Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids

Article abstract of DOI:10.1021/acs.joc.7b02510

Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr)₄ afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et₂AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.

Full text of DOI:10.1021/acs.joc.7b02510

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Article
Stereoselective Total Synthesis of Macrophage-produced
Prohealing 14,21-Dihydroxydocosahexaenoic Acids
Keita Nishimura, Tsuyoshi Sakaguchi, Yutaro Nanba, Yuta Suganuma, Masao Morita,
Song Hong, Yan Lu, Bokkyoo Jun, Nicolas G. Bazan, Makoto Arita, and Yuichi Kobayashi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02510 • Publication Date (Web): 11 Dec 2017
Downloaded from http://pubs.acs.org on December 11, 2017
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Stereoselective Total Synthesis of Macrophage-produced Prohealing 14,21-
Dihydroxydocosahexaenoic Acids
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Keita Nishimura,† Tsuyoshi Sakaguchi,† Yutaro Nanba,† Yuta Suganuma,† Masao Morita,†
Song Hong,‡,§ Yan Lu,‡ Bokkyoo Jun,‡ Nicolas G. Bazan,‡,§ Makoto Arita,II,III and Yuichi
Kobayashi*†
† Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho
4259, Midori-ku, Yokohama 226-8501, Japan
‡ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center,
New Orleans, LA 70112, U.S.A.
§ Department of Ophthalmology, Louisiana State University Health Sciences Center, New
Orleans, LA 70112, U.S.A.
II Laboratory for Metabolommics, RIKEN Center for Integrative Medical Sciences, 1-7-22,
Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan
III Division of Physiological Chemistry and Metabolism, Keio University Faculty of
Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
Table of Contents/Abstract Graphic
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ABSTRACT:
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Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible
stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a
C20–C22 fragment (DHA numbering), was converted to the C17–C22 phosphonium salt,
which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12–C16 part
with the TMS and TBS-oxy groups at C12 and C14, yielding the C12–C22 derivative with
14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the
TBS-deprotected allylic alcohol with L-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol
and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was
introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was
also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL
afforded the key aldehyde corresponding to the C11–C22 moiety. The Wittig reaction of
this aldehyde with a phosphonium salt of the remaining C1–C10 part followed by
functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99%
ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated
that each of these two 14,21-diHDHAs synthesized using the presented total organic
synthesis was highly stereoselective and is identical to the macrophage-produced
counterpart.
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INTRODUCTION
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Dihydroxydocosahexaenoic acid (14,21-diHDHA) is a novel endogenous derivative of
docosahexaenoic acid (DHA) by macrophages and in wounded skin.1,2 12-Lipoxygenase and
cytochrome P450 are enzymes that catalyze the oxidation at the C14 and C21 carbons of
DHA, respectively. Four possible stereoisomers have been detected by chiral liquid
chromatography/mass spectrometry using 14S,21R/S- and 14R,21R/S-isomers as references,
which were, in turn, synthesized by incubating 14S- and 14R-hydroxy-DHA with P450.
Among the isomers, the 14S,21R-isomer was the major component and promoted wound
healing in wounded macrophages and skin.1b These results suggest that 14S,21R- or 14,21-
diHDHA will be a lead compound in the development of novel therapeutic drugs for
ameliorating wound healing impaired by diabetes1b or ethanol intoxication/exposure2 as well
as aging and/or other diseases.3 Formation of the 14S,21R-isomer has also been found from
peripheral blood4 and leucocytes.5 During the investigation, the 14R,21R/S-isomer was found
to be as efficient as the 14S-isomer in promoting splinted excisional-wound closure.1a
However, the biological properties and potency of these stereoisomers in pure forms have
not been assessed thus far. Since the 14S,21R-diHDHA, even though it is the most abundant
of the four stereoisomers, has been obtained only in minute quantity by the enzymatic
synthesis followed by chromatographic separation, organic synthesis of the isomers is
required for supplying them for further investigation. In this report, we established for the
first time, the stereoselective synthesis of 14S,21R-diHDHA and 14S,21S-diHDHA. We also
verified the stereochemistry of these diastereomers using aqueous reversed-phase chiral lipid
chromatography coupled with ultraviolet spectrometry and tandem mass spectrometry
(acLC-UV-MS/MS) and macrophage-produced counterparts of these diastereomers
following the methodology we previously established.1–3
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Figure 1. Two stereoisomers among possible four of 14,21-diHDHA.
To develop a method for the synthesis of the four possible stereoisomers of 14,21-
diHDHA, we chose 14S,21R-diHDHA (1a) and 14S,21S-diHDHA (1b) as the synthetic
targets (Figure 1). These are diastereomeric to each other, while the remaining two are
enantiomers thereof. Retrosynthesis of 1a delineated in Scheme 1 disconnected the C10–
C11 double bond to phosphonium salt 2 and aldehyde 3. Allylic alcohol 4, a diastereomeric
mixture at C14, was envisaged to afford 3 by Sharpless asymmetric epoxidation6 using L-
(+)-DIPT/Ti(O-i-Pr)4 followed by the addition of a formyl group to the resulting epoxide
through a reaction with Et2AlCN.7 This intermediate 4 was disconnected in two ways: (1)
via Castro–Stephens coupling8 of acetylene 5 with bromide 6; and (2) via Wittig reaction of
aldehyde 7 with phosphonium salt 8. Compounds 6 and 8 would be synthesized from (R)-3-
butyn-2-ol and (R)-lactate, respectively. A similar disconnection of 1b reached (S)-
enantiomers. Both the enantiomers are commercially available. Meanwhile, the use of D-
(–)-DIPT/Ti(O-i-Pr)4 for the Sharpless asymmetric epoxidation would surely furnish R
chirality on the C14 carbon for the synthesis of the remaining 14R-isomers of 14,21-
diHDHA. Since the TBDPS-oxy group on the C21 stereogenic carbon is a large substituent,
influence of the group on the construction of the diastereoisomeric R or S stereogenic center
at C14 was a concern. In the following paragraphs, we will discuss the synthesis of 1a and
1b and the results associated with the substituent.
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Scheme 1. Retrosynthetic Analysis of 1a
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RESULTS AND DISCUSSION
The synthesis of 4 was first studied using the Castro–Stephens coupling of acetylene 5 with
bromide rac-6 under the conditions of Spinella9 with modification (Bu4NI instead of NaI),
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which gave a mixture of 11 (<25% yield) and unidentified compounds (Scheme 2).
Attempted couplings of TBS ether 9 and the α-ethoxyethyl (EE) ether 10 with rac-6 were
also unsuccessful. In contrast, the coupling of 5 with bromo alcohol 14, the alcohol version
of rac-6, proceeded smoothly to afford 17 in 77% yield. Other bromides 15 and 16
underwent coupling with 5 as well. These results clearly indicated the reason for the
unsuccessful coupling using rac-6. The incompatibility of the TBDPS group with the
Castro–Stephens coupling will be informative in organic synthesis. The hydroxyl groups in
diol 17 cannot be discriminated for a further transformation to 4, while two steps of
protection/deprotection are necessary for the modified synthesis of 4 using 14. With these
inconvenient steps in mind, we decided to move on to the other synthesis of 4.
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Scheme 2. Unsuccessful Castro-Stephens Coupling
Silyl ether 20 obtained from commercially available methyl (R)-lactate (>97% ee, TCI)
was converted to aldehyde 21 (Scheme 3), which was subjected to a Wittig reaction with
2210 using NaHMDS as a base. Subsequently, deprotection of the TBS group afforded cis
olefin alcohol 23 as a sole product in 88% yield from ester 20. This product was then
converted to phosphonium salt 8 in good yield via iodide 24.
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Scheme 3. Synthesis of Phosphonium Salt 8
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As delineated in Scheme 4, the DIBAL reduction of ester 25, prepared from propargyl
alcohol in four steps,11 gave aldehyde 7, which upon a Wittig reaction with the ylide
derived from 8 and NaHMDS afforded 26 stereoselectively. Attempts to remove the TBS
group in 26 using PPTS in MeOH at ca. 40 °C gave a mixture of 4, the corresponding diol,
and unreacted 26 in varying ratios, whereas CAN12 produced 4 in steady yields; however,
though a small quantity of the diol and 26 was detected by TLC in every run.
Scheme 4. Synthesis of Intermediate 4
Epoxidation of 4 (diastereomeric mixture at C14) with L-(+)-DIPT/Ti(O-i-Pr)4
proceeded under the reported conditions6a,b to afford 27 and 28 in 39% and 42% yields with
>99% diastereomeric excess (de) for both products (Scheme 5). These results indicated that
the kinetic resolution was not affected by the TBDPS-oxy substituent. Silylation of 27 with
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TBSOTf13 followed by reaction with Et2AlCN afforded nitrile 29 in 87% yield via the
epoxide ring opening by CN– followed by Peterson-type olefination. The other product 28
was also converted to nitrile 29 in five steps, which started with epoxidation using D-(–)-
DIPT/Ti(O-i-Pr)4 to afford 30 in 87% yield. Subsequently, Mitsunobu inversion delivered
alcohol 31 in 86% yield. Protection of 31 with TBSOTf13 and the subsequent reaction with
Et2AlCN produced nitrile 29 in 72% yield (two steps), an almost same yield as that
obtained from 27. Finally, reduction of the nitrile with DIBAL furnished aldehyde 3 in 94%
yield.
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Scheme 5. Synthesis of Aldehyde 3 via Nitrile 29
Phosphonium intermediate 2 was synthesized by a sequential method depicted in stages
1 and 2 of Scheme 6. Briefly, alkylation of bromide 33 with acetylene 34 and LiNH2 in
liquid NH3 afforded 35 in 80% yield (stage 1). Since the attempted semi-hydrogenation of
35 to 36 using commercial Pd/CaCO3 (poisoned with Pb) was competitive with over-
reduction, the catalyst was further deactivated with quinoline in EtOAc to produce 36
selectively. Iodination of 36 followed by a reaction with PPh3 in MeCN proceeded
smoothly, giving 38 in good yield. In stage 2, aldehyde 39 derived from propane-1,3-diol in
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two steps (TBDPSCl; PCC) underwent a Wittig reaction with 38/NaHMDS to produce 40
stereoselectively. Among the two silyl groups, the TBDPS group was removed selectively
using TBAF/AcOH (0.3 equiv)14 to give alcohol 41 in 58% yield from aldehyde 39. Finally,
iodination followed by reaction with PPh3 afforded 2 in a good yield.
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Scheme 6. Synthesis of Phosphonium Salt 2
As summarized in Scheme 7, the whole structure of 1a was constructed by the Wittig
reaction of aldehyde 3 with 2 using NaHMDS as a base. The resulting silyl ether 43 was
exposed to PPTS in MeOH to afford alcohol 44 site selectively in 50% yield from aldehyde
3. The oxidation of 44 gave acid 45 in 55% yield in two steps. Finally, deprotection of the
silyl groups furnished 1a in high yield. The structure of 1a was supported by 1H, 13C, and
13C–APT NMR spectra (APT: attached proton test), IR and UV spectra, and HRMS. High
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purity of the olefins constructed by Wittig reaction was confirmed by the 1H and 13C NMR
spectra of 1a as well as precursors 44 and 45. Furthermore, acLC-UV-MS/MS
chromatogram and spectrum were in agreement with macrophage-produced 14S,21R-
diHDHA (Figure 2).
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Scheme 7. Synthesis of 14S,21R-diHDHA (1a)
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Figure 2. acLC-UV-MS/MS chromatogram and spectra.a
a The acLC-MS/MS chromatogram (m/z 253.3 of MS/MS m/z 359.3, left) and spectrum
(full scan MS/MS of m/z 359.3, right). Left insert: acLC-UV spectrum. Right insert: the
interpretation of MS/MS fragmentation). Parent or molecular ion: M–H+ = 359.3. (A) 1a
(chemically-synthesized 14S,21R-diHDHA). (B) 1b (chemically-synthesized 14S,21S-
diHDHA). (C) Macrophage-produced four 14,21-diHDHA diastereomers (i.e., 14R,21R-,
14R,21S-, 14S,21R-, and 14S,21S-diHDHA).1a,b,3a
The synthesis of 14S,21S-diHDHA (1b) is summarized in Scheme 8, in which ent-4 was
the key intermediate. First, TBDPS ether 46 derived from ethyl (S)-lactate (TCI, >99% ee
by 1H NMR analysis of the derived MTPA ester) was converted to ent-8 in an overall yield
similar to that calculated for 8. The Wittig reaction of 7 with ent-8 followed by the
deprotection of TBS ether 47 with CAN furnished alcohol ent-4 in 62% yield over two
steps. The asymmetric epoxidation of ent-4 with L-(+)-DIPT/Ti(O-i-Pr)4 afforded ent-30
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and 48 in 41% and 42% yields, respectively, and with >99% de for both products after
chromatography on silica gel. The observed yield and de were comparable to those for 27
and 28 (Scheme 5), indicating that the asymmetric epoxidation was little affected by the
TBDPS-oxy group at C21. The silylation of epoxy alcohol ent-30 with TBSOTf gave
epoxide 49, which was then transformed to aldehyde 51 in 45% yield through nitrile 50.15
The Wittig reaction of aldehyde 51 with 2 followed by the selective desilylation of the TBS
group afforded primary alcohol 52, which was converted to acid 53 by oxidation. Finally,
desilylation gave 14S,21S-diHDHA (1b) in 30% yield from aldehyde 51 over five steps.
The spectral data (1H and 13C NMR, 13C–APT NMR, IR, and UV) as well as HRMS of 1b
were in agreement with the structure. High purity of the olefins constructed by Wittig
reaction was confirmed by the 1H and 13C NMR spectra of 1b as well as precursors 52 and
53. Moreover, the acLC-UV-MS/MS chromatogram and spectrum of 1b were in agreement
with macrophage-produced 14S,21R-diHDHA (Figure 2).1a,b,3a
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Scheme 8. Synthesis of 14S,21S-diHDHA (1b)
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Comparison of the 1H and 13C NMR spectra of two diastereomer sets, i.e., 1a vs. 1b and
their silyl ethers 45 vs. 54, revealed diagnostic absorbance in the former set as shown below
in Table 1, whereas the spectra of the silyl ethers are superimposed each other. Thus, the
characteristic absorbance of 1a and 1b are useful for the determination of the
stereochemistry at C14 and C21 of the 14,21-diHDHA diastereomers. Furthermore, the
signs of the observed specific rotations of 1a and 1b are opposite, and the rotations would
be useful for determination of the absolute configuration of 14,21-diHDHA that will be
isolated from natural sources: 1a, [α]D20 +19 (c 0.56, CHCl3); 1b, [α]D19 –24 (c 0.70,
CHCl3). Furthermore, 1a and 1b were distinguished by acLC-UV-MS/MS, and their acLC-
UV-MS/MS chromatograms and spectra were in agreement with those of the same
diastereomer produced by macrophages (Figure 2).1a,b,3a
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Table 1. Diagnostic NMR Spectra and [α]D Values of 1a and 1b
1a
1b
1H NMR spectraa
4.20–4.28 (m, 1 H) ppm
4.38–4.45 (m, 1 H) ppm
13C NMR spectrab,c 35.5, 72.0, 125.5 ppm
34.8, 71.5, 124.9 ppm
[α]D value
[α]D20 +19 (c 0.56, CHCl3) [α]D19 –24 (c 0.70, CHCl3)
a400 MHz in CDCl3. b100 MHz in CDCl3. cΔδ of >0.5 ppm.
CONCLUSION
A method for the synthesis of diastereomers 1a and 1b was developed. The C14
stereocenter was secured by the Sharpless asymmetric epoxidation, while the C21 center
was derived from commercially available (R)- and (S)-lactates. This method is surely
applicable to the synthesis of the remaining stereoisomers (enantiomers of 1a and 1b).
Diagnostic absorbance of 1a and 1b in the 1H and 13C NMR spectra was found, and the
observed [α]D values were different from each other. Moreover, the acLC-UV-MS/MS
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study indicated that the structures of 1a and 1b were in agreement with macrophage-
produced 14S,21R- and 14S,21S-diHDHA, respectively. These data will be useful for the
elucidation of the stereochemistry of 14,21-diHDHA newly isolated from cells and tissues.
Furthermore, the method would spur the biological investigation and development of drugs
against impaired wound healing.
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EXPERIMENTAL SECTION
General Remarks. The 1H (300 or 400 MHz) and 13C NMR (75 or 100 MHz)
spectroscopic data were recorded in CDCl3 using Me4Si (δ = 0 ppm) and the centerline of
the triplet (δ = 77.1 ppm), respectively, as internal standards. Signal patterns are indicated
as br s (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet).
Coupling constants (J) are given in Hertz (Hz). Chemical shifts of carbons are accompanied
by minus (for C and CH2) and plus (for CH and CH3) signs of the attached proton test
(APT) experiments. High-resolution mass spectroscopy (HRMS) was performed with a
double-focusing mass spectrometer with an ionization mode of positive FAB or EI as
indicated for each compound. The solvents that were distilled prior to use are THF (from
Na/benzophenone), Et2O (from Na/benzophenone), and CH2Cl2 (from CaH2). After the
reactions were completed, the organic extracts were concentrated by using an evaporator,
and then the residues were purified by chromatography on silica gel (Kanto, spherical silica
gel 60N).
(R,Z)-5-[(tert-Butyldiphenylsilyl)oxy]hex-3-en-1-ol (23). A solution of methyl
lactate (>97% ee, 0.95 mL, 10.0 mmol), TBDPSCl (3.40 mL, 13.1 mmol), and imidazole
(1.03 g, 15.1 mmol) in DMF (50 mL) was stirred at rt for 10 h and diluted with saturated
NaHCO3. The resulting mixture was extracted with EtOAc three times. The combined
extracts were washed with brine, dried over MgSO4, and concentrated. The residue was
purified by chromatography on silica gel (hexane/EtOAc) to afford silyl ether 20 (3.39 g,
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98%): liquid; Rf 0.67 (hexane/EtOAc 3:1).
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To a solution of ester 20 (1.36 g, 3.97 mmol) in CH2Cl2 (20 mL) cooled to –78 °C was
added a solution of DIBAL (1.02 M in hexane, 4.90 mL, 5.00 mmol) dropwise. The
solution was stirred at –78 °C for 1.5 h and poured to a mixture of H2O (2.0 mL, 110 mmol)
and NaF (3.20 g, 76.2 mmol). The resulting mixture was stirred at rt for 30 min and filtered
through a pad of Celite. The filtrate was concentrated to afford aldehyde 21, which was
used for the next reaction without further purification: liquid; Rf 0.49 (hexane/EtOAc 10:1).
To an ice-cold suspension of phosphonium salt 22 (2.56 g, 4.97 mmol) in THF (30 mL)
was added a solution of NaHMDS (1.0 M in THF, 4.30 mL, 4.30 mmol). The mixture was
stirred at 0 °C for 1 h and cooled to –90 °C (liquid N2 + hexane). A solution of the above
aldehyde 21 in THF (4 mL) was added to the mixture. The mixture was allowed to warm to
0 °C gradually over 4.5 h and diluted with saturated NH4Cl. The resulting mixture was
extracted with EtOAc three times. The combined extracts were washed with brine, dried
over MgSO4, and concentrated to afford TBS ether of 23, which was used for the next
reaction without further purification: liquid; Rf 0.74 (hexane/EtOAc 10:1).
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A mixture of the above product and PPTS (955 mg, 3.80 mmol) in MeOH (30 mL) was
stirred at rt for 14 h, diluted with brine, and concentrated to remove most of MeOH. The
resulting mixture was extracted with EtOAc three times. The combined extracts were dried
over MgSO4 and concentrated. The residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford alcohol 23 (1.24 g, 88% over three steps): liquid; Rf 0.29
(hexane/EtOAc 5:1); [α]D25 –18 (c 1.07, CHCl3); IR (neat) 3326, 1111, 703 cm –1; 1H NMR
(400 MHz, CDCl3) δ 1.04 (s, 9 H), 1.18 (d, J = 6.4 Hz, 3 H), 1.79–1.98 (m, 2 H), 3.39 (q, J
= 6.4 Hz, 2 H), 4.58 (ddq, J = 8.4, 1.2, 6.4 Hz, 1 H), 5.17 (ddt, J = 11.2, 1.2, 7.4 Hz, 1 H),
5.65 (ddt, J = 11.2, 8.4, 1.6 Hz, 1 H), 7.32–7.45 (m, 6 H), 7.64–7.72 (m, 4 H); 13C–ATP
NMR (100 MHz, CDCl3) δ 19.2 (–), 24.7 (+), 27.0 (+), 31.0 (–), 62.1 (–), 66.0 (+), 123.8
(+), 127.5 (+),127.6 (+), 129.57 (+), 129.63 (+), 134.3 (–), 134.5 (–), 135.9 (+), 136.0 (+),
137.7 (+); HRMS (FAB+) calcd for C22H31O2Si [(M+H)+] 355.2093, found 355.2096.
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(R,Z)-tert-Butyl[(6-iodohex-3-en-2-yl)oxy]diphenylsilane (24). To an ice-cold
solution of alcohol 23 (2.88 g, 8.12 mmol) in CH2Cl2 (50 mL) were added PPh3 (3.25 g,
12.4 mmol), imidazole (855 mg, 12.6 mmol), and I2 (3.31 g, 12.6 mmol). The mixture was
stirred at 0 °C ford 3 h and diluted with aqueous Na2S2O3 with vigorous stirring. The
resulting mixture was extracted with CH2Cl2 three times. The combined extracts were dried
over MgSO4 and concentrated. The residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford iodide 24 (3.68 g, 97%): liquid; Rf 0.80 (hexane/EtOAc 5:1);
[α]D23 –15 (c 1.20, CHCl3); IR (neat) 1112, 702, 613 cm –1; 1H NMR (400 MHz, CDCl3) δ
1.04 (s, 9 H), 1.19 (d, J = 6.2 Hz, 3 H), 2.07–2.23 (m, 2 H), 2.81 (t, J = 7.4 Hz, 2 H), 4.48
(ddq, J = 8.6, 1.2, 6.2 Hz, 1 H), 5.10 (ddt, J = 11.0, 1.2, 7.4 Hz, 1 H), 5.61 (ddt, J = 11.0,
8.6, 1.4 Hz, 1 H), 7.33–7.46 (m, 6 H), 7.62–7.71 (m, 4 H); 13C–ATP NMR (100 MHz,
CDCl3) δ 4.8 (–), 19.2 (–), 24.6 (+), 27.0 (+), 31.4 (–), 66.0 (+), 126.4 (+), 127.5 (+), 127.6
(+), 129.6 (+), 129.7 (+), 134.1 (–), 134.3 (–), 135.86 (+), 135.95 (+), 136.7 (+); HRMS
(FAB+) calcd for C22H29OSiNaI [(M+Na)+] 487.0930, found 487.0931.
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(E)-3-{(tert-Butyldimethylsilyl)oxy}-5-(trimethylsilyl)pent-4-enal (7). To a
solution of ester 25 (2.00 g, 5.58 mmol) in CH2Cl2 (35 mL) was added a solution of DIBAL
(1.02 M in hexane, 7.10 mL, 7.24 mmol) at –78 °C. The solution was stirred at –78 °C for
1.5 h and poured to a mixture of H2O (2.0 mL, 110 mmol) and NaF (2.34 g, 55.7 mmol).
The resulting mixture was stirred at rt for 20 min and filtered through a pad of Celite. The
filtrate was concentrated and the residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford aldehyde 7 (1.46 g, 91%): liquid; Rf 0.49 (hexane/EtOAc 5:1); IR
(neat) 1729, 1250, 839 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3 H), 0.04 (s, 3 H),
0.05 (s, 9 H), 0.87 (s, 9 H), 2.50 (ddd, J = 15.6, 4.8, 2.4 Hz, 1 H), 2.58 (ddd, J = 15.6, 7.2,
2.4 Hz, 1 H), 4.61 (dddd, J = 7.2, 5.2, 4.8, 1.0 Hz, 1 H), 5.88 (dd, J = 18.6, 1.0 Hz, 1 H),
6.00 (dd, J = 18.6, 5.2 Hz, 1 H), 9.75 (t, J = 2.4 Hz, 1 H); 13C–APT NMR (100 MHz,
CDCl3) δ –4.9 (+), –4.2 (+), –1.4 (+), 18.2 (–), 25.8 (+), 51.1 (–), 71.3 (+), 130.3 (+), 147.1
(+), 201.8 (+); HRMS (FAB+) calcd for C14H31O2Si2 [(M+H)+] 287.1863, found 287.1865.
(1E,5Z,8Z,10R)-10-[(tert-Butyldiphenylsilyl)oxy]-1-(trimethylsilyl)undeca-
1,5,8-trien-3-ol (4). A solution of iodide 24 (3.53 g, 7.60 mmol) and PPh3 (3.91 g, 14.9
mmol) in MeCN (76 mL) was heated under reflux for 17 h, cooled to rt, and concentrated.
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The residue was washed with ether six times to afford phosphonium salt 8 (5.04 g, 91%):
solids; 1H NMR (300 MHz, CDCl3) δ 0.95 (s, 9 H), 1.07 (d, J = 6.3 Hz, 3 H), 1.80–2.06 (m,
2 H), 2.99–3.19 (m, 1 H), 3.57–3.78 (m, 1 H), 4.21 (dq, J = 7.2, 6.3 Hz, 1 H), 5.53–5.65 (m,
2 H), 7.18–7.82 (m, 25 H).
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To an ice-cold suspension of phosphonium salt 8 (4.96 g, 6.82 mmol) in THF (46 mL)
was added a solution of NaHMDS (1.0 M in THF, 5.50 mL, 5.50 mmol). The mixture was
stirred at 0 °C for 1.5 h and cooled to –90 °C (liquid N2 + hexane). A solution of aldehyde 7
(1.46 g, 5.09 mmol) in THF (5 mL) was added to the mixture dropwise. The solution was
allowed to warm to rt gradually over 12 h and diluted with saturated NH4Cl. The resulting
mixture was extracted with EtOAc three times. The combined extracts were washed with
brine, dried over MgSO4, and concentrated. The residue was purified by chromatography
on silica gel (hexane/EtOAc) to afford olefin 26 (2.92 g, 94%): liquid; Rf 0.74
(hexane/EtOAc 10:1); 1H NMR (300 MHz, CDCl3) δ –0.002 (s, 6 H), 0.04 (s, 9 H), 0.87 (s,
9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.0 Hz, 3 H), 2.06 (t, J = 6.3 Hz, 1 H), 2.23–2.48 (m, 2 H),
4.00 (dt, J = 5.4, 6.3 Hz, 1 H), 4.58 (dq, J = 8.4, 6.0 Hz, 1 H), 5.07–5.23 (m, 2 H), 5.25–
5.36 (m, 1 H), 5.50 (dd, J = 10.5, 8.4 Hz, 1 H), 5.74 (d, J = 18.6 Hz, 1 H), 5.92 (dd, J =
18.6, 5.4 Hz, 1 H), 7.30–7.45 (m, 6 H), 7.63–7.71 (m, 4 H).
To a solution of olefin 26 (1.20 g, 1.98 mmol) in EtOH (19 mL) was added CAN (1.63
g, 2.97 mmol) at 15 °C. The solution was stirred at 15 °C for 23 h and diluted with
saturated NaHCO3. The resulting mixture was extracted with EtOAc three times. The
combined extracts were washed with saturated NaHCO3, dried over MgSO4, and
concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to
afford alcohol 4 as a diastereomeric mixture (662 mg, 67%): liquid; Rf 0.71 (hexane/EtOAc
3:1); [α]D22 –8 (c 1.07, CHCl3); IR (neat) 3309, 1427, 1248, 1111, 867, 838; 1H NMR (400
MHz, CDCl3) δ 0.07 (s, 9 H), 1.04 (s, 9 H), 1.17 (d, J = 6.0 Hz, 3 H), 1.516 and 1.521 (2 d,
J = 4.4 and 4.4 Hz, 1 H), 2.04–2.18 (m, 2 H), 2.24–2.48 (m, 2 H), 4.00–4.08 (m, 1 H), 4.57
(dq, J = 8.4, 6.0 Hz, 1 H), 5.13 (dtt, J = 10.8, 7.2, 1.2 Hz, 1 H), 5.22–5.35 (m, 2 H), 5.52
(ddt, J = 10.8, 8.4, 1.6 Hz, 1 H), 5.84 (dd, J = 18.8, 1.2 Hz, 1 H), 6.00 (ddd, J = 18.8, 5.2,
0.4 Hz, 1 H), 7.31–7.48 (m, 6 H), 7.63–7.76 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ
–1.2 (+), 19.2 (–), 24.6 (+), 25.9 (–), 27.0 (+), 34.9 (–), 66.0 (+), 73.7 (+), 125.0 (+), 126.1
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(+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 131.0 (+), 134.3 (–), 134.6 (–), 135.3 (+),
135.9 (+), 136.0 (+), 147.6 (+); HRMS (FAB+) calcd for C30H44O2Si2Na [(M+Na)+]
515.2778, found 515.2760.
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(1S,3Z,6Z,8R)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2S,3S)-3-
(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (27). To a solution of Ti(O-i-Pr)4
(0.14 mL, 0.478 mmol) in CH2Cl2 (1.5 mL) at –10 °C was added L-(+)-DIPT (0.12 mL,
0.571 mmol). The solution was stirred at –10 °C for 30 min and cooled to –20 °C. A
solution of allylic alcohol 4 (218 mg, 0.442 mmol) in CH2Cl2 (0.5 mL) was added. The
solution was stirred at –20 °C for 30 min and cooled to –40 °C. A solution of t-BuOOH
(3.50 M in CH2Cl2, 0.21 mL, 0.735 mmol) was added dropwise. After the addition, the
solution was stirred at –18 °C for 6 h, and added Me2S (0.11 mL, 1.5 mmol). The solution
was stirred at –20 °C for 30 min before addition of aqueous 10% tartaric acid (0.27 mL),
NaF (308 mg, 7.33 mmol), and Celite (180 mg). The mixture was vigorously stirred at rt
for 30 min and filtered through a pad of Celite. The filtrate was concentrated and the
residue was diluted with ether (2 mL) and aqueous 10% NaOH (1.6 mL) at 0 °C. The
mixture was vigorously stirred at 0 °C for 20 min and extracted with ether three times. The
combined extracts were dried over MgSO4 and concentrated. The residue was purified by
chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 27 (88 mg, 39%) and
allylic alcohol 28 (91 mg, 42%). Diastereomeric excesses of the epoxy and allylic alcohols
were determined to be >99% and >99% by 1H NMR spectroscopy of the derived MTPA
esters. Epoxy alcohol 27: liquid; Rf 0.43 (hexane/EtOAc 5:1); [α]D20 –9 (c 0.80, CHCl3); IR
(neat) 3449, 1250, 1111, 1078, 842 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 9 H), 1.04
(s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 1.75 (d, J = 2.4 Hz, 1 H), 2.10–2.23 (m, 2 H), 2.30–2.49
(m, 2 H), 2.32 (d, J = 3.6 Hz, 1 H), 2.82 (t, J = 3.6 Hz, 1 H), 3.73–3.79 (m, 1 H), 4.58 (ddq,
J = 8.4, 1.2, 6.4 Hz, 1 H), 5.13 (ddt, J = 10.8, 1.2, 7.6 Hz, 1 H), 5.27 (dtt, J = 10.8, 7.2, 1.6
Hz, 1 H), 5.36 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H), 5.53 (ddt, J = 10.8, 8.4, 2.0 Hz, 1 H), 7.32–
7.45 (m, 6 H), 7.63–7.71 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –3.6 (+), 19.2 (–),
24.6 (+), 25.8 (–), 27.0 (+), 31.6 (–), 47.6 (+), 58.0 (+), 65.9 (+), 69.2 (+), 124.4 (+), 126.0
(+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.7 (+), 134.3 (–), 134.6 (–), 135.4 (+),
135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C30H44O3Si2Na [(M+Na)+] 531.2727, found
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531.2726. Allylic alcohol 28: liquid; Rf 0.57 (hexane/EtOAc 5:1); [α]D19 –5 (c 1.05,
CHCl3); IR (neat) 3327, 1427, 1248, 1110, 866, 838 cm–1; 1H NMR (400 MHz, CDCl3) δ
0.08 (s, 9 H), 1.05 (s, 9 H), 1.17 (d, J = 6.0 Hz, 3 H), 1.59 (br s, 1 H), 2.12 (t, J = 6.0 Hz, 2
H), 2.29–2.49 (m, 2 H), 4.01–4.10 (m, 1 H), 4.58 (dq, J = 8.8, 6.0 Hz, 1 H), 5.14 (dt, J =
10.8, 7.2 Hz, 1 H), 5.24–5.38 (m, 2 H), 5.53 (dd, J = 10.4, 8.8 Hz, 1 H), 5.85 (d, J = 18.8
Hz, 1 H), 6.00 (dd, J = 18.8, 4.8 Hz, 1 H), 7.32–7.45 (m, 6 H), 7.64–7.72 (m, 4 H); 13C–
APT NMR (100 MHz, CDCl3) δ –1.2 (+), 19.2 (–), 24.6 (+), 25.9 (–), 27.0 (+), 34.9 (–),
66.0 (+), 73.7 (+), 125.0 (+), 126.1 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 131.0 (+),
134.3 (–), 134.6 (–), 135.3 (+), 135.9 (+), 136.0 (+), 147.7 (+); HRMS (FAB+) calcd for
C30H43O2Si2 [(M–H)+] 491.2802, found 491.2806.
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(5R,6Z,9Z,12S)-2,2,5,14,14,15,15-Heptamethyl-3,3-diphenyl-12-[(2S,3S)-3-
(trimethylsilyl)oxiran-2-yl]-4,13-dioxa-3,14-disilahexadeca-6,9-diene (TBS
ether of 27). To an ice-cold solution of epoxy alcohol 27 (87 mg, 0.17 mmol) in CH2Cl2
(1.7 mL) were added 2,6-lutidine (0.10 mL, 0.86 mmol) and TBSOTf (0.12 mL, 0.52
mmol). The solution was stirred at 0 °C for 3.5 h and diluted with H2O. The resulting
mixture was extracted with CH2Cl2 three times. The combined extracts were dried over
MgSO4 and concentrated. The residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford TBS ether of 27 (107 mg, 100%): liquid; Rf 0.80 (hexane/EtOAc
5:1); [α]D20 –4 (c 0.93, CHCl3); IR (neat) 1251, 1111, 839 cm–1; 1H NMR (400 MHz,
CDCl3) δ 0.01 (s, 6 H), 0.05 (s, 9 H), 0.86 (s, 9 H), 1.04 (s, 9 H), 1.16 (d, J = 6.4 Hz, 3 H),
2.11–2.26 (m, 2 H), 2.15 (d, J = 3.6 Hz, 1 H), 2.29–2.51 (m, 2 H), 2.68 (dd, J = 5.6, 3.6 Hz,
1 H), 3.43 (q, J = 5.6 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.14 (dt, J = 10.6, 7.6 Hz, 1
H), 5.20 (dt, J = 11.0, 6.8 Hz, 1 H), 5.37 (dt, J = 11.0, 6.8 Hz, 1 H), 5.52 (dd, J = 10.6, 8.4
Hz, 1 H), 7.31–7.44 (m, 6 H), 7.64–7.71 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –
4.6 (+), –4.3 (+), –3.5 (+), 18.2 (–), 19.3 (–), 24.7 (+), 25.87 (+), 25.91 (–), 27.0 (+), 33.7
(–), 49.9 (+), 58.5 (+), 66.0 (+), 73.2 (+), 125.4 (+), 126.3 (+), 127.5 (+), 127.6 (+), 129.5
(+), 129.6 (+), 134.3 (–), 134.7 (–), 135.2 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd
for C36H58O3Si3Na [(M+Na)+] 645.3592, found 645.3575.
(2E,4S,6Z,9Z,11R)-4-[(tert-Butyldimethylsilyl)oxy]-11-[(tert-
butyldiphenylsilyl)oxy]dodeca-2,6,9-trienenitrile (29). To an ice-cold solution of
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TBS ether of 27 (191 mg, 0.307 mmol) in toluene (3 mL) was added a solution of Et2AlCN
(0.67 M in toluene, 1.20 mL, 0.804 mmol). The reaction was carried out at rt for 4 h and
quenched by adding H2O (0.20 mL, 11 mmol), NaF (386 mg, 9.19 mmol), and Celite at
0 °C. The resulting mixture was vigorously stirred at rt for 20 min and filtered through a
pad of Celite. The filtrate was concentrated and the residue was purified by
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chromatography on silica gel (hexane/EtOAc) to afford nitrile 29 (150 mg, 87%): liquid; Rf
0.69 (hexane/EtOAc 5:1); [α]D20 +5 (c 1.33, CHCl3); IR (neat) 2225, 1112, 1083, 837, 703
cm–1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.90 (s, 9 H), 1.05 (s, 9 H),
1.18 (d, J = 6.4 Hz, 3 H), 2.10 (t, J = 6.8 Hz, 2 H), 2.23–2.44 (m, 2 H), 4.22 (ddt, J = 3.6,
2.0, 6.0 Hz, 1 H), 4.56 (dq, J = 8.4, 6.4 Hz, 1 H), 5.12 (dt, J = 10.8, 6.8 Hz, 1 H), 5.23 (dt, J
= 10.8, 6.8 Hz, 1 H), 5.26 (dt, J = 10.8, 6.8 Hz, 1 H), 5.55 (dd, J = 10.8, 8.4 Hz, 1 H), 5.58
(dd, J = 16.0, 2.0 Hz, 1 H), 6.64 (dd, J = 16.0, 3.6 Hz, 1 H), 7.33–7.47 (m, 6 H), 7.65–7.72
(m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –4.83 (+), –4.79 (+), 18.2 (–), 19.2 (–), 24.6
(+), 25.8 (+), 25.9 (–), 27.0 (+), 34.9 (–), 65.9 (+), 71.2 (+), 98.7 (+), 117.5 (–), 123.6 (+),
125.7 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.9 (+), 134.3 (–), 134.5 (–), 135.4
(+), 135.9 (+), 136.0 (+), 156.7 (+); HRMS (FAB+) calcd for C34H49NO2Si2Na [(M+Na)+]
582.3200, found 582.3208.
(1R,3Z,6Z,8R)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2R,3R)-3-
(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (30). To an ice-cold solution of Ti(O-
i-Pr)4 (0.11 mL, 0.37 mmol) in CH2Cl2 (1 mL) was added D-(–)-DIPT (0.09 mL, 0.43
mmol). The solution was stirred at 0 °C for 30 min and cooled to –10 °C. A solution of
allylic alcohol 28 (168 mg, 0.341 mmol) in CH2Cl2 (1 mL) was added. The solution was
stirred at –10 °C for 30 min and cooled to –40 °C. A solution of t-BuOOH (2.96 M in
CH2Cl2, 0.40 mL, 1.18 mmol) was added dropwise. After the addition, the solution was
stirred at –18 °C for 24 h, and Me2S (0.15 mL, 2.0 mmol) was added. The solution was
stirred at –18 °C for 30 min before addition of aqueous 10% tartaric acid (0.1 mL), NaF (98
mg, 2.3 mmol), and Celite (60 mg). The mixture was vigorously stirred at rt for 30 min and
filtered through a pad of Celite. The filtrate was mixed with 1 N NaOH (3.4 mL) and the
mixture was vigorously stirred at rt for 30 min and extracted with CH2Cl2 two times. The
combined extracts were dried over MgSO4 and concentrated. The residue was purified by
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chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 30 (150 mg, 87%):
liquid; Rf 0.43 (hexane/EtOAc 5:1); IR (neat) 3461, 1250, 1111, 1079, 842 cm–1; 1H NMR
(400 MHz, CDCl3) δ 0.06 (s, 9 H), 1.05 (s, 9 H), 1.18 (d, J = 6.4 Hz, 3 H), 1.82 (br s, 1 H),
2.17 (t, J = 7.2 Hz, 2 H), 2.33 (d, J = 3.6 Hz, 1 H), 2.35 (dt, J = 15.6, 7.2 Hz, 1 H), 2.44 (dt,
J = 15.6, 7.2 Hz, 1 H), 2.82 (t, J = 3.6 Hz, 1 H), 3.73–3.80 (m, 1 H), 4.59 (dq, J = 8.4, 6.4
Hz, 1 H), 5.15 (dt, J = 10.8, 7.2 Hz, 1 H), 5.28 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H), 5.37 (dtt, J
= 10.8, 7.2, 1.6 Hz, 1 H), 5.54 (ddt, J = 10.8, 8.4, 2.0 Hz, 1 H), 7.32–7.46 (m, 6 H), 7.65–
7.72 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –3.6 (+), 19.2 (–), 24.6 (+), 25.8 (–),
27.0 (+), 31.6 (–), 47.6 (+), 58.0 (+), 65.9 (+), 69.2 (+), 124.4 (+), 126.0 (+), 127.5 (+),
127.6 (+), 129.5 (+), 129.6 (+), 130.7 (+), 134.3 (–), 134.6 (–), 135.3 (+), 135.9 (+), 136.0
(+); HRMS (FAB+) calcd for C30H44O3Si2Na [(M+Na)+] 531.2727, found 531.2724.
(1S,3Z,6Z,8R)-8-[(tert-Butyldiphenylsilyl)oxy]-1-[(2R,3R)-3-
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(trimethylsilyl)oxiran-2-yl]nona-3,6-dien-1-ol (31). A mixture of epoxy alcohol 30
(201 mg, 0.395 mmol), 4-NO2-C6H4CO2H (104 mg, 0.622 mmol), DIAD (0.16 mL, 0.812
mmol), and PPh3 (162 mg, 0.618 mmol) in THF (4 mL) was stirred at rt for 4 h and diluted
with saturated NaHCO3. The resulting mixture was extracted with EtOAc three times. The
combined extracts were washed with brine, dried over MgSO4, and concentrated. The
residue was purified by chromatography on silica gel (hexane/EtOAc) to afford the
corresponding ester, which was used for the next reaction: liquid; Rf 0.63 (hexane/EtOAc
5:1).
To an ice-cooled solution of the above ester in THF (3 mL) and MeOH (3 mL) was
added 2 N NaOH (2 mL). The mixture was stirred at 0 °C for 1 h and diluted with saturated
NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined
extracts were washed with brine, dried over MgSO4, and concentrated. The residue was
purified by chromatography on silica gel (hexane/EtOAc) to afford epoxy alcohol 31 (174
mg, 86%): liquid; Rf 0.34 (hexane/EtOAc 5:1); [α]D20 –7 (c 1.03, CHCl3); IR (neat) 3431,
1250, 1111, 1078, 842 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 9 H), 1.04 (s, 9 H),
1.17 (d, J = 6.4 Hz, 3 H), 1.93 (d, J = 5.2 Hz, 1 H), 2.14–2.28 (m, 2 H), 2.19 (d, J = 3.6 Hz,
1 H), 2.30–2.49 (m, 2 H), 2.77 (dd, J = 5.2, 3.6 Hz, 1 H), 3.38 (tt, J = 6.8, 5.2 Hz, 1 H),
4.58 (ddq, J = 8.4, 0.8, 6.4 Hz, 1 H), 5.13 (ddt, J = 10.8, 0.8, 7.2 Hz, 1 H), 5.26 (dt, J =
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10.8, 7.2 Hz, 1 H), 5.32 (dt, J = 10.8, 7.2 Hz, 1 H), 5.53 (ddt, J = 10.8, 8.4, 1.6 Hz, 1 H),
7.32–7.45 (m, 6 H), 7.64–7.71 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –3.6 (+),
19.2 (–), 24.6 (+), 25.8 (–), 27.0 (+), 32.6 (–), 49.3 (+), 58.7 (+), 65.9 (+), 72.4 (+), 124.4
(+), 126.0 (+), 127.5 (+), 127.6 (+), 129.5 (+), 129.6 (+), 130.8 (+), 134.3 (–), 134.6 (–),
135.4 (+), 135.9 (+), 136.0 (+); HRMS (FAB+) calcd for C30H43O3Si2 [(M–H)+] 507.2751,
found 507.2773.
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(5R,6Z,9Z,12S)-2,2,5,14,14,15,15-Heptamethyl-3,3-diphenyl-12-[(2R,3R)-3-
(trimethylsilyl)oxiran-2-yl]-4,13-dioxa-3,14-disilahexadeca-6,9-diene (32). To an
ice-cold solution of epoxy alcohol 31 (172 mg, 0.338 mmol) in CH2Cl2 (3.4 mL) were
added 2,6-lutidine (0.14 mL, 1.21 mmol) and TBSOTf (0.17 mL, 0.74 mmol). The solution
was stirred at 0 °C for 2.5 h and diluted with H2O. The resulting mixture was extracted with
CH2Cl2 three times. The combined extracts were dried over MgSO4 and concentrated. The
residue was purified by chromatography on silica gel (hexane/EtOAc) to afford silyl ether
32 (173 mg, 82%): liquid; Rf 0.77 (hexane/EtOAc 5:1); [α]D20 –2 (c 1.07, CHCl3); IR (neat)
1251, 1110, 839 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.026 (s, 9 H), 0.034 (s, 3 H), 0.10 (s,
3 H), 0.90 (s, 9 H), 1.05 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.01 (d, J = 3.6 Hz, 1 H), 2.14
(t, J = 7.2 Hz, 2 H), 2.27–2.37 (m, 1 H), 2.38–2.49 (m, 1 H), 2.71 (dd, J = 6.8, 3.6 Hz, 1 H),
3.21 (q, J = 6.8 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.13 (dt, J = 10.8, 7.2 Hz, 1 H),
5.17 (dt, J = 10.8, 7.2 Hz, 1 H), 5.29 (dtt, J = 10.8, 7.2, 1.2 Hz, 1 H), 5.53 (ddt, J = 10.8,
8.4, 1.6 Hz, 1 H), 7.32–7.45 (m, 6 H), 7.64–7.72 (m, 4 H); 13C–APT NMR (100 MHz,
CDCl3) δ –4.9 (+), –4.3 (+), –3.5 (+), 18.2 (–), 19.3 (–), 24.6 (+), 25.8 (–), 25.9 (+), 27.0
(+), 33.2 (–), 49.0 (+), 59.5 (+), 66.0 (+), 75.9 (+), 125.4 (+), 126.2 (+), 127.5 (+), 127.6
(+), 129.5 (+), 129.6 (+), 134.3 (–), 134.6 (–), 135.3 (+), 135.9 (+), 136.0 (+); HRMS
(FAB+) calcd for C36H57O3Si3 [(M–H)+] 621.3616, found 621.3611.
(2E,4S,6Z,9Z,11R)-4-[(tert-Butyldimethylsilyl)oxy]-11-[(tert-
butyldiphenylsilyl)oxy]dodeca-2,6,9-trienenitrile (29). To an ice-cold solution of
epoxide 32 (168 mg, 0.270 mmol) in toluene (2.7 mL) was added a solution of Et2AlCN
(0.70 M in toluene, 0.97 mL, 0.68 mmol). The solution was stirred at rt for 3 h and added
H2O (0.40 mL, 22 mmol), NaF (361 mg, 8.60 mmol), and Celite at 0 °C. The resulting
mixture was vigorously stirred at rt for 20 min and filtered through a pad of Celite. The
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filtrate was concentrated and the residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford nitrile 29 (134 mg, 88%). The 1H NMR spectrum and Rf value
were identical with those prepared from epoxy alcohol 27.
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(2E,4S,6Z,9Z,11R)-4-{(tert-Butyldimethylsilyl)oxy}-11-{(tert-
butyldiphenylsilyl)oxy}dodeca-2,6,9-trienal (3). To a solution of nitrile 29 (115 mg,
0.205 mmol) in toluene (2.1 mL) was added a solution of DIBAL (1.02 M in toluene, 0.26
mL, 0.265 mmol) at –78 °C. The solution was stirred at –78 °C for 1 h and poured into 3 N
HCl. The resulting mixture was extracted with EtOAc three times. The combined extracts
were washed successively with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to
afford aldehyde 3 (109 mg, 94%): liquid; Rf 0.41 (hexane/EtOAc 10:1); [α]D22 +10 (c 0.75,
CHCl3); IR (neat) 1695, 1256, 1109, 837 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3 H),
0.04 (s, 3 H), 0.90 (s, 9 H), 1.04 (s, 9 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.17 (t, J = 6.4 Hz, 2 H),
2.25–2.46 (m, 2 H), 4.35 (ddt, J = 4.4, 1.6, 6.4 Hz, 1 H), 4.56 (ddq, J = 8.2, 0.8, 6.4 Hz, 1
H), 5.07–5.16 (m, 1 H), 5.25 (dt, J = 10.8, 6.4 Hz, 1 H), 5.28 (dt, J = 10.8, 7.2 Hz, 1 H),
5.54 (ddt, J = 10.8, 8.2, 1.6 Hz, 1 H), 6.24 (ddd, J = 15.6, 8.0, 1.6 Hz, 1 H), 6.69 (dd, J =
15.6, 4.4 Hz, 1 H), 7.32–7.45 (m, 6 H), 7.64–7.72 (m, 4 H), 9.53 (d, J = 8.0 Hz, 1 H); 13C–
APT NMR (100 MHz, CDCl3) δ –4.81 (+), –4.70 (+), 18.2 (–), 19.2 (–), 24.6 (+), 25.8 (+),
25.9 (–), 27.0 (+), 35.1 (–), 65.9 (+), 71.4 (+), 124.1 (+), 125.8 (+), 127.5 (+), 127.6 (+),
129.5 (+), 129.6 (+), 130.6 (+), 130.8 (+), 134.3 (–), 134.5 (–), 135.4 (+), 135.86 (+),
135.93 (+), 159.4 (+), 193.6 (+); HRMS (FAB+) calcd for C34H50O3Si2Na [(M+Na)+]
585.3196 found 585.3199.
(Z)-7-[(tert-Butyldimethylsilyl)oxy]hept-3-en-1-ol (36). To a solution of Li (ca.
30 mg, 4.3 mmol) in liq. NH3 (ca. 30 mL) and THF (15 mL) was added Fe(NO3)3·9H2O (7
mg, 0.017 mmol) at –78 °C. The mixture was stirred under reflux for 20 min and cooled to
–78 °C. Li (380 mg, 55 mmol) was added portionwise. The mixture was stirred under
reflux for 1 h and cooled to –78 °C. 3-Butyn-1-ol (34) (1.70 mL, 22.5 mmol) was added.
The mixture was stirred under reflux for 1 h and cooled to –78 °C. A solution of silyl ether
33 (3.71 g, 14.6 mmol) in THF (5 mL) was added. The mixture was stirred under reflux for
2 h and added a mixed solution of H2O (10 mL) and THF (10 mL) carefully. The mixture
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was stirred at rt for 1 h and diluted with saturated NH4Cl. The resulting mixture was
extracted with Et2O three times. The combined extracts were washed with brine, dried over
MgSO4, and concentrated. The residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford alcohol 35 (2.85 g, 80%): liquid; Rf 0.27 (hexane/EtOAc 5:1); 1H
NMR (400 MHz, CDCl3) δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.67 (tt, J = 6.8, 6.0 Hz, 2 H), 2.22
(tt, J = 6.8, 2.4 Hz, 2 H), 2.40 (tt, J = 6.0, 2.4 Hz, 2 H), 3.66 (t, J = 6.0 Hz, 4 H); 13C–APT
NMR (100 MHz, CDCl3) δ –5.3 (+), 15.2 (–), 18.4 (–), 23.2 (–), 26.0 (+), 32.0 (–), 61.4 (–),
61.7 (–), 76.6 (–), 82.1 (–).
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To a solution of alcohol 35 (854 mg, 3.52 mmol) in EtOAc (20 mL) were added 5%
Pd/CaCO3 (poisoned with Pb, TCI, 9 mg, 0.0042 mmol) and quinoline (0.1 M in EtOAc,
1.4 mL, 0.14 mmol). The mixture was stirred at rt for 1 h under H2 and filtered through a
pad of Celite. The filtrate was concentrated and the residue was purified by
chromatography on silica gel (hexane/EtOAc) to afford alcohol 36 (835 mg, 97%): liquid;
Rf 0.27 (hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 6 H), 0.88 (s, 9 H),
1.56 (tt, J = 7.2, 6.4 Hz, 2 H), 1.81 (br s, 1 H), 2.12 (q, J = 7.2 Hz, 2 H), 2.32 (q, J = 6.4 Hz,
2 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.62 (t, J = 6.4 Hz, 2 H), 5.34–5.43 (m, 1 H), 5.49–5.58 (m,
1 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.2 (+), 18.4 (–), 23.6 (–), 26.0 (+), 30.8 (–),
32.7 (–), 62.3 (–), 62.5 (–), 125.8 (+), 132.6 (+); HRMS (FAB+) calcd for C13H29O2Si
[(M+H)+] 245.1937, found 245.1933.
(Z)-tert-Butyl[(7-iodohept-4-en-1-yl)oxy]dimethylsilane (37). To an ice-cold
solution of alcohol 36 (1.26 g, 5.15 mmol) in CH2Cl2 (30 mL) were added PPh3 (2.05 g,
7.82 mmol), imidazole (542 mg, 7.96 mmol), and I2 (2.04 g, 7.73 mmol). The mixture was
stirred at 0 °C for 1.5 h and diluted with aqueous Na2S2O3. The resulting mixture was
extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4 and
concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc) to
afford iodide 37 (1.60 g, 88%): liquid; Rf 0.78 (hexane/EtOAc 5:1); 1H NMR (400 MHz,
CDCl3) δ 0.05 (s, 6 H), 0.90 (s, 9 H), 1.58 (tt, J = 7.2, 6.4 Hz, 2 H), 2.09 (q, J = 7.2 Hz, 2
H), 2.63 (q, J = 7.2 Hz, 2 H), 3.13 (t, J = 7.2 Hz, 2 H), 3.61 (t, J = 6.4 Hz, 2 H), 5.29–5.38
(m, 1 H), 5.49–5.58 (m, 1 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.2 (+), 5.6 (–), 18.4
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(–), 23.8 (–), 26.1 (+), 31.5 (–), 32.6 (–), 62.5 (–), 128.3 (+), 132.1 (+); HRMS (FAB+)
calcd for C13H28OSiI [(M+H)+] 355.0954, found 355.0957.
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iodide 37 (1.47 g, 4.15 mmol) and PPh3 (1.63 g, 6.21 mmol) in MeCN (40 mL) was heated
under reflux for 19 h, cooled to rt, and concentrated. The residue was washed with ether six
times to afford phosphonium salt 38 (2.34 g, 91%): viscous liquid.16
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To an ice-cold suspension of phosphonium salt 38 (2.17 g, 3.52 mmol) in THF (20 mL)
was added a solution of NaHMDS (1.0 M in THF, 2.80 mL, 2.80 mmol). The mixture was
stirred at 0 °C for 1 h and cooled to –78 °C. A solution of aldehyde 39 (732 mg, 2.34
mmol) in THF (3 mL) was added to the mixture dropwise. The solution was allowed to
warm to rt gradually, stirred overnight, and diluted with saturated NH4Cl. The resulting
mixture was extracted with EtOAc three times. The combined extracts were washed with
brine, dried over MgSO4, and concentrated. The residue was purified by chromatography
on silica gel (hexane/EtOAc) to afford olefin 40: liquid; Rf 0.82 (hexane/EtOAc 5:1); 1H
NMR (300 MHz, CDCl3) δ 0.04 (s, 6 H), 0.89 (s, 9 H), 1.05 (s, 9 H), 1.51–1.63 (m, 2 H),
2.09 (dt, J = 7.5, 6.9 Hz, 2 H), 2.33 (dt, J = 5.7, 6.9 Hz, 2 H), 2.74 (t, J = 5.5 Hz, 2 H), 3.60
(t, J = 6.5 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 5.25–5.48 (m, 4 H), 7.32–7.46 (m, 6 H), 7.64–
7.71 (m, 4 H).
A solution of the above olefin 40, TBAF (1.0 M in THF, 0.66 mL, 0.66 mmol), and
AcOH (0.040 mL, 0.70 mmol) in DMF (26 mL) was stirred at rt overnight and diluted with
brine. The resulting mixture was extracted with EtOAc three times. The combined extracts
were washed with saturated NaHCO3, dried over MgSO4, and concentrated. The residue
was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 41 (2.21 g,
58% from aldehyde 39): liquid; Rf 0.46 (hexane/EtOAc 5:1); IR (neat) 3345, 1255, 1101,
836 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6 H), 0.89 (s, 9 H), 1.57 (tt, J = 7.2, 6.4
Hz, 2 H), 1.62 (br s, 1 H), 2.11 (q, J = 7.2 Hz, 2 H), 2.35 (dt, J = 7.2, 6.4 Hz, 2 H), 2.82 (t, J
= 6.8 Hz, 2 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.64 (t, J = 6.4 Hz, 2 H), 5.30–5.44 (m, 3 H), 5.53
(dtt, J = 10.8, 7.2, 1.6 Hz, 1 H); 13C–APT NMR (100 MHz, CDCl3) δ –5.2 (+), 18.4 (–),
23.6 (–), 25.8 (–), 26.0 (+), 30.9 (–), 32.8 (–), 62.3 (–), 62.7 (–), 125.5 (+), 128.0 (+), 129.9
(+), 131.4 (+); HRMS (FAB+) calcd for C16H33O2Si [(M+H)+] 285.2250, found 285.2243.
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tert-Butyl[{(4Z,7Z)-10-iododeca-4,7-dien-1-yl}oxy]dimethylsilane (42). To an
ice-cold solution of alcohol 41 (320 mg, 1.12 mmol) in CH2Cl2 (11 mL) were added PPh3
(465 mg, 1.77 mmol), imidazole (115 mg, 1.69 mmol), and I2 (451 mg, 1.71 mmol). The
mixture was stirred at 0 °C for 2 h and diluted with aqueous Na2S2O3 with vigorous stirring.
The resulting mixture was extracted with CH2Cl2 three times. The combined extracts were
dried over MgSO4 and concentrated. The residue was purified by chromatography on silica
gel (hexane/EtOAc) to afford iodide 42 (418 mg, 94%): liquid; Rf 0.83 (hexane/EtOAc 5:1);
IR (neat) 1255, 1102, 836, 775 cm –1; 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 6 H), 0.89 (s,
9 H), 1.56 (tt, J = 7.2, 6.4 Hz, 2 H), 2.11 (q, J = 7.2 Hz, 2 H), 2.64 (q, J = 7.2 Hz, 2 H), 2.77
(t, J = 7.2 Hz, 2 H), 3.12 (t, J = 7.2 Hz, 2 H), 3.60 (t, J = 6.4 Hz, 2 H), 5.28–5.44 (m, 3 H),
5.49 (dtt, J = 10.8, 7.2, 1.6 Hz, 1 H); 13C–ATP NMR (100 MHz, CDCl3) δ –5.2 (+), 5.4 (–),
18.4 (–), 23.7 (–), 25.9 (–), 26.1 (+), 31.5 (–), 32.8 (–), 62.6 (–), 127.7 (+), 128.2 (+), 130.1
(+), 130.8 (+); HRMS (FAB+) calcd for C16H32OSiI [(M+H)+] 395.1267, found 395.1264.
(4Z,7Z,10Z,12E,14S,16Z,19Z,21R)-14-[(tert-Butyldimethylsilyl)oxy]-21-[(tert-
butyldiphenylsilyl)oxy]docosa-4,7,10,12,16,19-hexaen-1-ol (44). A solution of
iodide 42 (418 mg, 1.06 mmol) and PPh3 (460 mg, 1.75 mmol) in MeCN (11 mL) was
heated under reflux for 21 h, cooled to rt, and concentrated. The residue was washed with
ether six times to afford phosphonium salt 2 (605 mg, 87%): viscous liquid; 1H NMR (300
MHz, CDCl3) δ 0.02 (s, 6 H), 0.87 (s, 9 H), 1.50 (tt, J = 7.2, 6.6 Hz, 2 H), 1.95 (q, J = 7.2
Hz, 2 H), 2.40–2.60 (m, 2 H), 2.55 (t, J = 6.9 Hz, 2 H), 3.55 (t, J = 6.6 Hz, 2 H), 3.77–3.94
(m, 2 H), 5.10–5.47 (m, 3 H), 5.56–5.68 (m, 1 H), 7.66–7.91 (m, 15 H).
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To an ice-cold suspension of phosphonium salt 2 (364 mg, 0.554 mmol) in THF (3.7
mL) was added a solution of NaHMDS (1.0 M in THF, 0.48 mL, 0.48 mmol). The mixture
was stirred at 0 °C for 1 h and cooled to –78 °C. A solution of aldehyde 3 (208 mg, 0.369
mmol) in THF (1 mL) was added to the mixture dropwise. The mixture was allowed to
warm to rt gradually, stirred overnight, and diluted with saturated NH4Cl. The resulting
mixture was extracted with EtOAc three times. The combined extracts were washed with
brine, dried over MgSO4, and concentrated. The residue was passed through a short silica
gel column and the product 43 was used for the next reaction without further purification:
liquid; Rf 0.80 (hexane/EtOAc 5:1) ; 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 6 H), 0.04 (s, 6
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H), 0.88 (s, 9 H), 0.89 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.0 Hz, 3 H), 1.54–1.63 (m, 2 H),
1.97–2.18 (m, 4 H), 2.22–2.48 (m, 2 H), 2.81 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 6.3 Hz, 2 H),
3.61 (t, J = 6.6 Hz, 2 H), 4.06–4.16 (m, 1 H), 4.57 (dq, J = 8.4, 6.0 Hz, 1 H), 5.05–5.22 (m,
2 H), 5.25–5.45 (m, 6 H), 5.50 (ddt, J = 10.8, 8.4, 1.5 Hz, 1 H), 5.58 (dd, J = 15.0, 6.3 Hz, 1
H), 5.95 (t, J = 11.1 Hz, 1 H), 6.43 (dd, J = 15.0, 11.1 Hz, 1 H), 7.29–7.45 (m, 6 H), 7.62–
7.71 (m, 4 H).
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A mixture of the above olefin 43 and PPTS (97 mg, 0.39 mmol) in MeOH (4 mL) was
stirred at rt for 7 h, diluted with brine, and concentrated to remove most of MeOH. The
resulting mixture was extracted with EtOAc three times. The combined extracts were dried
over MgSO4 and concentrated. The residue was purified by chromatography on silica gel
(hexane/EtOAc) to afford alcohol 44 (130 mg, 50% from aldehyde 3): liquid; Rf 0.32
(hexane/EtOAc 5:1); [α]D21 +5 (c 1.08, CHCl3); IR (neat) 3316, 1255, 1110, 1075, 836 cm–
1; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 6 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.4
Hz, 3 H), 1.27 (t, J = 5.6 Hz, 1 H), 1.64 (tt, J = 6.8, 6.4 Hz, 2 H), 2.04–2.20 (m, 4 H), 2.25–
2.46 (m, 2 H), 2.83 (t, J = 5.2 Hz, 2 H), 2.94 (t, J = 6.2 Hz, 2 H), 3.65 (dt, J = 5.6, 6.4 Hz, 2
H), 4.12 (q, J = 6.0 Hz, 1 H), 4.57 (dq, J = 8.8, 6.4 Hz, 1 H), 5.12 (dt, J = 10.8, 7.2 Hz, 1
H), 5.17 (dt, J = 10.8, 7.2 Hz, 1 H), 5.26–5.46 (m, 6 H), 5.51 (dd, J = 10.8, 8.8 Hz, 1 H),
5.59 (dd, J = 15.2, 6.0 Hz, 1 H), 5.96 (t, J = 11.2 Hz, 1 H), 6.44 (dd, J = 15.2, 11.2 Hz, 1
H), 7.31–7.44 (m, 6 H), 7.63–7.71 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –4.7 (+),
–4.3 (+), 18.3 (–), 19.2 (–), 23.6 (–), 24.6 (+), 25.7 (–), 25.9 (+), 26.1 (–), 27.0 (+), 32.5 (–),
36.3 (–), 62.5 (–), 66.0 (+), 72.8 (+), 124.3 (+), 125.8 (+), 126.4 (+), 127.5 (+), 127.6 (+),
127.8 (+), 128.3 (+), 128.5 (+), 128.7 (+), 129.36 (+), 129.42 (+), 129.5 (+), 129.57 (+),
129.58 (+), 134.3 (–), 134.6 (–), 135.1 (+), 135.87 (+), 135.94 (+), 136.8 (+); HRMS
(FAB+) calcd for C44H66O3Si2Na [(M+Na)+] 721.4448, found 721.4450.
(4Z,7Z,10Z,12E,14S,16Z,19Z,21R)-14-[(tert-Butyldimethylsilyl)oxy]-21-[(tert-
butyldiphenylsilyl)oxy]docosa-4,7,10,12,16,19-hexaenoic acid (45). A mixture
of alcohol 44 (75 mg, 0.107 mmol), TPAP (5 mg, 0.014 mmol), NMO (20 mg, 0.171
mmol), and MS4A (55 mg) in CH2Cl2 (1.1 mL) was stirred at rt for 2.5 h and diluted with
hexane. The resulting mixture was filtered through a pad of Celite. The filtrate was
concentrated and the residue was purified by chromatography on silica gel (hexane/EtOAc)
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to afford the corresponding aldehyde (51 mg, 68%): liquid; Rf 0.57 (hexane/EtOAc 5:1); 1H
NMR (300 MHz, CDCl3) δ 0.02 (s, 6 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.15 (d, J = 6.3 Hz, 3
H), 2.04–2.14 (m, 2 H), 2.23–2.45 (m, 4 H), 2.50 (tt, J = 6.9, 1.5 Hz, 2 H), 2.84 (t, J = 6.0
Hz, 2 H), 2.94 (t, J = 6.0 Hz, 2 H), 4.12 (q, J = 6.0 Hz, 1 H), 4.57 (dq, J = 8.7, 6.3 Hz, 1 H),
5.06–5.24 (m, 2 H), 5.24–5.45 (m, 6 H), 5.51 (dd, J = 10.8, 8.7 Hz, 1 H), 5.59 (dd, J = 15.0,
6.0 Hz, 1 H), 5.96 (t, J = 11.1 Hz, 1 H), 6.44 (dd, J = 15.0, 11.1 Hz, 1 H), 7.30–7.45 (m, 6
H), 7.60–7.72 (m, 4 H), 9.77 (t, J = 1.5 Hz, 1 H).
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A mixture of the above aldehyde (51 mg, 0.073 mmol), 2-methyl-2-butene (0.16 mL,
1.51 mmol), and NaClO2 (79% purity, 16 mg, 0.14 mmol) in phosphate buffer (pH 5.0, 1.4
mL) and t-BuOH (1.4 mL) was stirred at rt for 1 h and diluted with H2O. The resulting
mixture was extracted with EtOAc three times. The combined extracts were washed with
brine, dried over MgSO4, and concentrated. The residue was purified by chromatography
on silica gel (hexane/EtOAc) to afford acid 45 (42 mg, 81%): liquid; Rf 0.20
(hexane/EtOAc 5:1); [α]D21 +5 (c 0.86, CHCl3); IR (neat) 1712, 1255, 1110, 1078, 836 cm–
1; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6 H), 0.90 (s, 9 H), 1.06 (s, 9 H), 1.17 (d, J = 6.4
Hz, 3 H), 2.04–2.18 (m, 2 H), 2.26–2.48 (m, 6 H), 2.85 (t, J = 5.6 Hz, 2 H), 2.96 (t, J = 6.2
Hz, 2 H), 4.13 (q, J = 6.0 Hz, 1 H), 4.59 (dq, J = 8.4, 6.4 Hz, 1 H), 5.14 (dt, J = 10.8, 7.2
Hz, 1 H), 5.19 (dt, J = 10.8, 7.2 Hz, 1 H), 5.26–5.57 (m, 7 H), 5.60 (dd, J = 15.0, 6.0 Hz, 1
H), 5.98 (t, J = 11.2 Hz, 1 H), 6.46 (dd, J = 15.0, 11.2 Hz, 1 H), 7.30–7.46 (m, 6 H), 7.62–
7.74 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ –4.7 (+), –4.3 (+), 18.3 (–), 19.2 (–),
22.5 (–), 24.6 (+), 25.7 (–), 25.9 (+), 26.1 (–), 27.0 (+), 34.0 (–), 36.3 (–), 66.0 (+), 72.9 (+),
124.3 (+), 125.8 (+), 126.4 (+), 127.5 (+), 127.6 (+), 127.7 (+), 128.1 (+), 128.3 (+), 128.4
(+), 129.4 (+), 129.5 (+), 129.6 (+), 134.3 (–), 134.6 (–), 135.1 (+), 135.88 (+), 135.95 (+),
136.8 (+), 179.2 (–); HRMS (FAB+) calcd for C44H64O4Si2Na [(M+Na)+] 735.4241, found
735.4239.
14S,21R-diHDHA (1a). A solution of acid 45 (21 mg, 0.029 mmol) and TBAF (1.0 M
in THF, 0.29 mL, 0.29 mmol) in THF (0.3 mL) was stirred at rt for 8 h and diluted with
phosphate buffer (pH 5.0). The resulting mixture was extracted with EtOAc three times.
The combined extracts were dried over MgSO4 and concentrated. The residue was purified
by chromatography on silica gel (CH2Cl2/MeOH) to afford 14S,21R-diHDHA (1a) (10 mg,
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94%): liquid; Rf 0.37 (CH2Cl2/MeOH 10:1); [α]D20 +19 (c 0.56, CHCl3); UV (MeOH) λmax
235 nm; lit. UV (MeOH/H2O/AcOH) λmax 236 nm,1b UV (MeOH) λmax 235 nm;3a IR (neat)
3468, 1710, 1411, 1274, 1057 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.26 (d, J = 6.4 Hz, 3
H), 2.20–2.28 (m, 1 H), 2.32–2.50 (m, 5 H), 2.58–2.67 (m, 1 H), 2.72–3.08 (m, 4 H), 3.12–
3.23 (m, 1 H), 3.5–5.1 (m, 3 H), 4.20–4.28 (m, 1 H), 4.74 (dq, J = 8.0, 6.4 Hz, 1 H), 5.32–
5.50 (m, 8 H), 5.57–5.68 (m, 1 H), 5.73 (dd, J = 15.2, 6.0 Hz, 1 H), 5.99 (t, J = 11.2 Hz, 1
H), 6.60 (dd, J = 15.2, 11.2 Hz, 1 H); 13C–APT NMR (100 MHz, CDCl3) δ 22.9 (–), 23.0
(+), 25.8 (–), 26.25 (–), 26.31 (–), 33.9 (–), 35.5 (–), 63.4 (+), 72.0 (+), 125.5 (+), 125.8 (+),
127.5 (+), 127.7 (+), 127.9 (+), 128.8 (+), 129.1 (+), 129.4 (+), 130.5 (+), 130.7 (+), 133.4
(+), 135.3 (+), 176.8 (–); HRMS (FAB–) calcd for C22H31O4 [(M–H)–] 359.2222, found
359.2219.
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(S,Z)-5-[(tert-Butyldiphenylsilyl)oxy]hex-3-en-1-ol (ent-23). A solution of ethyl
lactate (>99% ee, 2.03 mL, 17.2 mmol), TBDPSCl (5.80 mL, 22.3 mmol), and imidazole
(1.87 g, 27.5 mmol) in DMF (50 mL) was stirred at rt for 16 h and diluted with saturated
NaHCO3. The product was extracted with EtOAc and purified by chromatography on silica
gel (hexane/EtOAc) to afford silyl ether 46 (5.87 g, 96%). The 1H NMR spectrum was
identical with that reported.17
To a solution of ester 46 (1.29 g, 3.62 mmol) in CH2Cl2 (20 mL) cooled to –78 °C was
added a solution of DIBAL (1.02 M in hexane, 4.60 mL, 4.69 mmol) dropwise. The
solution was stirred at –78 °C for 1 h and poured to a mixture of H2O (1.3 mL, 72 mmol)
and NaF (1.5 g, 36 mmol). The mixture was filtered through a pad of Celite and the filtrate
was concentrated to afford the corresponding aldehyde. A solution of the aldehyde
dissolved in THF (4 mL) was added to a suspension of phosphonium salt 22 (2.42 g, 4.69
mmol) and NaHMDS (1.0 M in THF, 3.96 mL, 3.96 mmol) in THF (27 mL) at –90 °C. The
mixture was warmed to 0 °C over 5 h and diluted with saturated NH4Cl. The product was
extracted with EtOAc to afford the corresponding olefin, which was mixed with PPTS (955
mg, 3.80 mmol) in MeOH (25 mL). After 12 h at rt, the solution was diluted with brine and
concentrated to remove most of MeOH. The product was extracted with EtOAc and
purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol ent-23 (1.08 g,
84% from ester 46). The 1H NMR spectrum was identical with that of 23.
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