introduction
{chem1}, with a unique cyclopentyl enolic [beta]-diketone group conjugated to a polyene chain, was first isolated from Mytilus californianus by Scheer in 1940.2 Its structure and synthesis of the 9Z-isomer were reported by Weedon's group,3 they developed the new synthetic route to polyene [beta]-diketones using Claisen type condensation between polyene esters and methyl ketones. The absolute configuration was determined by Maoka and Fujiwara in 1996. The cyclopentyl end group of mytiloxanthin {chem1} is believed to be formed in Nature from the epoxide end group of 5,6-epoxy carotenoids such as halocynthiaxanthin {chem2} by cleavage of the oxirane ring at the C-5 position and successive ring contraction (a pinacolic rearrangement)
(Scheme 1, route a).
We found5 that the acyclic-tetrasubstituted olefinic compounds and the cyclopentyl ketone were derived by Lewis acid-promoted stereoselective rearrangement of epoxy compounds. Then, the biomimetic total synthesis of crassostreaxanthin B {chem3} possessing the acyclic-tetrasubstituted olefinic end group was achieved using this rearrangement reaction.
In a previous communication,7 we reported the first total synthesis of {chem1} which includes the new construction of conjugated {chem10a chem10b} through the cyclopentyl compound {chem8} (Scheme 2), prepared by application of the stereoselective rearrangement of epoxide {chem5}. The present paper is concerned with a full account of the experiments.
experimental
UV-VIS spectra were recorded on a JASCO Ubest-55 instrument for ethanolsolution s unless otherwise stated. IR spectra were measured on a Perkin Elmer FT-IR spectrometer, model Paragon 1000, for chloroformsolution s. 1H NMR spectra at 300 or 500 MHz were determined on a Varian Gemini-300 or a Varian VXR-500 superconducting FT-NMR spectrometer, respectively, for deuteriochloroformsolution s (lbracket
tetramethylsilane as internal reference). J-Values aregiven in Hz. NMR assignments aregiven using the carotenoid numbering system. Mass spectra were taken on a Hitachi M-4100 spectrometer. Optical rotations were measured on a JASCO DIP-181 polarimeter ([[alpha]]D-values are in units of 10-1 deg cm2 g-1). CD spectra were measured on a Shimadzu-AVIV 62A DS circular dichroism spectrometer.
Column chromatography (CC) was performed on silica gel (Merck Art. 7734). Short-column chromatography (SCC) was carried out on silica gel (Merck Art. 7739) under reduced pressure. Preparative TLC (PTLC) was conducted on silica gel [osc:solidstate=plates
] (Merck silica gel 60F254 precoated [osc:solidstate=plates
], [osc:conc=0.5(oscUnits:unknown)
] thickness). Low-pressure CC was performed on a Yamazen Low Pressure [osc:nonsolidstate=Liquid
] Chromatography System using a Lobar column (Merck LiChroprep Si 60). Analytical and PHPLC were carried out on Shimadzu LC-6A, or Waters 510 instruments with UV-VIS detectors.
Standard work-up means that the organic layers orACTION extractcml:extracts were finallyACTION washedcml:washed with brine, [=
] over [=
] sodium sulfate (Na2SO4), filtered and [=
] in vacuo below [osc:temperature=30.0(oscUnits:C)
] using a rotary evaporator. All operations were carried out under nitrogen or argon. Hexane refers to n-hexane.
|reactionScheme|HEADER HEADER|
To asolution of the {chem11} (balancedBrackets[osc:mass=11.9(oscUnits:g)
]
) in [=
] Py (balancedBrackets[osc:volume=20.0(oscUnits:mL)
]
)ACTION was addedcml:addedAc2O (balancedBrackets[osc:volume=15.0(oscUnits:mL)
]
) at [osc:temperature=298.15(oscUnits:k)
]and the{mixture}wasACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=16.0(oscUnits:h)
]. The{mixture}wasACTION pouredcml:poured into ice-water andACTION extractcml:extracted with Et2O. TheACTION extractcml:extracts wereACTION washedcml:washed successively with [=
] 5% HCl, [=
] [=
] NaHCO3 and brine.ACTION Evaporationcml:evaporation of the [=
]ACTION extractcml:extractsgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsEt2O-hexane, 1 : 9) toafford the acetate {chem12} as a [osc:colour=colorless
]; [[alpha]]26D
-42.6 (c 1.22, MeOH
); [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem12}
| reactionScheme|
|reactionScheme|HEADER2-[(1
S,4
S,6
R)- and and
HEADER|
Asolution of MCPBA (72%, [osc:mass=552.0(oscUnits:mg)
]rbracket
) in [=
] CH2Cl2 (balancedBrackets[osc:volume=5.0(oscUnits:mL)
]
)ACTION was addedcml:addedto an ice-cooledsolution of the {chem12} (balancedBrackets[osc:mass=600.0(oscUnits:mg)
]
) in [=
] CH2Cl2 (balancedBrackets[osc:volume=5.0(oscUnits:mL)
]
). After beingACTION stirredcml:stirred at [osc:temperature=0.0(oscUnits:C)
] for [osc:time=1.0(oscUnits:h)
], the reaction{mixture}ACTION was dilutedcml:dilutedwith Et2OandACTION washedcml:washed successively with [=
] 1% Na2S2O3, [=
] [=
] NaHCO3 and brine.ACTION Evaporationcml:evaporation of the [=
]solventgavea{residue}, whichACTION was purified bycml:purifiedSCC (lbracket
Et2O-hexane, 1 : 5) followed by low-pressure CC (lbracket
Et2O-benzene, 1 : 19) toafford the anti-epoxide {chem5a} and the syn- epoxide {chem5b} as [osc:colour=colorless
] oils, respectively.
|reactionScheme|HEADER HEADER|[[alpha]]22D
-10.0 (c 1.00, MeOHrbracket
); [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem5a}
| reactionScheme|
|reactionScheme|HEADER HEADER|[[alpha]]22D
-30.0 (c 1.00, MeOHrbracket
); [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem5b}
| reactionScheme|
| | | {chem5a} {chem5b}
| reactionScheme|
|reactionScheme|HEADER HEADER|
To asolution of the compound {chem8} (balancedBrackets[osc:mass=255.0(oscUnits:mg)
]
) in MeOH (balancedBrackets[osc:volume=5.0(oscUnits:mL)
]
)ACTION was addedcml:addedNaBH4 (balancedBrackets[osc:mass=27.2(oscUnits:mg)
]
) at [osc:temperature=0.0(oscUnits:C)
]and the{mixture}wasACTION stirredcml:stirred at [osc:temperature=0.0(oscUnits:C)
] for [osc:time=30.0(oscUnits:min)
]. The reaction{mixture}wasACTION pouredcml:poured into ice-water, andACTION extractcml:extracted with Et2O. Standard work-upaffordeda{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsEt2O-hexane, 1 : 5) toyieldthe alcohol as a [osc:colour=colorless
]. Pri2NEt (lbracket
[osc:volume=0.98(oscUnits:mL)
] ) and PMBMCl11 (balancedBrackets[osc:mass=626.0(oscUnits:mg)
]
) were added to asolution of the above alcohol (balancedBrackets[osc:mass=200.0(oscUnits:mg)
]
) in [=
] CH2Cl2 (balancedBrackets[osc:volume=2.0(oscUnits:mL)
]
) at [osc:temperature=298.15(oscUnits:k)
]. After beingACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=16.0(oscUnits:h)
], the reaction{mixture}ACTION was dilutedcml:dilutedwith Et2Oand the organic layer wasACTION washedcml:washed successively with [=
] 5% HCl, [=
] [=
] NaHCO3 and brine.ACTION Evaporationcml:evaporation of the [=
]solution gavea{residue}, which was purified
by SCC (balancedBracketsacetone-hexane, 1 : 19) toafford the PMBM ether {chem14} (lbracket
[osc:mass=229.0(oscUnits:mg)
], 80%; 62% from {chem8} ) as a [osc:colour=colorless
]; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem14}
| reactionScheme|
|reactionScheme|HEADER HEADER|
ACTION To acml:tosuspension of LAH (balancedBrackets[osc:mass=24.0(oscUnits:mg)
]
) in [=
] Et2O (balancedBrackets[osc:volume=5.0(oscUnits:mL)
]
)ACTION was addedcml:addeddropwise asolution of {chem14} (balancedBrackets[osc:mass=323.0(oscUnits:mg)
]
) in [=
] Et2O (balancedBrackets[osc:volume=15.0(oscUnits:mL)
]
) at [osc:temperature=0.0(oscUnits:C)
]. After beingACTION stirredcml:stirred at [osc:temperature=0.0(oscUnits:C)
] for [osc:time=30.0(oscUnits:min)
], the [=
] LAH was decomposed by dropwise addition of water. The{mixture} wasACTION extractcml:extracted with Et2Oand theACTION extractcml:extracts wereACTION washedcml:washed successively with [=
] 5% HCl, [=
] [=
] NaHCO3 and brine.ACTION Evaporationcml:evaporation of the [=
]solventgavea{residue}, whichACTION was purified bycml:purifiedSCC (lbracket
acetone-hexane, 1 : 9) toafford the alcohol {chem15} as a [osc:colour=colorless
]; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem15}
| reactionScheme|
|reactionScheme|HEADER HEADER|
To asolution of the {chem15} (balancedBrackets[osc:mass=125.0(oscUnits:mg)
]
) in DMSO (balancedBrackets[osc:volume=1.0(oscUnits:mL)
]
)ACTION was addedcml:addedasolution of IBX12 (balancedBrackets[osc:mass=188.0(oscUnits:mg)
]
) in DMSO (balancedBrackets[osc:volume=0.67(oscUnits:mL)
]
) at [osc:temperature=298.15(oscUnits:k)
]and the{mixture}wasACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=1.0(oscUnits:h)
]. The reaction{mixture}ACTION was dilutedcml:dilutedwith water (balancedBrackets[osc:volume=5.0(oscUnits:mL)
]
) and the [osc:colour=white
]precipitate was filtered. The filtrate wasACTION extractcml:extracted with Et2O. Standard work-upgavea{residue}, whichACTION was purified bycml:purifiedSCC (lbracket
acetone-hexane, 1 : 9) toACTION providecml:providethe aldehyde {chem16} as a [osc:colour=colorless
]; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem16}
| reactionScheme|
|reactionScheme|HEADER HEADER|
To asolution of the {chem17} (balancedBrackets[osc:mass=403.0(oscUnits:mg)
]
) in [=
] Et2O (balancedBrackets[osc:volume=4.0(oscUnits:mL)
]
)ACTION was addedcml:addedButLi (balancedBrackets[osc:conc=1.64(oscUnits:unknown)
] in pentane; [osc:volume=0.93(oscUnits:mL)
]
) at -[osc:temperature=78.0(oscUnits:C)
]and the{mixture}wasACTION stirredcml:stirred at -[osc:temperature=78.0(oscUnits:C)
] for [osc:time=10.0(oscUnits:min)
]. Asolution of the aldehyde {chem16} (balancedBrackets[osc:mass=235.0(oscUnits:mg)
]
) in [=
] Et2O (balancedBrackets[osc:volume=6.0(oscUnits:mL)
]
)ACTION was addedcml:addedto this{mixture} at -[osc:temperature=78.0(oscUnits:C)
] for [osc:time=1.0(oscUnits:h)
]. After being quenched with [=
] [=
] NH4Cl, the{mixture} wasACTION extractcml:extracted with Et2O. Standard work-upgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsEt2O-hexane, 1 : 4) toafford the adduct as a [osc:colour=colorless
]. Then, to asolution of the adduct (lbracket
[osc:mass=313.0(oscUnits:mg)
] ) in DMSO (balancedBrackets[osc:volume=1.5(oscUnits:mL)
]
)ACTION was addedcml:addedasolution of IBX12 (balancedBrackets[osc:mass=337.0(oscUnits:mg)
]
) in DMSO (balancedBrackets[osc:volume=1.2(oscUnits:mL)
]
) at [osc:temperature=298.15(oscUnits:k)
]and the{mixture}wasACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=16.0(oscUnits:h)
]. The reaction{mixture}ACTION was dilutedcml:dilutedwith water (balancedBrackets[osc:volume=5.0(oscUnits:mL)
]
) and the [osc:colour=white
]precipitate was filtered. The filtrate wasACTION extractcml:extracted with Et2O. Standard work-upgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsEt2O-hexane, 3 : 17) toACTION providecml:providethe [=
] ketone {chem18} (lbracket
[osc:mass=197.0(oscUnits:mg)
], 63%; 60% from {chem16} ) as a [osc:colour=colorless
]; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem18}
| reactionScheme|
|reactionScheme|HEADER HEADER|
To asolution of the {chem18} (balancedBrackets[osc:mass=197.0(oscUnits:mg)
]
) dissolved in a{mixture} of CH2Cl2-H2O (18 : 1, [osc:volume=6.54(oscUnits:mL)
]rbracket
)ACTION was addedcml:addedDDQ11b (balancedBrackets[osc:mass=86.0(oscUnits:mg)
]
). After beingACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=2.0(oscUnits:h)
], the reaction{mixture} was filtered through Celite.ACTION Evaporationcml:evaporation of the filtrategavea{residue}, whichACTION was purified bycml:purifiedSCC (lbracket
Et2O-hexane, 1 : 9) toafford the alcohol {chem19} as a [osc:colour=colorless
]; [lambda]
SPECTRUM OMITTED
; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem19}
| reactionScheme|
|reactionScheme|HEADER HEADER|
Ac2O (balancedBrackets[osc:volume=0.5(oscUnits:mL)
]
)ACTION was addedcml:addedto asolution of the {chem20} (balancedBrackets[osc:mass=104.0(oscUnits:mg)
]
), Et3N (balancedBrackets[osc:volume=0.04(oscUnits:mL)
]
) and DMAP (balancedBrackets[osc:mass=28.0(oscUnits:mg)
]
) in [=
] CH2Cl2 (balancedBrackets[osc:volume=1.0(oscUnits:mL)
]
) at [osc:temperature=298.15(oscUnits:k)
]. After beingACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=30.0(oscUnits:min)
], the{mixture}wasACTION pouredcml:poured into ice-water andACTION extractcml:extracted with Et2O. TheACTION extractcml:extracts wereACTION washedcml:washed successively with [=
] 5% HCl, [=
] [=
] NaHCO3 and brine.ACTION Evaporationcml:evaporation of the [=
]ACTION extractcml:extractsgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsEt2O-hexane, 1 : 4) toafford the enol acetate {chem22} as a [osc:colour=colorless
]; [[alpha]]20D
-10.3 (c 0.98, CHCl3
); [lambda]
SPECTRUM OMITTED
; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem22}
| reactionScheme|
|reactionScheme|HEADER HEADER|
Asolution of TBAF (balancedBrackets[osc:conc=1.0(oscUnits:unknown)
] in THF; [osc:volume=0.19(oscUnits:mL)
]
)ACTION was addedcml:addedto asolution of the {chem22} (balancedBrackets[osc:mass=104.0(oscUnits:mg)
]
) in [=
] THF (balancedBrackets[osc:volume=4.0(oscUnits:mL)
]
) at [osc:temperature=0.0(oscUnits:C)
]and the{mixture}wasACTION stirredcml:stirred at [osc:temperature=0.0(oscUnits:C)
] for [osc:time=1.0(oscUnits:h)
]. The reaction{mixture}ACTION was dilutedcml:dilutedwith Et2O. Standard work-upgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsEt2O-hexane, 1 : 4 [~~] acetone-hexane, 1 : 4) toafford the alcohol {chem23} as a [osc:colour=colorless
]; [[alpha]]24D
+0.98 (c 1.02, CHCl3
); [lambda]
SPECTRUM OMITTED
; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem23}
| reactionScheme|
|reactionScheme|HEADER HEADER|
To asolution of the {chem23} (balancedBrackets[osc:mass=54.0(oscUnits:mg)
]
) in DMSO (balancedBrackets[osc:volume=0.25(oscUnits:mL)
]
)ACTION was addedcml:addedasolution of IBX12 (balancedBrackets[osc:mass=72.0(oscUnits:mg)
]
) in DMSO (balancedBrackets[osc:volume=0.26(oscUnits:mL)
]
) at [osc:temperature=298.15(oscUnits:k)
]and the{mixture}wasACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=1.0(oscUnits:h)
]. The reaction{mixture}ACTION was dilutedcml:dilutedwith water (balancedBrackets[osc:volume=3.0(oscUnits:mL)
]
) and the [osc:colour=white
]precipitate was filtered. The filtrate wasACTION extractcml:extracted with Et2O. Standard work-upgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsacetone-hexane, 3 : 17) toafford the aldehyde as a [osc:colour=pale
]. A{mixture} of 47% [=
] HF-CH3CN (1 : 19; [osc:volume=0.4(oscUnits:mL)
]
)ACTION was addedcml:addedto asolution of this aldehyde (balancedBrackets[osc:mass=33.0(oscUnits:mg)
]
) in a{mixture} of CH3CN-THF (9 : 1; [osc:volume=4.0(oscUnits:mL)
]rbracket
) at [osc:temperature=298.15(oscUnits:k)
]. After beingACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=1.5(oscUnits:h)
], the reaction{mixture} was quenched with [=
] [=
] NaHCO3andACTION extractcml:extracted with Et2O. Standard work-upgavea{residue}, whichACTION was purified bycml:purifiedSCC (balancedBracketsacetone-hexane, 3 :
7) toACTION providecml:providethe desilylated aldehyde {chem10b} (lbracket
[osc:mass=22.0(oscUnits:mg)
], 92%; 55% from {chem23} ) as a [osc:colour=pale
]; [[alpha]]26D
-10.0 (c 0.40, CHCl3rbracket
); [lambda]
SPECTRUM OMITTED
; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem10b}
| reactionScheme|
|reactionScheme|HEADER HEADER|
An [=
]solution (balancedBrackets[osc:volume=0.1(oscUnits:mL)
]
) prepared from PTSA (balancedBrackets[osc:mass=500.0(oscUnits:mg)
]
) and H3PO4 (balancedBrackets[osc:mass=725.0(oscUnits:mg)
]
) in MeOH (balancedBrackets[osc:volume=37.5(oscUnits:mL)
]
) and (balancedBrackets[osc:volume=0.1(oscUnits:mL)
]
) were added to asolution of the Wittig salt {chem24} (balancedBrackets[osc:mass=35.6(oscUnits:mg)
]
) in MeOH (balancedBrackets[osc:volume=1.0(oscUnits:mL)
]
). The{mixture}wasACTION stirredcml:stirred at [osc:temperature=298.15(oscUnits:k)
] for [osc:time=1.0(oscUnits:h)
] and neutralized with NaOMe (balancedBrackets[osc:conc=1.0(oscUnits:unknown)
] in MeOH
) until just before the [osc:colour=red
] color of an appeared.ACTION Evaporationcml:evaporationof the solventACTION providedcml:provide the Wittig salt {chem25}, to which asolution of the aldehyde {chem10b} (balancedBrackets[osc:mass=9.8(oscUnits:mg)
]
) in propan-2-ol (balancedBrackets[osc:volume=1.5(oscUnits:mL)
]
) was added. To the{mixture}, a [=
]solution (balancedBrackets[osc:volume=1.0(oscUnits:mL)
]
) of KOH (balancedBrackets[osc:mass=500.0(oscUnits:mg)
]
) dissolved in water (balancedBrackets[osc:volume=1.0(oscUnits:mL)
]
) and propan-2-ol (balancedBrackets[osc:volume=10.0(oscUnits:mL)
]
)ACTION was addedcml:addeddropwise at [osc:temperature=0.0(oscUnits:C)
]. After beingACTION stirredcml:stirred at [osc:temperature=0.0(oscUnits:C)
] for [osc:time=1.0(oscUnits:h)
], the{mixture}wasACTION pouredcml:poured into ice-water, andACTION extractcml:extracted with Et2O. TheACTION extractcml:extracts were shaken with [=
] 5% HCl
until the fine structure disappeared on UV-VIS,ACTION washedcml:washed successively with [=
] [=
] NaHCO3 and brine.ACTION Evaporationcml:evaporation of the [=
]ACTION extractcml:extractsACTION providedcml:providea{residue}, whichACTION was purified bycml:purifiedSCC (lbracket
acetone-hexane, 1 : 4) toafford an isomeric{mixture} of apocarotenal {chem26} in which the main product was all-Eisomer. Purification of a part of the isomeric{mixture} by PTLC (lbracket
acetone-hexane, 3 : 7)ACTION providedcml:provide the all-E isomer as an [osc:colour=orange
]; [lambda]
SPECTRUM OMITTED
; [nu]
SPECTRUM OMITTED
; [delta]
SPECTRUM OMITTED
.
| | | {chem26}
| reactionScheme|