Total synthesis of dolabelide C: A phosphate-mediated approach

Article abstract of DOI:10.1021/jo2003506

The first synthesis of dolabelide C (1), a cytotoxic marine macrolide, is reported utilizing a phosphate tether-mediated approach. Bicyclic phosphates (S,S,S_P)-5 and (R,R,R_P)-5 serve as the central building blocks for the constructio

Full text of DOI:10.1021/jo2003506

FEATURED ARTICLE
pubs.acs.org/joc
Total Synthesis of Dolabelide C: A Phosphate-Mediated Approach
Paul R. Hanson,* Rambabu Chegondi, John Nguyen, Christopher D. Thomas, Joshua D. Waetzig, and
Alan Whitehead
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
S Supporting Information
b
ABSTRACT:
The first synthesis of dolabelide C (1), a cytotoxic marine macrolide, is reported utilizing a phosphate tether-mediated approach.
Bicyclic phosphates (S,S,SP)-5 and (R,R,RP)-5 serve as the central building blocks for the construction of two major 1,3-anti-diol
subunits in 1 through selective cleavage pathways, regioselective olefin reduction, and cross-metathesis. Overall, phosphate-
mediated processes provided copious amounts of both major subunits allowing for a detailed RCM macrocyclization study to the
24-membered macrolactone 1.
’ INTRODUCTION: THE DOLABELIDE FAMILY
In 1995, the isolation and structural characterization of two new
22-membered macrolides, dolabelides A and B, from the sea hare
Dolabella auricularia was reported (Figure 1). These compounds
exhibited cytotoxicity against cervical cancer HeLa-S3 cells with IC50
values of 6.3 and 1.3 μg/mL, respectively.1 Two years later,
dolabelides C and D,2 24-membered macrolides, were isolated from
the same source and were found to possess cytotoxicity toward
HeLa-S3 cells with IC50 values of 1.9 and 1.5 μg/mL, respectively.
To the best of our knowledge, the mechanism of action of these
compounds remains unknown to date.
Common features among the dolabelide family are 11 stereo-
genic centers, eight of which bear oxygen, and two E-configured
trisubstituted olefins. Other structural features possessed by this
family of macrolactones include 1,3-anti-diol fragments found at
C7/C9 and C19/C21, along with an accompanying 1,3-syn-diol
at C9/C11 and polypropionate fragments at C1/C4 and C21/
C23. The stereochemical complexity and biological profile of this
class of compounds has attracted synthetic interest from several
groups,3 and in 2006, the first total synthesis of dolabelide D was
reported by Leighton and co-workers.4
Dolabelide C (1) can be disconnected into C1ꢀC14 and
C15ꢀC30 subunits, 2 and 3, respectively (Scheme 1). The
endgame for this approach is similar to Leighton’s strategy
toward dolabelide D,4 employing a macrocyclization sequence
to install the C14/C15 trisubstituted olefin through a late-stage
ring-closing metathesis (RCM) reaction. Macrocyclization, via
RCM, is preceded by Yamaguchi coupling between the C1
carboxylic acid of the northern subunit 2 and the C23 carbinol
center in the southern subunit 3. Central to this approach are the
1,3 anti-diol motifs at C7/C9 and C19/C21, which can be
Figure 1. Dolabelide family, isolated from Dollabella auricularia.
assembled and elaborated from bicyclic phosphates (R,R,RP)-5
and (S,S,SP)-5, respectively, utilizing a phosphate tether-
mediated approach.
’ RESULTS AND DISCUSSION
I. Construction of P-Chiral, Nonracemic Bicyclo[4.3.1]-
phosphates (R,R,RP)-5 and (S,S,SP)-5. The enantiomeric phos-
phate triester building blocks (R,R,RP)-5 and (S,S,SP)-5
(Scheme 2) were assembled via a phosphate tether, RCM
desymmetrization approach5 inspired by Burke and co-workers.6
In this method, a phosphate tether effectively serves to mediate
the tripodal coupling of anti-diol 87 with an allylic alcohol
component via either a phosphoryl monochloride or through a
Received: February 17, 2011
Published: April 29, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
Scheme 1. Retrosynthesis of Dolabelide C
Scheme 2. Tether-Mediated Desymmetrization of C2-Symmetric 1,3-anti-Diol 8a
a Reagents and conditions: (a) allyl tetraisopropylphosphorodiamidite, 1H-tetrazole, MeCN, 2 h, rt, then m-CBPA, 1 h, 64%; (b) cat-B, CH2Cl2,
85ꢀ90%.
one-step coupling/oxidation sequence from commercially avail-
able allyl tetraisopropylphosphorodiamidite to yield pseudo-C2-
symmetric triene 9. Desymmetrization8 by ring-closing metathesis
(RCM) using Grubbs catalyst [(IMesH2)(PCy3)(Cl)2RudCHPh
(cat-B)]9ꢀ11 affords P-chiral bicyclo[4.3.1]phosphate (S,S,SP)-5
and is based on the premise that only the terminal olefin cis to the
phosphate-tethered olefin reacts to generate 5 possessing two
sterically differentiated olefins.
II. Construction of C1ꢀC14 Subunit. We embarked upon the
synthesis of the C1ꢀC14 subunit of dolabelide beginning with
an elaborate cross-methesis (CM) between bicyclic phosphate
(R,R,Rp)-5 possessing a type III exocyclic terminal olefin and
type I olefin 10.12 As shown previously,13 CM of (R,R,Rp)-5 is
high yielding with both type I and type II olefins in the presence
of the HoveydaꢀGrubbs catalyst (cat-C).14 Various conditions
for the desired CM of 10 and (R,R,Rp)-5 were probed, and it was
found that employing 6 mol % of HoveydaꢀGrubbs catalyst at
90 °C in DCE gave the CM adduct 4 in 72% yield (Scheme 3).
This notable CM event between two complex olefins assembles
in a single operation five of the six stereocenters contained within
the C1ꢀC14 subunit of dolabelide C. Moreover, excess amounts
of 10, a type II CM partner, could be recovered in near-
quantitative yield and recycled in future CM events.
C5ꢀC6 olefin in the CM adduct 4 in the presence of the
C10ꢀC11 internal olefin, which sets the stage for subsequent
regioselective hydride opening of the bicyclic system. Upon
probing several hydrogenation conditions (Wilkinson’s cata-
lyst, Crabtree’s catalyst, Pd/C), it was found that a mild
diimide reduction, generated in situ from o-nitrobenzenesul-
fonyl hydrazine,15 provided the necessary hydrogenated phos-
phate moiety 11 with near-complete regioselectivity for the
exocyclic olefin. In comparison, other diimide conditions
(tosylhydrazine, NaOAc, H2O, DCE, 90 °C) gave drastically
lower yields, likely due to bicyclic phosphate instability under
basic medium.16
Having achieved the regioselectively hydrogenated product
11, a regioselective opening with hydride was probed as an
additional method to unmask the phosphate tether. Initial studies
focused on allylic copper hydride addition using various reagents
(Stryker’s reagent, CuCN 2LiCl/PhSiH3, CeCl3 7H2O/
3
3
NaBH4) (Scheme 3). Unfortunately, all conditions probed
provided only unreacted starting material or total decomposition
of the reaction mixture. Pd-catalyzed formate reductions were
next investigated for generation of the requisite terminal olefin.17
Employment of 1.5 equiv of formic acid and 5 mol % of
Pd(OAc)2 at 40 °C in DCE selectively opened phosphate 11
to provide the desired terminal olefin in 12. Methylation
of the phosphate acid intermediate showed that a highly
Two related regioselective processes were next investigated.
The first involved a regioselective removal of the exocyclic
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FEATURED ARTICLE
Scheme 3. Phosphate-Mediated Sequence for Assembly of the C1ꢀC14 Subunita
a Reagents and conditions: (a) cat-C (6 mol %), DCE, 90 °C, 72%; (b) o-NO2C6H5SO2NHNH2, Et3N, CH2Cl2, 72%; (c) Pd(OAc)2 (5 mol %),
HCO2H, Et3N, DCE, 40 °C, then MeOH, TMSCHN2, 87%. Abbreviations: DCE = 1,2-dichloroethane.
Scheme 4. Synthesis of C1ꢀC14 Carbon Frameworka
at the terminal C12 position would afford an allylic phosphate
anion that is capable of additional ionization events with the
C9 phosphate. Ultimately, the success of this reaction results
in a net olefin transposition expediting the route to the
C1ꢀC14 subunit, as well as showcasing an additional facet
of the phosphate-mediated methodology.
Upon completion of the synthesis of phosphate 12, work
began toward the installation of the C11ꢀC14fragment(Scheme4).
Cleavage of the phosphate was achieved using LiAlH4, which
generated a diol that was subsequently protected (PPTS, 2,
2-dimethoxypropane, CH2Cl2) to yield acetonide 13. Subse-
quent ozonolysis (O3, pyridine, CH2Cl2/MeOH 1:1, Me2S)
of the terminal olefin produced the requisite aldehyde, which
was subjected to the corresponding Grignard18 derived from
1-iodo-3-methyl-3-butene affording 14 in a 95% yield.
DessꢀMartin periodinane (DMP, NaHCO3, CH2Cl2) oxida-
tion of the free alcohol in 14 produced the corresponding
ketone in 90% yield. Attempts to selectively reduce the
acetonide-protected ketone, using an assortment of reduc-
ing agents, failed to give any diastereoselectivity at C11.
This problem was circumvented by deprotection of the aceto-
nide and subsequent syn reduction utilizing the C9 alcohol.
Selective removal of the acetonide was achieved by the addition
of CeCl3 7H2O and water,19 which efficiently (86% yield)
3
cleaved the acetonide-protecting group without loss of the
primary TBS group to provide diol 15. Final reduction of
ketone 15 using Evan’s conditions (Et2BOMe, NaBH4)20
afforded triol 16 in 60% (95% brsm) with excellent diastereo-
selectivity (ds g 20:1).
a Reagents and conditions: (a) LiAlH4, Et2O, 75%; (b) PPTS, 2,2-DMP,
CH2Cl2, 96%; (c) O3, pyridine, 1:1 MeOH/CH2Cl2, ꢀ78 °C, then
Me2S, 72%; (d) 1-iodo-3-methylbutene, Mg, Et2O, ꢀ78 °C, 95%; (e)
DessꢀMartin periodinane, NaHCO3, CH2Cl2, 90%; (f) CeCl3 7H2O,
3
H2O/MeCN (1:7), 87%; (g) Et2BOMe, NaBH4, THF/MeOH 4:1,
ꢀ78 °C, ds g 20:1, 60% (95% brsm).
III. First-Generation Synthesis of the C15ꢀC30 Subunit of
Dolabelide C. The construction of the C15ꢀC30 subunit
of dolabelide began with the enantiomeric bicyclic phosphate
(S,S,SP)-5 possessing unique orbital symmetry of the bicyclic
phosphate (Scheme 5).21 Initial studies probed the possibility of
an oxidation of the exocyclic olefin of 5 in the presence of the
cyclic olefin. After testing various conditions, a chemoselective
hydroboration of (S,S,SP)-5 was achieved using 9-BBN followed
by mild NaBO3 oxidation to yield the primary alcohol. Because of
the aforementioned instability of (S,S,SP)-5 to basic hydrolysis, a
mild perborate oxidation protocol developed by Burke and
co-workers was implemented. Burke has shown this protocol
to be compatible with multiple acetate protecting groups;22
regioselective process was operative (>20:1 ratio of regioi-
somers as evident by 31P NMR analysis). Purification pro-
vided phosphate 12 in 87% yield. The remarkable
regioselectivity reveals another feature of the phosphate
tether, whereby orthogonal orbital alignment within 11
allows for selective Pd(0)-catalyzed ionization of C12 over
the C9 allylic phosphate position. This ionization allows Pd
to deliver the hydride selectively at the internal C10 position
to provide the desired terminal olefin. Addition of the hydride
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Scheme 5. First-Generation Synthesis of the C15ꢀC30
produced cyclic phosphate ester 18 in excellent overall yield
(87%). This reaction again highlights the remarkable orbital
alignment of the bicyclic phosphate system and its concave
nature, where only one of four possible products for this SN20
cuprate reaction is generated. Reductive cleavage, followed by
sequential protection of the diol systems with TIPS and MOM
groups, and final ozonolysis of the olefin afforded aldehyde 19
in good yield.
Subunita
With aldehyde 19 and vinyl iodide 20 in hand, studies aimed at
a diastereoselective addition to aldehyde 19 to set the C23
stereogenic carbinol center began (Scheme 5). Initial efforts to
generate the C23 stereocenter by lithiate additions gave pre-
dominately the undesired 1,2-Felkin product. To overcome this
problem, investigation focused on reagent-controlled, ephe-
drine-based asymmetric vinylzincate additions, described by
Marshall.23 Aldehyde 19 reacted with 20 under these conditions
to obtain the desired 1,3-syn isomer 21 in an 11:1 ratio of
diastereomers in 65% yield. Successful formation of 21 provided
the advance intermediate bearing the requisite stereochemistry
of the C15ꢀC30 subunit. With 21 in place, only the installation
of the C14ꢀC15 terminal olefin was needed to complete the
C15ꢀC30 subunit of dolabelide C. MOM protection of the C23
alcohol, DDQ removal of the PMB ether, tosylation, and cuprate
displacement all proceeded in good yield to afford the terminal
olefin 22 and complete the C15ꢀC30 subunit of dolabelide C.
Overall, a 12-step sequence to 22 from 5 was achieved, bearing
the requisite stereochemistry for the C15ꢀC30 subunit of
dolabelide C.
IV. Second-Generation Synthesis of the C15ꢀC30 Subunit
of Dolabelide C. A second-generation synthesis was next devel-
oped when attempts to remove the three MOM-protecting
groups from 22 proved problematic. To our dismay, all condi-
tions tested for cleavage of these groups in the presence of the
more labile TIPS-protecting groups provided unreacted starting
material or total decomposition of the substrate (Scheme 6). The
difficulty in removing these protecting groups prompted a
reevaluation of protecting groups to access a suitable C15ꢀC30
subunit of dolabelide. This alternative strategy coincided with a
planned installation of the C23 carbinol at the last step of the
sequence to streamline the route.
a Reagents and conditions: (a) 9-BBN, then H2O, NaBO3 4H2O, 80%;
(b) p-OMeC6H4OCH2OCdNH(CCl3), PPTS, CH2Cl2, 89%; (c) (1)
3
CuCN 2LiCl, Me2Zn, THF, ꢀ30 °C to rt; (2) TMSCHN2, MeOH,
3
87%; (d) LiAlH4, Et2O, 0 °C, 96%; (e) TIPSCl, imidazole, DMAP,
CH2Cl2, 86%; (f) MOMCl, iPr2NEt, CH2Cl2, 91%; (g) O3, pyridine,
ꢀ78 °C, Me2S, 75%; (h) t-BuLi, ZnBr2, 20, then n-BuLi, (R,S,)-NME,
then 19, 65%, 11:1 dr; (i) MOMCl, iPr2NEt, DCE, 82%; (j) DDQ, pH 7
buffer, CH2Cl2, 92%; (k) TsCl, DABCO, CH2Cl2, 90%; (l) allylMgBr,
CuI, ꢀ20 to 0 °C, 89%. Abbreviations: 9-BBN = 9-borabicyclo-
(3.3.1)nonane; TMS = trimethylsilyl; TIP = triisopropylsilyl; MOM =
methoxymethyl; DMAP = 4-(dimethylamino)pyridine; NME = N-
methylephedrine; DDQ = 2,3-dichloro-5,6-dicyanobenzoquinone; Ts
= tosyl; DABCO = 1,4-diazabicyclo(2.2.2)octane.
Scheme 6. MOM Deprotection Conditions
The alternative approach to the C15ꢀC30 subunit began
by employing previously established CM/reduction metho-
dology (Scheme 7).12 As anticipated, 5 underwent CM with
23 in the presence of 6 mol % of cat-C14 (DCE, 90 °C)
providing E-configured (>20:1) product in 82% yield. Selec-
tive reduction of the external olefin was again achieved using o-
nitrobenzenesulfonyl hydrazine15 furnishing 24 in 75%
yield.24 Compound 24 was also synthesized through a one-
pot, sequential cross-metathesis/olefin reduction protocol in
59% overall yield utilizing the same reagents shown in
Scheme 6. This yield averages to 77% per synthetic step over
the two-step combined transformation. Regio- and diastereose-
lective methyl cuprate addition into 24 and subsequent
phosphate cleavage produced diol 25 in good yield.21 Diol
25 was protected as the acetonide (PPTS, 2,2-dimethoxypropane)
in 96% yield.
optimization of this hydroboration reaction with phosphate 5
found the reaction to be highly dependent on the amount of
oxidant, equivalents of H2O, and reaction time. Subsequent
PMB ether formation using p-methoxybenzyl trichloroacetimi-
date produced 17 in good yields, demonstrating the acid stability
of bicyclic phosphate (S,S,SP)-5. Employing the previously
reported regio- and diastereoselective cuprate addition protocol,
The terminal olefin was next converted into primary alcohol 26
by an oxidative cleavage/reduction sequence in good yields. TBS
protection of alcohol 26 proceeded in 86% yield and was followed
by removal of the PMB ether to provide the corresponding primary
alcohol. Conversion of the alcohol to a terminal olefin through an
iodination/elimination sequence occurred in excellent yield over the
displacement of 17 (CuCN 2LiCl, ZnMe2, THF, ꢀ30 °C to rt)
3
afforded the SN20-displaced phosphate acid exclusively (ds g
20:1), which upon methylation (TMSCHN2 and MeOH)
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Scheme 7. Second-Generation Synthesis of C15ꢀC30
Scheme 8. Generation of Ready-to-Couple C1ꢀC14
Subunita
Subunita
a Reagents and conditions: (a) Ac2O, DMAP, pyridine, 95%; (b) TBAF,
THF, 93%; (c) (COCl)2, DMSO, Et3N, CH2Cl2; (d) NaClO2, 2-meth-
yl-2-butene, H3PO4, 81% over two steps.
oxidation of 32 generated the desired aldehyde that was prone
to epimerization and was taken on without purification. Pinnick
oxidation of the aldehyde provided carboxylic acid 2 in 81% yield
over the two-step sequence, which was ready for coupling with
the C15ꢀC30 subunit.
a Reagents and conditions: (a) cat-C (6 mol %), 23, DCE, 90 °C, 82%;
(b) o-NO2C6H5SO2NHNH2, Et3N, CH2Cl2, 75%; (c) (1) CuCN 2
3
LiCl, Me2Zn, THF, ꢀ30 °C to rt; (2) TMSCHN2, MeOH, 91%;
(d) LiAlH4, Et2O, 0 °C, 92%; (e) 2,2-DMP, PPTS, CH2Cl2, 96%;
(f) OsO4, NMO, t-BuOH/THF/H2O, then NaIO4, phosphate buffer
pH 7, then NaBH4, EtOH, 0 °C, 81%; (g) TBSCl, pyridine, 95%; (h)
H2, Pd/C, EtOAc, NaHCO3, 90%; (i) Ph3P, I2, imidazole, then t-
BuOK, THF, 94%; (j) TBAF, THF, 98%; (k) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 °C to rt; (l) t-BuLi, Et2O, 29, ꢀ78 to 0 °C, 30 min, 28,
ꢀ78 °C, ∼1:1 syn:anti, 79% over two steps; (m) DessꢀMartin, CH2Cl2,
85%; (n) NaBH4, MeOH, 0 °C, 89%, ∼2.7:1 syn:anti. Abbreviations:
DMP = dimethoxypropane; PPTS = pyridinium p-toluenesulfonate;
NMO = N-methylmorpholine N-oxide; TBS = tert-butyldimethylsilyl;
TBAF = tetra-n-butylammonium fluoride.
Final coupling of the C1ꢀC14 carboxylic acid 2 and the
C15ꢀC30 alcohol 30 was achieved using Yamaguchi conditions26
as previously described by Leighton and co-workers (Scheme 9).4
The addition of 2,4,6-trichlorobenzoyl chloride, Et3N, and DMAP
at ꢀ78 °C for 21 h avoided epimerization at C2 and yielded the
desired coupled 33 in 77% yield. Deprotection of the C27-TES
protecting group was achieved with TBAF in 94% yield. Subsequent
acylation provided 34 in 98% yield. The final two protecting groups
were removed using PPTS in MeOH, followed by treatment with
DDQ to provide metathesis precursor 35 in excellent yield over two
steps. Efforts to close the ring were attempted prior to PMB ether
removal and provided the desired RCM product as observed by
HRMS, albeit in poor overall conversion. As a result, subsequent
investigations focused on RCM of the deprotected triol 35.
Portionwise addition of 20 mol % of (IMesH2)(PCy3)(Cl)2-
RudCHPh (cat-B)11 to triol 35 afforded approximately a 1:1 E/
Z mixture of dolabelide C 1 and its (Z)-isomer in a 57ꢀ60% yield.
VI. Purification Attempts and RCM/Isomerization Side
Reaction. Initial attempts utilizing repeated standard normal-
phase chromatography removed the Z-isomer (higher Rf),
leaving what was believed to be pure dolabelide C (1) as a
two-step sequence. Achievement of the C14/C15 olefin left only a
deprotection/oxidation/nucleophilic addition sequence to obtain the
necessary C15ꢀC30 subunit. TBAF removal of the TBS-protecting
group to 27 and Swern oxidation provided aldehyde 28 necessary
for the addition of the C24ꢀC30 fragment.
Despite previous success with the Marshall asymmetric zincate
addition protocol,21 difficulties in reaction reproducibility and
low product yields, also recently noted by Marshall,23 prompted
investigation of an alternative addition sequence. Thus, vinyl
iodide 29 was converted to the lithiate with 2 equiv of t-BuLi
followed by the addition of aldehyde 28 to afford a 1:1 mixture of
C23 epimers of alcohol 30 in 79% yield. The two diastereoisomers of
30 were easily separated by column chromatography, allowing for
isolation of the correct stereoisomer of alcohol 30 as well as facile
recycling (oxidation/reduction) of the undesired diastereomer
(dr = 2.7:1).25 Overall, this alternative 13-step route to 30 from
phosphate (S,S,SP)-5 provided a C15ꢀC30 fragment ready to
couple with the C1ꢀC14 subunit of dolabelide C.
1
single spot on TLC. H NMR analysis, however, revealed
impurities, which were originally presumed to be the Z-
isomer. Attempted purification using preparative reversed-
1
phase LCꢀMS revealed the major byproduct, as seen by H
NMR, to be a demethylenated analogue (M ꢀ 14), along with
trace amounts of a constitutional isomer and two byproduct
resulting from formal loss of an ethylene (M ꢀ 28) as seen in
the total-ion chromatogram (Figure 2). These byproducts
(35a and 35b) are presumed to occur from isomerization of 35
followed by RCM, resulting in the smaller macrocycles
(Scheme 10).27 Numerous reports are consistent with this
observation,28 and to the best of our knowledge, this is the first
report of a detailed LCꢀMS analysis of the aforementioned
side reaction.
V. Completion of the Total Synthesis. Studies toward the
completion of dolabelide C next commenced with the complete
acetylation of triol 16 to install the proper acetylation pattern for
C1ꢀC14 subunit of dolabelide C (Scheme 8). This was accom-
plished by adding acetic anhydride and pyridine to triol 16 to
afford triacetate 31 in excellent yield. Deprotection of the TBS
protecting group provided alcohol 32 in 93% yield. Swern
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Scheme 9. Completion of Dolabelide C (1)a
a Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, DMAP, Et3N, toluene, 77%; (b) TBAF, 94%; (c) Ac2O, pyridine, DMAP, 98%; (d)
PPTS, 83%; (e) DDQ, phosphate buffer pH = 7, CH2Cl2, 95%; (f) cat-B (20 mol %), CH2Cl2 (0.5 mM), 57%, E:Z = ∼1:1.
complete conversion and a similar ratio to what was previously
observed. Screening of other catalysts by varying the phosphine
or NHC-ligand showed a significant increase of byproduct
formation (entries 3ꢀ5). While no significant changes in E/Z
ratio were obtained from catalyst screening, rigorous degassing
and purification of the solvent were shown to reduce deleterious
side products.31
Due to the scalability of this synthesis,32 ample material was
provided for characterization, where all NMR spectra matched
with the previous reported data.2,33 In addition, sufficient quan-
tities of the unnatural C14/15 Z-isomer34 were generated for
both NMR analysis and collection of biological data to determine
its bioactivity and potential potency against cervical cancer.35
’ CONCLUSION
In conclusion, dolabelide C (1) and its non-natural C14ꢀC15
Z-diastereomer were produced and isolated from a scalable phos-
phate-mediated synthesis. A complex mixture was generated in the
final RCM step resulting in byproduct, which arose from a net loss of
CH2 and C2H4, that proved to be difficult to separate via repeated
flash chromatography (8:1 CH2Cl2:acetone). Since the material
produced at the end of the first synthesis of 1 was sparse, a
resynthesis provided 175 mg of the C1ꢀC14 subunit (32), 300 mg
of the C15ꢀC30 subunit (30), and 160 mg of RCM precursor 35.
This allowed a detailed optimization study through a screening of
various metathesis catalysts, concluding that the originally devel-
oped conditions (20 mol % cat-B, 0.5 μm, 40 °C) provided the
optimum results. Overall, 14 mg of pure dolabelide C and 10 mg
of the pure Z-isomer were produced in a 24-step longest linear
Figure 2. LCꢀMS analysis of mixture from final RCM.
In an attempt to understand and optimize the final RCM
sequence, the final metathesis precursor was scaled up. Both
syntheses to each subunit proved to be scalable, providing 300
mg of 30 and 175 mg of 32.29 This material was carried through the
same endgame steps (Scheme 9) affording 160 mg of RCM
precursor 35 to apply toward the goal of optimizing the C14/15
E:Z ratio and minimizing the amount of deleterious side reactions
occurring in the final RCM step. For this study, metathesis catalyst
cat-B and three other candidates shown in Figure 3 were screened.30
Initially, the conditions shown from Scheme 9 were repro-
duced (Table 1, entry 1), where LCꢀMS analysis showed nearly
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Scheme 10. Possible Isomerization Pathways from Metathesis Step
Table 1. Catalyst Screening of Final RCM
Figure 3. Metathesis catalysts screened on final RCM step.
entry
catalyst
conversion (%)
E/Za
E/Z/byproductsa
sequence (LLS) from commercially available material utilizing the
(R,R,RP) antipode of 5 (sequence streamlined to a 22-step LLS
using one-pot, sequential protocols).
1
2
3
4
5
cat-B
cat-Bb
cat-D
cat-E
cat-F
>99
87
1:1
1.2:1
1:1
1:1:0.17
1.2:1:0.26
1:1:0.80
100
100
87
1:1.1
1:1.1:0.45
’ EXPERIMENTAL SECTION
1.2:1
1.2:1:0.61
a Ratios determined through peak area integration from LCꢀMS
analysis of crude mixtures. b Purified newly purchased catalyst through
SiO2 plug in 10:1 hexanes/EtOAc. c All reactions were run with stepwise
addition of 20 mol % of catalyst over 6 h at 40 °C in 0.5 μM CH2Cl2.
General Methods. All reactions were carried out in oven- or flame-
dried glassware, under an argon atmosphere, using standard gastight
syringes, cannulae, and septa. Stirring was achieved with oven-dried
magnetic stir bars. Et2O, THF, and CH2Cl2 were passed through a
purification system employing activated Al2O3. Et3N was eluted through
basic alumina and stored over KOH. Butyllithium was titrated prior to
use. All olefin metathesis catalysts were obtained commercially and used
without further purification. All 1H and 13C NMR spectra were recorded
in CDCl3 or C5D5N at 400 or 500 MHz and 126 MHz, respectively, and
calibrated to the solvent peak. All mass spectra were obtained using
electrospray ionization (ESI) (MeOH) coupled to high-resolution mass
spectrometry (HRMS). Observed rotations at 589 nm were measured
using an automatic polarimeter. Infrared spectra were obtained using a
Fourier-transform infrared (FTIR) spectrometer.
(8 mL) and PPTS (150 mg, 0.595 mmol) were added, respectively, and
the clear solution was stirred until completion. The reaction was
quenched with saturated NaHCO3 (15 mL) and diluted with CH2Cl2.
The aqueous layer was extracted with CH2Cl2 (3 ꢁ 25 mL), and the
combined organic layers were washed once with brine (30 mL), dried
(Na2SO4), and concentrated under reduced pressure. Compound SI-1
was isolated using flash chromatography (19:1 hexanes/EtOAc) as a
clear oil (2.18 g, 98%): [R]D = ꢀ36.3 (c = 0.40, CH2Cl2); FTIR (neat)
2983, 2935, 2856, 1612, 1512, 819 cm ꢀ1; 1H NMR (500 MHz, CDCl3)
δ 7.25 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.83 (ddd, J = 17.4,
10.5, 7.3 Hz, 1H), 5.03 (ddd, J = 17.5, 11.0, 2.6 Hz, 2H), 4.43 (s, 2H),
3.80 (s, 3H), 3.74ꢀ3.66 (m, 1H), 3.63 (ddd, J = 9.7, 6.3, 6.3 Hz, 1H),
(4S,6R)-4-((R)-But-3-en-2-yl)-6-(5-(4-methoxybenzyloxy)-
pentyl)-2,2-dimethyl-1,3-dioxane (SI-1). Diol 25 (2.00 g, 5.95
mmol) was dissolved in CH2Cl2 (8 mL) at rt. 2,2-Dimethoxypropane
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FEATURED ARTICLE
3.45 (t, J = 6.6 Hz, 2H), 2.18ꢀ2.26 (m, 1H), 1.71ꢀ1.64 (m, 1H),
1.63ꢀ1.53 (m, 2H), 1.55ꢀ1.35 (m, 6H), 1.32 (s, 6H), 1.30ꢀ1.24 (m,
1H), 0.98 (d, J = 6.9 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 159.1,
140.9, 130.7, 129.3, 114.4, 113.7, 100.3, 72.5, 70.1, 70.0, 66.8, 55.3, 42.1,
36.3, 35.9, 29.7, 26.2, 25.3, 24.7, 24.4, 15.3; HRMS calcd for
C23H36NaO4 (M þ Na)þ 399.2511, found 399.2498 (ESI).
3.34 mmol) were added sequentially, and the flask was pressurized with a
H2 balloon. After 10 h, the mixture was filtered through pad of Celite and
rinsed thoroughly with EtOAc. The filtrate was concentrated under
reduced pressure and purified with flash chromatography (10:1 hexanes/
EtOAc) to yield alcohol SI-3 (1.12 g, 90% yield) as a clear oil: [R]D =ꢀ0.11
(c = 0.40, CH2Cl2); FTIR (neat) 3357, 2933, 2858, 1379, 1251, 1224,
835, 775 cmꢀ1; 1H NMR (500 MHz, CDCl3)36a δ 3.75ꢀ3.68 (m, 2H),
3.63 (t, J = 6.6 Hz, 2H), 3.55 (dd, J = 4.7 and 1.3 Hz, 2H), 1.70ꢀ1.38 (m,
10H), 1.33 (s, 6H), 1.28ꢀ1.22 (m, 1H), 0.89 (s, 9H), 0.84 (d, J = 6.9 Hz,
3H), 0.04 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 100.2, 67.1, 66.8,
64.1, 63.0, 40.5, 36.6, 35.9, 32.7, 25.9 (3), 25.7, 25.3, 24.6, 24.5, 18.2,
12.2, ꢀ5.5, ꢀ5.5; HRMS calcd for C20H42NaO4Si (M þ Na)þ
397.2750, found 397.2773 (ESI).
(R)-2-((4S,6R)-2,2-Dimethyl-6-(pent-4-enyl)-1,3-dioxan-4-
yl)propan-1-ol (27). Alcohol SI-3 (1.12 g, 2.99 mmol) was dissolved
in THF (30 mL) at rt. Triphenylphosphine (941 mg, 3.59 mmol) and
imidazole (477 mg, 6.59 mmol) were added, respectively, and the
solution was cooled to 0 °C. I2 (912 mg, 3.59 mmol) was added, and
the reaction was stirred for approximately 30 min (monitored by TLC).
The solution was diluted with hexane and filtered through a pad of silica,
while washing with hexane, and concentrated under reduced pressure.
The crude product was taken onto the next step.
The iodo compound was dissolved in THF (35 mL) at rt followed by
stepwise addition of t-BuOK (1.0 g, 8.98 mmol). The reaction was
stirred for ∼30 min and was quenched with H2O. The aqueous layer was
extracted with EtOAc (3 ꢁ 20 mL portions), and the organic layers were
combined, washed with brine (20 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification with flash chroma-
tography (20:1 hexanes/EtOAc) yielded the resultant terminal olefin
(1.0 g, 94%) as a clear oil.
The resultant silyl ether (1.00 g, 2.81 mmol) was dissolved in THF
(10 mL) and cooled to 0 °C. A solution of TBAF in THF (8.5 mL, 1.0 M
in THF) was added dropwise. The reaction was stirred at 0 °C until
completion (∼45 min) and quenched with saturated NH4Cl (10 mL),
and the aqueous layer was extracted with Et2O (3 ꢁ 20 mL). The
organic layers were combined, washed with brine (20 mL), dried (Na2-
SO4), filtered, and concentrated under reduced pressure. Purification
using flash chromatography (10:1 hexanes/EtOAc) afforded 27 (670 mg,
98%) as a clear oil: [R]D = ꢀ78.6 (c = 0.50, CH2Cl2); FTIR (neat) 3446,
2983, 2935, 2879, 1379, 1224, 908 cmꢀ1; 1H NMR (500 MHz, CDCl3)
δ 5.86ꢀ5.75 (m, 1H), 5.07ꢀ4.93 (m, 2H), 3.82ꢀ3.76 (m, 1H), 3.69
(ddd, J = 9.2, 9.2, and 6.2 Hz, 1H), 3.61ꢀ3.55 (m, 2H), 3.08 (s, 1H),
2.06 (dd, J = 14.1 and 7.1 Hz, 2H), 1.80ꢀ1.40 (m, 7H), 1.38 (s, 3H),
1.33 (s, 3H), 0.81 (d, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
138.7, 114.7, 100.5, 73.0, 68.2, 66.6, 40.6, 37.8, 35.3, 33.6, 24.7, 24.6,
24.6, 12.6; HRMS calcd for C14H27O3 (M þ H)þ 243.1960, found
243.2895 (ESI).
(R)-2-((4S,6R)-6-(5-(4-Methoxybenzyloxy)pentyl)-2,2-di-
methyl-1,3-dioxan-4-yl)propan-1-ol (26). Olefin SI-1 (1.50 g,
3.99 mmol) was dissolved in t-BuOH/THF/H2O (10:2:1, 20 mL) at rt.
N-Methylmorpholine N-oxide (933 mg, 7.98 mmol) and OsO4
(0.19 mL, 0.08 mmol, 4% aq) were added, and the reaction was stirred
for approximately 12 h until olefin was completely consumed. The
mixture was then diluted with phosphate buffer pH 7 (twice the volume
of t-BuOH), and NaIO4 was added (3.41 mg, 16.0 mmol). The reaction
was stirred vigorously for approximately 2 h until the diol was completely
consumed (monitored by TLC). The reaction was quenched with solid
Na2SO3 (2.0 g), and acetone was removed under reduced pressure. The
residue was partitioned with EtOAc (20 mL) and H2O (10 mL), and the
aqueous layer was extracted with EtOAc (3 ꢁ 20 mL). The collected
organics were washed once with brine (20 mL), dried (Na2SO4), and
filtered. After concentration under reduced pressure, the crude product
was purified using flash chromatography (5:1 hexanes/EtOAc) to
generate intermediate aldehyde as a yellow oil.
The resultant aldehyde was dissolved in EtOH (16 mL) and cooled to
0 °C. NaBH4 (303 mg, 7.98 mmol) was added, and the reaction was
slowly brought back to rt. Upon completion (∼45 min), the solution
was partitioned with 2:1 Et2O/H2O (40 mL), the aqueous layer was
extracted with Et2O (3 ꢁ 5 mL), and the organic layers were combined,
washed with brine (30 mL), dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification with flash chromatography (1:2
hexanes/EtOAc) afforded 26 (88% over two steps, 1.35 mg) as a clear
oil: [R]D = ꢀ0.26 (c = 0.18, CH2Cl2); FTIR (neat) 3442, 2933, 2856,
1612, 1512, 819 cm ꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.5
Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.79ꢀ3.73
(m, 1H), 3.68 (ddd, J = 9.2, 6.3, and 6.3 Hz, 1H), 3.58 (d, J = 5.1 Hz, 2H),
3.43 (t, J = 6.6 Hz, 2H), 3.08 (s, 1H), 1.20ꢀ1.80 (m, 11H), 1.38 (s, 3H),
1.33 (s, 3H), 0.82 (d, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
159.1, 130.8, 129.2, 113.7, 100.5, 73.1, 72.5, 70.1, 68.3, 66.6, 55.3, 40.6,
37.9, 35.8, 29.7, 26.2, 25.2, 24.6, 24.6, 12.7; HRMS calcd for
C22H36NaO5 (M þ Na)þ 403.2460, found 403.2413 (ESI).
tert-Butyl((R)-2-((4S,6R)-6-(5-(4-methoxybenzyloxy)pen-
tyl)-2,2-dimethyl-1,3-dioxan-4-yl)propoxy)dimethylsilane
(SI-2). Alcohol 26 (1.34 mg, 3.53 mmol) was dissolved in CH2Cl2
(23 mL) at rt. Imidazole (720 mg, 10.6 mmol), DMAP (10 mg, 0.08
mmol), and TBSCl (800 mg, 5.29 mmol) were added, respectively. The
reaction was quenched upon completion (∼90 min, monitored by
TLC) with saturated NH4Cl (25 mL) and diluted with Et2O (50 mL).
The aqueous layer was extracted with Et2O (3 ꢁ 25 mL), and the
organic layers were washed with brine (25 mL). The combined organic
layers were dried (Na2SO4) and concentrated under reduced pressure.
Purification with flash chromatography (20:1 hexanes/EtOAc) afforded
SI-2 (1.70 g, 97%) as a yellow oil: [R]D = ꢀ16.6 (c = 0.35, CH2Cl2);
FTIR (neat) 2933, 2856, 2881, 1247, 835 cm ꢀ1; 1H NMR (500 MHz,
CDCl3) δ 7.26 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.24 (s, 2H),
3.80(s, 3H), 3.74ꢀ3.66 (m, 2H), 3.56 (d, J= 4.4 Hz, 2H), 3.44 (t, J=6.6Hz,
2H), 1.37ꢀ1.67 (m, 11H), 1.31 (s, 6H), 0.89 (s, 9H), 0.85 (d, J = 6.8 Hz,
3H), 0.02 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 159.0, 130.7, 129.2,
113.7, 100.1, 72.5, 70.1, 67.0, 66.8, 64.1, 55.2, 40.5, 36.6, 35.9, 29.7, 26.1,
25.9, 25.3, 24.6, 24.5, 18.2, 12.2, ꢀ5.5, ꢀ5.5; HRMS calcd for
C28H50NaO5Si (M þ Na)þ 517.3325, found 517.3334 (ESI).
(2R,3R,7R,E)-2-((4S,6R)-2,2-Dimethyl-6-(pent-4-enyl)-1,3-
dioxan-4-yl)-5-methyl-7-(triethylsilyloxy)dec-4-en-3-ol (30).
A solution of oxalyl chloride (0.158 mL, 1.86 mmol) in CH2Cl2
(4.8 mL) was cooled to ꢀ78 °C, and DMSO (0.220 mL, 3.01 mmol)
was added slowly by syringe (gas evolution). After being stirred for 10
min, a solution of alcohol 27 (300 mg, 1.24 mmol) in CH2Cl2 (3.0 mL)
was added by cannula and rinsed with CH2Cl2 (2 ꢁ 0.5 mL). The cloudy
mixture was stirred at ꢀ78 °C for 15 min at which time Et3N (0.700 mL,
4.96 mmol) was added dropwise. The reaction mixture was stirred for
1hatꢀ78 °C, quenched cold with saturated NaHCO3 (5mL), andallowed
to warm to rt. After dilution with CH2Cl2, the layers were separated, and the
aqueous layer was re-extracted with CH2Cl2 (3 ꢁ 12 mL). The organic
layer was dried (Na2SO4), filtered through a silica plug, and rinsed (3 ꢁ
25 mL) with EtOAc/CH2Cl2(1:1). The filtrate was concentrated under
reduced pressure to give aldehyde 28 as a yellow oil. The crude aldehyde
was taken immediately to the next reaction without further purification.
5-((4R,6S)-6-((R)-1-(tert-Butyldimethylsilyloxy)propan-2-
yl)-2,2-dimethyl-1,3-dioxan-4-yl)pentan-1-ol (SI-3). PMB
ether SI-2 (1.65 g, 3.34 mmol) was dissolved in EtOAc (16 mL) at rt.
A catalytic amount of 10% Pd/C (50 mg) and NaHCO3 (280 mg,
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FEATURED ARTICLE
To a solution of the vinyl iodide 29 (1.01 mg, 2.75 mmol) in Et2O
(10 mL) at ꢀ78 °C was added t-BuLi (1.7 M in pentane, 3.40 mL, 5.75
mmol), and the reaction was immediately warmed to 0 °C for 25 min.
The reaction was recooled to ꢀ78 °C, and the aldehyde 28 was slowly
added via syringe in Et2O (2.5 mL, 0.60 mL rinse). After 1 h, the reaction
was quenched at ꢀ78 °C with saturated NH4Cl and warmed to rt, and
the layers were separated. The aqueous layer was extracted with Et2O
(2 ꢁ 10 mL), and the combined organic layers washed with brine
(15 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. Flash chromatography (10:1 hexanes/EtOAc) afforded a 1:1
mixture of 1,3-syn and 1,3-anti 30 (ratio determined by 1H NMR analysis
of crude reaction mixture, 464 mg, combined yield of diastereomers 77%
over two steps).
Oxidation/Reduction Sequence. The 1,3-anti diastereomer (65
mg, 0.135 mmol) of 30 was dissolved in CH2Cl2 (2.6 mL) at rt.
DessꢀMartin periodinane (115 mg, 0.270 mmol) was added to the
stirring solution, where upon completion (monitored by TLC) the
reaction was diluted with Et2O (5 mL). The organic layer was washed
with saturated NaHCO3 (2 ꢁ 5 mL) and dried (Na2SO4). After
filtration, the solvent was removed under reduced pressure, and the
residual oil was purified through a short plug of SiO2 (1:1 hexanes/
EtOAc) to provide a clear oil (40 mg, 85%).
The ketone (6 mg, 0.0125 mmol) was dissolved in MeOH and cooled
to 0 °C. NaBH4 (11 mg, 0.035 mmol) was added slowly, and the mixture
was stirred until the ketone was completely consumed (monitored by
TLC). The mixture was partitioned with H2O/Et2O (1:1, 10 mL), and
the resultant aqueous layer was extracted with Et2O (3 ꢁ 5 mL). The
collected organic layers were washed with brine (5 mL) and dried
(Na2SO4). The epimeric ratio of the crude material was determined by
1H NMR analysis after filtration and removal of solvent under reduced
pressure (∼2.7:1). Flash chromatography (5:1 hexanes/EtOAc) pro-
vided both isomers (4 mg, 89%) as a clear oil: [R]D = ꢀ8.1 (c = 1.3,
CH2Cl2); FTIR (neat) 3456, 2954, 2935, 2875, 1458, 1379, 1224,
908 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 5.82 (dddd, J = 16.9, 10.1,
6.7, 6.7 Hz, 1H), 5.16 (d, J = 9.1 Hz, 1H), 5.01 (ddd, J = 17.1, 3.4, 1.5 Hz,
1H), 4.95 (d, J = 10.2 Hz, 1H), 4.27 (t, J = 8.7 Hz, 1H), 3.99 (s, 1H),
3.84ꢀ3.74 (m, 3H), 2.27 (dd, J = 14.1, 4.3 Hz, 1H), 2.16 (dd, J = 8.7,
3.0 Hz, 1H), 2.06 (q, J = 7.0 Hz, 2H), 1.70 (s, 3H), 1.41 (s, 3H), 1.35 (s,
3H), 1.72ꢀ1.20 (m, 11H), 0.96 (t, J = 8.2 Hz, 9H), 0.88 (t, J = 7.3 Hz, 3H),
0.71 (d, J = 6.9 Hz, 3H), 0.59 (q, J = 8.2 Hz, 6H); 13C NMR (126 MHz,
CDCl3) δ 138.6, 136.0, 128.8, 114.6, 100.6, 72.9, 72.4, 70.7, 66.6, 48.5, 44.1,
38.7, 38.0, 35.2, 33.6, 24.7, 24.6, 24.5, 18.4, 17.3, 14.2, 11.6, 7.0, 5.0; HRMS
calcd for C28H54NaO4Si (M þ Na)þ 505.3689, found 505.3674 (ESI).
(5S,7R,9S,12R,13S,14R)-15-(tert-Butyldimethylsilyloxy)-13-
(4-methoxybenzyloxy)-2,12,14-trimethylpentadec-1-ene-
5,7,9-triyl Triacetate (31). To a solution of triol 16 (132 mg,
0.232 mmol) in CH2Cl2 (3.3 mL) were added DMAP (3 mg, 0.023
mmol), pyridine (0.750 mL, 9.30 mmol), and acetic anhydride (0.45 mL,
4.65 mmol). The reaction was stirred until the disappearance of starting
material at rt (∼2 h). The reaction was diluted with EtOAc (5 mL) and
quenched with saturated NH4Cl (5 mL), and the aqueous layer was re-
extracted with EtOAc (3 ꢁ 10 mL). The organic layer was washed with
brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. Flash chromatography (5:1 hexanes/EtOAc) provided 31
(151 mg, 94%) as a clear oil: [R]D = þ12.4 (c = 0.50, CH2Cl2); FTIR
(neat) 2956, 2929, 2883, 2856, 1739, 1514, 1461, 1247 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H),
4.97 (dddd, J = 9.5, 6.2, 6.2, 3.1 Hz, 1H), 4.89 (m, 2H), 4.71
(s, 1H), 4.66 (s, 1H), 4.53 (d, J = 10.9 Hz, 1H), 4.46 (d, J = 10.9 Hz,
1H), 3.80 (s, 3H), 3.71 (dd, J = 9.7, 5.3 Hz, 1H), 3.63 (dd, J = 9.7, 3.3 Hz,
1H), 3.25 (dd, J = 8.7, 2.4 Hz, 1H), 2.07ꢀ1.99 (m, 2H), 2.05 (s, 3H),
2.03 (s, 3H), 1.99 (s, 3H), 1.92 (dddd, J = 18.7, 10.2, 4.4, 4.4 Hz, 1H),
1.84ꢀ1.68 (m, 5H), 1.71 (s, 3H), 1.64ꢀ1.54 (m, 4H), 1.46ꢀ1.38 (m,
1H), 1.34ꢀ1.22 (m, 1H), 0.92 (s, 9H), 0.90 (d, J = 2.3 Hz, 3H), 0.88 (d, J =
2.3 Hz, 3H), 0.06 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 170.8, 170.7,
170.6, 159.1, 144.9, 131.7, 129.3, 113.9, 110.5, 83.3, 74.6, 70.9, 70.3, 67.5,
65.1, 55.4, 39.2, 38.7, 38.6, 35.4, 33.5, 33.1, 32.3, 30.5, 26.1, 22.6, 21.3,
21.3, 21.2, 18.5, 14.8, 13.6, ꢀ5.2, ꢀ5.2; HRMS calcd for C38H64NaO9Si
(M þ Na)þ 715.4217, found 715.4213 (ESI).
(5S,7R,9S,12R,13S,14R)-15-Hydroxy-13-(4-methoxybenz-
yloxy)-2,12,14-trimethylpentadec-1-ene-5,7,9-triyl Triace-
tate (32). To a solution of 31 (150 mg, 0.216 mmol) in THF
(2.3 mL) was added TBAF (0.70 mL, 1.0 M in THF). The reaction
was stirred until disappearance of starting material at rt (∼3 h). The
reaction was diluted with EtOAc (3 mL) and quenched with saturated
NH4Cl (5 mL), and the aqueous layer was re-extracted with EtOAc (2 ꢁ
5 mL). The organic layer was dried (Na2SO4), filtered, and concentrated
under reduced pressure. Flash chromatography (2:1 hexanes/EtOAc)
provided 32 (118 mg, 94%) as a clear oil: [R]D = þ13.1 (c = 2.4,
CH2Cl2); FTIR (neat) 3502, 3072, 2964, 2935, 2875, 1737, 1514, 1454,
1245 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.5 Hz, 2H),
6.88 (d, J = 8.6 Hz, 2H), 4.98 (dddd, J = 9.6, 6.3, 6.3, 3.3 Hz, 1H),
4.99ꢀ4.85 (m, 2H), 4.73 (s, 1H), 4.67 (s, 1H), 4.58 (d, J = 10.6 Hz, 1H),
4.51 (d, J = 10.6 Hz, 1H), 3.81 (s, 3H), 3.62ꢀ3.67 (m, 2H), 3.25 (dd, J =
7.6, 3.3 Hz, 1H), 2.71 (s, 1H), 2.07ꢀ1.99 (m, 2H), 2.06 (s, 3H), 2.04 (s,
3H), 2.02 (s, 3H), 1.95ꢀ1.86 (m, 2H) 1.84ꢀ1.68 (m, 6H), 1.72 (s, 3H),
1.64ꢀ1.56 (m, 2H), 1.54ꢀ1.44 (m, 1H), 1.34ꢀ1.22 (m, 1H), 0.96 (d, J =
6.9 Hz, 3H), 0.94 (d, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
170.7, 170.6, 170.5, 159.3, 144.7, 130.4, 129.4 (2), 113.9 (2), 110.4, 87.6,
74.8, 70.6, 70.0, 67.3, 66.5, 55.3, 39.0, 38.4, 37.7, 36.1, 33.3, 32.8, 32.2,
30.0, 22.4, 21.2, 21.1, 21.1, 15.4, 14.3; HRMS calcd for C32H50NaO9 (M
þ Na)þ 601.3353, found 601.3354 (ESI).
(2S,3S,4R,7S,9R,11S)-7,9,11-Triacetoxy-3-(4-methoxyben-
zyloxy)-2,4,14-trimethylpentadec-14-enoic Acid (2). A solu-
tion of oxalyl chloride (0.046 mL, 0.539 mmol) in CH2Cl2 (1.67 mL)
was cooled to ꢀ78 °C, and DMSO (0.077 mL, 1.08 mmol) was added
slowly by syringe (gas evolution). After the mixture was stirred for 10
min, a solution of alcohol 32 (125 mg, 0.21 mmol) in CH2Cl2 (2.0 mL)
was added by cannula and rinsed with CH2Cl2 (2 ꢁ 0.2 mL). The cloudy
mixture was stirred at ꢀ78 °C for 15 min, at which time Et3N (0.18 mL,
1.29 mmol) was added dropwise. The reaction mixture was stirred for 2
h at ꢀ78 °C. The reaction was quenched at ꢀ78 °C with saturated
NaHCO3 (3 mL) and allowed to warm to rt. The reaction was diluted
with CH2Cl2, and the layers were separated. The aqueous layer was re-
extracted with CH2Cl2 (3 ꢁ 5 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure to give
aldehyde as a yellow oil. The crude aldehyde was taken immediately to
the next reaction with further purification.
To a solution of crude aldehyde were added tert-butyl alcohol
(4.5 mL) and 2-methyl-2-butene (1.5 mL). A solution of NaClO2
(390 mg, 4.30 mmol) and sodium dihydrogen phosphate (470 mg,
3.01 mmol) in H2O (2.0 mL) was prepared and added to the reaction
mixture by syringe. The yellow solution was stirred vigorously for 2 h at
rt, diluted with Et2O (15 mL), and poured into H2O (9 mL). The layers
were separated, and the aqueous phase was extracted with Et2O (3 ꢁ
10 mL). The combine organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure. Flash chromatography (1:1
hexanes/EtOAc) provided 2 (104 mg, 81% over two steps) as a clear
oil: [R]D = þ8.13 (c = 0.16, CH2Cl2); FTIR (neat) 3251, 3076, 2964,
2923, 2854, 1737, 1714, 1512, 1454, 1245 cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.10ꢀ4.85
(m, 3H), 4.73 (s, 1H), 4.67 (s, 1H), 4.56 (d, J = 10.7 Hz, 1H), 4.50 (d, J =
10.6 Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J = 7.2, 3.5 Hz, 1H), 2.78 (dddd, J =
14.33, 7.1, 7.1, 7.1 Hz, 1H), 2.07ꢀ1.99 (m, 2H), 2.06 (s, 3H), 2.04 (s,
3H), 2.02 (s, 3H), 1.95ꢀ1.86 (m, 2H), 1.84ꢀ1.64 (m, 5H), 1.72 (s, 3H),
1.64ꢀ1.40 (m, 3H), 1.39ꢀ1.20 (m, 2H), 1.17 (d, J = 7.1 Hz, 3H), 0.93
(d, J = 6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 179.9, 170.8, 170.7,
170.5, 159.4, 144.7, 130.0, 129.5 (2), 113.9 (2), 110.3, 84.2, 74.4, 70.8,
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FEATURED ARTICLE
69.9, 67.3, 55.3, 42.3, 39.0, 38.1, 35.6, 33.3, 32.5, 32.3, 28.9, 22.4, 21.2,
21.1, 21.1, 14.7, 14.4; HRMS calcd for C32H48NaO10 (M þ Na)þ
615.3145, found 615.3131 (ESI).
33.3, 32.8, 32.2, 29.8, 29.7, 24.8, 24.6, 22.4, 21.2, 21.1, 21.0, 18.9, 17.5,
14.8, 14.2, 13.6, 9.9; HRMS calcd for C54H86NaO13 (M þ Na)þ
965.5966, found 965.5897 (ESI).
(5S,7R,9S,12R,13S,14S)-15-((2S,3R,7R,E)-2-((4S,6R)-2,2-Di-
methyl-6-(pent-4-enyl)-1,3-dioxan-4-yl)-5-methyl-7-(trieth-
ylsilyloxy)dec-4-en-3-yloxy)-13-(4-methoxybenzyloxy)-2,12,
14-trimethyl-15-oxopentadec-1-ene-5,7,9-triyl Triacetate
(33). To a solution of alcohol 30 (77 mg, 0.159 mmol), carboxylic acid
2 (106 mg, 0.175 mmol), and DMAP (975 mg, 7.98 mmol) in toluene
(32 mL) at ꢀ78 °C was added Et3N (0.5 mL, 3.61 mmol) dropwise
followed by the slow addition of 2,4,6-trichlorobenzoyl chloride
(0.56 mL, 3.58 mmol), which caused the white solution to thicken.
The mixture was stirred for 21 h at ꢀ78 °C ensuring that the bath
temperature did not rise above ꢀ65 °C. The reaction flask was then
moved to a dry ice/CH3CN bath and stirred for 2.5 h maintaining the
temperature between ꢀ30 and ꢀ42 °C. At the end of the 2.5 h, the
solution was slowly allowed to warm to rt in the bath over 1 h. The flask
was placed in an ice bath for 2 h while being stirred. The reaction was
quenched by the addition of saturated NaHCO3 (15 mL). The layers were
separated, and the aqueous layer was back-extracted with Et2O (25 mL).
The combined organic layers were dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification by flash chromatography (5:1
hexanes/EtOAc) provided ester 33 (130 mg, 77%) as a colorless oil: [R]D
þ3.63 (c = 0.28, CH2Cl2); FTIR (neat) 3076, 2954, 2935, 2875, 1739,
1515, 1442, 1244 cmꢀ1;1H NMR (400 MHz, CDCl3) δ7.19 (d, J=8.7Hz,
2H), 6.83 (d, J = 8.7 Hz, 2H), 5.82 (dddd, J = 17.0, 10.2, 6.8, 6.8 Hz, 1H),
5.68 (dd, J = 9.9, 5.7 Hz, 1H), 5.17 (d, J = 9.8 Hz, 1H), 5.02 (ddd, J = 17.1,
3.2, 1.6 Hz, 1H), 5.00ꢀ4.93 (m, 3H), 4.94ꢀ4.85 (m, 2H), 4.74 (s, 1H),
4.67 (s, 1H), 4.51 (d, J = 10.8 Hz, 1H), 4.34 (d, J = 10.8 Hz, 1H), 3.79 (s,
3H), 3.70ꢀ3.80 (m, 2H), 3.69ꢀ3.60 (m, 3H), 2.69 (dt, J = 14.2, 7.1 Hz,
1H), 2.20ꢀ1.89 (m, 8H), 2.06 (s, 3H), 2.04 (s, 3H), 2.00 (s, 3H), 1.80ꢀ1.20
(m, 18H), 1.76 (s, 3H), 1.73 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H), 1.08 (d, J =
7.1 Hz, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.93ꢀ0.84 (m, 9H) 0.58 (q, J = 7.9 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 175.3, 170.6, 170.6, 170.5, 158.9,
144.7, 139.6, 138.8, 131.2, 129.0, 122.7, 114.6, 113.6, 110.3, 100.1, 83.1, 73.9,
71.4, 70.7, 70.2, 70.0, 67.3, 67.1, 66.5, 55.2, 53.5, 48.8, 43.5, 42.1, 39.1, 38.5,
38.5, 35.4, 34.7, 33.7, 33.3, 32.1, 30.3, 29.9, 29.7, 24.9, 24.9, 24.8, 22.4, 21.2,
21.1, 21.1, 18.3, 17.6, 15.3, 14.8, 14.2, 13.2, 9.8, 7.0 (3), 5.0 (3); HRMS calcd
for C60H100NaO13Si (M þ Na)þ 1079.6831, found 1079.7115 (ESI).
(5S,7R,9S,12R,13S,14S)-15-((2S,3R,7R,E)-2-((4S,6R)-2,2-Di-
methyl-6-(pent-4-enyl)-1,3-dioxan-4-yl)-7-hydroxy-5-meth-
yldec-4-en-3-yloxy)-13-(4-methoxybenzyloxy)-2,12,14-tri-
methyl-15-oxopentadec-1-ene-5,7,9-triyl Triacetate (SI-4).
Ester 33 (75 mg, 0.071 mmol) was dissolved in THF (1 mL) and cooled
to 0 °C. A solution of TBAF in THF (0.214 mL, 1.0 M in THF) was added
dropwise. The reaction stirred at 0 °C until completion (approximately
45 min). The reaction was quenched with saturated NH4Cl, and the aqueous
layer was extracted with EtOAc (3 ꢁ 10 mL). The organic layers were
combined, washed with brine (5 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification by flash chromatog-
raphy (2:1 hexanes/EtOAc) afforded SI-4 (63 mg, 94%) as a clear oil:
[R]D = ꢀ11.4 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.22 (d,
J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.81 (dddd, J = 17.0, 10.2, 6.7,
and 6.7 Hz, 1H), 5.64 (dd, J = 9.9 and 5.2 Hz, 1H), 5.20 (d, J = 9.6 Hz, 1H),
5.01 (ddd, J= 17.1, 3.4, and 1.6 Hz, 1H), 5.00ꢀ4.93(m, 2H), 4.93ꢀ4.85 (m,
2H), 4.72 (s, 1H), 4.67 (s, 1H), 4.53 (d, J = 10.7 Hz, 1H), 4.38 (d, J =
10.7 Hz, 1H), 3.79 (s, 3H), 3.76ꢀ3.69 (m, 1H), 3.66ꢀ3.59 (m, 1H),
3.60ꢀ3.54 (m, 1H), 3.53 (dd, J = 8.4, 3.0 Hz, 1H), 2.70 (dt, J = 15.2 and
7.2 Hz, 1H), 2.15ꢀ1.87 (m, 8H), 2.06 (s, 3H), 2.04 (s, 3H), 2.00 (s, 3H),
1.80ꢀ1.20 (m, 21H), 1.76 (s, 3H), 1.73 (s, 3H), 1.33 (s, 3H), 1.28 (s, 3H),
1.10 (d, J = 7.1 Hz, 3H), 0.93ꢀ0.84 (m, 9H);13C NMR (126 MHz, CDCl3)
δ 175.1, 170.7, 170.6, 170.5, 158.9, 144.7, 139.6, 138.7, 131.2, 128.8,
123.1, 114.6, 113.5, 110.3, 100.2, 83.7, 73.8, 71.8, 70.7, 70.0, 68.4, 67.3,
66.4, 55.2, 53.5, 48.1, 43.4, 42.1, 39.2, 39.1, 38.5, 36.3, 35.4, 35.1, 33.7,
(5S,7R,9S,12R,13S,14S)-15-((2S,3R,7R,E)-7-Acetoxy-2-((4S,
6R)-2,2-dimethyl-6-(pent-4-enyl)-1,3-dioxan-4-yl)-5-methy-
ldec-4-en-3-yloxy)-13-(4-methoxybenzyloxy)-2,12,14-tri-
methyl-15-oxopentadec-1-ene-5,7,9-triyl Triacetate (34). To
a solution of SI-4 (58 mg, 0.062 mmol) in CH2Cl2 (3.0 mL) were added
DMAP (1 crystal), pyridine (0.2 mL, 2.46 mmol), and acetic anhydride
(0.117 mL, 1.23 mmol). The reaction was stirred at rt until disappear-
ance of starting material (∼2 h). The reaction was diluted with EtOAc
(3 mL) and quenched with saturated NH4Cl (3 mL), and the aqueous
layer was re-extracted with EtOAc (3 ꢁ 5 mL). The organic layer was
washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. Flash chromatography (1.5:1 hexanes/EtOAc)
provided 34 (60 mg, 98%) as a clear oil: [R]D = þ2.2 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6
Hz, 2H), 5.80 (dddd, J = 16.9, 10.2, 6.7, and 6.7 Hz, 1H), 5.67 (dd, J =
9.9, 5.6 Hz, 1H), 5.16 (d, J = 9.7 Hz, 1H), 5.00 (ddd, J = 17.1, 3.4, 1.6 Hz,
1H), 5.00ꢀ4.92 (m, 3H), 4.92ꢀ4.84 (m, 2H), 4.73 (s, 1H), 4.66 (s, 1H),
4.50 (d, J = 10.9 Hz, 1H), 4.35 (d, J = 10.9 Hz, 1H), 3.79 (s, 3H),
3.75ꢀ3.68 (m, 1H), 3.62ꢀ3.55 (m, 2H), 2.68 (dt, J = 16.0, 6.9 Hz, 1H),
2.15ꢀ1.87 (m, 8H), 2.06 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s,
3H), 1.80ꢀ1.20 (m, 20H), 1.77 (s, 3H), 1.73 (s, 3H), 1.33 (s, 3H), 1.27
(s, 3H), 1.06 (d, J = 7.1 Hz, 3H), 0.93ꢀ0.84 (m, 9H); 13C NMR (126
MHz, CDCl3) δ 175.1, 170.6, 170.6, 170.6, 170.5, 158.9, 144.7, 138.7,
138.6, 131.3, 128.8, 122.5, 114.6, 113.5, 110.3, 100.2, 83.2, 73.8, 72.1,
71.2, 70.7, 70.0, 67.3, 66.4, 55.2, 53.5, 44.2, 42.1, 39.2, 39.1, 35.9, 35.4,
33.7, 33.3, 32.2, 31.9, 31.6, 29.9, 24.8, 24.8, 22.7, 21.3, 21.2, 21.1, 21.0,
18.4, 17.8, 14.7, 14.2, 14.2, 14.0, 13.2, 9.7; HRMS calcd for
C56H88NaO14 (M þ Na)þ 1007.6072, found 1007.6210 (ESI).
(5S,7R,9S,12R,13S,14S)-15-((4R,8R,9S,10S,12R,E)-4-Acetoxy-
10,12-dihydroxy-6,9-dimethylheptadeca-6,16-dien-8-ylo-
xy)-13-(4-methoxybenzyloxy)-2,12,14-trimethyl-15-oxope-
ntadec-1-ene-5,7,9-triyl Triacetate (SI-5). To a solution of tetra-
acetate 34 (60 mg, 0.061 mmol) in MeOH (6 mL) was added PPTS
(2.5 mg, 0.03 mmol). The reaction was stirred until disappearance of
starting material at rt (∼ 4 h). The reaction was diluted with EtOAc and
quenched with saturated NaHCO3, and the aqueous layer was re-extracted
with EtOAc (3 ꢁ 10 mL). The organic layer was washed with brine
(10 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. Flash chromatography (1.5:1 hexanes/EtOAc) provided SI-5
(47 mg, 82%) as a clear oil: [R]D = þ8.97 (c = 1.7, CHCl3); 1H NMR
(400 MHz, CDCl3) δ7.21 (d, J=8.3Hz, 2H), 6.85(d, J= 8.4 Hz, 2H), 5.82
(dddd, J = 15.8, 12.1, 5.4, 5.4 Hz, 1H), 5.69 (dd, J = 9.7, 6.0 Hz, 1H), 5.18
(d, J = 9.8 Hz, 1H), 5.05ꢀ4.85 (m, 6H), 4.73 (s, 1H), 4.67 (s, 1H), 4.51 (d,
J = 10.9 Hz, 1H), 4.34 (d, J = 11.0 Hz, 1H), 3.92ꢀ3.86 (m, 1H), 3.80 (s,
3H), 3.71 (m, 1H), 3.58 (dd, J = 8.4, 2.0 Hz, 1H), 2.73 (dddd, J = 14.2, 6.8,
6.8, 6.8 Hz, 1H), 2.50ꢀ1.19 (m, 28H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s,
3H), 1.82 (s, 3H), 1.72 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H), 0.89 (t, J = 7.3 Hz,
3H), 0.86ꢀ0.81 (m, 9H); 13C NMR (126 MHz, CDCl3) δ 175.1, 170.7,
170.6, 170.6, 170.5, 158.9, 144.7, 138.7, 138.6, 131.1, 128.4, 123.4, 114.7,
113.7, 110.3, 83.5, 73.8, 73.5, 72.5, 70.7, 70.1, 68.8, 67.3, 60.4, 55.2, 44.3,
43.4, 43.0, 39.5, 39.1, 38.5, 37.1, 36.3, 34.9, 33.7, 33.3, 32.2, 31.6, 29.8, 25.1,
22.7, 21.3, 21.2, 21.1, 21.1, 18.4, 17.8, 14.2, 14.0, 13.6, 10.8; HRMS calcd for
C53H84NaO14 (M þ Na)þ 967.5759, found 967.5789 (ESI).
(5S,7R,9S,12R,13S,14S)-15-((4R,8R,9S,10S,12R,E)-4-Acet-
oxy-10,12-dihydroxy-6,9-dimethylheptadeca-6,16-dien-
8-yloxy)-13-hydroxy-2,12,14-trimethyl-15-oxopentadec-1-
ene-5,7,9-triyl Triacetate (35). Ester SI-5 (105 mg, 0.112 mmol)
was taken up in CH2Cl2 (5.0 mL) followed by the addition of pH = 7
buffer solution (5.0 mL) and DDQ (51 mg, 0.224 mmol) at rt. Upon
completion (∼0.5 h, monitored by TLC), CH2Cl2 (13 mL) was added
followed by saturated NaHCO3 (1 mL). The layers were separated, and
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FEATURED ARTICLE
the aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL). The
combined organic layers were washed with brine (10 mL), dried
(anhydrous Na2SO4), filtered, and concentrated under reduced pres-
sure. Flash chromatography (2:1 hexanes/EtOAc) afforded 35 (89 mg,
97%) as a clear oil: [R]D = þ4.4 (c = 0.50, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.79 (dddd, J = 17.0, 10.2, 6.7, 6.7 Hz, 1H), 5.19 (dd, J = 9.7,
9.5 Hz, 1H), 5.07ꢀ4.87 (m, 6H), 4.73 (s, 1H), 4.66 (s, 1H), 4.15ꢀ4.09
(m, 2H), 3.96ꢀ3.89 (m, 1H), 3.71 (dd, J = 9.9, 1.2 Hz, 1H), 2.54 (dddd,
J = 14.1, 7.0, 7.0, 7.0 Hz, 1H), 2.17ꢀ1.19 (m, 28H), 2.07 (s, 3H), 2.03
(s, 3H), 2.02 (s, 3H), 1.82 (s, 3H), 1.72 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H),
0.89 (t, J = 7.3 Hz, 3H), 0.86ꢀ0.81 (m, 9H); 13C NMR (126 MHz,
CDCl3) δ 174.0, 172.4, 170.8, 170.8, 170.6, 144.6, 138.7, 138.0, 125.3,
114.6, 110.4, 72.6, 72.6, 72.4, 71.9, 70.7, 68.1, 67.1, 66.9, 45.3, 44.2, 42.7,
39.0, 37.6, 37.3, 36.9, 36.0, 33.7, 33.6, 33.3, 32.3, 31.5, 29.0, 25.3, 22.4,
21.4, 21.3, 21.2, 21.1, 18.5, 17.8, 13.9, 13.6, 12.5, 9.5; HRMS calcd for
C45H76NaO13 (M þ Na)þ 847.5184, found 847.5183 (ESI).
H), 1.64ꢀ1.58 (m, 3 H); 1.49ꢀ1.31 (m, 4 H), 1.29 (d, J = 7.0 Hz, 6 H),
1.04 (d, J = 6.6 Hz, 3 H), 0.94 (t, J = 7.3 Hz, 3 H); 13C NMR (126 MHz,
pyridine-d5) δ 174.2, 170.9, 170.9, 170.7, 170.6, 137.2, 134.3, 127.3, 126.9,
75.2, 73.6, 72.2, 71.8, 70.1, 68.3, 68.2, 68.1, 46.6, 44.8, 44.3, 39.9, 39.2, 39.0,
37.6, 36.7, 34.4, 32.8, 32.0, 29.3, 28.4, 27.9, 27.5, 23.3, 21.4, 21.4, 21.3, 21.3,
1
19.1, 17.9, 14.3, 14.3, 13.0, 11.4; H NMR (500 MHz, CDCl3)36d
δ
5.13ꢀ5.07 (m, 2H), 5.03ꢀ4.97 (m, 3H), 4.96ꢀ4.91 (m, 1H), 4.90ꢀ4.85
(m, 1H), 4.27 (s, 1H), 4.05ꢀ4.01 (m, 1H), 3.68 (d, J = 9.7 Hz, 1H), 2.54
(tt, J = 7.0 Hz, 1H), 2.31ꢀ2.20 (m, 4H), 2.13ꢀ2.11 (m, 1H), 2.11ꢀ2.08
(m, 1H), 2.06ꢀ2.04 (m, 2H), 2.04ꢀ2.03 (m, 6H), 2.02 (s, 3H), 2.01 (s,
3H), 2.00ꢀ1.97 (m, 1H), 1.97ꢀ1.95 (m, 1H), 1.82 (s, 3H), 1.81ꢀ
1.76 (m, 2H), 1.76ꢀ1.74 (m, 1H), 1.74ꢀ1.71 (m, 1H), 1.66 (s, 3H),
1.61 (s, 1H), 1.58ꢀ1.56 (m, 1H), 1.48ꢀ1.46 (m, 2H), 1.45ꢀ1.43 (m, 2H),
1.42ꢀ1.39 (m, 2H), 1.38ꢀ1.25 (m, 6H), 1.01 (d, J= 7.0 Hz, 3H), 0.89 (t, J=
7.3 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 173.6, 171.6, 171.3, 170.7, 170.4, 137.6, 133.9,
125.9, 125.8, 74.0, 72.8, 72.3, 71.3, 70.8, 68.0, 67.0, 66.6, 45.7, 44.1, 42.9,
38.0, 37.4, 37.0, 35.9, 34.9, 33.6, 32.2, 31.1, 28.2, 26.7, 25.9, 22.8, 21.4,
21.2, 21.2, 21.2, 21.2, 18.5, 17.8, 13.9, 13.4, 11.5, 9.36; HRMS calcd for
C43H72NaO13 (M þ Na)þ 819.4871, found 819.4877 (ESI).
Dolabelide C (1). To a refluxing solution of ester 23 (70 mg, 0.085
mmol) in degassed CH2Cl2 (175 mL) was added Grubbs cat-B catalyst
(8.0 mg, 0.0085 mmol). The reaction was refluxed 2 h with the addition
of more catalyst (4.0 mg, 0.00425 μmol) after 2 h. A third portion of
catalyst (4.0 mg, 0.00425) was added after an additiona 2 h; the reaction
was refluxed for 6 h (monitored by TLC and LCꢀMS). The solution
was cooled to rt and concentrated under reduced pressure. The resultant
residue was purified via flash chromatography through two sequential
columns (8:1 CH2Cl2/acetone) and (5:1 pentane/EtOAc) to afford 1
(14.0 mg, 21% yield) as an analytically pure sample and its C14ꢀC15 Z-
configured diastereomer (10.0 mg, 15% yield) (vide infra): [R]D = þ2.9
(c = 0.63, CHCl3); 1H NMR (500 MHz, pyridine-d5)36b δ 6.10ꢀ5.90
(br m, 1H), 5.70 (t, J = 9.3 Hz, 1H), 5.67 (s, 1H), 5.40 (d, J = 9.5 Hz, 1H),
5.38ꢀ5.31 (m, 2H), 5.30ꢀ5.23 (m, 2H), 5.16ꢀ5.10 (m, 1H), 4.88ꢀ4.82
(m, 1H), 4.37ꢀ4.32 (m, 1H), 4.03 (br d, J = 9.1 Hz, 1H), 2.93ꢀ
2.85 (m, 1H), 2.52ꢀ2.48 (m, 1H), 2.32 (dd, J = 14.0, 7.9 Hz, 1H),
2.28 (dd, J = 13.9, 5.4 Hz, 1H), 2.21ꢀ2.15 (m, 1H), 2.11ꢀ2.00 (m, 6H),
2.08 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H), 1.96ꢀ
1.92 (m, 2H), 1.90ꢀ1.80 (m, 4H), 1.79ꢀ1.58 (m, 7H), 1.59 (s, 3H),
1.53ꢀ1.49 (m, 3H), 1.32ꢀ1.28 (m, 2H), 1.19 (d, J = 7.3 Hz, 3H), 1.16
(d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H); 13C
NMR (126 MHz, pyridine-d5) δ 173.9, 170.6, 170.5, 170.4, 170.3, 136.7,
132.6, 127.3, 127.2, 74.3, 73.5, 71.8, 69.9, 69.9, 68.0, 67.9, 67.3, 46.4, 44.5,
43.7, 38.8, 38.5, 38.0, 37.2, 36.3, 35.2, 34.1, 31.8, 31.6, 29.3, 28.0, 27.0, 21.1,
21.0, 20.9, 20.9, 18.8, 17.6, 15.2, 14.0, 13.8, 12.6, 11.0; 1H NMR (500 MHz,
CDCl3) δ 5.35 (t, J = 9.1 Hz, 1H), 5.10ꢀ5.05 (m, 2H), 5.04ꢀ5.00 (m,
1H), 4.98ꢀ4.92 (m, 1H), 4.88ꢀ4.82 (m, 2H), 4.08 (s, 1H), 3.93 (s, 1H),
3.57 (s, 1H), 3.24 (s, 1H), 2.60ꢀ2.54 (m, 1H), 2.54ꢀ2.47 (m, 1H), 2.25
(dd, J = 13.8, 7.1 Hz, 1H), 2.21 (dd, J = 14.1, 5.7 Hz, 1H), 2.07 (s, 3H), 2.03
(s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.90ꢀ1.83 (m, 2H), 1.81 (s, 3H),
1.78ꢀ1.64 (m, 3H), 1.64ꢀ1.62 (m, 4H), 1.58 (s, 3H), 1.56 (m, 9H),
1.43ꢀ1.27 (m, 5H), 1.25 (s, 3H), 1.23ꢀ1.20 (m, 1H), 1.07 (d, J = 7.1 Hz,
3H), 0.89 (t, J = 7.3 Hz, 3H), 0.84 (m, 6H); 13C NMR (126 MHz, CDCl3)
δ 173.8, 171.2, 171.0, 170.7, 170.4, 137.9, 133.1, 126.1, 125.0, 74.6, 73.1,
72.2, 69.8, 69.2, 68.7, 68.1, 67.7, 45.1, 44.3, 42.7, 39.1, 36.8, 36.1, 35.1, 34.6,
31.9, 31.7, 29.7, 28.3, 26.7, 25.0, 21.2, 21.2, 21.2, 21.1, 18.5, 17.7, 15.2, 13.9,
13.6, 12.6, 10.6; HRMS calcd for C43H72NaO13 (M þ Na)þ 819.4871,
found 819.4858 (ESI).
HPLC-MS Analysis of 1. HPLC data was collected using the
following gradient over 35 min:
A (%)
(99:1 H2O/
MeCN)
95.0
B (%)
(99:1 MeCN/
H2O)
time
(min)
0.00
flow rate
(mL/min)
1.000
5.0
60.0
1.00
40.0
1.000
31.00
30.0
70.0
1.000
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and spec-
b
troscopic data of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: phanson@ku.edu.
’ ACKNOWLEDGMENT
This investigation was kindly supported by funds provided
by NSF CHE-0503875, NIH-NIGMS RO1 GM077309, and
the NIH Dynamic Aspects in Chemical Biology Training Grant
(A.W., J.D.W.). We thank the University of Kansas Honors
Department for a KU Undergraduate Research Award (J.N., KU-
UGRA), Dr. Marc Anderson and Dr. Todd D. Williams for
LCꢀMS analysis, Dr. Justin T. Douglas and Sarah Neuenswan-
der for assistance in NMR analysis, and Materia, Inc., for
supplying catalyst and helpful discussions. We also thank Dr.
Kigoshi, Dr. Ojika, and Dr. Suenaga for supplying us with a
natural sample of dolabelide C.
Non-Natural C14ꢀC15 Z-Isomer of 1: [R]D = þ10.0 (c = 0.30,
CHCl3); 1H NMR (500 MHz, pyridine-d5)36c δ 6.28 (br s, 1H),
6.20ꢀ6.05 (br m, 1H), 5.85 (t, J = 9.4 Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H),
5.48ꢀ5.40 (m, 2H), 5.38ꢀ5.29 (m, 2H), 5.27ꢀ5.18 (m, 1H), 4.88ꢀ
4.84 (m, 1H), 4.53ꢀ4.46 (m, 1H), 4.14 (br d, J = 7.4 Hz, 1H), 3.03ꢀ
2.97 (m, 1H), 2.64ꢀ2.56 (m, 1H), 2.43 (dd, J = 7.5, 13.8 Hz, 1H), 2.37
(dd, J = 5.3, 13.1 Hz, 1H), 2.34ꢀ2.23 (m, 3H), 2.22ꢀ2.19 (m, 1H),
2.18ꢀ2.14 (m, 12H), 2.13ꢀ2.12 (m, 2 H), 2.08 (s, 3 H), 2.06ꢀ2.02 (m,
1 H), 2.02ꢀ2.00 (m, 1 H), 1.99ꢀ1.95 (m, 2 H), 1.95ꢀ1.91 (m, 1 H),
1.91ꢀ1.86 (m, 2 H), 1.84ꢀ1.78 (m, 2 H), 1.77 (s, 3 H), 1.75ꢀ1.66 (m, 3
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(31) Rigorous purification and degassing of the solvent was achieved
through distillation over CaH2 and a conventional freeze/thaw
technique.
(32) The RCM was performed on 70 mg scale providing 14 mg of an
analytically pure sample of the desired E-isomer and 10 mg of the
Z-isomer.
(33) Optical rotation was measured over several trials resulting in
variation of both the value and sign of analytically pure 1 (determined by
LCꢀMS analysis, see the Supporting Information). This phenomenon
is consistent with hydrogen-bonding systems, where inconsistency is
frequently observed. Abraham, E.; Davies, S. G.; Roberts, P. M.; Russell,
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(34) The major diastereomer was determined to be E due to
resonances matching with listed resonances in reference.3 The E
geometry is confirmed from comparison of 13C NMR, in which the
C-14 methyl has a chemical shift of 15.7 ppm and the Z-isomer has a
chemicals shift of 23.3 ppm, which is consistent with ref 3 and the paper
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FEATURED ARTICLE
of vinyl methyl and vinyl methylene carbon atoms associated with
isolated trisubstituted double bonds are critically dependent on the
configuration of the double bond as a result of the well-known γ-effect.”
For example:
(35) Purification of each isomer was achieved using two to three
consecutive runs on normal-phase flash chromatography (see the
Supporting Information).
(36) (a) Spectrum integrated to 41 total H, where the unassigned H
was presumed to be an O-H peak undergoing HꢀD exchange. (b)
Spectrum integrated to 71 total H, where the unassigned H was
presumed to be an O-H peak undergoing HꢀD exchange. Only the
O-H peaks did not match exactly to the reported data. (c) Spectrum
integrated to 71 total H, where the unassigned H was presumed to be an
O-H peak undergoing HꢀD exchange. (d) Spectrum integrated to 69
total H, where the unassigned Hs were presumed to be O-H peaks
undergoing HꢀD exchange.
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