The enantioselective total synthesis of nemotin

Article abstract of DOI:10.1039/b923123d

The allene-diyne natural product nemotin was synthesized for the first time through an enantioselective route with the stereogenic center at the lactone moiety derived from l-glutamic acid and the allene axis constructed from the corresponding propargylic

Full text of DOI:10.1039/b923123d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The enantioselective total synthesis of nemotin†
Ya-Jun Jian and Yikang Wu*
Received 4th November 2009, Accepted 25th November 2009
First published as an Advance Article on the web 4th January 2010
DOI: 10.1039/b923123d
The allene–diyne natural product nemotin was synthesized for the first time through an enantioselective
route with the stereogenic center at the lactone moiety derived from L-glutamic acid and the allene axis
constructed from the corresponding propargylic tosylate, and the absolute configuration was thus
established as (4S,5aS).
antibacterial activity, making these types of molecules worthy
Introduction
targets for synthesis. Besides, as all the investigations on nemotin
(1) were performed before NMR spectroscopy became a routine
structural analysis tool, neither 1H nor 13C NMR data of 1 and 2
are available to date. All these factors prompted us to carry out
the work described below.
Nemotin (1) and the closely related nemotinic acid (2) were first
isolated from fungi by Robbins1 and co-workers in the 1940s. The
preliminary biotesting showed that these two natural products
possessed significant activity against a range of microorganisms.
In 1955, Jones2 and co-workers finished determination of the
“planar” structure (Fig. 1) based on UV, IR, hydrogenation and
elemental analysis data.
Results and discussion
Our strategy for the synthesis of 1 is depicted in Fig. 2. The allene
axis was planned to be derived from the propargylic tosylate
6, either directly or via the bromoallene 5, through a coupling
reaction with a proper diyne species. The configuration of the
allene axis in either case is governed by that of the propargylic
stereogenic center. Consequently, the relative configuration of the
end product, nemotin 1, is decided by that of the hidden vicinal
diol unit embedded in the propargylic tosylate.
Fig. 1 The structure of nemotin, nemotic acid and phomallenic acids.
More detailed structural information, including the optical
rotations of 1 and 2, were disclosed later in 1966.3 However,
to the best of our knowledge, the relative as well as absolute
configurations of these two compounds has never been assigned.
Recently, phomallenic acids (3) were identified4 as potent
inhibitors for FabF, an essential enzyme in the bacterial type II
fatty acid synthesis pathway (FAS II). As such a mode of action is
entirely different from that of all previous antibacterial agents,
the high antibacterial activity reported for phomallenic acids,
nemotin and cepacin seems to imply that the allene–diyne unit
shared by these compounds might be a pharmacophore for the
Fig. 2 Outline of our retrosynthetic analysis of nemotin.
Because both the relative and absolute configuration of 1 was
unknown at the outset, we arbitrarily chose one of the four possible
isomers in the initial trial. The hidden diol motif carried in 7 can
be derived from D-arabinose, an inexpensive and readily available
chiral pool, and was therefore selected. The alkyne functionality
was planned to be built up from the chloride 8 by treatment with
LDA (lithium diisopropylamide) as similar5 transformations had
been documented in the literature.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shang-
hai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lin-
gling Road, Shanghai, 200032, China. E-mail: yikangwu@mail.sioc.ac.cn
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of all new compounds, and HPLC spectra of 48 and 51. See DOI:
10.1039/b923123d
The synthetic endeavor was directed towards 8. As shown in
Scheme 1, starting from D-arabinose via diol protection and chain
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Fig. 3 The possible cause for the formation of methyl ketone 18.
in 16 with a MOM, the synthesis took a bypass from alcohol
13 (Scheme 2). After masking the hydroxyl group as a MOM
ether, the benzyl group was cleaved to free the terminal OH for
transformation into a chloride. Unexpectedly, under the same
conditions that were successful for converting 15 into 16 no
discernible amount of chloride 23 was formed at all. The THF
species 24 turned out to be the only isolable product. Conversion
of 22 into 25 was possible (90%), but further transformation of the
tosylate 25 into chloride 23 by treatment with LiCl and DMSO
at rt again led to 24 (20%) as the only identifiable product in the
complex product mixture.
Scheme 1 Reagents and conditions: (a) (i) Me2C(OMe)2, DMF, p-TsOH;
(ii) Ph3P CHCO2Et, toluene, PhCO2H (cat.), 90 ◦C, 62% from
=
D-arabinose; (b) Pd–C, H2, EtOAc, 89%; (c) NaH, BnBr, DMF, 53%,
(d) LiAlH4, THF, 89%; (e) PivCl, Et3N, DMAP (cat.), 66%; (f) TBSOTf
(1.5 eq.), 2,6-lutidine (2.0 eq.), 99%; (g) Pd(OH)2, H2 (1 atm), EtOH, 81%;
(h) PPh3, CCl4, K2CO3, reflux, 69%.
extension, a,b-unsaturated ester 9 was obtained in 62% yield. The
C–C double bond was subsequently saturated by hydrogenation
over 10% Pd–C to deliver diol 10. Further treatment with NaH
and BnBr in DMF led to lactonisation of the secondary OH, while
the primary one was masked as a benzyl ether.
The lactone was then reduced with LiAlH4 to afford diol 12,
which was elaborated into 14 by selective protection of the primary
OH as a Piv (pivaloyl) ester and TBS (tert-butyldimethylsilyl)
protection of the secondary one. The Bn group was cleaved by
hydrogenolysis over Pearlman’s6 catalyst, providing alcohol 15.
Finally, replacement of the terminal OH group with a Cl by
treatment with Ph3P and CCl4 gave desired 16 (which corresponds
to 8 with R and R¢ being Piv and TBS, respectively) in 69% yield.
With chloride 16 in hand, we proceeded with the planned
elimination. Unexpectedly, treatment of 16 with LDA did not lead
to the corresponding alkyne 17, but the methyl ketone 18 (Fig. 3).
Close inspection of the molecular structure suggested that because
of the relative configuration of the hidden diol motif, the one on the
chlorinated methylene group may be more hindered than those at
the 1,3-dioxolane (Fig. 3).‡ As a consequence, the LDA-mediated
deprotonation occurred through pathway b rather than the usual
one a, leading to the enol ether 20 instead of 19. Further hydrolysis
of the acid-sensitive enol ether/acetonide during work-up gave the
unexpected product 18.
Scheme 2 Reagents and conditions: (a) NaI (3.0 eq.), MOMCl (4.0 eq.),
DIPEA (4.4 eq.), MeO(CH2)2OMe, 68%; (b) Pd(OH)2 (20%), H2, 100%;
(c) PPh3, CCl4–CH2Cl2 (4 : 1), K2CO3, 78.6%.
The difficulties with the elimination and the length of the
synthesis urged us to redirect our efforts to a more efficient
approach, the one shown in Scheme 3. Thus, the known7 D-
tartrate-derived acetonide 26 was reduced with DIBAL-H (di-
isobutylaluminium hydride) to give an intermediate dialdehyde,
which upon further reaction with Ohira–Bestmann8 reagent,
afforded diyne 27. Introduction of only one ester group into 27
was troublesome. Use of commonly employed conditions9 (n-BuLi
(1.5 eq.), -78 → -40 ◦C, 1.5 h; then ClCO2Et (1.3 eq.), -78 ◦C, 2 h,
and then warmed to rt) led to 28 in only 30% yield, along with 21%
of the undesired bis-ester. However, deprotonation with n-BuLi
Under the given circumstances, it seemed to us that using a
smaller sized protecting group such as MOM (methoxymethyl)
might increase the chance for the desired deprotonation to occur
at the chlorinated methylene group. By then, all 16 had been
consumed. To find a shorter route to 23, the substrate needed
for testing the elimination, instead of replacing the TBS group
‡ One of the referees suggested that coordination of LDA may also
contribute to this unexpected outcome.
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Scheme 3 Reagents and conditions: (a) (i) DIBAL-H (2.0 eq.), toluene,
-78 ◦C, 2 h, (ii) CH3COC(N2)PO(OMe)2 (3.0 eq.), K2CO3 (4.0 eq.), MeOH,
54% from 26; (b) (i) n-BuLi (1.0 eq.), THF, -78 → 0 ◦C, 2 h, (ii) ClCO2Et
(0.8 eq.), -78 ◦C, 4 h, 49% (along with 48% of recovered 27); (c) CuCl
(0.5 eq.), NaBH4 (4.0 eq.), MeOH, 60–90%; (d) (i) 50% aq. CF3CO2H,
CH2Cl2, (ii) p-TsOH, CH2Cl2, 74% from 29; (e) p-TsCl, NEt3,◦ DMAP,
≡
≡
CH2Cl2, 79%; (f) (i) TMSC C–C CTMS, MeLi·LiBr, THF, -78 C, 1.5 h,
Scheme 4 Reagents and conditions: (a) CuBr, LiBr, THF, (b) (i) Ph3P,
DEAD, p-NO2-benzoic acid, (ii) NaOH, H2O, 76%; (c) p-TsCl, Et3N,
then rt, 2 h, (ii) ZnBr2, Pd(Ph3P)4, -78 → -20 ◦C, 3 h, 64%.
≡
≡
under more forcing conditions (-78 → 0 ◦C, 2 h) and introduction
of less ClCO2Et (0.8 eq.) resulted in a substantially increased
yield (49%), together with 48% of recovered recyclable starting
27. We also tried the t-BuOK (1.0 eq.), DMSO, ClCO2Et (0.8 eq.)
conditions,10 but the product mixture was very complicated.
As we were not aware of any literature precedents of selective
saturation of a conjugated C–C triple bond without affecting a
co-existing isolated one, reduction of 28 to 29 was achieved under
DMAP, CH2Cl2, 68%; (d) (i) TMSC C–C CTMS, MeLi·LiBr, THF,
-78 ◦C, 1.5 h, then rt, 2 h, (ii) ZnBr2, Pd(Ph3P)4, -78 → -20 ◦C, 3 h,
cf. the text.
isomer 37 is even more unstable than 32; it deteriorated almost
instantly on removal of the last drop of solvent. The sample of 37
for HPLC analyses thus had to be kept in solution all the time.
Another problem we encountered then was that 32 and 37 were
inseparable by HPLC on several different types of columns, which
made direct measurement of the d.e. values of these compounds
impossible. Further derivatization of 32/37 was hence inevitable.
However, the modified route (Schemes 3 and 4) leading to 32/37
was still rather lengthy. Accumulation of adequate amounts of
the allenediynes for derivatization was still difficult—a better
alternative had to be found. Then, we noticed a small detail that
Jones1b et al. had reported the specific rotation for the g-lactone 38
(Fig. 4). Through literature searching, we also found the rotation
data15 for such a lactone of an (S) configuration (39, Fig. 4).
Judging from the sign of the specific rotations, the configuration of
natural nemotin at C-4 should be opposite to that in 39 and those
intermediates we synthesized above. The subsequent efforts were
therefore directed to the lactone of the opposite configuration.
11
the CuCl/NaBH4 conditions, which had been developed for
similar reduction of conjugated C–C double bonds. The desired
29 was indeed formed; however, the yield fluctuated considerably
and the over reduction product (with both triple bonds reduced)
was very close to 29 on TLC, making the separation rather
difficult. Mg/MeOH12 conditions were also tested, but only the
fully reduced product was observed.
Removal of the acetonide protecting group and formation of the
lactone ring were then achieved by sequential treatment with 50%
aq. CF3CO2H and p-TsOH in CH2Cl2, resulting in the propargylic
alcohol 30, which, on further reaction with p-TsCl, yielded the
corresponding tosylate 31. The coupling with the diyne unit
was carried out under conditions similar to those in Negishi13
couplings, affording the (4R,5aR)-allenediyne 32 in 64% yield.
This compound, like nemotin, is rather unstable. On removal of the
solvent, it deteriorated rapidly. Using usual techniques to acquire
its spectroscopic data was therefore very difficult (vide infra).
To measure the diastereomeric ratio of 32, we needed the
other allene axial isomer (37) for comparison. One of the
possible approaches would be conversion of 31 into bromoal-
lene 33 (Scheme 4) because the coupling of bromoallenes with
alkynes/diynes is known4c,14 to proceed with conversion of the
allene axial configuration. However, the polarity of bromo-allene
33 and the concurrently formed 34 turned out to be very similar
to each other, which made isolation of pure 33 unfeasible.
Fortunately, Mitsunobu conversion of 30 led smoothly to 35.
These two diastereomers turned out to readily separable from
each other on silica gel, ensuring us of the enantiopurity for each.
Alcohol 35 was then tosylated to give 36, which was further
converted into 37 under the same conditions as employed for
transformation of 31 to 32. It is noteworthy that the (4R,5aS)
Fig. 4 Comparison of the two g-lactones (38 and 39) reveals the C-4
configuration of 1 and 2. Note that saturation of the allene changes the
substituent priority at the C-4: The (S)-isomer after saturation corresponds
to the (R)-isomer in nemotin.
The new route (Scheme 5) started with the lactone-carboxylic
acid 40, which was readily derived from L-glutamic acid following
the well-established literature16 procedure. Treatment with SOCl2
at reflux for 3 h gave the crude acid chloride 41 in 99% yield.17
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≡
≡
(Scheme 6). The latter was treated with TMSC C–C C–Zn in
the presence of Pd(PPh3)4 to give the (4S,5aS)-allenediyne 47.
Similar to its diastereomers 32 and 37, 47 is also very unstable.
However, because this isomer is of the same configuration as
natural nemotin, and hence is more important than the other
ones, extra efforts were made to estimate the yield of the coupling
step (cf. the Experimental).
Scheme 5 Reagents and conditions: (a) SOCl2, reflux, 3 h, 99% (crude);
(b) HC CMgCl, CuCl, -78 ◦C, 4 h, then -20 ◦C, 10 h, 31% for 42;
≡
cf. also the text and Table 1; (c) BH3·SMe2 (1.0 eq.), THF, -40 ◦C,
(R)- or (S)-2-methyl-CBS-oxaza-borolidine (2 eq.), 92% (44/45 = 7 : 4)
or 95% (44/45 = 4 : 17) with (R)- or (S)-2-methyl-CBS-oxaza-borolidine,
respectively, or NaBH4, CeCl3, MeOH, 1 h, 34% (44/45 = 1.7 : 1).
Subsequent addition of an acetylene moiety to 41 was not as facile
Scheme 6 Reagents and conditions: (a) p-TsCl, Et3N, DMAP, CH2Cl2,
as expected in the beginning. Under the simplest conditions18
90%; (b) (i) TMSC C–C CTMS, MeLi·LiBr, THF, -78 ◦C, 1.5 h, then
rt, 2 h, (ii) ZnBr2, Pd(Ph3P)4, -78 → -20 ◦C, 3 h, 64%; (c) (i) AgNO3,
MeOH, (ii) NaCN, sat. NH4Cl, 71% from 47; (d) (i) DIBAL-H (5.0 eq.),
CH2Cl2, (ii) Ac2O, py, DMAP, CH2Cl2, rt, 73% from 47.
≡
≡
(TMSC C–Li, -78 ◦C, 4 h), the product mixture was rather
≡
complex (Table 1, entry 1). Addition of a catalytic amount of
CuCl19 to this system did not lead to any discernible improvements
20
≡
(entry 2). Use of TMSC CTMS and AlCl3 to generate the
corresponding aluminium species in situ also failed to afford
the desired 42 (entry 3). The depressing situation then took a
Because we had already encountered difficulty in the HPLC
separation of 32/37 (vide supra), a pair of isomers similar to
47/50, no efforts were made on direct measurement of the d.e.
value of 47 and/or 50. Instead, 47 was reduced with DIBAL-H
(diisobutylaluminium hydride) and acylated with Ac2O to afford
diacetate 48. For comparison, the other diastereomer 51 was also
prepared in a similar fashion from 50 (which was even more
unstable than 47) as shown in Scheme 7. The d.e. values of 48 and
51 (and consequently 47 and 50) were then successfully determined
on a CHFT-IRALPAK IC column to be 88.7% and 49.1%,
respectively. Finally, the isomer (47) of the desired configuration
favaorable turn when attempts were made to use the corresponding
19
≡
magnesium reagents. With HC CMgCl as the nucleophile, the
desired 42 was obtained, though the yield was only 7% (entry 4).
The introduction of 0.1 molar equivalents of CuCl increased the
yield of 42 to 14% (entry 5). However, further reaction at higher
temperatures did not lead to more 42. Instead, the undesired 43
became the only isolable product (entry 6). Therefore, in the end
we decided to use only a small amount of CuCl and keep the
reaction at temperatures below -20 ◦C.
The ketone 42 was reduced to corresponding alcohols 44 and
45. Under Luche21 conditions (NaBH4, CeCl3, MeOH, 0 ◦C)
the total yield was 45%, with a 44/45 (which were readily
separable from each other on silica gel) ratio of 7 : 4. CBS22
(Corey–Bakshi–Shibata) reduction (BH3, (R)- or (S)-2-methyl-
CBS-oxaza-borolidine, 0 ◦C) gave better total yields (92% or 95%
with the (R)- or (S)-oxazaborolidine catalyst, respectively).
The (S,S) propargyl alcohol 44 was then converted to the
corresponding tosylate 46 under the conventional conditions
23
was desilyated with AgNO3 in MeOH to give the end product
(4S,5aS)-1.
Table 1 Addition of various acetylene species to acid chloride 41
Entry
Conditions
Outcome
≡
1
2
3
4
5
6
TMSC CLi, -78 ◦C, 4 h
Complex
Complex
Complex
42 (7%)
42 (14%)
43 (26%)
TMSC CLi, CuCl (0.1 eq.), -78 ◦C, 4 h
≡
≡
TMSC CTMS, AlCl3, rt
HC CMgCl, -78 ◦C, 4 h
≡
HC CMgCl, CuCl (0.1 eq.), -78 ◦C, 4 h
≡
HC CMgCl, CuCl (0.1 eq.), -78 ◦C, 4 h,
≡
Scheme 7 Reagents and conditions: (a) p-TsCl, Et3N, DMAP, CH2Cl2,
then slowly to rt
90%; (b) (i) TMSC C–C CTMS, MeLi·LiBr, THF, -78 ◦C, 1.5 h, then
rt, 2 h, (ii) ZnBr2, Pd(Ph3P)4, -78 → -20 ◦C, 3 h; (c) (i) DIBAL-H (5.0 eq.),
CH2Cl2, (ii) Ac2O, py, DMAP, CH2Cl2, rt, 15% from 49.
≡
≡
≡
7
HC CMgCl, CuCl (0.04 eq.), -78 ◦C, 4 h,
42 (31%)
then -20 ◦C, 10 h
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As mentioned for the natural nemotin earlier by the previous
investigators, the (4S,5aS)-1 we obtained is also very unstable.
Near the end of rotary evaporation, an insoluble brown precipitate
formed suddenly, and essentially (4S,5aS)-1 no longer could be
detected by TLC in the remaining supernatant. To acquire the
yield as well as optical rotation data, low-boiling point solvents
(CH2Cl2–pentane) were utilized in the column chromatography,
which could be removed gradually by repeated dilution with
CH2Cl2 followed by partial concentration on a rotary evaporator
Elemental analyses were performed on an Elementar VarioEL III
instrument. Dry solvents were obtained as follows: THF, Et2O,
MeO(CH2)2OMe and toluene were refluxed and distilled over
Na/PhCOPh under argon prior to use. CH2Cl2, DMF, Et3N,
pyridine, i-Pr2NEt and i-Pr2NH were distilled over CaH2 prior
to use. PE (chromatography solvent) stands for petroleum ether
◦
(b.p. 60–90 C). Other chemicals were all commercially available
and were used as received.
Ethyl (2E,4R,5S,6R)-4,7-dihydroxy-5,6-(isopropylidendioxy)-
1
until the signals for pentane could no longer be detected on H
hept-2-enoate (9).
A solution of D-arabinose (8.000 g,
NMR. The (4S,5aS)-1 in the solution was quantitized by 1H NMR
in CD2Cl2 with methyl 4-iodobenzoate as the internal reference.
The optical rotation was then measured to be +356.10 (c 0.20,
CH2Cl2), which is in excellent agreement with the value reported in
the literature for the natural nemotin ([a]2D0 +350 (c 0.20, CH2Cl2).
The specific rotation data also indicate that the natural nemotin
must be a mixture of allene axial isomers similar to our syn-
thetic (4S,5aS)-1, which was approximately a 16.7 : 1 mixture
as estimated from the 88.7% d.e. value (determined on 48). As
phomallenic acid C, another natural allendiyne, has also been
shown4c to be a mixture instead of a single enantiomer, perhaps
co-existence of the allene axial isomers is a common phenomenon
for natural allenediynes.
53.29 mmol), Me2C(OMe)2 (20 cm3), and p-TsOH (monohydrate,
120 mg, 0.63 mmol) in dry DMF (100 cm3) was stirred at ambient
temperature for 4 h. Powdered Na2CO3 (74 mg, 0.63 mmol)
was added in portions with stirring. The solids were filtered
off. The filtrate was concentrated on a rotary evaporator. The
residue was chromatographed on silica gel (20 : 1 CH2Cl2–MeOH)
to give the known24 intermediate acetonide-hemiacetal as a
white solid (9.509 g, 50 mmol, 93.8%). A portion of this
solid (2.982 g, 15.7 mmol) was dissolved in toluene (70 cm3)
=
and treated with Ph3P CHCO2Et (8.187 g, 23.5 mmol) and
PhCO2H (96 mg, 0.79 mmol) at 90 ◦C with stirring for 10 h. The
solvent was removed on a rotary evaporator. The residue was
chromatographed (1 : 2 PE : Et2O) on silica gel to afford ester
9 (2.534 g, 9.73 mmol, 62% from the intermediate hemiacetal
or 58.2% from arabinose) as a colorless oil: [a]2D6 -8.90 (c 2.40,
CHCl3). FT-IR (film) nmax: 3456, 2985, 2937, 1717, 1659, 1460,
Conclusions
Nemotin, an allenediyne lactone isolated nearly 60 years ago, has
been synthesized through an efficient route. The relative as well as
absolute configuration of this natural product is thus established
to be (4S,5aS). The 1H and 13C NMR data for the given structure
are also available for the first time. En route to the total synthesis
of natural nemotin, some interesting results were also obtained,
including the abnormal formation of methyl ketone 18 in the LDA-
mediated elimination of 16, selective reduction of conjugated
triple bond in the presence of an isolated one (reduction of 28
to 29), and direct coupling of a diyne unit with an optically-active
propargylic tosylate mediated by zinc salt to yield the allenediyne
motif. The new observations with the allenediyne species also help
to accumulate the essential knowledge about this unstable and so
far underinvestigated structural motif.
1
1371, 1307, 1270, 1217, 1040, 869 cm-1; H NMR (300 MHz,
CDCl3): d 6.98 (dd, J = 4.6, 15.4 Hz, 1H), 6.16 (dd, J = 1.7,
16.0 Hz, 1 H), 4.52-4.45 (m, 1H), 4.30 (dt, J = 6.7, 5.0 Hz, 1H),
4.25-4.15 (m, 3H), 3.95-3.77 (m, 2H), 3.47 (d, J = 6.2 Hz, OH,
1H), 2.98 (t, J = 5.7 Hz, OH, 1H), 1.51 (s, 3H), 1.36 (s, 3H), 1.29
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 166.3, 146.4,
122.2, 108.7, 78.4, 76.9, 68.8, 60.7, 60.5, 26.9, 24.7, 14.2; ESI-MS
m/z: 283.0 ([M + Na]+); ESI-HRMS calcd for C12H20O6Na ([M +
Na]+): 283.11521; found 283.11392.
Ethyl
(4R,5S,6R)-4,7-dihydroxy-5,6-(isopropylidendioxy)-
heptanoate (10). A mixture of 9 (3.924 g, 15.1 mmol) and 10%
Pd–C (400 mg) in EtOAc (75 cm3) was stirred under H2 (1 atm)
for 5 h. The catalyst was filtered off. The filtrate was concentrated
on a rotary evaporator and the residue was chromatographed
(1 : 2 PE : Et2O) on silica gel to afford 10 (3.500 g, 13.35 mmol,
89.1%) as a colorless oil: [a]2D3 +18.68 (c 1.70, CHCl3). FT-IR
Experimental
1
(film) nmax: 3450, 2985, 2936, 1732, 1456, 1381, 1034 cm-1; H
General
NMR (300 MHz, CDCl3): d 4.32 (dt, J = 6.9, 5.3 Hz, 1 H), 4.11
(q, J = 7.1 Hz, 2H), 4.02 (dd, J = 3.6, 6.8 Hz, 1H), 3.86-3.66 (m,
3 H), 3.10 (t, J = 6.2 Hz, 1 H, OH), 2.99 (d, J = 6.2 Hz, 1H,
OH), 2.50 (t, J = 7.2 Hz, 2H), 1.84 (q, J = 7.0 Hz, 2H), 1.47 (s,
3H), 1.34 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 173.9, 108.2, 79.4, 77.2, 68.0, 60.8, 60.5, 30.2, 29.6,
27.1, 24.9, 14.1; ESI-MS m/z 285.1 ([M + Na]+); ESI-HRMS
calcd for C12H22O6Na ([M + Na]+): 285.13086; found 285.1317.
1H and 13C NMR were recorded on either a Varian Mercury
300 or a Bruker Avance 300 or a Bruker Avance 500 NMR
Spectrometer. FT-IR spectra were taken on an FT-IR 440 or a
Perkin Elmer 983 or a Nicolet Avatar 360 Infrared Spectrometer.
EI-MS and EI-HRMS data were recorded on a HP5989A and a
Waters Micromass GCT instrument, respectively. ESI-MS were
measured on a PE Mariner API-TOF or an Agilent Technologies
LC/MSD SL or a Shimadzu LCMS-2010EV Mass Spectrometer.
ESI-HRMS and MALDI-HRMS were collected on a Bruker
APEXIII 7.0 Tesla FT-MS and an IonSpec 4.7 Tesla FTMS
spectrometer, respectively. Optical rotations were recorded on a
Perkin-Elmer Polarimeter 341or an Agilent Technologies P-1030
Polarimeter. Melting points were taken on a micro melting point
apparatus equipped with a microscope and were uncorrected.
(4R,5S,6R)-4-Hydroxy-5,6-(isopropylidendioxy)-7-benzyloxy-
heptanoic acid-1,4-lactone (11). A solution of 10 (279 mg,
1.07 mmol) in dry DMF (3 cm3) was added to a suspension of
NaH (60% in mineral oil, 128 mg, 3.21 mmol) and BnBr◦(1.830 g,
1.3 mL, 10.70 mmol) in dry DMF (2 cm3) stirred at -40 C. After
completion of the addition, the bath temperature was allowed to
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warm naturally to ambient temperature. The mixture was stirred
at the same temperature for 4 h before being diluted with EtOAc,
washed with aq. sat. NH4Cl, water, and brine, and dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1 : 1 PE : Et2O) on silica gel afforded
11 (172 mg, 0.56 mmol, 53%) as a colorless oil: [a]2D4 -91.23 (c
1.10, CHCl3). FT-IR (film) nmax: 3030, 2984, 2924, 1775, 1455,
1381, 1261, 1215, 1171, 1085, 739, 699 cm-1; 1H NMR (300 MHz,
CDCl3): d 7.42-7.24 (m, 5H), 4.69-4.38 (m, 4H), 4.15 (d, J =
7.0 Hz, 1H), 3.77 (d, J = 6.5 Hz, 2H), 2.71-2.55 (m, 1H), 2.49-
2.09 (m, 3H), 1.44 (s, 3H), 1.36 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 177.5, 137.6, 128.4, 127.89, 127.85, 109.3, 79.0, 77.1,
75.2, 73.6, 68.7, 27.9, 26.5, 25.0, 24.9; ESI-MS m/z 329.1 ([M +
Na]+); ESI-HRMS calcd for C17H22O5Na ([M + Na]+): 329.13594;
found 329.13595.
(821 mg, 2.08 mmol) in dry CH2Cl2 (10 cm3) stirred at 0 ◦C,
followed by TBSOTf (0.72 cm3, 3.12 mmol). The mixture was
stirred at the same temperature for 1 h before being diluted with
EtOAc, washed with water and brine, and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (8 : 1 PE : Et2O) on silica gel gave 14 (1.048 g,
2.07 mmol, 99%) as a colorless oil: [a]2D3 +21.03 (c 2.10, CHCl3).
FT-IR (film) nmax: 3064, 3030, 2954, 2928, 2856, 1731, 1479, 1461,
1379, 1251, 1154, 1101, 834, 777, 698 cm-1; 1H NMR (300 MHz,
CDCl3): d 7.39-7.22 (m, 5H), 4.57 (d, J = 12.0 Hz, 1H), 4.48 (d, J =
11.9 Hz, 1 H), 4.22 (dd, J = 5.8, 11.2 Hz, 1H), 4.05-3.89 (m, 3H),
3.71 (dt, J = 2.4, 7.9 Hz, 1H), 3.57 (dd, J = 5.7, 9.7 Hz, 1H), 3.43
(dd, J = 6.0, 9.8 Hz, 1H), 1.86-1.71 (m, 1H), 1.73-1.52 (m, 3H),
1.41 (s, 3H), 1.32 (s, 3H), 1.18 (s, 9H), 0.85 (s, 9H), 0.05 (s, 3H),
0.03 (s, 3H); 13C NMR (75 MHz, CDCl3): d 178.5, 137.8, 128.4,
127.8, 108.1, 80.3, 76.0, 73.4, 70.8, 69.1, 64.3, 38.7, 30.7, 27.9, 27.2,
26.0, 25.4, 25.1, 18.3, -4.0, -4.6; ESI-MS m/z 531.4 ([M + Na]+);
MALDI-HRMS calcd for C28H48O6SiNa ([M + Na]+): 531.31124;
found 531.3125.
(4R,5S,6R)-4-Hydroxy-5,6-(isopropylidendioxy)-7-bezyloxy-
heptanol (12). LiAlH4 (285 mg, 7.5 mmol) was added to a
solution of 11 (1.173 g, 3.83 mmol) in dry THF (15 cm3) stirred
at 0 ◦C. The mixture was stirred at ambient temperature over
night. Na2SO4·10H2O was added. The mixture was stirred for 2 h.
Solids were filtered off. The filtrate was washed with water and
brine before being dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (2 : 3
PE : Et2O) on silica gel gave 12 (1.058 g, 3.41 mmol, 89%) as a
colorless oil: [a]2D3 -2.36 (c 0.92, CHCl3). FT-IR (film) nmax: 3431,
2984, 2926, 2869, 1454, 1380, 1246, 1217, 1166, 1089, 1028, 737,
(4R,5S,6R)-4-(Dimethyl-tert-butylsilyloxy)-5,6-(isopropyliden-
dioxy)-7-hydroxy-heptanyl 2,2-dimethylpropionate (15). A mix-
ture of 14 (852 mg, 1.67 mmol) and Pd(OH)2 (320 mg) in EtOH
(10 cm3) was stirred under H2 (1 atm) for 7 h. The solids were
filtered off. The filtrate was concentrated on a rotary evaporator.
The residue was chromatographed (7 : 1 PE : EtOAc) on silica gel
to afford 15 (564 mg, 1.35 mmol, 81%) as a colorless oil: M.p. 63–
65 ◦C. [a]D24 +45.28 (c 3.20, CHCl3). FT-IR (film) nmax: 3277, 2855,
1724, 1481, 1370, 1291, 1003, 721, 661 cm-1; 1H NMR (300 MHz,
CDCl3): d 4.14 (dt, J = 6.2, 11.9 Hz, 1H), 4.11-4.01 (m, 3H),
3.79 (dt, J = 3.0, 8.0 Hz, 1H), 3.61 (t, J = 5.9 Hz, 2H), 2.28 (t,
J = 6.0 Hz, 1H), 1.93-1.51 (m, 4H), 1.47 (s, 3H), 1.35 (s, 3H),
1.18 (s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 178.5, 108.3, 80.0, 77.5, 70.6, 64.0, 61.4,
38.7, 30.4, 28.0, 27.1, 25.9, 25.8, 25.3, 18.3, -4.1, -4.7; ESI-MS
m/z 441.3 ([M + Na]+); MALDI-HRMS calcd for C21H42O6SiNa
([M + Na]+): 441.26429; found 441.2645.
1
699 cm-1; H NMR (300 MHz, CDCl3): d 7.40-7.28 (m, 5H),
4.57 (s, 2H), 4.33 (dd, J = 5.6, 11.7 Hz, 1H), 4.03 (dd, J = 4.1,
6.3 Hz, 1H), 3.76-3.60 (m, 5H), 2.89 (broad, OH, 1H), 2.31 (broad,
OH, 1H), 1.76-1.52 (m, 4H), 1.49 (s, 3H), 1.37 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 137.4, 128.4, 127.94, 127.87, 108.3, 79.7,
75.8, 73.6, 69.2, 68.5, 62.6, 31.5, 29.4, 27.2, 25.0; ESI-MS m/z
333.2 ([M + Na]+); ESI-HRMS calcd for C17H26O5Na ([M + Na]+):
333.16725; found 333.16704.
(4R,5S,6R)-4-Hydroxy-5,6-(isopropylidendioxy)-7-bezyloxy-
heptanyl 2,2-dimethylpropionate (13). To a solution of 12
(1.010 g, 3.26 mmol) in dry CH2Cl2 (15 cm3) stirred at 0 ◦C
were added in turn Et3N (1.36 cm3, 9.78 mmol), PivCl (0.52 cm3,
4.24 mmol), and DMAP (40 mg, 0.33 mmol). The mixture was
stirred at ambient temperature overnight before being diluted
with EtOAc, washed with aq. sat. NH4Cl, water, 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 13 (847 mg, 2.15 mmol, 66%) as a colorless oil: [a]D23
-2.24 (c 0.60, CHCl3). FT-IR (film) nmax: 3505, 2959, 2932, 2872,
1727, 1480, 1285, 1160, 1092, 737, 698 cm-1; 1H NMR (300 MHz,
CDCl3): d 7.40-7.28 (m, 5 H), 4.60 (d, J = 12.4 Hz, 1H), 4.56 (d,
J = 12.8 Hz, 1H), 4.35 (dd, J = 5.6, 12.1 Hz, 1H), 4.10-3.98 (m,
3H), 3.77-3.58 (m, 3H), 2.51 (d, J = 6.7 Hz, OH, 1H), 1.94-1.77
(m, 1H), 1.73-1.52 (m, 3H), 1.50 (s, 3H), 1.37 (s, 3H), 1.19 (s, 9H);
13C NMR (75 MHz, CDCl3): d 178.6, 137.5, 128.5, 127.94, 127.89,
108.3, 79.3, 75.9, 73.7, 68.8, 68.6, 64.2, 38.7, 31.2, 27.2, 27.1, 25.1,
24.9; ESI-MS m/z 417.2 ([M + Na]+). Anal. calcd. for C22H34O6:
C, 66.98, H, 8.69; found C, 67.00, H, 8.86.
(4R,5S,6S)-4-(Dimethyl-tert-butylsilyloxy)-5,6-(isopropyliden-
dioxy)-7-chloro-heptanyl 2,2-dimethylpropionate (16). A mixture
of 15 (64 mg, 0.15 mmol), Ph3P (100 mg, 0.38 mmol) and K2CO3
(42 mg, 0.31 mmol) in CCl4 (1.5 cm3) was refluxed with stirring
overnight. The solvent was removed by rotary evaporation. The
residue was chromatographed (25 : 1 PE : EtOAc) on silica gel to
give 16 (46 mg, 0.11 mmol, 69%) as a colorless oil: [a]2D7 +38.93 (c
1
0.65, CHCl3). H NMR (300 MHz, CDCl3): d 4.22 (dt, J = 8.0,
5.2 Hz, 1 H), 4.12-4.00 (m, 3 H), 3.79 (dt, J = 2.9, 8.2 Hz, 1H), 3.61
(dd, J = 4.6, 11.4 Hz, 1H), 3.50 (dd, J = 8.2, 11.5 Hz, 1H), 1.94-
1.39 (m, 4H), 1.49 (s, 3H), 1.36 (s, 3H), 1.20 (s, 9H), 0.89 (s, 9H),
0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (75 MHz, CDCl3): d 178.5,
108.7, 80.4, 77.4, 70.3, 63.9, 43.4, 38.7, 30.7, 27.9, 27.2, 25.9, 25.3,
25.0, 18.3, -4.0, -4.5; FT-IR (film) nmax: 2958, 2930, 2857, 1731,
1480, 1381, 1284, 1254, 1222, 1157, 836, 778 cm-1; ESI-MS m/z
459.3 ([M + Na]+); ESI-HRMS calcd for C21H41O5SiNaCl ([M +
Na]+) 459.23040; found 459.23056.
(4R,5S)-4-(Dimethyl-tert-butylsilyloxy)-6-oxo-heptanyl
2,2-
(4R,5S,6R)-4-(Dimethyl-tert-butylsilyloxy)-5,6-(isopropyliden-
dioxy)-7-bezyloxy-heptanyl 2,2-dimethylpropionate (14). 2,6-
Lutidine (0.49 cm3, 4.16 mmol) was added to a solution of 13
dimethylpropionate (18). n-BuLi (1.6 M in hexanes, 0.69 cm3,
1.10 mmol) was added to a solution of i-Pr2NH (0.15 cm3,
1.10 mmol) in dry THF (2 cm3) and stirred at -78 ◦C under
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argon. The mixture was stirred at the same temperature for 1 h.
A solution of 16 (87 mg, 0.20 mmol) in dry THF (1 cm3) was
introduced. The bath was allowed to warm slowly (over ca. 6
h) to 0 ◦C before being re-cooled to -78 ◦C. The mixture was
partitioned between EtOAc and aq. sat. NH4Cl. The phases
were separated. The organic layer was washed with water and
brine before being dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (20 : 1
PE : Et2O) on silica gel gave 18 (38 mg, 0.105 mmol, 53%) as a
colorless oil: [a]2D8 +49.94 (c 0.90, CHCl3). FT-IR (film) nmax: 3477,
2958, 2931, 2859, 1728, 1481, 1463, 1362, 1285, 1256, 1158, 1088,
837, 777 cm-1; 1H NMR (300 MHz, CDCl3): d 4.13-3.94 (m, 4 H),
3.51 (d, J = 6.3 Hz, OH, 1 H), 2.28 (s, 3H), 1.78-1.52 (m, 3H),
1.41-1.28 (m, 1H), 1.19 (s, 9H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR (125 MHz, CDCl3): d 209.6, 178.5, 79.2, 73.1,
63.9, 38.7, 29.4 (2¢C), 27.2, 25.8, 25.2, 18.0, -4.4, -4.6; ESI-MS
m/z 383.2 ([M + Na]+); ESI-HRMS calcd for C18H37O5Si ([M +
H]+): 361.24048; found 361.24033.
2-((3aS,4R,6aR)-2,2-Dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-
4-yl)-propyl 2,2-dimethylpropionate (24). A mixture of 22 (72 mg,
0.21 mmol), Ph3P (136 mg, 0.52 mmol) and K2CO3 (58 mg,
0.42 mmol) in CH2Cl2–CCl4 (1 : 4 v/v, 2 cm3) was refluxed with
stirring overnight. The solvent was removed by rotary evaporation.
The residue was chromatographed (12 : 1 PE : EtOAc) on silica gel
to give 24 (48 mg, 0.17 mmol, 80%) as a colorless oil: [a]2D3 -30.82
(c 0.82, CHCl3). FT-IR (film) nmax: 2975, 2933, 2853, 1728, 1481,
1459, 1380, 1371, 1284, 1208, 1162, 1101, 1073, 862 cm-1; 1H NMR
(500 MHz, CDCl3): d 4.76 (dd, J = 3.8, 6.1 Hz, 1H), 4.57 (dd, J =
3.7, 6.0 Hz, 1H), 4.17-4.04 (m, 2H), 3.99 (d, J = 10.7 Hz, 1H),
3.44 (dd, J = 3.7, 10.8 Hz, 1H), 3.42-3.37 (m, 1H), 1.86-1.71 (m,
4H), 1.47 (s, 3H), 1.36 (s, 3H), 1.20 (s, 9H); 13C NMR (125 MHz,
CDCl3): d 178.6, 112.0, 82.2, 81.2, 81.0, 72.6, 64.2, 38.7, 27.2, 26.0,
25.4, 24.9 (2¢C); ESI-MS m/z 309.2 ([M + Na]+); ESI-HRMS calcd
for C15H26O5Na ([M + Na]+): 309.16725; found 309.1669.
(4R,5S,6R)-4-(Methoxymethyloxy)-5,6-(isopropylidendioxy)-7-
(p-tosyloxy)-heptanyl 2,2-dimethylpropionate (25). To a solution
of alcohol 22 (28 mg, 0.08 mmol) in dry CH2Cl2 (1 cm3) stirred
(4R,5S,6R)-4-(Methoxymethyloxy)-5,6-(isopropylidendioxy)-
7-benzyloxy-heptanyl 2,2-dimethylpropionate (21). MOMCl
(0.18 cm3, 2.37 mmol) was added to a solution of NaI (267 mg,
1.78 mmol) in dry MeO(CH2)2OMe (1 cm3) stirred at ambient
temperature. The stirring was continued for 10 min before
i-Pr2NEt (0.45 cm3, 2.61 mmol) was introduced. A solution of
13 (234 mg, 0.59 mmol) in dry MeO(CH2)2OMe (2 cm3) was
then added. The mixture was heated to reflux overnight. After
being cooled to ambient temperature, the mixture was diluted
with EtOAc, washed with aq. sat. NH4Cl, water 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 21 (176 mg, 0.40 mmol, 68%) as a colorless oil: [a]D23
+59.63 (c 0.90, CHCl3). FT-IR (film) nmax: 3031, 2980, 2934, 1727,
1496, 1480, 1455, 1398, 1380, 1369, 1284, 1249, 1220, 1159, 1100,
◦
at 0 C were added in turn Et3N (0.017 cm3, 0.12 mmol), p-
TsCl (18 mg, 0.096 mmol), and DMAP (1 mg, 0.008 mmol). The
mixture was stirred at ambient temperature overnight. EtOAc was
added, followed by aq. sat. NH4Cl. The phases were separated.
The organic layer was washed with water and brine before being
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (6 : 1 PE : EtOAc) on
silica gel gave tosylate 25 (37 mg, 0.074 mmol, 92%) as a colorless
oil: [a]2D7 +53.62 (c 0.95, CHCl3). FT-IR (film) nmax: 2960, 1728,
1598, 1481, 1368, 1285, 1190, 1178, 1097, 1035, 973, 815, 665 cm-1;
1H NMR (300 MHz, CDCl3): d 7.81 (d, J = 8.4 Hz, 2H), 7.36 (d,
J = 8.0 Hz, 2H), 4.79 (d, J = 7.0 Hz, 1H), 4.62 (d, J = 7.2 Hz,
1H), 4.24 (dd, J = 5.8, 11.6 Hz, 1H), 4.19-3.99 (m, 4H), 3.95 (dd,
J = 6.5, 10.2 Hz, 1H), 3.62 (dt, J = 3.9, 7.4 Hz, 1H), 3.38 (s, 3H),
2.46 (s, 3H), 1.91-1.44 (m, 4H), 1.31 (s, 6H), 1.20 (s, 9H); ESI-MS
m/z 525.4 ([M + Na]+); ESI-HRMS calcd for C24H38O9SNa ([M +
Na]+): 525.21287; found 525.21305.
1
1031, 738, 699 cm-1; H NMR (300 MHz, CDCl3): d 7.39-7.24
(m, 5H), 4.85 (d, J = 7.0 Hz, 1H), 4.63 (d, J = 6.6 Hz, 1H), 4.53
(s, 2H), 4.23 (dd, J = 5.8, 11.6 Hz, 1H), 4.14 (dd, J = 5.6, 8.4 Hz,
1H), 4.05-3.86 (m, 2 H), 3.66 (dt, J = 2.6, 7.8 Hz, 1 H), 3.56 (dd,
J = 6.4, 9.7 Hz, 1H), 3.44 (dd, J = 5.8, 10.0 Hz, 1H), 3.38 (s, 3H),
1.91-1.70 (m, 1H), 1.68-1.44 (m, 3H), 1.42 (s, 3H), 1.35 (s, 3H),
1.18 (s, 9H). ESI-MS m/z 461.4 ([M + Na]+); MALDI-HRMS
calcd for C24H38O7Na ([M + Na]+): 461.25098; found 461.2514.
(4R,5R)-4,5-Diethynyl-2,2-dimethyl-[1,3]dioxolane
(27).
DIBAL-H (1 M in cyclohexane, 13 cm3, 13 mmol) was
added to a solution of 26 (1.418 g, 6.50 mmol) in dry toluene
(28 cm3) and stirred at -78 ◦C under argon. After completion
of the addition, the mixture was stirred at the same temperature
for 2 h when a solution (already stirred at 0 ◦C for 5 min) of
MeC(O)C(N2)P(O)(OMe)3 (3.740 g, 19.5 mmol) and K2CO3
(3.588 g, 26 mmol) in anhydrous MeOH (100 cm3) was introduced
dropwise. The cooling bath was allowed to warm naturally while
the stirring was continued overnight. The mixture was diluted
with EtOAc, washed with aq. sat. NH4Cl, water and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (6 : 1 PE : Et2O) on
silica g◦el gave 27 (529 mg, 3.53 mmol, 54%) as a white solid: M.p.
51–53 C. [a]2D6 +81.29 (c 0.96, CHCl3). FT-IR (film) nmax: 3267,
2989, 2939, 2929, 2857, 2125, 1735, 1457, 1382, 1240, 1055,
870 cm-1; 1H NMR (300 MHz, CDCl3): d 4.65 (s, 2 H), 2.57 (s, 2
H), 1.47 (s, 6 H); 13C NMR (75 MHz, CDCl3): d 112.0, 79.0, 75.3,
(4R,5S,6R)-4-(Methoxymethyloxy)-5,6-(isopropylidendioxy)-7-
hydroxy-heptanyl 2,2-dimethylpropionate (22). A mixture of 21
(128 mg, 0.29 mmol) and Pd(OH)2 (25 mg) in EtOH (4 cm3) was
stirred under H2 (1 atm) for 7 h. The catalyst was filtered off. The
filtrate was concentrated on a rotary evaporator and the residue
was chromatographed (3 : 1 PE : EtOAc) on silica gel to afford
22 (105 mg, 0.29 mmol, 100%) as a colorless oil: [a]2D2 +65.83 (c
1.40, CHCl3). FT-IR (film) nmax: 3488, 2961, 2936, 1728, 1481,
1
1460, 1380, 1370, 1286, 1249, 1221, 1161, 1034 cm-1; H NMR
(300 MHz, CDCl3): d 4.86 (d, J = 7.0 Hz, 1H), 4.66 (d, J =
6.5 Hz, 1H), 4.23-4.04 (m, 4H), 3.73 (dt, J = 3.6, 7.6 Hz, 1H), 3.62
(t, J = 5.9 Hz, 2H), 3.40 (s, 3H), 2.24 (t, J = 6.2 Hz, OH, 1H),
1.92-1.50 (m, 4H), 1.48 (s, 3H), 1.36 (s, 3H), 1.19 (s, 9H); ESI-MS
m/z 371.3 ([M + Na]+); MALDI-HRMS calcd for C17H32O7Na
([M + Na]+): 371.20403; found 371.2049.
+
70.8, 26.4; EI-MS m/z (%) 135 (M–CH3 , 6.18), 96 (9), 53 (12), 43
(100), 41 (17). Anal. calcd. for C9H10O2: C, 71.98, H, 6.71. Found:
C, 71.68, H, 6.93.
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Ethyl ((4R,5R)-5-ethynyl-2,2-dimethyl-[1,3]dioxolan-4-yl)pro-
pynoate (28). n-BuLi (2.5 M, in hexanes, 1.4 cm3, 3.45 mmol)
was added to a solution of 27 (517 mg, 3.45 mmol) in dry THF
(35 cm3) stirred at -78 ◦C under argon. The stirring was continued
for 30 min. The cooling bath was allowed to warm slowly to
81.3, 80.0, 75.2, 64.2, 28.1, 23.2. EI-MS m/z (%): 140 (M+, 0.07), 85
(100), 57 (8), 55 (10); EI-HRMS calcd for C7H8O3 (M+): 140.0473;
found 140.0472.
(4R,5R)-4-Hydroxy-5-(p-tosyloxy)-hept-6-yne-1,4-lactone (31).
To a solution of alco◦hol 30 (45 mg, 0.32 mmol) in dry CH2Cl2
(3 cm3) stirred at 0 C were added in turn Et3N (0.089 cm3,
0.64 mmol), p-TsCl (91 mg, 0.48 mmol), and DMAP (12 mg,
0.096 mmol). The mixture was stirred at ambient temperature
overnight. EtOAc was added, followed by aq. sat. NH4Cl. The
phases were separated. The organic layer was washed with water
and brine before being dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(2 : 1 PE : EtOAc) on silica gel gave tosylate 31 (104 mg, 0.32 mmol,
0
◦C (ca. 2 h) and at that temperature for 1 h. The bath was
re-cooled to -78 ◦C. ClCO2Et (299 mg, 2.76 mmol) was added.
The mixture was stirred at the same temperature for 4 h, diluted
with EtOAc, washed with aq. sat. NH4Cl, water and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (40 : 1 PE : Et2O) on
silica gel gave 28 (302 mg, 1.35 mmol, 49%) as a colorless oil
along with recovered starting 27 (300 mg, 2.00 mmol, 58%). Data
for 28: [a]2D4 +116.58 (c 1.00, CHCl3). FT-IR (film) nmax: 3285,
2990, 2939, 2245, 2123, 1716, 1455, 1384, 1246, 1160, 1058, 845,
◦
100%) as a white solid: M.p. 116–117 C. [a]2D6 -62.50 (c 0.93,
CHCl3). FT-IR (KBr) nmax: 3269, 2950, 2130, 1783, 1595, 1369,
1
751 cm-1; H NMR (300 MHz, CDCl3): d 4.79 (d, J = 5.8 Hz,
1
1345, 1190, 1178, 938, 833, 810, 699 cm-1; H NMR (300 MHz,
2H), 4.76 (dd, J = 1.7, 6.0 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 2.60
(d, J = 1.3 Hz, 1H), 1.50 (s, 3H), 1.49 (s, 3H), 1.31 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 152.8, 112.8, 81.7, 78.9, 77.9,
75.7, 70.7, 70.4, 62.4, 26.5, 26.4, 13.9. EI-MS m/z (%) 222 (M+,
0.01), 207 (100), 168 (19), 165 (34), 123 (26), 119 (32), 96 (41), 53
(28), 43 (97); EI-HRMS calcd for C12H14O4 (M+) 222.0892; found
222.0894.
CDCl3): d 7.83 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
5.19 (dd, J = 2.4, 4.4 Hz, 1H), 4.69 (dt, J = 7.4, 5.3 Hz, 1H),
2.74-2.20 (m, 8H); 13C NMR (75 MHz, CDCl3): d 175.8, 145.6,
132.7, 129.9, 128.1, 78.3, 78.0, 74.9, 70.4, 27.5, 22.9, 21.7. ESI-
MS m/z 316.9 ([M + Na]+); EI-HRMS calcd for C14H14O5S (M+):
294.0562; found 294.0564.
(4R,5S)-4,5-Dihydroxy-hept-6-yne-1,4-lactone (35). A solu-
tion of 30 (99 mg, 0.71 mmol), Ph3P (741 mg, 2.83 mmol),
p-NO2PhCO2H (473 mg, 2.83 mmol) in THF (10 cm3) was
Ethyl ((4R,5R)-5-ethynyl-2,2-dimethyl-[1,3]dioxolan-4-yl)pro-
panoate (29). NaBH4 (247 mg, 6.50 mmol) was added quickly
in one portion to a mixture of 28 (288 mg, 1.30 mmol) and
CuCl (96 mg, 0.97 mmol) in anhydrous MeOH (26 cm3) stirred
at -50 ◦C. The mixture was stirred at the same temperature for
3 h. EtOAc was added, followed by aq. sat. NH4Cl. The phases
were separated. The organic layer was washed with water and
brine before being dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (20 : 1
PE : EtOAc) on silica gel gave 29 (263 mg, 1.16 mmol, 89%) as
=
stirred at ambient temperature for 10 min. EtO2CN NCO2Et
(0.44 cm3, 2.83 mmol) was added. The mixture was stirred at
ambient temperature overnight. Solvent was removed by rotary
evaporation. The residue was chromatographed (3 : 1 PE : EtOAc)
on silica gel to give the intermediate ester (205 mg, 0.709 mmol)
as a colorless oil. MeOH (12 cm3) was added to the residue. The
resulting solution was cooled to -15 ◦C. With stirring, aq. NaOH
(1 N, 0.7 cm3) was added. The mixture was stirred at -15 ◦C
for 30 min. EtOAc was added, followed by aq. sat. NH4Cl. The
phases were separated. The organic layer was washed with water
and brine before being dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(3 : 1 PE : EtOAc) on silica gel gave 35 (75 mg, 0.54 mmol, 76%
from 30) as a colorless oil: [a]2D7 +28.68 (c 0.58, CHCl3). FT-IR
a colorless oil: [a]D25 +15.66 (c 1.05, CHCl3). FT-IR (film) nmax
:
3271, 2987, 2935, 2114, 1736, 1456, 1373, 1248, 1072, 872 cm-1;
1H NMR (300 MHz, CDCl3): d 4.24 (dd, J = 2.1, 7.7 Hz, 1H),
4.15 (q, J = 7.1 Hz, 2H), 4.07 (ddd, J = 4.6, 7.6, 7.6 Hz, 1H),
2.59-2.34 (m, 3H), 2.13-1.99 (m, 1H), 1.98-1.84 (m, 1H), 1.46 (s,
3H), 1.41 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 172.8, 110.2, 80.5, 80.3, 74.9, 70.0, 60.5, 30.3, 27.3,
27.0, 26.1, 14.2. ESI-MS m/z 249.1 ([M + Na]+); EI-HRMS calcd
for C12H18O4 (M+): 226.1205; found 226.1203.
1
(film) nmax: 3407, 3290, 2092, 1739, 1471, 1256, 1091 cm-1; H
NMR (300 MHz, CDCl3): d 4.72-4.61 (m, 2H), 3.30 (broad, OH,
1H), 2.79-2.62 (m, 1H), 2.60-2.24 (m, 4H); 13C NMR (75 MHz,
CDCl3): d 177.6, 81.3, 79.8, 75.4, 63.7, 28.1, 21.7; EI-MS m/z
(%): 140 (M+, 0.10), 85 (100); EI-HRMS calcd for C7H8O3 (M+):
140.0473; found 140.0470.
(4R,5R)-4,5-Dihydroxy-hept-6-yne-1,4-lactone (30). A solu-
tion of 29 (115 mg, 0.51 mmol) and aq. F3CCO2H (50% v/v,
0.73 cm3) in CH2Cl2 (8 cm3) was stirred at ambient temperature
overnight. EtOAc was added, followed by aq. sat. NaHCO3. The
phases were separated. The organic layer was washed with water
and brine, and dried over anhydrous Na2SO4. The solvent was
removed on a rotary evaporator. The residue was dissolved in
CH2Cl2 (8 cm3). To the solution was added p-TsOH (monohydrate,
5 mg, 0.026 mmol). The solution was stirred at ambient tempera-
ture overnight. Removal of the solvent by rotary evaporation and
column chromatography (2 : 1 PE : EtOAc) on silica gel gave 30
(62 mg, 0.44 mmol, 87%) as a colorless oil: [a]2D9 -30.10 (c 0.37,
CHCl3). FT-IR (film) nmax: 3407, 3271, 2960, 2927, 2852, 2122,
1743, 1459, 1184, 1047 cm-1; 1H NMR (300 MHz, CDCl3): d 4.67-
4.57 (m, 1H), 4.54-4.45 (m, 1H), 2.93 (d, J = 5.0 Hz, 1H), 2.75-2.48
(m, 3H), 2.46-2.14 (m, 2H); 13C NMR (75 MHz, CDCl3): d 177.0,
(4R,5S)-4-Hydroxy-5-(p-tosyloxy)-hept-6-yne-1,4-lactone (36).
To a solution of alco◦hol 35 (26 mg, 0.19 mmol) in dry CH2Cl2
(2 cm3) stirred at 0 C were added in turn Et3N (0.052 cm3,
0.37 mmol), p-TsCl (53 mg, 0.28 mmol), and DMAP (7 mg,
0.056 mmol). The mixture was stirred at ambient temperature
overnight. EtOAc was added, followed by aq. sat. NH4Cl. The
phases were separated. The organic layer was washed with water
and brine before being dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(2 : 1 PE : EtOAc) on silica gel gave tosylate 25 (37 mg, 0.13 mmol,
◦
68%) as a white solid: M.p. 103–105 C. [a]2D3 +45.69 (c 0.95,
CHCl3). FT-IR (KBr) nmax: 3287, 3041, 2990, 2938, 2124, 1774,
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1698, 1600, 1533, 1366, 1180, 935, 821, 674 cm-1; 1H NMR
4H); 13C NMR (75 MHz, CDCl3): d 183.1, 175.5, 84.6, 81.6, 78.4,
26.6, 24.7; EI-MS m/z (%): 139 (M+ + 1, 5), 85 (100); EI-HRMS
calcd for C7H6O3 (M+): 138.0317; found 138.0318.
(300 MHz, CDCl3): d 7.80 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.0 Hz,
2H), 5.26-5.19 (m, 1H), 4.73-4.63 (m, 1H), 2.69-2.22 (m, 8H); 13
C
NMR (75 MHz, CDCl3): d 175.8, 145.6, 132.6, 129.9, 128.1, 78.6,
78.5, 75.0, 70.7, 27.4, 22.1, 21.7; ESI-MS m/z 316.9 ([M + Na]+);
EI-HRMS calcd for C14H14O5S (M+): 294.0562; found 294.0572.
(4S,5S)-4,5-Dihydroxy-hept-6-yne-1,4-lactone (44) and (4S,5R)-
4,5-dihydroxy-hept-6-yne-1,4-lactone (45).
Method A. (R)-2-Me-CBS-oxazaborolidine (1.0 M in toluene,
1.82 cm3, 1.82 mmol) was added dropwise to a solution of 42
(126 mg, 0.91 mmol) in dry THF (9 cm3) stirred at -40 ◦C
under argon, followed by BH3·Me2S (2.0 M, in THF, 0.46 cm3,
0.92 mmol). The mixture was stirred at the same temperature
for 1 h. EtOH (2 cm3) was added. The stirring was continued
for 15 min. Water was added, followed by Et2O. The phases
were separated. The organic layer was washed with water and
brine before being dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (2 : 1
PE : EtOAc) on silica gel gave (S,S)-alcohol 44 (74 mg, 0.53 mmol,
58.2%) and (S,R)-alcohol 45 (42 mg, 0.30 mmol, 33.0%).
Method B. The procedure was the same as in Method A, except
that (S)-2-Me-CBS-oxazaborolidine was utilized instead of (R)-
2-Me-CBS-oxazaborolidine. From 42 (91 mg, 0.66 mmol) were
obtained (S,S)-alcohol 44 (17 mg, 0.12 mmol, 18.2%) and (S,R)-
alcohol 45 (71 mg, 0.51 mmol, 77.2%).
(R)-5-(Hepta-(1aR)-1,2-diene-7-trimethylsilyl-4,6-diynyl)-dihy-
dro-furan2-one (32). MeLi·LiBr (ca. 1.5 M, 0.67 cm3, 1.0 mmol)
≡
≡
was added to a solution of TMSC C–C CTMS (194 mg,
1.0 mmol) in dry THF (5 cm3) stirred at -78 ◦C under argon.
The cooling bath was allowed to warm to ambient temperature
slowly. The stirring was then continued at ambient temperature
for 2 h before a solution of anhydrous ZnBr2 in dry THF (1.0 M,
1.0 cm3, 1.0 mmol) was introduced. The resulting mixture was
stirred at the same temperature for 10 min to give a THF solution
≡
≡
of TMSC C–C CZnBr (ca. 0.14 M).
≡
≡
The above prepared THF solution of TMSC C–C CZnBr
(0.14 M, 1.5 cm3, 0.21 mmol) was transferred via a cannula to a
flame-dried flask containing Pd(Ph3P)4 (11 mg, 0.010 mmol) and
31 (30 mg, 0.10 mmol) in dry THF (1 cm3) stirred at -78 ◦C
under argon. The bath was allowed to warm slowly to -20 ◦C
(ca. 3 h). The mixture was diluted with Et2O, washed with aq.
sat. NH4Cl, water and brine, before being dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (2 : 1 PE : Et2O) on silica gel gave 32 (16 mg,
0.066 mmol, 64%) as a yellowish oil (which deteriorated quickly
on removal of the solvent; from a partially concentrated sample of
32 the following data were acquired: 1H NMR (300 MHz, CDCl3)
d 5.68 (d, J = 4.0 Hz, 2H), 5.10-5.00 (m, 1H), 2.69-2.39 (m, 3H),
2.23-2.08 (m, 1H), 0.21 (s, 9H). This sample was mainly used for
exploring HPLC separation of the allene axial isomers (cf. 37).
Method C. NaBH4 (10 mg, 0.27 mmol) was added in one
portion to a solution of 42 (24 mg, 0.174 mmol) and CeCl3 (57 mg,
0.23 mmol) in MeOH (2 cm3) stirred at ambient temperature.
Stirring was continued for 1 h before the mixture was diluted
with EtOAc, washed with aq. sat. NH4Cl, water and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (2 : 1 PE : EtOAc) on
silica gel gave (S,S)-alcohol 44 (7 mg, 0.050 mmol, 21.7%) and
(S,R)- alcohol 45 (4 mg, 0.029 mmol, 12.6%).
Data for (S,S)-alcohol 44 (a colorless oil): [a]2D3 +37.86 (c 1.00,
CHCl3); other data the same as its antipode 30.
(R)-5-(Hepta-(1aS)-1,2-diene-7-trimethylsilyl-4,6-diynyl)-dihy-
dro-furan2-one (37). The same procedure for conversion of 31
into 32 given above was adopted. From a partially concentrated
sample of 37 the following data were acquired: 1H NMR
(300 MHz, CDCl3) d 5.76-5.63 (m, 2H), 5.10-5.00 (m, 1H), 2.72-
2.07 (m, 4H), 0.21 (s, 9H). This sample was mainly used as a
reference in HPLC analysis of 32.
Data for (R,S)-alcohol 45 (a colorless oil): [a]2D3 -29.56 (c 0.58,
CHCl3); other data the same its antipode 35.
(4S,5S)-4-Hydroxy-5-(p-tosyl)-hept-6-yne-1,4-lactone
(46).
Using the same procedure for conversion of 30 into 31 given
above, tosylate 46 (270 mg, 0.92 mmol, 90%) was obtained
as a whi◦te solid from alcohol 44 (143 mg, 1.02 mmol); M.p.
116–117 C. [a]2D2 +81.25 (c 0.73, CHCl3); other data the same its
antipode 31.
(S)-5-(Prop-2-ynoyl)-dihydro-furan2-one (42). A mixture of
acid 40 (780 mg, 6 mmol) in SOCl2 (6 cm3) was heated to reflux
for 3 h. The volatiles were removed on a rotary evaporator. The
residue was dissolved in dry THF (24 cm3). To this solution
(S)-5-(Hepta-(1aS)-1,2-diene-7-trimethylsilyl-4,6-diynyl)-dihy-
drofuran2-one (47). The same procedure for conversion of 31
into 32 given above was employed for converting 46 into 47,
except that chromatography on silica gel was performed using
2 : 1 pentane–Et2O as elutent. The fractions containing 47 were
combined and partially concentrated and diluted with CHCl3.
The partial concentration and dilution with CHCl3 was repeated
several times until no pentane–Et2O could be detected on 1H
NMR. The yield of 47 (obtained from 46 (200 mg, 0.68 mmol)) was
determined to be 64% by 1H NMR with methyl 4-iodobenzoate as
the internal reference. Data for 47: [a]2D2 +262.97 (c 0.38, CHCl3).
FT-IR (film) nmax: 2956, 2921, 2850, 2200, 2101, 1950, 1775, 1249,
1149, 843 cm-1; 1H NMR (300 MHz, CDCl3): d 5.68 (d, J = 4.0 Hz,
2H), 5.10-5.00 (m, 1H), 2.69-2.39 (m, 3H), 2.23-2.08 (m, 1H), 0.21
(s, 9H); 13C NMR (75 MHz, CDCl3): d 214.4, 175.7, 94.3, 91.0,
87.7, 79.0, 77.0, 76.3, 67.9, 28.1, 27.9, -0.4. EI-MS m/z (%): 244
was added CuCl (18 mg, 0.18 mmol). The mixture was cooled
◦
≡
to -78 C. With stirring, a solution of HC CMgCl (0.5 M, in
THF, 11.5 cm3, 5.75 mmol) was added over 1 h. The bath was
then allowed to warm naturally to -20 ◦C and the stirring was
continued at that temperature for 15 h. The mixture was diluted
with EtOAc, washed with aq. sat. NH4Cl, water 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 42 (240 mg, 1.74 mmol, 31%): [a]2D5 +6.89 (c 0.57, CHCl3),
99.0% e.e. as determined by HPLC analysis (tR(Major) = 22.53 min,
tR(Minor) = 18.13 min) on a CHFT-IRALPAK IC column (0.46 cm ¥
25 cm) eluting with 70 : 30 n-hexane : i-PrOH at a flow rate of
0.7 cm3 min-1 with the UV detector set to 214 nm. FT-IR (film)
n
max: 3255, 2961, 2095, 1804, 1686, 1461, 1420, 997 cm-1; 1H NMR
(300 MHz, CDCl3): d 5.01-4.94 (m, 1H), 3.57 (s, 1H), 2.69-2.30 (m,
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(M+, 11.31), 162 (13), 85 (100); EI-HRMS calcd for C14H16O2Si
(M+): 244.0920; found 244.0922.
NMR (75 MHz, CDCl3): d 214.4, 171.1, 170.2, 94.3, 90.5, 87.7,
77.9, 75.9, 70.4, 68.8, 63.8, 30.5, 24.4, 21.0, 20.9, -0.5; ESI-MS
m/z 355.1 ([M + Na]+); ESI-HRMS calcd for C18H24O4SiNa ([M +
Na]+): 355.13361; found 355.13318.
(S)-5-(Hepta-(1aS)-1,2-diene-4,6-diynyl)-dihydro-furan-2-one
((4S,5aS)-1). A solution of AgNO3 (24 mg, 0.14 mmol) in H2O
(0.5 cm3) was added to a solution of 47 (estimated to be 29 mg,
0.119 mmol, using the partial concentration-dilution technique
(4S,5R)-4-Hydroxy-5-(p-tosyl)-hept-6-yne-1,4-lactone
(49).
Using the same procedure for conversion of 35 into 36 given
above, tosylate 49 (403 mg, 1.37 mmol, 90%) was obtained
as a whi◦te solid from alcohol 45 (213 mg, 1.52 mmol); M.p.
104–106 C. [a]2D2 -58.72 (c 0.95, CHCl3); other data the same as
its antipode 36.
1
to change the solvent and H NMR to measure the quantity) in
MeOH (2 cm3) stirred at 0 ◦C with precaution against light. A
yellow precipitate formed. The mixture was stirred at the same
temperature for 1 h. Et2O was added, followed by aq. sat. NaCN
and aq. sat. NH4Cl. The phases were separated. The organic
layer was washed three times with water and once with brine
before being dried over anhydrous Na2SO4. Solvent was removed
(not to dryness) by rotary evaporation and the residue was chro-
matographed (2 : 1 pentane–CH2Cl2) on silica gel to give (4S,5aS)-
1. The fractions containing this compound were combined and
partially concentrated by rotary evaporation and diluted with
CH2Cl2. The concentration-dilution was repeated several times
until no more pentane was detected on 1H NMR, giving a solution
of (4S,5aS)-1 in CH2Cl2. The total amount of (4S,5aS)-1 formed
in this run was estimated to be 14 mg (0.081 mmol, 71% from 47)
by 1H NMR with methyl 4-iodobenzoate as the internal reference.
Data for (4S,5aS)-1 (same as natural nemotin): UV (MeOH) lmax
208 (shoulder), 235, 249, 263, 278 nm. [a]2D3 +356.10 (c 0.20,
(8S,5aR)-Undeca-1-trimethylsilyl-5,6-diene-8,11-diacet-oxy-1,
3-diyne (51). Using the same procedure for the conversion of
31 into 32 given above (with 49 to replace 31) starting from 49
(74 mg, 0.25 mmol), (4S,5aR)-allenediyne 50 was obtained as a
solution in CHCl3 and kept at -20 ◦C. A portion of this solution
(2/3) was dissolved in CH2Cl2 (1 cm3). The solution was stirred at
-20 ◦C under argon while DIBAL-H (1 M, in cyclohexane, 0.5 cm3,
0.5 mmol) was added dropwise. After completion of the addition,
the bath was allowed to warm naturally to ambient temperature
(over ca. 2 h). MeOH (1 cm3) was added, followed by Et2O and
aq. sat. potassium sodium tartrate. The mixture was stirred until
it became clear. The phases were separated. The organic layer was
washed with water and brine before being dried over anhydrous
Na2SO4. The solvent was removed (not to dryness) by rotary
evaporation and the residue was diluted with CH2Cl2 (1 cm3). To
this solution were added Ac2O (0.024 cm3, 0.25 mmol), pyridine
(0.010 cm3, 0.12 mmol) and DMAP (1 mg). The mixture was
stirred at ambient temperature overnight before being diluted with
Et2O, washed with aq. sat. NH4Cl, water and brine, and dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (4 : 1 PE : Et2O) on silica gel gave 51
(10 mg, 0.024 mmol, 15% from 49) as a colorless oil: [a]2D2 -10.54
(c 0.55, CHCl3), 49.2% d.e. (cf. the details given above for 48). 1H
NMR (300 MHz, CDCl3): d 5.63-5.53 (m, 2H), 5.35-5.24 (m, 1H),
4.08 (t, J = 5.9 Hz, 2H), 2.07 (s, 3H), 2.06 (s, 3H), 1.82-1.62 (m,
4H), 0.20 (s, 9H); FT-IR (film): 2957, 2924, 2853, 2199, 2102, 1945,
1741, 1235; ESI-MS m/z 355.1 ([M + Na]+); ESI-HRMS calcd for
C18H24O4SiNa ([M + Na]+): 355.13361; found 355.13403.
CH2Cl2), (lit.1d [a]D20 +350 (c 0.20, CH2Cl2)). FT-IR (film) nmax
:
3257, 2960, 2925, 2854, 2204, 2096, 1953, 1774, 1458, 1261, 1097,
1019, 800 cm-1; 1H NMR (300 MHz, CD2Cl2): d 5.68-5.58 (m, 2
H), 5.00-4.90 (m, 1 H), 2.54-2.30 (m, 4 H), 2.12-1.96 (m, 1 H); 13
C
NMR (75 MHz, CD2Cl2): d 214.6, 175.8, 94.8, 78.5, 76.4, 75.8,
71.7, 67.9, 67.2, 28.2, 28.1. EI-MS m/z (%): 172 (M+) (5.72), 142
(15), 107 (9), 90 (23), 85 (100); EI-HRMS calcd. for C11H8O2 (M+):
172.0524; found 172.0526.
(8S,5aS)-Undeca-1-trimethylsilyl-5,6-diene-8,11-diacetoxy-1,3-
diyne (48). DIBAL-H (1 M, in cyclohexane, 0.5 cm3, 0.5 mmol)
was added to a solution of 47 (10 mg, 0.041 mmol) in CH2Cl2
(1 cm3) stirred at -78 ◦C under argon. After completion of the
addition, the bath was allowed to warm naturally to ambient
temperature (over ca. 2 h). MeOH (1 cm3) was added, followed
by Et2O and aq. sat. potassium sodium tartrate. The mixture
was stirred until it became clear. The phases were separated. The
organic layer was washed with water and brine before being dried
over anhydrous Na2SO4. Solvent was removed (not to dryness)
by rotary evaporation and the residue was diluted with CH2Cl2
(1 cm3). To this solution were added Ac2O (0.024 cm3, 0.25 mmol),
pyridine (0.010 cm3, 0.12 mmol) and DMAP (1 mg). The mixture
was stirred at ambient temperature overnight before being diluted
with Et2O, washed with aq. sat. NH4Cl, water and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (4 : 1 PE : Et2O) on silica
gel gave diacetate 48 (10 mg, 0.030 mmol, 73%) as a colorless oil:
[a]2D2 +55.90 (c 0.18, CHCl3), 88.7% d.e. (tR(Major) = 25.10 min,
tR(Minor) = 27.15 min) as determined by HPLC on a CHFT-
IRALPAK IC column (0.46 cm ¥ 25 cm) eluting with 95 : 5 n-
hexane/i-PrOH at a flow rate of 0.5 cm3 min-1 with the UV detector
set to 214 nm. FT-IR (film) nmax: 2957, 2923, 2852, 2200, 2096,
1941, 1741, 1736, 1369, 1232, 1020, 846 cm-1; 1H NMR (300 MHz,
CDCl3): d 5.65-5.51 (m, 2H), 5.36-5.24 (m, 1H), 4.08 (t, J = 5.7 Hz,
Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (20672129, 20621062, 20772143) and the
Chinese Academy of Sciences (“Knowledge Innovation”,
KJCX2.YW.H08) is gratefully acknowledged.
Notes and references
1 (a) F. Kavanagh, A. Hervey and W. J. Robbins, Proc. Natl. Acad. Sci.
U. S. A., 1950, 36, 1–7; (b) J. D. Bu’Lock, E. R. H. Jones and P. R.
Leeming, J. Chem. Soc., 1955, 4270–4276; (c) J. D. Bu’Lock, E. R. H.
Jones, P. R. Leeming and J. M. Thompso, J. Chem. Soc., 1956, 3767–
3771; (d) R. E. Bew, R. C. Cambie, E. R. H. Jones and G. Lowe, J. Chem.
Soc. C, 1966, 135–138. For reviews on allenic natural products, see:
(e) A. Hoffmann-Ro¨der and N. Krause, Angew. Chem., Int. Ed., 2002,
41, 2933–2935; (f) A. Hoffmann-Ro¨der and N. Krause, Angew. Chem.,
Int. Ed., 2004, 43, 1196–1216; (g) A. Hoffmann-Ro¨der and N. Krause,
in Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi,
Wiley-VCH, Weinheim, 2004, vol. 1, pp 51-92.
2 J. D. Bu’Lock, E. R. H. Jones and P. R. Leeming, J. Chem. Soc., 1955,
4270–4276.
2H), 2.08 (s, 3H), 2.07 (s, 3H), 1.83-1.61 (m, 4H), 0.20 (s, 9H); 13
C
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3 R. E. Bew, R. C. Cambie, E. R. H. Jones and G. Lowe, J. Chem. Soc.
C, 1966, 135–138.
13 (a) A. O. King, N. Okukado and E.-i. Negishi, J. Chem. Soc., Chem.
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