Coibacins a and b: Total synthesis and stereochemical revision

Article abstract of DOI:10.1021/jo402339y

The interface between synthetic organic chemistry and natural products was explored in order to unravel the structure of coibacin A, a metabolite isolated from the marine cyanobacterium cf. Oscillatoria sp. that exhibits selective antileishmanial activity and potent antiinflammatory properties. Our synthetic plan focused on a convergent strategy that allows rapid access to the desired target by coupling of three key fragments involving E-selective Wittig and modified Julia olefinations. CD measurements and comparative HPLC analyses of the natural product and four synthetic stereoisomers led to determination of its absolute configuration, thus correcting the original assignment at C-5 and unambiguously establishing those at C-16 and C-18. Additionally, we synthesized coibacin B on the basis of the assignment of configuration for coibacin A.

Full text of DOI:10.1021/jo402339y

Article
pubs.acs.org/joc
Coibacins A and B: Total Synthesis and Stereochemical Revision
Vania M. T. Carneiro,†,∥ Carolina M. Avila,†,∥ Marcy J. Balunas,‡ William H. Gerwick,§
̂
and Ronaldo A. Pilli*,†
†Institute of Chemistry, University of Campinas (UNICAMP), C.P. 6154, CEP 13084-971 Campinas, Sao Paulo, Brazil
̃
‡Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269,
United States
§Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, and Skaggs School of Pharmacy and
Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States
S
* Supporting Information
ABSTRACT: The interface between synthetic organic chemistry and
natural products was explored in order to unravel the structure of coibacin
A, a metabolite isolated from the marine cyanobacterium cf. Oscillatoria
sp. that exhibits selective antileishmanial activity and potent anti-
inflammatory properties. Our synthetic plan focused on a convergent
strategy that allows rapid access to the desired target by coupling of three
key fragments involving E-selective Wittig and modified Julia olefinations.
CD measurements and comparative HPLC analyses of the natural product
and four synthetic stereoisomers led to determination of its absolute
configuration, thus correcting the original assignment at C-5 and
unambiguously establishing those at C-16 and C-18. Additionally, we
synthesized coibacin B on the basis of the assignment of configuration for
coibacin A.
1. INTRODUCTION
Marine organisms are a rich source of diverse and biologically
active natural products that have inspired the development of
novel pharmacologically relevant compounds.1 The α,β-
unsaturated δ-lactone moiety is a privileged scaffold widely
distributed among natural products that display a broad range
of biological activities, such as fostriecin,2−4 leptomycins,5 and
callystatin A.6,7
The unequivocal assignment of the absolute configuration of
the structure of a novel compound is one of the key issues in
natural products chemistry. In this regard, and despite the fact
that spectroscopic and crystallographic techniques are highly
advanced, chemical synthesis still makes important contribu-
tions in natural product elucidation.8,9
Recently, we described the isolation and structure elucidation
of four unsaturated polyketide lactone derivatives named
coibacins A−D (compounds 1−4, Figure 1) from the marine
cyanobacterium cf. Oscillatoria sp. that display the dihydropyr-
an-2-one moiety as well as either a cyclopropyl ring (coibacins
Figure 1. Structures of marine cyanobacterial metabolites: coibacins
A and B) or a methyl vinyl chloride (coibacins C and D).10 The
A−D (1−4), curacin A (5), and jamaicamide A (6).
methylcyclopropyl ring and methyl vinyl chloride are similar to
those observed in other marine cyanobacterial metabolites such
as curacin A (5)11 and jamaicamide A (6),12 respectively. These
B (2) was less active as a leishmanicidal drug (IC50 = 7.2 μM);
however, it exhibited higher cytotoxicity against human cancer
co-occurring metabolites in a single organism suggest an
intriguing flexibility in the biosynthetic pathway.10
lung cell lines (NCI-H460), with an IC50 value of 17.0 μM
Among these cyanobacterial metabolites, coibacin A (1)
displayed potent and selective activity against axenic
Received: October 31, 2013
amastigotes of Leishmania donovani (IC50 = 2.4 μM). Coibacin
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthetic Plan for Coibacin A (1) Isomers
Scheme 2. Preparation of Aldehyde (5S)-7
compared with 31.5 μM for coibacin A (1). Evaluation of anti-
inflammatory activity by cell-based nitric oxide (NO) inhibition
assay13 revealed that coibacin B (2) was the most active
coibacin representative (IC50 = 5 μM). Because coibacin A (1)
was isolated in the largest amount, it was further evaluated and
shown to reduce gene transcription of several inflammatory
cytokines, including TNF-α, IL1-β, IL-6, and iNOS (1 at 10
μg/mL).10
The absolute configuration of the dihydropyran-2-one
moiety was determined to be S on the basis of a positive
Cotton effect at λ = 259 nm observed in circular dichroism
(CD) measurements, while the trans relationship of the
substituents in the methylcyclopropyl ring was established
using NOESY correlations and J coupling constant analysis.
However, because of the scarcity of the natural products, the
absolute configuration of the cyclopropyl portion could not be
assigned.10
Because of our interest in the synthesis and biological
properties of α,β-unsaturated δ-lactones,14−18 we embarked on
the total synthesis of stereoisomers of coibacin A (1) with the
aim of establishing its absolute configuration and providing
enough material for further exploration of its biological
properties. Additionally, coibacin B (2) was synthesized on
the basis of the assignment of configuration for coibacin A (1)
by a similar synthetic route.
2. RESULTS AND DISCUSSION
Assuming the S absolute configuration of the δ-lactone moiety
and the trans relationship between the substituents in the
cyclopropyl ring, we envisioned a convergent strategy based on
the coupling of three key fragments to quickly provide the two
possible isomers (5S,16S,18S)- and (5S,16R,18R)-1 (Scheme
1). This synthetic route would be carried out by E-selective
Wittig olefination of dihydropyran aldehyde (5S)-7 with a tri-n-
butylphosphorane derived from alcohol 8. The resulting
tetrahydropyran would be converted to the corresponding
aldehyde for the final modified Julia olefination with a sulfone
derived from (1S,2S)- or (1R,2R)-9. The enantiomerically pure
fragment (5S)-7 would be synthesized from commercially
available (R)-glycidol [(R)-10] by methodology similar to that
previously reported for its enantiomer (5R)-7, involving as key
steps the ring opening of a chiral epoxide and the ring-closing
metathesis reaction of the corresponding diene.19,20 The
preparation of fragment 8 could be performed in a few steps
from 1,4-butanediol (11) using tandem oxidation/Wittig
olefination.21 The synthesis of trans-cyclopropyl fragment
(1S,2S)-9 using Charette asymmetric cyclopropanation of
trans-crotyl alcohol (12) mediated by dioxaborolane-derived
chiral ligand (4R,5R)-13 has been described.22 Similarly, the
enantiomer (1R,2R)-9 could be obtained by employing
(4S,5S)-13.
B
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Scheme 3. Synthesis of Tri-n-butylphosphonium Salt 20
Our synthesis began with the preparation of aldehyde (5S)-7
from (R)-10 according to a modification of the procedures
described by Crimmins and King20 and Boger et al.19 for (5R)-
7. Protection of (R)-10 with tert-butyldiphenylsilyl chloride
(TBDPSCl) and Cu(I)-mediated epoxide opening with vinyl-
magnesium bromide were carried out to provide allylic alcohol
(S)-14 in 82% overall yield.20 The dihydropyran-2-one (S)-15
was obtained in good yield after conversion of secondary
alcohol (S)-14 to the corresponding ester followed by ring-
closing metathesis using Grubbs I catalyst (71% yield, two
steps). Reduction of (S)-15 with diisobutylaluminum hydride
(DIBALH) and protection of the resulting lactol as the
corresponding isopropyl ketal afforded (5S)-16 in 86% yield as
a single isomer.19,23 Deprotection of the silyl ether group of
(5S)-16 (83% yield) and Swern oxidation furnished the desired
aldehyde (5S)-7,20 which was synthesized from (R)-10 in eight
steps and 42% overall yield (Scheme 2).
afforded phosphonium salt 20 in quantitative yield. Therefore,
20 was prepared in six steps and 31% overall yield from readily
available diol 11 (Scheme 3).
trans-Cyclopropyl fragment (1S,2S)-9 was obtained from
Charette asymmetric cyclopropanation of trans-crotyl alcohol
(12) mediated by dioxaborolane-derived chiral ligand (4R,5R)-
13.22,25 Treatment of (1S,2S)-9 with 2-mercaptobenzothiazole
(BTSH), Ph3P and diisopropyl azodicarboxylate (DIAD)
afforded (1S,2S)-21 after Mitsunobu reaction.25 Oxidation
with ammonium molybdate/H2O2 provided sulfone (1S,2S)-22
in 39% yield for three steps with an enantiomeric ratio (er) of
94:6 (Scheme 4). The preparation of (1R,2R)-22 was
Scheme 4. Synthesis of Sulfone (1S,2S)-22
The synthesis of fragment 8 started with the conversion of
1,4-butanediol (11) to the diester 18. Two reaction steps were
necessary to perform this transformation because treatment of
11 with 20 equiv of magnesium dioxide (MnO2) and 2.5 equiv
of [(ethoxycarbonyl)methylene]triphenylphosphorane in di-
chloromethane or chloroform furnished the desired bisolefi-
nated compound 18 in very poor yield (15−18%) even after
reflux for 3 days. Thus, mild conditions were employed to
conduct a desymmetrization reaction via tandem oxidation of
unactivated 11 with MnO2 and in situ Wittig olefination to
provide olefin (E)-17 in 75% yield.21 The scale-up of this
reaction (from 2 to 30 mmol of substrate) required increased
reaction time from 2 to 7 days, and optimization studies
indicated that a 50% reduction in the amount of MnO2 did not
affect the yield. The byproducts diester 18 (about 4% yield)
and (Z)-17 (10% yield) were obtained from this reaction.
Intermediate 17 was homologated to afford 18 in good yield
(77%) after one-pot oxidation with pyridinium chlorochromate
(PCC) and Wittig olefination. In this reaction, the (2E,6Z)
isomer of 18 was isolated as a byproduct in 7% yield (Scheme
3).
Reduction of 18 to the corresponding diol with DIBALH and
monoprotection with tert-butyldimethylsilyl chloride (TBSCl)
afforded fragment 8 (PG = TBS) in 55% yield for two steps.
Conversion to the allylic bromide 19 upon treatment with
triphenylphosphine (Ph3P) and carbon tetrabromide (CBr4) in
the presence of 2,6-lutidine was accomplished in high yield
(98%);24 however, in the absence of base the yield decreased to
45% and the dibromide byproduct was obtained in 28% yield.
Subsequently, substitution with tri-n-butylphosphine (n-Bu3P)
accomplished from the same starting material 12 using
dioxaborolane (4S,5S)-13, and the overall yield was 31%. The
enantiomeric ratio of (1S,2S)-22 and (1R,2R)-22 was
determined by chiral HPLC analysis.26
The synthesis of the C-1/C-14 fragment of isomers
(5S,16R,18R)- and (5S,16S,18S)-1 (Scheme 1) involved the
coupling of aldehyde (5S)-7 with tri-n-butylphosphonium salt
20 by E-selective Wittig olefination (Scheme 5). When this
reaction was performed with potassium tert-butoxide (t-BuOK)
in a 5:1 toluene/THF mixture, the desired product (5S)-23 was
obtained as a 5:1 mixture of E and Z isomers. With the DMSO-
derived lithium base LiCH2S(O)CH3 in toluene, a E:Z isomeric
ratio of 7:1 was formed. However, in both cases the yields were
low (46% or less) regardless of the reaction scale and
modifications in the amount of base or Wittig salt 20
employed. Therefore, we used sodium hexamethyldisilazide
(NHMDS) as a more hindered base to prevent deprotonation
α to the carbonyl group of (5S)-7. Fortunately, the yield was
C
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Scheme 5. Synthesis of Aldehyde (5S)-24
Table 1. Modified Julia Olefination Involving Aldehyde (5S)-24 and Racemic Sulfone 22
a
b
entry
solvent
MHMDS
time
E:Z ratio at C-14
yield (%)
c
1
2
3
4
5
6
7
8
DMF
THF
THF
DME
NHMDS
NHMDS
NHMDS
NHMDS
NHMDS
NHMDS
LHMDS
KHMDS
1.5 h (−78 °C), 1.5 h (rt)
1.5 h (−78 °C), 1.5 h (rt)
10 min
20 min
1.5 h
1.7:1
1.7:1
1.7:1
2.7:1
1.7:1
2:1
4
28
65
95
66
53
54
95
c
de
,
d
d
d
d
d
4:1 THF/HMPA
4:1 DME/HMPA
DME
1.5 h
10 min
10 min
1:10
2.4:1
DME
a
b
Scale: 0.06 mmol of (5S)-24. Volume of solvent: 2.5 mL. E:Z ratio of the double bond at C-14 for the isomers with E geometry of the C-6 double
c
d
e
bond. Addition order: sulfone, NHMDS, and aldehyde. Addition order: sulfone, aldehyde, and NHMDS. When the scale was duplicated, the yield
was 70%.
increased to about 70% (E:Z ratio = 6:1) by using 2 equiv of
NHMDS and 1.5 equiv of 20 in toluene. The moderate E
selectivity of this reaction may be attributed to the low steric
hindrance of the ylide.27 The triene (5S)-23 was converted
uneventfully to aldehyde (5S)-24 upon deprotection of the
TBS ether followed by MnO2-mediated allylic alcohol oxidation
in 86% yield for two steps (Scheme 5).
(entry 7), KHMDS displayed results similar to those reported
for NHMDS (entry 8).
The isomers (5S,16S,18S)- and (5S,16R,18R)-1 were
prepared as described in Scheme 6. Coupling of aldehyde
(5S)-24 with sulfones (1S,2S)- and (1R,2R)-22 provided the
tetraenes (5S,16S,18S)- and (5S,16R,18R)-25, respectively, as
mixtures of four geometric isomers, with the major isomer
displaying the all-E configuration.31 The mixtures of isomers
(5S,16S,18S)- and (5S,16R,18R)-1′ were obtained after
oxidation of (5S,16S,18S)- and (5S,16R,18R)-25 with PCC
and CaCO332 in 22% and 29% yield, respectively. Separation of
the major isomers by semipreparative reversed-phase HPLC33
afforded dihydropyran-2-ones (5S,16S,18S)- and (5S,16R,18R)-
1, with 1H- and 13C-NMR data identical to each other as well as
to those reported for natural coibacin A (1) in spite of their
diastereoisomeric relationship.
Comparison of the specific optical rotations of the synthetic
samples of (5S,16S,18S)-1 ([α]2D0 −10, c 0.1, CHCl3) and
(5S,16R,18R)-1 ([α]2D0 −100, c 0.1, CHCl3) with that reported
for natural coibacin A (1) ([α]2D0 +46, c 0.1, CHCl3) indicated
the nonidentity of the compounds. On the basis of the opposed
signal of the specific optical rotation of the synthetic and
natural compounds, we suspected that the original assignment
of the absolute configuration of the lactone moiety was in error.
Therefore, we conducted the total synthesis of the isomers
(5R,16S,18S)- and (5R,16R,18R)-1 by a route similar to that
The final coupling between aldehyde (5S)-24 and
sulfonylbenzothiazole 22 required extensive optimization in
order to improve the E:Z ratio of the newly formed double
bond.28 To avoid the use of expensive enantiomerically
enriched substrate, racemic 22 was employed in the modified
Julia olefination reaction (Table 1). When NHMDS was used,
either DMF or THF afforded (5S)-25 as a 1.7:1 mixture of E
and Z isomers at C-14 in moderate to low yields (entries 1−3).
Under the same conditions, a reduction in the reaction time led
to an increase in the yield from 28% to 65%, probably as a
result of reduced decomposition of the product in the reaction
medium (entries 2 and 3). Using DME as the solvent increased
the E:Z ratio at C-14 to 2.7:1 and the yield to 95% (entry 4).
Addition of hexamethylphosphoramide (HMPA) did not affect
the selectivity (entries 5 and 6), although studies in the
literature have shown improvement of the E selectivity in the
presence of this additive.29,30 While LHMDS, as expected,
favored the Z configuration of the newly formed double bond
D
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Scheme 6. Synthesis of Enantiomerically Pure Isomers (5S,16S,18S)- and (5S,16R,18R)-1
described above for their enantiomers (see the Experimental
Section for further details). As expected, these compounds also
displayed 1H and 13C NMR data identical to those reported for
natural coibacin A (1). Despite their dextrorotatory values, the
specific optical rotations of (5R,16S,18S)-1 ([α]2D0 +100, c 0.1,
CHCl3) and (5R,16R,18R)-1 ([α]2D0 +10, c 0.1, CHCl3) proved
to be significantly different from that reported for the natural
coibacin A (1).
Because of the difficulty of unequivocal assignment of the
absolute configuration of coibacin A (1) based only on NMR
and specific optical rotation data, we carried out HPLC
comparisons34 of natural coibacin A (1) with all four synthetic
stereoisomers displaying a trans configuration of the cyclo-
propane ring (Figure 2). When a mixture of these four
compounds was coinjected with natural coibacin A (1), an
enhancement in the intensity of the peak corresponding to
(5R,16S,18S)-1 was observed, unequivocally establishing the
absolute configuration of the natural product. Additionally, the
CD curve of (5R,16S,18S)-1 was identical to the one described
for coibacin A (1), with both displaying a positive Cotton effect
(see the CD curves in the Supporting Information). Therefore,
these results led to the revision of the configuration at C-5 in
our original publication, which was previously assigned to be
S,10 possibly as a result of a misapplication of the rules
described by Beecham.35
It is interesting to compare the chirality established here for
coibacin A (1) with that of curacin A (5) (Figure 1), a
methylcyclopropane-containing metabolite isolated from an-
other marine cyanobacterium, Moorea producens (formerly
Lyngbya majuscula). There, detailed biosynthetic mechanism
studies have shown that the S configuration of the secondary
methyl group appended to the cyclopropyl ring is established
by the trajectory of hydride delivery to the β-position of an
achiral enone.36 However, the adjacent cyclopropylmethine
center is rendered chiral (and in the case of curacin A, cis-
configured relative to the methyl substituent) after collapse of
the enolate to displace chloride and form the three-membered
ring. Thus, because curacin A (5) and coibacin A (1) possess
secondary methyl groups of identical chirality, the divergence in
their biosynthetic pathways must lie within this second step. A
range of possibilities exist, including the geometry of the
intermediate enone formed by the enoyl CoA hydratase 1, the
relative positions of the oxyanion and primary chloride
substituents to the methyl group prior to cyclopropyl ring
formation, and the overall orientation of the substrate in the
enoyl reductase. Thus, similar to the subtle alternate
functioning of β-branch-forming enzymes that lead to the
diverse functional groups observed in curacin A (5) and
Figure 2. Specific optical rotations of the four isomers of coibacin A
(1).
E
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jamaicamide A (6) (cyclopropyl ring vs vinyl chloride; Figure
1),37 the stereostructures of the coibacins implicate additional
dimensions of flexibility in this biosynthetic manifold.
A similar synthetic approach was applied to the synthesis of
coibacin B (2) displaying the 5R,14S,16S configuration, the
same one found for coibacin A (1) (Scheme 7). Fragment 26
was planned to be obtained after two steps from alcohol 17,
which was already prepared from diol 11 for the synthesis of
coibacin A (1).
explained by the instability of the aldehyde derived from
alcohol (5R)-30. The mixture containing (5R,14S,16S)-31 was
treated with PCC in the presence of CaCO3 to give a mixture
of four geometric isomers (5R,14S,16S)-2′ in 46% yield. The
major isomer (5R,14S,16S)-2, with all of the double bonds
displaying the E configuration, was isolated by semipreparative
reversed-phase HPLC (Scheme 9).38
Synthetic (5R,14S,16S)-2 and natural coibacin B displayed
identical spectra within the limits of NMR data (see the
Supporting Information). As for coibacin A (1), the specific
optical rotation for the synthetic sample of coibacin B (2)
([α]2D0 +95, c 0.1, CHCl3) was higher than that reported for the
natural compound ([α]D +59, c 0.1, CHCl3). Fortunately, the
CD curve of synthetic (5R,14S,16S)-2 closely resembles that of
natural coibacin A (1), providing strong evidence that this
represents the correct isomer of coibacin B (2).
Scheme 7. Retrosynthetic Plan for the Correct Isomer of
Coibacin B (2)
3. CONCLUSION
In summary, total syntheses of four coibacin A (1) stereo-
isomers displaying a trans-configured cyclopropane ring
revealed the natural substance to possess the 5R,16S,18S
absolute configuration. The total synthesis of coibacin A (1)
was carried out in 12 steps (longest linear route) and 3.4%
overall yield. Additionally, we synthesized the correct isomer of
coibacin B (2) on the basis of the assignment of configuration
for coibacin A (1). Studies aimed at assessing the cytotoxic and
anti-inflammatory properties of these compounds are under-
way.
4. EXPERIMENTAL SECTION
General Information. THF and DME were freshly distilled from
sodium/benzophenone. DCM, DMF, HMPA, and Et3N were freshly
distilled over CaH2. PhMe and MeCN were dried over 4 Å molecular
sieves for 48 h prior to use. TLC analyses were performed on silica gel
plates, and the spots were revealed using UV and/or the following
solutions: phosphomolybdic acid in EtOH, vanillin in EtOH/H2SO4,
and p-anisaldehyde in EtOH/AcOH/H2SO4. Flash column chroma-
Protection of alcohol 17 with TBSCl followed by reduction
of ester group with excess DIBALH furnished fragment 26 (PG
= TBS) in high yield (94%, two steps). Appel reaction
converted alcohol 26 to the corresponding bromide 27 in 91%
yield, and 27 was treated with n-Bu3P to give tri-n-
butylphosphonium salt 28 in quantitative yield (Scheme 8).
The E-selective Wittig reaction between (5R)-7 and 28
mediated by NHMDS in toluene furnished (5R)-29 as a 6:1
mixture of E and Z isomers at C-6 in 69% yield. Alcohol (5R)-
30, obtained in 94% yield from deprotection of TBS ether
(5R)-29, was oxidized under Swern conditions, and the
unstable crude product was immediately used in the modified
Julia olefination with sulfone (1S,2S)-22 to afford
(5R,14S,16S)-31 as a mixture of geometric isomers. While the
use of NHMDS in DME provided a 1:1 mixture of geometric
isomers at the C-12 double bond, better E selectivity (E:Z ratio
= 2.2:1) was obtained by using KHMDS. The moderate yield
for the Swern oxidation and Julia olefination (41%) can be
1
tography was carried out using silica gel 60 (35−60 μm). H−1H
1
COSY (90°) and H−13C HSQC NMR experiments were used for
confirmation of NMR peak assignments. The HPLC analyses were
performed at room temperature with a photodiode array detector. All
melting points were measured in open capillaries and are uncorrected.
HRMS analyses were performed using an ESI-TOF mass spectrom-
eter. IUPAC names of the compounds were generated using
ChemBioDraw Ultra 13.0; however, the usual numbering of the
carbon atoms as shown in Scheme 1 was adopted to refer to the
compounds and NMR peak assignments.
(S)-1-((tert-Butyldiphenylsilyl)oxy)pent-4-en-2-ol [(S)-14]. To
a solution of (R)-10 (3.35 g, 45.2 mmol) and imidazole (4.00 g, 58.8
mmol) in anhydrous DCM (100 mL) was added TBDPSCl (15.4 mL,
54.3 mmol) at 0 °C under N2. The solution was allowed to warm to rt
and stirred for 2 h. The reaction was quenched by the addition of
Scheme 8. Synthesis of Tri-n-butylphosphonium Salt 28
F
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Scheme 9. Synthesis of (5R,14S,16S)-2 (Coibacin B)
water (100 mL). The layers were separated, and the aqueous phase
was extracted with Et2O (2 × 50 mL). The combined organic layers
were washed with brine (100 mL), dried over Na2SO4, filtered, and
concentrated. The crude product was purified by flash column
chromatography (hexanes/Et2O 9:1) to provide (S)-tert-butyl(oxiran-
2-ylmethoxy)diphenylsilane (13.5 g, 43.3 mmol, 87%) as a colorless
oil. [α]2D0 −2.6 (c 9.4, CHCl3) {lit.39 [α]D23 −2.46 (c 9.07, CHCl3)}.
The spectral data (1H NMR and 13C NMR) are in accordance with
those reported in the literature.39
To a solution of (S)-tert-butyl(oxiran-2-ylmethoxy)diphenylsilane
(13 g, 42 mmol) in anhydrous THF (19 mL) under N2 was added CuI
(0.634 g, 3.32 mmol, 8 mol %) at rt. This suspension was stirred for 15
min. After that, the temperature was reduced to −30 °C, and
vinylmagnesium bromide (100 mL, 100 mmol, 1 M in THF) was
added by syringe pump (over 1 h). The mixture was then stirred for an
additional 1 h at this temperature, and the reaction was carefully
quenched with saturated NH4Cl solution (100 mL) at −30 °C. The
cooling bath was removed, and the reaction mixture was stirred for
more 20 min. The layers were separated, and the aqueous phase was
extracted with Et2O (2 × 100 mL). The combined organic layers were
washed with brine (100 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography (hexanes/Et2O 7:3) to afford alcohol
(S)-14 (13.4 g, 39.4 mmol, 94%) as a colorless oil. [α]2D0 −2.4 (c 9.6,
CHCl3) {lit.40 [α]D20 −2.6 (c 9.17, CHCl3)}. The spectral data (1H
NMR and 13C NMR) are in accordance with those reported in the
literature.40
(S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-
pyran-2-one [(S)-15]. To a solution of alcohol (S)-14 (12.97 g, 38.08
mmol) and Et3N (10.6 mL, 76.2 mmol) in anhydrous DCM (131 mL)
was added freshly prepared acryloyl chloride41 (4.62 mL, 57.1 mmol)
dropwise at 0 °C under N2. At this time a color change from light
yellow to dark yellow was observed. The mixture was stirred for 1 h at
the same temperature, and then the reaction was quenched by the
addition of brine (50 mL) and saturated Rochelle’s salt solution (50
mL). The emulsion was stirred until complete layer separation (∼3 h).
The layers were separated, and the aqueous phase was extracted with
Et2O (2 × 100 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (hexanes/Et2O
7:3) to give (S)-1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl acrylate
(12.92 g, 32.74 mmol, 86%) as a yellow oil. [α]2D0 −9 (c 1.05, CHCl3)
{lit.42 (antipode) [α]D26 +8.3 (c 1, CHCl3)}. The spectral data (1H
NMR and 13C NMR) are in accordance with those reported in the
literature for its enantiomer.42
added first-generation Grubbs catalyst (0.823 g, 1.03 mmol, 10 mol %)
in three portions (275 mg each hour) dissolved in anhydrous DCM
(10 mL). The reaction mixture was refluxed for 20 h and then cooled
to rt, and the solvent was evaporated under reduced pressure. The
crude product was purified by flash column chromatography (hexanes/
AcOEt 6:4) to provide lactone (S)-15 (3.08 g, 8.40 mmol, 83%) as a
brown oil. [α]2D0 −48 (c 1.03, CHCl3) {lit.42 (antipode) [α]2D6 +47.8 (c
1, CHCl3)}. The spectral data (1H NMR and 13C NMR) are in
accordance with those reported in the literature for its enantiomer.42
tert-Butyl(((2S)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl)-
methoxy)diphenylsilane [(5S)-16]. To a solution of lactone (S)-15
(1.2 g, 3.27 mmol) in anhydrous DCM (40 mL) under N2 was added a
solution of DIBALH (4 mL, 1.2 M in toluene) at −78 °C. The
reaction mixture was stirred for 1 h at the same temperature, and then
the reaction was quenched by the addition of saturated NaHCO3
solution (40 mL) and Rochelle’s salt solution (60 mL). The emulsion
formed was stirred until complete phase separation was achieved (∼3
h). The layers were separated, and the aqueous phase was extracted
with DCM (3 × 100 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure. The
product was used in the next step without purification.
The crude product was taken up in toluene (16 mL), and then
isopropyl alcohol (8.00 mL, 105 mmol) and PPTS (0.025 g, 0.098
mmol, 3 mol %) were added at rt. The reaction mixture was stirred for
12 h at the same temperature, and the reaction was quenched by the
addition of saturated NaHCO3 solution (20 mL). The mixture was
stirred for 30 min. The layers were separated, and the aqueous phase
was extracted with DCM (3 × 40 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The product was purified by flash column chromatography
(hexanes/AcOEt 6:4) to give (5S)-16 (1.16 g, 2.82 mmol, 86%, two
steps) as a yellow oil and as a single isomer. [α]2D0 −28 (c 0.66, DCM)
{lit.20 (antipode) [α]2D4 +28.2 (c 0.68, DCM)}. The spectral data (1H
NMR and 13C NMR) are in accordance with those reported in the
literature for its enantiomer.20,23
(R)-1-((tert-Butyldiphenylsilyl)oxy)pent-4-en-2-ol [(R)-14].
(R)-tert-Butyl(oxiran-2-ylmethoxy)diphenylsilane was prepared from
(S)-10 (3.66 g, 49.5 mmol) by a procedure similar to that described
above for its enantiomer. The crude product was purified by flash
column chromatography (gradient elution, 2 to 4% AcOEt in hexanes)
to provide the expected product (13.6 g, 43.5 mmol, 88%) as a
colorless oil. [α]D20 +2.5 (c 2, CHCl3) {lit.43 [α]D20 +2.3 (c 2, CHCl3)}.
The spectral data (1H NMR and 13C NMR) are in accordance with
those reported in the literature.43
Alcohol (R)-14 was obtained from (R)-tert-butyl(oxiran-2-
ylmethoxy)diphenylsilane (13.4 g, 42.9 mmol) as described above
for (S)-14. The crude product was purified by flash column
To a solution of (S)-1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl
acrylate (4.00 g, 10.1 mmol) in anhydrous DCM (1 L) at reflux was
G
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Article
chromatography (hexanes/AcOEt 75:25) to give (R)-14 (12.8 g, 37.6
mmol, 87%) as a colorless oil. [α]2D0 +3 (c 1, CHCl3) {lit.43 [α]2D0 +2.9
(c 1, CHCl3)}. The spectral data (1H NMR and 13C NMR) are in
accordance with those reported in the literature.43
(R)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-
pyran-2-one [(R)-15]. (R)-1-((tert-Butyldiphenylsilyl)oxy)pent-4-en-
2-yl acrylate was prepared from (R)-14 (12.7 g, 37.3 mmol) using a
procedure similar to that reported above for its enantiomer. The crude
product was purified by flash column chromatography (hexanes/Et2O
8:2) to furnish the desired product (13.9 g, 35.2 mmol, 94%) as a
yellow oil. [α]D20 +11 (c 1, CHCl3) {lit.42 [α]D26 +8.3 (c 1, CHCl3)}.
The spectral data (1H NMR and 13C NMR) are in accordance with
those reported in the literature.42
Lactone (R)-15 was obtained from (R)-1-((tert-butyldiphenylsilyl)-
oxy)pent-4-en-2-yl acrylate (5.0 g, 13 mmol) by procedure similar to
that described for (S)-15. The crude product was purified by flash
column chromatography (hexanes/AcOEt 7:3) to provide (R)-15
(3.81 g, 10.4 mmol, 82%) as a brown oil. [α]2D0 +41 (c 1, CHCl3) {lit.42
[α]D26 +47.8 (c 1, CHCl3); lit.43 [α]D23 +34.2 (c 1.5, CHCl3)}. The
spectral data (1H NMR and 13C NMR) are in accordance with those
reported in the literature.42,43
tert-Butyl(((2R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl)-
methoxy)diphenylsilane [(5R)-16]. Compound (5R)-16 was
prepared from (R)-15 (3.0 g, 8.4 mmol) in the same manner as
described for (5S)-16. The product was purified by flash column
chromatography (hexanes/AcOEt 6:4) to give (5R)-16 (3.05 g, 7.42
mmol, 88%, two steps) as a yellow oil and as a single isomer. [α]2D0 +30
(c 0.65, DCM) {lit.20 [α]D24 +28.2 (c 0.68, DCM)}. The spectral data
(1H NMR and 13C NMR) are in accordance with those reported in the
literature.20,23
combined organic phases were washed with brine (50 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (AcOEt) to afford the
corresponding diol (2E,6E)-octa-2,6-diene-1,8-diol (1.539 g, 10.82
mmol, 94%) as a light-yellow oil. The spectral data (IR, 1H NMR, and
13C NMR) are in accordance with those reported in the literature.44
To a solution of (2E,6E)-octa-2,6-diene-1,8-diol (1.27 mg, 8.93
mmol) in anhydrous DMF (18 mL) were added TBSCl (897 mg, 5.95
mmol) and imidazole (608 mg, 8.93 mmol). The resulting mixture was
stirred at rt for 24 h, and the reaction was quenched by addition of
H2O (50 mL). After extraction with AcOEt (3 × 100 mL), the
combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (gradient elution, 10 to 100% AcOEt in
hexanes) affording the monoprotected compound 8 (894 mg, 3.49
mmol, 59%), the bis(silyl ether) (6E,10E)-2,2,3,3,14,14,15,15-
octamethyl-4,13-dioxa-3,14-disilahexadeca-6,10-diene (251 mg, 0.677
mmol, 11%) as a byproduct, and recovered starting material (532 mg,
3.74 mmol, 42%). The spectral data (IR, 1H NMR, and 13C NMR) of
the isolated compounds are in agreement with the literature data.44
(((2E,6E)-8-Bromoocta-2,6-dien-1-yl)oxy)(tert-butyl)-
dimethylsilane (19). To a solution of 8 (611 mg, 2.38 mmol) in
anhydrous MeCN (14 mL) were added Ph3P (1.25 mg, 4.77 mmol),
2,6-lutidine (0.55 mL, 4.75 mmol), and CBr4 (1.58 g, 4.76 mmol) at 0
°C. The resulting solution was stirred at rt for 10 min. The reaction
was quenched with H2O (50 mL), and the mixture was extracted with
Et2O (2 × 100 and 1 × 50 mL). The combined organic phases were
washed with brine (50 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (hexanes/AcOEt 95:5) to give 19 (744 mg,
2.3 mmol, 98%) as a colorless oil. Rf: 0.64 (hexanes/AcOEt 95:5). IR
Ethyl (E)-6-Hydroxyhex-2-enoate (17). To a solution of 1,4-
butanediol (11) (3.10 g, 34.3 mmol) in DCM (1.2 L) were
successively added (ethoxycarbonylmethylene)triphenylphosphorane
(14.3 g, 41.2 mmol) and MnO2 (10.0 g, 115 mmol), and the mixture
was stirred at rt. After 24 and 48 h, two additional portions of MnO2
(2 × 10.0 g) were added. The mixture was stirred for a further 5 days
and filtered through Celite using DCM for washing. The solvent was
evaporated under reduced pressure, and the residue was treated with
Et2O to allow precipitation of Ph3PO. After filtration and solvent
evaporation, the crude product was purified by flash chromatography
(hexanes/AcOEt 1:1) to afford the E isomer 17 (4.595 g, 25.92 mmol,
75%) as the major product together with its Z isomer ethyl (Z)-6-
hydroxyhex-2-enoate (622 mg, 3.93 mmol, 11%) and diester 18 (316
mg, 1.40 mmol, 4%) as byproducts. All three compounds were
1
(ATR) νmax/cm−1: 2928, 2856, 1472, 1254, 966, 835, 775. H NMR
(500 MHz, CDCl3) δ: 0.06 (s, 6H), 0.90 (s, 9H), 2.14 (br s, 4H), 3.93
(d, J = 5.0 Hz, 2H), 4.11 (d, J = 2.5 Hz, 2H), 5.49−5.73 (m, 4H). 13C
NMR (125 MHz, CDCl3) δ: −5.1 (2C), 18.4, 26.0 (3C), 31.4, 31.6,
33.3, 63.8, 126.8, 129.7, 130.3, 135.6. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C14H27BrOSiNa 341.09067; found 341.09049.
2-((((1S,2S)-2-Methylcyclopropyl)methyl)sulfonyl)benzo[d]-
thiazole [(1S,2S)-22]. To a mixture of DME (2 mL, 19 mmol) and
anhydrous DCM (18 mL) was added a solution of diethylzinc (1 M in
hexanes, 19 mL) at −10 °C under N2. Diiodomethane (3 mL, 37
mmol) was added dropwise, and the solution was stirred at −10 °C for
20 min. This fresh Zn(CH2I)2·DME solution was added by cannula
over a solution of trans-crotyl alcohol (12) (540 mg, 7.50 mmol) and
butylboronic acid N,N,N′,N′-tetramethyl-L-tartaric acid diamide ester
[(4R,5R)-13] (2.2 g, 8.1 mmol) in DCM (37 mL) at −10 °C, and the
mixture was stirred at 0 °C for 4 h. Saturated aqueous NH4Cl (50 mL)
was added, and the mixture was extracted with Et2O (4 × 50 mL). The
combined organic phases were stirred with 2 M NaOH (100 mL)
overnight. After phase separation, the organic layer was washed with
an aqueous solution of 1 M HCl (50 mL), a saturated solution of
NaHCO3 (50 mL), and brine (50 mL). The organic phase was dried
over MgSO4, filtered, and concentrated under reduced pressure (450
mbar). The crude product ((1S,2S)-2-methylcyclopropyl)methanol
[(1S,2S)-9] was obtained as a light-yellow oil and used in the next step
without purification to avoid losses due to its volatility. The
enantiomeric ratio was determined to be 94:6 after analysis of the
1
obtained as colorless oils, and their spectral data (IR, H NMR, and
13C NMR) are in accordance with those reported in the literature.21
Diethyl (2E,6E)-Octa-2,6-dienedioate (18). A mixture of 17
(2.35 g, 14.9 mmol) and PCC (6.5 g, 30.1 mmol, ground with 12.9 g
of silica) in DCM (0.6 L) was stirred at rt for 5 h. Imidazole was added
(2.02 g, 29.7 mmol), and the reaction mixture was stirred for an
additional 1 h. After addition of (ethoxycarbonylmethylene)-
triphenylphosphorane (12.4 g, 35.6 mmol), stirring was continued
for 24 h. The mixture was filtered through Celite using DCM for
washing. The solvent was removed under reduced pressure, and the
crude material was treated with Et2O to promote precipitation of
Ph3PO. After filtration, the solvent was evaporated, and the residue
was purified by flash chromatography (hexanes/AcOEt 8:2) to give
(E,E)-diester 18 (2.598 g, 11.48 mmol, 77%) and its Z,E isomer
diethyl (2Z,6E)-octa-2,6-dienedioate (228 mg, 1.00 mmol, 7%) as
1
corresponding Mosher’s ester by H NMR (500 MHz).
To a solution of the (1S,2S)-9 obtained above in THF (15 mL)
were successively added 2-mercaptobenzothiazole (1.0 g, 6.0 mmol),
Ph3P (1.57 g, 5.97 mmol), and DIAD (1.3 mL, 6.6 mmol). The
mixture was stirred at rt for 24 h, and the excess solvent was removed
under reduced pressure. Et2O was added to the residue, and the
precipitate was removed by filtration. After solvent evaporation, the
crude material was partially purified by flash chromatography
(hexanes/AcOEt 95:5) to give 2-((((1S,2S)-2-methylcyclopropyl)-
methyl)thio)benzo[d]thiazole [(1S,2S)-21] (1.033 g), as a light-yellow
oil. This intermediate was not characterized because it was still impure.
To a solution of (1S,2S)-21 (1.033 g) in EtOH (40 mL) was added
a solution of ammonium molybdate tetrahydrate (540 mg, 0.437
1
colorless oils. The spectral data (IR, H NMR, and 13C NMR) of 18
and its geometric isomer are in accordance with those reported in the
literature.21
(2E,6E)-8-((tert-Butyldimethylsilyl)oxy)octa-2,6-dien-1-ol (8).
To a solution of 18 (2.598 g, 11.48 mmol) in anhydrous DCM (50
mL) was slowly added via cannula a solution of DIBALH (9 mL, 50.5
mmol) in DCM (15 mL) at −78 °C under N2. The reaction mixture
was stirred under reduced temperature for 2 h. After that, Et2O (150
mL) and a saturated solution of Rochelle’s salt (50 mL) were added,
while vigorous stirring was maintained for 1 h. After phase separation,
the aqueous layer was extracted with Et2O (2 × 50 mL). The
H
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The Journal of Organic Chemistry
Article
mmol) in H2O2 (30% v/v, 2 mL) at 0 °C under N2. The resulting
mixture was stirred at rt for 18 h, and the solvent was removed under
reduced pressure. The residue was diluted with H2O (50 mL) and
extracted with DCM (5 × 50 mL). The combined organic phases were
washed with brine (50 mL), dried with MgSO4, and evaporated, and
the residue was purified by flash chromatography (hexanes/AcOEt
8:2) to afford (1S,2S)-22 (890 mg, 3.33 mmol, 39% for three steps, er
94:6) as a white solid. Mp: 77−80 °C (lit.25 94−96 °C). [α]D20 +8 (c
1.13, CHCl3) {lit.25 [α]D20 +7 (c 1.14, CHCl3)}. The enantiomeric ratio
of (1S,2S)-22 was determined by chiral HPLC analysis,26 and its
spectral data (IR, 1H NMR, and 13C NMR) are in agreement with the
literature data.25
mixture was warmed slowly and stirred over 6 h. The reaction was
quenched with H2O (50 mL), and the mixture was extracted with
AcOEt (3 × 100 mL). The combined organic phases were washed
with brine (50 mL) and dried over MgSO4, and the solvent was
removed under reduced pressure. The crude product was purified by
flash chromatography (hexanes/AcOEt 95:5) to furnish (5S)-23 (383
mg, 0.975 mmol, 70%) as a light-yellow oil and as a 6:1 mixture of the
two isomers at the C-6/C-7 double bond. Rf: 0.50 (hexanes/AcOEt
95:5). IR (ATR) νmax/cm−1: 2958, 2926, 2895, 2851, 1254, 1125,
1
1099, 1028, 988, 836, 776. H NMR (500 MHz, CDCl3) δ: (major
isomer) 0.06 (s, 6H, Si(CH3)2), 0.90 (s, 9H, C(CH3)3), 1.16 (d, J =
5.0 Hz, 3H, C(CH3)2), 1.22 (d, J = 5.0 Hz, 3H, C(CH3)2), 1.97−2.26
(m, 6H, H-4, H-10, and H-11), 4.00 (sept, J = 5.0 Hz, 1H,
CH(CH3)2), 4.11 (d, J = 4.7 Hz, 2H, H-14), 4.42−4.46 (m, 1H, H-5),
5.10 (br s, 1H, H-1), 5.52−5.72 (m, 5H, H-13, H-6, H-12, H-9, and H-
2), 5.97−6.08 (m, 2H, H-3 and H-8), 6.22 (dd, J = 15.3 and 10.5 Hz,
1H, H-7). 13C NMR (125 MHz, CDCl3) δ: (major isomer) −5.1 (2
CH3, Si(CH3)2), 18.4 (C, Si−C), 22.0 (CH3, C(CH3)2), 23.8 (CH3,
C(CH3)2), 26.0 (3CH3, C(CH3)3), 30.7 (CH2, C-4), 31.8 (CH2, C-
11), 32.2 (CH2, C-10), 63.9 (CH2, C-14), 66.4 (CH, C-5), 69.4 (CH,
C(CH3)2), 93.1 (CH, C-1), 126.1 (CH, C-2), 128.4 (CH, C-3), 129.7
(CH, C-13), 130.0 (CH, C-8), 130.2 (CH, C-12*), 130.8 (CH, C-6*),
131.1 (CH, C-7), 134.5 (CH, C-9) (asterisks indicate that the
assignments may be interchanged). HRMS (ESI-TOF) m/z: [M −
OCH(CH3)2]+ calcd for C20H33O2Si 333.22443; found 333.22458.
(2E,6E,8E)-9-((2S)-6-Isopropoxy-3,6-dihydro-2H-pyran-2-yl)-
nona-2,6,8-trienal [(5S)-24]. To a solution of (5S)-23 (0.375 g,
0.955 mmol) in anhydrous THF (48 mL) was added a solution of
TBAF (1 mL, 1 mmol, 1 M in THF) at 0 °C under N2. The yellow
solution was allowed to warm to rt and stirred for 2 h. The reaction
was quenched by the addition of H2O (30 mL) and AcOEt (60 mL).
The layers were separated, and the aqueous phase was extracted with
AcOEt (4 × 50 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
product was used in the next step without purification.
2-((((1R,2R)-2-Methylcyclopropyl)methyl)sulfonyl)benzo[d]-
thiazole [(1R,2R)-22]. Sulfone (1R,2R)-22 was prepared from 12 in
31% overall yield and er 94:6 employing a procedure similar to that
described above for (1S,2S)-22 but using butylboronic acid N,N,N′,N′-
tetramethyl-D-tartaric acid diamide ester [(4S,5S)-13]. Mp: 79−82 °C.
[α]D20 −8 (c 1.11, CHCl3) {lit.25 [α]D20 (antipode) +7 (c 1.14, CHCl3)}.
The enantiomeric ratio of (1R,2R)-22 was determined by chiral HPLC
analysis,26 and its spectroscopic data (IR, 1H NMR, and 13C NMR) are
in accordance with those for its enantiomer reported by Charette.25
2-((((trans)-2-Methylcyclopropyl)methyl)sulfonyl)benzo[d]-
thiazole (22). Racemic sulfone 22 was produced from 12 in 83%
overall yield using a procedure similar to that described for (1S,2S)-22
but employing Simmons−Smith cyclopropanation in place of
asymmetric Charette’s reaction. Mp: 84−86 °C. The spectral data
1
for racemic 22 (IR, H NMR, and 13C NMR) are in accordance with
those for (1S,2S)-22 reported by Charette.25
tert-Butyl(((2E,6E,8E)-9-((2S)-6-isopropoxy-3,6-dihydro-2H-
pyran-2-yl)nona-2,6,8-trien-1-yl)oxy)dimethylsilane [(5S)-23].
To a solution of 19 (664 mg, 2.08 mmol) in anhydrous MeCN (9.5
mL) was added n-Bu3P (0.77 mL, 3.1 mmol), and the mixture was
stirred at rt for 12 h. After that, the excess solvent was removed under
reduced pressure, and the crude product was maintained under high
vacuum (0.2 mmHg) for 8 h. The tri-n-butylphosphonium salt 20 was
used in the Wittig olefination without purification.
To a solution of dihydropyran (5S)-16 (1.41 g, 3.43 mmol) in
anhydrous THF (35 mL) at 0 °C under N2 was added a solution of
TBAF (3.6 mL, 1 M in THF). The solution was allowed to warm to rt
and stirred for 3 h. The reaction was quenched by the addition of H2O
(35 mL). The layers were separated, and the aqueous layer was
extracted with AcOEt (5 × 40 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography (hexanes/
AcOEt 6:4) to give the corresponding alcohol ((2S)-6-isopropoxy-3,6-
dihydro-2H-pyran-2-yl)methanol (0.492 g, 2.85 mmol, 83%) as a
white solid. Mp: 43−45 °C. [α]2D0 −47 (c 1, DCM) {lit.20 (antipode)
[α]2D4 +40.4 (c 0.47, DCM)}. The spectral data (1H NMR and 13C
NMR) are in accordance with those reported in the literature for its
enantiomer.20
To a solution of oxalyl chloride (0.192 mL, 2.23 mmol) in
anhydrous DCM (10 mL) at −78 °C under N2 was added dropwise
DMSO (0.227 mL, 3.12 mmol). After 15 min of stirring, a solution of
the alcohol obtained above (0.240 g, 1.39 mmol) in anhydrous DCM
(4 mL) was added dropwise by cannula. The resultant white emulsion
was stirred for an additional 15 min, and then Et3N (1.0 mL, 6.9
mmol) was added. After 5 min, the mixture was allowed to warm to rt.
The reaction was quenched by the addition of saturated NH4Cl
solution (15 mL). The layers were separated, and the aqueous phase
was extracted with Et2O (3 × 25 mL). The organic layers were
combined, washed with brine (20 mL), dried over Na2SO4, filtered,
and carefully concentrated (bath temperature 30 °C, pressure 400−
420 mbar) to prevent loss of the volatile aldehyde. The crude product,
(2S)-6-isopropoxy-3,6-dihydro-2H-pyran-2-carbaldehyde [(5S)-7],
was obtained as a colorless oil and was used in the next step without
purification because of its instability. Rf: 0.57 (hexanes/AcOEt 7:3).
Wittig Olefination. To a solution of freshly prepared aldehyde
(5S)-7 (236 mg, 1.39 mmol) and tri-n-butylphosphonium salt 20 (2.08
mmol) in anhydrous PhMe (25 mL) was added dropwise a solution of
NHMDS (2.8 mL, 2.8 mmol, 1 M in THF) at −78 °C under N2. The
To a solution of the alcohol obtained above in anhydrous DCM (95
mL) was added MnO2 (5 g, 57.3 mmol, ≥ 85% activated, Sigma-
Aldrich) in three portions (one every 24 h). The reaction mixture was
allowed to stir for an additional 24 h. The crude reaction mixture was
directly filtered through a plug of silica gel, eluted with a mixture of
hexanes/AcOEt 1:1, and concentrated under reduced pressure. The
product was purified by flash chromatography (hexanes/AcOEt 6:4)
to give (5S)-24 (227 mg, 0.821 mmol, 86%, two steps) as a light-
yellow oil and as a 6:1 mixture of the two isomers at the C-6/C-7
double bond. Rf: 0.54 (hexanes/AcOEt 1:1). IR (ATR) νmax/cm−1:
1
2959, 2922, 2850, 1691, 1124, 1099, 1026, 993, 668, 651. H NMR
(500 MHz, CDCl3) δ: (major isomer) 1.19 (d, J = 6.1 Hz, 3H,
C(CH3)2), 1.25 (d, J = 6.1 Hz, 3H, C(CH3)2), 2.01−2.14 (m, 2H, H-
4), 2.32−2.36 (m, 2H, H-10), 2.45−2.49 (m, 2H, H-11), 4.02 (sept, J
= 6.1 Hz, 1H, CH(CH3)2), 4.46−4.49 (m, 1H, H-5), 5.13 (br s, 1H,
H-1), 5.66−5.79 (m, 3H, H-6, H-9, and H-2), 6.00−6.03 (m, 1H, H-
3), 6.09−6.17 (m, 2H, H-8 and H-13), 6.25 (dd, J = 15.4 and 10.5 Hz,
1H, H-7), 6.85 (dd, J = 15.6 and 6.7 Hz, 1H, H-12), 9.52 (d, J = 7.9
Hz, 1H, H-14). 13C NMR (125 MHz, CDCl3) δ: (major isomer) 22.0
(CH3, C(CH3)2), 23.8 (CH3, C(CH3)2), 30.6 (CH2, C-4), 30.7 (CH2,
C-10), 32.2 (CH2, C-11), 66.2 (CH2, C-5), 69.5 (CH, C(CH3)2), 93.1
(CH, C-1), 126.1 (CH, C-2), 128.3 (CH, C-3), 130.5 (CH, C-7),
131.1 (CH, C-8), 131.9 (CH, C-9*), 132.5 (CH, C-6*), 133.3 (CH,
C-13), 157.4 (CH, C-12), 193.9 (CHO, C-14) (asterisks indicate that
the assignments may be interchanged). HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C17H24O3Na 299.1623; found 299.1637.
(2S)-6-Isopropoxy-2-((1E,3E,7E,9E)-10-((1S,2S)-2-
methylcyclopropyl)deca-1,3,7,9-tetraen-1-yl)-3,6-dihydro-2H-
pyran [(5S,16S,18S)-25] (Julia Olefination with THF). To a
solution of aldehyde (5S)-24 (16 mg, 0.058 mmol) and sulfone
(1S,2S)-22 (23 mg, 0.086 mmol) in anhydrous THF (2.5 mL) was
added dropwise a solution of NHMDS (120 μL, 0.12 mmol, 1 M in
THF) at −78 °C under N2. The resulting light-yellow mixture was
stirred for 10 min, and the reaction was quenched with H2O (6 mL).
The mixture was extracted with AcOEt (30 + 10 mL), and the organic
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Article
layer was washed with brine (10 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (hexanes/AcOEt 95:5) to afford
(5S,16S,18S)-25 as 1.7:1 E:Z mixture at the C-14 double bond
(12.4 mg, 0.0377 mmol, 65%) contaminated with minor amounts of
the 6Z double-bond isomers as a light-yellow oil. Rf: 0.67 (hexanes/
AcOEt 9:1). IR (ATR) νmax/cm−1: 2969, 2925, 1654, 1447, 1380,
crude product was purified by flash chromatography (hexanes/AcOEt
95:5) to afford (5S,16R,18R)-25 as a 2.7:1 E:Z mixture at the C-14
double bond (116 mg, 0.353 mmol, 95%) contaminated with minor
amounts of the 6Z double-bond isomers as a light-yellow oil. Rf: 0.67
(hexanes/AcOEt 9:1). The IR and NMR data for (5S,16R,18R)-25 are
identical to those described for (5S,16S,18S)-25 despite their
diastereoisomeric relationship. HRMS (ESI-TOF) m/z: [M + K]+
calcd for C22H32O2K 367.2039; found 367.2030.
1
1316, 1181, 1099, 1027, 985, 718. H NMR (500 MHz, CDCl3) δ:
(S)-6-((1E,3E,7E,9E)-10-((1R,2R)-2-Methylcyclopropyl)deca-
1,3,7,9-tetraen-1-yl)-5,6-dihydro-2H-pyran-2-one
[(5S,16R,18R)-1]. A mixture of PCC (361 mg, 1.67 mmol) and
CaCO3 (670 mg, 6.70 mmol) in anhydrous DCM (7 mL) was stirred
at rt for 2 h. Then a solution of (5S,16R,18R)-25 (111 mg, 0.338
mmol) in DCM (12 mL) was added by cannula, and the reaction
mixture was stirred at rt for 2 h. After filtration over silica gel and
solvent evaporation under reduced pressure, the crude product was
purified by flash chromatography (gradient elution, 20 to 30% AcOEt
in hexanes) to afford (5S,16R,18R)-1′ (28 mg, 0.098 mmol, 29%) as a
mixture of E and Z isomers at the C-14/C-15 double bond
contaminated with minor amounts of the 6Z isomers. This mixture
was separated using preparative HPLC with a SunFire Prep C18 OBD
column (particle size 5 μm, dimensions 19 mm × 100 mm, 60%
MeCN/40% H2O, 17 mL/min) to give the major isomer with E-
configured double bonds, (5S,16R,18R)-1 (12.9 mg, tR = 18.4 min), as
a colorless oil. Rf: 0.41 (hexanes/AcOEt 7:3). [α]2D0 −100 (c 0.1,
CHCl3). The IR and NMR data for (5S,16R,18R)-1 are identical to
those described for (5S,16S,18S)-1 despite their diastereoisomeric
relationship. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H25O2
285.1855; found 285.1866.
tert-Butyl(((2E,6E,8E)-9-((2R)-6-isopropoxy-3,6-dihydro-2H-
pyran-2-yl)nona-2,6,8-trien-1-yl)oxy)dimethylsilane [(5R)-23].
To a solution of 19 (568 mg, 1.78 mmol) in anhydrous MeCN (8
mL) was added n-Bu3P (0.70 mL, 2.8 mmol), and the mixture was
stirred at rt for 12 h. After that, the excess solvent was removed under
reduced pressure, and the crude product was maintained under high
vacuum (0.2 mmHg) for 8 h. The tri-n-butylphosphonium salt 20 was
used without purification.
Deprotection of (5R)-16 (3.05 g, 7.31 mmol) employing a
procedure similar to that described above for its enantiomer provided
the corresponding alcohol. The crude product was purified by column
chromatography (hexanes/AcOEt 6:4) to give the desired product
((2R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl)methanol (1.14 g, 6.62
mmol, 90%) as a white solid. Mp: 42−44 °C. [α]2D0 +46 (c 1, DCM)
{lit.20 [α]2D4 +40.4 (c 0.47, DCM)}. The spectral data (1H NMR and
13C NMR) are in accordance with those reported in the literature.20
The aldehyde (2R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-carbalde-
hyde [(5R)-7] was prepared from the alcohol prepared above (0.205 g,
1.19 mmol) as described for (5S)-7. The crude product was obtained
as a colorless oil that was used in the next step without purification
because its instability. Rf: 0.57 (hexanes/AcOEt 7:3).
Wittig Olefination. Compound (5R)-23 was obtained from freshly
prepared aldehyde (5R)-7 (202 mg, 1.19 mmol) and tri-n-
butylphosphonium salt 20 (1.78 mmol) following the procedure
described above for (5S)-23. The crude product was purified by flash
chromatography (gradient elution, 0 to 10% AcOEt in hexanes) to
furnish (5R)-23 (368 mg, 0.937 mmol, 79%) as a light-yellow oil and
as a 5:1 mixture of the two isomers at the C-6/C-7 double bond. Rf:
0.50 (hexanes/AcOEt 95:5). The IR and NMR data for (5R)-23 are
identical to those described for its enantiomer (5S)-23. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C23H40O3SiNa 415.2644; found
415.2633.
(2E,6E,8E)-9-((2R)-6-Isopropoxy-3,6-dihydro-2H-pyran-2-yl)-
nona-2,6,8-trienal [(5R)-24]. Aldehyde (5R)-24 was obtained from
(5R)-23 (0.699 g, 1.78 mmol) using a procedure similar to that
described for (5S)-24 except for the reaction time of the MnO2
oxidation, which was reduced from 96 to 72 h by using another batch
of MnO2 (6.19 g, 71.2 mmol, ≥90% activated, Fluka Analytical). The
product was purified by flash chromatography (hexanes/AcOEt 6:4)
to give (5R)-24 (371 mg, 1.34 mmol, 75%, two steps) as a light-yellow
oil and as a 5:1 mixture of the two isomers at the C-6/C-7 double
(major isomer) 0.47−0.50 (m, 1H), 0.53−0.57 (m, 1H), 0.72−0.79
(m, 1H), 1.04−1.10 (m, 1H), 1.06 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.2
Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H), 2.03−2.25 (m, 6H), 4.01 (sept, J =
6.2 Hz, 1H), 4.42−4.47 (m, 1H), 5.10 (br s, 1H), 5.15 (dd, J = 14.8
and 8.9 Hz, 1H), 5.48−5.56 (m, 1H), 5.62 (d, J = 15.3 and 6.1 Hz,
1H), 5.68−5.76 (m, 2H), 5.94−6.09 (m, 4H), 6.22 (dd, J = 15.3 and
10.2 Hz, 1H); (second-largest isomer) 0.53−0.57 (m, 2H), 0.72−0.79
(m, 1H), 1.04−1.10 (m, 1H), 1.09 (d, J = 5.8 Hz, 3H), 1.17 (d, J = 6.1
Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H), 2.03−2.25 (m, 6H), 4.01 (sept, J =
6.2 Hz, 1H), 4.42−4.47 (m, 1H), 4.72 (t, J = 10.4 Hz, 1H), 5.10 (br s,
1H), 5.48−5.56 (m, 1H), 5.68−5.76 (m, 2H), 5.87 (t, J = 10.9 Hz,
1H), 5.94−6.09 (m, 4H), 6.47 (dd, J = 14.8 and 11.2 Hz, 1H). 13C
NMR (63 MHz, CDCl3) δ: (major isomer) 15.6 (2C), 18.5, 22.0, 22.9,
23.9, 30.7, 32.3, 32.6, 66.4, 69.4, 93.1, 126.1, 127.5, 128.5, 130.0, 130.1,
130.7, 130.9, 131.2, 134.6, 136.1; (second-largest isomer) 15.8, 16.0,
18.5, 19.3, 21.9, 23.9, 30.8, 32.2, 32.7, 62.7, 69.3, 92.8, 126.3, 126.5,
128.6, 130.0, 130.9, 131.2, 132.8, 134.2, 134.6, 136.2. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C22H32O2Na 351.2300; found
351.2288.
(S)-6-((1E,3E,7E,9E)-10-((1S,2S)-2-Methylcyclopropyl)deca-
1,3,7,9-tetraen-1-yl)-5,6-dihydro-2H-pyran-2-one
[(5S,16S,18S)-1]. A mixture of PCC (323 mg, 1.50 mmol) and
CaCO3 (600 mg, 6 mmol) in anhydrous DCM (6 mL) was stirred at rt
for 30 min. Then a solution of (5S,16S,18S)-25 (100 mg, 0.304 mmol)
in DCM (13 mL) was added by cannula, and the reaction mixture was
stirred at rt for 1 h. After filtration over silica gel and solvent
evaporation under reduced pressure, the crude product was purified by
flash chromatography (gradient elution, 20 to 30% AcOEt in hexanes)
to give (5S,16S,18S)-1′ (19 mg, 0.067 mmol, 22%) as a mixture of E
and Z isomers at the C-14/C-15 double bond contaminated with
minor amounts of the 6Z isomers. This mixture was separated using
preparative HPLC with a SunFire Prep C18 OBD column (particle size
5 μm, dimensions 19 mm × 100 mm, 60% MeCN/40% H2O, 17 mL/
min) to yield the major isomer with E-configured double bonds,
(5S,16S,18S)-1 (6.7 mg, tR = 18.4 min), as a colorless oil. Rf: 0.41
(hexanes/AcOEt 7:3). [α]2D0 −10 (c 0.1, CHCl3). IR (ATR) νmax
/
1
cm−1: 2995, 2918, 1720, 1658, 1381, 1244, 986, 816. H NMR (500
MHz, CDCl3) δ: 0.47−0.51 (m, 1H, H-17), 0.54−0.58 (m, 1H, H-17),
0.73−0.80 (m, 1H, H-18), 1.05 (d, J = 6.0 Hz, 3H, H-19), 1.05−1.10
(m, 1H, H-16), 2.14−2.18 (m, 4H, H-10 and H-11), 2.43−2.45 (m,
2H, H-4), 4.92−4.96 (m, 1H, H-5), 5.15 (dd, J = 14.7 and 9.0 Hz, 1H,
H-15), 5.50 (dt, J = 14.1 and 6.6 Hz, 1H, H-12), 5.64 (dd, J = 15.3 and
6.6 Hz, 1H, H-6), 5.77 (dt, J = 15.2 and 6.6 Hz, 1H, H-9), 5.94−6.06
(m, 4H, H-2, H-8, H-13, and H-14), 6.30 (dd, J = 15.3 and 10.4 Hz,
1H, H-7), 6.85−6.89 (m, 1H, H-3). 13C NMR (125 MHz, CDCl3) δ:
15.7 (CH2, C-17; CH, C-18), 18.5 (CH3, C-19), 22.8 (CH, C-16),
29.8 (CH2, C-4), 32.1 (CH2, C-11), 32.6 (CH2, C-10), 77.9 (CH, C-
5), 121.6 (CH, C-2), 126.7 (CH, C-6), 127.4 (CH, C-14), 129.1 (CH,
C-8), 129.9 (CH, C-12), 130.8 (CH, C-13), 133.7 (CH, C-7), 136.3
(CH, C-15), 136.8 (CH, C-9), 144.6 (CH, C-3), 164.0 (CO, C-1).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H24ONa 307.1674;
found 307.1663.
(2S)-6-Isopropoxy-2-((1E,3E,7E,9E)-10-((1R,2R)-2-
methylcyclopropyl)deca-1,3,7,9-tetraen-1-yl)-3,6-dihydro-2H-
pyran [(5S,16R,18R)-25] (Julia Olefination with DME). To a
solution of aldehyde (5S)-24 (103 mg, 0.373 mmol) and sulfone
(1R,2R)-22 (150 mg, 0.561 mmol) in anhydrous DME (17 mL) was
added dropwise a solution of NHMDS (0.78 mL, 0.78 mmol, 1 M in
THF) at −78 °C under N2. The light-yellow mixture was stirred for 10
min, and the reaction was quenched with brine (50 mL). The mixture
was extracted with AcOEt (3 × 50 mL), and the organic layer was
dried over MgSO4 and concentrated under reduced pressure. The
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bond. Rf: 0.54 (hexanes/AcOEt 1:1). The IR and NMR data for (5R)-
24 are identical to those described for its enantiomer (5S)-24. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C17H24O3Na 299.1623; found
299.1618.
mL/min), the major isomer with E-configured double bonds,
(5R,16R,18R)-1 (6.2 mg, tR = 18.4 min), was obtained as a colorless
oil. Rf: 0.41 (hexanes/AcOEt 7:3). [α]2D0 +10 (c 0.1, CHCl3). The IR
and NMR data for (5R,16R,18R)-1 are identical to those described for
(5S,16S,18S)-1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H24O2Na 307.1674; found 307.1663.
(2R)-6-Isopropoxy-2-((1E,3E,7E,9E)-10-((1S,2S)-2-
methylcyclopropyl)deca-1,3,7,9-tetraen-1-yl)-3,6-dihydro-2H-
pyran [(5R,16S,18S)-25]. Intermediate (5R,16S,18S)-25 was pre-
pared from aldehyde (5R)-24 (105 mg, 0.380 mmol) and sulfone
(1S,2S)-22 (150 mg, 0.561 mmol) as described for (5S,16R,18R)-25.
The crude product was purified by flash chromatography (hexanes/
AcOEt 95:5) to afford (5R,16S,18S)-25 as a 2.7:1 E:Z mixture at the
C-14 double bond (117 mg, 0.356 mmol, 94%) contaminated with
minor amounts of the 6Z double-bond isomers as a light-yellow oil. Rf:
0.67 (hexanes/AcOEt 9:1). The IR and NMR data for (5R,16S,18S)-
25 are identical to those described for (5S,16S,18S)-25 despite their
diastereoisomeric relationship. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C22H32O2Na 351.2300; found 351.2306.
Ethyl (E)-6-Hydroxyhex-2-enoate (26). To a solution of 17
(1.54 g, 9.74 mmol) in anhydrous DCM (40 mL) were added Et3N
(3.3 mL, 23.4 mmol), DMAP (120 mg, 1.15 mmol), and TBSCl (1.76
g, 11.7 mmol) under N2. The resulting mixture was stirred at rt for 4.5
h, and the solvent was removed under reduced pressure. The residue
was purified by flash chromatography (hexanes/AcOEt 95:5) to afford
ethyl (E)-6-((tert-butyldimethylsilyl)oxy)hex-2-enoate (2.54 g, 9.32
mmol, 96%) as a colorless oil. The spectral data (1H NMR and 13C
NMR) are in accordance with those reported in the literature.45
To a solution of ethyl (E)-6-((tert-butyldimethylsilyl)oxy)hex-2-
enoate (2.35 g, 8.63 mmol) in anhydrous DCM (40 mL) was slowly
added via cannula a solution of DIBALH (3.9 mL, 21.6 mmol) in
DCM (10 mL) at −78 °C under N2. The reaction mixture was stirred
under reduced temperature for 2 h. After that, Et2O (100 mL) and
saturated solution of Rochelle’s salt (50 mL) were added while
maintaining vigorous stirring for 30 min at 0 °C and 1 h at rt. After
phase separation, the aqueous layer was extracted with Et2O (2 × 100
mL). The combined organic phases were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (hexanes/AcOEt 7:3) to afford 26
(1.95 g, 8.46 mmol, 98%) as a colorless oil. The spectral data (1H
NMR and 13C NMR) are in accordance with those reported in the
literature.46
(R)-6-((1E,3E,7E,9E)-10-((1S,2S)-2-Methylcyclopropyl)deca-
1,3,7,9-tetraen-1-yl)-5,6-dihydro-2H-pyran-2-one
[(5R,16S,18S)-1]. Compound (5R,16S,18S)-1 was synthesized from
(5R,16S,18S)-25 (111 mg, 0.338 mmol) using a procedure similar to
that described for (5S,16R,18R)-1. The crude product was purified by
flash chromatography (gradient elution, 20 to 30% AcOEt in hexanes)
to give (5R,16S,18S)-1′ (31 mg, 0.11 mmol, 33%) as a mixture of E
and Z isomers at the C-14/C-15 double bond contaminated with
minor amounts of the 6Z isomers. After separation by preparative
HPLC with a SunFire Prep C18 OBD column (particle size 5 μm,
dimensions 19 mm × 100 mm, 60% MeCN/40% H2O, 17 mL/min),
the major isomer with E-configured double bonds, (5R,16S,18S)-1
(11.9 mg, tR = 18.4 min), was obtained as a colorless oil. Rf: 0.41
tert-Butyl(((4E,6E)-7-((2R)-6-isopropoxy-3,6-dihydro-2H-
pyran-2-yl)hepta-4,6-dien-1-yl)oxy)dimethylsilane [(5R)-29].
To a solution of 26 (1.00 g, 4.34 mmol) in anhydrous MeCN (14
mL) were added 2,6-lutidine (1.0 mL, 8.9 mmol), Ph3P (2.28 mg, 8.69
mmol), and CBr4 (2.88 g, 8.68 mmol) at 0 °C, and the resulting
solution was stirred for 10 min. The reaction was quenched with H2O
(50 mL), and the mixture was extracted with Et2O (3 × 100 mL). The
combined organic phases were washed with brine (50 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (gradient elution, 0 to
5% AcOEt in hexanes) to give (E)-((6-bromohex-4-en-1-yl)oxy)(tert-
butyl)dimethylsilane (27) (1.16 g, 3.97 mmol, 91%) as a colorless oil.
Rf: 0.64 (hexanes/AcOEt 95:5). IR (ATR) νmax/cm−1: 2929, 2857,
(hexanes/AcOEt 7:3). [α]2D0 +100 (c 0.1, CHCl3). IR (ATR) νmax
/
1
cm−1: 2995, 2918, 1720, 1658, 1381, 1244, 986, 816. H NMR (500
MHz, CDCl3) δ: 0.47−0.51 (m, 1H, H-17), 0.54−0.58 (m, 1H, H-17),
0.73−0.80 (m, 1H, H-18), 1.05 (d, J = 6.0 Hz, 3H, H-19), 1.05−1.10
(m, 1H, H-16), 2.14−2.18 (m, 4H, H-10 and H-11), 2.43−2.45 (m,
2H, H-4), 4.92−4.96 (m, 1H, H-5), 5.15 (dd, J = 14.7 and 9.0 Hz, 1H,
H-15), 5.50 (dt, J = 14.1 and 6.6 Hz, 1H, H-12), 5.64 (dd, J = 15.3 and
6.6 Hz, 1H, H-6), 5.77 (dt, J = 15.2 and 6.6 Hz, 1H, H-9), 5.94−6.06
(m, 4H, H-2, H-8, H-13, and H-14), 6.30 (dd, J = 15.3 and 10.4 Hz,
1H, H-7), 6.85−6.89 (m, 1H, H-3). 13C NMR (125 MHz, CDCl3) δ:
15.7 (CH2, C-17; CH, C-18), 18.5 (CH3, C-19), 22.8 (CH, C-16),
29.8 (CH2, C-4), 32.1 (CH2, C-11), 32.6 (CH2, C-10), 77.9 (CH, C-
5), 121.6 (CH, C-2), 126.7 (CH, C-6), 127.4 (CH, C-14), 129.1 (CH,
C-8), 129.9 (CH, C-12), 130.8 (CH, C-13), 133.7 (CH, C-7), 136.3
(CH, C-15), 136.8 (CH, C-9), 144.6 (CH, C-3), 164.0 (CO, C-1).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H24O2Na 307.1674;
found 307.1678.
1
1472, 1255, 1104, 835, 775. H NMR (250 MHz, CDCl3) δ: 0.04 (s,
6H), 0.89 (s, 9H), 1.54−1.65 (m, 2H), 2.04−2.17 (m, 2H), 3.60 (t, J =
6.3 Hz, 2H), 3.94 (d, J = 6.6 Hz, 2H), 5.63−5.85 (m, 2H). 13C NMR
(63 MHz, CDCl3) δ: −5.3 (2C), 18.3, 25.9 (3C), 28.4, 31.9, 33.5,
62.3, 126.6, 136.1. We were unable to obtain HRMS data for 27 using
ESI-TOF and APCI mass spectrometry techniques.
To a solution of 27 (912 mg, 3.12 mmol) in anhydrous MeCN
(17.2 mL) was added n-Bu3P (1.15 mL, 4.66 mmol), and the mixture
was stirred at rt for 12 h. After that, the excess solvent was removed
under reduced pressure, and the crude product was maintained under
high vacuum (0.2 mmHg) for 8 h. The tri-n-butylphosphonium salt 28
was employed in the Wittig reaction without purification.
(2R)-6-Isopropoxy-2-((1E,3E,7E,9E)-10-((1R,2R)-2-
methylcyclopropyl)deca-1,3,7,9-tetraen-1-yl)-3,6-dihydro-2H-
pyran [(5R,16R,18R)-25]. Intermediate (5R,16R,18R)-25 was
synthesized from aldehyde (5R)-24 (105 mg, 0.380 mmol) and
sulfone (1R,2R)-22 (145 mg, 0.543 mmol) as described for
(5S,16R,18R)-25. The crude product was purified by flash
chromatography (hexanes/AcOEt 95:5) to furnish (5R,16R,18R)-25
as a 2.7:1 E:Z mixture at the C-14 double bond (118 mg, 0.359 mmol,
95%) contaminated with minor amounts of the 6Z double-bond
isomers as a light-yellow oil. Rf: 0.67 (hexanes/AcOEt 9:1). The IR
and NMR data for (5R,16R,18R)-25 are identical to those described
for (5S,16S,18S)-25. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C22H32O2Na 351.2300; found 351.2294.
(R)-6-((1E,3E,7E,9E)-10-((1R,2R)-2-Methylcyclopropyl)deca-
1,3,7,9-tetraen-1-yl)-5,6-dihydro-2H-pyran-2-one
[(5R,16R,18R)-1]. Compound (5R,16R,18R)-1 was synthesized from
(5R,16R,18R)-25 (110 mg, 0.335 mmol) using a procedure similar to
that described above for (5S,16R,18R)-1. The crude product was
purified by flash chromatography (gradient elution, 20 to 30% AcOEt
in hexanes) to furnish (5R,16R,18R)-1′ (23 mg, 0.081 mmol, 24%) as
a mixture of E and Z isomers at the C-14/C-15 double bond
contaminated with minor amounts of the 6Z isomers. After separation
by preparative HPLC with a SunFire Prep C18 OBD column (particle
size 5 μm, dimensions 19 mm × 100 mm, 60% MeCN/40% H2O, 17
Wittig Olefination. To a solution of freshly prepared aldehyde
(5R)-7 (354 mg, 2.08 mmol) and tri-n-butylphosphonium salt 28
(3.12 mmol) in anhydrous PhMe (38 mL) was added dropwise a
solution of NHMDS (4.2 mL, 4.2 mmol, 1 M in THF) at −78 °C
under N2. The mixture was stirred for 13 h at −78 °C and for 1 h at rt.
The reaction was quenched with H2O (50 mL), and the mixture was
extracted with AcOEt (100 mL and 2 × 50 mL). The combined
organic phases were washed with brine (50 mL) and dried over
MgSO4, and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (hexanes/AcOEt
95:5) to furnish (5R)-29 (526 mg, 1.43 mmol, 69%) as a colorless oil
and as a 6:1 mixture of the two isomers at the C-6/C-7 double bond.
Rf: 0.50 (hexanes/AcOEt 95:5). IR (ATR) νmax/cm−1: 2955, 2929,
1
2893, 2857, 1255, 1181, 1100, 1028, 988, 835, 775. H NMR (600
MHz, CDCl3) δ: (major isomer) 0.04 (s, 6H, Si(CH3)2), 0.89 (s, 9H,
C(CH3)3), 1.17 (d, J = 6.2 Hz, 3H, C(CH3)2), 1.23 (d, J = 6.2 Hz, 3H,
K
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1
C(CH3)2), 1.57−1.63 (m, 2H, H-11), 1.99−2.04 (m, 1H, H-4), 2.07−
2.10 (m, 1H, H-4), 2.12−2.16 (m, 2H, H-10), 3.61 (t, J = 6.4 Hz, 1H,
H-12), 4.01 (sept, J = 6.2 Hz, 1H, CH(CH3)2), 4.43−4.47 (m, 1H, H-
5), 5.11 (br s, 1H, H-1), 5.62 (dd, J = 15.4 and 6.3 Hz, 1H, H-6),
5.70−5.75 (m, 2H, H-9 and H-2), 5.99−6.01 (m, 1H, H-3), 6.05 (dd, J
= 15.4 and 10.6 Hz, 1H, H-8), 6.23 (dd, J = 15.4 and 10.6 Hz, 1H, H-
7). 13C NMR (150 MHz, CDCl3) δ: (major isomer) −5.3 (2CH3,
Si(CH3)2), 18.3 (C, Si−C), 22.0 (CH3, C(CH3)2), 23.9 (CH3,
C(CH3)2), 26.0 (3CH3, C(CH3)3), 28.9 (CH2, C-10), 30.7 (CH2, C-
4), 32.3 (CH2, C-11), 62.5 (CH2, C-12), 66.4 (CH, C-5), 69.5 (CH,
C(CH3)2), 93.1 (CH, C-1), 126.1 (CH, C-2), 128.5 (CH, C-3), 129.9
(CH, C-8), 130.7 (CH, C-6), 131.3 (CH, C-7), 135.0 (CH, C-9).
HRMS (ESI-TOF) m/z: [M − C(CH3)2 + Na]+ calcd for
C18H32O3SiNa 347.20129; found 347.20134.
1380, 1316, 1181, 1099, 1027, 988. H NMR (600 MHz, CDCl3) δ:
(major isomer) 0.39−0.41 (m, 1H), 0.46−0.49 (m, 1H), 0.66−0.72
(m, 1H), 1.00−1.10 (m, 1H), 1.05 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.2
Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.99−2.28 (m, 6H), 4.01 (sept, J =
6.2 Hz, 1H), 4.43−4.47 (m, 1H), 5.01 (dd, J = 15.3 and 8.6 Hz, 1H),
5.11 (br s, 1H), 5.44 (dt, J = 15.3 and 6.7 Hz, 1H), 5.62 (d, J = 15.3
and 6.2 Hz, 1H), 5.68−5.76 (m, 2H), 5.99−6.11 (m, 2H), 6.23 (dd, J
= 15.3 and 10.2 Hz, 1H); (second-largest isomer) 0.46−0.49 (m, 2H),
0.76−0.72 (m, 1H), 1.00−1.10 (m, 1H), 1.07 (d, J = 5.9 Hz, 3H), 1.17
(d, J = 6.1 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.99−2.28 (m, 6H), 4.01
(sept, J = 6.2 Hz, 1H), 4.43−4.47 (m, 1H), 4.79 (t, J = 10.3 Hz, 1H),
5.11 (br s, 1H), 5.26 (dt, J = 10.3 and 7.4 Hz, 1H), 5.60−5.65 (m,
1H), 5.68−5.76 (m, 2H), 5.99−6.11 (m, 2H), 6.21−6.27 (m, 1H). 13C
NMR (150 MHz, CDCl3) δ: (major isomer) 15.1, 15.5, 18.5, 22.0,
22.4, 23.9, 30.7, 32.2, 32.8, 66.4, 69.5, 93.1, 126.1, 126.6, 128.5, 129.8,
130.8, 131.3, 134.1, 134.9; (second-largest isomer) 15.1, 15.5, 18.6,
18.7, 22.0, 23.9, 27.3, 30.7, 32.8, 66.5, 69.5, 93.1, 126.1, 126.5, 128.5,
129.9, 130.8, 131.3, 134.2, 135.0. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C20H30O2Na 325.21380; found 325.21354.
(4E,6E)-7-((2R)-6-Isopropoxy-3,6-dihydro-2H-pyran-2-yl)-
hepta-4,6-dien-1-ol [(5R)-30]. To a solution of (5R)-29 (520 mg,
1.42 mmol) in anhydrous THF (71 mL) was added a solution of
TBAF (1.5 mL, 1.5 mmol, 1 M in THF) at 0 °C under N2. The yellow
solution was allowed to warm to rt and stirred for 5.5 h. The reaction
was quenched by the addition of H2O (50 mL) and AcOEt (3 × 100
mL). The combined organic layers were washed with brine (50 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography (hexanes/
AcOEt 7:3) to give (5R)-30 (334.5 mg, 1.326 mmol, 94%) as a
colorless oil and as a 6:1 mixture of the two isomers at the C-6/C-7
double bond. Rf: 0.30 (hexanes/AcOEt 7:3). IR (ATR) νmax/cm−1:
(R)-6-((1E,3E,7E)-8-((1S,2S)-2-Methylcyclopropyl)octa-1,3,7-
trien-1-yl)-5,6-dihydro-2H-pyran-2-one [(5R,14S,16S)-2]. A mix-
ture of PCC (395 mg, 1.82 mmol) and CaCO3 (730 mg, 7.28 mmol)
in anhydrous DCM (10 mL) was stirred at rt for 2 h. Then a solution
of (5R,14S,16S)-31 (110 mg, 0.364 mmol) in DCM (10 mL) was
added by cannula, and the reaction mixture was stirred at rt for 2 h.
After filtration over silica gel and solvent evaporation under reduced
pressure, the crude product was purified by flash chromatography
(hexanes/AcOEt 7:3) to afford (5R,14S,16S)-2′ (43 mg, 0.166 mmol,
46%) as a mixture of E and Z isomers at the C-12/C-13 double bond
contaminated with minor amounts of the 6Z isomers. This mixture
was separated using preparative HPLC with a SunFire Prep C18 OBD
column (particle size 5 μm, dimensions 19 mm × 100 mm, 55%
MeCN/45% H2O, 17 mL/min) to yield the major isomer with E-
configured double bonds, (5R,14S,16S)-2 (14.5 mg, tR = 18.6 min), as
a colorless oil. Rf: 0.64 (hexanes/AcOEt 7:3). [α]2D0 +95 (c 0.1,
CHCl3). IR (ATR) νmax/cm−1: 2996, 2925, 1720, 1382, 1244, 991,
1
3409, 2971, 2930, 2887, 1657, 1181, 1099, 1027, 989. H NMR (500
MHz, CDCl3) δ: (major isomer) 1.17 (d, J = 6.2 Hz, 3H, C(CH3)2),
1.23 (d, J = 6.2 Hz, 3H, C(CH3)2), 1.64−1.70 (m, 2H, H-11), 1.98−
2.04 (m, 1H, H-4), 2.06−2.13 (m, 1H, H-4), 2.16−2.20 (m, 2H, H-
10), 3.66 (t, J = 6.4 Hz, 1H, H-12), 4.00 (sept, J = 6.2 Hz, 1H,
CH(CH3)2), 4.43−4.47 (m, 1H, H-5), 5.10 (br s, 1H, H-1), 5.63 (dd, J
= 15.4 and 6.3 Hz, 1H, H-6), 5.69−5.75 (m, 2H, H-9 and H-2), 5.99−
6.01 (m, 1H, H-3), 6.07 (dd, J = 14.8 and 10.5 Hz, 1H, H-8), 6.23 (dd,
J = 15.4 and 10.5 Hz, 1H, H-7). 13C NMR (125 MHz, CDCl3) δ:
(major isomer) 22.0 (CH3, C(CH3)2), 23.8 (CH3, C(CH3)2), 28.9
(CH2, C-10), 30.7 (CH2, C-4), 32.1 (CH2, C-11), 62.4 (CH2, C-12),
66.4 (CH, C-5), 69.5 (CH, C(CH3)2), 93.1 (CH, C-1), 126.1 (CH, C-
2), 128.4 (CH, C-3), 130.2 (CH, C-8), 131.0 (CH, C-6*), 131.1 (CH,
C-7*), 134.4 (CH, C-9) (asterisks indicate that the assignments may
be interchanged). HRMS (ESI-TOF) m/z: [M − CH2(CH3)2 + H]+
calcd for C12H17O3 209.11722; found 209.11709.
( 2 R ) - 6 - I s o p r o p o x y - 2 - ( ( 1 E , 3 E , 7 E ) - 8 - ( ( 1 S , 2 S ) - 2 -
methylcyclopropyl)octa-1,3,7-trien-1-yl)-3,6-dihydro-2H-
pyran [(5R,14S,16S)-31]. To a solution of oxalyl chloride (133 μL,
1.54 mmol) in DCM (16 mL) was added DMSO (160 μL, 2.19
mmol) at −78 °C under N2. After 15 min, (5R)-30 (240 mg, 0.951
mmol) in DCM (7 mL) was added dropwise, and the mixture was
stirred for a further 15 min. Et3N (0.7 mL, 4.8 mmol) was added, and
after 5 min the mixture was allowed to warm to rt. The reaction was
quenched by the addition of saturated NH4Cl solution (20 mL). The
layers were separated, and the aqueous phase was extracted with Et2O
(3 × 50 mL). The organic layers were combined, washed with brine
(20 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was obtained as a yellow oil, which was
used in the next step without purification. Rf: 0.67 (hexanes/AcOEt
7:3).
To a solution of the crude aldehyde obtained in the previous step
and sulfone (1S,2S)-22 (390 mg, 1.46 mmol) in anhydrous DME (40
mL) was added dropwise a solution of potassium hexamethyldisilazide
(1.9 mL, 1.9 mmol, 1 M in THF) at −78 °C under N2. The resulting
dark-brown mixture was stirred for 30 min, and the reaction was
quenched with brine (100 mL). The mixture was extracted with
AcOEt (3 × 100 mL), and the organic layer was washed with brine (50
mL), dried over MgSO4, and concentrated under reduced pressure.
The crude product was purified by flash chromatography (hexanes/
AcOEt 9:1) to afford (5R,14S,16S)-31 as 2.2:1 E:Z mixture at the C-12
double bond (119.3 mg, 0.394 mmol, 41%) contaminated with minor
amounts of the 6Z double-bond isomers as a light-yellow oil. Rf: 0.58
(hexanes/AcOEt 9:1). IR (ATR) νmax/cm−1: 2969, 2924, 1659, 1400,
1
961, 816. H NMR (500 MHz, CDCl3) δ: 0.38−0.42 (m, 1H, H-15),
0.46−0.49 (m, 1H, H-15), 0.66−0.71 (m, 1H, H-16), 0.99−1.05 (m,
1H, H-14), 1.04 (d, J = 6.2 Hz, 3H, H-17), 2.04−2.08 (m, 2H, H-11),
2.10−2.16 (m, 2H, H-10), 2.43−2.45 (m, 2H, H-4), 4.92−4.96 (m,
1H, H-5), 5.00 (dd, J = 15.2 and 8.6 Hz, 1H, H-13), 5.43 (dt, J = 15.3
and 6.9 Hz, 1H, H-12), 5.64 (dd, J = 15.3 and 6.6 Hz, 1H, H-6), 5.77
(dt, J = 15.2 and 6.6 Hz, 1H, H-9), 6.01−6.05 (m, 2H, H-2, H-8), 6.31
(dd, J = 15.4 and 10.5 Hz, 1H, H-7), 6.85−6.89 (m, 1H, H-3). 13C
NMR (125 MHz, CDCl3) δ: 14.7 (CH, C-16), 14.8 (CH2, C-15), 18.5
(CH3, C-17), 22.4 (CH, C-14), 29.8 (CH2, C-4), 32.0 (CH2, C-11),
32.8 (CH2, C-10), 77.9 (CH, C-5), 121.7 (CH, C-2), 126.3 (CH, C-
12), 126.5 (CH, C-6), 128.9 (CH, C-8), 133.7 (CH, C-7), 134.3 (CH,
C-13), 137.1 (CH, C-9), 144.6 (CH, C-3), 164.0 (CO, C-1). HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C17H22O2Na 281.15120; found
281.15065.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full spectroscopic data for new
compounds, HPLC chromatograms, and CD curves. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pilli@iqm.unicamp.br.
Author Contributions
∥V.M.T.C. and C.M.A. contributed equally to this work.
Notes
The authors declare no competing financial interest.
L
dx.doi.org/10.1021/jo402339y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(26) Chiralpak IA column (particle size 5 μm, dimensions 4.6 mm ×
250 mm, 98% hexanes/2% i-PrOH, 1 mL/min). For chromatograms,
see the Supporting Information.
(27) Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem.
1988, 53, 2723.
ACKNOWLEDGMENTS
■
R.A.P., V.M.T.C., and C.M.A. acknowledge FAPESP (Research
Grants 2009/51602-5 and 11/00457-5 to V.M.T.C. and 2010/
08673-6 to C.M.A.) and the Institute of Chemistry/UNICAMP
for financial and academic support. W.H.G. and M.J.B.
acknowledge the Fogarty International Center (FIC) and the
International Cooperative Biodiversity Group (ICBG) for a
grant based in Panama (U01 TW006634) and an FIC
International Research Scientist Development Award
(IRSDA) (K01 TW008002 to M.J.B.). The authors thank Dr.
(28) Aissa, C. Eur. J. Org. Chem. 2009, 1831.
(29) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.
(30) Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685.
(31) The yield and diastereoisomeric ratio for the preparation of
(5S,16S,18S)-25 were not optimized because they were obtained
before the studies shown in Table 1.
(32) Li, D.; Zhao, Y.; Ye, L.; Chen, C.; Zhang, J. Synthesis 2010, 3325.
(33) SunFire Prep C18 OBD column (particle size 5 μm, dimensions
19 mm × 100 mm, 60% MeCN/40% H2O, 17 mL/min).
(34) Chiralpak IA (particle size 5 μm, dimensions 4.6 mm × 250
mm, 90% MeCN/10% MeOH, 0.7 mL/min). For chromatograms, see
the Supporting Information.
́
Clecio F. Klitzke (LECO Corporation) and Marcos N. Eberlin
(Thomson Laboratory) for HRMS analyses.
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