Total synthesis of dermostatin A

Article abstract of DOI:10.1021/jo2012658

The concise total synthesis of dermostatin A is described. Highlights include a two-directional application of the asymmetric acetate aldol method developed in our lab, a novel diastereotopic-group-selective acetal isomerization for terminus differentiation, and a selective cross-metathesis reaction between a terminal olefin and a trienal. A study of the scope and viability of similar cross-metathesis reactions is also described. The synthesis is convergent and utilizes fragments of roughly equal complexity.

Full text of DOI:10.1021/jo2012658

FEATURED ARTICLE
pubs.acs.org/joc
Total Synthesis of Dermostatin A
Yingchao Zhang,† Carolynn C. Arpin, Aaron J. Cullen,‡ Mark J. Mitton-Fry,§ and Tarek Sammakia*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, United States
S Supporting Information
b
ABSTRACT: The concise total synthesis of dermostatin A is described. High-
lights include a two-directional application of the asymmetric acetate aldol
method developed in our lab, a novel diastereotopic-group-selective acetal
isomerization for terminus differentiation, and a selective cross-metathesis
reaction between a terminal olefin and a trienal. A study of the scope and
viability of similar cross-metathesis reactions is also described. The synthesis is
convergent and utilizes fragments of roughly equal complexity.
’ INTRODUCTION
Scheme 1. Initial Retrosynthetic Disconnection
The oxopolyene macrolides are a structurally complex class
of natural products that possess a hydrophilic skipped polyol
domain and a hydrophobic polyene domain.1 They display
diverse biological activities, including antifungal activity against
a variety of human pathogens, and their combination of biolo-
gical activity and structural complexity has rendered them
popular targets for synthesis.2 Among the synthetic challenges
posed by these molecules are the stereocontrolled synthesis of
the polyol and polyene fragments as well as the fragment
couplings required to produce the full-length carbon chain. We
have described a method for the construction of acetate aldol
subunits with control of absolute stereochemistry,3 and in this
article we describe a two-directional application of this method to
the synthesis of dermostatin A (1) along with a novel terminus
differentiation. Our synthesis also utilizes an alkene cross-
metathesis reaction4 between an electron-deficient triene and a
terminal olefin,2p and we describe the scope of this reaction
herein as well.
Dermostatin A (1, Scheme 1) is one of the more complex
oxopolyene macrolides. It was first isolated nearly 50 years ago,5
and its structure, devoid of stereochemical assignment, was
determined about 10 years later by a combination of UV and
NMR spectroscopy, mass spectrometry, and chemical derivatiza-
tion and degradation.6 In 1997, Rychnovsky et al.7 published the
full stereochemical assignment of dermostatins A and B by means
of extensive NMR studies using the acetonide analysis method
developed in his lab. Subsequently, Sinz and Rychnovsky8
reported the total synthesis of dermostatin A.
the two fragments, it provides a product with 1,5-oxygenation
bearing an anti relationship and a ketone at the 3-position.
Reduction of the ketone directed10 by the hydroxyl group of
the aldol product allows for the creation of either hydroxyl
stereochemistry at the 3-position of this stereotriad, thus provid-
ing added flexibility. An analysis of the connectivity and stereo-
chemistry of the linear polyol chain suggests disconnection at the
C-25ꢀC-26 bond to provide two fragments, 2 and 3, which are of
approximately equal complexity and can be coupled by a 1,5-anti
aldol reaction (Scheme 1).
A more detailed retrosynthesis is shown in Scheme 2. Late-
stage macrocyclization11 would be preceded by installation of the
full polyene via a vinylogous HornerꢀWadsworthꢀEmmons
reaction between phosphonate 4 and aldehyde 5. Synthesis of 5
’ RESULTS AND DISCUSSION
We wished to synthesize dermostatin A in a convergent
fashion by a route that utilizes the stereoselective coupling of
fragments of roughly equal complexity. The 1,5-anti aldol reac-
tion developed by Evans and Paterson and co-workers9 was
deemed an expeditious approach because, in addition to coupling
Received: June 18, 2011
Published: August 10, 2011
r
2011 American Chemical Society
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Scheme 2. Retrosynthesis
Scheme 3. Preparation of Bis-acetal 18
which requires terminus differentiation in order to establish the
stereocenter at C-21.12 The implementation of this strategy is
described below.
Our synthesis began with the protection [tert-butyldimethyl-
silyl chloride (TBSCl) and imidazole] and reduction (diisobutyl-
aluminium hydride, DIBAL-H) of glutarate ester 13, which
provides the glutaraldehyde product as a complex mixture due
to reversible hydration and cyclizaton to a lactol, followed by
polymerization (Scheme 3). Dehydration of this polymeric
material by heating to 100 °C at reduced pressure (∼2 mmHg)
cleanly provided the monomeric dialdehyde (15) with only
traces of oligomers detectable by NMR.13 Subjection of 15
to our standard acetate aldol reaction conditions3 [PhBCl2,
(ꢀ)-sparteine, N-acetylthiazolidinethione 1114] provided the
desired product (16) in 70% yield after chromatography. Anal-
1
ysis of the H NMR spectrum of the crude reaction mixture
indicated that the product is formed as a >20:1 diastereomeric
mixture. Reduction to tetraol 17 (NaBH4, 80%) was followed
by treatment with pyridinium p-toluenesulfonate (PPTS) and
p-anisaldehyde dimethyl acetal to provide bis-acetal 18 in
90% yield.
was envisioned via a selective olefin cross-metathesis reaction
with terminal alkene 6 and an electron-deficient polyene: either
a diene, triene, or tetraene (7, n = 2ꢀ4) depending on the
suitability of these substrates in this reaction. Synthesis of 6
would be accomplished by aldol condensation of ketone 8 and
aldehyde 9. This disconnection also offers the advantage of using
a common precursor in our synthesis of RK-397, ketone 8.2p
We envisioned the synthesis of aldehyde 9 by a two-directional
strategy using our previously developed asymmetric acetate
aldol method with reagent 11.3 This strategy would proceed
via a bis-aldol reaction on an achiral dialdehyde to produce a
1,3- 1,5-, or 1,7-stereodiad with the two stereocenters bearing
the same absolute stereochemistry. An examination of the
structure of 9 suggests the use of a 3-hydroxyglutaraldehyde
derivative centered on C-21 (12), wherein the double aldol
addition would set the stereochemistry at C-23 and C-19.
This would provide a pseudo-C2-symmetric product (10),
Compound 18 is pseudo-C2-symmetric, and the central
carbon (C-21) is not stereogenic. A diastereotopic-group-
selective differentiation12 of the termini is required in order to set
this stereocenter and differentiate the termini for subsequent
elaboration. This was accomplished by a stereoselective acetal
isomerization reaction that was induced by deprotection of the
tert-butyldimethylsilyl (TBS) ether of 18 [tetrabutylammonium
fluoride (TBAF), 87%] to provide alcohol 19, followed by
treatment with PPTS in toluene at 80 °C (Scheme 4). Under
these conditions we obtained a 90:10 mixture of the desired
internal acetal (20, wherein acetal B migrates) to starting
terminal acetal (19) from which the desired acetal could be
isolated in 82% yield. The isomeric internal acetal (21, wherein
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Scheme 4. Preparation of Aldehyde 28
acetal A migrates) was not observed, presumably because of the
axial substituent that would be present at the 4-position of the
newly formed 1,3-dioxane (acetal C). The A-value for substitu-
ents at the 4-position of a 1,3-dioxane is significantly higher than
that in cyclohexane due to the decreased bond lengths and angles
of the oxygen, thereby leading to the high selectivity in this
reaction.15 This reaction not only sets the stereocenter at C-21
to the desired configuration but also provides material wherein
the termini are differentiated; C-17 bears a primary alcohol
while C-25 is part of a p-methoxyphenyl (PMP) acetal. Oxidation
of the C-17 alcohol [DessꢀMartin periodinane (DMP), 90%]
provides aldehyde 22, which was subjected to an anti-selective
aldol reaction using the Masamune reagent (23)16 to provide
ester 24 (91%, 20:1 desired/all other isomers). Protection of the
hydroxyl group of 24 [tert-butyldimethylsilyl triflate (TBSOTf),
2,6-lutidine, 92%], conversion to the Weinreb amide via the
Scheme 5. Completion of Polyol Portion of Dermostatin A
Merck procedure17 (MeNHOMe HCl, i-PrMgCl; 88%), and
3
allylation (allylMgBr) provided ketone 25, which was reduced
with NaBH4 to provide the desired alcohol [26, 80% over two
steps, diastereomeric ratio (dr) = 10:1].8 Deprotection of the
TBS ether (TBAF) and acetonide formation (2,2-dimethoxy-
propane, PPTS; 80% for two steps) provided 27. Compound 27
was then treated with DIBAL-H to cleave the terminal PMP
acetal selectively (81%). Oxidation of the resulting primary
alchol (DMP, 78%) provided aldehyde 28 for use in the fragment
coupling.
With aldehyde 28 in hand, we turned our attention to
fragment coupling using the 1,5-anti aldol method developed
by Evans and Paterson and co-workers.9 Methyl ketone 8,
prepared in nine steps from isobutyraldehyde in 9% overall yield
and previously used in our synthesis of RK-397,18 and aldehyde
28 were subjected to the aldol reaction under the Paterson
conditions9 (Cy2BCl, NEt3) to provide aldol product 29
(93%, dr = 15:1, Scheme 5). Anti-selective reduction of
the C-27 ketone, directed by the hydroxyl group at C-25
[Me4NBH(OAc)3, dr > 20:1],19 and protection of the resulting
diol as the acetonide (2,2-dimethoxypropane, PPTS; 96% for
two steps) provided 30, which contains the full polyol portion of
the molecule with the C-35 hydroxyl group unprotected.
With the successful completion of the synthesis of the polyol
domain of dermostatin A, we turned our attention to installation
of the polyene domain to complete the total synthesis. We
envisioned this occurring via the cross-metathesis of the terminal
alkene of compound 30 with an unsaturated polyenal or
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Scheme 6. Cross-Metathesis with Electron-Deficient Polyenes
polyenoate in order to construct the polyene in minimal steps. In
our previous synthesis of RK-397, we employed the cross-
metathesis of a trienal with a terminal alkene resembling 30;2p
however, the presence of a hexaene in dermostatin A as com-
pared to the pentaene of RK-397 presents a greater challenge.
Grubbs and co-workers4a have described a general model for
selectivity in olefin cross-metathesis reactions wherein they place
alkenes into one of four reactivity types, according to their ability
to undergo homodimerization with a particular catalyst and
whether that dimerization is reversible.4 Cross-metathesis will
then be selective for olefins of two different reactivities and less so
when the olefins are of similar reactivity. To assess the viability
of various cross-metathesis substrates, we undertook a model
study with terminal alkene 31,20 which mimics our terminal
alkene substrate and falls into the highest reactivity type for all
common Ru metathesis catalysts (type 1, according to Grubbs’
nomenclature).21 We studied the cross-metathesis of 31 with
alkenes, dienes, trienes, and tetraenes conjugated to an aldehyde
or ester as shown in Scheme 6.22 These compounds are of
different reactivity types (we speculated types 1ꢀ3, depending
on the choice of catalyst), and as such, we suspected they would
require different catalysts and conditions to promote selective
cross-metathesis with 31. The problems we anticipated included
the reticence of electron-deficient olefins to participate in
metathesis reactions and, in the case of dienesꢀtetraenes, issues
of selectivity with respect to metathesis of the terminal versus
internal olefins. Reactions were run with a 10% catalyst loading in
dichloromethane at reflux at a concentration of 0.1 M with
2.0 equiv of the R,β-unsaturated alkene. We then studied each
substrate pair with each catalyst and noted the following general
trends. In many cases we observed incomplete consumption of
31, indicating that the reactions had stalled after some time,
presumably due to catalyst inactivation or decomposition. In
some reactions, conversion of 31 to the corresponding dimer
(32) was prominent; thus, while consumption of 31 was high,
conversion to the desired product was low. At times, complex
mixtures of products were observed, again with consumption of
31. Our results with each aldehyde-derived substrate and cata-
lysts 33ꢀ35 are shown in Table 1.
Table 1. Cross-Metathesis of 31 with Enal and Polyenal
Substrates (Scheme 6)
a Isolated yield; numbers in parentheses are conversions as determined
by NMR. b 3.0 equiv of 37 were used. c Conducted at room temperature.
d Ratio of terminal to internal olefin metathesis. e Isomeric at the alkene
distal to the aldehyde.
both provided complete consumption of 31 and cleanly provided
the desired product in 91% and 94% yields, respectively. Acrolein
required the more active catalyst, 35, to proceed to complete
conversion, presumably because it is less reactive than crotonal-
dehyde, and provided the product in a yield of 75%.
For the cross-metathesis of acrolein and crotonaldehyde, we
found that these electron-deficient substrates failed with the less
active first-generation Grubbs catalyst (33).23 In the case of
acrolein, the reaction stalled at low conversion, and in the case of
crotonaldehyde, most of 31 was converted to dimer 32 (36%
conversion to 32, which consumes 72% of 31) and provided the
desired product in only 16% yield. The more active second-
generation Grubbs catalyst (34)24 or the phosphine-free variant
(35) described by Hoveyda and co-workers25 and by Blechert
and co-workers26 provided superior results. In the case of
crotonaldehyde, catalysts 34 and 35 were essentially equivalent;
We were unable to obtain satisfactory results with dienal 3818
due to either reactivity or selectivity problems. In the case of the
least reactive first-generation Grubbs catalyst (33), the reaction
cleanly proceeded to the desired product but consistently stalled
at about 12% conversion. The more reactive catalysts (34 and
35) provided higher conversion but suffered from poor selec-
tivity for the terminal alkene (2.2:1 ratio of terminal to internal
metathesis with catalyst 34, and 1.2:1 ratio with catalyst 35).
In contrast, we were pleased to find that trienal 3918 is a com-
petent substrate, but only with the least active of the catalysts. In
this substrate, it appears that the electron-withdrawing aldehyde
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is sufficiently removed from the terminal alkene that it is reactive
enough for the first-generation Grubbs catalyst while the internal
alkenes are not. The product is formed as a 4:1 mixture of E- to
Z-olefin isomers at the distal (ε,ζ) alkene. A variety of conditions
were studied; however, we were unable to improve this ratio.
Surprisingly, reactions with the more reactive catalysts stalled
after 32ꢀ33% consumption of 31 and were not clean. Similarly,
reactions with tetraenal substrate 40 provided complex mixtures
by NMR with all catalysts under all conditions studied and stalled
after low consumption of 31 (30ꢀ41%).
Similar results were obtained with the ester-derived substrates
(Table 2). In the case of ethyl acrylate or ethyl crotonate, again,
the less active first-generation Grubbs catalyst (33) provided
significant amounts of dimer 32 (32%, which consumes 64% of
31, and 36%, which consumes 72% of 31; Table 2, entries 1 and 4,
respectively). The more reactive catalysts (34 and 35) provided
the desired product in 70ꢀ92% yield (Table 2, entries 2, 3, 5
and 6). Dienoate 4327 did not provide satisfactory results with
any of the catalysts studied: while the consumption of 31 was
high in many reactions, several unidentified side products were
observed, and we were unable to devise conditions that provided
clean reactions.
Table 2. Cross-Metathesis of 31 with Enoate and Polyenoate
Substrates (Scheme 6)
As in the case of trienal 39, cross-metathesis with trienoate
4418 provided good conversion and high yields with the first-
generation Grubbs catalyst (96% consumption of 31, 84% yield)
and a 5:1 ratio of E- to Z-olefin isomers at the distal (ε,ζ) alkene.
The more active catalysts stalled at lower conversion, again
presumably due to catalyst inactivation or decomposition.28
The tetraenoate substrate provided slightly better results than
the tetraenal. With the first-generation Grubbs catalyst, we
observed a 62% conversion to the desired product by NMR;
however, we were unable to isolate the product cleanly by flash
chromatography. The more active catalysts stalled at low
conversion.
With these results in hand, we settled on cross-metathesis
between trienal 3918 and terminal alkene 30. Using the first-
generation Grubbs catalyst, the reaction proceeded as expected,
and the desired trienal (46) was isolated in 82% yield as a 4:1
mixture of isomers at the olefin distal to the aldehyde (C-12ꢀ
C-13; Scheme 7). HornerꢀWadsworthꢀEmmons olefination
with the doubly vinylogous reagent 4729 proceeded uneventfully
to provide conjugated hexaenoate 48, from which isomerically
a Isolated yield; numbers in parentheses are conversions as determined
by NMR. b Isomeric at the alkene distal to the ester.
Scheme 7. Completion of the Synthesis of Dermostatin A (1)
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pure material was isolated in 66% yield. Due to the potential
photoreactivity of the conjugated hexaenoate, the products of
this and subsequent reactions were protected from exposure to
light by conducting reactions in glassware wrapped with alumi-
num foil and by performing chromatography in dimmed lighting.
Hydrolysis to the seco acid (LiOH) and cyclization (Yamaguchi
conditions)30 provided the fully protected macrolide in 75%
yield for the two steps. The final deprotection proved challen-
ging. Although the acetonide and p-methoxybenzylidine acetal
functionalities were easily hydrolyzed under mildly acidic con-
ditions, the PMB ether was more stable and resistant to removal.
Attempts to deprotect under various acidic conditions (acidic
Dowex resin, acidic Amberlyst 15 resin, and pTsOH in MeOH)
led to partial deprotection or decomposition at longer reaction
times. Conditions with trimethylsilyl triflate (TMSOTf),
N-trimethylsilylimidazole (TMSI), and BCl3 also failed to
effect deprotection without decomposition. Ultimately, the use
of concentrated HCl in MeOH (12 h at room temperature) was
found to be effective,31,2p and purification by flash chromatogra-
phy followed by reverse-phase HPLC provided synthetic der-
mostatin A (1) in 76% yield. Synthetic dermostatin A exhibited
spectroscopic and physical properties identical to those reported
for the natural material [1H and 13C NMR, circular dichroism
(CD), and high-resolution mass spectrometry (HRMS)].
a digital polarimeter at 28 °C (ambient temperature). Exact mass was
obtained by electrospray ionization in positive ion mode (M + H or M +
Na or M + Li) or in negative ion mode (M + Cl) as indicated.
Dimethyl 3-(tert-Butyldimethylsilyloxy)pentanedioate (14). To a
cooled (0 °C) solution of 3-hydroxypentanedioic acid dimethyl ester
(13; 10.44 g, 59.26 mmol, 1.0 equiv) and imidazole (5.23 g, 76.8 mmol,
1.3 equiv) in N,N-dimethylformamide (DMF) (20 mL) was added
TBSCl (9.4 g, 62 mmol, 1.1 equiv) in one portion. The reaction was
allowed to stir for 14 h, warming slowly to room temperature, and then
diluted with 100 mL of Et2O and washed with H2O (15 mL) and brine
(2 ꢁ 10 mL). The combined aqueous phases were extracted with ether
(10 mL). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. Distillation under reduced pres-
sure (113ꢀ121 °C at ca. 1 mmHg) afforded the diester 14 (14.40 g,
49.56 mmol, 84%). 1H NMR (500 MHz, CDCl3) δ 4.53 (quintet, J = 6.0
Hz, 1H), 3.65 (s, 6H), 2.49ꢀ2.58 (m, 4H), 0.82 (s, 9H), 0.04 (s, 6H).
13C NMR (100 MHz, CDCl3) δ 171.4, 66.3, 51.6, 42.4, 25.6, 17.8, ꢀ5.0.
IR (cmꢀ1) 2925, 2946, 2913, 1730, 1432. HRMS m/z calcd for
C13H26O5Si + Na+, 313.1441; found, 313.1431.
3-(tert-Butyldimethylsilyloxy)pentanedial (15). A solution of ester
14 (5.0 g, 17.22 mmol, 1.0 equiv) in ether (80 mL) was cooled to
ꢀ78 °C. DIBAL-H (45 mL, 0.95 M in hexanes, 43 mmol, 2.5 equiv) was
added dropwise via a cannula over 50 min. The solution was stirred for
1 h at ꢀ78 °C and then quenched by addition of dry acetone (1 mL)
followed by saturated potassium sodium tartrate (80 mL). The mixture
was stirred vigorously for 3 h at room temperature. The phases were
separated, and the aqueous phase was extracted with ether (6 ꢁ 30 mL).
The combined organic phases were dried (MgSO4), concentrated under
reduced pressure, and heated at 100 °C for 40 min under vacuum
(ca. 2 mmHg) to give the largely monomeric dialdehyde 1513a as a red
’ CONCLUSIONS
In conclusion, the synthesis of dermostatin A is described; a
key step is the acetate aldol method developed in our group with
glutaradehyde 15 in a two-directional chain synthesis approach,
illustrating the robustness of this method. Other key steps
include a diastereotopic-group-selective acetal isomerization
and a cross-metathesis reaction between a terminal alkene and
a trienal. The synthesis is convergent and utilizes fragments of
roughly equal complexity in an efficient fashion.
1
oil. H NMR (500 MHz, CDCl3) δ 9.77 (t, J = 2.0 Hz, 2H), 4.70
(quintet, J = 6.0 Hz, 1H), 2.60ꢀ2.70 (m, 4H), 0.83 (s, 9H), 0.06 (s, 6H).
13C NMR (100 MHz, CDCl3) δ 200.6, 63.4, 51.0, 25.6, 17.9, ꢀ4.7.
Upon prolonged standing exposed to the atmosphere, the dialdehyde
1
undergoes reversible partial hydration and polymerization.13a The H
NMR spectrum of such polymerized material displays broad indiscern-
ible signals. Thus, the dialdehyde prepared as above was used in the next
aldol reaction immediately.
’ EXPERIMENTAL SECTION
(3R,7R)-1,9-Bis[(S)-4-tert-butyl-2-thioxothiazolidin-3-yl]-5-(tert-
butyldimethylsilyloxy)-3,7-dihydroxynonane-1,9-dione (16). To a
250 mL round-bottom flask were added the N-acetyl thiazolidinethione
1114 (7.66 g, 35.26 mmol, 2.05 equiv) and CH2Cl2 (50 mL). The flask
was cooled to 0 °C and PhBCl2 (4.7 mL, 35.26 mmol, 2.05 equiv) was
then added dropwise to provide an orange-colored solution. After
the solution was stirred for 3 min, (ꢀ)-sparteine (0.12 mL, 0.50 mmol,
2.6 equiv) was added dropwise, at which point the solution turned
yellow and cloudy. After being stirred for about a minute, the solution
turned translucent but remained yellow. The ice bath was then removed,
and the reaction was allowed to warm to room temperature and stir
for 30 min. The reaction was then cooled to 0 °C, and the dialdehyde
(3.96 g, 17.22 mmol, 1.0 equiv) in 4 mL of CH2Cl2 was added dropwise
via cannula over a period of about 10 min. The flask containing the
aldehyde was rinsed with 2 ꢁ 0.8 mL of CH2Cl2, which was also added
to the reaction via cannula. The reaction was stirred for 15 h at 0 °C and
then warmed to room temperature and stirred for 1 h. The reaction was
placed in an ice bath, quenched by the addition of hexanes (50 mL) and
H2O2 (30%, 20 mL), warmed to room temperature, and stirred rapidly
for 15 min at room temperature. (Note that rapid stirring is required
at this step. If the rate of stirring is too slow, incomplete oxidation of
the borane occurs, and boron species are observed in the product.) The
solution was diluted with 1:1 hexanes/CH2Cl2 (80 mL), and the layers
were separated. The organic layer was washed with distilled water and
brine. The combined aqueous layer was then extracted with 1:1 hexanes/
CH2Cl2 (80 mL) and washed with distilled water and brine.
General Information. All air- and moisture-sensitive reactions
were conducted under a dry nitrogen atmosphere in oven-dried glass-
ware, using standard syringe/cannula transfer techniques. Dichlorophe-
nylborane (97%) was purchased from Aldrich, distilled under nitrogen,
and then stored in a resealable container bearing a Teflon valve at
ꢀ26 °C under a nitrogen atmosphere until used. (ꢀ)-Sparteine was
distilled and stored under a nitrogen atmosphere at ꢀ26 °C until used.
2,2-Dimethoxypropane was predried with MgSO4 and passed through a
plug of basic alumina and was used immediately. Acrolein, crotonalde-
hyde, ethyl acrylate, and ethyl crotonate were distilled under nitrogen
prior to use. Triethylamine was distilled from CaH2 under nitrogen.
Dichloromethane was distilled from CaH2 under nitrogen. Toluene was
distilled from CaH2 under nitrogen. Tetrahydrofuran (THF) and Et2O
were distilled from sodium benzophenone ketyl under nitrogen. All
other starting materials were used as received. In order to avoid
hydrolysis, flash chromatography of the acetate aldol adducts was
performed on neutral silica gel [Mallinckrodt Silicar silica gel 150,
60ꢀ200 mesh (75ꢀ250 μm)] following the procedure of Still et al.32
All other flash chromatography was performed by use of Sorbent
Technologies 60 Å silica gel (32ꢀ63 mm). 1H NMR spectra were
recorded at 500 or 400 MHz, with CDCl3 (internal reference 7.24 ppm)
as solvent. 13C NMR spectra were obtained at 100 MHz with CDCl3
(internal reference 77.23 ppm) as solvent. Infrared spectra were
recorded as thin films on NaCl plates. Melting points were determined
in capillaries and are uncorrected. Optical rotations were determined on
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The combined organics were dried over anhydrous MgSO4, filtered, and
concentrated at reduced pressure to provide an orange oil. Analysis of
this material by 1H NMR provided a diastereomeric ratio (dr) value of
>20:1. The product was purified by flash chromatography on neutral
silica gel (20:1 to 5:1 hexanes/EtOAc) to provide the aldol adduct 16
as a translucent yellow oil (8.0 g, 12.1 mmol, 70% over two steps). 1H
NMR (500 MHz, CDCl3) δ 5.33 (d, J = 7.8 Hz, 1H), δ 5.31 (d, J = 7.8
Hz, 1H), 4.34ꢀ4.20 (m, 2H), 4.17ꢀ4.07 (m, 1H), 3.56ꢀ3.26 (m,
8H), 3.10 (d, J = 11.8 Hz, 1H), 1.87ꢀ1.73 (m, 2H), 1.73ꢀ1.58 (m,
2H), 1.01 (s, 9H), 0.86 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 205.3, 205.2, 173.0, 172.6, 72.4, 72.3, 67.8, 46.1,
45.7, 43.7, 42.1, 38.2, 30.8, 30.7, 27.1, 26.1, 18.2, ꢀ4.3, ꢀ4.5. IR
Celite, and concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel (4:5 hexanes/EtOAc) to
give alcohol 19 as a white foam (2.50 g, 5.65 mmol, 90%). H NMR
1
(400 MHz, CDCl3) δ 7.44ꢀ7.32 (m, 4H), 6.90ꢀ6.80 (m, 4H), 5.47
(s, 1H), 5.46 (s, 1H), 4.26ꢀ4.17 (m, 3H), 4.17ꢀ4.06 (m, 2H),
3.99ꢀ3.88 (m, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.40 (br s, 1H),
1.96ꢀ1.76 (m, 3H), 1.76ꢀ1.58 (m, 3H), 1.54ꢀ1.40 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 160.2, 160.0, 131.6, 130.9, 127.5, 127.4,
113.9, 113.7, 101.3, 101.2, 78.0, 74.0, 67.3, 67.1, 55.5, 43.9, 43.4, 31.8,
31.6. IR (cmꢀ1) 3510, 2950, 2913, 1614, 1511. [R]28D = +181.6 (c 0.07,
CH2Cl2). HRMS m/z calcd for C25H32O7 + H+, 445.2220; found,
445.2215.
(cmꢀ1) 3421, 2951, 2897, 1642. [R]28 = +182.5 (c 0.06, EtOH).
2-[(2S,4S,6S)-2-(4-Methoxyphenyl)-6-{[(2S,4S)-2-(4-methoxyphenyl)-
1,3-dioxan-4-yl]methyl}-1,3-dioxan-4-yl]ethanol (20). To a solution of
alcohol 19 (1.50 g, 3.39 mmol, 1.0 equiv) in toluene (15 mL) was added
p-anisaldehyde dimethyl acetal (577 μL, 3.39 mmol, 1.0 equiv) dropwise by
syringe. PPTS (804 mg, 3.39 mmol, 1.0 equiv) was then added in one
portion, and the solution was heated to 90 °C and stirred for 3 h. A sample
of the reaction mixture was analyzed by 1H NMR and was found to provide
alcohol 20/alcohol 19 > 85:15. The reaction was then quenched with 5 mL
of saturated NaHCO3 solution. The organic layer was separated and
the aqueous layer was extracted with Et2O (2 ꢁ 20 mL). The combined
organic extracts were dried over MgSO4, filtered through Celite, and
concentrated under reduced pressure. The crude residue was purified by
flash chromatography on silica gel (25:1 CH2Cl2/acetone) to give alcohol
20 as a white solid (1.23 g, 2.78 mmol, 82%). Also, 180 mg (12%) of alcohol
D
HRMS m/z calcd for C29H52N2O5S4Si + Na+, 687.2420; found,
687.2445.
(3S,7S)-5-(tert-Butyldimethylsilyloxy)nonane-1,3,7,9-tetraol (17). To
a cooled (0 °C) yellow solution of compound 16 (7.50 g, 11.28 mmol,
1.00 equiv) in ethanol (50 mL) was added NaBH4 (2.56 g, 67.66 mmol,
6.00 equiv) in five portions over 10 min. The reaction was warmed to
room temperature and stirred until the yellow solution became colorless.
The reaction was quenched by addition of excess solid NH4Cl (50 g) and
stirred for 2.5 h. This mixture was filtered through Celite (washing with
1:1 EtOAc/MeOH) and concentrated under reduced pressure to give a
cloudy, viscous residue indicative of incomplete borate methanolysis. The
residue was dissolved in methanol (500 mL) and NH4Cl (20 g) was
added. Distillation of 450 mL of MeOH removed trimethylborate
azeotropically. The remainder was diluted with EtOAc, filtered, and con-
centrated under reduced pressure. The residue was taken up in EtOAc,
filtered through Celite, and concentrated under reduced pressure. The
product was then purifiedbyflashchromatographyonsilica gel (EtOAc to
10:1 EtOAc/MeOH) to provide tetraol 17 (2.90 g, 9.02 mmol, 80%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.34ꢀ4.07 (m, 2H),
4.01ꢀ3.90 (m, 1H), 3.90ꢀ3.73 (m, 3H), 3.0ꢀ3.50 (br s, 4H),
1.89ꢀ1.77 (m, 2H), 1.77ꢀ1.58 (m, 6H), 0.87 (s, 9H), 0.11 (s, 3H),
0.09 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 70.0, 69.6, 69.0, 61.6, 43.8,
42.2, 39.3, 39.1, 26.0, 18.1, ꢀ4.4, ꢀ4.5. IR (cmꢀ1) 3367, 2921, 2856.
[R]28D = +9.7 (c 1.11, CH2Cl2). HRMS m/z calcd for C15H34O5Si + H+,
323.2248; found, 323.2244.
{1,3-Bis[(2S,4S)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propan-2-
yloxy}(tert-butyl)dimethylsilane (18). To a cooled (0 °C) solution of
tetraol 17 (2.50 g, 7.76 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was added
p-anisaldehyde dimethyl acetal (3.31 mL, 19.41 mmol, 2.5 equiv)
dropwise by syringe. PPTS (1.95 g, 7.76 mmol, 1.0 equiv) was then
added in one portion and the solution was warmed to room temperature,
and stirred for 3 h. The reaction was then filtered through a short plug of
silica with a layer of Celite on top with CH2Cl2 as the eluent and
concentrated at reduced pressure. Flash chromatography on silica gel
(5:1 hexanes/EtOAc) provided analytically pure 18 as a colorless oil
(3.67 g, 6.60 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.32
(m, 4H), 6.84ꢀ6.76 (m, 4H), 5.45 (s, 1H), 5.42 (s, 1H), 4.33ꢀ4.18 (m,
3H), 4.05ꢀ3.88 (m, 4H), 3.76 (s, 3H), 3.75 (s, 3H), 1.96ꢀ1.73 (m, 4H),
1.69ꢀ1.59 (m, 2H), 1.51ꢀ1.42 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H).
13C NMR (100 MHz, CDCl3) δ 159.9, 159.8, 131.6, 131.5, 127.4, 127.3,
113.7, 113.6, 100.9, 100.8, 73.9, 73.5, 67.3, 67.2, 65.0, 55.4, 44.4, 43.8,
32.2, 32.1, 26.1, 18.3, ꢀ4.0, ꢀ4.4. IR (cmꢀ1) 2950, 2856, 1622, 1516.
[R]28D = +79.3 (c 0.33, CH2Cl2). HRMS m/z calcd for C31H46O7Si +
H+, 559.3085; found, 559.3106.
1
19 was recovered and could be reused. H NMR (400 MHz, CDCl3)
δ 7.43ꢀ7.36 (m, 4H), 6.92ꢀ6.84 (m, 4H), 5.51 (s, 1H), 5.47 (s, 1H),
4.26ꢀ4.18 (m, 1H), 4.18ꢀ4.10 (m, 2H), 4.10ꢀ4.02 (m, 1H), 3.99ꢀ3.88
(m, 1H), 3.87ꢀ3.79 (m, 2H), 3.79 (s, 6H), 2.16 (br t, 1H), 1.90ꢀ1.73 (m,
5H), 1.60ꢀ1.46 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 160.1, 160.0,
131.6, 131.4, 127.5, 127.4, 113.8, 113.7, 101.1, 100.7, 76.3, 73.1, 72.7, 67.2,
60.7, 55.5, 42.8, 38.2, 37.4, 32.0. IR (cmꢀ1) 3420, 2946, 2913, 1610, 1511.
[R]28D = +101.7 (c 0.10, CH2Cl2). HRMS m/z calcd for C25H32O7 + H+,
445.2220; found, 445.2211.
2-[(2R,4R,6R)-2-(4-Methoxyphenyl)-6-{[(2S,4S)-2-(4-methoxyphenyl)-
1,3-dioxan-4-yl]methyl}-1,3-dioxan-4-yl]acetaldehyde (22). Toa cooled
solution (0 °C) of alcohol 20 (1 g, 2.26 mmol, 1.0 equiv) in CH2Cl2
(10mL) wasaddedsolidK2CO3 (468mg, 3.39 mmol, 1.5 equiv), followed
byDessꢀMartin periodinane (1.44 g, 3.39 mmol, 1.5 equiv). The resulting
solution was allowed to warm to room temperature and stirred for 15 h.
The mixture was diluted with 10 mL of CH2Cl2, 10 mL of saturated
aqueous NaHCO3, and 10 mL of saturated aqueous Na2S2O3 and stirred
for 15 min. The aqueous phase was extracted with Et2O (2 ꢁ 20 mL) and
the combined organic layers were washed with 3 mL of saturated aqueous
Na2S2O3, saturated aqueous NaHCO3, and brine and then dried over
MgSO4 and filtered through Celite. After evaporation, the crude residue
was purified by flash chromatography on silica gel (15:1 CH2Cl2/EtOAc)
to give aldehyde 22 as a clear, colorless oil (910 mg, 2.07 mmol, 92%). 1H
NMR (400 MHz, CDCl3) δ 9.82 (t, J = 1.7 Hz, 1H), 7.46ꢀ7.34 (m, 4H),
6.93ꢀ6.83 (m, 4H), 5.54 (s, 1H), 5.48 (s, 1H), 4.43ꢀ4.33 (m, 1H),
4.24ꢀ4.10 (m, 3H), 3.99ꢀ3.88 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 2.77
(ddd, J = 2.2, 7.3, 16.8 Hz, 1H), 2.57 (ddd, J = 1.7, 5.1, 16.8 Hz, 1H),
1.86ꢀ1.71 (m, 3H), 1.71ꢀ1.62 (m, 1H), 1.53ꢀ1.40 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 200.6, 160.1, 160.0, 131.6, 131.1, 127.5, 127.5,
113.8, 101.1, 100.8, 73.1, 72.6, 72.0, 67.1, 55.5, 49.6, 42.8, 37.2, 31.9.
IR (cmꢀ1) 2954, 2913, 1728, 1615, 1511. [R]28 = +188.4 (c 0.06,
D
1,3-Bis[(2S,4S)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propan-2-ol (19).
To a solution of acetal 18 (3.50 g, 6.28 mmol, 1.0 equiv) in THF (8 mL)
was added a solution of TBAF (12.56 mL, 1 M solution in THF,
2.0 equiv). The reaction mixture was stirred for 6 h at room temperature
and then was quenched with 20 mL of H2O. The organic layer was
separated and the aqueous layer was extracted with Et2O (2 ꢁ 20 mL).
The combined organic extracts were dried over MgSO4, filtered through
CH2Cl2). HRMS m/z calcd for C25H30O7 + H+, 443.2064; found,
443.2071.
(2R,3R)-[(1R,2S)-2-(N-Benzyl-2,4,6-trimethylphenylsulfonamido)-1-
phenylpropyl] 3-Hydroxy-4-[(2S,4S,6R)-2-(4-methoxyphenyl)-6-{[(2S,4S)-
2-(4-methoxyphenyl)-1,3-dioxan-4-yl]methyl)-1,3-dioxan-4-yl]-2-methyl-
butanoate (24). Dicyclohexylborontriflate33 (5.40 mmol in 6 mL of
CH2Cl2, 2.60 equiv) was added dropwise to a ꢀ78 °C solution of 2316
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The Journal of Organic Chemistry
FEATURED ARTICLE
(2.48 g, 5.18 mmol, 2.50 equiv) and Et3N (0.96 mL, 6.89 mmol, 3.33
equiv) in CH2Cl2 (30 mL).34 After 2 h, aldehyde 22 (910 mg, 2.07 mmol,
1.0 equiv) in 3 mL of CH2Cl2 was added dropwise via cannula. The flask
containing the aldehyde was rinsed with 2 ꢁ 0.5 mL of CH2Cl2, which
was also added to the reaction via cannula. The reaction was stirred for
an additional hour at ꢀ78 °C and then warmed to room temperature
and stirred for 2 h. The reaction was quenched by the addition of pH 7
buffer (12 mL), MeOH (30 mL), and hydrogen peroxide (4 mL of a
30% solution). The resulting mixture was vigorously stirred overnight
and then diluted with water (30 mL) and CH2Cl2 (40 mL). The
layers were separated, and the aqueous layer was extracted with CH2Cl2
(3 ꢁ 40 mL). The combined organic extracts were washed with
brine (20 mL), dried over MgSO4, filtered, and concentrated at reduced
pressure. The product was determined to be a 20:1 mixture of
diastereomers by 1H NMR analysis of the crude reaction mixture. Flash
chromatography on silica gel (3:1 hexanes/EtOAc) provided alcohol
and the mixture was allowed to warm to room temperature where the
slurry turned into a homogeneous brown solution, which was then
cooled to 0 °C and quenched with saturated NH4Cl solution (10 mL).
The organic layer was separated and the aqueous layer was extracted
with Et2O (2 ꢁ 10 mL). The combined organic extracts were washed
with brine, dried over MgSO4, filtered through Celite, and concentrated
under reduced pressure. Flash chromatography on silica gel (3:4
hexanes/EtOAc) provided the amide (825 mg, 1.25 mmol, 81%) as a
white foam. 1H NMR (400 MHz, CDCl3) δ 7.46ꢀ7.38 (m, 4H),
6.93ꢀ6.84 (m, 4H), 5.51 (s, 1H), 5.50 (s, 1H), 4.24ꢀ4.08 (m, 5H), 3.95
(m, 1H), 3.79 (s, 6H), 3.58 (s, 3H), 3.48ꢀ3.35 (m, 1H), 3.12 (s, 3H),
2.04ꢀ1.93 (m, 1H), 1.87ꢀ1.72 (m, 3H), 1.68ꢀ1.60 (m, 1H),
1.55ꢀ1.48 (m, 2H), 1.48ꢀ1.38 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H),
0.85 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
176.6, 160.0, 159.8, 131.7, 131.6, 127.5, 127.3, 113.8, 113.6, 101.2, 100.2,
73.2, 72.9, 72.7, 71.6, 67.2, 61.4, 55.5, 55.5, 42.9, 40.6, 39.3, 38.2, 32.0,
26.0, 18.2, 13.8, ꢀ4.4, ꢀ4.8. IR (cmꢀ1) 2933, 2852, 1659, 1614,
1
24 (1.76 g, 1.90 mmol, 92%) as a white foam. H NMR (400 MHz,
CDCl3) δ 7.48ꢀ7.36 (m, 4H), 7.34ꢀ7.27 (m, 2H), 7.25ꢀ7.13 (m, 6H),
6.95ꢀ6.83 (m, 8H), 5.82 (d, J = 3.9 Hz, 1H), 5.51 (s, 1H), 5.47 (s, 1H),
4.76 (d, A of AB, J = 16.7 Hz, 1H), 4.58 (d, B of AB, J = 16.7 Hz, 1H),
4.30ꢀ4.19 (m, 1H), 4.18ꢀ3.90 (m, 6H), 3.79 (s, 3H), 3.77 (s, 3H), 3.41
(d, J = 2.5 Hz, OH), 2.63ꢀ2.52 (m, 1H), 2.49 (s, 6H), 2.26 (s, 3H),
1.81ꢀ1.60 (m, 5H), 1.60ꢀ1.40 (m, 3H), 1.15 (d, J = 7 Hz, 3H), 1.10 (d,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.0, 160.1, 160.0,
142.7, 140.4, 138.8, 138.6, 133.6, 132.3, 131.5, 131.0, 128.5, 128.5, 128.0,
127.7, 127.4, 127.4, 127.2, 126.0, 113.8, 113.7, 101.1, 100.6, 78.4, 73.0,
72.7, 72.3, 67.1, 57.0, 55.5, 48.4, 45.8, 42.7, 39.1, 37.5, 31.9, 23.1,
21.1, 13.4, 13.0. IR (cmꢀ1) 3448, 3064, 2942, 2852, 1740, 1614, 1511.
[R]28D = +107.5 (c 0.14, CH2Cl2). HRMSm/z calcd forC53H63NO11S +
H+, 922.4194; found, 922.4216.
1516, 1242. [R]28 = +17.7 (c 1.30, CH2Cl2). HRMS m/z calcd for
D
C36H55NO9Si + H+, 674.3718; found, 674.3691.
In a 25 mL flask were placed the above amide (800 mg, 1.21 mmol,
1.0 equiv) and THF (6 mL). The reaction mixture was cooled to 0 °C
with an ice bath. To the solution was added a 1 M solution of
allylmagnesium bromide in Et2O (1.46 mL, 1.46 mmol, 1.2 equiv)
dropwise over 2 min. The reaction mixture was stirred for 30 min. The
reaction was then quenched with saturated aqueous NH4Cl solution
(2 mL) and was transferred to a separatory funnel. The phases were
separated and the aqueous phase was extracted with CH2Cl2 (2 ꢁ
5 mL). The combined organics were washed with brine (5 mL), dried
over MgSO4, filtered through Celite, and concentrated under reduced
pressure, providing the expected ketone (775 mg, >99%) as a translu-
cent yellow oil, which was used immediately.
(4S,5S,6R)-6-(tert-Butyldimethylsilyloxy)-7-[(2R,4R,6R)-2-(4-meth-
oxyphenyl)-6-{[(2S,4S)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]methyl}-
1,3-dioxan-4-yl]-5-methylhept-1-en-4-ol (26). To a solution of alcohol
24 (1.70 g, 1.84 mmol, 1.0 equiv) and 2,6-lutidine (0.96 mL, 8.30 mmol,
4.50 equiv) in dichloromethane (3 mL) was added triethylsilyl triflate
(TESOTf) (1.27 mL, 5.53 mmol, 3.00 equiv) at 0 °C. The reaction was
warmed to room temperature and stirred for 4 h, and then the reaction
was diluted with dichloromethane (20 mL) and quenched with saturated
NaHCO3 (5 mL). The layers were separated, and the aqueous layer
was extracted with dichloromethane (2 ꢁ 10 mL). The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and
concentrated at reduced pressure. Flash chromatography on silica gel
(4:1 hexanes/EtOAc) provided the ester (1.68 g, 1.62 mmol, 88%) as a
To a cooled (ꢀ50 °C, acetonitrileꢀdry ice bath) solution of the
above ketone (775 mg, 1.212 mmol, 1.0 equiv) in methanol (6 mL) was
added NaBH4 (230 mg, 6.060 mmol, 5.0 equiv) in a single portion. After
15 h, the reaction was quenched by the addition of saturated aqueous
NH4Cl solution (6 mL). The mixture was warmed to room temperature
and was diluted with CH2Cl2 (20 mL) and H2O (6 mL). The mixture
was transferred to a separatory funnel, and the phases were separated.
The aqueous phase was extracted with CH2Cl2 (2 ꢁ 20 mL). The
combined organic extracts were washed with brine, dried over MgSO4,
filtered through Celite, and concentrated under reduced pressure.
The product was determined to be a 10:1 mixture of diastereomers by
1H NMR analysis of the crude reaction mixture. Flash chromatography
on silica gel (3:1 hexanes/EtOAc) provided alcohol 26 (620 mg,
1
white foam. H NMR (100 MHz, CDCl3) δ 7.44ꢀ7.38 (m, 2H), δ
1
7.38ꢀ7.33 (m, 2H), δ 7.32ꢀ7.26 (m, 2H), 7.23ꢀ7.12 (m, 4H),
7.12ꢀ7.07 (m, 2H), 6.91ꢀ6.80 (m, 8H), 5.72 (d, J = 5.0 Hz, 1H), 5.47
(s, 1H), 5.38 (s, 1H), 4.74 (d, A of AB, J = 16.4 Hz, 1H), 4.48 (d, B of AB,
J = 16.4 Hz, 1H), 4.24ꢀ4.17 (m, 1H), 4.15ꢀ3.98 (m, 4H), 3.97ꢀ3.84
(m, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 2.66ꢀ2.56 (m, 1H), 2.41 (s, 6H),
2.22 (s, 3H), 1.84ꢀ1.74 (m, 2H), 1.72ꢀ1.65 (m, 2H), 1.50ꢀ1.35 (m,
2H), 1.28ꢀ1.17 (m, 2H), 1.15 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 7.10 Hz,
3H), 0.84 (s, 9H), 0.01 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 172.6,
160.0, 160.0, 142.7, 140.5, 138.6, 138.4, 133.3, 132.3, 131.6, 131.6, 128.6,
128.5, 128.0, 127.9, 127.5, 127.4, 126.6, 113.8, 113.7, 101.1, 100.4, 78.4,
73.6, 73.1, 72.6, 70.5, 67.2, 56.9, 55.5, 48.3, 45.2, 42.8, 40.1, 37.6, 32.0,
26.1, 23.1, 21.1, 18.2, 14.2, 12.5, ꢀ4.3, ꢀ4.4. IR (cmꢀ1) 2921, 2855, 1732,
0.95 mmol, 78% over 2 steps) as a translucent yellow oil. H NMR
(400 MHz, CDCl3) δ 7.46ꢀ7.36 (m, 4H), 6.94ꢀ6.78 (m, 4H),
5.93ꢀ5.75 (m, 1H), 5.50 (s, 1H), 5.49 (s, 1H), 5.19ꢀ5.07 (m, 2H),
4.27ꢀ4.19 (m, 1H), 4.17ꢀ3.94 (m, 5H), 3.80 (s, 3H), 3.79 (s, 3H),
3.55ꢀ3.45 (m, 1H), 2.45 (br s, OH), 2.48ꢀ2.35 (m, 1H), 2.13ꢀ2.00
(m, 1H), 1.90ꢀ1.65 (m, 7H), 1.54ꢀ1.46 (m, 1H), 1.46ꢀ1.32 (m, 1H),
0.89 (s, 9H), 0.86 (d, J = 6.9 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 160.0, 159.9, 135.2, 131.7, 131.6, 127.5,
127.5, 118.3, 113.8, 113.7, 101.1, 100.6, 74.2, 73.3, 72.8, 72.7, 71.4,
67.2, 55.5, 43.4, 42.9, 39.9, 39.6, 37.7, 32.0, 26.1, 18.2, 12.1, ꢀ4.2,
ꢀ4.3. IR (cmꢀ1) 3488, 2942, 2854, 1616, 1517. [R]28D = +76.5 (c 3.30,
CH2Cl2). HRMS m/z calcd for C37H56O8Si + H+, 657.3817; found,
657.3796.
(4S,5S,6R)-4-Allyl-6-{[(2R,4R,6R)-2-(4-methoxyphenyl)-6-{[(2S,4S)-
2-(4-methoxyphenyl)-1,3-dioxan-4-yl]methyl}-1,3-dioxan-4-yl]methyl}-
2,2,5-trimethyl-1,3-dioxane (27). To a solution of alcohol 26 (500 mg,
0.76 mmol, 1.0 equiv) in THF (4 mL) was added a solution of
tetrabutylammonium fluoride (1.52 mL, 1 M solution in THF, 2.0
equiv). The reaction mixture was stirred for 6 h at room temperature
and then quenched with 5 mL of H2O. The layers were separated and the
1614, 1511. [R]28 = +88.7 (c 0.04, CH2Cl2). HRMS m/z calcd for
D
C59H77NO11SSi + H+, 1036.5059; found, 1036.5041.
To a slurry of the above ester (1.60 g, 1.54 mmol, 1.0 equiv) and N,O-
dimethylhydroxylamine hydrochloride (1.66 g, 16.98 mmol, 11.0 equiv)
in THF (30 mL) was added isopropylmagnesium chloride (2 M solution
in Et2O, 15.5 mL, 30.88 mmol, 20 equiv) at ꢀ20 °C over 20 min and
under vigorous stirring. The reaction mixture was then stirred at ꢀ20 °C
for 1 h and warmed to 5 °C over 1 h. The cooling bath was then removed
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The Journal of Organic Chemistry
FEATURED ARTICLE
1
aqueous layer was extracted with Et2O (2 ꢁ 10 mL). The combined
organic extracts were dried over MgSO4, filtered through Celite, and
concentrated under reduced pressure to provide the expected diol as
a translucent yellow oil, which was used immediately.
(139 mg, 0.24 mmol, 82%). Rf 0.29 (2:1 hexanes/EtOAc). H NMR
(400 MHz, CDCl3) δ 9.80 (t, J = 2.4 Hz, 1H), 7.40ꢀ7.31 (m, 2H),
7.30ꢀ7.20 (m, 2H), 6.92ꢀ6.80 (m, 4H), 5.99ꢀ5.83 (m, 1H), 5.43 (s,
1H), 5.13ꢀ4.99 (m, 2H), 4.59 (d, A of AB, J = 11.2 Hz, 1H), 4.47 (d, B of
AB, J = 11.2 Hz, 1H), 4.34ꢀ4.24 (m, 1H), 4.17ꢀ3.98 (m, 2H), 3.80 (s,
3H), 3.74 (s, 3H), 3.63ꢀ3.48 (m, 2H), 2.76ꢀ2.60 (m, 2H), 2.44ꢀ2.34
(m, 1H), 2.24ꢀ2.12 (m, 1H), 1.97ꢀ1.85 (m, 1H), 1.85ꢀ1.68 (m, 3H),
1.65ꢀ1.55 (m, 1H), 1.41 (s, 3H), 1.51ꢀ1.28 (m, 2H), 1.39 (s, 3H), 0.79
(d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 201.5, 159.8, 159.5,
135.1, 131.4, 130.2, 129.8, 127.3, 116.5, 114.1, 113.6, 100.3, 98.0, 77.6,
77.2, 76.9, 74.2, 73.5, 72.9, 71.9, 70.8, 70.3, 55.4, 55.3, 49.1, 42.2, 39.1,
38.0, 37.6, 36.7, 30.3, 19.7, 12.3. IR (cmꢀ1) 3072, 2991, 1929, 2905,
1724, 1618, 1511. [R]28D = +56.3 (c 1.90, CH2Cl2). HRMS m/z calcd
for C34H46O8 + H+, 583.3265; found, 583.3274.
To a cooled (0 °C) solution of the above diol in CH2Cl2 (3 mL) was
added 2,2-dimethoxypropane (1 mL, 8.16 mmol, 1.1 equiv, predried
with MgSO4 and passed through a plug of basic alumina) dropwise by
syringe. PPTS (90 mg, 0.38 mmol, 0.5 equiv) was then added in one
portion, and the solution was warmed to room temperature and stirred
for 3 h. The reaction was then filtered through a short plug of silica with
a layer of Celite on top, with CH2Cl2 as the eluent, and concentrated
at reduced pressure. Flash chromatography on silica gel (4:1 hexanes/
EtOAc) provided analytically pure 27 as a colorless oil (355 mg,
1
0.61 mmol, 80% over two steps). H NMR (400 MHz, CDCl3) δ
7.47ꢀ7.37 (m, 4H), 6.94ꢀ6.83 (m, 4H), 5.97ꢀ5.82 (m, 1H), 5.52 (s,
1H), 5.50 (s, 1H), 5.10ꢀ4.97 (m, 2H), 4.27ꢀ4.20 (m, 1H), 4.20ꢀ4.04
(m, 3H), 4.00ꢀ3.89 (m, 1H), 3.79 (s, 6H), 3.58ꢀ3.46 (m, 2H),
2.42ꢀ2.31 (m, 1H), 2.23ꢀ2.10 (m, 1H), 1.93ꢀ1.81 (m, 2H),
1.81ꢀ1.70 (m, 4H), 1.65ꢀ1.46 (m, 1H), 1.46ꢀ1.37 (m, 2H), 1.36 (s,
3H), 1.35 (s, 3H), 0.77 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 160.0, 159.9, 135.1, 131.8, 131.6, 127.5, 127.5, 116.6, 113.8,
113.7, 101.1, 100.4, 98.0, 74.2, 73.5, 73.2, 72.5, 70.8, 67.2, 55.5, 43.0,
39.3, 38.7, 37.6, 36.9, 32.0, 30.3, 19.7, 12.3. IR (cmꢀ1) 3064, 2942, 2913,
(4S,6S)-7-[(2R,4R,6R)-6-{[(4R,5S,6S)-6-Allyl-2,2,5-trimethyl-1,3-dioxan-
4-yl]methyl}-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-4-hydroxy-1-
{(4S,6R)-6-[(3S,4S,E)-4-hydroxy-3,5-dimethylhex-1-enyl]-2,2-dimethyl-
1,3-dioxan-4-yl}-6-(4-methoxybenzyloxy)heptan-2-one(29).To a cooled
(ꢀ10 °C) solution of ketone 818 (105 mg, 0.35 mmol, 1.5 equiv) in Et2O
(1.5 mL) was added NEt3 (110 μL, 0.79 mmol, 3.35 equiv) dropwise by
syringe. Chlorodicyclohexylborane (706 μL, 1.0 M in hexanes, 0.71 mmol,
3.0 equiv) was then added by cannula over 10 min, resulting in the
formation of a white precipitate. The resulting mixture was stirred for 40
min at ꢀ10 °C and then cooled to ꢀ78 °C. A solution of aldehyde 28 (137
mg, 0.235 mmol, 1.0 equiv) in Et2O (1 mL) was added dropwise by cannula
over 5 min. The flask originally containing the aldehyde was rinsed with
Et2O (2 ꢁ 0.6 mL), and this solution was also added to the reaction by
cannula. The resulting mixture was stirred for 3 h at ꢀ78 °C and 28 h at
ꢀ26 °C. The reaction was quenched by the addition of pH 7 buffer (3 mL),
MeOH (6 mL), and hydrogen peroxide (3 mL of a 30% solution). The
resulting mixture was then warmed to room temperature and vigorously
stirred for 3 h. The reaction mixture was transferred to a separatory funnel
and diluted with brine (5 mL) and CH2Cl2 (20 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL).
The combined organic extracts were diluted with Et2O (60 mL), washed
with 1 M NaOH aqueous solution (2 ꢁ 5 mL) and brine (1 ꢁ 5 mL), and
then dried over MgSO4, filtered through Celite, and concentrated under
reduced pressure. The product was determined to be a >15:1 mixture of
1614, 1511. [R]28 = +73.0 (c 3.20, CH2Cl2). HRMS m/z calcd for
D
C34H46O8 + H+, 583.3265; found, 583.3269.
(R)-4-[(2R,4R,6R)-6-{[(4R,5S,6S)-6-Allyl-2,2,5-trimethyl-1,3-dioxan-4-yl]-
methyl}-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-3-(4-methoxybenzyloxy)-
butanal (28). To a cooled (0 °C) solution of 27 (350 mg, 0.60 mmol,
1.0 equiv) in CH2Cl2 (5 mL) was added DIBAL-H (1.09 mL, 0.99 M in
hexanes, 1.08 mmol, 1.8 equiv) dropwise over 5 min. The resulting
solution was stirred for 10 min at 0 °C and then allowed to warm to room
temperature. After an additional 4 h, the reaction was quenched by
addition of saturated potassium sodium tartrate (5 mL) and stirred
vigorously for 2 h. The aqueous phase was saturated with NaCl and the
phases were separated. The aqueous phase was extracted with 1:1
CH2Cl2/Et2O (3 ꢁ 10 mL). The combined organic phases were dried
over MgSO4 and concentrated under reduced pressure. Flash chroma-
tography on silica gel (3:2 hexanes/EtOAc) gave the alcohol (281 mg,
0.48 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.30 (m, 2H),
7.27ꢀ7.22 (m, 2H), 6.90ꢀ6.77 (m, 4H), 5.99ꢀ5.80 (m, 1H), 5.41
(s, 1H), 5.10ꢀ4.98 (m, 2H), 4.56 (d, A of AB, J = 11.1 Hz, 1H), 4.46
(d, B of AB, J = 11.1 Hz, 1H), 4.14ꢀ4.04 (m, 1H), 4.04ꢀ3.93 (m, 2H),
3.78 (s, 3H), 3.85ꢀ3.74 (m, 1H), 3.72 (s, 3H), 3.74ꢀ3.64 (m, 1H),
3.61ꢀ3.47 (m, 2H), 2.41ꢀ2.33 (m, 1H), 2.32 (br s, OH), 2.23ꢀ2.11
(m, 1H), 2.00ꢀ1.83 (m, 2H), 1.83ꢀ1.64 (m, 4H), 1.63ꢀ1.52 (m, 1H),
1.39 (s, 3H), 1.49ꢀ1.27 (m, 2H), 1.37 (s, 3H), 0.77 (d, J = 6.6 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 159.8, 159.5, 135.1, 131.5, 130.5,
129.9, 127.4, 116.6, 114.1, 113.6, 101.3, 98.1, 74.2, 73.6, 73.5, 73.2, 71.8,
70.9, 60.1, 55.5, 55.4, 41.6, 39.2, 38.0, 37.6, 36.9, 36.4, 30.3, 19.7, 12.3. IR
1
diastereomers by H NMR analysis of the crude reaction mixture. Flash
chromatography on silica gel (3:2 hexanes/EtOAc) provided diol 29 (193
mg, 0.22 mmol, 93%) as a white viscous oil. 1H NMR (100 MHz, CDCl3) δ
7.36ꢀ7.30 (m, 2H), 7.27ꢀ7.20 (m, 2H), 6.89ꢀ6.78 (m, 4H), 5.96ꢀ5.81
(m, 1H), 5.63 (ddd, J = 0.8, 7.4, 15.7 Hz, 1H), 5.45 (ddd, J = 1, 6.2, 15.7 Hz,
1H), 5.39 (s, 1H), 5.08ꢀ4.98 (m, 2H), 4.58 (d, A of AB, J = 11.0 Hz, 1H),
4.47 (d, B of AB, J= 11.0 Hz, 1H), 4.37ꢀ4.32 (m, 3H), 4.12ꢀ4.01 (m, 2H),
4.01ꢀ3.91 (m, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.60ꢀ3.46 (m, 2H), 3.42
(br s, 1H, OH), 3.13 (t, J = 3.9 Hz, 1H), 2.68 (dd, J = 7.3, 16.1 Hz, 1H), 2.54
(br d, 2H), 2.37 (dd, J = 5.2, 16.1 Hz, 1H), 2.44ꢀ2.27 (m, 2H), 2.22ꢀ2.10
(m, 1H), 1.93ꢀ1.83 (m, 1H), 1.80ꢀ1.62 (m, 5H), 1.61ꢀ1.54 (m, 2H),
1.55ꢀ1.20 (m, 5H), 1.44 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H),
1.00 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 7.3 Hz, 3H),
0.77 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 209.2, 159.9,
159.6, 135.5, 135.2, 131.6, 130.8, 130.5, 130.1, 127.4, 116.6, 114.1, 113.7,
100.3, 99.1, 98.1, 79.9, 74.3, 73.6, 73.2, 72.6, 72.4, 70.9, 70.6, 65.7, 64.9, 55.5,
55.4, 51.5, 49.9, 41.8, 40.8, 39.5, 39.2, 38.1, 37.7, 37.2, 36.9, 30.8, 30.3, 30.3,
20.0, 19.9, 19.7, 17.3, 14.0, 12.3. IR (cmꢀ1) 3480, 2936, 2897, 1705, 1612,
(cmꢀ1) 3452, 3077, 2995, 2929, 1614, 1516. [R]28 = +51.8 (c 4.50,
D
CH2Cl2). HRMS m/z calcd for C34H48O8 + H+, 585.3421; found,
585.3428.
To a cooled solution (0 °C) of the above alcohol (170 mg, 0.29 mmol,
1.0 equiv)in CH2Cl2 (3 mL) was added solid K2CO3 (60 mg, 0.43 mmol,
1.5 equiv), followed by DessꢀMartin periodinane (184 mg, 0.43 mmol,
1.5 equiv). The resulting solution was allowed to warm to room
temperature and stirred for 15 h. The mixture was diluted with 3 mL
of CH2Cl2, 3 mL of saturated aqueous NaHCO3, and 3 mL of saturated
aqueous Na2S2O3 and stirred for 15 min. The aqueous phase was
extracted with Et2O (2 ꢁ 10 mL), and the combined organic layers were
washed with 3 mL of saturated aqueous Na2S2O3, saturated aqueous
NaHCO3, and brine. The organics were then dried over MgSO4, filtered
through Celite, and concentrated under reduced pressure. Flash chro-
matography on silica gel (5:2 hexanes/EtOAc) provided aldehyde 28
1511. [R]28D = +37.2 (c 2.90, CH2Cl2). HRMS m/z calcd for C51H76O12
+
Clꢀ, 915.5030; found, 915.5015.
(3S,4S,E)-6-[(4R,6R)-6-{[(4R,6S)-6-{(R)-3-[(2R,4R,6R)-6-{[(4R,5S,6S)-
6-Allyl-2,2,5-trimethyl-1,3-dioxan-4-yl]methyl}-2-(4-methoxyphenyl)-
1,3-dioxan-4-yl]-2-(4-methoxybenzyloxy)propyl}-2,2-dimethyl-1,3-di-
oxan-4-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl]-2,4-dimethylhex-5-
en-3-ol (30). To a solution of diol 29 (190 mg, 0.22 mmol, 1.0 equiv) in
5 mL of CH3CN at ꢀ30 °C was added (CH3)4NHB(OAc)3 (909 mg,
7649
dx.doi.org/10.1021/jo2012658 |J. Org. Chem. 2011, 76, 7641–7653

The Journal of Organic Chemistry
FEATURED ARTICLE
3.46 mmol, 16 equiv) as a solution in 2 mL of AcOH over a period of
10 min. The mixture was warmed to ꢀ25 °C and stirred for 48 h and
then quenched with 5 mL of half-saturated aqueous sodium potassium
tartrate. The reaction mixture was warmed to room temperature, diluted
with 5 mL of EtOAc, and neutralized with saturated sodium carbonate.
The reaction mixture was then transferred to a separatory funnel and
diluted with saturated sodium carbonate (5 mL) and EtOAc (20 mL).
The layers were separated, and the aqueous layer was extracted with
EtOAc (3 ꢁ 20 mL). The combined organic layers were washed with
5 mL of saturated aqueous NaHCO3 and brine before being dried over
MgSO4, filtered through Celite, and concentrated at reduced pressure to
provide the triol as a yellow oil (ca. 190 mg, >99%), which was used
immediately in the next step.
(100 MHz, CDCl3) δ 193.7, 159.8, 159.4, 152.5, 143.2, 138.3, 135.1,
131.7, 131.2, 131.0, 130.9, 129.6, 128.4, 127.3, 114.0, 113.6, 100.4,
100.2, 98.7, 98.1, 79.9, 74.1, 73.5, 72.3, 72.1, 70.9, 70.2, 65.5, 63.7, 63.0,
55.5, 55.4, 42.5, 42.3, 39.5, 39.2, 39.0, 38.1, 37.2, 36.9, 36.8, 30.8, 30.4,
30.3, 25.1, 20.0, 19.8, 19.7, 17.3, 14.0, 12.3. IR (cmꢀ1) 3510, 2983, 2933,
1736, 1679, 1614, 1511, 1377. [R]28D = +22.6 (c 6.30, CH2Cl2). HRMS
m/z calcd for C59H86O13 + Na+, 1025.5960; found, 1025.5926.
(2E,4E,6E,8E,10E,12E)-Ethyl 14-[(4S,5S,6R)-6-{[(2R,4R,6R)-6-{(R)-3-
[(4S,6R)-6-{[(4R,6R)-6-[(3S,4S,E)-4-Hydroxy-3,5-dimethylhex-1-enyl]-
2,2-dimethyl-1,3-dioxan-4-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl]-
2-(4-methoxybenzyloxy)propyl}-2-(4-methoxyphenyl)-1,3-dioxan-4-
yl]methyl}-2,2,5-trimethyl-1,3-dioxan-4-yl]tetradeca-2,4,6,8,10,12-hex-
aenoate (48). To a cooled (ꢀ78 °C) solution of diisopropylamine
(32.3 μL, 0.23 mmol, 3.70 equiv) in THF (1 mL) was added dropwise
over 2 min n-BuLi (142 μL, 1.55 M in hexanes, 0.22 mmol, 3.50 equiv).
The resulting cloudy mixture was allowed to warm to room temperature
and stirred for 10 min and was then cooled to ꢀ78 °C. Phosphonate 4729
(60.8 mg, 0.22 mmol, 3.50 equiv) in 1 mL of THF was added to the above
LDA solution by cannula over 5 min to give a bright yellow solution,
which was stirred for 30 min before aldehyde 46 (63 mg, 0.06 mmol,
1.0 equiv) was added via cannula as a solution in 0.8 mL of THF (plus
0.8 mL of THF rinse). After 30 min at ꢀ78 °C, the solution was warmed
to room temperature and stirred for 10 h. Then the reaction was
quenched with 3 mL of saturated aqueous NaHCO3 and diluted with
5 mL of Et2O. The aqueous material was extracted with Et2O (3 ꢁ 5 mL)
and the combined organic layers was washed with 5 mL of brine, dried
over MgSO4, filtered through Celite, and concentrated under reduced
pressure. Flash chromatography on silica gel (2:1 hexanes/EtOAc)
To the above triol in CH2Cl2 (2 mL) was added dropwise 2,2-
dimethoxypropane (1 mL, 8.16 mmol, 37.8 equiv, predried with MgSO4
and passed through a plug of basic alumina). PPTS (51 mg, 0.22 mmol,
1.0 equiv) was then added in one portion and the solution was stirred for
15 h at room temperature The reaction was then filtered through a short
plug of silica with a layer of Celite on top, with Et2O as the eluent,
and concentrated at reduced pressure. The product was determined
to be a >20:1 mixture of diastereomers by 1H NMR analysis of the crude
reaction mixture. Flash chromatography on silica gel (3:1 hexanes/
EtOAc) provided analytically pure 30 as a white foam (191 mg,
1
0.21 mmol, 96% over two steps). H NMR (400 MHz, CDCl3) δ
7.39ꢀ7.33 (m, 2H), 7.26ꢀ7.20 (m, 2H), 6.89ꢀ6.79 (m, 4H),
5.95ꢀ5.81 (m, 1H), 5.64 (ddd, J = 0.7, 7.3, 15.7 Hz, 1H), 5.50 (ddd,
J = 0.9, 6.1, 15.7 Hz, 1H), 5.41 (s, 1H), 5.09ꢀ4.97 (m, 2H), 4.51 (d, A of
AB, J = 10.9 Hz, 1H), 4.45 (d, B of AB, J = 10.9 Hz, 1H), 4.35ꢀ4.26 (m,
1H), 4.10ꢀ3.91ꢀ3.81 (m, 5H), 3.60ꢀ3.46 (m, 1H), 3.78 (s, 3H), 3.72
(s, 3H), 3.53 (m, 2H), 3.13 (q, J = 5.5 Hz, 1H), 2.41ꢀ2.28 (m, 2H),
2.22ꢀ2.11 (m, 1H), 1.90ꢀ1.50 (m, 10H), 1.50ꢀ1.21 (m, 6H), 1.42 (s,
3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.32 (s, 3H),
1.01 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H),
0.76 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.8, 159.4,
135.1, 131.7, 131.2, 130.9, 129.7, 127.4, 116.6, 114.0, 113.6, 100.5, 100.2,
98.7, 98.0, 79.9, 76.9, 74.2, 73.6, 73.2, 72.1, 72.0, 70.9, 70.2, 65.5, 63.7,
63.0, 55.5, 55.4, 42.5, 42.4, 39.5, 39.2, 39.0, 38.0, 37.6, 37.2, 36.9, 30.8,
30.4, 30.3, 25.1, 20.0, 19.9, 19.7, 17.3, 14.0, 12.3. IR (cmꢀ1) 3501, 2987,
2942, 1614, 1516, 1458. [R]28D = +36.3 (c 5.00, CH2Cl2). HRMS m/z
calcd for C54H82O12 + H+, 923.5879; found, 923.5907.
(2E,4E,6E)-8-[(4S,5S,6R)-6-{[(2R,4R,6R)-6-[(2S,4S)-4-Hydroxy-7-
{(4S,6R)-6-[(3S,4S,E)-4-hydroxy-3,5-dimethylhex-1-enyl]-2,2-dimethyl-
1,3-dioxan-4-yl}-2-(4-methoxybenzyloxy)-6-oxoheptyl]-2-(4-meth-
oxyphenyl)-1,3-dioxan-4-yl]methyl}-2,2,5-trimethyl-1,3-dioxan-4-yl]-
octa-2,4,6-trienal (46). Alcohol 30 (226 mg, 0.25 mmol, 1.0 equiv) and
trienal 3918 (132 mg, 1.02 mmol, 4.16 equiv) were dissolved in CH2Cl2
(10 mL). Grubbs catalyst first generation (10 mg, 0.01 mmol, 0.05
equiv) was added in one portion, and the resulting solution was heated
to reflux for 24 h. The reaction was cooled to room temperature, and
the solvent was removed under reduced pressure. Purification by flash
column chromatography on silica gel (1:1 hexanes/EtOAc) provided
analytically pure aldehyde 46 as a yellow foam (216 mg, 0.22 mmol,
88%). 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 8.0, 1H), 7.41ꢀ7.33
(m, 2H), 7.33ꢀ7.21 (m, 2H), 7.09 (dd, J = 11.5, 15.5 Hz, 1H),
6.91ꢀ6.80 (m, 4H), 6.65 (dd, J = 11.3, 15.0 Hz, 1H), 6.32 (dd, J =
11.1, 15.0 Hz, 1H), 6.21 (dd, J = 10.5, 15.0 Hz, 1H), 6.17ꢀ6.05 (m,
2H), 5.64 (ddd, J = 0.7, 7.3, 15.6 Hz, 1H), 5.49 (ddd, J = 0.7, 6.1, 15.7
Hz, 1H), 5.42 (s, 1H), 4.53 (d, A of AB, J = 10.9 Hz, 1H), 4.46 (d, B of
AB, J = 10.9 Hz, 1H), 4.37ꢀ4.26 (m, 1H), 4.10ꢀ3.90 (m, 5H),
3.93ꢀ3.83 (m, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.63ꢀ3.51 (m, 2H),
3.15 (t, J = 5.70 Hz, 1H), 2.59ꢀ2.41 (m, 1H), 2.40ꢀ2.23 (m, 2H),
1.90ꢀ1.25 (m, 16H), 1.42 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H), 1.36 (s,
3H), 1.32 (s, 3H), 1.32 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.7
Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H). 13C NMR
1
provided ester 48 (46.7 mg, 0.04 mmol, 66%) as a yellow foam. H
NMR (400 MHz, CDCl3) δ 7.40ꢀ7.34 (m, 2H), 7.28 (dd, J = 3.3, 15.1
Hz, 1H), 7.29ꢀ7.22 (m, 2H), 6.90ꢀ6.79 (m, 4H), 6.58 (dd, J = 11.3, 14.8
Hz, 1H), 6.42 (dd, J = 10.7, 14.9 Hz, 1H), 6.40ꢀ6.23 (m, 5H), 6.16 (dd,
J = 10.0, 14.5 Hz, 1H), 6.13 (dd, J = 10.4, 14.7 Hz, 1H), 5.93ꢀ5.80 (m,
1H), 5.83 (d, J = 15.2 Hz, 1H), 5.62 (ddd, J = 0.7, 6.6, 15.0 Hz, 1H), 5.49
(ddd, J = 0.7, 6.3, 15.5 Hz, 1H), 5.41 (s, 1H), 4.51 (d, A of AB, J = 10.8 Hz,
1H), 4.44 (d, B of AB, J = 10.8 Hz, 1H), 4.37ꢀ4.27 (m, 1H), 4.18 (q, J =
7.0 Hz, 2H), 4.10ꢀ3.90 (m, 5H), 3.93ꢀ3.82 (m, 1H), 3.78 (s, 3H), 3.73
(s, 3H), 3.62ꢀ3.47 (m, 2H), 3.14 (q, J = 5.5 Hz, 1H), 2.51ꢀ2.40 (m,
1H), 2.40ꢀ2.31 (m, 1H), 2.31ꢀ2.20 (m, 1H), 1.90ꢀ1.20 (m, 16H), 1.55
(s, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.32 (s,
3H), 1.27 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.7 Hz,
3H), 0.87 (d, J = 6.9 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 167.4, 159.8, 159.4, 144.6, 141.0, 137.6, 136.0, 135.1,
132.7, 132.5, 131.7, 131.2, 131.1, 130.9, 129.9, 129.7, 127.4, 120.6, 114.0,
113.6, 100.5, 100.2, 98.7, 98.1, 79.9, 77.6, 74.4, 73.5, 73.2, 72.1, 72.0, 70.9,
70.2, 65.5, 63.7, 62.9, 60.4, 55.5, 55.4, 42.5, 42.3, 39.5, 39.2, 39.0, 38.1,
37.2, 36.9, 30.8, 30.4, 30.3, 25.1, 20.0, 19.9, 19.7, 17.3, 14.5, 14.0, 12.3. IR
(cmꢀ1) 3501, 2987, 2933, 1716, 1621, 1565, 1516. [R]D = 47.922 (c 0.19,
CH2Cl2). HRMS m/z calcd for C67H96O14 + H+, 1125.6872; found,
1125.6858.
Protected Dermostatin A (49). To a solution of ester 48 (35 mg,
0.03 mmol, 1.0 equiv) in 6 mL of 4:1:1 THF/H2O/MeOH was added
LiOH (2 mL, 1 M in H2O, 2.00 mmol, 64.5 equiv). This suspension was
stirred for 5 h and then diluted with 3 mL of water and 10 mL of EtOAc.
The aqueous material was extracted with EtOAc (5 ꢁ 10 mL) and the
combined organic layers were washed with 5 mL of brine, dried over
MgSO4, filtered through Celite, and concentrated under reduced
pressure to provide the crude hydroxy acid as a pale yellow oil.
To the above hydroxy acid in 4 mL of THF was added triethylamine
(44.3 μL, 0.32 mmol, 10.25 equiv), followed by 2,4,6-trichlorobenzoyl
chloride (33.9 μL, 0.22 mmol, 7.00 equiv). The reaction mixture was
stirred for 15 h and then filtered through a short plug of Celite
(prewashed with copious amounts of dry THF) and rinsed with excess
THF. The filtrate was concentrated under reduced pressure and
7650
dx.doi.org/10.1021/jo2012658 |J. Org. Chem. 2011, 76, 7641–7653

The Journal of Organic Chemistry
FEATURED ARTICLE
dissolved in 12 mL of toluene (0.002 M solution). This solution was
added, via syringe pump over 6 h, to 70 mL of toluene containing
4-(dimethylamino)pyridine (DMAP) (77.5 mg, 0.63 mmol, 20 equiv)
at room temperature. After addition was complete, the syringe was
rinsed with 2 mL of toluene and this was also added to the reaction.
The reaction mixture was stirred for 12 h and then was concentrated
under reduced pressure. Rapid flash chromatography on silica gel
(3:1 hexanes/EtOAc) provided protected dermostatin A 49 and its
isomeric compounds (ca. 25 mg, 0.02 mmol, 75% over two steps) as a
yellow foam. Rapid olefin isomerization prevented further isolation, via
HPLC, of a single, pure product that was not contaminated with varying
amounts of isomeric structures. HRMS m/z calcd for C65H90O13 + Clꢀ,
1113.6075; found, 1113.6040.
15.0 Hz, 1H), 5.21 (d, J = 9.5 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 1.28 (t,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.3, 144.5, 140.5,
137.6, 136.8, 132.5, 130.7, 121.2, 120.1, 60.6, 14.6. IR (cmꢀ1) 3016,
2991, 1703, 1263, 1156, 1013. HRMS m/z calcd for C11H14O2 + Li+,
185.1148; found, 185.1159.
(2E,4E,6E)-Nona-2,4,6,8-tetraenal (40). To a cooled (ꢀ78 °C) solu-
tion of 45 (500 mg, 2.81 mmol, 1.0 equiv) in CH2Cl2 (7 mL) was slowly
added diisobutylaluminum hydride (5.9 mL, 1 M in hexanes, 5.9 mmol,
2.1 equiv) by cannula. The ice bath was removed and the reaction was
stirred for 4 h, at which point it was at room temperature. The reaction
was diluted with Et2O (7 mL) and quenched by sequential addition
of water (0.5 mL), 1 M sodium hydroxide (1 mL), and additional
water (0.5 mL), resulting in the formation of a white precipitate. This
suspension was stirred for 30 min, then magnesium sulfate was added,
and the mixture was stirred for an additional 5 min. The solution was
filtered through Celite and concentrated under reduced pressure to
provide the desired tetraenol (355 mg, 2.61 mmol, 93%) as a white solid.
A portion of this material was used directly in the next reaction without
further purification.
Dermostatin A (1). To a solution of protected dermostatin A (49)
(ca. 15 mg of pure 49, 0.01 mmol, 1.0 equiv) in 10 mL of MeOH was
added concentrated HCl (70 μL, 0.84 mmol, 60.0 equiv). The reaction
was stirred for 12 h and then was neutralized by use of polymer-bound
piperidine (440 mg, ca. 1.68 mmol, ca. 120 equiv). The polymer was
removed by filtration and the filtrate was concentrated under reduced
pressure. The resulting crude yellow solid was purified by flash chro-
matography on silica gel (EtOAc to EtOAc/MeOH 3:1) to afford
dermostatin A (1) and partially deprotected 49. The partially depro-
tected macrolactone was resubjected to the reaction conditions de-
scribed above to afford ca. 8.0 mg of dermostatin A (1). After silica gel
chromatography, the synthetic dermostatin A (1) was further purified by
reversed-phase analytical HPLC (Alltima C18 5u, 250 mm ꢁ 10.0 mm
with a guard column33 mmꢁ 7 mm. MeOH/H2O 5:1, flow 1.8 mL/min,
UV detector at 390 nm; retention time 37.8 min). The HPLC purifica-
tion was repeated twice to obtain pure synthetic dermostatin A (1) (7.6
mg, 10.6 μmol, 76%) as a yellow powder. 1H NMR (500 MHz, CD3OD)
δ 7.30 (dd, J = 11.5, 15.1 Hz, 1H, H3), 6.70 (dd, J = 11.3, 14.5 Hz, 1H,
H5), 6.52 (dd, J = 11.2, 14.5 Hz, 1H, H7), 6.44ꢀ6.12 (m, 7H, H4, H6,
H8, H9, H10, H11, and H12), 5.88 (d, J = 15.0 Hz, 1H, H2), 5.84ꢀ5.79
(m, 1H, H13), 5.58 (dd, J = 5.4, 15.8 Hz, 1H, H33), 5.48 (dd, J = 5.1, 16.0
Hz, 1H, H32), 4.84ꢀ4.79 (m, 1H, H35), 4.27ꢀ4.24 (m, 1H, H15),
4.14ꢀ4.10 (m, 1H, H31), 4.10ꢀ3.89 (m, 6H, H19, H21, H23, H25,
H27, and H29), 3.56ꢀ3.54 (m, 1H, H17), 2.62ꢀ2.59 (m, 1H, H34),
2.48ꢀ2.34 (m, 2H, H14 and H140), 1.90ꢀ1.13 (m, 16H, H36, H16,
H18, H180, H20, H200, H22, H220, H24, H240, H26, H260, H28, H280,
H30, and H300), 1.01 (d, J = 6.9 Hz, 3H, H39), 0.94 (d, J = 6.7 Hz, 3H,
H37/H38), 0.87 (d, J = 6.9 Hz, 3H, H40), 0.85 (d, J = 6.4 Hz, 3H, H37/
H38). 13C NMR (100 MHz, CD3OD) δ 169.2, 147.1, 143.2, 139.6, 137.7,
136.1, 134.7, 133.8, 133.7, 133.5, 133.3(2), 132.8, 131.1, 121.4, 82.4, 72.5,
71.9, 71.3, 71.0, 70.6, 69.8, 69.6, 65.2, 64.7, 48.0, 47.6, 47.4, 46.1, 45.8, 44.8,
43.8, 38.7, 37.5, 30.9, 30.8, 20.4, 19.1, 11.4, 10.6. IR (cmꢀ1) 3354, 2942,
1565, 1430, 1131, 1246. [R]D = ꢀ99.162 (c 0.22, MeOH). Circular
dichroism: positive Cotton effect (max λ = 226 nm, min λ = 206 nm).
HRMS m/z calcd for C40H64O11 + H+, 719.4375; found, 719.4392.
(2E,4E,6E)-Ethyl Nona-2,4,6,8-tetraenoate (45). To a cooled (0 °C)
suspension of sodium hydride (776 mg, 19.4 mmol, 1.2 equiv) in THF
(75 mL) was added triethyl phosphonoacetate (3.85 mL, 19.4 mmol,
1.2 equiv) slowly by syringe. Rapid hydrogen gas evolution occurred
as the sodium hydride was consumed. After the mixture was stirred
at 0 °C for 30 min, a solution of 3918 (1.75 g, 16.2 mmol, 1.0 equiv) in
THF (6 mL) was added by cannula and the resulting red solution was
heated to reflux. After 16 h, the reaction was quenched by the addition of
saturated sodium bicarbonate (10 mL). The phases were separated and
the aqueous layer was extracted with Et2O (3 ꢁ 10 mL). The combined
organic layers were washed with brine, dried over magnesium sulfate,
filtered through Celite, and concentrated under reduced pressure. Flash
chromatography on silica gel (20:1 hexanes/EtOAc) provided tetra-
To a cooled (0 °C) solution of the tetraenol (28 mg, 0.21 mmol,
1.0 equiv) in CH2Cl2 (2 mL) was added DessꢀMartin periodinane
(96 mg, 0.23 mmol, 1.1 equiv) in one portion. The suspension was
slowly warmed to room temperature and stirred overnight. The mixture
was then filtered through a plug of silica over a pad of Celite, washed
with CH2Cl2 (5 mL), and then quenched with saturated 1:1 sodium
thiosulfate/sodium bicarbonate (10 mL) and allowed to stir for 1 h.
The phases were separated and the aqueous layer was extracted with
CH2Cl2 (3 ꢁ 3 mL); the combined organic layers were washed with
sodium bicarbonate (2 ꢁ 3 mL) and brine (1 ꢁ 3 mL). The organic layer
was dried over magnesium sulfate, filtered through Celite, and concen-
trated under reduced pressure. Flash chromatography on silica gel
(CH2Cl2) provided tetraenal 40 as a yellow oil (22.5 mg, 0.17 mmol,
82%). 1H NMR (500 MHz, CDCl3) δ 9.55 (d, J = 8.0 Hz, 1H), 7.12 (dd,
J = 15.5, 11.0 Hz, 1H), 6.68 (dd, J = 14.5, 11.0 Hz, 1H), 6.50ꢀ6.30 (m,
4H), 6.14 (dd, J = 15.0, 8.0 Hz, 1H), 5.37 (d, J = 16.5 Hz, 1H), 5.26 (d,
J = 10.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 193.8, 151.9, 142.5,
139.2, 136.7, 132.1, 131.5, 130.6, 121.2. IR (cmꢀ1) 1676, 1591, 1140,
1021. HRMS m/z calcd for C9H10O + Li+, 141.0886; found, 141.0879.
General Metathesis Procedure. Reactions were carried out in a
coldfinger apparatus in which there was no ground glass joint between
the condenser and reaction flask. This was done in order to prevent
evaporation of the solvent while the reaction was carried out under
nitrogen at reflux overnight. To a solution of alkene 3120 (50 mg,
0.17 mmol, 1.0 equiv) and metathesis partner (1ꢀ3 equiv) in CH2Cl2
(1.72 mL) was quickly added the ruthenium metathesis catalyst
(0.1 equiv) with brief exposure to atmosphere. The reaction was heated
at reflux overnight. The suspension was then cooled to room tempera-
ture, filtered through a silica plug over a pad of Celite, washed with
CH2Cl2, and concentrated under reduced pressure. Flash chromatog-
raphy on silica gel (40:1 hexanes/EtOAc) provided the product.
(E)-5-(tert-Butyldimethylsilyloxy)-7-phenylhept-2-enal (Table 1, En-
tries 3ꢀ6). Product was a colorless oil (51.2 mg, 0.16 mmol, 94%).
1H NMR (500 MHz, CDCl3) δ 9.47 (d, J = 8.0 Hz, 1H), 7.25ꢀ7.21
(m, 2H), 7.16ꢀ7.11 (m, 3H), 6.84 (dt, J = 15.0, 7.5 Hz, 1H), 6.10 (dd,
J = 15.0, 7.5 Hz, 1H), 3.87 (quintet, J = 6.0 Hz, 1H), 2.68ꢀ2.62 (m, 1H),
2.60ꢀ2.44 (m, 3H), 1.80ꢀ1.69 (m, 2H), 0.86 (s, 9H), 0.03 (s, 3H), 0.01
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 194.1, 155.2, 142.1, 135.2,
128.7, 128.5, 126.2, 70.8, 40.7, 39.3, 32.0, 22.3, 18.3, ꢀ4.16, ꢀ4.24. IR
(cmꢀ1) 3027, 2929, 2857, 1697, 1471, 1255, 1090, 776. HRMS m/z
calcd for C19H30O2Si + Na+, 341.1907; found, 341.1893.
(E)-Ethyl 5-(tert-Butyldimethylsilyloxy)-7-phenylhept-2-enoate (Table 2,
Entries 2, 3, 5, and 6). Product was a colorless oil (43.7 mg, 0.12 mmol,
70%). 1H NMR (500 MHz, CDCl3) δ 7.28ꢀ7.24 (m, 2H), 7.17ꢀ7.15
(m, 3H), 6.95 (dt, J = 15.5, 7.5 Hz, 1H), 5.82 (d, J = 15.5 Hz, 1H), 4.17
1
enoate 45 as a white, flaky solid (1.84 g, 10.3 mmol, 64%). H NMR
(500 MHz, CDCl3) δ 7.30 (dd, J = 26.5, 11.5 Hz, 1H), 6.55 (dd, J = 14.5,
10.5 Hz, 1H), 6.34ꢀ6.26 (m, 4H), 5.86 (d, J = 15.5 Hz, 1H), 5.32 (d, J =
7651
dx.doi.org/10.1021/jo2012658 |J. Org. Chem. 2011, 76, 7641–7653

The Journal of Organic Chemistry
FEATURED ARTICLE
(q, J = 7.5 Hz), 3.83 (quintet, J = 6.0 Hz, 1H), 2.71ꢀ2.65 (m, 1H),
2.61ꢀ2.55 (m, 1H), 2.43ꢀ2.34 (m, 2H), 1.77ꢀ1.73 (m, 2H), 1.27 (t, J =
7.5 Hz, 3H), 0.89 (s, 9H), 0.5 (s, 3H), 0.4 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.6, 145.9, 142.4, 128.65, 128.56, 126.1, 123.7, 71.1, 60.4,
40.4, 39.3, 32.0, 26.1, 18.3, 14.5, ꢀ4.2, ꢀ4.3. IR (cmꢀ1) 3027, 2930,
2857, 1721, 1257, 1092, 836. HRMS m/z calcd for C21H34O3Si + H+,
363.2350; found, 363.2350.
’ ACKNOWLEDGMENT
Financial support for this work was provided by the National
Institutes of Health (Grant GM48498) and by a Sharrah Fellow-
ship to C.C.A.
’ REFERENCES
(2E,4E,6E)-9-(tert-Butyldimethylsilyloxy)-11-phenylundeca-2,4,6-tri-
enal (Table 1, Entry 10). Product was a colorless oil (46 mg, 0.12 mmol,
70%). 1H NMR (500 MHz, CDCl3) δ 9.54 (d, J = 8.0 Hz, 1H),
7.28ꢀ7.24 (m, 2H), 7.18ꢀ7.15 (m, 3H), 7.10 (dd, J = 15.0, 11.0 Hz,
1H), 6.63 (dd, J = 15.0, 10.5 Hz, 1H), 6.34 (dd, J = 15.0, 11.0 Hz, 1H),
6.24ꢀ6.10 (m, 2H), 6.02 (dd, J = 22.5, 7.5 Hz, 1H), 3.80 (quintet, J = 6.0
Hz, 1H), 2.73ꢀ2.65 (m, 1H), 2.62ꢀ2.54 (m, 1H), 2.41ꢀ2.31 (m, 2H),
1.76ꢀ1.72 (m, 2H), 0.90 (s, 9H), 0.50 (s, 3H), 0.3 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 193.9, 152.6, 143.1, 142.5, 138.6, 132.2, 131.1,
(1) For reviews on oxo-polyene macrolide natural products, see
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T. K. J. Am. Chem. Soc. 1988, 110, 4672. (b) Poss, C. S.; Schreiber, S. L. J.
Am. Chem. Soc. 1993, 115, 3360. (c) Dreher, S. D.; Leighton, J. L. J. Am.
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Okumura, A.; Furukawa, H. Tetrahedron Lett. 1994, 35, 6503. (f) Mori,
Y.; Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron 1995, 51, 5299.
(g) Mori, Y.; Asai, M.; Kawade, J.-i.; Furukawa, H. Tetrahedron 1995,
51, 5315. (h) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003,
125, 10899. (i) Filipin III: Richardson, T. I.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1997, 119, 12360. (j) Roflamycoin: Rychnovsky, S. D.; Khire,
U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058. (k) Dermostatin: Sinz,
C. J.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2001, 40, 3224.
(l) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187.
(m) Schneider, C.; Tolksdorf, F.; Rehfeuter, M. Synlett 2002, 2098.
(n) RK-397:Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126,
2495. (o) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971.
(p) Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem., Int. Ed.
2007, 46, 1066. (q) Guo, H.; Mortensen, M. S.; O’Doherty, G. A. Org.
Lett. 2008, 10, 3149. (r) (+)-Roxaticin: Han, S. B.; Hassan, A.; Kim, I. S.;
Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559.
(3) (a) Zhang, Y; Phillips, A. J.; Sammakia, T. Org. Lett. 2004, 6, 23.
(b) Zhang, Y.; Sammakia, T. Org. Lett. 2004, 6, 3139. (c) Zhang, Y.;
Sammakia, T. J. Org. Chem. 2006, 71, 6262.
(4) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360. (b) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900. (c) Prunet, J. Curr. Top. Med. Chem. 2005,
5, 1559.
(5) Dermostatin A was isolated from the mycelium of Streptomyces
viridogriseus Thirum: Bhate, D. S.; Ambekar, G. R.; Bhatnagar, K. K.
Hind. Antibiot. Bull. 1962, 4, 159.
(6) Pandey, R. C.; Rinehart, K. L.; Millington, D. S.; Swami, M. B.
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(7) (a) Rychnovsky, S. D.; Griesgraber, G.; Schlegel, R. J. Am. Chem.
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(8) (a) Sinz, C. J.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2001,
40, 3224. (b) Sinz, C. J.; Rychnovsky, S. D. Tetrahedron 2002, 58, 6561.
(9) (a) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett.
1996, 37, 8585. (b) Evans, D. A.; Coleman, P. J.; C^otꢀe, B. J. Org. Chem.
1997, 62, 788. (c) Evans, D. A.; C^otꢀe, B.; Coleman, P. J.; Connell, B. T.
J. Am. Chem. Soc. 2003, 125, 10893. For a recentreview, see (d) Dias, L. C.;
Aguilar, A. M. Chem. Soc. Rev. 2008, 37, 451. For a recent advance, see
(e) Yamaoka, Y.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5354.
(10) Hoveyda, H. A.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
128.6, 128.5, 126.0, 71.6, 41.2, 39.3, 32.1, 18.4, ꢀ4.1, ꢀ4.3. IR (cmꢀ1
)
3026, 2929, 2856, 1682, 1614, 1255, 1112, 836. HRMS m/z calcd for
C23H34O2Si + Na+, 393.2220; found, 393.2202.
(2E,4E,6E)-Ethyl9-Hydroxy-11-phenylundeca-2,4,6-trienoate (Table2,
Entry 10). To a solution of alkene 3120 (100 mg, 0.34 mmol, 1.0 equiv) and
trienoate 45 (79 mg, 0.52 mmol, 1.5 equiv) in CH2Cl2 (3.44 mL) in a
coldfingerwasquicklyaddedtherutheniumcatalyst33 (28 mg, 0.03 mmol,
0.1 equiv) with brief exposure to atmosphere. The reaction was heated
to reflux and allowed to stir overnight. The suspension was then cooled to
room temperature, filtered through a silica plug over a pad of Celite,
washed with CH2Cl2 (5 mL), and concentrated under reduced pressure.
The crude mixture was then taken up in acetonitrile and transferred to a
plastic, conical vial and then concentrated again under reduced pressure.
To a cooled (0 °C) solution of this crude mixture (143 mg, 0.34 mmol, 1.0
equiv) and acetonitrile (3.45 mL) was added hydrofluoric acid (48% in
water, 0.2 mL, 14 equiv). After being stirred at 0 °C for 5 min, the reaction
was allowed to come to room temperature and was stirred overnight.
The reaction was then diluted with CHCl3 (5 mL), the layers were
separated, and the aqueous layer was extracted with CHCl3 (3 ꢁ 3 mL).
The combined organic layers were then dried over magnesium sulfate,
filtered through Celite, and concentrated under reduced pressure. Flash
chromatography on silica gel (5:1 hexanes/EtOAc) yielded the alcohol as
a yellow oil (87 mg, 0.29 mmol, 84%). 1H NMR (500 MHz, CDCl3) δ
7.29ꢀ1.23 (m, 2H), 7.18ꢀ7.14 (m, 3H), 6.49 (dd, J = 14.5, 11.0 Hz, 1H),
6.23ꢀ6.15 (m, 2H), 5.92ꢀ5.82 (m, 2H), 4.17 (q, J = 7.5 Hz, 2H),
3.70ꢀ3.66 (m, 1H), 2.82ꢀ2.75 (m, 1H), 2.69ꢀ2.62 (m, 1H), 2.42ꢀ2.24
(m, 1H), 1.80ꢀ1.73 (m, 2H), 1.91 (br s, 1H), 1.28ꢀ1.23 (m, 3H). 13C
NMR (100 MHz, CDCl3) δ 167.4, 144.7, 142.0, 140.6, 135.5, 132.9, 129.0,
128.6, 126.1, 120.9, 70.5, 60.5, 41.4, 38.8, 32.2, 14.5. IR (cmꢀ1) 3454, 3025,
2930, 1708, 1617, 1262, 1136. HRMS m/z calcd for C19H24O3 + Na+,
323.1617; found, 323.1619.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org/.
’ AUTHOR INFORMATION
(11) For related macrolactonization approaches to oxopolyene
macrolides, see (a) Mori, Y.; Asai, M; Kawade, J-i.; Okumura, A.;
Furukawa, H. Terahedron Lett. 1994, 35, 6503. (b) Evans, D. A.; Connell,
B. T. J. Am. Chem. Soc. 2003, 125, 10899. (c) Poss, C. S.; Rychnovsky,
S. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 3360. (d) Denmark,
S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971.
(12) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9.
(13) The polymerization of 15 is reversible and the dialdehyde can
be obtained cleanly by dehydration. See ref 2p for details and
(a) Buckley, S. L.; Drew, M. G. B.; Harwood, L. M.; Macías-Sꢀanchez,
Corresponding Author
*E-mail Sammakia@colorado.edu.
Present Addresses
†Hoffmann-La Roche Inc., Nutley, NJ 07110.
‡Gilead Sciences, Inc., Foster City, CA 94404.
§Department of Chemistry and Biochemistry, Denison Univer-
sity, Granville, OH 43023.
7652
dx.doi.org/10.1021/jo2012658 |J. Org. Chem. 2011, 76, 7641–7653

The Journal of Organic Chemistry
FEATURED ARTICLE
A. J. Tetrahedron Lett. 2002, 43, 3593. For an example of an aldol
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2006, 8, 2631. For a similar asymmetric allylation of a 3-alkoxyglutar-
aldehyde derivative, see (c) Shepherd, J. N.; Myles, D. C. Org. Lett. 2003,
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Wang, Z.; Desch^enes, D. J. Am. Chem. Soc. 1992, 114, 1090. For an
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Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J. Angew. Chem.,
Int. Ed. 2009, 48, 5018. For an example of an enantioselective double
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(31) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971.
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(34) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc.
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(14) See reference;3 purity was assessed by 1H NMR.
(15) Eliel, E. L.; Knoeber, M. C., Sr. J. Am. Chem. Soc. 1968, 90, 3444.
(16) Prepared by the method of Masamune; purity was assessed by
1H NMR. See Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586.
(17) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(18) See ref 2p; purity was assessed by 1H NMR.
(19) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
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(20) Prepared by the method of Phillips and Keaton; purity was
assessed by 1H NMR. See Keaton, K. A.; Phillips, A. J. Org. Lett. 2007,
9, 2717.
(21) For selected examples of related cross-metathesis reactions,
see (a) Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162.
(b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783. (c) Morgan, J. P.; Morrill, C.; Grubbs, R. H.
Org. Lett. 2002, 4, 67. (d) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360. (e) Funk, T. W.;
Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187. (f) Dewi, P.; Randl, S.;
Blechert, S. Tetrahedron Lett. 2005, 46, 577. (g) Ferriꢀe, L.; Amans, D.;
Reymond, S.; Bellosta, V.; Capdevielle, P.; Cossy, J. J. Organomet. Chem.
2006, 691, 5456. (h) Yoshimura, T.; Yakushiji, F.; Kondo, S.; Wu, X.;
Shindo, M.; Shishido, K. Org. Lett. 2006, 8, 475. (i) Moura-Letts, G.;
Curran, D. P. Org. Lett. 2007, 9, 5. (j) Kummer, D. A.; Brenneman, J. B.;
Martin, S. F. Tetrahedron 2006, 62, 11437. (k) Paul, T.; Andrade, R. B.
Tetrahedron Lett. 2007, 48, 5367. (l) Morita, A.; Kuwahara, S. Tetra-
hedron Lett. 2007, 48, 3163. (m) Murelli, R. P.; Snapper, M. L. Org. Lett.
2007, 9, 1749. (n) Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Czaicki,
N. L.; Koide, K. J. Am. Chem. Soc. 2007, 129, 2648. (o) Steinhardt, S. E.;
Silverston, J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130, 7560.
(22) After the completion of our work, Lipshutz described the use of
CuI to facilitate metathesis reactions between electron-deficient alkenes
and olefins. See Voigtritter, K.; Ghorai, S.; Lipshutz, B. H. J. Org. Chem.
2011, 76, 4697.
(23) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 203. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W.
J. Am. Chem. Soc. 1996, 118, 100. (c) Belderrain, T. R.; Grubbs, R. H.
Organometallics 1997, 16, 4001.
(24) (a) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 6543.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(26) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41,
9973.
(27) Prepared by the method of Waegell; purity was assessed by 1H
NMR. See Rodriguez, J.; Waegell, B. Synthesis 1988, 534.
(28) Sanford, M. S.; Love, J. A. In Handbook of Metathesis; Grubbs,
R. H., Ed.; WileyꢀVCH: Weinheim,Germany, 2003; Vol. 1, pp118ꢀ120.
(29) Prepared by the method of Kinoshita; purity was assessed by 1H
NMR. See Kinoshita, M.; Takami, H.; Taniguchi, M.; Tamai, T. Bull.
Chem. Soc. Jpn. 1987, 60, 2151.
(30) Inanaga, J. H. K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
7653
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