Total synthesis of Iejimalide B

Article abstract of DOI:10.1021/jo200514m

Iejimalide B, a structurally unique 24-membered polyene macrolide having a previously underutilized mode of anticancer activity, was synthesized according to a strategy employing Julia-Kocienski olefinations, a palladium-catalyzed Heck reaction, a palladium-catalyzed Marshall propargylation, a Keck-type esterification, and a palladium-catalyzed macrolide-forming, intramolecular Stille coupling of a highly complex cyclization substrate. The overall synthesis is efficient (19.5% overall yield for 15 linear steps) and allows for more practical scaled-up synthesis than previously reported strategies that differed in the order of assembly of key subunits and in the method of macrocyclization. The present synthesis paves the way for efficient preparation of analogues for drug development efforts.

Full text of DOI:10.1021/jo200514m

FEATURED ARTICLE
pubs.acs.org/joc
Total Synthesis of Iejimalide B†
Qingshou Chen,‡,§ Dirk Schweitzer,‡ John Kane,‡ V. Jo Davisson,*,§ and Paul Helquist*,‡
‡Department of Chemistry and Biochemistry and Harper Cancer Research Center, University of Notre Dame,
Notre Dame, Indiana 46556, United States
§Department of Medicinal Chemistry & Molecular Pharmacology, Laboratory for Chemical Biology & Drug Development,
Bindley Bioscience Center at Purdue Discovery Park, West Lafayette, Indiana 47907-2057, United States
S Supporting Information
b
ABSTRACT: Iejimalide B, a structurally unique 24-membered polyene macrolide
having a previously underutilized mode of anticancer activity, was synthesized
according to a strategy employing JuliaꢀKocienski olefinations, a palladium-
catalyzed Heck reaction, a palladium-catalyzed Marshall propargylation, a Keck-
type esterification, and a palladium-catalyzed macrolide-forming, intramolecular
Stille coupling of a highly complex cyclization substrate. The overall synthesis is
efficient (19.5% overall yield for 15 linear steps) and allows for more practical
scaled-up synthesis than previously reported strategies that differed in the order of
assembly of key subunits and in the method of macrocyclization. The present
synthesis paves the way for efficient preparation of analogues for drug develop-
ment efforts.
’ INTRODUCTION
Natural products have long served as invaluable resources in
the search for structurally novel compounds as leads for the
development of drugs having many therapeutic applications,
including antibiotics and anticancer agents. More than two
decades ago, a bioassay-guided screen of marine organism
metabolites led to the discovery of the iejimalides,1 a class of
natural macrolides originally isolated from the tunicate species
Eudistoma cf. rigida native to the coral reefs of Ie Island (Iejima)
near Okinawa, Japan. As disclosed by Kobayashi and co-
workers,1a,b the unique structural architecture of the iejimalides
Figure 1. Structures of iejimalide AꢀD.
consists of a novel 24-membered polyene macrolide core struc-
ture containing five chiral centers and four dienes. Of these
dienes, three have the E,E-configuration, one has the E,Z-con-
figuration, and one is a skipped triene. Three of the dienes reside
in the macrocyclic ring, whereas the fourth is seen in an
interesting side chain terminated in an N-formyl L-serine residue
(Figure 1).1c This structural assignment resulted from a correc-
tion of previous studies.1a,b
and an apoptotic cascade in some cell lines. The V-ATPase is an
intracellular membrane-bound multicomponent protein com-
plex, which maintains the proton gradient of intracellular com-
partments, organelles, and extracellular microenvironments,
which have critical roles in many biological processes.5,6 Also,
certain pathologies are associated with the functional status of
V-ATPase including association with invasiveness and metastasis
of some cancers.7 Iejimalides are among a privileged class of
natural products that show inhibition of V-ATPase.2a,8 Recent
proteomic evidence supports a similar cellular mode of action for
the iejimalides when compared with established natural product
V-ATPase inhibitors.9 Despite the increasing significance of the
cellular regulatory features associated with V-ATPase,10,11 little is
Bioassays2 showed that the iejimalides possess potent growth
inhibitory activity against a wide range of human tumor cell lines,
with iejimalide B being especially potent. Recently reported data
from the NCI,3 obtained for samples provided by our labora-
tories, showed that iejimalide B is cytostatic (GI50) at <5 nM
against 40 of the 60 cell lines tested in the NCI cancer screen. A
recent study showed that the iejimalides may have an under-
explored mode of anticancer activity, which may lead to new
cancer therapy modalities.4 Treatment of cancer cells in culture
leads to inhibition of vacuolar ATPase (V-ATPase) and down-
stream effects including promotion of reactive oxygen species
Received: March 8, 2011
Published: April 13, 2011
r
2011 American Chemical Society
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Figure 2. Retrosynthetic analysis of iejimalide B.
known about other specific cellular target(s) of the iejimalides
and the pathways leading to growth arrest and apoptosis.4a,b
A major limitation regarding studies of the biological action
and therapeutic development of iejimalides is that the original
natural source provides only miniscule amounts of the iejimalides
(0.0003ꢀ0.0006% of the tunicate wet weight). The Kobayashi
laboratory performed re-extraction from a Cystodytes sp. to
accumulate enough material to assign the absolute configuration
of all the stereocenters (4R,9S,17S,22S,23S,32S) and to revise the
configuration of the C13ꢀC14 double bond from E to Z.1c,d Our
laboratories conducted five collections of E. rigida over a period
of a few years to obtain milligram quantities of the iejimalides for
initial studies of biological activity.2b,3,4
The potent antitumor activity of the iejimalides through an
important cellular mechanism, their challenging, unique struc-
tures, natural scarcity, and unique biological origins have aroused
diverse interests in these compounds,12ꢀ14 which deserve more
comprehensive studies and evaluation for anticancer drug devel-
opment. To this end, an objective has been to provide sufficient
amounts of these fascinating compounds for further biological
evaluation through high-efficiency chemical synthesis. A rather
elegant ring closing alkene metathesis reaction of a highly
functionalized, polyunsaturated macrocyclization substrate was
the most prominent feature of the F€urstner approach.12d,e In
contrast, in an initial synthesis of iejimalide B reported by our
laboratory,12f the key macrocyclization was accomplished by a
Shiina lactonization as one of the earliest reports of the use of this
method in a synthesis of a complex natural product whereas
other, longer established methods such as the Yamaguchi pro-
cedure were unsuccessful. Although our overall synthetic route
was relatively short and highly convergent with a longest linear
sequence of 13 steps, it lacked good efficiency as reflected in an
overall yield of 3%, due in no small part to the difficult macro-
lactonization proceeding in no more than 35% yield. Herein, we
present a full account of a significantly enhanced second-gen-
eration synthesis of iejimalide B in which the key macrocycliza-
tion is accomplished by an efficient intramolecular Stille coupling
reaction of a richly functionalized alkenylstannane/alkenyl io-
dide substrate.
’ RESULTS AND DISCUSSION
The rationale for improving the total synthesis of iejimalides is
focused on providing a more practical source of the iejimalides
that would also permit facile access to novel structural analogues
for drug development through a modular convergent approach.
In order to have the greatest flexibility in controlling the absolute
configurations of the chiral centers and to permit modification of
individual regions of the structures of the natural products, we
adopted a highly convergent strategy based upon the generation
of fragments carrying individual stereochemical elements,12a,b
which could be derived either from the chiral pool or from use of
enantioselective transformations (Figure 2). F€urstner and co-
workers have also adopted a fragment-based strategy in their
work but using distinct methods of assembly.12cꢀe
For the synthesis of macrolides, the Yamaguchi macrolacto-
nization is quite commonly the method of choice.15 We had
therefore originally targeted the seco-acid 2 as a macrolactoniza-
tion substrate. Disconnection of 2 at C19ꢀC20 within a diene
moiety reveals two fragments 4 and 5, which could be joined by
an intermolecular Suzuki, Stille, or related coupling reaction. The
alternative reverse order of these late-stage steps were considered
whereby the ring closure would be accomplished by an intramo-
lecular coupling reaction of a richly functionalized organometallic
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Scheme 1
Scheme 2
Scheme 3
substrate 3. In turn, the precursor would be obtained by an
intermolecular esterification of the same two fragments 4 and 5
employed in the original strategy.12f Construction of the alkenyl
iodide fragment 4 was envisioned using two JuliaꢀKocienski
olefination reactions based upon 6, 7, and 8 as intermediates. The
first two of these fragments could be derived from the chiral pool
compounds, Roche ester (R)-methyl 2-methyl-3-hydroxypropio-
nate and L-malic acid, respectively, whereas the last of them could
be obtained by various enantioselective processes. The organo-
metallic component 5 could be derived from alkyne 9, which in
turn could be prepared by an enantioselective Marshall propar-
gylation reaction of aldehyde 10. We have previously reported
the synthesis of this final fragment through use of a Heck
coupling reaction.12a
The synthesis began with the C(1)ꢀC(5) subunit 6 based
upon use of the R-enantiomer of the Roche ester 11 as described
previously (Scheme 1).12a,b A sequence of alcohol protection,
DIBAL-H reduction, Wittig reaction, and alcohol deprotection
led to alcohol 13, which was purified by column chromatography
to give the pure E isomer in an overall yield of 68%. This alcohol
was converted into the desired sulfone 6 via a Mitsunobu reaction
with benzo[d]thiazole-2-thiol (BTSH) and molybdate-catalyzed
oxidation.
The synthesis of the C(6)ꢀC(11) subunit makes use of the
commercially available hydroxylactone 14 derived from malic
acid (Scheme 2).12b O-methylation provides methoxylactone 15.
Subsequent DIBAL-H reduction and Wittig reaction afford key
intermediate 17 with 10:1 E:Z-selectivity. Protection as the
TBDPS derivative, reduction with DIBAL-H, separation of the
E/Z mixture, and MnO2 oxidation provides enal 7 as the desired
C(6)ꢀC(11) subunit.
5Z analogues of the iejimalides. Further elaboration of 18 led to
the C(1)ꢀC(11) sulfone 19.
Construction of the C(12)ꢀC(19) subunit began with gen-
eration of the C(13)ꢀC(14) trisubstituted Z-alkene by a Wittig
reaction of the ylide generated from phosphonium salt 2017 and
the TBDPS-protected acetol 2118 (Scheme 4). Selective TBS
deprotection of 22 and oxidation with sulfur trioxide pyridine
3
afforded aldehyde 23. Although generation of the (17S)-stereo-
center could be accomplished through a one-step Carreira
enantioselective addition of TMS-acetylene to 23,19 the yield
was disappointingly low (ca. 40%), and isolation of pure product
from the complex reaction mixture was tedious. Consequently,
we turned our attention to an alternative three-step approach:
introduction of the alkynyl group through nonstereoselective
addition of TMS-acetylene to 23, PDC oxidation to give the
ketone 24, and subsequent enantioselective reduction with (S)-
Alpine borane. The resulting enantiomerically enriched pro-
pargylic alcohol (91% ee) was subjected to phase transfer-
catalyzed, one-pot O-methylation and alkynyl TMS removal20
to provide the terminal alkyne 25. Hydrozirconation-iodina-
tion,21 removal of the TBDPS group, and allylic alcohol oxidation
with TPAP/NMO22 gave the C(12)ꢀC(19) subunit 8 contain-
ing the trisubstituted unsaturated aldehyde and E-alkenyl iodide
moieties required for further coupling reactions.
With the first two subunits 6and 7inhand, wewerepositionedto
investigate their coupling by the JuliaꢀKocienski12f,16 olefination
en route to the C(1)ꢀC(11) subassembly (Scheme 3). We
explored the use of both the sulfonylbenzothiazole derivative
depicted as 6 and the corresponding 1-phenyltetrazole derivative
(not pictured), but under comparable conditions using either
LiHMDS or KHMDS as the base in THF, the former sulfone
outperformed the latter both in terms of yield and stereoselec-
tivity. Under the optimum conditions investigated, enal 7 under-
went condensation with 1.2 molar equiv of sulfone 6 treated with
1.4 molar equiv of LiHMDS in THF to give 18 in nearly
quantitative yield and with 25:1 E:Z selectivity. On the other
hand, in HMPA/THF,16e both sulfones exhibited an preference
for formation of the undesired Z alkene with a ratio of 7.7/1 in
48% yield for 6, which would in principle permit the synthesis of
With the two preceding major subunits available, we explored
the second JuliaꢀKocienski olefination between aldehyde 8 and
sulfone 19 (Scheme 5). This step proceeded smoothly under
conditions similar to those above to form the C(11)ꢀC(12)
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E-double bond and to afford the fully functionalized C(1)ꢀC(19)
segment as the alkenyl iodide-terminated ester 26.
generated the two 22S,23S chiral centers with good anti/syn
selectivity (5:1 dr). Selective cleavage of the alkynyl TMS group
by K2CO3 in MeOH gave the desired subunit 9.
Synthesis of the C(20)ꢀC(34) subunit was based upon use of
the aminodienoate ester 27, which we had previously obtained
through use of a Heck coupling.12a,23 DEPC-promoted
amidation24 with the O-TBS-protected N-formylserine deriva-
tive 2825 produced the amide 29 (Scheme 6). Reduction of the
ester with DIBAL-H followed by DessꢀMartin oxidation af-
forded the aldehyde 10. A diastereoselective Marshall propargy-
lation reaction26,12d,12e of an enantioenriched allenylindium
reagent derived from (R)-1-trimethylsilyl-1-butyn-3-yl mesylate
In an initial approach for joining the two major subassemblies,
we performed a saponification of the ester 26 followed by a
Yamaguchi esterification15 of the crude acid 4 and the alcohol 9
to give 31 in ca. 40% yield (Scheme 7). The 1H NMR and mass
spectra of the crude product indicated that all of the skeletal
atoms of the iejimalide system were joined in one overall
assembly. However, further use of this material was abandoned
due to a subsequent problem. In an attempt to prepare the
substrate for the desired intramolecular Stille coupling reaction,
we failed to obtain any of the desired alkenylstannane 3 by a
standard hydrostannylation procedure that we had employed in
our first-generation synthesis.12f Among the reaction products
suggested by a combination of NMR and ESI-MS studies of the
crude project mixture were the deiodination product 32 and the
bis(alkenylstannane) 33.
Scheme 4
This difficulty in functionalizing the intact skeleton prompted
a reverse order of key steps leading to the macrocyclization
precursor whereby the alkyne hydrometalation would precede
the esterification step. As there have been many elegant applica-
tions of the SuzukiꢀMiyaura coupling reaction under mild
conditions in very complex natural products syntheses,27 we
attempted to convert the unprotected homopropargyl alcohol 9
into an alkenylboron derivative 5a (Scheme 8). However, all of
our efforts at effecting this conversion were unsuccessful. Neither
uncatalyzed28 nor palladium- or platinum-catalyzed hydrobora-
tions29 were effective. Although we did not characterize the
resulting products, we concluded that the multiple functional
groups present in the substrate (two amides, one diene and a free
hydroxyl groups) interfered with the desired reaction. Consider-
ing that alkyne hydrostannylation is tolerant of many functional
groups, we altered our approach slightly to explore formation of
the corresponding alkenylstannane and its use in a ring-closing
Stille coupling.30 Evaluation of conditions revealed that Pd-
(dppf)Cl2 is a superior catalyst for conversion of 9 to alkenyl-
stannane 5b.
Scheme 5
With the final subunits now in hand, the end game of the
synthesis could be pursued (Scheme 9). As depicted in the
retrosynthetic analysis in Figure 2, the macrolide ring of iejima-
lide B could be constructed from 4 and 5b by employing the
esterification and Stille coupling steps (a and b, respectively) in
either order. In our previously reported synthesis, performing the
Scheme 6
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Scheme 7
Scheme 9
yield (ca. 20%). Optimization efforts based upon varying the
stoichiometry of the reactants led to progressively higher yields.
For example, the use of acid 4 and alcohol 5b in a 1:1 ratio along
with EDC (2 molar equiv), DMAP (2 molar equiv), and DMAP
3
HCl (2.1 molar equiv) gave ester 3 in ca. 60% yield. Finally, when
the ratio of 4 and 5b was changed to 1.3:1, the yield increased
quite satisfactorily to ca. 80%, which permitted procurement of
conveniently serviceable quantities of the final cyclization
candidate.
Scheme 8
The critical and potentially quite challenging intramolecular
Stille coupling reaction required careful consideration of condi-
tions to obtain good results. We systematically evaluated some of
the most often employed procedures, including the use of (CH3CN)2-
PdCl2,35 (Ph3P)4PdꢀCuCl,36 and Pd2(dba)3ꢀPh3AsꢀDIPEA37
catalytic systems. Of the conditions that we examined for our
substrate 3, Pd2(dba)3 CHCl3ꢀPh3AsꢀDIPEA proved to be
3
most effective. Optimization studies revealed that employing
Pd2(dba)3 CHCl3, Ph3As, and DIPEA in a ratio of 1:4:65 in
3
DMF (c = 7 ꢁ 10ꢀ4 M) at 23 °C for 48 h under argon gave
reproducibly quite good yields for this complex system in the
range of 60ꢀ80%, with 72% being typical. The synthesis was
completed by removal of the TBS protecting group through use
of TAS-F38 to give iejimalide B (1b) in 80% yield. The product
proved to be identical to an authentic sample39 by direct
Stille reaction first led to difficulties in the subsequent intramo-
lecular esterification whereby only a low to modest yield of the
macrolide was obtained. Therefore, in the presently reported
synthesis, we focused on the opposite order of these steps. As
shown above, the methyl ester 26 was saponified to give the free
acid 4 with which we attempted the esterification using 5b under
several conditions. However, the use the Yamaguchi conditions,
Mukaiyama’s salt,31 DCC-DMAP,32 EDC-DMAP, and EDC-
1
comparison by H NMR, 13C NMR, HPLC, optical rotation,
and activity in the MCF-7 breast cancer cell line.2b,4a
’ CONCLUSIONS
33
DMAP-Sc(OTf)3 failed in our hands. Promisingly, when we
The F€urstner laboratory and our laboratory had previously
succeeded in the synthesis of iejimalides. The practicality and
efficiency of our previous route was hampered by a very difficult
macrolactonization in the penultimate step. We have greatly
improved upon this earlier synthesis by accomplishing the
construction of the macrocycle by a Keck-type intermolecular
esterification of the two major subassemblies followed by a
remarkably efficient intramolecular Stille coupling reaction in a
complex, highly functionalized system. Iejimalide B is obtained
by means of a highly convergent strategy in an overall yield of
applied the Keck protocol employing DCC (1 molar equiv),
DMAP (cat.), and DMAP HCl (cat.),34 4 and 5b did undergo
3
the desired reaction, albeit in low yield and with formation of a
mixture from which the ester 3 was difficult to separate from the
dicyclohexylurea byproduct. As is well-known, the urea bypro-
duct from use of EDC is water-soluble, which facilitates the
isolation and purification of products. Accordingly, when we first
employed EDC (1 molar equiv), DMAP (cat.), and DMAP HCl
3
(cat.), the reaction was successful but again proceeded in low
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19.5% for the longest linear pathway of 15 steps from the
commercially available chiral lactone 14. The convergent frag-
ment strategy enables the practical incorporation of structural
analogues into the total synthesis. Other key features of this
synthesis include the use of two JuliaꢀKocienski olefinations of
complex substrates, a diastereoselective Marshall propargylation,
and the use of Pd(dppf)Cl2 as a superior catalyst for the
hydrostannylation of a richly functionalized alkyne. The effi-
ciency of this route provides us with the opportunity to obtain
sufficient quantities of iejimalide B itself and analogues for our
ongoing studies of activity and drug discovery efforts upon which
we will report in due course.
at ꢀ78 °C and stirred for another 30 min. When the reaction was
complete (monitored by TLC), it was quenched by the dropwise
addition of MeOH (20 mL). The reaction mixture was allowed to stir
at ꢀ78 °C for an additional 10 min and then transferred (cold) directly
into a 1 L Erlenmeyer flask that contained a vigorously stirred mixture of
Et2O (250 mL) and a satd aq solution of Rochelle’s salt (potassium
sodium tartrate) (250 mL). The resulting emulsion was stirred for 3 h, by
which time two layers formed. The mixture was filtered through Celite
using a Buchner funnel, and the filtrate was collected. The layers were
separated, and the aqueous phase was extracted with Et2O (3 ꢁ 75 mL).
The combined organic extracts were dried over anhyd Na2SO4, filtered,
and then concentrated under reduced pressure to afford the 3-OTBS-
protected aldehyde 12. All of this crude product was dissolved in toluene
(100 mL), and then methyl 2-(triphenylphosphoranylidene)propanoate
(7.79 g, 20.6 mmol, 1.2 equiv) was added in one portion under Ar. The
mixture was stirred at 70 °C for 8 h. The solvent was removed under
reduced pressure, and the residue was purified by flash column chro-
matography (SiO2), eluting with hexane/EtOAc = 20/1, to afford the
pure (4S,2E)-methyl 5-((tert-butyldimethylsilyl)oxy)-2,4-dimethyl-
pent-2-enoate (3.93 g, 84% for 2 steps, E/Z = 14/1) as a light yellow
oil: 1H NMR (300 MHz, CDCl3, 23 °C) δ = 6.55 (dd, J = 9.9, 1.2 Hz,
1 H), 3.73 (s, 3 H), 3.57ꢀ3.49 (m, 2 H), 2.76ꢀ2.62 (m, 1 H), 1.86 (d,
J = 1.2, 3 H), 1.01 (d, J = 7.1 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.02
(s, 3 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 168.9, 145.1, 127.9,
67.3, 51.9, 36.5, 26.1, 16.4, 12.9, ꢀ0.53 (lit.41 1H NMR).
’ EXPERIMENTAL SECTION
General Methods. Unless stated otherwise, all reagents and
solvents were used as received from commercial suppliers. Unless stated
otherwise, all reactions were conducted in dried, anhydrous solvents.
Triethylamine (Et3N) was distilled from CaH2 under an Ar atmosphere
and stored over CaH2. All moisture-sensitive reactions were performed
using dried solvent in flame-dried glassware under an atmosphere of Ar.
All low-temperature reactions were performed under an atmosphere of
Ar. Filtration was generally performed through a pad of Celite. TLC
analyses were performed on aluminum-backed F254 silica gel plates.
Flash chromatography was performed using silica gel (60 Å silica gel,
32ꢀ63 μm). NMR spectra were measured on a 300, 400, or 500 MHz
The previous product (3.81 g, 13.98 mmol) was dissolved in THF
(50 mL), to which TBAF (1.0 M in THF, 15.38 mL, 15.38 mmol) was
added dropwise. The reaction was stirred at 23 °C and monitored by
TLC. When the reaction was complete, solvent was removed under
reduced pressure, and the residue was purified by flash column chro-
matography (SiO2), eluting with gradient hexane/EtOAc = 10/1ꢀ1/1,
to afford pure (4S,2E)-methyl 5-hydroxy-2,4-dimethylpent-2-enoate
1
instrument. All H chemical shifts (δ) are relative to residual protic
solvent (CHCl3: δ 7.26 ppm), and all 13C chemical shifts (δ) are relative
to the solvent (CDCl3: δ 77.23 ppm). Mass spectral data were measured
with FAB or ESI positive ion mode. Infrared spectra were recorded on
FT-IR spectrophotometer as neat thin films between NaCl plates in the
case of liquid substances or as KBr pellets in the case of solids. Optical
rotations were determined using the sodium D line (589 nm). All HPLC
separations were performed using a C18 reversed-phase column.
Synthesis of the C(1)ꢀC(5) Subunit. (4S,2E)-Methyl 5-Hydro-
1
(1.78 g, 81%) as a clear colorless oil: H NMR (300 MHz, CDCl3,
23 °C) δ = 6.56 (d, J = 9.7 Hz, 1 H), 3.70 (s, 3 H), 3.59ꢀ3.42 (m, 2 H),
2.80ꢀ2.65 (m, 1 H), 2.12 (s, br, 1 H), 1.85 (s, 3 H), 0.99 (d, J = 6.9 Hz,
3 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 168.8, 144.6, 128.8, 67.2,
xy-2,4-dimethylpent-2-enoate (13). To
a
stirred solution of
51.9, 36.3, 16.2, 12.9; [R]2D3 = ꢀ9.1 (c = 0.22, CH2Cl2); (lit.12e 1
H
methyl-(R)-Roche ester 11 (10.7 g, 90.6 mmol), imidazole (9.2 g,
135.4 mmol, 1.5 equiv), and DMF (90 mL) in a 250 mL round-bottom
flask, at 0 °C was added TBSCl (20.4 g, 135.4 mmol, 1.5 equiv) in one
portion. The reaction mixture was warmed to 23 °C and stirred
overnight. To facilitate removal of excess TBSCl, anhyd methanol
(20 mL) was added to the reaction mixture, and the mixture was allowed
to stir for 30 min. The reaction was diluted with 20% EtOAc/hexanes
(500 mL) and water (500 mL), and the layers were separated. The
organic phase was washed with water (2 ꢁ 150 mL). The combined
aqueous layers were back-extracted with 20% EtOAc/hexanes
(250 mL). The organic extracts were combined, washed with brine
(200 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the material was accomplished
by flash column chromatography SiO2 column, eluting with 10%
EtOAc/hexanes. The product-containing fractions were combined and
then concentrated under reduced pressure to give (2R)-methyl 2-methyl-
3-(1,1,2,2-tetramethyl-1-silapropoxy)propanoate (21.0 g, quantitative)
as a clear, colorless oil: 1H NMR (300 MHz, CDCl3, 23 °C) δ = 3.77
(dd, J = 9.5, 7.1 Hz, 1 H), 3.67 (s, 3 H), 3.65 (dd, J = 9.5, 5.8 Hz, 1 H),
2.65 (tq, J = 7.1, 6.6 Hz, 1 H), 1.14 (d, J = 7.1 Hz, 3 H), 0.87 (s, 9 H), 0.03
NMR).
(4S,2E)-Methyl 5-(Benzo[d]thiazol-2-ylsulfonyl)-2,4-dimethylpent-
2-enoate (6). The primary alcohol 13 (4.14 g, 26.17 mmol), PPh3
(7.62 g, 29.05 mmol), and benzo[d]thiazole-2-thiol (4.86 g, 29.05
mmol) were dissolved in anhyd toluene (70 mL, Aldrich) in a water
bath at 23 °C. Diisopropyl azodicarboxylate (DIAD, 5.72 mL, 29.05
mmol) was slowly added dropwise to the above rapidly stirring solution.
After the mixture was stirred overnight at 23 °C, all solvent was removed
on a rotary evaporator and the crude material was purified by flash
column chromatography (SiO2), eluting with gradient hexane/EtOAc =
10/1ꢀ2/1, to afford the intermediate benzothiazole sulfide in quanti-
tative yield, which was used immediately for the oxidation. The product
was dissolved in 120 mL of MeOH and cooled to 0 °C. In a separate
flask, (NH4)6Mo7O24 4H2O (32.34 g, 26.17 mmol) and 30% aq H2O2
3
(53.4 mL, 20 equiv) were combined, cooled to 0 °C, and added dropwise
to the above MeOH solution. The reaction mixture was stirred for 11 h
at 0 °C, diluted with 120 mL H2O, and stirred vigorously for 30 min. The
mixture was then extracted with CH2Cl2 (3 ꢁ 200 mL). The combined
organic phases were dried over MgSO4, filtered, and concentrated under
vacuum. The remaining residue was purified by flash column chroma-
tography (SiO2), eluting with gradient hexane/EtOAc/DCM = 4/1/
0.5ꢀ2/1/0.5, to afford the sulfone 6 (8.8 g, 99% for two steps): 1H NMR
(300 MHz, CDCl3, 23 °C) δ = 8.20 (d, J = 7.8 1 H), 7.73 (d, J = 7.8 1 H),
7.67ꢀ7.55 (m, 2 H), 6.28 (dd, J = 10.2, 1.5 Hz, 1 H), 3.78 (dd, J = 14.7,
8.7 Hz, 1 H), 3.50 (dd, J = 14.7, 5.1 Hz, 1 H), 3.35 (s, 3 H), 3.35ꢀ3.27
(m, 1 H), 1.80 (d, J = 1.5 Hz, 3 H), 1.20 (d, J = 6.6 Hz, 3 H); 13C NMR
(75 MHz, CDCl3, 23 °C) δ = 167.7, 166.5, 152.8, 142.1, 136.9, 128.4,
(s, 3 H), 0.02 (s, 3 H); [R]2D3 = ꢀ15.6 (c = 0.4, CH2Cl2);(lit.40 1
H
NMR).
To a stirred solution of the preceding product (4.0 g, 17.2 mmol) and
hexane (150 mL) in a 500 mL round-bottom flask under an argon
atmosphere, at ꢀ78 °C, was added a 1.0 M solution of DIBAL (17.2 mL,
17.2 mmol, 1.0 equiv) in toluene dropwise via additional funnel into the
flask. After the addition was complete, the reaction mixture was kept
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128.2, 127.8, 125.5, 122.5, 60.1, 51.7, 29.2, 20.1, 12.6; IR υ~ = 1704, 1468,
1437, 1337, 1310, 1267, 1141, 763 cmꢀ1 [R]D23 = þ8.0 (c = 0.25,
CH2Cl2); HR-MS (ESI) m/z ([M þ Na]þ) calcd for C15H17NNaO4S2
362.0497, found 362.0488.
toluene, 2.82 mL, 14.6 mmol) was added dropwise over 30 min. The
resulting mixture was stirred for another 30 min at ꢀ78 °C and was
quenched by dropwise addition of saturated ethanolic tartaric acid
(3.2 mL) followed by a mixture of sodium sulfate and silica (1:1 v/v,
7 mL). The mixture was warmed to 0 °C, and 2.3 mL of H2O was added
dropwise. The mixture was then warmed slowly to 23 °C, and the slurry
was stirred vigorously for 8 h. The mixture was filtered, and the solids
were rinsed with excess ether. The filtrate was concentrated in vacuo to
yield the crude material, which was purified by flash chromatography
(Hex/EtOAc = 4/1ꢀ3/1) to provide (4S,2E)-6-((tert-butyldiphenyl-
silyl)oxy)-4-methoxy-2-methylhex-2-en-1-ol (0.85 g, 83%), which was
further purified by bulb to bulb distillation under vacuum to afford the
pure Eisomer: 1H NMR (300 MHz, CDCl3,23°C) δ=7.65ꢀ7.70 (m, 4 H),
7.26ꢀ7.43 (m, 6 H), 5.28ꢀ5.32 (m, 1 H), 4.24ꢀ4.27 (m, 1 H), 4.03 (s,
2 H), 3.67ꢀ3.80 (m, 2 H), 3.24 (s, 3 H), 1.82ꢀ1.89 (m, 1 H), 1.73 (s,
3 H), 1.61ꢀ1.70 (m, 1 H), 1.06 (s, 9 H); 13C NMR (75 MHz, CDCl3,
23 °C) δ = 139.1, 135.76, 135.73, 134.11, 134.04, 129.8, 127.8, 126.2,
73.9, 68.3, 60.3, 56.2, 38.6, 27.0, 19.4, 14.3; IR υ~ = 3430 (s, b), 3072, 2960,
2930, 2889, 2860, 1474, 1427, 1110, 823, 737, 704 cmꢀ1; [R]D23 = ꢀ10.5
(c = 0.8, CH2Cl2).
The previous product (380 mg, 0.953 mmol) was dissolved in anhyd
DCM (10 mL). Activated MnO2 (826 mg, 10 equiv) was added in
several portions. The reaction was stirred for 16 h and monitored by
TLC until the reaction was complete. The mixture was diluted with
DCM and filtered through Celite to afford a clear filtrate. Removal of the
solvent under reduced pressure gave the pure R,β-unsaturated aldehyde
7 (374 mg, 99%), which was used immediately for the following
JuliaꢀKocienski coupling, without further purification: 1H NMR
(300 MHz, CDCl3, 23 °C) δ = 9.45 (s, 1 H), 7.71ꢀ7.62 (m, 4 H),
7.48ꢀ7.35 (m, 6 H), 6.36 (dq, J = 9.5, 1.4 Hz, 1 H), 4.61ꢀ4.45 (m, 1 H),
3.91ꢀ3.82 (m, 1 H), 3.77ꢀ3.68 (m, 1 H), 3.32 (s, 3 H), 1.93ꢀ1.66 (m,
2 H), 1.83 (d, J = 1.5 Hz, 3 H), 1.11 (s, 9 H); 13C NMR (75 MHz,
CDCl3, 23 °C) δ = 195.0, 154.0, 140.6, 135.74, 135.69, 133.8, 129.9,
127.9, 74.4, 59.7, 57.3, 37.7, 27.0, 19.4, 9.8.
Synthesis of the C(6)ꢀC(11) Subunit. (2S)-3-Methoxydihy-
drofuran-2(3H)-one. The hydroxylactone 14 (2.4 g, 23.5 mmol) was
dissolved in anhyd acetonitrile (60 mL) under an argon atmosphere, and
methyl iodide (17.1 g, 120.47 mmol) was added. Silver(I) oxide (6.12 g,
26.41 mmol) was added, and the resulting mixture heated to reflux
(75 °C oil bath) in the absence of light (aluminum foil cover). After 12 h,
the mixture was filtered through Celite, and the filter rinsed with diethyl
ether (50 mL). The filtrate was concentrated in vacuo to afford a black
oil. Purification by flash column chromatography (SiO2, hexane/EtOAc =
3/1ꢀ1/1) provided 2.59 g (95%) of the (S)-3-methoxydihydrofuran-
2(3H)-one 15 as a light yellow oil: 1H NMR (300 MHz, CDCl3, 23 °C)
δ = 4.43ꢀ4.36 (m, 1 H), 4.26ꢀ4.18 (m, 1 H), 4.02 (t, J = 7.8 Hz, 1 H),
3.54 (s, 3 H), 2.56ꢀ2.46 (m, 1 H), 2.27ꢀ2.15 (m, 1 H) (lit.12b).
(4S,2E)-Methyl 6-hydroxy-4-methoxy-2-methylhex-2-enoate (17)12b
.
To a solution of the lactone 15 (4.06 g, 34.97 mmol) in anhyd diethyl
ether (160 mL) at ꢀ78 °C under argon gas was added diisobutylaluminum
hydride (1.0 M in hexane, 38.46 mL) via an addition funnel over 1 h. After
2 h, the reaction was quenched by careful dropwise addition of satd ethanolic
tartaric acid (18 mL) followed by a mixture of sodium sulfate and silica (1:1
v/v, 20 mL). The mixture was stirred at 0 °C, and 8.7 mL of H2O was added
dropwise. The mixture was then warmed to 23 °C slowly and stirred
vigorously for 8 h. The mixture was filtered, and the solids were rinsed with
excess ether. The filtrate was concentrated in vacuo to yield the lactol 16
(4.13 g, quantitative yield) as clear colorless oil, which was used without
further purification.
The lactol (6.48 g, 54.8 mmol) was dissolved in toluene (300 mL) to
which was added methyl 2-(triphenylphosphoranylidene)propanoate
(38.2 g, 109.7 mmol). The mixture was placed in an oil bath at 90 °C for
3 h under Ar. When the reaction was complete, as monitored by TLC,
the solvent was evaporated in vacuo to give a yellow oil, which was then
purified by flash column chromatography (SiO2, 30% EtOAc/hexane)
to provide (4S,2E)-methyl 6-hydroxy-4-methoxy-2-methylhex-2-enoate
17 in almost quantitative yield (∼10.2 g, 99%), with selectivity of E/Z =
10/1. The pure E isomer could not be obtained readily at this point by
silica gel chromatography: 1H NMR (300 MHz, CDCl3, 23 °C) δ = 6.65
(d, J = 9.3 Hz, 1 H), 4.15ꢀ4.32 (m, 2 H), 3.78 (m, 1 H), 3.77 (s, 3 H),
3.27 (s, 3 H), 2.50 (s, 1H, br, OH), 1.87 (d, J = 1.5 Hz, 3 H), 1.80ꢀ1.90
(m, 1 H), 1.65ꢀ1.75 (m, 1 H).
Completion of the C(1)ꢀC(11) Subunit12f. Sulfone 6 (369.2
mg, 1.088 mmol) and aldehyde 7 (359 mg, 0.905 mmol) were placed in a
flask and azeotropically dried three times with anhydrous benzene. The
mixture was further dried under high vacuum and placed under Ar.
Freshly dried THF (22 mL) was added to dissolve the above mixture,
which was cooled to ꢀ78 °C. LiHMDS (1.31 mL of an 1.0 M solution in
THF, 1.31 mmol) was added dropwise. The mixture was stirred
at ꢀ78 °C for another 30 min and then was warmed to 23 °C over
1.5 h. After being stirred for 30 min, the mixture was cooled to ꢀ78 °C
and was quenched by addition of 12 mL of satd aq NH4Cl. The solution
was warmed to 23 °C over 30 min. The mixture was then extracted with
ethyl acetate (3 ꢁ ), and the organic phases were combined, washed with
brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude
product was purified by flash silica gel chromatography (Hex/EA =
20/1) to afford pure compound 18 (456 mg, 97% with a selectivity of E/Z=
(4S,2E)-6-((tert-Butyldiphenylsilyl)oxy)-4-methoxy-2-methylhex-2-
enal (7). The alcohol 17 (54.86 mmol) was dissolved in 45 mL of
anhydrous DMF to which imidazole (8.68 g, 127.5 mmol) was added at
23 °C, and TBDPSCl (16.6 mL, 63.8 mmol) was added dropwise. The
mixture was stirred at 23 °C under Ar for 8 h. The mixture was diluted
with Et2O and washed successively with H2O (3 ꢁ 50 mL) and brine.
The aqueous solution was combined and back-extracted with Et2O (3 ꢁ
50 mL). The organic phases were combined and dried over MgSO4.
After filtration, the solvent was concentrated in vacuo, and the residue
was purified by flash column chromatography (SiO2) with gradient
eluting (hexane/EtOAc = 10/1ꢀ1/1), to provide the OTBDPS-pro-
tected intermediate (∼23.5 g, quantitative, as a 10/1 E/Z mixture): 1H
NMR (300 MHz, CDCl3, 23 °C) δ = 7.65ꢀ7.70 (m, 4 H), 7.35ꢀ7.46
(m, 6 H), 6.36 (dq, J = 9.5, 1.4 Hz, 1 H), 4.28ꢀ4.37 (m, 1 H), 3.85ꢀ3.79
(m, 1 H), 3.76 (s, 3 H), 3.76ꢀ3.68 (m, 1 H), 3.26 (s, 3 H), 1.93 (d, J = 1.5
Hz, 3 H), 1.93ꢀ1.65 (m, 2 H), 1.07 (s, 9 H); 13C NMR (75 MHz,
CDCl3, 23 °C) δ = 168.3, 142.7, 136.2, 135.73, 135.71, 133.9, 129.8,
127.9, 74.4, 59.9, 56.9, 52.1, 27.0, 37.9, 19.4, 13.1; IR υ~ = 3074, 3050,
1
25/1): H NMR (300 MHz, CDCl3, 23 °C) δ = 7.63ꢀ7.69 (m, 4 H),
7.36ꢀ7.43 (m, 6 H), 6.65 (dq, J = 9.6, 1.4 Hz, 1 H), 6.10 (d, J = 15.6 Hz, E
H6), 5.81(d, J= 11.7 Hz, ZH, H6), 5.59 (dd, J = 15.9, 6.9 Hz, 1 H), 5.28 (d,
J = 9.3 Hz, E H, H8), 5.19 (d, J = 8.7 Hz, Z H, H8), 4.26- 4.37 (m, 1 H, H9),
3.73 (s, 3 H), 3.64ꢀ3.86 (m, 2 H), 3.22ꢀ3.32 (m, 1 H), 3.23 (s, 3 H), 1.90
(d, J = 1.2 Hz, 3 H), 1.82 (d, J = 0.9 Hz, 3 H), 1.88ꢀ1.78 (m, 1 H),
1.71ꢀ1.60 (m, 1 H), 1.18 (d, J = 6.9 Hz, 3 H), 1.07 (s, 9 H); 13C NMR (75
MHz, CDCl3, 23 °C) δ = 168.9, 145.4, 136.5, 135.73, 135.68, 134.06,
133.99, 133.7, 132.3, 131.3, 129.72, 129.71, 127.8, 126.5, 74.2, 60.3, 56.2,
52.0, 38.7, 36.5, 27.0, 20.5, 19.4, 13.1, 12.7; IR υ~ = 3075, 3050, 2960, 2934,
2901, 2862, 1715, 1429, 1392, 1265, 1192, 1112, 824, 747, 704 cmꢀ1
;
2952, 2929, 2893, 2860, 1764, 1429, 1261, 1110, 737, 704 cmꢀ1; [R]D23
þ6.7 (c = 0.6, CH2Cl2).
=
[R]2D3 = ꢀ8.3 (c = 0.24, CH2Cl2); HR-MS (ESI) m/z ([M þ Na]þ) calcd
for C32H44NaO4Si 543.2901, found 543.2908.
A solution of the previous product (1.1 g, 2.56 mmol) in toluene
C(1)ꢀC(11) Sulfone (19). Compound 18 (456 mg, 0.876 mmol) was
dissolved in MeOH (8.8 mL) to which NH4F (648 mg, 17.5 mmol,
(20 mL) was cooled to ꢀ78 °C under Ar, to which DIBAL (1.0 M in
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20 equiv) was added. The mixture was stirred for 24 h at 23 °C and
monitored by TLC. The reaction was quenched with satd aq NaHCO3
and extracted with CH2Cl2 (3 ꢁ ). The organic phases were combined,
washed with brine, dried over Na2SO4, filtered, and evaporated to
dryness. The crude product was purified by flash silica gel chromatog-
raphy (SiO2, hexane/EtOAc = 5/1 ꢀ 2/1) to afford alcohol inter-
mediate (247 mg, quantitative): 1H NMR (300 MHz, CDCl3, 23 °C)
δ = 6.57 (dq, J = 9.9, 1.5 Hz, 1 H), 6.06 (d, J = 15.9 Hz, E H, H6), 5.78 (d,
J = 11.1 Hz, Z H, H6), 5.55 (dd, J = 15.6, 6.9 Hz, 1 H), 5.26 (d, J = 9.0 Hz,
E H, H8), 4.19- 4.26 (m, 1 H), 3.70 (s, 3H), 3.62ꢀ3.77 (m, 2 H),
3.18ꢀ3.32 (m, 1 H), 3.21 (s, 3 H), 2.78 (s, br 1 H, OH), 1.84 (d, J = 1.2
Hz, 3 H), 1.75 (d, J = 0.9 Hz, 3 H), 1.74ꢀ1.86 (m, 1 H), 1.59ꢀ1.69 (m,
1 H), 1.12 (d, J = 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3, 23 °C)
δ = 168.9, 145.2, 136.6, 133.4, 131.7, 131.3, 126.5, 77.1, 60.8, 56.2,
51.9, 37.8, 36.4, 20.4, 13.0, 12.6; IR υ~ = 3450 (s, b), 2952, 2933, 1725,
1443, 1380, 1268, 1196, 1100 cmꢀ1; [R]D23 = þ14.4 (c = 0.18, CH2Cl2);
HR-MS (ESIþ) m/z ([M þ Na]þ) calcd for C16H26NaO4 305.1723,
found 305.1708.
(ꢀ78 °C) solution of 1-O-TBDPS-propane-2-one 21 (3.45 g, 11.0 mmol)
in THF (75 mL) was added through a cannula. After being stirred for 8 h at
ꢀ78 °C, the mixture was warmed to 23 °C and stirred for 8 h. During that
time, a large amount of pale-white solid separated. The reaction was
quenched with satd aq NH4Cl at 0 °C and stirred vigorously for 30 min.
The solid was filtered off through Celite and washed thoroughly with Et2O.
The organic phase was separated, and the aq phase was extracted with Et2O
(3 ꢁ ). The combined organic phase was washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by flash
chromatography (SiO2, hexane/EtOAc = 50/1ꢀ30/1) to provide the
desired olefinic product 22 as a nearly colorless oil (4.04 g, E/Z = 1/12.5,
1
80% yield based on BuLi), which was used directly for the next step: H
NMR (300 MHz, CDCl3, 23°C) δ=7.67ꢀ7.73 (m, 4 H), 7.37ꢀ7.46 (m, 6
H), 5.22 (t, J = 7.2 Hz, 1 H), 4.21 (s, 2 H), 3.52 (t, J = 6.3 Hz, 1 H), 1.90 (q,
J = 7.2 Hz, 2 H), 1.85 (s, 3 H), 1.42ꢀ1.52 (m, 2 H), 1.07 (s, 9 H), 0.87 (s, 9
H), 0.02 (s, 6 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 135.8, 134.9,
134.1, 129.7, 127.8, 126.4, 62.9, 62.7, 33.3, 27.0, 26.2, 24.0, 21.4, 19.5, 18.5,
ꢀ5.1; IR υ~ = 3074, 2960, 2929, 2891, 2856, 1474, 1433, 1257, 1108, 837,
781, 739, 700 cmꢀ1; HR-MS (ESIþ) m/z ([M þ Na]þ) calcd for
C29H46NaO2Si2 505.2929, found 505.2909.
The previous product (247 mg, 0.876 mmol), PPh3 (255 mg, 0.972
mmol), and benzo[d]thiazole-2-thiol (163 mg, 0.972 mmol) were
dissolved in anhyd toluene (8 mL). To the above solution was added
DIAD (192 μL, 0.972 mmol) dropwise. After the mixture was vigorously
stirred for 8 h at 23 °C, solvent was removed on a rotary evaporator. The
crude material was purified by flash silica gel chromatography (SiO2,
hexane/EtOAc = 20/1ꢀ15/1) to afford the benzothiazole sulfide (359
mg, 95%): 1H NMR (300 MHz, CDCl3, 23 °C) δ = 7.82ꢀ7.88 (m, 1 H),
7.71ꢀ7.76 (m, 1 H), 7.36ꢀ7.44 (m, 1 H), 7.25ꢀ7.31 (m, 1 H), 6.60 (dd,
J = 9.9, 1.2 Hz, 1 H), 6.07 (d, J = 15.9 Hz, 1 H), 5.57 (dd, J = 15.9, 6.9 Hz,
1 H), 5.30 (d, J = 8.1 Hz, 1 H), 4.17ꢀ4.25 (m, 1 H), 3.73 (s, 3 H),
3.36ꢀ3.44 (m, 2 H), 3.20ꢀ3.33 (m, 1 H), 3.26 (s, 3 H), 2.04ꢀ2.16 (m,
1 H), 1.90ꢀ2.01 (m, 1 H), 1.86 (d, J = 1.5 Hz, 3 H), 1.78 (d, J = 0.6 Hz,
3 H), 1.15 (d, J = 6.9 Hz, 3 H); IR υ~ = 2928, 1715, 1466, 1433, 1270,
1241, 1098, 998, 751 cmꢀ1; [R]D23 = ꢀ16.7 (c = 0.12, CH2Cl2).
The material (239 mg, 0.554 mmol) from the previous reaction was
dissolved in MeOH (3.6 mL) and cooled to 0 °C. In a separate flask,
(4Z)-6-((tert-Butyldiphenylsilyl)oxy)-5-methylhex-4-enal (23). The
olefinic product 22 (1.7 g, 3.52 mmol) was dissolved in 40 mL of
absolute EtOH, and pyridinium p-toluenesulfonate (180 mg, 0.72
mmol) was added in one portion. After being stirred for 24 h at
23 °C, the mixture was concentrated under vacuum, and the remaining
residue was purified by a flash chromatography column (SiO2, gradient:
hexane/EA = 10/1ꢀ5/1) to provide the TBS selectively deprotected
alcohol as a colorless oil (1.23 g, 95%), which was used directly for the
following oxidation: 1H NMR (300 MHz, CDCl3, 23 °C) δ = 7.68ꢀ7.73
(m, 4 H), 7.37ꢀ7.45 (m, 6 H), 5.25 (tq, J = 7.5, 0.9 Hz, 1 H), 4.20 (s, 2 H),
3.54 (t, J = 6.3 Hz, 1 H), 1.92 (q, J = 7.5 Hz, 2 H), 1.82 (d, J = 1.2 Hz, 3
H), 1.47ꢀ1.56 (m, 2 H), 1.07 (s, 9 H); 13C NMR (75 MHz, CDCl3,
23 °C) δ = 135.8, 135.2, 133.9, 129.8, 127.8, 126.4, 62.7, 62.3, 32.7, 27.0,
23.9, 21.5, 19.4; IR υ~ = 2931, 2857, 1722, 1471, 1112, 832, 701 cmꢀ1
;
HR-MS (ESIþ) m/z ([M þ Na]þ) calcd for C23H32NaO2Si 391.2064,
(NH4)6Mo7O24 4H2O (178.2 mg, 0.144 mmol) and 30% aq H2O2
found 391.2040.
3
(1.47 mL, 25 equiv) were combined, cooled to 0 °C, and added dropwise
to the above MeOH solution. The reaction mixture was warmed to 0 °C
slowly and stirred vigorously for 8 h. When the reaction was complete,
monitored by TLC, the mixture was diluted with 8 mL of H2O, stirred
vigorously for 30 min and extracted with CH2Cl2 (3 ꢁ 20 mL). The
combined organic phases were dried over MgSO4, filtered, and evapo-
rated under vacuum. The remaining residue was purified by flash column
chromatography (SiO2), eluting with gradient hexane/EtOAc = 5/1ꢀ4/
The previously prepared alcohol (1.0 g, 2.7 mmol) was dissolved in
DMSO (8 mL) to which NEt3 (2.4 mL) was added. The mixture was
placed in a water bath, and a solution of SO3 Py (1.30 g, 8.2 mmol) in
3
DMSO (4 mL) was added dropwise. After being stirred for 20 min at
23 °C, the reaction was quenched by addition of iceꢀwater and
extracted with Et2O. The organic phase was washed with water and
brine, dried (MgSO4), filtered, and concentrated to dryness. The
remaining residue was purified by flash chromatography (SiO2, hex-
ane/EtOAc = 30/1) to provide the desired aldehyde 23 as a colorless oil
(890 mg, 90%, E/Z = 1/12.5): 1H NMR (300 MHz, CDCl3, 23 °C) δ =
9.66 (t, J = 1.8 Hz, 1 H), 7.68ꢀ7.74 (m, 4 H), 7.37ꢀ7.47 (m, 6 H), 5.45
(t, J = 6.9 Hz, 1 H, E = minor), 5.16 (tq, J = 7.2, 1.2 Hz, 1 H, Z = major),
4.22 (s, 2 H, Z = major), 4.07 (s, 2 H, E = minor), 2.32 (td, J = 7.3, 1.0 Hz,
2 H), 2.14 (app. q, J = 6.9 Hz, 2 H), 1.85 (d, J = 1.2 Hz, 3 H), 1.08
(s, 9 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 202.3, 136.4, 135.8,
135.7, 133.9, 129.8, 127.9, 127.8, 124.2, 62.7, 44.1, 27.0, 21.4, 20.4, 19.5;
IR υ~ = 2931, 2857, 1722, 1471, 1112, 832, 701 cmꢀ1; HR-MS (ESI) m/z
([M þ Na]þ) calcd for C23H30NaO2Si 389.1907, found 389.1898.
(Z)-8-((tert-Butyldiphenylsilyl)oxy)-7-methyl-1-(trimethylsilyl)oct-
6-en-1-yn-3-one (24). A solution of trimethylsilylacetylene (873 μL,
6.17 mmol) in THF (13 mL) was cooled to 0 °C under Ar, and n-BuLi
(2.6 mL of a 1.6 M solution in THF, 4.1 mmol) was added dropwise.
After the solution was stirred for 30 min at 0 °C, the aldehyde 23
(505 mg, 1.38 mmol) in THF (15 mL) was added dropwise. The
mixture was stirred for 4.5 h and monitored by TLC. When the reaction
was complete, it was quenched by addition of satd aq NH4Cl and stirred
for 30 min. The mixture was extracted with ethyl acetate (3ꢁ), washed
with brine, dried over MgSO4, filtered, and concentrated under vacuum.
1
1, to afford the sulfone 19 (∼260 mg, quantitative): H NMR (500
MHz, CDCl3, 23 °C) δ = 8.20 (ddd, J = 8.2, 1.3, 0.7 Hz, 1 H), 8.00 (ddd,
J = 7.9, 1.4, 0.7 Hz, 1 H), 7.50ꢀ7.63 (m, 2 H), 6.58 (dq, J = 9.8, 1.4 Hz,
1 H), 6.01 (d, J = 15.8 Hz, 1 H), 5.58 (dd, J = 15.6, 6.7 Hz, 1 H), 5.18 (d,
J = 8.9 Hz, 1 H), 4.08ꢀ4.16 (m, 1 H), 3.72 (s, 3 H), 3.55ꢀ3.63 (m, 2 H),
3.19ꢀ3.26 (m, 1 H), 3.15 (s, 3 H), 1.97ꢀ2.07 (m, 2 H), 1.85 (d, J = 1.5
Hz, 3 H), 1.75 (d, J = 1.2 Hz, 3 H), 1.13 (d, J = 6.8 Hz, 3 H); 13C NMR
(75 MHz, CDCl3, 23 °C) δ = 168.9, 165.8, 152.9, 145.0, 137.9, 136.9,
133.1, 132.4, 129.9, 128.2, 127.8, 126.7, 125.6, 122.5, 75.0, 56.2, 52.0,
51.4, 36.4, 28.5, 20.4, 13.2, 12.7; IR υ~ = 2928, 1712, 1473, 1330, 1151,
1093, 763 cmꢀ1; [R]D23 = ꢀ30.3 (c = 0.55, CHCl3); HR-MS (FABþ)
m/z ([M ꢀ CH3O]þ) calcd for C22H26NO4S2 432.1303, found
432.1307 (lit.12f 1H NMR).
Synthesis of the C(12)ꢀC(19) Subunit. (2Z)-1-((tert-Butyl-
diphenylsilyl)oxy)-6-((tert-butyldimethyl)silyloxy)-2-methylhexene (22)12f
.
4-O-TBS-butyltriphenylphosphonium iodide 2017a,b (6.34 g, 11.0 mmol)
was added to a 250-mL flask and dried under high vacuum for 1 h. After
freshly dried THF (45 mL) was added under Ar, n-BuLi (4.4 mL of a 2.4 M
solution in THF, 10.5 mmol) was added dropwise. After being stirred for 1 h
at 23 °C, the deep-red suspension was cooled to ꢀ78 °C, and a precooled
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FEATURED ARTICLE
The remaining residue was purified by flash chromatography (SiO2)
using hexane/EtOAc = 30/1 to elute the less polar impurities and
hexane/EtOAc = 20/1 to afford the pure product as a colorless oil (641
mg, quantitative), which was used directly for the next step: 1H NMR
(300 MHz, CDCl3, 23 °C) δ = 7.71ꢀ7.74 (m, 4 H), 7.41- 7.46 (m, 6 H),
5.22 (t, J = 7.5 Hz, 1 H, Z = major), 4.25 (dd, J = 12.0, 5.4 Hz, 3 H),
1.96ꢀ2.03 (m, 3 H), 1.85 (s, 3 H), 1.66 (qd, J = 6.9, 3 Hz 2 H), 1.09 (s, 9
H), 0.15 (s, 9 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 135.81,
135.79, 135.72, 133.94, 133.91, 129.8, 127.8, 125.5, 106.9, 89.4, 62.7,
62.2, 37.9, 27.0, 23.4, 21.4, 19.5, 0.05; IR υ~ = 3400, 3071, 2959, 2857,
2171, 1472, 1428, 1250, 1112, 1071, 843, 702, 615 cmꢀ1; HR-MS (ESI)
m/z ([M þ Na]þ) calcd for C28H40NaO2Si2 487.2459, found 487.2463.
The previously prepared racemic C(12)ꢀC(19) propargylic alcohol
(641 mg, 1.38 mmol) was dissolved in dry CH2Cl2 (50 mL) to which
freshly dried molecular sieves (4 Å, 700 mg) were added. After the
mixture was stirred for 15 min at 23 °C under Ar, pyridinium dichromate
(PDC, 1.09 g, 2.89 mmol) was added, and the mixture was stirred for 8 h.
After being filtered through a short neutral aluminum oxide column with
Celite on the top and washed with CH2Cl2, the filtrate was concentrated
under vacuum. The remaining residue was purified by flash chromatog-
raphy (SiO2), eluting with hexane/EtOAc = 50/1 to afford the pure
product 24 as a colorless oil (549 mg, 86% for two steps, E/Z = 1/12.5):
1H NMR (300 MHz, CDCl3, 23 °C) δ = 7.65ꢀ7.72 (m, 4 H),
7.35ꢀ7.48 (m, 6 H), 5.13 (tq, J = 7.2, 1.2 Hz, 1 H, Z = major), 4.19
(s, 2 H, Z = major), 4.03 (s, 2 H, E = minor), 2.60 (t, 2 H, J = 7.5 Hz, E =
minor), 2.47 (t, 2 H, J = 7.8 Hz, Z = major), 2.15 (app q, 2 H, J = 7.5 Hz),
1.81 (d, J = 1.2 Hz, 3 H), 1.05 (s, 9 H), 0.21 (s, 9 H); 13C NMR (75 MHz,
CDCl3, 23 °C) δ = 187.2, 136.3, 135.8, 133.9, 129.8, 127.9, 124.1, 102.1,
97.9, 62.6, 45.6, 27.0, 22.3, 21.4, 19.5, ꢀ0.6; IR υ~ = 2969, 2151, 1683,
1428, 1253, 1112, 847, 702 cmꢀ1; HR-MS (ESI) m/z ([M þ Na]þ)
calcd for C28H38NaO2Si2 485.2303, found 485.2310.
(3S,6Z)-8-((tert-Butyldiphenylsilyl)oxy)-7-methyl-3-methoxy-oct-6-
en-1-yne (25). The alkynyl ketone 24 (2.36 g, 5.10 mmol) was
azeotropically dried two times with anhyd toluene, further dried under
high vacuum for another 15 min, and placed under Ar. After the ketone
was cooled to 0 °C, (S)-Alpine borane (21 mL of 0.5 M solution in THF,
10.5 mmol) was added, and most of the solvent was removed immedi-
ately under vacuum to ensure that the reaction was performed at high
concentration. The oily mixture was stirred at 23 °C for 8 h, diluted with
Et2O, and cooled to 0 °C, and acetaldehyde (8.8 mL) was added drop-
wise followed by ethanolamine (8.8 mL) while gas was evolved vigor-
ously. The mixture was stirred for 30 min and was washed successively
with water and brine. The aq phases were combined and back extracted
with Et2O (2ꢁ). The organic phases were combined, washed with
brine, dried (MgSO4), filtered, and concentrated. The remaining
residue was purified by flash chromatography (SiO2, eluting with
hexane/EtOAc = 20/1) to afford the pure product as a colorless oil
(2.37 g, quantitative): 1H NMR (300 MHz, CDCl3, 23 °C) δ =
7.71ꢀ7.74 (m, 4 H), 7.41- 7.46 (m, 6 H), 5.22 (t, J = 7.5 Hz, 1 H, Z =
major), 4.25 (dd, J = 12.0, 5.4 Hz, 3 H), 1.96ꢀ2.03 (m, 3 H), 1.85 (s,
3 H), 1.66 (qd, J = 6.9, 3 Hz 2 H), 1.09 (s, 9 H), 0.15 (s, 9 H); 13C NMR
(75 MHz, CDCl3, 23 °C) δ = 135.81, 135.79, 135.72, 133.94, 133.91,
129.8, 127.8, 125.5, 106.9, 89.4, 62.7, 62.2, 37.9, 27.0, 23.4, 21.4, 19.5,
0.05; IR υ~ = 3400, 3071, 2959, 2857, 2171, 1472, 1428, 1250, 1112,
1071, 843, 702, 615 cmꢀ1; [R]D23 = þ10.5 (c = 0.37, CH2Cl2); HR-MS
(ESI) m/z ([M þ Na]þ) calcd for C28H40NaO2Si2 487.2459, found
487.2446 (lit.12f 1H NMR).
vigorous stirring for 10 min. The resulting mixture was poured into ice
water and partitioned with Et2O. The organic phase was separated, and
the aq phase was extracted with Et2O (3ꢁ). The combined organic
phases were washed successively with water and brine, dried over
MgSO4, filtered, and concentrated under vacuum. The remaining resi-
due was purified by flash chromatography (SiO2, eluting with hexane/
EtOAc = 30/1) to afford the desired product 25 as a clear colorless oil
(1.99 g, 96% for two steps E/Z = 1/13.6): 1H NMR (300 MHz, CDCl3,
23 °C) δ = 7.67ꢀ7.76 (m, 4 H), 7.36ꢀ7.49 (m, 6 H), 5.43 (t, J = 7.9 Hz,
1 H, E = minor), 5.17 (tq, J = 7.5, 1.2 Hz, 1 H, Z = major), 4.20 (s, 2 H,
Z = major), 4.05 (s, 2 H, E = minor), 3.80 (dt, J = 6.9, 2.1 Hz, 1 H), 3.33
(s, 3 H), 2.32 (d, J = 1.8 Hz, 1 H), 1.99 (app. q, J = 7.5, 2 H), 1.83 (d, J =
0.9 Hz, 3 H), 1.60ꢀ1.72 (m, 2 H), 1.05 (s, 9 H); 13C NMR (75 MHz,
CDCl3, 23 °C) δ = 135.79, 135.72, 134.0, 129.7, 127.8, 125.3, 82.6, 74.0,
70.4, 62.7, 56.5, 35.8, 27.0, 23.4, 21.4, 19.5; IR υ~ = 3303, 3071, 3048, 2955,
2930, 2857, 2113, 1472, 1428, 1255, 1112, 836, 701 cmꢀ1; [R]D23 = ꢀ7.7
(c = 0.78, CH2Cl2); HR-MS (ESI) m/z ([M þ Na]þ) calcd for
C26H34NaO2Si 429.2220, found 429.2210.
(S,2Z,7E)-8-Iodo-6-methoxy-2-methylocta-2,7-dienal (8). The
alkyne 25 (260 mg, 0.64 mmol) was dissolved in freshly dried THF
(6 mL) at 23 °C, to which solid Cp2ZrHCl (174 mg, 0.672 mmol, 1.1
equiv) was added followed by N-iodosuccinimide (158 mg, 0.704 mmol,
1.1 equiv) 30 min later. After being stirred for 1 h at 23 °C, the mixture
was diluted with Et2O and EtOAc. The organic phase was separated and
washed successively with satd aq NaHCO3 and brine. After the organic
phase was dried over MgSO4 and filtered, the solvent was concentrated
under vacuum, and the remaining residue was purified by flash chro-
matography (SiO2, eluting with hexane/EtOAc = 15/1) to provide the
desired TBDPS-protected vinyl iodide as a colorless oil (342 mg,
1
quantitative): H NMR (300 MHz, CDCl3, 23 °C) δ = 7.68ꢀ7.72
(m, 4 H), 7.36ꢀ7.48 (m, 6 H), 6.31 (dd, J = 14.6, 7.3 Hz, 1 H), 6.20 (d,
J = 14.6 Hz, 1 H), 5.10ꢀ5.20 (m, 1 H), 4.18 (s, 2 H), 3.32ꢀ41(m, 1 H),
3.19 (s, 3 H), 1.91ꢀ1.82 (m, 2 H), 1.85 (s, 3 H), 1.32ꢀ1.61 (m, 2 H),
1.06 (s, 9 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 146.8, 135.9,
135.6, 134.06, 134.04, 129.8, 127.9, 125.7, 83.4, 78.2, 62.7, 56.7, 35.0,
27.0, 23.3, 21.4, 19.5; IR υ~ = 3070, 3048, 2959, 2931, 2892, 2856, 1604,
1471, 1458, 1428, 1389, 1263, 1170, 1110, 949 cmꢀ1; [R]D23 = þ17.3 (c =
0.15, CH2Cl2); HR-MS (ESI) m/z ([M þ Na]þ) calcd for C26H35I-
NaO2Si 557.1343, found 557.1356.
The previously prepared TBDPS-protected vinyl iodide (342 mg,
0.64 mmol) was dissolved in THF (7.0 mL), and 1.0 M TBAF/THF
(1.28 mL, 1.28 mmol, 2 equiv) was added dropwise at 23 °C. After 6 h,
TLC indicated that conversion was complete, the mixture was concen-
trated on a rotary evaporator, and the remaining oil was purified by flash
chromatography (SiO2, gradient: hexane/EtOAc = 6/1ꢀ3/1) to pro-
vide the desired allylic alcohol as a colorless oil (162 mg, 85% for two
steps): 1H NMR (300 MHz, CDCl3, 23 °C) δ = 6.38 (dd, J = 12.3, 6.5
Hz, 1 H), 6.29 (d, J = 12.3 Hz, 1 H), 5.19ꢀ5.30 (m, 1 H), 4.09 (s, 2 H),
3.46ꢀ3.57 (m, 1 H), 3.25 (s, 3 H), 2.05ꢀ2.19 (m, 2 H), 1.79 (s, 3 H),
1.45ꢀ1.71 (m, 3 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 146.7,
135.5, 127.4, 83.1, 78.6, 61.6, 56.6, 34.8, 23.3, 21.6; IR υ~ = 3384 (s, br),
2969, 2929, 2859, 1604, 1449, 1171, 1102, 1006, 948 cmꢀ1; [R]D23
=
ꢀ10.0 (c = 0.3, CH2Cl2); HR-MS (ESI) m/z ([M þ Na]þ) calcd for
C10H17INaO2 319.0165, found 319.0157.
The above allylic alcohol (130 mg, 0.44 mmol) was dissolved in
CH2Cl2 (7 mL), to which freshly flame-dried molecular sieves (4 Å)
were added followed by N-methylmorpholine N-oxide (NMO) (78 mg,
0.67 mmol). Ten minutes later, tetrapropylammonium perruthenate
(TPAP) (7.8 mg, 0.022 mmol) was added, and the mixture was stirred
for 11 h at 23 °C under Ar. The mixture was diluted with CH2Cl2 and
washed with satd aq Na2SO3 containing some brine. After separation,
the aqueous phase was back-extracted with CH2Cl2 (2ꢁ). The com-
bined organic phases were dried (MgSO4), filtered, and carefully
concentrated. Purification by flash chromatography (SiO2, eluting with
The previously prepared propargylic alcohol (2.37 g, 5.10 mmol) was
dissolved in 22 mL of PhMe (4 mL) and cooled to 0 °C, to which was
added NaOH (22 mL, 50 wt % aq) followed by addition of tetrabuty-
lammonium hydrogen sulfate (620 mg, 1.83 mmol) and dimethyl sulfate
(3.9 mL, 41.1 mmol). The resulting two-phase mixture was stirred for
5 min at 0 °C and warmed to 23 °C. After being stirred for 3 h, the
reaction was quenched by addition of MeOH (12 mL), followed by
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hexane/EtOAc = 4/1) provided the fully functionalized aldehyde 8
containing the terminal vinyl iodide (ca. 129 mg) as a colorless oil in
quantitative yield. This product was used immediately for the following
Julia-Kocienski coupling reaction: 1H NMR (300 MHz, CDCl3, 23 °C)
δ = 10.12 (s, 1 H, Z), 6.46 (tq, J = 7.8, 1.2 Hz, 1 H), 6.41 (dd, J = 14.4, 6.6
Hz, 1 H), 6.32 (d, J = 14.4 Hz, 1 H), 3.49ꢀ3.56 (m, 1 H), 3.25 (s, 3 H),
2.52ꢀ2.77 (m, 2 H), 1.76 (q, J = 1.2 Hz, 3 H), 1.57ꢀ1.75 (m, 2 H); 13C
NMR (75 MHz, CDCl3, 23 °C) δ = 191.3, 148.3, 146.2, 136.8, 82.8,
79.0, 56.8, 34.6, 22.6, 16.8; IR υ~ = 3048, 2924, 2850, 1677, 1604, 1447,
1351, 1253, 1170, 1103, 950 cmꢀ1; [R]D23 = þ11.0 (c = 0.23, CH2Cl2);
HRMS (FAB) m/z ([M þ H]þ) calcd for C10H16IO2 295.0195, found
295.0188.
(15 mL) was cooled to ꢀ78 °C, and DIBAL-H (4.74 mL, 1.0 M in
hexanes, 4.74 mmol, 3.0 equiv) was added dropwise. After 3 h, another
portion of DIBAL-H (1.5 mL, 1.0 M in hexanes) was added dropwise to
ensure complete reaction as monitored by TLC. After being stirred for
another 3 h, the reaction was quenched at ꢀ78 °C by addition of MeOH
(30 mL), and the cooling bath was removed 10 min later. Saturated
aqueous Rochelle’s salt solution (50 mL) was added dropwise once the
mixture warmed to 0 °C. After being vigorously stirred over 10 h at
23 °C, the mixture was extracted with CH2Cl2 (4ꢁ). The combined
organic phases were dried over MgSO4, filtered, and concentrated under
reduced pressure. The remaining crude material was purified by flash
chromatography (SiO2, gradient: MeOH/CH2Cl2 = 1/100ꢀ3/100) to
provide the intermediate allylic alcohol (585 mg, quantitative): 1H NMR
(300 MHz, CDCl3, 23 °C) δ = 8.15 (s, 1 H), 7.04 (d, J = 7.2 Hz, 1 H),
6.89 (t, J = 5.7 Hz, 1 H), 6.18 (d, J = 11.1 Hz, 1 H), 6.08 (d, J = 11.1 Hz,
1 H), 4.46ꢀ4.52 (m, 1 H), 4.02 (s, 2 H), 3.96 (dd, J = 9.9, 4.2 Hz, 1 H),
3.83 (br, d, J = 4.8 Hz, 2 H), 3.62 (dd, J = 9.6, 7.8 Hz, 1 H), 2.69 (br, s,
1 H), 1.70 (s, 3 H), 1.69 (s, 3 H), 0.83 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3
H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 169.9, 161.5, 137.7, 133.3,
122.3, 119.9, 68.4, 62.9, 53.2, 47.5, 25.9, 18.2, 15.0, 14.2, ꢀ5.4, ꢀ5.5.
The previously prepared intermediate alcohol (354 mg, 0.96 mmol)
was dissolved in CH2Cl2 (10 mL) and cooled to 0 °C. DessꢀMartin
periodinane (486 mg, 1.15 mmol, 1.2 equiv) was added in one portion.
After being stirred for 15 min at 0 °C, the mixture was warmed to 23 °C
and stirred for 45 min. The reaction was quenched by addition of a basic
aq Na2S2O3 solution, and the resulting mixture was vigorously stirred for
15 min. After being extracted with CH2Cl2 (3ꢁ), the organic phases
were washed successively with water and brine, dried overNa2SO4,
filtered, and concentrated in vacuo. The remaining residue was purified
by flash chromatography (SiO2, gradient eluting with MeOH/DCM =
0.5/100ꢀ1.5/100) to provide the desired aldehyde 10 (330 mg, 94%) as
a light grayish white solid: 1H NMR (300 MHz, CDCl3, 23 °C) δ = 9.42
(s, 1 H), 8.22 (s, 1 H), 7.04 (d, J = 11.6 Hz, 1 H), 6.98 (t, J = 5.9 Hz, 1 H),
6.85 (d, J = 6.4 Hz, 1 H), 6.39 (d, J = 11.6 Hz, 1 H), 4.48ꢀ4.58
(m, 1 H), 4.03 (dd, J = 9.8, 4.1 Hz, 1 H), 3.93ꢀ4.01 (m, 2 H), 3.63 (dd,
J = 9.8, 7.9 Hz, 1 H), 1.88 (s, 3 H), 1.78 (s, 3 H), 0.83 (s, 9 H), 0.06
(s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 195.3,
170.0, 161.4, 145.3, 143.7, 137.7, 120.9, 62.8, 53.2, 47.0, 25.8, 18.2, 15.8,
9.5, ꢀ5.4, ꢀ5.5; IR υ~ = 3276, 2951, 2930, 2860, 1665, 1646, 1561, 1385,
1229, 1127, 839 cmꢀ1; [R]D23 = þ10.0 (c = 0.2, CH2Cl2); mp 110 °C;
HR-MS (FAB) m/z ([M þ H]þ) calcd for C18H33N2O4Si 369.2210,
found 369.2231.
Completion of the C(1)ꢀC(19) Subunit. C(1)ꢀC(11) sulfone
19 (165 mg, 0.356 mmol) and C(12)ꢀC(19) aldehyde (S)-8 (129 mg,
0.44 mmol) were combined in the same flask, azeotropically dried with
benzene three times, and dissolved in freshly dried THF (7.5 mL). After
the solution was cooled to ꢀ78 °C, LiHMDS (0.48 mL, 1.0 M in THF,
0.48 mmol) was added dropwise. After the solution was stirred for 2 h
at ꢀ78 °C, the cooling bath was removed, and the reaction was warmed
to 23 °C over 1.5 h. After 30 min, it was cooled with dry ice and
quenched with satd aq NH4Cl. The mixture was warmed to 23 °C,
stirred vigorously for 30 min, and extracted with CH2Cl2 (3ꢁ). The
combined organic phase was washed successively with water and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The remaining
residue was purified by flash chromatography (SiO2, gradient eluting
with DCM/hexane =2/1ꢀ5/1) to provide the desired product 26
1
(135 mg, 70%) as a clear oil: H NMR (300 MHz, CDCl3, 23 °C)
δ = 6.61 (dq, J = 9.8, 1.4 Hz, 1 H), 6.44 (d, J = 15.6 Hz, 1 H), 6.39 (dd, J =
14.5, 7.7 Hz, 1 H), 6.27 (d, J = 14.5 Hz, 1 H), 6.08 (d, J = 15.7 Hz, 1 H),
5.53ꢀ5.68 (m, 2 H), 5.29 (d, J = 9.2 Hz, 1 H), 5.20 (t, J = 7.6 Hz, 1 H),
4.01ꢀ4.08 (m, 1 H), 3.74 (s, 3 H), 3.48 (app q, J = 6.0 Hz, 1 H), 3.25
(s, 6 H), 3.23ꢀ3.28 (m, 1 H), 2.05ꢀ2.50 (m, 4 H), 1.87 (d, J = 1.5 Hz,
3 H), 1.78 (d, J = 1.1 Hz, 3 H), 1.77 (d, J = 1.2 Hz, 3 H), 1.58ꢀ1.70 (m,
1 H), 1.47ꢀ1.60 (m, 1 H), 1.15 (d, J = 6.6 Hz, 3 H); 13C NMR
(75 MHz, CDCl3, 23 °C) δ = 169.0, 146.8, 145.4, 136.6, 133.7, 132.9,
131.9, 131.5, 129.4, 128.2, 126.6, 126.4, 83.3, 78.5, 77.5, 56.8, 56.3, 52.0,
39.7, 36.5, 35.0, 23.1, 20.9, 20.5, 13.3, 12.7; IR υ~ = 2960, 2927, 1715, 1647,
1606, 1435, 1261, 1099, 1018, 965, 873, 800, 750 cmꢀ1; [R]D23 = þ2.4
(c = 0.2, CHCl3); HRMS (FABþ) m/z ([M ꢀ H]þ) calcd for C26H38IO4
541.1815, found 541.1838.
Synthesis of the C(20)ꢀC(34) Subunit. O-TBS-Protected Ieji-
malide Side Chain Ester (29). Diene amine 27 (718 mg, 4.24 mmol)23a,b
and N-formyl-O-TBS-(S)-serine 28 (1.05 g, 4.24 mmol)25 were azeo-
tropically dried with toluene three times and further dried under high
vacuum for 1 h. Freshly dried CH2Cl2 (25 mL) was added to the mixture
under Ar, the resulting suspension was cooled to 0 °C, and diethyl
cyanophosphonate (diethylphosphoryl cyanide, DEPC, 713 μL, 93%,
4.37 mmol) was added dropwise followed by CaH2-distilled NEt3 (652
μL, 4.67 mmol). The solution was warmed to 23 °C and stirred 10 h.
When the reaction was complete as monitored by TLC, the mixture,
without workup, was directly purified by flash chromatography (SiO2,
eluting with DCM containing 1% NEt3) to provide the desired of O-
C(20)ꢀC(34) Alkyne (9). C(23)ꢀC(34) aldehyde 10 (328 mg, 0.89
mmol) and PPh3 (19.4 mg, 0.074 mmol) were dissolved in THF
(8 mL) and HMPA (2 mL) to which (R)-4-TMS-3-butyn-2-ylmetha-
nesulfonate 30 (246 mg, 1.12 mmol) was added. The mixture was
placed into a preheated oil bath a 55 °C, and Pd(OAc)2 (14.7 mg, 0.065
mmol) was added in one portion followed by powdered InI (272 mg,
1.13 mmol) 1 min later. After being stirred for 8 h at 55 °C under Ar,
the mixture was removed from the oil bath and cooled to 23 °C. The
reaction was quenched by being poured into satd aq NH4Cl in an
iceꢀwater cooling bath, stirred for 5 min, and extracted with CH2Cl2
(3ꢁ). The combined organic phases were dried over MgSO4, filtered,
and concentrated. The remaining residue was purified by flash
chromatography (SiO2, gradient eluting with DCM/MeOH = 100/
0ꢀ100/1.5) to provide the desired TMS-alkyne intermediate contami-
nated with HMPA: HR-MS (ESI) m/z ([M þ H]þ) calcd for
C25H46N2NaO4Si2 517.2888, found 517.2864.
1
TBS-protected iejimalide side chain ester 29 (1.35 g, 80%): H NMR
(300 MHz, CDCl3, 23 °C) δ = 8.22 (s, 1 H), 7.38 (d, J = 11.8 Hz, 1 H),
6.82ꢀ6.90 (m, 2 H), 6.20 (d, J = 11.8 Hz, 1 H), 4.47ꢀ4.53 (m, 1 H),
4.03 (dd, J = 9.8, 4.2 Hz, 1 H), 3.90ꢀ3.96 (m, 2 H), 3.73 (s, 3 H), 3.62
(dd, J = 9.7, 8.0 Hz, 1 H), 1.89 (s, 3 H), 1.83 (s, 3 H), 0.84 (s, 9 H), 0.07
(s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz, CDCl3, 23 °C) δ = 170.0,
169.2, 161.3, 142.2, 133.4, 127.0, 121.4, 62.8, 53.1, 52.0, 47.1, 25.9, 18.2,
The above HMPA-contaminated intermediate TMS-alkyne was
dissolved in MeOH (15 mL), and K2CO3 (271 mg, 1.96 mmol) was
added in one portion. After being stirred for 6 h at 23 °C, the mixture was
poured into satd aq NH4Cl, stirred vigorously for 30 min, and then
extracted with CH2Cl2 (3ꢁ). The organic phases were combined, dried
over MgSO4, filtered, and evaporated to dryness. The remaining residue
15.7, 12.7, ꢀ5.3, ꢀ5.4; IR υ~ = 3275, 2953, 2931, 1708, 1666, 1641 cmꢀ1
;
[R]2D3 = þ7.9 (c = 0.14, CHCl3); mp 112 °C; HR-MS (ESI) m/z
([M þ H]þ) calcd for C19H35N2O5Si 399.2310, found 399.2311.
Iejimalide Side-Chain Aldehyde (10)12f. A solution of O-TBS-pro-
tected iejimalide side chain ester 29 (630 mg, 1.58 mmol) in CH2Cl2
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FEATURED ARTICLE
was purified by flash chromatography (SiO2, gradient eluting with
DCM/MeOH = 100/1ꢀ100/2, to provide the desired C(20)ꢀC(34)
alkyne 9 (301 mg, 80% for two steps) with a ratio of diastereomers for
this batch of 4.97/1: 1H NMR (400 MHz, CDCl3, 23 °C) δ = 8.26 (s,
1 H), 6.59 (br s, 2 H), 6.23 (d, J = 11.1 Hz, 1 H), 6.15 (d, J = 11.1 Hz, 1 H),
4.46 (m, 1 H), 4.09 (dd, J = 9.7, 4.1 Hz, 1 H), 3.91 (m, 3 H), 3.58 (dd, J =
9.7, 8.3 Hz, 1 H), 2.65ꢀ2.73 (m, 1 H), 2.22 (d, J = 3.6 Hz, 1 H), 2.17 (d,
J = 2.4 Hz, 1 H), 1.76 (s, 3 H), 1.73 (s, 3 H), 1.12 (d, J = 7.0 Hz, 3 H),
0.88 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3 H); 13C NMR (75 MHz, CDCl3,
23 °C) δ = 169.8, 161.2, 136.8, 134.6, 123.5, 122.2, 85.8, 81.1, 71.1, 62.7,
53.1, 47.5, 31.5, 26.0, 18.3, 17.8, 15.2, 12.0, ꢀ5.3, ꢀ5.4; IR υ~ = 3307,
1.47ꢀ1.59 (m, 1 H), 1.17 (d, J = 6.9 Hz, 3 H); 13C NMR (75 MHz,
CDCl3, 23 °C) δ = 173.5, 147.6, 146.8, 136.6, 133.9, 132.9, 131.9, 131.2,
129.4, 128.2, 126.3, 126.1, 83.3, 78.5, 77.6, 56.7, 56.3, 39.6, 36.7, 34.9,
23.1, 20.9, 20.4, 13.3, 12.4; IR υ~ = 3450 (b), 2960, 2926, 2852, 1690,
1453, 1267, 1096, 965, 802 cmꢀ1; [R]D23 = þ18.2 (c = 0.06, CH2Cl2);
HR-MS (ESIþ) m/z ([M þ Na]þ) calcd for C25H37INaO4 551.1629,
found 551.1617.
To a flame-dried 5-mL flask were added EDCI (29.7 mg, 0.155
mmol), DMAP (18.9 mg, 0.155 mmol), and DMAP HCl (25.8 mg,
3
0.162 mmol), and the mixture was further dried under high vacuum for
3.5 h and placed under Ar. After the mixture was cooled to 0 °C, 4 (53.1
mg, 0.101 mmol) was added with 0.8 mL of DCM. After the mixture was
stirred for 10 min at 0 °C, 5b (55.2 mg, 0.077 mmol) in 0.8 mL of DCM
was added dropwise. The reaction flask was sealed under Ar and stirred
for 48 h in the dark at 23 °C. When the reaction was complete as
monitored by TLC, the mixture was diluted with DCM, washed with
water, and back-extracted with DCM. The organic phases were com-
bined, washed with brine (2 ꢁ 5 mL), dried over Na2SO4, filtered, and
concentrated under vacuum. The remaining residue was purified by flash
chromatography (SiO2, eluting with hexane/EtOAc/MeOH = 4/1/
0.5% to 4/1/1%) to afford the desired intermolecular Keck esterification
product 3 (74 mg, 78%) as an oil, which was used immediately in the
following intramolecular Stille coupling reaction: 1H NMR (300 MHz,
CDCl3, 23 °C) δ = 8.25 (s, 1 H), 6.53ꢀ6.68 (m, 3 H), 6.45 (d, J =
16.5 Hz, 1 H), 6.39 (dd, J = 14.4, 7.5 Hz, 1 H), 6.27 (d, J = 14.4 Hz, 1 H),
6.05ꢀ6.23 (m, 3 H), 5.96 (d, J = 15.6 Hz, 1 H), 5.82 (dd, J = 19.0, 8.0 Hz,
1 H), 5.53ꢀ5.68 (m, 2 H), 5.28 (d, J = 9.0 Hz, 1 H), 5.20 (t, J = 6.6 Hz,
1 H), 5.09 (dd, J = 8.7, 5.4 Hz, 1 H), 4.42ꢀ4.50 (m, 1 H), 4.09 (dd, J =
9.6, 3.9 Hz, 1 H), 4.01ꢀ4.09 (m, 1 H), 3.81ꢀ3.97 (m, 2 H), 3.57 (dd, J =
9.3, 8.4 Hz, 1 H), 3.45ꢀ3.52 (m, 1 H), 3.25 (s, 6 H), 3.18ꢀ3.30 (m,
1 H), 2.12ꢀ2.65 (m, 5 H), 1.84 (d, J = 0.6 Hz, 3 H), 1.78 (s, 3 H), 1.77
(s, 3 H), 1.73 (br, s, 6 H), 1.59ꢀ1.70 (m, 1 H), 1.50ꢀ1.59 (m, 1 H),
1.39ꢀ1.50 (m, 6 H), 1.22ꢀ1.32 (m, 6 H), 1.13 (d, J = 6.9 Hz, 3 H),
0.79ꢀ0.93 (m, 27 H), 0.10 (s, 3 H), 0.07 (s, 3 H); 13C NMR (75 MHz,
CDCl3, 23 °C) δ = 169.7, 167.3, 161.2, 150.5, 146.8, 145.0, 136.6, 134.9,
134.4, 133.5, 132.9, 131.7, 131.6, 129.3, 128.6, 128.2, 126.9, 126.4, 124.1,
122.3, 83.2, 82.9, 78.5, 77.5, 62.7, 56.7, 56.3, 53.1, 47.6, 44.1, 39.7, 36.5,
34.9, 29.2, 27.4, 25.9, 23.1, 20.9, 20.5, 18.2, 16.9, 15.3, 13.9, 13.3, 12.8,
12.7, 9.6, ꢀ5.3, ꢀ5.4; IR υ~ = 3300 (m, b), 2958, 2927, 2872, 2856, 1708,
1655, 1600, 1553, 1465, 1387, 1259, 1223, 1104, 1008, 990, 965, 839,
779 cmꢀ1; [R]D23 = þ21.5 (c = 0.65, CH2Cl2); HR-MS (ESI) m/z
([M þ Na]þ) calcd for C59H101IN2NaO7SiSn 1247.5342, found:
1247.5338.
2929, 2857, 2112, 1659, 1550, 1462, 1388, 1254, 1112, 1028, 837 cmꢀ1
;
[R]2D3 = þ24.5 (c = 0.22, CHCl3); HR-MS (ESI) m/z ([M þ Na]þ)
calcd for C22H38N2NaO4Si 445.2493, found 445.2490.
Fully Functionalized C(20)ꢀC(34) Segment (5b). C(20)ꢀC(34)
alkyne 9 (98 mg, 0.23 mmol) was dissolved in freshly dried THF
(10 mL), and Pd(dppf)Cl2 CH2Cl2 (8.5 mg, 0.012 mmol, 0.05 equiv)
3
was added at 23 °C under Ar. After 5 min, Bu3SnH (0.25 mL, 0.93 mmol,
4 equiv) was added dropwise over 20 min, and during the addition,
vigorous bubbling occurred, and the color of the mixture changed from
red to orange and then to deep red-orange. After the addition, the
mixture was stirred for 30 min at 23 °C and concentrated on a rotary
evaporator. 1H NMR of the crude material indicated a 16/1 E/Z isomer
ratio. The crude product was purified by flash chromatography. The
prepared column was first washed with 1% Et3Nꢀhexane to basify the
column, and the crude material was loaded on the column with toluene
and eluted with DCM/Et3N = 100/1 to afford the product contami-
nated with colloidal SiO2 and adsorbed NEt3. The presence of NEt3 in
the eluent was found to avoid the partial decomposition of vinyl
stannane 5b during silica gel chromatography. Further purification
was accomplished by dissolving the product in toluene and filtering
the mixture through Celite to remove the colloidal SiO2 and adsorbed
NEt3 to give the pure alkenylstannane 5b (123 mg, 75%) as an oil: 1H
NMR (300 MHz, CDCl3, 23 °C) δ = 8.26 (s, 1 H), 6.56ꢀ6.65 (m, 2 H),
6.08ꢀ6.18 (m, 3 H), 5.82 (dd, J = 19.0, 8.0 Hz, 1 H), 4.42ꢀ4.50 (m,
1 H), 4.10 (dd, J = 9.6, 4.1 Hz, 1 H), 3.84- 3.98 (m, 2 H), 3.70 (d, J =
8.9 Hz, 1 H), 3.58 (dd, J = 9.7, 8.4 Hz, 1 H), 2.28ꢀ2.40 (m, 1 H), 1.75 (s,
3 H), 1.74 (s, 3 H), 1.43ꢀ1.54 (m, 6 H), 1.24ꢀ1.36 (m, 6 H), 0.85ꢀ0.93
(m, 27 H), 0.12 (s, 3 H), 0.08 (s, 3 H); 13C NMR (75 MHz, CDCl3,
23 °C) δ = 169.8, 161.2, 151.4, 138.0, 133.7, 131.8, 123.4, 122.7, 81.1,
62.8, 53.1, 47.7, 46.9, 29.4, 27.5, 26.0, 18.3, 17.0, 15.2, 13.9, 11.9, 9.8,
ꢀ5.2, ꢀ5.3; IR υ~ = 3297, 2956, 2855, 1652, 1556, 1464, 1386, 1258,
1108, 1006, 838, 779 cmꢀ1; [R]D23 = þ16.8 (c = 0.4, CHCl3); HR-MS
(FAB) m/z ([M ꢀ OH]þ) calcd for C34H65N2O3SiSn 697.3793, found
697.3776.
The previous product 3 (24 mg, 0.0196 mmol) was dissolved in
anhyd DMF (28 mL, c ≈ 7 ꢁ 10 ꢀ4) and transferred to a flame-dried
Schlenk tube. The mixture was degassed under high vacuum at ꢀ78 °C
three times, and the tube was backfilled with Ar. After the mixture was
End Game: Ester Hydrolysis, Keck Esterification, Intramolecular
Stille Coupling Reaction, and Deprotection. Iejimalide B (1b). The
methyl ester 26 of the C(1)ꢀC(19) subunit (53 mg, 0.098 mmol) was
suspended in a freshly prepared LiOH solution (0.1 M LiOH in 1.2/1
i-PrOH/H2O, 10 equiv, 0.982 mmol, 9.8 mL), which was stirred at 23 °C
for 10 h. The mixture was neutralized with aq NaHSO4 (1.04 eq, 0.15
M), diluted with EtOAc, and washed with brine (2 ꢁ 7.5 mL). After the
organic phase was dried over MgSO4 and filtered, the solvent was
evaporated under vacuum to give the free acid 4 of the fully functiona-
lized C(1)ꢀC(19) segment (52 mg), which was immediately used in the
subsequent Keck intermolecular esterification. A portion was purified by
flash chromatography with a short SiO2 column (hexane/EtOAc/
warmed to 23 °C, Pd2(dba)3 CHCl3 (6.5 mg, 0.0063 mmol, 0.32
3
equiv), Ph3As (7.7 mg, 0.0251 mmol, 1.28 equiv), and DIPEA (71 μL,
0.408 mmol, 20.8 equiv) were added successively to the mixture, which
was stirred at 23 °C under Ar. After 24 h, another portion of Pd2-
(dba)3 CHCl3 (6.5 mg, 0.0063 mmol, 0.32 equiv), Ph3As (7.7 mg,
3
0.0251 mmol, 1.28 equiv), and DIPEA (71 μL, 0.408 mmol, 20.8 equiv)
was added and the mixture stirred for another 24 h. When the reaction
was complete as monitored by TLC, the mixture was diluted with DCM,
washed with water (3 ꢁ 20 mL), and back-extracted with DCM. The
organic phases were combined, dried over Na2SO4, filtered, and con-
centrated under vacuum. The remaining crude material was purified by
flash chromatography (SiO2, DCM/MeOH = 100/0.3ꢀ100/1) to
afford the desired O-TBS-protected iejimalide B 34 (11.3 mg, 72%) as
an oil, which was used in the following deprotection step. A portion was
further purified by HPLC using a C18 reversed-phase column
(semiprep, 9.4 ꢁ 250, 5 μm; gradient: MeCN/H2O = 85/15ꢀ98/2,
3 mL/min, tR = 21 min): 1H NMR (600 MHz, CDCl3, 23 °C) δ = 8.28
1
MeOH = 4/1/1% to 4/1/2%): H NMR (300 MHz, CDCl3, 23 °C)
δ = 6.76 (dq, J = 9.6, 1.2 Hz, 1 H), 6.44 (d, J = 15.0 Hz, 1 H), 6.39 (dd, J =
14.7, 7.5 Hz, 1 H), 6.27 (d, J = 14.7 Hz, 1 H), 6.08 (d, J = 15.6 Hz, 1 H),
5.53ꢀ5.68 (m, 2 H), 5.30 (d, J = 9.0 Hz, 1 H), 5.20 (t, J = 7.2 Hz, 1 H),
4.02ꢀ4.09 (m, 1 H), 3.45ꢀ3.52 (m, 1 H), 3.26 (s, 3 H), 3.25 (s, 3 H),
3.23ꢀ3.35 (m, 1 H), 2.14ꢀ2.52 (m, 4 H), 1.87 (d, J = 1.2 Hz, 3 H), 1.78
(d, J = 1.1 Hz, 3 H), 1.77 (d, J = 1.2 Hz, 3 H), 1.59ꢀ1.70 (m, 1 H),
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The Journal of Organic Chemistry
FEATURED ARTICLE
(s, 1 H), 6.62 (dd, 1 H, J = 1.4, 10.4 Hz), 6.57 (m, 2 H), 6.50 (d, 1 H, J =
15.8 Hz), 6.28 (d, 1 H, J = 11.2 Hz), 6.14 (d, 1 H, J = 11.2 Hz), 6.02 (m,
2 H), 5.86 (d, 1 H, J = 15.4 Hz), 5.54ꢀ5.35 (m, 4 H), 5.19 (dd, 1 H, J =
5.8, 11.2 Hz), 5.15 (d, 1 H, J = 10.4 Hz), 5.09 (d, 1 H, J = 9.6 Hz), 4.46
(m, 1 H), 4.12 (m, 2 H), 3.91 (m, 2 H), 3.59 (app. t, 1 H), 3.28 (m, 1 H),
3.26 (s, 3 H), 3.14 (m, 1 H), 2.95 (s, 3 H), 2.67 (m, 1 H), 2.55 (m, 2 H),
2.32 (m, 1 H), 1.90 (m, 1 H), 1.81ꢀ1.75 (5 overlapping s, 15 H), 1.63
(m, 1 H), 1.33 (m, 1 H), 1.05 (d, 3 H, J = 6.8 Hz), 0.92 (d, 3 H, J = 7.4
Hz), 0.88 (s, 9 H), 0.12 (s, 3 H), 0.09 (s, 3 H); 13C NMR (125 MHz,
CDCl3, 23 °C) δ = 169.8, 167.8, 161.2, 145.8, 137.1, 136.1, 135.2, 134.0,
133.55, 133.34, 133.25, 132.3, 131.97, 131.96, 131.1, 129.8, 128.7, 125.6,
125.5, 125.0, 122.1, 83.1, 79.7, 77.0, 62.7, 56.4, 56.1, 53.1, 47.5, 41.2, 40.9,
38.4, 35.0, 26.0, 23.0, 21.6, 21.0, 18.3, 16.9, 15.3, 13.2, 12.2, 12.1, ꢀ5.3, ꢀ5.4;
IR υ~ = 3290 (m, b), 2925, 2856, 1715, 1674, 1557, 1484, 1449, 1386, 1331,
1261, 1184, 1100, 1023, 968, 916, 700 cm; HR-MS (ESI) m/z ([M þ
Na]þ) calcd for C47H74N2NaO7Si 829.5158, found 829.5188.
Sciences Award. We also express our deepest appreciation to
many previous co-workers and collaborators who have made key
contributions to earlier stages of this work, including (in alphabe-
tical order) Dr. Muriel Cottard, Prof. Tatsuo Higa, Mr. Jakob
Jensen, Dr. Peter McHenry, Dr. Matthew Mendlik, Mr. David
Miller, Prof. Rudolph Navari, Prof. Per-Ola Norrby, Dr. Torben
Pedersen, Prof. George R. Pettit, Prof. Tobias Rein, Prof. Daniel
Strand, Prof. Junichi Tanaka, Prof. Martin Tenniswood, Dr. James
Ulager, Prof. Lauri Vares, Prof. Olaf Wiest, and Dr. David Young.
DEDICATION
†This paper is dedicated to Professor Elias J. Corey.
’ REFERENCES
O-TBS-protected iejimalide B 34 (7.5 mg, 9.3 μmol) was transferred
into a plastic vial by using EtOAc (600 μL), and DMF (600 μL, to which
TAS-F (10 equiv, 0.5 M in DMF, 186 μL, 0.093 mmol) was added. The
mixture was stirred and monitored by TLC (silica gel). After being
stirred for 2 h at 23 °C, the mixture was diluted with pH 7 buffer and
extracted with EtOAc (3ꢁ). The organic phases were combined, dried
over Na2SO4, filtered, and concentrated under vacuum. The resulting
crude material was purified by flash chromatography (SiO2, gradient
DCM/MeOH = 50/1ꢀ30/1) to afford the synthetic iejimalide B (1b)
(5 mg, 80%), which was further purified by HPLC using a C18 reversed-
phase column (semiprep, 9.4 ꢁ 250, 5 μm; isocratic elution: MeCN/
H2O = 80/20, 3 mL/min, tR = 8.6 min): 1H NMR (600 MHz, CDCl3,
23 °C) δ = 8.28 (s, 1 H), 6.81 (d, 1 H, J = 6.6 Hz), 6.80 (m, 1 H), 6.63
(dd, 1 H, J = 1.5, 10.3 Hz), 6.48 (d, 1 H, J = 15.6 Hz), 6.28 (d, 1 H, J =
11.4 Hz), 6.13 (d, 1 H, J = 11.2 Hz), 6.03 (m, 2 H), 5.86 (d, 1 H, J = 15.4
Hz), 5.54ꢀ5.37 (m, 4 H), 5.19 (dd, 1 H, J = 6.2, 11.0 Hz), 5.15 (d, 1 H,
J = 10.0 Hz), 5.08 (d, 1 H, J = 9.0 Hz), 4.50 (m, 1 H), 4.23 (dd, 1 H, J =
2.5, 11.5 Hz), 4.13 (m, 1 H), 3.90 (m, 2 H), 3.65 (m, 1 H), 3.28 (m, 1 H),
3.27 (s, 3 H), 3.14 (m, 1 H), 2.97 (s, 3 H), 2.68 (m, 1 H), 2.55 (m, 2 H),
2.32 (m, 1 H), 1.90 (m, 1 H), 1.80ꢀ1.75 (5 overlapping s, 15 H), 1.62
(m, 1 H), 1.33 (m, 1 H), 1.05 (d, 3 H, J = 6.8 Hz), 0.94 (d, 3 H, J = 6.6
Hz); 13C NMR (125 MHz, CDCl3, 23 °C) δ = 170.6, 167.7, 161.9,
145.8, 137.1, 136.0, 134.9, 134.0, 133.5, 133.3, 133.2, 132.3, 132.0, 131.9,
131.1, 129.8, 128.7, 125.6, 125.3, 124.9, 121.5, 83.0, 79.8, 76.9, 62.5, 56.4,
56.1, 52.6, 47.2, 41.0, 40.8, 38.2, 35.0, 23.1, 21.6, 20.9, 16.9, 15.3, 13.3,
12.3, 12.2; IR υ~ = 3320 (br), 2964, 2926, 1651 (br), 1538, 1448, 1386,
1260, 1217, 1098, 1023, 967, 871, 800 cmꢀ1; [R]D23 = ꢀ15.0 (c = 0.2,
CH2Cl2); HR-MS (ESI) m/z ([M þ Na]þ) calcd for C41H60N2NaO7
715.4298, found 715.4283.
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Supporting Information. 1H and 13C NMR spectra of all
S
b
key reaction products. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: phelquis@nd.edu; davisson@purdue.edu.
’ ACKNOWLEDGMENT
We are grateful for the financial support of this research
provided by the Walther Cancer Institute and the Indiana
Clinical and Translational Sciences Institute funded by Grant
No. RR025761 from the National Institutes of Health, National
Center for Research Resources, Clinical and Translational
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FEATURED ARTICLE
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