, 2 H), 1.46 (m, 2 H), 1.38–1.16 (m, 18 H), 0.88 (t, J = 11.4 Hz, 2 H), 3.44 (br. s, 2 H), 2.31–1.89 (m, 3 H), 1.60 (dd,
J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.4
J = 13.0, 6.5 Hz, 2 H), 1.53–1.34 (m, 6 H), 1.26 (s, 19 H), 0.88 (t,
(C=O), 141.2 (C), 124.0 (CH2), 60.5 (CH2), 31.9 (CH2), 31.8 (CH2), J = 6.7 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 102.1
29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CHO2), 74.7 (CH2OH), 68.0 (C), 66.9 (2 C, CH2O), 35.8 (CH2),
(CH2), 28.4 (CH2), 22.7 (CH2), 14.2 (CH3), 14.1 (CH3) ppm.
35.5 (CH2), 35.4 (CH2), 31.9 (CH2), 30.2 (CH2), 29.6 (CH2), 29.6
(CH2), 29.3 (CH2), 25.8 (CH2), 23.4 (CH2), 22.7 (CH2), 17.9 (CH2),
14.1 (CH3) ppm. HRMS (ESI): calcd. for C20H41O4 [M + H]+
345.3005; found 345.2995.
HRMS (ESI): calcd. for C16H30O2 [M]+ 254.2236; found 254.2246.
2-Methylenetridecan-1-ol (16): Ethyl 2-methylenetridecanoate (15;
4.535 g, 17.83 mmol) was dissolved in dry THF (50 mL) under an
inert atmosphere in a dry 100-mL round-bottomed flask. The reac-
tion mixture was cooled to –30 °C and DIBAL (25 wt.-% in tolu-
ene, 26.37 mL, 39.23 mmol) was added dropwise over 40 min, and
the reaction mixture was stirred for 1 h. The reaction mixture was
quenched with diethyl ether (5 mL) and a saturated solution of
Rochelle’s salt (50 mL). The reaction mixture was stirred for 14 h
at room temperature. The product was extracted with diethyl ether
(3ϫ100 mL). The combined organic layers were washed with H2O
(100 mL) and brine (100 mL) and dried with anhydrous Na2SO4.
The product was concentrated and purified by silica gel column
chromatography (pentane/ethyl acetate, 9:1) to yield alcohol 16 as
(1R,5S)-1-Undecyl-6,8-dioxabicyclo[3.2.1]octane (18): Diol
8
(0.344 g, 1.0 mmol) and ZrCl4 (0.023 g, 1.0 mmol) were dissolved
in methanol (1.0 mL) and stirred under microwave irradiation at
50 °C at 150 W for 5 min. The reaction progress was monitored by
TLC (pentane/ethyl ether, 9:1). The crude product was concen-
trated in vacuo and purified by silica gel column chromatography
(pentane/ethyl ether, 9:1) to yield 18 as a colorless liquid (0.241 g,
90% yield). Rf = 0.92 (pentane/ethyl ether, 9:1). 1H NMR
(400 MHz, CDCl3): δ = 5.52 (s, 1 H), 3.91 (d, J = 6.8 Hz, 1 H),
3.42 (d, J = 6.8 Hz, 1 H), 1.94–1.78 (m, 1 H), 1.73–1.53 (m, 7 H),
1.46–1.14 (m, 18 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 102.6 (CHO2), 81.2 (C), 72.4 (CH2), 37.0
(CH2), 32.4 (CH2), 31.9 (CH2), 30.9 (CH2), 30.1 (CH2), 29.6 (2 C,
CH2), 29.5 (2 C, CH2), 29.3 (CH2), 24.0 (CH2), 22.7 (CH2), 16.6
(CH2), 14.1 (CH3) ppm. HRMS (ESI): calcd. for C17H32O2 [M]+
268.2402; found 268.2407.
a colorless oil (3.635 g, 96%). Rf = 0.20 (pentane/ethyl acetate, 9:1).
1
IR (neat): ν = 3326, 2925, 2854, 1655, 1469, 1028 cm–1. H NMR
˜
(400 MHz, CDCl3): δ = 5.07–4.95 (m, 1 H), 4.86 (dd, J = 2.5,
1.1 Hz, 1 H), 4.07 (br. s, 2 H), 2.05 (t, J = 8.0 Hz, 2 H), 1.43 (dd,
J = 14.8, 7.2 Hz, 2 H), 1.28 (m, 16 H), 0.98–0.82 (t, J = 8.0 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 149.3 (-C, C=C), 108.9
(-CH2, C=C), 65.9 (-CH2OH), 33.0 (-CH2), 31.9 (-CH2), 29.6 (3
C, -CH2), 29.5 (-CH2), 29.4 (-CH2), 29.3 (-CH2), 27.8 (-CH2), 22.7
(-CH2), 14.1 (-CH3) ppm. HRMS (ESI): calcd. for C14H28O [M]+
212.2140; found 212.2138.
(R)-2-[(Benzyloxy)methyl]-2-undecyloxirane (11): NaH (60% in
mineral oil, 0.117 g, 2.93 mmol) was placed in a dry Schlenk tube
under an inert atmosphere and washed with anhydrous hexanes
(2ϫ2.5 mL) and dried under high vacuum. Dry THF (22 mL) was
added, and the reaction vessel was cooled to 0 °C. (S)-Epoxide 10
(S)-(2-Undecyloxiran-2-yl)methanol (10): Molecular sieves (4 Å, was dissolved in dry THF (2 mL) and added to the reaction mix-
200 mg) and dry CH2Cl2 (5 mL) was taken in a 50-mL two-necked
round-bottomed flask followed by addition of Ti(OiPr)4 (0.14 mL,
ture and stirred for 30 min. Benzyl bromide (0.267 g, 2.25 mmol)
was added dropwise followed by Bu4N+I– (0.416 g, 1.13 mmol).
0.504 mmol) and (+)-diisopropyltartrate (0.16 mL, 0.770 mmol) at The reaction mixture was stirred at 0 °C for 30 min and then at
–35 °C under an atmosphere of nitrogen and stirred for 30 min.
Alcohol 16 was added (1.07 g, 5.04 mmol), the mixture was stirred
for 30 min, and then cumene hydroperoxide (1.15 mL, 7.70 mmol)
was added over 20 min. The reaction temperature was increased to
–25 °C, and the progress of the reaction was monitored by TLC
until the consumption of cumene hydroperoxide. The reaction was
complete in 20 h then quenched with saturated sodium sulfate
(0.5 mL) and ether (5 mL), and the resulting mixture was stirred
room temperature for 1 h. The reaction mixture was quenched with
H2O (5 mL), and the aqueous layer was extracted with diethyl ether
(3ϫ20 mL). The organic layers were combined and washed with
H2O (20 mL) and brine (20 mL) and dried with anhydrous Na2SO4.
The solvent was removed in vacuo, and the crude product was puri-
fied by silica gel column chromatography (pentane/dichlorometh-
ane, 1:1) to yield 11 as a pale yellow oil (0.604 g, 84%). Rf = 0.83
(pentane/ethyl acetate, 4:1). IR (neat): ν = 2925, 2854, 1467,
˜
7102
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7097–7106

Asymmetric Synthesis of (+)-Tanikolide
1098 cm–1. [α]20 = +4.5 (c = 0.5, CHCl3). 1H NMR (400 MHz, H), 2.53–2.41 (m, 2 H), 1.96–1.80 (m, 3 H), 1.77–1.68 (m, 2 H),
CDCl3): δ = 7.38–7.21 (m, 4 H), 4.61–4.50 (m, 2 H), 3.60 (d, J =
11.1 Hz, 1 H), 3.46 (d, J = 11.1 Hz, 1 H), 2.71 (d, J = 4.8 Hz, 1
1.66–1.57 (m, 1 H), 1.26 (br. s, 18 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 171.9, 86.6, 67.5, 36.7, 31.9,
H), 2.64 (d, J = 4.8 Hz, 1 H), 1.85–1.76 (m, 1 H), 1.60–1.51 (m, 1 30.0, 29.8, 29.6 (2 C), 29.5, 29.4, 29.3, 26.6, 23.4, 22.7, 16.7,
H), 1.44–1.19 (m, 18 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR 14.1 ppm.
(101 MHz, CDCl3): δ = 138.1, 128.4, 127.7, 127.6, 73.2, 71.9, 58.7,
(R)-(2-Undecyloxiran-2-yl)methanol (30): (R)-Epoxide 30 was syn-
50.3, 32.0, 31.9, 29.7, 29.6, 29.6, 29.5, 29.5, 29.3, 24.7, 22.7,
thesized according to the same procedure as that outlined for 10
14.1 ppm. HRMS (ESI): calcd. for C21H34O2Na [M + Na]+
by using (–)-DIPT to yield 30 as a colorless oil in 79% yield and
341.2457; found 341.2451.
95%ee based on HPLC analysis of benzyl-protected epoxide 31.
(R)-4-(Benzyloxymethyl)-1-(1,3-dioxan-2-yl)pentadecan-4-ol
Compound 9 was synthesized according to a published pro-
cedure[18] in 85% yield. Rf = 0.12 (pentane/ethyl acetate, 9:1). [α]20
(9): Rf = 0.67 (pentane/ethyl acetate, 4:1). [α]20 = +13.2 (c = 1.0,
CH Cl ). IR (neat): ν = 3424, 2925, 2854, 1467, 1048 cm–1. 1H
˜
2
2
NMR (300 MHz, CDCl3): δ = 3.77 (dd, J = 12.2, 4.2 Hz, 1 H),
3.64 (dd, J = 12.2, 8.5 Hz, 1 H), 2.88 (d, J = 4.7 Hz, 1 H), 2.66 (d,
J = 4.7 Hz, 1 H), 1.84–1.71 (m, 1 H), 1.64 (dd, J = 8.5, 4.4 Hz, 1
H), 1.59–1.45 (m, 1 H), 1.42–1.20 (m, 18 H), 0.88 (t, J = 6.7 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 62.8, 59.9, 49.8, 31.9,
1
= –1.1 (c = 2.8, CH3Cl). H NMR (400 MHz, CDCl3): δ = 7.37–
7.23 (m, 5 H), 4.53 (s, 2 H), 4.50 (t, J = 5.2 Hz, 1 H), 4.09 (dd, J
= 10.8, 4.9 Hz, 2 H), 3.74 (td, J = 12.4, 2.0 Hz, 2 H), 3.32 (s, 2 H),
2.18 (s, 1 H), 2.13–1.99 (m, 1 H), 1.62–1.53 (m, 2 H), 1.52–1.32 (m,
7 H), 1.31–1.19 (m, 18 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR 31.9, 29.7, 29.6, 29.6, 29.5, 29.5, 29.3, 24.6, 22.6, 14.1 ppm. HRMS
(101 MHz, CDCl3): δ = 138.2, 128.3, 128.1, 127.7, 127.6, 127.6, (ESI): calcd. for C14H28O2Na [M + Na]+ 251.1987; found 251.1984.
102.2, 75.6, 73.9, 73.4, 66.9, 36.5, 36.3, 35.6, 31.9, 30.3, 29.7, 29.6,
(S)-2-[(Benzyloxy)methyl]-2-undecyloxirane (31): The synthesis of
29.3, 25.8, 23.4, 22.7, 18.0, 14.1 ppm.
31 was carried out according to the same procedure as that outlined
(R)-2-(Benzyloxymethyl)-6-methoxy-2-undecyltetrahydro-2H-pyran for 11 to yield the product as a pale yellow oil in 87% yield. Rf =
(7b): Diol 9 (0.434 g, 1.00 mmol) and ZrCl4 (0.023 g, 0.10 mmol) 0.83 (pentane/ethyl acetate, 4:1). [α]20 = –3.8 (c = 1.0, CH2Cl2). IR
were dissolved in anhydrous methanol (1.0 mL) and stirred under
microwave irradiation at 50 °C at 150 W for 5 min. The reaction
progress was monitored by TLC (pentane/ethyl ether, 9:1). The
crude product was concentrated in vacuo and purified by silica gel
column chromatography (pentane/ethyl ether, 9:1) to yield acetal
7b as a colorless liquid (0.331 g, 85% yield). Rf = 0.92 (pentane/
ethyl ether, 9:1). [α]20 = –16.2 (c = 2.2, CH3Cl). 1H NMR
(400 MHz, CDCl3): δ = 7.37–7.24 (m, 5 H), 4.62 (dd, J = 6.6,
2.7 Hz, 0.33 H), 4.59 (dd, J = 5.7, 2.9 Hz, 0.67 H), 4.56 (d, J =
1.3 Hz, 0.67 H), 4.54 (d, J = 2.8 Hz, 1.34 H), 3.49 (s, 1 H), 3.43 (s,
0.67 H), 3.42 (s, 1.34 H), 3.41 (s, 2 H), 1.96–1.39 (m, 9 H), 1.27
(br. s, 17 H), 0.89 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3, major diastereomer): δ = 138.7, 128.2 (2 C), 127.5 (3 C),
98.2 (O-CHOMe), 76.5 (CH2OBn), 74.1 (OCH2Ph), 73.3 (qC), 55.5
(OMe), 31.9, 30.8, 30.6, 30.3, 29.7 (2 C), 29.6 (4 C), 29.4 (2 C),
22.7, 14.2 ppm. 13C (100 MHz, CDCl3, minor diastereomer): δ =
138.6, 128.3 (2 C), 127.5 (1 C), 127.4 (2 C), 98.6 (O-CHOMe), 76.7
(CH2OBn), 73.4 (OCH2Ph), 72.1 (qC), 55.5 (OMe), 38.1, 30.3,
30.1, 29.7 (4 C), 29.6 (2 C), 23.4, 22.7 (2 C), 16.7, 16.5 ppm.
(neat): ν = 2925, 2854, 1467, 1098 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 7.38–7.24 (m, 5 H), 4.56 (q, J = 12.0 Hz, 2 H), 3.60
(d, J = 11.1 Hz, 1 H), 3.47 (d, J = 11.1 Hz, 1 H), 2.70 (d, J =
4.9 Hz, 1 H), 2.63 (d, J = 4.8 Hz, 1 H), 1.87–1.74 (m, 1 H), 1.62–
1.49 (m, 1 H), 1.42–1.20 (m, 18 H), 0.88 (t, J = 6.6 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 138.07, 128.36, 127.67, 127.65,
73.23, 71.90, 58.64, 50.29, 31.97, 31.91, 29.73, 29.63, 29.61, 29.53,
29.51, 29.33, 24.66, 22.68, 14.11 ppm. HRMS (ESI): calcd. for
C21H34O2Na [M + Na]+ 341.2457; found 341.2443.
2-(2-Bromopropyl)-1,3-dioxane (22): Anhydrous acetonitrile
(50 mL) was added to a 250-mL round-bottomed flask under an
atmosphere of nitrogen and cooled to 0 °C. Crotonaldehyde
(4.14 mL, 50.0 mmol) was added followed by the dropwise addition
of TMSBr (4.50 mL, 60.0 mmol), and the reaction mixture was
stirred for 5 min prior to the dropwise addition of propane-1,3-diol
(9.18 mL, 60.0 mmol). The reaction mixture was stirred for 2.5 h
at 0 °C then warmed to room temperature and quenched into a
solution of pentane (150 mL) and Na2CO3 (50 mL, 10% solution).
The solution was stirred for 5 min and added to a separating fun-
nel. Three layers were observed, the top layer containing pentane
and the product, the middle layer containing CH3CN and the prod-
uct, and the bottom aqueous layer. The aqueous layer was run off
(R)-6-(Benzyloxymethyl)-6-undecyltetrahydropyran-2-one
(19):
Benzyl-protected (+)-tanikolide 19 was synthesized according to a
published procedure[19] in 83% yield. Rf = 0.92 (pentane/ethyl acet-
1
ate, 0.85:0.15). H NMR (400 MHz, CDCl3): δ = 7.39–7.23 (m, 5 and extracted with pentane (10 mL) and sodium thiosulfate
H), 4.54 (d, J = 2.4 Hz, 2 H), 3.46 (d, J = 1.6 Hz, 2 H), 2.52–2.36 (50 mL, 10% w/v). The organic fractions were combined, washed
(m, 2 H), 2.03–1.95 (m, 1 H), 1.93–1.83 (m, 1 H), 1.81–1.61 (m, 4
with water (3ϫ60 mL), and dried with anhydrous Na2SO4. Excess
H), 1.45–1.18 (m, 18 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR pentane was removed under moderate vacuum (≈850 mbar, 40 °C),
(101 MHz, CDCl3): δ = 171.6, 137.9, 128.4 (2 C), 127.7, 127.6 (2
C), 84.9, 74.2, 73.6, 38.1, 31.9, 29.9 (2 C), 29.6 (2 C), 29.5 (2 C),
29.3, 27.9, 22.9, 22.7, 16.8, 14.1 ppm.
and the remaining yellow solution was purified by high-vacuum
distillation (bath temperature 120 °C, neck temperature 86 °C) and
silica gel column chromatography (pentane/ethyl acetate, 9:1) to
yield bromine 22 as a colorless liquid (8.905 g, 85%). Rf = 0.83
(+)-Tanikolide (1): Protected lactone 19 (0.187 g, 0.50 mmol) was
dissolved in ethyl acetate (2 mL) and Pd(OH)2/C (20 mg,
0.14 mmol, 20 wt.-%) was then added. The reaction vessel was
placed in a Parr reactor under 20 bar H2 pressure for 24 h. The
reaction was monitored by TLC (pentane/ethyl acetate, 85:15) and
vanillin stain visualization. When product formation was complete,
the crude product was run through a small silica gel column (ethyl
acetate) to yield 1 as a colorless oil (0.140 g, 97% yield). Rf = 0.05
(pentane/ethyl acetate, 85:15). [α]20 = +2.9 (c = 0.65, CH3Cl) {ref.[1]
[α]20 = +2.3 (c = 0.65, CH3Cl)}. 1H NMR (400 MHz, CDCl3): δ =
3.70–3.62 (m, 1 H), 3.55 (dd, J = 11.8, 4.4 Hz, 1 H), 2.58 (br. s, 1
(pentane/ethyl acetate, 9:1). IR (neat): ν = 2966, 2856, 1379,
˜
1339 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.74 (dd, J = 7.1,
3.5 Hz, 1 H), 4.29–4.19 (m, 1 H), 4.15–4.05 (m, 2 H), 3.84–3.75 (m,
2 H), 2.16–1.97 (m, 3 H), 1.72 (d, J = 6.8 Hz, 3 H), 1.39–1.32 (m,
1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 100.7, 66.9, 66.9,
46.1, 45.6, 26.8, 25.8 ppm. HRMS (ESI): calcd. for C7H13O279Br
[M]+ 208.0099 and C7H13O281Br [M]+ 210.0078; found 208.0099
and 210.0079, respectively.
(R)-4-(Benzyloxymethyl)-1-(1,3-dioxan-2-yl)-3-methylhexadecan-5-
ol (24): Alcohol 24 was synthesized according to a published pro-
Eur. J. Org. Chem. 2011, 7097–7106
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7103

R. Doran, L. Duggan, S. Singh, C. D. Duffy, P. J. Guiry
FULL PAPER
cedure[18] in 64% yield as a colorless oil. Rf = 0.12 (pentane/ethyl
1.71–1.56 (m, 3 H), 1.44–1.18 (m, 18 H), 0.96 (d, J = 6.4 Hz, 3 H),
acetate, 9:1). IR (neat): ν = 3483, 2925, 2853, 1455, 1143, 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
˜
1
1100 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H), 171.5, 137.8, 128.4, 127.8, 127.7, 127.6, 84.6, 73.9, 73.5, 39.2, 38.3,
4.60–4.48 (m, 3 H), 4.08 (dd, J = 11.5, 4.3 Hz, 2 H), 3.77–3.68 (m,
37.0, 31.9, 29.9, 29.8, 29.7, 29.5, 29.4, 29.3, 23.8, 22.7, 22.6, 22.5,
2 H), 3.36–3.27 (m, 2 H), 2.44 (s, 1 H), 2.13–1.99 (m, 1 H), 1.87 (t,
21.5, 14.1, 1.0 ppm. HRMS (ESI, mixture of 28/29): calcd. for
J = 13.6, 5.5 Hz, 1 H), 1.75–1.44 (m, 6 H), 1.42–1.34 (m, 1 H), C25H41O3 [M + H]+ 389.3050; found 389.3054.
1.34–1.19 (m, 18 H), 0.99 (dd, J = 8.3, 6.8 Hz, 3 H), 0.88 (t, J =
(4R,6R)-6-[(Benzyloxy)methyl]-4-methyl-6-undecyltetrahydro-2H-
6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3, major dia-
stereomer): δ = 138.3, 128.3, 128.3, 127.6, 127.6, 127.5, 101.4, 75.6,
74.3, 73.3, 66.8, 43.7, 43.2, 37.5, 31.9, 30.3, 29.7, 29.6, 29.6, 29.6,
29.3, 25.8, 24.0, 23.6, 22.7, 22.7, 14.1 ppm. 13C NMR (101 MHz,
CDCl3, minor diastereomer): δ = 138.3, 128.3, 128.3, 127.6, 127.6,
127.5, 101.4, 75.9, 74.3, 73.4, 73.3, 66.8, 66.8, 43.5, 43.5, 43.2, 37.4,
31.9, 30.3, 29.7, 29.6, 29.6, 29.6, 29.3, 25.8, 24.0, 23.6, 23.6, 22.7,
22.6, 14.1 ppm. HRMS (ESI): calcd. for C28H49O4 [M + H]+
449.3631; found 449.3624.
pyran-2-one (29): The oxidation of 27 (0.159 g, 0.393 mmol) was
carried out according to the same procedure as that outlined for
28 by using m-chloroperbenzoic acid (0.114 g, Ͻ77%, 0.511 mmol)
and BF3·OEt2 (0.063 mL, 0.511 mmol) to yield 29 (0.118 g, 77%)
as a colorless oil. Rf = 0.51 (pentane/ethyl acetate, 85:15). IR (neat):
ν = 3426, 2925, 2854, 1710, 1458, 1250, 1072 cm–1. [α]20 = –15.9 (c
˜
1
= 1.1, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.29–7.19 (m, 5
H), 4.61–4.50 (m, 2 H), 3.49–3.41 (m, 2 H), 2.60–2.53 (m, 1 H),
2.06–2.02 (m, 1 H), 1.81–1.76 (m, 1 H), 1.73–1.54 (m, 4 H), 1.44–
1.20 (m, 18 H), 1.01 (d, J = 6.1 Hz, 3 H), 0.88 (t, J = 6.9 Hz, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.8, 138.0, 128.4,
127.7, 127.6, 110.0, 85.1, 75.3, 74.1, 73.6, 38.3, 37.7, 36.4, 36.3,
31.9, 30.0, 29.6, 29.6, 29.5, 29.3, 24.1, 23.4, 22.7, 21.3, 14.1,
1.0 ppm. HRMS (ESI, mixture of 28/29): calcd. for C25H41O3 [M
+ H]+ 389.3050; found 389.3054.
(2R,4S)-2-(Benzyloxymethyl)-6-methoxy-4-methyl-2-undecyltetra-
hydro-2H-pyran (26) and (2R,4R)-2-[(Benzyloxy)methyl]-6-methoxy-
4-methyl-2-undecyltetrahydro-2H-pyran (27): Dioxane 24 (0.402 g,
0.924 mmol) and ZrCl4 (0.021 g, 0.093 mmol) were dissolved in
methanol (1.0 mL) and stirred under microwave irradiation at
50 °C at 100 W for 3 min The crude product was concentrated in
vacuo and purified by silica gel column chromatography (pentane/
ethyl acetate, 9:1) to separate the stereoisomers of the C3 chiral
center to yield both 26 (0.143 g, 38%) and 27 (0.159 g, 43%) giving
0.302 g, 81% overall yield as colorless oils. Data for 26: Rf = 0.51
(3S,5R)-3-Methyltanikolide (3): Protected lactone 28 (0.036 g,
0.093 mmol) was dissolved in EtOAc (2 mL) with Pd(OH)2/C
(3.6 mg, 10 wt.-%) and placed in a Parr reactor at 20 bar H2 pres-
sure for 24 h. The reaction was monitored by TLC (pentane/ethyl
acetate, 85:15). The reduction mixture was run through a small
silica gel column (ethyl acetate) to yield 3 (0.028 g, 100%) as an
(pentane/ethyl acetate, 9:1). IR (neat): ν = 2925, 2854, 1455, 1100,
˜
1054 cm–1. [α]20 = –13.2 (c = 0.55, CHCl3). 1H NMR (600 MHz,
CDCl3): δ = 7.35–7.24 (m, 4 H), 4.72 (d, J = 3.6 Hz, 1 H), 4.54 (d,
J = 12.2 Hz, 1 H), 4.46 (d, J = 12.2 Hz, 1 H), 3.70 (d, J = 9.0 Hz,
1 H), 3.52 (d, J = 9.0 Hz, 1 H), 3.36 (s, 3 H), 1.98–1.88 (m, 1 H),
1.79 (d, J = 13.3 Hz, 1 H), 1.70 (d, J = 13.3 Hz, 1 H), 1.61–1.51
(m, 2 H), 1.39–1.14 (m, 19 H), 0.98 (t, J = 13.0 Hz, 1 H), 0.88 (dd,
J = 12.9, 6.6 Hz, 6 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
138.8, 128.2, 128.0, 127.4, 127.4, 99.5, 76.2, 73.2, 72.6, 55.3, 39.8,
39.2, 38.6, 31.9, 30.3, 29.7, 29.7, 29.7, 29.6, 29.3, 22.8, 22.7, 22.3,
20.2, 14.1 ppm. HRMS (ESI): calcd. for C26H44O3Na [M + Na]+
427.3188; found 427.3194. Data for 27: Rf = 0.62 (pentane/ethyl
off-white solid. R = 0.05 (pentane/ethyl acetate). IR (neat): ν =
˜
f
3426, 2925, 2854, 1710, 1458, 1250, 1072 cm–1. [α]20 = –15.8 (c =
0.6, CHCl3). 1H NMR (600 MHz, CDCl3): δ = 3.65 (d, J =
11.6 Hz, 1 H), 3.58 (d, J = 10.6 Hz, 1 H), 2.60 (ddd, J = 17.4, 4.6,
2.3 Hz, 1 H), 2.26–2.16 (m, 1 H), 2.08 (s, 1 H), 1.94–1.87 (m, 2 H),
1.70–1.58 (m, 3 H), 1.43–1.20 (m, 18 H), 1.01 (d, J = 6.5 Hz, 3 H),
0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
171.8, 85.8, 67.9, 38.4, 38.3, 38.2, 37.0, 31.9, 29.9, 29.6, 29.6, 29.5,
29.3, 24.3, 22.9, 22.7, 21.5, 14.1 ppm. HRMS (ESI): calcd. for
C18H34O3Na [M + Na]+ 321.2406; found 321.2391.
acetate, 9:1). IR (neat): ν = 2925, 2854, 1455, 1102, 1054 cm–1
.
˜
[α]20 = +22.5 (c = 1.15, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.37–7.24 (m, 5 H), 4.80 (d, J = 3.2 Hz, 0.33 H), 4.61–4.48 (m, 2.67
H), 3.49–3.39 (m, 4 H), 3.30–3.24 (m, 1 H), 2.10–1.46 (m, 7 H),
1.34–0.97 (m, 18 H), 0.96–0.85 (m, 6 H) ppm. 13C NMR (101 MHz,
CDCl3, major and minor diastereomers): δ = 138.63, 128.23,
128.21, 127.59, 127.42, 127.38, 99.78, 97.68, 77.15, 75.87, 73.44,
55.87, 55.54, 40.31, 39.73, 38.90, 38.83, 31.90, 30.74, 30.43, 30.18,
29.67, 29.63, 29.34, 25.01, 22.68, 22.66, 22.42, 22.15, 14.10 ppm.
HRMS (ESI): calcd. for C26H44O3Na [M + Na]+ 427.3188; found
427.3194.
1
(3R,5R)-3-Methyltanikolide (4): The hydrogenolysis of 29 (0.118 g,
0.304 mmol) was carried out according to the same procedure as
that outlined for acetal 28 by using Pd(OH)2/C (11.8 mg, 10 wt.-
%) to yield 4 (0.091 g, 100%) as an off-white solid Rf = 0.05 (pen-
tane/ethyl acetate, 85:15). IR (neat): ν = 3411, 2925, 2854, 1726,
˜
1458, 1249, 1079 cm–1. [α]20 = +8.3 (c = 0.9, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 3.68 (d, J = 12.0 Hz, 1 H), 3.45 (d, J =
12.0 Hz, 1 H), 2.62 (ddd, J = 17.4, 4.6, 2.0 Hz, 1 H), 2.15–2.05 (m,
1 H), 2.02–1.94 (m, 1 H), 1.80–1.70 (m, 2 H), 1.61–1.55 (m, 3 H),
1.43–1.22 (m, 18 H), 1.04 (d, J = 6.4 Hz, 3 H), 0.88 (t, J = 6.9 Hz,
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.5, 86.6, 67.8,
38.1, 36.5, 34.6, 31.9, 30.0, 29.6, 29.6, 29.5, 29.4, 29.3, 23.8, 23.5,
22.6, 21.4, 14.1 ppm. HRMS (ESI): calcd. for C18H34O3Na [M +
Na]+ 321.2406; found 321.2409.
(4S,6R)-6-(Benzyloxymethyl)-4-methyl-6-undecyltetrahydropyran-2-
one (28): Acetal 26 (0.081 g, 0.201 mmol) was dissolved in dichloro-
methane (10 mL) and cooled to 0 °C. m-Chloroperbenzoic acid
(0.067 g, Ͻ77%, 0.300 mmol) was added followed by BF3·OEt2
(0.032 mL, 0.261 mmol), and the reaction was stirred at room tem-
perature for 30 min. The reaction mixture was cooled back to 0 °C,
quenched slowly with Et3N (0.138 mL, 1.002 mmol), and the excess
amount of solvent was removed in vacuo. The residue was purified
by column chromatography (pentane/ethyl acetate, 85:15) to yield
28 (53 mg, 82%) as a colorless oil.[19] Rf = 0.51 (85:15 pentane/
(2R,4S)-4-[(Benzyloxy)methyl]-1-(1,3-dioxan-2-yl)-2-methylpenta-
decan-4-ol (33) and (2S,4S)-4-[(Benzyloxy)methyl]-1-(1,3-dioxan-2-
yl)-2-methylpentadecan-4-ol (34): Protected epoxide 31 (0.931 g,
2.92 mmol) was treated with the Grignard derivative of 2-(2-bro-
mopropyl)-1,3-dioxane (22) as described previously[18] to yield 33
and 34 as a mixture (1.065 g, 82% yield) of colorless oils. Subse-
quent silica gel column chromatography was carried out on 803 mg
to yield 33 as a colorless oil (0.233 g, 29%) and 34 as a colorless
oil (0.227 g, 28%) and a mixture (0.320 g, 43%) of the two. Data
EtOAc). IR (neat): ν = 2925, 2854, 1455, 1102, 1054 cm–1. [α]20
+13.6 (c = 0.99, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.38–
=
˜
1
7.25 (m, 5 H), 4.63–4.38 (m, 2 H), 3.44 (s, 2 H), 2.60–2.54 (m, 1
H), 2.20–2.10 (m, 1 H), 2.06–1.97 (m, 1 H), 1.92–1.85 (m 1 H), for 33: R = 0.58 (pentane/ethyl acetate, 4:1). IR (neat): ν = 3486,
˜
f
7104
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7097–7106

Asymmetric Synthesis of (+)-Tanikolide
2925, 2853, 1455, 1143, 1100 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.37–7.25 (m, 5 H), 4.59–4.48 (m, 3 H), 4.08 (dd, J = 11.7,
4.2 Hz, 2 H), 3.72 (td, J = 12.2, 2.4 Hz, 2 H), 3.32 (q, J = 9.0 Hz,
(4R,6S)-6-[(Benzyloxy)methyl]-4-methyl-6-undecyltetrahydro-2H-
pyran-2-one (39): Acetals 35/36 as a mixture (0.081 g, 0.201 mmol)
were subjected to the literature procedure[19] to yield 39 (88 mg,
2 H), 2.41 (s, 1 H), 2.13–1.99 (m, 1 H), 1.92–1.80 (m, 1 H), 1.68– 90%) as a colorless oil. Rf = 0.51 (pentane/ethyl acetate, 85:15). IR
1.59 (m, 2 H), 1.56–1.20 (m, 23 H), 1.00 (d, J = 6.7 Hz, 3 H), 0.88 (neat): ν = 2925, 2854, 1739, 1455, 1247, 1092 cm–1. [α]20 = +22.2
˜
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.3,
128.3, 127.6, 127.6, 101.4, 75.7, 74.3, 73.4, 66.8, 66.8, 43.7, 43.3,
37.5, 31.9, 30.3, 29.7, 29.6, 29.6, 29.3, 25.8, 24.0, 23.6, 22.7, 22.6,
14.1 ppm. HRMS (ESI): calcd. for C28H48O4Na [M + Na]+
471.3450; found 471.3460. Data for 34: Rf = 0.58 (pentane/ethyl
(c = 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.25 (m,
5 H), 4.55–4.47 (m, 2 H), 3.44 (s, 2 H), 2.57 (ddd, J = 17.5, 4.8,
2.1 Hz, 1 H), 2.22–2.07 (m, 1 H), 2.05–1.97 (m, 1 H), 1.88 (dd, J
= 17.5, 12.1 Hz, 1 H), 1.72–1.57 (m, 2 H), 1.44–1.19 (m, 19 H),
0.96 (d, J = 6.4 Hz, 3 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
acetate, 4:1). IR (neat): ν = 3486, 2925, 2853, 1455, 1143, (101 MHz, CDCl3): δ = 171.5, 137.8, 128.4, 127.8, 127.6, 84.6, 73.9,
˜
1
1100 cm–1. H NMR (400 MHz, CDCl3): δ = 7.37–7.24 (m, 4 H), 73.5, 39.2, 38.2, 37.0, 31.9, 29.9, 29.6, 29.6, 29.6, 29.5, 29.3, 23.7,
4.60–4.49 (m, 3 H), 4.07 (dd, J = 6.1, 4.7 Hz, 2 H), 3.77–3.66 (m,
2 H), 3.33 (q, J = 9.0 Hz, 2 H), 2.41 (s, 1 H), 2.13–1.99 (m, 1 H),
1.92–1.81 (m, 1 H), 1.74–1.65 (m, 1 H), 1.61–1.20 (m, 24 H), 0.98
(d, J = 6.7 Hz, 3 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 138.4, 128.3, 127.6, 127.5, 101.4, 75.9, 74.3,
73.4, 66.8, 66.8, 43.6, 43.5, 37.4, 31.9, 30.3, 29.7, 29.6, 29.3, 25.8,
24.1, 23.6, 22.7, 22.7, 14.1 ppm. HRMS (ESI): calcd. for
C28H48O4Na [M + Na]+ 471.3450; found 471.3453.
22.7, 22.7, 21.5, 14.1 ppm. HRMS (ESI): calcd. for C25H40O3Na
[M + Na]+ 411.2875; found 411.2892.
(4S,6S)-6-[(Benzyloxy)methyl]-4-methyl-6-undecyltetrahydro-2H-
pyran-2-one (40): Acetals 37/38 as a mixture (0.081 g, 0.201 mmol)
were subjected to the literature procedure[19] to yield 40 (0.082 g,
61%) as a pale yellow oil. Rf = 0.51 (pentane/ethyl acetate, 85:15).
IR (neat): ν = 2925, 2854, 1455, 1102, 1054 cm–1. [α]20 = –23.6 (c
˜
1
= 1.0, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 4
H), 4.55 (q, J = 12.1 Hz, 2 H), 3.47–3.41 (m, 2 H), 2.60–2.52 (m,
1 H), 2.09–1.92 (m, 2 H), 1.82–1.75 (m, 1 H), 1.73–1.53 (m, 2 H),
1.45–1.18 (m, 19 H), 1.01 (d, J = 6.1 Hz, 2 H), 0.88 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.69, 137.99, 128.36,
127.64, 127.56, 85.04, 75.25, 73.57, 38.26, 37.60, 36.37, 31.88,
29.97, 29.59, 29.56, 29.52, 29.42, 29.30, 24.01, 23.33, 22.65, 21.24,
14.07 ppm. HRMS (ESI): calcd. for C25H41O3 [M + H]+ 389.3056;
found 389.3061.
(2S,4R)-2-[(Benzyloxy)methyl]-6-methoxy-4-methyl-2-undecyltetra-
hydro-2H-pyran (35/36): Dioxane 33 (0.203 g, 0.452 mmol) and
ZrCl4 (0.011 g, 0.047 mmol) were dissolved in anhydrous methanol
(0.50 mL) and stirred under microwave irradiation at 50 °C at
100 W for 6 min. The crude product was purified directly by silica
gel column chromatography (pentane/ethyl acetate, 9:1) to yield 35
and 36 as a mixture (0.167 g, 91%) of colorless oils. Rf (35) = 0.89
(pentane/ethyl acetate, 9:1). Rf (36) = 0.80 (pentane/ethyl acetate,
9:1). IR (neat): ν = 2925, 2854, 1455, 1100, 1054 cm–1. [α]20 = –46.4 (3R,5S)-3-Methyltanikolide (5): Protected lactone 39 (0.086 g,
(c = 1.0, CH2Cl2). Data for 35: H NMR (500 MHz, CDCl3): δ = 0.221 mmol) was subjected to the same procedure as that described
˜
1
7.40–7.20 (m, 5 H), 4.73 (d, J = 3.5 Hz, 1 H), 4.55 (d, J = 12.2 Hz, for the preparation of 3 to yield 5 (0.065 g, 98%) as an off-white
1 H), 4.46 (d, J = 12.2 Hz, 1 H), 3.70 (d, J = 9.0 Hz, 1 H), 3.52 (d,
J = 9.0 Hz, 1 H), 3.36 (s, 3 H), 1.99–1.87 (m, 1 H), 1.79 (d, J =
13.4 Hz, 1 H), 1.73–1.67 (m, 1 H), 1.63–1.49 (m, 2 H), 1.37–1.15
(m, 19 H), 0.98 (t, J = 12.9 Hz, 1 H), 0.90–0.84 (m, 6 H) ppm. 13C
solid. R = 0.05 (pentane/ethyl acetate, 85:15). IR (neat): ν = 3426,
˜
f
2925, 2854, 1710, 1458, 1250, 1072 cm–1. [α]20 = +34.2 (c = 1.0,
CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 3.65 (dd, J = 11.5,
2.8 Hz, 1 H), 3.59 (dd, J = 11.5, 5.6 Hz, 1 H), 2.60 (ddd, J = 17.4,
NMR (126 MHz, CDCl3): δ = 138.79, 128.21, 127.44, 127.36, 4.6, 2.3 Hz, 1 H), 2.49 (s, 1 H), 2.29–2.20 (m, 1 H), 1.95–1.87 (m,
99.52, 76.18, 73.19, 72.56, 55.26, 39.77, 39.20, 38.65, 31.92, 30.27, 2 H), 1.70–1.60 (m, 2 H), 1.43–1.19 (m, 19 H), 1.01 (d, J = 6.5 Hz,
29.72, 29.69, 29.67, 29.63, 29.35, 22.78, 22.67, 22.35, 20.17, 3 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
14.09 ppm. HRMS (ESI): calcd. for C26H44O3Na [M + Na]+
427.3188; found 427.3187.
δ = 171.9, 85.9, 67.9, 38.3, 38.3, 37.0, 31.9, 29.9, 29.6, 29.6, 29.5,
29.5, 29.3, 24.23, 22.9 22.6, 21.5, 14.1 ppm. HRMS (ESI, mixture
of 5/6): calcd. for C18H34O3Na [M + Na]+ 321.2406; found
321.2413.
(2S,4S)-2-[(Benzyloxy)methyl]-6-methoxy-4-methyl-2-undecyltetra-
hydro-2H-pyran (37/38): The same synthetic sequence as that de-
scribed for the preparation of 35/36 was carried to yield 37 and 38
as an inseparable mixture (0.197 g, 92%) of colorless oils. Rf (37/
(3S,5S)-3-Methyltanikolide (6): Protected lactone 39 (0.074 g,
0.190 mmol) was subjected to the same procedure as that outlined
for the preparation of 3, however, required a second addition of
catalyst, Pd(OH)2/C (20 wt.-%, 13.4 mg, 0.019 mmol), and the reac-
tion was stirred for a further 8 h under 20 bar H2 pressure. The
reaction mixture was purified directly by silica gel column
chromatography (pentane/ethyl acetate, 1:2) to yield 24 (0.036 g,
63%) as a colorless oil. Rf = 0.05 (pentane/ethyl acetate, 85:15). IR
38) = 0.80 (pentane/ethyl acetate, 9:1). IR (neat): ν = 2925, 2854,
˜
1
1455, 1102, 1054 cm–1. [α]20 = –13.4 (c = 0.8, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 7.36–7.23 (m, 5 H), 4.79 [d, J = 3.6 Hz, 1
H (minor diastereomer)], 4.61–4.48 (m, 3 H), 3.48–3.38 (m, 4 H),
3.31–3.24 (m, 1 H), 2.11–1.98 (m, 1 H), 1.90–1.70 (m, 2 H), 1.66–
1.47 (m, 2 H), 1.43–0.98 (m, 20 H), 0.96–0.85 (m, 6 H) ppm. 13C
NMR (126 MHz, CDCl3, major diastereomer): δ = 138.67 (Ar qC),
128.23, 128.20, 127.59, 127.42, 127.38, 97.70 (O-CHOMe), 77.17
(qC), 75.93 (CH2OBn), 73.46, 55.83 (OCH3), 40.32 [O(qC)-
CH2C10H21], 39.75 (ring CH2), 31.91, 30.80 (ring CH2), 30.44,
30.19, 29.67, 29.65, 29.63, 29.34, 25.02 (CH3CH), 24.41, 22.67,
22.14 (ring CH3), 14.09 (nCH3) ppm. 13C NMR (126 MHz, CDCl3,
minor diastereomer): δ = 138.69 (Ar qC), 128.23, 128.20, 127.59,
127.42, 127.38, 99.80 (O-CHOMe), 77.21 (qC), 76.41 (CH2OBn),
73.46, 55.54 (OCH3), 38.93 (ring CH2), 38.90 (ring CH2), 35.21
[O(qC)CH2C10H21], 31.91, 30.44, 30.19, 29.67, 29.65, 29.63, 29.34,
24.41, 22.67, 22.42 (ring CH3), 19.69 (CH3CH), 14.09 ppm. HRMS
(ESI): calcd. for C26H44O3Na [M + Na]+ 427.3188; found 427.3183.
(neat): ν = 3411, 2925, 2854, 1726, 1458, 1249, 1079 cm–1. [α]20
=
˜
–21.4 (c = 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 3.68 (d,
J = 11.9 Hz, 1 H), 3.45 (d, J = 12.0 Hz, 1 H), 2.60 (ddd, J = 17.3,
4.5, 2.1 Hz, 1 H), 2.42 (s, 1 H), 2.15–2.02 (m, 1 H), 1.98 (dd, J =
17.3, 12.1 Hz, 1 H), 1.78–1.69 (m, 2 H), 1.65–1.52 (m, 2 H), 1.44–
1.20 (m, 18 H), 1.04 (d, J = 6.3 Hz, 3 H), 0.88 (t, J = 6.9 Hz, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.8, 86.7, 67.7, 38.0,
36.6, 34.6, 31.9, 30.0, 29.6, 29.6, 29.5, 29.4, 29.3, 23.8, 23.6, 22.6,
21.3, 14.1 ppm. HRMS (ESI): calcd. for C18H34O3Na [M + Na]+
321.2406; found 321.2403.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all synthetic compounds.
Eur. J. Org. Chem. 2011, 7097–7106
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7105

R. Doran, L. Duggan, S. Singh, C. D. Duffy, P. J. Guiry
FULL PAPER
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R. D. is grateful for the award of an Irish Research Council for
Science, Engineering and Technology (IRCSET) EMBARK Initia-
tive PhD Scholarship, S. S. for a postdoctoral position funded by
the Programme for Research in Third-Level Institutions (PRTLI),
Cycle 4, of the Higher Education Authority, and C. D. for an Ad
Astra Scholarship from University College Dublin. We acknow-
ledge facilities provided by the Centre for Synthesis and Chemical
Biology (CSCB), funded by the Higher Education Authority’s
PRTLI. We would also like to thank Dr. Jimmy Muldoon, Mrs.
Geraldine Fitzpatrick, and Dr. Yannick Ortin for NMR spectra
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Published Online: October 19, 2011
7106
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7097–7106