An enantioselective total synthesis of natural antibiotic marasin

Article abstract of DOI:10.1039/c0ob00151a

Synthetic studies directed toward the allenediyne antibiotic marasin are presented. Different approaches to the installation of the optically active chiral allenediyne motif were explored en route to the synthesis of the natural product. The stereoselecti

Full text of DOI:10.1039/c0ob00151a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An enantioselective total synthesis of natural antibiotic marasin†
Yan Zhang and Yikang Wu*
Received 21st May 2010, Accepted 8th July 2010
DOI: 10.1039/c0ob00151a
Synthetic studies directed toward the allenediyne antibiotic marasin are presented. Different
approaches to the installation of the optically active chiral allenediyne motif were explored en route to
the synthesis of the natural product. The stereoselectivity for the construction of the chiral allenediyne
motif was dependent on not only the reaction employed but also the substrate structure.
as shown in Scheme 1. The known racemic propargyl alcohol
Introduction
( )-48 was resolved into (R)-49 and optically active acetate 510 using
Novozyme 435/vinyl acetate.11 The (R)-49 was then transformed
into the corresponding bromoallene 8 as in our previous6,7
work, with an intension to apply the same coupling reaction to
incorporate the diyne subunit. Unfortunately, in the present case,
the desired bromoallene 8 turned out to be inseparable from the
proparyl bromide formed concurrently (8 : 7 = 4.5 : 1 as determined
by 1H NMR) by chromatography. To get around this problem, we
tried to replace the TBS (tert-butyldimethylsilyl) protecting group
with an acetyl one, which according to our experience12 of similar
compounds often facilitated the chromatographic separation on
silica gel.
Marasin (1, Fig. 1) is an allenediyne active1a against numerous
bacteria including Mycobacterium tuberculosis. Both (aR)-(-)-
and (aS)-(+)-1 occur in nature, with the former isolated from
Marasmius ramealis1a as well as Cortinellus berkeleyanus,2 and
the latter from Aleurodiscus roseus.3 To date only two syntheses
of marasin are documented in the literature. The first one was
disclosed by Graaf4 and co-workers, which used a ferrocene-
derived chiral catalyst-mediated coupling of a zincated allene with
a bromodiyne as the key step and eventually resulted in (aR)-(-)-
marasin in 0.5% e.e. The second one was a biosynthesis, completed
by Davies and Hodge5 in 2005. In continuation of our studies
on structurally similar allenediynes including nemotin6 (2) and
phomallenic acids7 (3), we have also made efforts in developing an
enantioselective chemical synthetic route to this rather unstable
bioactive allenediyne. Herein we wish to detail the results.
Fig. 1 The structures for (-)-marasin ((-)-1), nemotin (2) and phomal-
lenic acids (3a–c).
Results and discussion
Scheme 1
Our initial plan was to use the coupling of a bromoallene
with a diyne as the tool to install the key allenediyne motif
An immediate advantage of using an acetyl group was that
tosylate 9 was a solid, which could be recrystallized to give higher
enantiopurity (97% e.e.). On treatment with LiBr/CuBr13 tosylate
9 was converted to bromoallene 11, which indeed could be isolated
in pure form as hoped. Further coupling of 11 with the zincated
diyne 10 (prepared6,14 in situ from bis-trimethylsilylbutadiyne via
reaction with MeLi and ZnBr2) gave (aR)- allenediyne 13a in 70%
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, 200032, China. E-mail: yikangwu@sioc.ac.cn
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of all new compounds, chiral HPLC chromatograms, and
experimental details for 5, 17, 18, 22, ( )-25, 26, 29, 30, ent-30, 31, ent-31,
ent-33, ent-34, ent-35, (Z)-39, (S)-41b. See DOI: 10.1039/c0ob00151a
4744 | Org. Biomol. Chem., 2010, 8, 4744–4752
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yield.14c However, the e.e. value was only 36% (determined on 13b
obtained by DIBAL-H reduction) if the coupling was performed at
temperatures below -20 ◦C. At 0 ◦C, the allenediyne obtained was
entirely racemic. Direct coupling of tosylate 9 with diyne anion 10
appeared to be much better in this case, giving the (aS)-isomer 12a
in 89% e.e. (determined on 12b‡ obtained via DIBAL-H reduction
of 12a) and 72% yield.
While working on the direct coupling-based strategy, we also
examined some other alternatives that might lead to the de-
sired chiral allenediyne motif. One of the potentially applicable
methodologies is that developed by Satoh15 and coworkers, which
introduces allenic axes via elimination of vinyl sulfoxide-allyl
acetates. In the present context, it would require a precursor such
as 20 (Scheme 2) before attempting the key elimination. Here, an
optically-active sulfinyl group was preferred because it would assist
clean separation of the two diastereomers of the allyl alcohols
generated in a non-stereoselective addition (vide infra).
Scheme 3
prepared14 in situ from bis-trimethylbutadiyne to afford racemic
propargyl alcohol 25.
Conversion of the racemic 25 into a single (R) isomer was
realized by a two-step sequence. The racemic alcohol was first
transformed into the corresponding ketone 26 through reaction
with Dess–Martin periodinane. The ketone carbonyl group was
then stereoselectively reduced with BH3 in the presence of (S)-
2-methyl-CBS-oxazaborolidine (CBS21 reduction). Further expo-
sure of the (R)-25 to Ac2O/Et3N/DMAP gave the acetate 27 in
90% yield.
Scheme 2
In execution of this plan, the known optically-active sulfoxide
1416 was treated with LDA (lithium diisopropylamide) followed by
aldehyde 1517 to afford the alcohol 16 as a pair of diastereomers
(38 : 46, separable on silica gel). Activation of the hydroxyl group
with MsCl (methanesulfonyl chloride) followed by DBU (1,8-
diaza-bicyclo[5.4.0]undec-7-ene) mediated b-elimination afforded
17 in 53% yield, along with 26% of the (Z)-isomer 18. However,
the subsequent reaction of 17 with 1918 in the presence of LDA
led to a complex mixture. Because the highly unstable nature
of aldehyde 19 made extensive screening of suitable reaction
conditions experimentally unfeasible, later we abandoned this plan
and switched to another route that could avoid involvement of 19.
As shown in Scheme 3, condensation of aldehyde 15 with
ethyl phenylthioacetate 2119 yielded an intermediate alcohol,
which was directly mesylated and eliminated to give 22 as
the major product. It may be noteworthy here that use of
a sulfinyl (sulfoxide) instead of a PhS- group in 21 failed
to give the corresponding condesation product because a
SPAC20 reaction (Sulfoxide Piperidine and Carbonyl reaction)
occurred.
Oxidation of the PhS- group in 27 into a sulfinyl one was
first attempted using NaIO4/EtOH/H2O. However, only the TBS
protecting group was cleaved.22 To make full use of this unexpected
product, the newly-freed hydroxyl group was acetylated with
Ac2O/Et3N/DMAP in CH2Cl2 and the resulting acetate was re-
submitted to a sulfur oxidation.
23
With H2O2/Sc(OTf)3 as the reagents, the oxidation of the
sulfur atom occurred smoothly. The sulfoxide 28 was formed as
a 3 : 2 (the less polar component : the more component) mixture
of diastereomers differing only at the configuration at the sulfur
center. Although the absolute configuration of the sulfur atom was
not determined, both isomers were of ca. 98% e.e. as measured by
chiral HPLC. Both isomers on treatment with i-PrMgBr in THF at
-100 ◦C underwent smooth elimination to yield (aS)-allenediyne
12a, but with different stereoselectivity as noted15 earlier by Satoh.
The more polar isomer of 28 (28b) led to formation of 12a in 85%
yield within 20 min. Because the polarity of 12a was not large
enough for facile HPLC analysis, the terminal acetyl protecting
group was cleaved with DIBAL-H in CH2Cl2 at -78 ◦C to give
alcohol 12b, which was determined to be of 72.5% e.e. If starting
with the less polar isomer of 28 (28a) under otherwise identical
conditions, the 12b was of only 49% e.e.
The ester group was then transformed into an aldehyde group
by a DIBAL-H reduction followed by a Dess–Martin oxidation.
The resulting enal 23 was directly treated with lithiated diyne 24
‡ Desilylation of 12b to yield marasin was not attempted in this work.
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As the efficiency for the chirality transfer in the above case
was only 74% (= 73% e.e. (for the product 12)/98% e.e. (for
the precursor 28)), which was apparently not as good as those
observed earlier with the corresponding elimination of iodides24
in our recent work, we next examined another route with an iodide
to replace the sulfinyl group in the elimination precursor.
The initial synthetic efforts along this line are depicted in
Scheme 4. From the preceding attempts we were already aware
that the diyne species such as 10, 19, and 24 were difficult to
handle. One of the possible means to get around this problem is to
incorporate the diyne subunit in steps, with only one triple bond at
a time. To execute this plan, (R)-4 was treated with TBSCl/Et3N
to give 29. Deprotonation of 29 with n-BuLi in THF followed by
acylation with ClCO2Et introduced an ester group at the terminal
alkyne.
In parallel to the transformations in Scheme 4, starting from
(S)-4, which was obtained through hydrolysis of the acetyl group
in 5 with K2CO3/MeOH), the antipode of 35 (ent-35) was also
synthesized, though of only 81% e.e. because the enantiopurity of
the starting 5 was not as high as that of (R)-4.
Up to this point, it seemed that appending another triple
bond onto the terminal alkyne via an alkyne–alkyne coupling
followed by removal of the acetyl protecting group would finish
the whole synthesis. Unfortunately, this seemingly simple coupling
turned out to be extremely difficult. Using Me3SiC C–X (X =
Br or I) to couple with 35 or its zinc or copper salt, or
with the copper or zinc salt of Me3SiC CH to couple with
a brominated (at the terminal alkyne) 35 we tried a range of
coupling conditions without success. The tested palladium catalyst
included Pd(PPh3)4, Pd2(dba)3 (dba = dibenzylidenacetone), and
Pd(dppe)Cl2 (dppe = 1,2-bis(di-phenylphosphino)-ethane), with
Et3N or i-Pr2NH or DABCO (1,4-diazabicyclo[2.2.2]octane) or
pyrrolidine as the base and DMSO or THF or toluene–THF as
the solvent at temperatures ranging from -20 ◦C through 0 ◦C up
to ambient temperature in the presence or absence of CuI and/or
LiBr.27 In most cases no reaction occurred at low temperatures (<
rt), while a complex mixture was normally obtained at ambient
temperature. The best result along this route was observed with
the coupling between 35 and Me3SiC C–I28 (36) under the
conditions of Pd(PPh3)4/CuI/Et3N/DMSO/rt, with an isolated
yield of 24% for 12a. However, chiral HPLC analysis revealed
that the e.e. value of the 12a thus obtained was only 15%
(measured after deacetylation into 12b). Racemization apparently
occurred during the alkyne-alkyne coupling. It is noteworthy that
to our knowledge no such coupling between an alkyne and an
allenyne has ever been documented to date, not even a racemic
version.
As the late-stage installation of the second triple bond onto
the substrate structure through an alkyne–allenyne coupling
was unfeasible, we decided to return to the earlier strategy—to
introduce diyne subunit in one step. However, construction of the
allenediyne via elimination of a vinyl iodide instead of a sulfoxide
was still preferred because of the high enantioselectivity observed
in the formation of 35 and some24 other cases.
Scheme 4
The synthesis was then started as shown in Scheme 5. The
reaction of the iodinated Horner reagent 3829 (prepared in situ
from 37) with aldehyde 15 gave the desired a,b-unsaturated ester
39. The configuration of the main isomer of 39 was not established
experimentally at this stage but deduced later as (Z) on the basis
of the results of the elimination reaction leading to the formation
of the allenic axis and the literature29 precedents.
The iodine atom was then incorporated using the method of Ma
and Lu25 to obtain a (Z)-iodoalkene. Because under the iodination
conditions some of the TBS protecting group was lost, the product
mixture was treated with TBSCl/Et3N to resume full protection
of the hydroxyl groups.
Installation of a terminal alkyne started with a reduction of
31 with DIBAL-H followed by an oxidation with Dess–Martin
periodinane. The resulting intermediate aldehyde was then treated
with a carbenoid generated in situ from 32, a stable/convenient
precursor to enynes recently developed by us,26 to give the
iodoenyne 33.
The TBS protecting groups in 33 were then replaced with
acetyl groups through an acid-mediated desilylation followed by
acetylation with Ac2O/py. Further treatment of the resulting
diacetate 34 with i-PrMgBr at -78 ◦C afforded allenyne 35 in
80% yield. The e.e. value of this allene was determined to be 94%,
which indicated that the chirality transfer from the allylic acetate
to the allenic axis in this case was highly stereospecific.
The ester 39 was transformed into the corresponding aldehyde
through a DIBAL-H reduction followed by a Dess–Martin
oxidation. The diyne subunit was then introduced via addition
of the lithiated diyne 24 to aldehyde 40. The resulting racemic
alcohol 41a was converted into a single (S)-isomer in the same
manner as used in the transformation of racemic 25 into (R)-25
(Scheme 3), but using (R)-2-methyl-CBS-oxazaborolidine as the
catalyst instead of the (S)-one.
The resulting (S)-41a, which was of 89% e.e. as determined on
the corresponding diol (S)-41b, was treated with K2CO3/MeOH
to remove the TMS protecting group on the alkyne terminal.
Acetylation of the intermediate alcohol with Ac2O/Et3N/DMAP
delivered the elimination precursor 43 in 79% yield. Finally, under
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Experimental
General
1
The H NMR and 13C NMR spectra were recorded at ambient
temperature using a Varian Mercury or a Bruker Avance instru-
ment operating at the frequencies indicated in each case. The
FTIR spectra were scanned with a Nicolet Avatar 360 FTIR.
EIMS and EI-HRMS were recorded with an HP 5989A and a
Finnigan MAT 8430 mass spectrometer, respectively. The ESIMS
and ESIHRMS were recorded with a PE Mariner API-TOF and
an APEX III (7.0 Tesla) FTMS mass spectrometer, respectively.
Dry THF and dry Et2O were distilled from Na/Ph2CO under
argon prior to use. Dry CH2Cl2 and dry i-Pr2NH were distilled over
CaH2 prior to use. Novozyme 435 (demobilized on resin as white
pellets of 0.3–0.9 mm in diameter) was purchased from Novozymes
A/S (www.novozymes.com). Unless otherwise specified, all other
solvents and reagents were commercially available and used as
received without any further purification. PE (chromatography
solvent) stands for petroleum ether (60–90 ◦C).
(R)-5-tert-Butyldimethylsilyl-3-tosyloxy-pentyne (6). To a so-
lution of (R)-4 (214 mg, 1.0 mmol) in dry CH2Cl2 (8 cm3) stirred in
an ice-water bath were added in turn p-TsCl (228 mg, 1.2 mmol),
Et3N (2.0 cm3, 1.5 mmol) and DMAP (12 mg, 0.1 mmol).
The mixture was then stirred at ambient temperature overnight
before being diluted with Et2O (40 cm3), washed with aq. sat.
NH4Cl (twice), and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography
(20 : 1 PE/EtOAc) on silica gel gave 6 (313 mg, 0.85 mmol, 85%)
as a colorless oil, which was of 91% e.e. (tR (major) = 10.68 min,
tR (minor) = 9.43 min) as determined by chiral HPLC analysis
on a CHIRALPAK AS column (4.6 ¥ 25 cm) eluting with 98 : 2
n-hexane/i-PrOH at a flow rate of 0.8 cm3 min-1 with the UV
detector set to 214 nm. 1H NMR (CDCl3, 300 MHz) d 7.81 (d, J =
8.1 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 5.24 (dt, J = 1.5, 7.2 Hz, 1H),
3.68 (t, J = 5.7 Hz, 2H), 2.44 (s, 4H, -PhCH3 and the acetylenic
proton), 2.42 (d, J = 1.5 Hz, 1H), 2.12–1.88 (m, 2H), 0.86 (s, 9H),
0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 114.8, 133.7, 129.6,
128.0, 78.9, 76.3, 68.4, 57.9, 38.7, 25.7, 21.6, 18.1, -5.5, -5.6; FT-
IR (film) 3282, 2955, 2930, 2857, 2884, 1595, 1370, 1190, 1178,
1098 cm-1; ESI-MS m/z 391.2 ([M+Na]+); ESI-HRMS calcd. for
C18H28SiO4SNa 391.1370 ([M+Na]+), found 391.1363.
Scheme 5
the same conditions as for converting 34 into 35 followed by
an acid-mediated hydrolysis of the TBS group afforded the end
product (aR)-marasin (75% e.e.).
Conclusions
A synthesis of the natural antibiotic marasin has been achieved
with an enantioselectivity much higher than that reported for
the previous chemical synthesis. En route to the total synthesis,
different approaches to the construction of the chiral allenediyne
motif were examined. Among these, coupling of an optically active
bromoallene (78% e.e., prepared from the corresponding propargyl
tosylate) with a zincated diyne gave the expected allenediyne in
36% e.e. Direct coupling of the tosylate precursor (97% e.e.) with
the same diyne species led to the allenediyne of higher enantiopu-
rity (89% e.e.), but of different axial configuration. Installation of
the same allenediyne arrangement through elimination of a diyne-
containing allyl acetate–vinyl sulfoxide (98% e.e.) afforded the
allenediyne in 73% e.e., with a chirality transfer efficiency of 74% (=
73% e.e. (for the allenediyne)/98% e.e. (for the precursor)). With an
iodine to replace the chiral sulfinyl in the elimination substrate, the
chirality was more efficiently transferred from the allylic acetate
to the allenix axis, with the efficiency being 84% (= 75% e.e./89%
e.e.). If the substrate for the elimination reaction contained one less
triple bond, the corresponding allenyne could be built with much
better enantiopurity (94% e.e.). However, subsequent attachment
of another acetylene unit via alkyne–alkyne coupling under a
variety sets of conditions was unsuccessful because of the substrate
instability.
(R)-3-Tosyloxy-pent-1-yn-5-yl acetate (9). A solution of 6
(240 mg, 0.65 mmol) and DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, 16 mg, 0.065 mmol) in 9 : 1 MeCN–H2O (6.5 cm3)
was stirred at ambient temperature for 2 h before being diluted with
EtOAc (40 cm3), washed in turn with aq. sat. NaHSO3, aq. sat.
NaHCO3, and brine, and dried over anhydrous Na2SO4. Removal
of the solvent on a rotary evaporator left an oily residue, which
was directly dissolved in dry CH2Cl2 (5 cm3). The resulting solution
was then cooled in an ice-water bath. Ac2O (0.2 cm3, 1.95 mmol),
pyridine (0.054 cm3, 0.65 mmol), and DMAP (8 mg, 0.065 mmol)
were added. The mixture was stirred at ambient temperature for
2 h before being diluted with Et2O (40 cm3), washed in turn with
aq. sat. CuSO4, aq. sat. NH4Cl, aq. sat. NaHCO3, and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (6 : 1 PE/EtOAc) on
silica gel gave acetate 9 (166 mg, 0.559 mmol, 86% from 6) as a
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colorless oil, which solidified on standing. Recrystallization from
petroleum ether twice raised the e.e. value to 96.5% (tR (major) =
40.03 min, tR (minor) = 33.58 min) as determined by chiral HPLC
on a CHIRALPAK AS column (4.6 ¥ 25 cm) eluting with 95 : 5
n-hexane/i-PrOH at a flow rate of 0.8 cm3 min-1 with the UV
detector set to 214 nm. [a]2D8 +51.7 (c 1.1, CHCl3). 1H NMR
(CDCl3, 300 MHz) d 7.80 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.4 Hz,
2H), 5.18 (dt, J = 2.1, 7.8 Hz, 1H), 4.18-4.07 (m, 2H), 2.46 (d, J =
2.1 Hz, 1H), 2.43 (s, 3H), 2.19–2.08 (m, 2H), 2.00 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 170.6, 145.1, 133.3, 129.7, 128.0, 78.1, 76.8,
67.6, 59.4, 34.6, 21.6, 20.7; FT-IR (film) 3278, 2965, 2115, 1738,
1598 cm-1; ESI-MS m/z 319.1 ([M+Na]+); ESI-HRMS calcd. for
C14H16SO5Na 319.0611 ([M+Na]+), found 319.0617.
98 : 2 n-hexane/i-PrOH at a flow rate of 0.7 cm3 min-1 with the
UV detector set to 214 nm. H NMR (CDCl3, 300 MHz) d 5.51
1
(q, J = 6.8 Hz, 1H), 5.45–5.38 (m, 1H), 3.71 (br t, J = 6.1 Hz,
2H), 2.38-2.26 (m, 2H), 2.03 (br s, 1H), 0.18 (s, 9H); 13C NMR
(CDCl3, 75 MHz) d 215.0, 90.6, 89.9, 87.8, 75.3, 74.8, 70.1, 61.4,
31.3, -0.50; FT-IR (film) 3292, 2958, 2202, 2085, 1948, 1252, 1047,
867, 758 cm-1; EI-MS m/z (%) 204 (M+, 4), 190 (19), 189 (100),
164 (14), 131 (13), 115 (19), 75 (16), 43 (16); EI-HRMS calcd. for
C12H16OSi 204.0970 (M+), found 204.0964.
(aS)-1-Bromo-5-acetoxypenta-1,2-diene (11). A solution of
tosylate 9 (100 mg, 0.34 mmol) in dry THF (1.0 cm3) was added
to a solution of CuBr·SMe2 (139 mg, 0.68 mmol), LiBr (60 mg,
0.68 mmol) in dry THF (1.5 cm3) stirred at ambient temperature.
Stirring was then continued for 4 h at the same temperature.
Et2O (30 cm3) was added. The mixture was washed with aq. sat.
NH4Cl (twice) and dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (20 : 1
PE/Et2O) on silica gel gave bromoallene 11 (66 mg, 0.322 mmol,
95%) as a colorless oil. [a]2D5 +74.7 (c 1.2, CHCl3); 78% e.e. (tR
(major) = 11.68 min, tR (minor) = 12.48 min) as determined by
chiral HPLC on a CHIRALPAK AS column (0.46 ¥ 25 cm) eluting
with 98 : 2 n-hexane/i-PrOH at a flow rate of 0.8 cm3 min-1 with
(aS)-1-Trimethylsilyl-9-acetoxynona-5,6-diene-1,3-diyne (12a)
derived from tosylate 9. MeLi (1.5 M, in Et2O, 0.4 cm3, 0.6 mmol)
was added to a solution of bis-trimethylsilylbutadiyne (117 mg,
0.6 mmol) in dry THF (4 cm3) stirred at -10 ◦C under argon.
The flask was wrapped up with aluminium foil to exclude light.
Stirring was then continued at ambient temperature for 50 min.
At 0 ◦C, a solution of anhydrous ZnBr2 in dry THF (1 M,
0.6 cm3, 0.6 mmol) was added. The resulting solution was stirred
at ambient temperature for 10 min before being added to another
flask containing Pd(PPh3)4 (29 mg, 0.025 mmol) stirred in a -78 ◦C
bath under argon. The mixture was stirred at -78 ◦C for 10 min. A
solution of tosylate 9 (148 mg, 0.5 mmol) in dry THF (2 cm3) was
introduced. Stirring was continued while the bath temperature was
allowed to warm slowly to -20 ◦C, when TLC showed completion
of the reaction. Aq. sat. NH4Cl was added, followed by Et2O.
The phases were separated. The organic layer was concentrated
on a rotary evaporator. The residue was chromatographed (15 : 1
PE/Et2O) on silica gel to give 12a (88 mg, 0.36 mmol, 72%) as a
yellowish oil (determination of the e.e. value was performed on the
corresponding 12b as given below). [a]2D6 +264.5 (c 0.5, CHCl3).
1H NMR (CDCl3, 300 MHz) d 5.47 (q, J = 6.8 Hz, 1H), 5.42–5.39
(m, 1H), 4.13 (t, J = 6.4 Hz, 2H), 2.38 (dq, J = 6.6, 3.0 Hz, 2H),
2.05 (s, 3H), 0.17 (s, 9H); 13C NMR (CDCl3, 75 MHz) d 215.1,
170.9, 90.1, 89.9, 87.8, 75.7, 74.9, 69.9, 62.6, 27.4, 20.8, -0.51;
FT-IR (film) 2960, 2202, 2103, 1947, 1743, 1365, 1237, 1047, 846,
761 cm-1; EI-MS m/z (%) 246 (M+, 50), 231 (12),189 (22), 171 (43),
129 (17), 121 (30), 75 (25), 73 (48), 43 (100); EI-HRMS calcd. for
C14H18O2Si 246.1076 (M+), found 246.1082.
1
the UV detector set to 214 nm. H NMR (CDCl3, 300 MHz) d
6.00 (dt, J = 5.9, 2.3 Hz, 1H), 5.39 (q, J = 6.4 Hz, 1H), 4.18 (t,
J = 6.3 Hz, 2H), 2.49 (dq, J = 2.4, 6.4 Hz, 2H), 2.08 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 202.7, 171.0, 96.5, 73.0, 62.4, 27.6, 20.9;
FT-IR (film) 3278, 2965, 2115, 1738, 1598 cm-1; EI-MS m/z (%)
205 (M+ (81Br), 0.06), 204 (M+ (79Br), 0.01), 125 (M–Br, 22), 83
(4), 73 (5), 66 (5), 65 (52), 43 (100); EI-HRMS calcd. for C7H9O2
125.0603 ([M–Br]+), found 125.0607.
(aR)-1-Trimethylsilyl-9-acetoxynona-5,6-diene-1,3-diyne (13a)
derived from bromoallene 11. Using the same procedure for
conversion of 9 into 12a given above (except with bromoallene 11
to replace tosylate 9 as the starting material), 11 was converted
into 13a in 70% yield (36% e.e. as measured by chiral HPLC
on the corresponding 13b obtained via a DIBAL-H reduction
as described for conversion of 12a into 12b given above). [a]2D7 -99
(c 0.3, CHCl3). For other spectroscopic data, cf. those reported
above for its antipode 12a.
(5R,6Z)-9-(tert-Butyldimethylsilyloxy)-6-phenylthio-1-trime-
thylsilylnon-6-ene-1,3-diyn-5-ol ((R)-25). To a solution of ketone
26 (◦100 mg, 0.226 mmol) in dry THF (1.5 cm3) stirred at
-15 C under argon was added a solution of (S)-2-methyl-CBS-
oxazaborolidine (1 M, in toluene, 0.566 cm3, 0.566 mmol). The
mixture was stirred at the same temperature for 15 min before
BH3·Me2S (2 M, in THF, 0.905 cm3, 1.81 mmol) was introduced.
(aS)-9-Trimethylsilylnona-3,4-diene-6,8-diyn-1-ol derived origi-
nally from tosylate 9 (12b). DIBAL-H (1.0 M, in cyclohexane,
1.1 cm3, 1.1 mmol) was added to a solution of acetate 12a
(derived from direct coupling of tosylate 9 with diyne 10 described
above, 90 mg, 0.366 mmol) in dry CH2Cl2 (2.0 cm3) stirred
at -78 ◦C under argon. After completion of the addition, the
mixture was stirred at the same temperature for 15 min. MeOH
(0.3 cm3) was carefully added to quench the excess hydride,
followed by 10% aq. sodium potassium tartrate. The mixture was
stirred at ambient temperature until a two-phase clear system
was formed. Et2O was added. The phases were separated. The
organic layer was concentrated on a rotary evaporator. The residue
was chromatographed (4 : 1 PE/Et2O) on silica gel to afford
allendiynol 12b (67 mg, 0.328 mmol, 90%) as a yellowish oil.
[a]2D7 +244.4 (c 0.95, CHCl3), 89% e.e. (tR (major) = 14.86 min,
tR (minor) = 14.09 min) as determined by chiral HPLC analysis
on a CHIRALPAK OJ-H column (0.46 ¥ 25 cm) eluting with
◦
Stirring was then continued at -15 C for 1 h. MeOH (0.5 cm3)
was added, followed by Et2O (30 cm3). The mixture was washed in
turn with aq. sat. NH4Cl, aq. sat. NaHCO3, and brine before being
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (30 : 1 PE/EtOAc) on
silica gel afforded (R)-25 (95 mg, 0.214 mmol, 95%) as a yellowish
oil. [a]2D4 +147.3 (c 1.0, CHCl3). For other spectroscopic data, cf.
those for racemic 25 given in the ESI†.
(5R,6Z)-5-Acetoxy-9-(tert-butyldimethylsilyloxy)-6-phenylthio-
1-trimethylsilylnon-6-ene-1,3-diyne (27). To a solution of (R)-
25 (86 mg, 0.194 mmol) in dry CH2Cl2 (5 cm3) stirred in an
4748 | Org. Biomol. Chem., 2010, 8, 4744–4752
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ice-water bath were added Ac2O (0.059 cm3, 0.582 mmol), Et3N
(0.081 cm3, 0.582 mmol), and DMAP (2.4 mg, 0.019 mmol). The
mixture was stirred at ambient temperature for 40 min before
being diluted with Et2O (20 cm3), washed in turn with aq. sat.
NH4Cl, aq. sat. NaHCO3, and brine, and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (60 : 1 PE/EtOAc) on silica gel provided acetate
27 (85 mg, 0.175 mmol, 90%) as a colorless oil. 1H NMR (CDCl3,
400 MHz) d 7.25–7.14 (m, 5H), 6.76 (t, J = 6.5 Hz, 1H), 5.91 (s,
1H), 3.71 (t, J = 6.3 Hz, 2H), 2.70–2.56 (m, 2H), 1.92 (s, 3H), 0.91
(s, 9H), 0.19 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d 169.2, 141.3, 134.4, 129.7, 129.0, 126.5, 88.7, 86.9, 72.4, 72.0,
66.7, 61.6, 33.6, 25.9, 20.5, 18.3, -0.58, -5.4; FT-IR (film) 3068,
2956, 2929, 2857, 2118, 1751, 1577, 1371, 1252, 1218, 1099, 844,
776 cm-1; ESI-MS m/z 509.2 ([M+Na]+); ESI-HRMS calcd. for
C26H38Si2O3SNa 509.1972 ([M+Na]+), found 509.1974.
(m, 1H), 3.01–2.92 (m, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 0.17 (s,
9H); 13C NMR (CDCl3, 100 MHz) d 170.9, 168.7, 143.0, 141.6,
139.4, 131.2, 129.4, 124.3, 89.2, 86.5, 72.2, 71.4, 62.1, 58.5, 28.5,
20.8, 20.7, -0.65; FT-IR (film) 3059, 2960, 2923, 2109, 1747, 1650,
1443, 1367, 1251, 1217, 1047, 956, 848, 757, 602 cm-1; ESI-MS
m/z 453.1 ([M+Na]+); MALDI-HRMS calcd. for C22H26SiO5SNa
453.1162 ([M+Na]+), found 453.1166.
Data for the more polar isomer of 28 (28b): [a]2D5 +156.6 (c 1.0,
CHCl3); 97.8% e. e.. 1H NMR (CDCl3, 400 MHz) d 7.57–7.52 (m,
2H), 7.51–7.41 (m, 3H), 6.84 (t, J = 7.7 Hz, 1H), 6.39 (s, 1H), 4.38–
4.27 (m, 2H), 3.18–3.09 (m, 1H), 3.05–2.96 (m, 1H), 2.13 (s, 3H),
1.41 (s, 3H), 0.19 (s, 9H); 13C NMR (CDCl3, 100 MHz) d 170.8,
168.4, 142.5, 141.9, 141.0, 130.5, 129.1, 124.0, 89.2, 86.6, 72.5, 71.6,
62.2, 57.2, 28.6, 20.8, 19.8, -0.64; FT-IR (film) 3059, 2961, 2925,
2108, 1747, 1444, 1368, 1218, 1083, 1049, 848, 753 cm-1; ESI-MS
m/z 453.0 ([M+Na]+); MALDI-HRMS calcd. for C22H26SiO5SNa
453.1162 ([M+Na]+), found 453.1168.
(5R,6Z)-5-Acetoxy-9-(tert-butyldimethylsilyloxy)-6-phenylsul-
finyl-1-trimethylsilylnon-6-ene-1,3-diyne (28a and 28b). NaIO4
(62 mg, 0.29 mmol) was added to a solution of 27 (28 mg,
0.0575 mmol) in a mixture of THF (0.6 cm3), EtOH (0.1 cm3),
and H2O (0.3 cm3) stirred at ambient temperature. Stirring was
continued overnight. The solids were filtered off (washing with
Et2O). The filtrate and washings were combined, washed with
water and brine before being dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column chro-
matography (5 : 1 PE/EtOAc) on silica gel gave the intermediate
alcohol (27a, 19 mg, 0.0510 mmol, 89% from 27) as a colorless
oil, which was directly dissolved in dry CH2Cl2 (1.0 cm3) and
cooled in an ice-water bath. To this solution were added Ac2O
(0.015 cm3, 0.153 mmol), Et3N (0.021 cm3, 0.153 mmol) and
DMAP (0.6 mg, 0.005 mmol). The mixture was stirred at ambient
temperature for 40 min before being diluted with Et2O (10 cm3),
washed with aq. sat. NH4Cl, aq. sat. NaHCO3, and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (20 : 1 PE/EtOAc) on
silica gel gave the intermediate phenylthio ether-diacetate (27b,
21 mg, 0.0507 mmol, 99% from 27a) as a colorless oil, which
was dissolved in CH2Cl2–EtOH (10 : 1 v/v, 0.3 cm3) and added
to a solution of Sc(OTf)3 (4.9 mg, 0.01 mmol) in CH2Cl2–EtOH
(10 : 1 v/v, 0.2 cm3) and aq. H2O2 (50%, 0.010 cm3, 0.15 mmol)
stirred at ambient temperature. The mixture was stirred at ambient
temperature overnight. Water was added, followed by Et2O. The
phases were separated. The organic layer was washed with water
(several times), aq. sat. Na2SO3, and brine before being dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1 : 1 PE/EtOAc) on silica gel gave
the less polar isomer (28a, 9 mg, 0.0209 mmol, 41% from 27b)
and the more polar isomer of 28 (28b, 6 mg, 0.0139 mmol, 27%
from 27b) as colorless oils, along with unreacted phenylthio ether-
diacetate (27b, 4 mg, 0.00965 mmol, 19% of the starting 27b).
Data for the less polar isomer of 28 (28a, which differs from
28b only in the configuration of the sulfoxide): [a]2D5 -132.6 (c 1.0,
CHCl3); 98% e.e. (tR (major) = 17.69 min, tR (minor) = 12.35 min)
as determined by chiral HPLC on a CHIRALPAK OD column
(0.46 ¥ 25 cm) eluting with 80 : 20 n-hexane/i-PrOH at a flow rate
(aS)-1-Trimethylsilyl-9-acetoxynona-5,6-diene-1,3-diyne (12a)
derived from sulfoxide 28b. A solution of the more polar isomer
of 28 (28b, 20 mg, 0.0465 mmol) in dry THF (1 cm3) was added
to a solution of i-PrMgBr (2.5 M, in Et2O, 0.11 cm3, 0.28 mmol)
in dry THF (1 cm3) stirred at -100 ◦C under argon. The mixture
was stirred at the same temperature for 20 min. Aq. sat. NH4Cl
was added. The mixture was extracted with Et2O, washed with
water and brine, and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography
(15 : 1 PE/Et2O) on silica gel gave 12a (10 mg, 0.0406 mmol, 87%)
as a colorless oil. [a]2D5 +156.6 (c 0.39, CHCl3). The e.e. value was
73% as determined on the corresponding 12b as described above.
If using 28a (the less polar isomer of 28) to replace 28b, the
product 12a was of much lower enantiopurity as indicated by the
specific rotation ([a]2D5 +81.4 (c 0.351, CHCl3)).
(2Z,5R)-5,7-Di-tert-butyldimethylsilyloxy-4-iodohept-2-en-1-
yne (33). DIBAL-H (1.0 M, in cyclohexane, 0.46 cm3, 0.46 mmol)
was added to a solution of 31 (110 mg, 0.208 mmol) in dry CH2Cl2
(2 cm3) stirred at -78 ◦C under argon. Stirring was continued
at the same temperature for 1 h. 1 N HCl (0.5 cm3) was added,
followed by EtOAc (10 cm3). The phases were separated. The
organic layer was washed with 1 N HCl. The combined aqueous
layers were back-extracted with EtOAc (4 ¥ 5 cm3). The combined
organic layers were washed with water and brine before being
dried over anhydrous Na2SO4. The solvent was removed by rotary
evaporation. The residue (the intermediate alcohol) was dissolved
in dry CH2Cl2 (2 cm3). NaHCO3 (35 mg, 0.416 mmol) was added,
followed by Dess–Martin periodinane (106 mg, 0.25 mmol). The
mixture was stirred at ambient temperature for 1 h. Aq. sat.
Na2SO3 (2 cm3) was added. The mixture was stirred until all solids
dissolved before being extracted with Et2O (2 ¥ 10 cm3), washed
with aq. sat. NH4Cl, and dried over anhydrous Na2SO4. Removal
of the solvent on a rotary evaporator and column chromatography
(80 : 1 PE/Et2O) on silica gel gave the intermediate aldehyde
(90 mg, 0.186 mmol, 89% from 31) as a yellowish-green oil.
NaHMDS (2.0 M, in THF, 0.12 cm3, 0.24 mmol) was added to
a solution of carbine precursor 32 (64 mg, 0.24 mmol) in dry THF
(1.5 cm3) stirred at -78 ◦C under argon. Stirring was continued
at the same temperature for 40 min (a yellow color developed).
A solution of the above obtained intermediate aldehyde (90 mg,
0.186 mmol) in dry THF (1.0 cm3) was introduced. After stirring
1
of 0.7 cm3 min-1 with the UV detector set to 214 nm. H NMR
(CDCl3, 400 MHz) d 7.62-7.57 (m, 2H), 7.56–7.46 (m, 3H), 6.70
(t, J = 7.7 Hz, 1H), 6.10 (s, 1H), 4.35–4.24 (m, 2H), 3.16–3.07
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at -78 ◦C for another 10 min, 15-crown-5 (0.037 cm3, 0.185 mmol)
was added. The color of the system darkened. The mixture was
stirred at -78 ◦C for another 2 h before the bath was allowed
to warm to ambient temperature. Aq. sat. NH4Cl (5 cm3) was
added, followed by Et2O (30 cm3). The phases were separated.
The organic layer was dried over anhydrous Na2SO4. Removal of
the solvent on a rotary evaporator and column chromatography
(300 : 1 PE/EtOAc) on silica gel gave the iodoenyne 33 (86 mg,
0.179 mmol, 96% from the intermediate aldehyde, 85% from 31)
along with unreacted 34 (16 mg, 0.048 mmol, 16%). Data for 35:
[a]2D3 +199.8 (c 0.78, CHCl3); 94% e.e. (tR (major) = 15.20 min, tR
(minor) = 20.14 min) as determined by chiral HPLC analysis on
a CHIRALPAK AS column (0.46 ¥ 25 cm) eluting with 90 : 10
n-hexane/i-PrOH at a flow rate of 0.8 cm3 min-1 with the UV
detector set to 214 nm. 1H NMR (CDCl3, 300 MHz) d 5.45 (dq,
J = 1.1, 6.4 Hz, 1H), 5.41–5.36 (m, 1H), 4.16 (t, J = 6.6 Hz, 2H),
2.86 (br t, J = 1.7 Hz, 1H), 2.45–2.08 (m, 2H), 2.07 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 213.5, 171.0, 89.6, 78.4, 75.5, 62.8,
27.4, 20.9; FT-IR (film) 3259, 2963, 2875, 2111, 1956, 1740, 1367,
1238, 1044 cm-1; EI-MS m/z (%) 150 (M+, 0.8), 109 (12), 108 (38),
90 (21), 89 (41), 63 (8), 51 (10), 43 (100); EI-HRMS calcd. for
C9H10O2 150.0681 (M+), found 150.0677.
1
as a colorless oil. [a]D23 +19.4 (c 1.0, CHCl3); H NMR (CDCl3,
300 MHz) d 6.40 (d, J = 1.2 Hz, 1H), 4.16 (dd, J = 7.2, 4.6 Hz, 1H),
3.74–3.55 (m, 2H), 3.35 (d, J = 2.2 Hz 1H), 1.91–1.64 (m, 2H), 0.92
(s, 9H), 0.90 (s, 9H), 0.09–0.05 (several singlets, 12H altogether);
13C NMR (CDCl3, 75 MHz) d 127.5, 115.9, 83.2, 82.7, 75.4, 58.4,
40.4, 25.9, 25.8, 18.14, 18.12, -4.5, -5.1, -5.3, -5.4; FT-IR (film)
3301, 2955, 2929, 2885, 2858, 1472, 1256, 1097 cm-1; EI-MS m/z
(%) 423 ([M–C4H9]+ 8), 395 (15), 295 (16), 267 (8), 219 (29),
189 (59), 147 (100), 133 (16); EI-HRMS calcd. for C19H37Si2O2I
480.1377 ([M]+), found 480.1363.
(aS)-Nona-3,4-diene-6,8-diyn-1-yl acetate (12a) derived from
35. A solution of 35 (15 mg, 0.10 mmol) and 1-iodo-2-
trimethylsilylacetylene 36 (34 mg, 0.15 mmol) in DMSO (0.6 cm3)
was added to a solution of Pd(PPh3)4 (6 mg, 0.005 mmol), CuI
(1.9 mg, 0.01 mmol) and Et3N (0.042 cm3, 0.3 mmol) in DMSO
(0.3 cm3) stirred at ambient temperature under argon. Stirring was
continued at the same temperature for 30 min. Aq. sat. NH4Cl was
added. The mixture was extracted with Et2O (3 ¥ 3 cm3), washed
with aq. sat. NH4Cl, and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(20 : 1 PE/Et2O) on silica gel delivered 12a (6 mg, 0.0244 mmol,
24%) as a colorless oil. [a]2D7 +44.1 (c 0.3, CHCl3); 14.8% e.e.
(2Z,5R)-5,7-Diacetoxy-4-iodohept-2-en-1-yne
(34). Conc.
HCl (0.8 cm3, 9.6 mmol) was added to a solution of 33 (250 mg,
0.52 mmol) in THF (4 cm3) stirred in an ice-water bath. Stirring
was continued at the same temperature for 1.5 h. EtOAc (30 cm3)
was added. The phases were separated. The organic layer was
washed with aq. sat. NaHCO3 and brine (twice). The aqueous
layers were back-extracted with EtOAc (2 ¥ 10 cm3). The
combined organic phases were washed with brine and dried
over anhydrous Na2SO4. The solvent was removed by rotary
evaporation. The residue was dissolved in dry CH2Cl2 (5 cm3) and
cooled in an ice-water bath. To this solution were added in turn
Ac2O (0.31 cm3, 3.12 mmol), pyridine (0.087 cm3, 1.04 mmol),
and DMAP (6 mg, 0.052 mmol). The mixture was stirred at
ambient temperature for 2 h before being diluted with Et2O
(40 cm3), washed in turn with aq. sat. CuSO4, aq. sat. NH4Cl,
aq. sat. NaHCO3, and brine, and dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column
chromatography (5 : 1 PE/Et2O) on silica gel afforded diacetate
34 (135 mg, 0.402 mmol, 77%) as a colorless oil. [a]2D2 +22.8 (c
1.1, CHCl3); 95% e.e. (tR (major) = 22.94 min, tR (minor) = 15.85
min) as determined by chiral HPLC analysis on a CHIRALPAK
AS column (0.46 ¥ 25 cm) eluting with 90 : 10 n-hexane/i-PrOH
at a flow rate of 0.8 cm3 min-1 with the UV detector set to 214
(Z)-9-tert-Butyldimethylsilyloxy-6-iodo-1-trimethylsilylnon-6-
ene-1,3-diyn-5-ol (( )-41a). DIBAL-H (1.0 M, in cyclohexane,
0.66 cm3, 0.66 mmol) was added to a solution of (Z)-39 (107 mg,
0.278 mmol) in dry CH2Cl2 (3 cm3) stirred at -78 ◦C under
argon. Stirring was continued at the same temperature for 1 h.
1 N HCl (0.6 cm3) was added, followed by EtOAc (10 cm3).
The phases were separated. The organic layer was washed with
1 N HCl. The combined aqueous layers were back-extracted with
EtOAc (4 ¥ 5 cm3). The combined organic layers were washed
with water and brine before being dried over anhydrous Na2SO4.
The solvent was removed by rotary evaporation. The residue
(the intermediate alcohol) was dissolved in dry CH2Cl2 (3 cm3).
NaHCO3 (46 mg, 0.54 mmol) was added, followed by Dess–Martin
periodinane (127 mg, 0.30 mmol). The mixture was stirred at
ambient temperature for 0.5 h. Aq. sat. Na2SO3 (2 cm3) was added.
The mixture was stirred until all solids dissolved before being
extracted with Et2O (2 ¥ 20 cm3), washed with aq. sat. NH4Cl, and
dried over anhydrous Na2SO4. Removal of the solvent on a rotary
evaporator and column chromatography (30 : 1 PE/EtOAc) gave
the intermediate aldehyde (80 mg, 0.235 mmol, 85% from (Z)-39)
as a colorless oil.
To a solution of bis-trimethylsilyl-butadiene (370 mg, 1.9 mmol)
in dry THF (10 cm3) stirred at -10 ◦C under argon was added MeLi
(1.5 M, in Et2O, 1.12 cm3, 1.68 mmol). The flask was wrapped up
with aluminium foil to exclude light. Stirring was then continued at
ambient temperature for 50 min to yield a solution of the lithiated
diyne 24. The bath was cooled down to -78 ◦C and the cold
solution of 24 was added dropwise to (via a cannula) another flask
containing a solution of the above obtained aldehyde 40 (380 mg,
1.12 mmol) in dry THF (5 cm3) stirred at -78 ◦C under argon. The
mixture was stirred at -78 ◦C for another 2 h before being diluted
with Et2O, washed with aq. sat. NH4Cl (twice), and dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
1
nm. H NMR (CDCl3, 300 MHz) d 6.48 (d, J = 1.4 Hz, 1H),
5.08 (t, J = 6.7 Hz, 1H), 4.18–4.00 (m, 2H), 3.43 (d, J = 1.7 Hz,
1H), 2.17–1.90 (m, 2H), 2.10 (s, 3H), 2.06 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 170.8, 169.5, 120.2, 118.3, 84.5, 82.5, 75.2,
59.6, 33.5, 21.0, 20.8; FT-IR (film) 3273, 2949, 2110, 1741, 1370,
1229, 1047 cm-1; ESI-MS m/z 358.8 ([M+Na]+); MALDI-HRMS
calcd. for C11H13O4INa 358.9751 ([M+Na]+), found 358.9749.
(aS)-Hepta-3,4-diene-6-yn-1-yl acetate (35). A solution of 34
(101 mg, 0.3 mmol) in dry THF (1.0 cm3) was added to a solution
of i-PrMgBr (2 M, in Et2O, 0.9 cm3, 1.8 mmol) in dry THF
(5 cm3) stirred at -78 ◦C under argon. Stirring was continued
at -60 ◦C for 4.5 h. Aq. sat. NH4Cl (10 cm3) was added, followed
by Et2O (50 cm3). The phases were separated. The organic layer
was dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography (20 : 1 PE/Et2O)
on silica gel gave 35 (36 mg, 0.24 mmol, 80%) as a colorless oil,
4750 | Org. Biomol. Chem., 2010, 8, 4744–4752
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and column chromatography (15 : 1 PE/Et2O) on silica gel gave
racemic 41 (510 mg, 1.10 mmol, 98% from aldehyde 40, 83% from
ester 39) as a colorless oil. 1H NMR (CDCl3, 400 MHz) d 6.21 (dt,
J = 0.6, 6.6 Hz, 1H), 4.83 (d, J = 7.3 Hz, 1H), 3.68 (t, J = 6.5 Hz,
2H), 2.62 (d, J = 7.6 Hz, 1H), 2.39 (q, J = 6.5 Hz, 2H), 0.89 (s, 9H),
0.19 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 136.0,
108.9, 88.9, 86.9, 75.1, 71.7, 70.0, 61.0, 39.2, 25.9, 18.3, -0.56, -5.3;
FT-IR (film) 3378, 2956, 2929, 2857, 2222, 2107, 1645, 1252, 1097,
844, 777 cm-1; ESI-MS m/z 484.9 ([M+Na]+); ESI-HRMS calcd.
for C18H31O2Si2INa 485.07995 ([M+Na]+), found 485.08008.
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (25 : 1 PE/Et2O) on silica gel afforded 43 (200 mg,
0.463 mmol, 79% from (S)-41a) as a colorless oil, which turned
yellow on standing. [a]D23 +7.7 (c 0.98, CHCl3); 1H NMR (CDCl3,
400 MHz) d 6.35 (t, J = 6.6 Hz, 1H), 5.98 (s, 1H), 3.70 (t, J = 6.4 Hz,
2H), 2.42 (q, J = 6.5 Hz, 2H), 2.29 (d, J = 1.1 Hz, 1H), 2.14 (s, 3H),
0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 168.9,
139.4, 101.2, 71.4, 70.9, 70.0, 69.7, 67.1, 60.8, 39.3, 25.8, 20.8,
18.2, -5.4; FT-IR (film) 3291, 2954, 2929, 2858, 2071, 1752, 1645,
1471, 1370, 1255, 1218, 1098, 1015, 837, 777 cm-1; ESI-MS m/z
455.1 ([M+Na]+); ESI-HRMS calcd. for C17H25O3SiINa 455.0510
([M+Na]+), found 455.0514.
(Z)-9-tert-Butyldimethylsilyloxy-6-iodo-1-trimethylsilylnon-6-
ene-1,3-diyn-5-one (42). Dess–Martin periodinane (149 mg,
0.35 mmol) was added to a solution of ( )-41 (135 mg, 0.292 mmol)
in dry CH2Cl2 (2 cm3) stirred at ambient temperature, followed
by NaHCO3 (22 mg, 0.526 mmol). Stirring was continued at the
same temperature for 30 min. Aq. Na2SO3 (2 cm3) was added.
The mixture was stirred until all solids dissolved before being
extracted with Et2O (2 ¥ 20 cm3), washed with aq. NH4Cl, and
dried over anhydrous Na2SO4. Removal of the solvent on a rotary
evaporator and column chromatography (50 : 1 PE/Et2O) on silica
gel afforded ketone 42 (122 mg, 0.265 mmol, 91%) as a yellowish
(3aR)-Nona-3,4-diene-6,8-diyn-1-ol ((aR)-1, (aR)-Marasin).
A
solution of 43 (100 mg, 0.23 mmol) in dry THF (1.0 cm3) was added
to a solution of i-PrMgBr (2.5 M, in Et2O, 0.9 cm3, 2.3 mmol) in
dry THF (10 cm3) stirred at -78 ◦C under argon. Stirring was
continued at -60 ◦C for 12 h. Aq. sat. NH4Cl (10 cm3) was added,
followed by Et2O (50 cm3). The phases were separated. The organic
layer was dried over anhydrous Na2SO4. The solvent was removed
by rotary evaporation. The residue was dissolved in Et2O–MeOH
(1.0 cm3 each) and cooled in an ice-water bath. Conc. HCl (6 drops
from a pipette) was added. The mixture was stirred at the same
temperature for 40 min before being diluted with Et2O (30 cm3),
washed with aq. sat. NaHCO3 and brine, and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (2 : 1 PE/Et2O) on silica gel gave (aR)-1 (marasin,
24 mg, 0.182 mmol, 79% from 43) as a colorless oil (neat marasin
turned yellow rapidly on standing, but could be kept for much
longer time in a freezer as a dilute solution in EtOH). [a]2D3 -266.0
(c 0.19, CH2Cl2) (lit.2 [a]D24 -360 (c 0.07, CH2Cl2)); [a]2D3 -271.2
(c 1.1, EtOH) (lit.1a [a]D25 -325 (EtOH)); 75% e.e. (tR (major) =
15.25 min, tR (minor) = 14.39 min) as determined by chiral HPLC
analysis on a CHIRALPAK OJ-H column (0.46 ¥ 25 cm) eluting
with 90 : 10 n-hexane/i-PrOH at a flow rate of 0.7 cm3 min-1 with
the UV detector set to 214 nm. 1H NMR (CDCl3, 300 MHz) d 5.56
(q, J = 6.9 Hz, 1H), 5.44–5.41 (m, 1H), 3.75 (t, J = 6.3 Hz, 2H),
2.40 (s, 1H), 2.40–2.32 (m, 2H), 1.77 (br s, 1H); 13C NMR (CDCl3,
100 MHz) d 215.1, 90.9, 75.0, 74.2, 70.7, 68.7, 68.1, 61.5, 31.3;
FT-IR (film) 3294, 2207, 1950, 1046 cm-1; UV nmax (EtOH) 278,
263, 249, 237, 212 nm; EI-MS m/z (%) 132 (M+, 14), 131 (76), 103
(100), 78 (62), 77 (62), 76 (47), 75 (79), 74 (65); EI-HRMS calcd.
for C9H8O 132.0575 (M+), found 132.0576.
1
oil. H NMR (CDCl3, 400 MHz) d 7.74 (t, J = 6.5 Hz, 1H),
3.81 (t, J = 6.1 Hz, 2H), 2.68 (q, J = 6.3 Hz, 2H), 0.90 (s, 9H),
0.22 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 172.0,
158.2, 111.5, 97.6, 85.5, 77.6, 68.1, 60.2, 41.0, 25.8, 18.2, -0.83,
-5.4; FT-IR (film) 2956, 2852, 2220, 2099, 1647, 1597, 1253, 1096,
847 cm-1; ESI-MS m/z 482.9 ([M+Na]+); ESI-HRMS calcd. for
C18H29O2Si2INa 483.0643 ([M+Na]+), found 483.0632.
(6Z,5S)-9-tert-Butyldimethylsilyloxy-6-iodo-1-trimethylsilyl-
non-6-ene-1,3-diyn-5-ol ((S)-41a). To a solution of ketone 42
(290 mg, 0.63 mmol) in dry THF (5 cm3) stirred at -15 ◦C under
argon was added a solution of (R)-2-methyl-CBS-oxazaborolidine
(1 M, in toluene, 1.26 cm3, 1.26 mmol). The mixture was stirred at
the same temperature for 15 min before BH3·Me2S (2 M, in THF,
0.79 ◦cm3, 1.58 mmol) was introduced. The mixture was stirred at
-15 C for 1 h. MeOH (1.0 cm3) was added, followed by Et2O
(50 cm3). The mixture was washed in turn with aq. sat. NH4Cl,
aq. sat. NaHCO3, and brine before being dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (15 : 1 PE/Et2O) on silica gel afforded (S)-41a
(275 mg, 0.595 mmol, 94%) as a colorless oil. [a]2D4 -31.5 (c 1.0,
CHCl3). For other spectroscopic data, cf. those for racemic 41
given above. The e.e. value was determined on the corresponding
(S)-41b as described in the ESI.†
Acknowledgements
This work was supported by the National Basic Research Pro-
gram of China (973 Program) (2010CB833200), the National
Natural Science Foundation of China (20921091, 20672129,
20621062, 20772143), and the Chinese Academy of Sciences
(KJCX2.YW.H08).
(6Z,5S)-5-Acetoxy-9-tert-butyldimethylsilyloxy-6-iodonon-6-
ene-1,3-diyne (43). K2CO3 (81 mg, 0.587 mmol) was added to
a solution of (S)-41a (270 mg, 0.587 mmol) in Et2O–MeOH
(1 : 1 v/v, 2.0 cm3) stirred at ambient temperature. The mixture was
stirred for another 10 min before being diluted with Et2O (50 cm3),
washed with aq. sat. NH4Cl and dried over anhydrous Na2SO4.
The solvent was removed on a rotary evaporator. The residue
was dissolved in dry CH2Cl2 (5.0 cm3) and cooled in an ice-water
bath. To this solution were added Ac2O (0.182 cm3, 1.76 mmol),
Et3N (0.245 cm3, 1.76 mmol), and DMAP (7 mg, 0.0587 mmol).
The mixture was stirred at ambient temperature for 40 min before
being diluted with Et2O (50 cm3), washed in turn with aq. sat.
NH4Cl, aq. sat. NaHCO3 and brine, and dried over anhydrous
Notes and references
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