Synthetic studies on the mycolactone core

Article abstract of DOI:10.1039/c0ob00540a

Two approaches are presented for the synthesis of the macrolide core of the mycolactone polyketides. The first intertwines ring closing metathesis (RCM) within a two-step Julia olefination protocol, while the second intercepts the optimized routes of Kishi, thereby providing formal access to the mycolactones.

Full text of DOI:10.1039/c0ob00540a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthetic studies on the mycolactone core†
Kwang-Seuk Ko,‡a Matthew D. Alexander,‡a,b Shaun D. Fontaine,a James E. Biggs-Houck,a James J. La Claira
and Michael D. Burkart*a
Received 3rd June 2010, Accepted 17th August 2010
DOI: 10.1039/c0ob00540a
Two approaches are presented for the synthesis of the macrolide core of the mycolactone polyketides.
The first intertwines ring closing metathesis (RCM) within a two-step Julia olefination protocol, while
the second intercepts the optimized routes of Kishi, thereby providing formal access to the
mycolactones.
Introduction
In 1999, Small identified mycolactones A (1a) and B (1b) as an
inseparable mixture of isomers that acts as the etiological agent of
Mycobacterium ulcerans.1 Since this discovery, studies conducted
in animal models indicate that mycolactones 1a and 1b are capable
of producing the lesion formation associated with Buruli ulcer.2
This evidence, along with detailed biosynthetic studies3 and the
isolation of congeners 1c–1f from fish and amphibians, has led
to significant understanding of this family of polyketides.4 To
date, the known mycolactones, 1a–1f, contain the common core
macrolide 2,5 and differ within their polyunsaturated side chain
(Fig. 1).
Since their initial characterization, a series of biological studies
have provided an early understanding of the role mycolactone
polyketides play in Buruli ulcer.6 However, the story is far from
complete. Recently, it was shown that 1a/1b induces apoptosis
and necrosis within cells involved in inflammation.7 Such effects
are associated with a lack of wound healing and the eventual
formation of large symptomatic ulcerations.8 These studies are
further complicated by the fact that there is a clear difference
between the in vivo and in vitro activity of 1a/1b.9 Given
these requirements, larger quantities (≥100 mg) of the natural
products and their associated probes are required to develop an
understanding as to the targets and the pathways modulated by the
mycolactones. Unfortunately, culturing efforts have been limited to
the production of milligrams of material,10 and therefore a viable
synthetic entry to developing an understanding of the mode of
action of these polyketides.
Results and Discussion
Fig. 1 Mycolactones A–F (1a–f) and the mycolactone core (2). While
modifications appear within the polyunstaturated side chain, each of the
mycolactones isolated to date bears a common core unit 2.
Strategy
Our efforts have focused on synthesis of core 2, as the routes of
Kishi, Negishi, and Minnaard provide access to the polyunsatu-
these syntheses by providing an effective access to the core 2. Our
rated acid side chain.11 The goal of our studies was to complement
approach focused on the use of olefin metathesis to install the C8–
C9 tri-substituted olefin providing access to macrolides such as 3
aDepartment of Chemistry and Biochemistry, University of California at
and 5 (Fig. 2). In 2006, we demonstrated this in the synthesis of 3
San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0358, USA. E-mail:
mburkart@ucsd.edu; Fax: +1-858-822-2182
(Fig. 2).12
bCurrent Address: TetraLogic Pharmaceuticals, 343 Phoenixville Pike,
Malvern, PA, 19355, USA
Unfortunately, the planned route for converting 3 into 2 resulted
in a dead end, as the attempts to install the C14–C15 olefin via a
Wittig or Julia–Kocienski olefination with 4a or 4b, respectively,
resulted in recovery starting material or decomposition (route A,
Fig. 2). Closely following this report, Altmann further confirmed
† Electronic supplementary information (ESI) available: Experimental
1
details and copies of selected H-, 13C- and 2D NMR spectra have been
provided. See DOI: 10.1039/c0ob00540a
‡ These authors contributed equally to these studies.
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Fig. 2 Retrosynthetic analyses of the mycolactone core 2. Four ap-
proaches are presented as given by routes A–D. PT = phenyltetrazol.
the potential of RCM for the formation of the 12 membered
lactone found in the mycolactones – although their substrate
similarly lacked the northern chain and the critical tri-substituted
olefin linker.13
We then examined the use of cross-metathesis (route B, Fig. 2),
as an alterative to the Wittig and Julia type olefination reactions
for installation of the northern chain. Alkene 5 (Fig. 2) was
prepared from ketone 3 in 82% yield by Wittig olefination with
Ph3P CH2 in THF and screened for its cross-metathesis with
4c11c and 4d11f Unfortunately, complex mixtures of products were
obtained including formation of cyclohexene ester 6 (Fig. 2).
Conversion to the desired core 2 could not be encouraged even
under high concentrations of the northern chain component 4c or
4d, or variance of the solvent, temperature, or catalyst.
Scheme 1 First-generation approach. (a) TBSCl, imidazole, DMF,
0 to 23 ◦C, 97%; (b) DIBAL-H, CH2Cl2, -78 ◦C, 90%; (c) al-
lyltri-n-butylstannane, SnCl4, THF, -78 ◦C, 80%, >95% de; (d)
p-methoxybenzyltrichloroacetimidate, BF3·Et2O, cyclohexane, CH2Cl2,
0 ◦C, 73% (23% recovered 10); (e) TBAF, THF, 93%; (f) I2, PPh3, imidazole,
toluene, 0 ◦C, 98%; (g) PhSO2Et, HMPA, n-BuLi, THF, -78 ◦C to rt, 95%;
(h) n-BuLi in hexanes to 13 in THF, -78 ◦C, then warm to -20 ◦C, then 14
in THF, -78 ◦C, warm to -20 ◦C, add BzCl, -78 ◦C to rt, 57%; (i) DDQ,
wet CH2Cl2, rt, 2 h, 95%; (j) 16, 17, DCC, DMAP, CSA, CH2Cl2, 8 h, 96%;
(k) Grubbs II generation catalyst, CH2Cl2, reflux, 2 d, 94%; (l) Na/Hg,
MeOH, -20 ◦C, 90% (2 : 1 E/Z); (m) TASF, DMF, 42% of E-isomer and
19% of Z-isomer.
First-generation approach: application of an intercepted Julia–
Lythgoe olefination to direct ring-closing metathesis. Next, we
sought a method for masking the C14–C15 olefin. The Julia–
Lythgoe olefination14 provided an excellent solution for this task
as the two step process could be interupted and the intermediate
adduct intercepted. The resulting product, a b-acyloxysulfone
(route C, Fig. 2), would effectively serve as a protecting group
for the C14–C15 olefin during formation of the C8–C9 double
bond by RCM, and prevent the undesired scrambling to 6. Of the
options (Fig. 2), placmement of the sulfone at C14 in 7a provided
the most logical entry due to the more stable alkoxide intermediate
generated from an aldehyde (i.e., 14) versus a ketone. Our focus
turned to components 13 and 14 (Scheme 1).
The preparation of sulfone 13 began from allyl alcohol 10,
which was prepared from commercially-available Roche’s ester
(9) using the methods of Keck (Scheme 1).15 Compound 10
was protected as PMB ether 11 using 4-methoxybenzyl 2,2,2-
trichloroacetimidate.16 The TBS either in 11 was removed by
treatment with TBAF in THF, and the resulting alcohol was
converted to iodide 12 by treatment with a mixture of I2, PPh3, and
imidazole in toluene. Component 13 was completed by alkylating
the monolithium anion of ethylphenylsulfone with iodide 12. The
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second component aldehyde 14, was prepared by ozonolysis of
olefin 4c.11b,11c
The first step of Julia–Lythgoe reaction provided adduct 15 as
~12 : 6 : 1 : 0.5 mixture of diastereomers17 in good yield after trap-
ping of the incipient alkoxysulfone in situ with benzoylchloride.
Higher yields were obtained by benzoylation versus acylation with
AcCl or Ac2O.
Continuing with the mixture of adducts 15, the PMB ether
was removed by oxidation with DDQ, and the resulting alcohol
16 was coupled with acid 1712 using a Keck-modified Steglich
esterification.18 Ester 18 was subjected to RCM with Grubbs II
generation catalyst.19 With the olefin protected as a benzoyloxysul-
fone, the RCM reaction occurred in high yield to deliver macrolide
19. Once the C8–C9 olefin was installed, the C14–C15 olefin was
generated. Reductive elimination of the benzyloxy and sulfone
groups in 20a with sodium-mercury amalgam in MeOH afforded
a 2 : 1 mixture of E- and Z-isomers 20a.20
We then turned to evaluate the influence of stereochemistry in
19 on the reduction to 20a. The isomers of 19 were separated using
flash chromatography and subjected individually to the reduction
conditions. Unfortunately, the same 2 : 1 E/Z ratio was obtained,
regardless of the choice of isomer.21
To add additional concern, the removal of TBS protection in 20a
provided complications. First, both of the TBS groups in the north-
ern chain (at C17 and C19) were removed by treatment with tris-
(dimethylamino)sulfonium-difluorotrimethylsilicate (TASF)22 af-
fording a single E-isomer 20b in 42% yield (along with 19% of the
Z-isomer) after chromatographic purification. Unfortunately, the
TBS ether at C5 proved challening to remove, as decomposition
occured under a number of conditions for silyl-deprotection (over
20 screened). Ultimately, we failed to identify an effective method
to remove the TBS ether at C5, as only small amounts of 2 could
be obtained using this strategy.
Second-generation approach: reorganizing to an optimized com-
ponent assembly. A solution to this problem was identified in
parallel with that recently published by Kishi11b in their elegant
synthesis of the core precursor, iodide 8 (route D, Fig. 2). The
complementary use of TBS protection at C17 and C19 with
PMB protection at C5 provided a logical solution to the sluggish
deprotection at C5, as well as allowing the orthagonal installation
of the polyunstaturated side chain. Kishi also demonstrated that
core 8 served as an effective intermediate for installation the C11–
C19 northern chain by developing a high-yielding and scalable
Negishi coupling with TBS protected vinyliodide 4e (route D,
Fig. 2).11b,11c Our studies therefore shifted to the synthesis of
macrolide 8.
A 14-step synthesis of 8 was developed, beginning with the pro-
pionylated Crimmins thiazolidinethione auxilary 21 (Scheme 2).23
Condesation of 21 with aldehyde 2224 afforded adduct 23 in
excellent yield. The auxiliary was released and recycled by
treatment with N,O-dimethylhydroxylamine.25 After PMB protec-
tion, reduction of the resulting Weinreb amide25 with DIBAL-H
afforded aldehyde 24.
Scheme 2 Second-generation synthesis delivering core unit 8. (a) TiCl4,
i-Pr2NEt, CH2Cl2, -78 ◦C, 96%; b) N,O-dimethylhydroxyamine hy-
drochloride, imidazole, CH2Cl2, 95%; (c) p-methoxybenzylbromide, NaH,
DMF, 89%, (d) DIBAL-H, toluene, -78 ◦C, 99%; (e) 2-propenylmagnesium
bromide, THF, -78 ◦C to rt, 92%; (f) Ac2O, DMAP, pyridine, 89%;
(g) HCO2NH4, Pd(PPh3)4, PBu3, dioxane, reflux, 88%; (h) TBAF, THF,
rt, 90%; (i) (ClCO)2, Et3N, DMSO; (j) NaClO2, NaH2PO4, t-BuOH,
2-methyl-2-butene, 97% over 2 steps; (k) DCC, DMAP, pyridine, CH2Cl2,
8 h, 87%; (l) Grubbs II generation catalyst, CH2Cl2, reflux, 2 d, 78%; (m)
TBAF, THF, 85%; (n) I2, PPh3, imidazole, toluene, 0 ◦C, 98%.
Tsuji reduction proved to be difficult to scale, requiring multiple
runs at the 5 mmol scale. The remaining steps including removal
of the TBDPS protecting group and oxidation of the resulting
carbinol 27 to acid 28 were scalable. Using this method, we were
able to scale this approach to deliver 30 mmol of 28.
Using established methods,12 alkene 26 was prepared by the
addition of propenylmagensium bromide to 24 with in situ
acylation of the resulting alkoxide to set up the regioselective
hydrogenolysis of allylic acetate 25 under Tsuji conditions.26 While
each of the processes to 25 were readily run at 100 mmol scale, the
With PMB protected acid 28 in hand, we applied our RCM
strategy12 to assemble the core unit 8. This process began by
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coupling 28 with alcohol 1027 using the Keck-modified Steglich
esterification conditions18 to afford 29. The resulting ester 29 was
subjected to RCM with Grubbs II generation catalyst19 to afford
a single olefin isomer 30. Removal of the TBS protection and
iodination completed the synthesis of 8. Spectroscopic data from
8 was identical to that reported by Kishi.11b,11c This route provides
a stereoselective entry to 8 that operates at gram scales without
the need for tedious chromatographic removal of stereoisomers.
The synthesis of 8 also enables a direct relay with the routes
developed in the Kishi laboratory11b,11c utilizing vinyliodide 33,
therein completing the formal synthesis of 2. As shown in
Scheme 3, aldehyde 1411b,11c was converted to alkyne 31 using
the Bestmann protocol.28 Methylation of 31 to 32, followed by
reduction with Schwartz’s reagent29 provided the vinyl iodide 33
in 3 steps and 70% yield from 14. Each step in this process
could be conducted at a 50 mmol scale, providing viable access
to the northern chain. Using Kishi’s optimized approach,11b,11c
orthagonally protected core 34 is obtained by a Negishi coupling
of 33 and 8, and the synthesis of 2 is completed by sequential
removal of the TBS and PMB protecting groups.
bonds without complication from side reactions. The olefin within
the 12-membered ring was formed with exclusively E-geometry
and the alkene in the northern chain was obtained as a 2 : 1 mixture
of E- and Z-isomers, respectively. Our second route rapidly and
efficiently delivered core 8, which can be converted to 34 and 2
using the methods of Kishi.11b,11c
Our second generation synthesis was convergent and incor-
porated the preparation of four components: (a) alcohol 10
(Scheme 1) prepared in 3 steps from Roche’s ester;27 (b) propi-
onylated Crimmins auxilary 21 (Scheme 2) prepared in 2 steps
from D-phenylalanine;23 (c) aldehyde 22 (Scheme 2) prepared in 2
steps from 1,5-pentanediol;24 and (d) vinyl iodide 33 (Scheme 3)
prepared in 7 steps from ethyl (R)-3-hydroxybutyrate.11bc The
assembly of these components requires 15 steps to achieve orthog-
onally protected core 34 with an overall yield of 24%. This outcome
compares favorably with the total syntheses developed by the Kishi
laboratory and provides an alternative for developing mycolactone
probes, a key next step in understanding the progression of Buruli
ulcer.
Experimental Section
General Experimental Information
Unless otherwise noted, all reagents and chemical compounds
were purchased from commercial sources (Alfa Aesar, GFS
Chemicals, Strem Chemicals, Sigma-Aldrich and TCI) and used
without further purification. High purity anhydrous solvents
(tetrahydrofuran, dichloromethane, N,N-dimethylformamide, di-
ethyl ether, and toluene) were obtained by passing through
a solvent column composed of dry activated A-1 alumina.
Triethylamine (Et3N) and N,N-diisopropylethylamine (i-Pr2NEt)
were distilled from ninhydrin, dried (Na2SO4), and then freshly
distilled from sodium. MeOH was distilled from magnesium.
Dioxane was distilled from sodium-benzophenone ketyl. All air
or moisture sensitive reactions were performed under a positive
pressure of dry Ar in oven-dried glassware sealed with a septum.
Reactions were magnetically stirred with a Teflon-coated stir bar.
Flash chromatography was performed on Silica Gel 60, 230–
400 mesh (EM Sciences). TLC analyses were conducted on 250 mm
Silica Gel 60 F254 glass plates (EM Sciences). Visualization was
achieved with UV light and/or an appropriate stain (I2 on SiO2,
KMnO4, bromocresol green, dinitrophenylhydrazine, ninhydrin,
and ceric ammonium molybdate). Yields and characterization
data correspond to isolated, homogeneous materials. Unless
otherwise noted all solvent mixtures are given in v : v ratios.
NMR spectra were recorded on a Varian Mercury Plus 400 MHz,
Varian Unity 500 MHz, Jeol ECA 500 MHz, Bruker DMX
500 MHz or Varian VX 500 MHz (equipped with XSens cold
probe) spectrometer. COSY, NOESY, TOCSY, HMBC and HSQC
spectra were collected on a Bruker DMX 500 with 5 mm 1H
(13C/15N) triple-resonance indirect XYZ gradient probe. FID files
were processed using MestRe-C software version 6.0.2 (MestreLab
Research) and were printed from MestraNova. Chemical shifts
for 1H-NMR and 13C-NMR analyses were reported using the
Scheme
3
Synthesis of the mycolactone core 2. (a) dimethyl-1-
diazo-2-oxopropylphosphonate, K2CO3, MeOH, rt., 87%; (b) n-BuLi,
MeI, THF, -78 ◦C to rt, 99%; (c) Cp2ZrHCl, THF, 65 ◦C, 3 h to -25 ◦C,
add I2, 82%; the optimized conversion of 8 to 2 via 34 was reported by
Kishi.11b,11c
Conclusions
1
In summary, we describe two approaches that apply RCM in the
synthesis of the mycolactone core 2. The first approach involved
a RCM reaction in between the two steps of a Julia–Lythgoe
olefination in order to efficiently form both trisubstituted double
signal from residual CHCl3 (7.26 ppm, H-NMR) or the CDCl3
signal (77.16 ppm, 13C-NMR). Mass spectra were collected by
Dr Yongxuan Su (UC San Diego). Electrospray (ESI) and
atmospheric pressure chemical ionization (APCI) analysis was
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performed using a Finnigan LCQDECA mass spectrometer, and
fast atom bombardment (FAB) analysis was carried out using a
ThermoFinnigan MAT900XL mass spectrometer. Spectral data
and procedures are provided for all new compounds and copies of
select spectra have been provided within the ESI. Procedures for
the preparation of select key intermediates have been provided in
the following discussion.
4.94 (m, 2H), 4.80 (m, 1H), 4.76–4.62 (m, 2H), 4.16–4.06 (m,
1H), 3.96–3.78 (m, 2H), 3.50 (m, 1.5H), 3.16 (m, 0.5H), 2.84–
2.64 (m, 1H), 2.46–2.10 (m, 6H), 2.01 (m, 2H), 1.78–1.70 (m,
2H), 1.68–1.57 (m, 6H), 1.54–1.44 (m, 3H), 1.44–1.26 (m, 4H),
1.18–1.04 (m, 4H), 1.02–0.94 (m, 3H), 0.90–0.72 (m, 21H), 0.01
(12H); 13C-NMR (100 MHz, CDCl3) d ppm 173.5, 173.1, 172.9,
165.3, 164.8, 144.9, 144.8, 138.4, 138.2, 136.5, 134.4, 134.2, 133.7,
133.6, 133.5, 133.1, 133.1, 131.2, 131.0, 130.7, 130.5, 130.4, 130.1,
130.0, 129.9, 128.9, 128.8, 128.6, 128.5, 128.5, 128.4, 117.2, 117.6,
111.5, 111.5, 77.3, 76.9, 76.0, 75.6, 74.8, 74.8, 73.2, 73.2, 72.2, 71.3,
71.2, 69.9, 66.1, 66.0, 65.6, 55.9, 45.0, 44.0, 43.9 40.7, 40.7, 40.5,
39.8, 37.5, 35.9, 35.7, 35.6, 35.6, 35.2, 35.0, 34.8, 34.7, 34.5, 32.8,
32.7, 32.6, 32.4, 32.1, 31.9, 31.8, 26.9, 26.2, 26.0, 25.5, 24.8, 24.2,
23.8, 22.4, 21.8, 21.720.0, 18.9, 18.8, 18.2, 18.2, 18.0, 17.8, 17.4,
14.2, 14.1, 14.1, 12.1, 11.36, 8.9, -3.6, -3.8 (4), -4.0, -4.1, -4.2,
-4.3, -4.4, -4.5; MS (ESI) m/z 1079.46 ([M+Na]+,100%). HRMS
(FAB) m/z calcd. for C58H100O9S1Si3 (M)+ 1056.6636, found
1056.6637.
Coupling of components 13 and 14 affords the intercepted Julia
adducts 15
A solution of sulfone 13 (30.0 mg, 0.075 mmol) in anhydrous THF
(2 mL) at -78 ◦C was treated with n-BuLi in hexanes (1.4 M, 64 mL,
0.05 mmol). After stirring for 30 min, a solution of aldehyde 14
(19 mg, 0.05 mmol) in THF (2 mL) was added drop wise and the
yellow solution was stirred at -78 ◦C for 1 h. Benzoyl chloride
(14.0 mL, 0.118 mmol) was added at -78 ◦C. The cooling bath was
removed and the reaction mixture was stirred for 1 h as it warmed
to rt. The reaction was quenched by addition of 1 : 1 MeOH/Et3N
(0.5 mL). The mixture was diluted with Et2O (30 mL) and washed
with H2O (10 mL). The combined organic layers were washed
sequentially with 10% HCl (10 mL), 5% NaHCO3 (10 mL) and
brine (10 mL) and then treated to flash chromatography (20 : 1
hexanes/EtOAc) to afford 37.4 mg (57%) of adducts 15 as a
colorless oil that contained a 12 : 6 : 1 : 1 (w : w : w : w) mixture of
diastereomers: IR (neat) n 2955, 2929, 2856, 1721, 1514, 1302,
Formation of macrolide 19 via ring-closing metathesis
Grubbs second-generation catalyst (1.0 mg, 0.001 mmol) was
added to a solution of diene 18 (24.3 mg, 0.023 mmol) in refluxing
CH2Cl2 (1 mL). The solution was refluxed for 72 h until TLC
indicated complete conversion. The solvent was removed by rotary
evaporation. The residue was diluted with hexanes (10 mL) and
filtered through a short pad of silica gel in order to remove the
catalyst. The crude product was purified by flash chromatography
(100 : 1 toluene–Et2O) to provide 22.2 mg (64%) of macrolide 19
as a colorless oil. IR (neat) n 2929, 2856, 1726, 1251, 1070, 836;
1H-NMR (400 MHz, CDCl3) d ppm 8.04–7.22 (m, 20H), 5.70
(m, 0.6H), 5.48 (m, 0.4H), 5.41–4.84 (m, 2H), 4.82–4.64 (m, 1H),
4.16–4.04 (m, 2H), 3.96–3.78 (m, 3H), 3.52 (m, 0.5H), 3.39–3.28
(m, 2H), 3.20 (m, 0.5H), 2.87–2.75 (m, 1H), 2.58–2.10 (m, 6H),
2.05 (m, 2H), 1.78–1.80 (m, 8H), 1.68–1.32 (m, 30H), 1126 (m,
8H), 1.18–0.80 (m, 56H), 0.01 (m, 36H); 13C-NMR (100 MHz,
CDCl3) d ppm 173.9, 173.6, 173.5, 165.4, 164.8, 138.4, 138.2,
137.7, 137.6, 136.6, 133.7, 133.6, 133.5, 133.0, 131.2, 131.0, 130.8,
130.4, 130.0 (2), 129.9, 128.9 (2), 128.6, 128.5, 128.5, 121.2, 121.1,
77.7, 77.5, 76.5, 76.3, 76.2, 75.9, 74.7, 74.4, 73.2, 73.2, 72.2, 71.3,
71.2, 70.1, 66.1, 66.0, 65.6, 60.5, 45.5, 45.3, 44.0, 43.9, 40.7, 39.7,
37.4, 36.3, 36.2, 36.1, 35.8, 35.3, 33.6, 33.5, 33.4, 33.3, 33.0 (2),
31.9, 30.9, 30.4, 30.1, 26.3, 26.2, 26.0, 24.3, 23.8, 23.8, 21.9,
20.1, 19.5, 18.6, 18.6, 18.3, 18.2, 18.1, 18.1, 18.0, 17.2, 15.8, 15.8,
15.6, 14.4, 12.1, 11.7, 8.7, -3.6, -3.7, -3.8, -3.9, -4.0, -4.1, -4.2,
-4.3, -4.4, -4.5, -4.6; MS (ESI) m/z 1051.28 ([M+Na]+, 100%);
HRMS (FAB) m/z calcd. for C56H97O9S1Si3 (M)+ 1028.6776, found
1028.6775.
1
1249, 1070, 835; H-NMR (400 MHz, CDCl3) d ppm 8.02–7.86
(m, 6H), 7.62–7.10 (m, 12H), 7.21–7.16 (m, 3H), 6.84 (m, 4H).
5.92–5.66 (m, 4H), 5.12–5.01 (m, 2H), 4.92 (m, 2H), 4.56–4.30 (m,
4H), 3.96–3.88 (m, 2H), 3.81 (m, 6H), 3.52 (m, 1H), 3.28 (m, 1H),
3.14 (m, 1H), 2.82 (m, 1H), 2.58 (m, 1H), 2.30–2.18 (m, 4H), 1.84
(m, 1H), 1.70 (m, 2H), 1.50 (m, 3H), 1.14 (m, 6H), 1.04 (m, 4H),
0.88–0.78 (m, 30H), 0.10–0.08 (m, 18H); 13C-NMR (100 MHz,
CDCl3) d ppm 164.9, 159.2, 159.1, 138.6, 138.3, 136.3, 136.4,
136.1, 135.4, 133.7, 133.6, 133.4, 133.1, 131.4, 131.2, 131.1, 131.0,
130.7, 130.6, 130.0, 129.8, 129.5, 129.4, 128.9, 128.8, 128.5116.8,
116.3, 113.8, 113.7, 83.2, 82.8, 82.6, 75.6, 73.7, 73.2, 71.4, 71.2,
70.9, 70.6, 70.5, 69.9, 66.2, 66.1, 65.6, 55.4, 44.6, 43.9, 43.9, 40.7,
39.6, 37.9, 37.3, 36.6, 34.8, 34.5, 33.9, 33.8, 31.7, 30.7, 30.326.3,
26.2, 26.1, 26.0, 25.4, 24.0, 23.8, 22.8, 20.0, 18.2, 18.2, 18.0, 17.4,
17.2, 16.1, 14.3, 12.1, 11.8, 9.6, -3.6 (3), -4.0 (4), -4.52; MS
(FAB) m/z 903.15 ([M+Na]+, 100%); HRMS (FAB) m/z calcd.
for C49H79O8SSi2 (M)+ 880.4799, found 880.4794.
Coupling of alcohol 16 to acid 17 to afford esters 18
DMAP (4.0 mg), CSA (7.2 mg, 0.031 mmol) and DCC (11.4 mg,
0.053 mmol) were added sequentially to a solution of the alcohol
16 (25.0 mg, 0.033 mmol) and acid 17 (11.4 mg, 0.036 mmol)
in CH2Cl2 (2 mL) at 0 ◦C. The resulting mixture was stirred
at rt. After 8 h, the starting material was no longer detectable
by TLC (4 : 1 hexanes/EtOAc). The reaction was diluted with
hexanes (20 mL) and EtOAc (40 mL). The mixture was filtered
and washed with 5% aqueous citric acid (10 mL), satd. NaHCO3
(10 mL) and brine (10 mL), dried (Na2SO4) and concentrated
by rotary evaporation. Purification by flash chromatography (2 : 1
hexanes/EtOAc) yielded 33.0 mg (96%) of ester 18 as a white
solid: IR (neat) n 2893, 1236, 1084, 917, 825; 1H-NMR (400 MHz,
CDCl3) d ppm 8.04–7.36 (m, 10H), 5.78–5.48 (m, 2H), 5.08–
Revealing the masked C14–C15 olefin in macrolide 20a
To a stirred suspension of 6% (m/m) Na/Hg in 3 mL of MeOH
at -20 ◦C was added lactone 19 (20.0 mg, 0.019 mmol). The
resulting mixture was stirred at 0 ◦C until TLC indicated complete
conversion of the substrate (~ 8 h). The reaction was quenched by
the addition of satd. NH4Cl (1 mL) and warmed to rt. The mixture
was extracted with Et2O (2 ¥ 20 mL), and the combined organic
layers washed sequentially with 5% NaHCO3 (10 mL), H2O
(10 mL), and brine (10 mL), dried over Na2SO2, and concentrated
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by rotary evaporation. Purification by flash chromatography (2 : 1
Completion of the macrolide intermediate 8
hexanes/EtOAc) yielded 13.0 mg (90%) of a 2 : 1 mixture 20a, as
a colorless oil: H-NMR (500 MHz, CDCl3) d ppm 5.50 (d, J =
A two step procedure was used to complete the synthesis of
1
intermediate 8. A solution of lactone 30 (1.2 g, 2.3 mmol) was
10.0 Hz, 0.3 H), 5.45 (d, J = 9.2 Hz, 0.7 H), 4.98 (m, 1H), 4.84
(m, 1H), 3.88 (m, 1H), 3.58 (m, 1H), 3.36 (m, 1H), 2.54–2.36 (m,
4H), 2.38 (m, 1H), 2.04–1.92 (m, 3H), 1.88–1.78 (m, 4H), 1.78–
1.54 (m, 15H), 1.42 (m, 3H), 1.26 (m, 3H), 1.02 (m, 4H), 0.98–0.82
(m, 40H), 0.04 (m, 18H); 13C-NMR (100 MHz, CDCl3) d ppm
173.7, 137.6, 137.4, 131.8, 131.7, 131.4, 130.5, 121.6, 75.9, 75.5,
73.5, 73.3, 66.3, 66.1, 46.3, 45.5, 45.2, 43.2, 38.2, 37.8, 36.1, 35.4,
35.2, 33.5, 30.3, 29.9, 26.2, 26.1, 26.0 (2), 24.1, 24.0, 23.6, 21.9,
18.7, 18.3, 16.1, 15.9, 15.8 (2), 15.3, -3.8, -3.9, -4.1, -4.1, -4.2,
-4.4, -4.5, -4.6; HRMS (FAB) m/z calcd. for C43H86O5Si3 (M)+
766.5774, found 766.5778.
◦
dissolved in dry THF (20 mL) under Ar and cooled to 0 C. A
solution of TBAF (3.4 mL, 3.5 mmol, 1 M in THF) was added
drop wise. The cooling bath was removed and the reaction mixture
stirred for 1 h at rt and then diluted with EtOAc (50 mL). The
mixture was washed with satd. aqueous NaHCO3 (20 mL), H2O
(20 mL), and brine (30 mL) and then dried over magnesium
sulfate. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and concentrated by rotary evaporation. The
crude product was purified by flash chromatography to obtain
864 mg (93%) of (6S,7S,12R,E)-12-((S)-1-hydroxypropan-2-yl)-6-
((4-methoxybenzyl)oxy)-7,9-dimethyloxacyclododec-9-en-2-one
as an oil: 1H-NMR (400 MHz, CDCl3) d ppm 7.26 (d, J = 3.2 Hz,
2H), 6.87 (dd, J = 8.4, 3.2 Hz, 2H), 4.98 (m, 2H), 4.50 (d, J =
10.8 Hz, 1 H), 4.32 (d, J = 10.8 Hz, 1H), 3.79 (s, 3H), 3.74 (m, 1H),
3.63 (m, 1H), 3.10 (m, 1H), 2.49 (m, 2H), 2.06 (m, 2H), 1.88 (m,
2H), 1.79 (m, 2H), 1.27 (m, 2H), 1.64 (s, 3H), 1.58 (m, 1H), 1.44
(m, 1H), 1.37 (m, 3H), 0.95 (m, 3H); 13C-NMR (100 MHz, CDCl3)
d ppm 174.1, 159.3, 137.6,131.3, 129.6, 121.9, 113.9, 83.3, 76.1,
71.1, 60.9, 55.5, 45.9, 36.2, 35.5, 34.4, 32.9, 30.6, 29.2, 20.8, 19.5,
15.9, 15.6; HRMS (FAB) m/z calcd. for C24H36O5 (M)+ 404.2762,
found 404.2763.
Imidazole (390 mg, 5.8 mmol), triphenylphosphine (750 mg,
2.9 mmol), and iodine (722 g, 2.9 mmol) were added sequentially to
a solution of the preceeding alcohol (774 mg, 1.92 mmol) in toluene
(25 mL) at 0 ◦C. The heterogeneous yellow mixture was stirred at rt
for 1 h. The reaction was quenched by diluting with satd. Na2S2O3
(25 mL) and the layers were separated. The aqueous layer was
further extracted with Et2O (3 ¥ 25 mL) and the combined organic
layers were washed with satd. Na2S2O3, H2O, and brine, dried
(Na2SO4), and the solvent was removed by rotary evaporation.
The crude product was purified by flash chromatography (4 : 1
hexanes/EtOAc) to provide 968 mg (98%) of 8 as a colorless oil:
1H-NMR (400 MHz, CDCl3) d ppm 7.29 (m, 2H), 6.89 (m, 2H),
4.96 (m, 2H), 4.52 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H),
3.82 (s, 3H), 3.33 (m, 1H), 3.34 (dd, J = 3.8, 10.0 Hz, 1H), 3.13
(m, 1H), 2.49 (m, 1H), 2.46 (m, 1H), 2.07 (m, 2H), 1.88–1.32 (m,
8H), 1.64 (s, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.1 Hz,
3H); 13C-NMR (100 MHz, CDCl3) d ppm 173.9, 159.3, 137.8,
131.3, 129.6, 121.6, 113.9, 83.3, 75.4, 71.1, 55.5, 45.9, 38.7, 36.6,
36.2, 32.9, 31.1, 29.2, 20.8, 19.5, 16.0, 14.9, 4.5; HRMS (FAB) m/z
calcd. for C24H35IO4 (M)+ 514.2676, found 514.2679.
Coupling of alcohol 10 to acid 28 to afford ester 29
Alcohol 10 (1.1 g, 4.8 mmol) and acid 28 (1.5 g, 4.8 mmol) were
dissolved in CH2Cl2 (30 mL) and cooled to 0 ◦C. DMAP (0.7 g),
and DCC (1.2 g), and pyridine (3 mL) were added sequentially
to this solution. The reaction was for 8 h at which point the
starting material had been consumed. The reaction was diluted
with hexanes (100 mL), filtered, and concentrated. Purification by
flash chromatography (20 : 1 hexanes/EtOAc) yielded 2.5 g (95%)
of ester 29 as a colorless oil: 1H-NMR (400 MHz, CDCl3) d ppm
7.26 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.73 (m, 1H),
5.06 (m, 1H), 5.01 (m, 1H), 4.86 (dt, J = 5.0, 7.5 Hz, 2H), 4.74 (s,
1H), 4.66 (s, 1H), 4.44 (dd, J = 11.6, 14.2 Hz, 2H), 3.79 (s, 3H),
3.67 (m, 1H), 3.60 (m, 1H), 3.26 (m, 1H), 3.19 (m, 1H), 2.24 (m,
3H), 1.81 (m, 4H), 1.68 (s, 3H), 1.54 (m, 2H), 1.29 (m, 3H), 0.90 (d,
J = 7.0 Hz, 3H), 0.85 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H), 0.04 (s, 6H);
13C-NMR (100 MHz, CDCl3) d ppm 173.4, 159.3, 144.7, 134.5,
131.4, 129.4, 117.6, 113.9, 111.8, 82.3, 76.9, 71.7, 61.3, 56.0, 55.5,
41.0, 35.8, 35.1, 35.0, 34.9, 33.4, 32.9, 30.3, 26.2, 25.7, 22.4, 22.0,
15.8, 14.9, -5.1, -5.1; HRMS (FAB) m/z calcd. for C32H54O5Si
(M)+ 546.4281 found 546.4283.
Formation of macrolide 30 via ring-closing metathesis
Grubbs second-generation catalyst (36 mg, 0.04 mmol) was
dissolved in CH2Cl2 (50 mL) under an Ar atmosphere. The flask
was fitted with a condenser and heated at reflux. A solution of
diene 29 (2.3 g, 4.2 mmol) in CH2Cl2 (200 mL) was added via
syringe. After 24 h, TLC analysis indicated the starting material
had been consumed. The reaction mixture was flushed through a
plug of silica gel with CH2Cl2 and concentrated to give a colorless
oil. Purification by flash chromatography (20 : 1 hexanes/EtOAc)
Acknowledgements
1
yielded 1.3 g (60%) of macrolide 30 as colorless oil: H-NMR
(400 MHz, CDCl3) d ppm 7.24 (d, J = 8.4 Hz, 2H), 6.84 (d, J =
8.5 Hz, 2H), 4.96 (d, J = 10.0 Hz, 1H), 4.91 (ddd, J = 2.9, 5.6,
11.6 Hz, 1H), 4.46 (d, J = 11.0 Hz, 1H), 4.28 (d, J = 11.0 Hz, 1H),
3.78 (s, 3H), 3.64 (m, 2H), 3.10 (m, 1H), 2.38 (m, 2H), 2.04 (m,
2H), 1.89–1.57 (m, 5H), 1.62 (s, 3H), 1.40 (m, 1H), 1.28 (m, 2H),
1.00 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.03
(s, 6H); 13C-NMR (100 MHz, CDCl3) d ppm 173.9, 159.3, 137.4,
131.3, 129.6, 122.1, 113.9, 83.4, 76.2, 71.1, 61.5, 55.5, 46.0, 36.2,
35.7, 34.4, 32.9, 30.6, 29.2, 26.2, 20.8, 19.5, 18.9, 15.7, -5.0, -5.1;
HRMS (FAB) m/z calcd. for C30H50O5Si (M)+ 518.3801, found
518.3802.
Financial support from the American Cancer Society (RSG-06-
011-01-CDD) is gratefully acknowledged. We thank Dr Yongxuan
Su for mass spectral analyses, and Dr Anthony Mrse for assistance
with acquiring the NMR data.
Notes and references
1 K. M. George, D. Chatterjee, G. Gunawardana, D. Welty, J. Hayman,
R. Lee and P. L. C. Small, Science, 1999, 283, 854.
2 K. M. George, L. Pascopella, D. M. Welty and P. L. Small, Infect.
Immun., 2000, 68, 877.
5164 | Org. Biomol. Chem., 2010, 8, 5159–5165
This journal is
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View Article Online
3 For articles describing the biosynthesis of the mycolactones, see: (a) T. P.
Stinear, A. Mve-Obiang, P. L. Small, W. Frigui, M. J. Pryor, R. Brosch,
G. A. Jenkin, P. D. Johnson, J. K. Davies, R. E. Lee, S. Adusumilli,
T. Garnier, S. F. Haydock, P. F. Leadlay and S. T. Cole, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 1345; (b) S. Bali and K. J. Weissman,
ChemBioChem, 2006, 7, 1935; (c) H. Hong, J. B. Spencer, J. L. Porter,
P. F. Leadlay and T. Stinear, ChemBioChem, 2005, 6, 643; (d) G. A.
Jenkin, T. P. Stinear, P. D. Johnson and J. K. Davies, J. Bacteriol., 2003,
185, 6870; (e) S. J. Pidot, H. Hong, T. Seemann, J. L. Porter, M. J.
Yip, A. Men, M. Johnson, P. Wilson, J. K. Davies, P. F. Leadlay and T.
P. Stinear, BMC Genomics, 2008, 9, 462; (f) J. L. Porter, N. J. Tobias,
H. Hong, K. L. Tuck, G. A. Jenkin and T. P. Stinear, Microbiology,
2009, 155, 1923; (g) P. Tafelmeyer, C. Laurent, P. Lenormand, J. C.
Rousselle, L. Marsollier, G. Reysset, R. Zhang, A. Sickmann, T. P.
Stinear, A. Namane and S. T. Cole, Proteomics, 2008, 8, 3124; (h) N. J.
Tobias, T. Seemann, S. J. Pidot, J. L. Porter, L. Marsollier, E. Marion,
F. Letournel, T. Zakir, J. Azuolas, J. R. Wallace, H. Hong, J. K. Davies,
B. P. Howden, J. D. Johnson, G. A. Jenkin and T. P. Stinear, PLoS
Neglected Trop. Dis., 2009, 3, e553.
4 (a) S. Aubry, R. E. Lee, E. A. Mahrous, P. L. Small, D. Beachboard
and Y. Kishi, Org. Lett., 2008, 10, 5385; (b) S. Fidanze, F. Song, M.
Szlosek-Pinaud, P. L. Small and Y. Kishi, J. Am. Chem. Soc., 2001,
123, 10117; (c) H. Hong, C. Demangel, S. J. Pidot, P. F. Leadlay and
T. Stinear, Nat. Prod. Rep., 2008, 25, 447; (d) H. Hong, T. Stinear, P.
Skelton, J. B. Spencer and P. F. Leadlay, Chem. Commun., 2005, 4306;
(e) H. J. Kim, K. L. Jackson, Y. Kishi, H. R. Williamson, L. Mosi and P.
L. Small, Chem. Commun., 2009, 7402; (f) A. Mve-Obiang, R. E. Lee,
E. S. Umstot, K. A. Trott, T. C. Grammer, J. M. Parker, B. S. Ranger,
R. Grainger, E. A. Mahrous and P. L. Small, Infect. Immun., 2005, 73,
3307; (g) B. S. Ranger, E. A. Mahrous, L. Mosi, S. Adusumilli, R. E.
Lee, A. Colorni, M. Rhodes and P. L. Small, Infect. Immun., 2006, 74,
6037.
9 (a) J. En, M. Goto, K. Nakanaga, M. Higashi, N. Ishii, H. Saito, S.
Yonezawa, H. Hamada and P. L. Small, Infect. Immun., 2008, 76, 2002;
(b) K. M. George, L. Pascopella, D. M. Welty and P. L. Small, PL.,
Infect. Immun., 2000, 68, 877; (c) H. Hong, E. Coutanceau, M. Leclerc,
L. Caleechurn, P. F. Leadlay and C. Demangel, PLoS Neglected Trop.
Dis., 2008, 2, e325; (d) G. M. Houngbe´dji, C. H. Coˆte´, P. L. Small and J.
Frenette, Microbes Infect., 2009, 11, 238; (e) M. S. Oliveira, A. G. Fraga,
E. Torrado, A. G. Castro, J. P. Pereira, A. L. Filho, F. Milanezi, F. C.
Schmitt, W. M. Meyers, F. Portaels, M. T. Silva and J. Pedrosa, Infect.
Immun., 2005, 73, 6299; (f) E. Peduzzi, C. Groeper, D. Schu¨tte, P. Zajac,
S. Rondini, E. Mensah-Quainoo, G. C. Spagnoli, G. Pluschke and C.
A. Daubenberger, J. Invest. Dermatol., 2007, 127, 638; (g) D. S. Snyder
and P. L. Small, Microb. Pathog., 2003, 34, 91; (h) K. M. Dobos, P. L.
Small, M. Deslauriers, F. D. Quinn and C. H. King, Infect. Immun.,
2001, 69, 7182.
10 L. D. Cadapan, R. L. Arslanian, J. R. Carney, S. M. Zavala, P. L. Small
and P. Licari, FEMS Microbiol. Lett., 2001, 205, 385.
11 (a) H. J. Kim and Y. Kishi, J. Am. Chem. Soc., 2008, 130, 1842; (b) K. L.
Jackson, W. Li, C.-L. Chen and Y. Kishi, Tetrahedron, 2010, 66, 2263;
(c) F. Song, S. Fidanze, A. B. Benowitz and Y. Kishi, Tetrahedron, 2007,
63, 5739; (d) N. Yin, G. Wang, M. Qian and E. Negishi, Angew. Chem.,
Int. Ed., 2006, 45, 2916; (e) R. P. van Summeren, B. L. Feringa and A.
J. Minnaard, Org. Biomol. Chem., 2005, 3, 2524; (f) F. Song, S. Fidanze,
A. B. Benowitz and Y. Kishi, Org. Lett., 2002, 4, 647; (g) A. B. Benowitz,
S. Fidanze, P. L. C. Small and Y. Kishi, J. Am. Chem. Soc., 2001, 123,
5128.
12 M. D. Alexander, S. D. Fontaine, J. J. La Clair, A. G. DiPasquale, A.
L. Rheingold and M. D. Burkart, Chem. Commun., 2006, 4602.
13 F. Feyen, A. Jantsch and K.-H. Altmann, Synlett, 2007, 3, 415.
14 (a) M. Julia and J.-M. Paris, Tetrahedron Lett., 1973, 14, 4833; (b) P. J.
Kocienski, B. Lythgoe and S. Ruston, J. Chem. Soc., Perkin Trans. 1,
1978, 829.
5 A. B. Benowitz, S. Fidanze, P. L. Small and Y. Kishi, J. Am. Chem.
15 G. E. Keck and D. E. Abbott, Tetrahedron Lett., 1984, 25, 1883.
16 K. Nakajima, K. Horita, R. Abe and O. Yonemitsu, Tetrahedron Lett.,
1988, 29, 4139.
17 Copies of the corresponding gCOSY, TOCSY, ROESY and HSQC
spectra on the mixture of isomers have been provided in the ESI†.
18 (a) B. Neises and W. Steglich, Angew. Chem., Int. Ed. Engl., 1978,
17, 522; (b) E. P. Boden and G. E. Keck, J. Org. Chem., 1985, 50,
2394.
Soc., 2001, 123, 5128.
6 (a) S. Adusumilli, A. Mve-Obiang, T. Sparer, W. Meyers, J. Hayman
and P. L. Small, Cell. Microbiol., 2005, 7, 1295; (b) E. Coutanceau,
J. Decalf, A. Martino, A. Babon, N. Winter, S. T. Cole, M. L. Albert
and C. Demangel, J. Exp. Med., 2007, 204, 1395; (c) E. Coutanceau, L.
Marsollier, R. Brosch, E. Perret, P. Goossens, M. Tanguy, S. T. Cole,
P. L. Small and C. Demangel, Cell. Microbiol., 2005, 7, 1187; (d) J. En,
M. Goto, K. Nakanaga, M. Higashi, N. Ishii, H. Saito, S. Yonezawa,
H. Hamada and P. L. Small, Infect. Immun., 2008, 76, 2002; (e) M.
Goto, K. Nakanaga, T. Aung, T. Hamada, N. Yamada, M. Nomoto, S.
Kitajima, N. Ishii, S. Yonezawa and H. Saito, Am. J. Pathol., 2006, 168,
805; (f) L. Marsollier, J. Aubry, E. Coutanceau, J. P. Andre´, P. L. Small,
G. Milon, P. Legras, S. Guadagnini, B. Carbonnelle and S. T. Cole, Cell.
Microbiol., 2005, 7, 935; (g) R. Phillips, F. S. Sarfo, L. Guenin-Mace´,
J. Decalf, M. Wansbrough-Jones, M. L. Albert and C. Demangel, J.
Infect. Dis., 2009, 200, 1675; (h) M. T. Silva, E. Portaels and J. Pedrosa,
Lancet Infect. Dis., 2009, 9, 699; (i) E. Torrado, S. Adusumilli, A. G.
Fraga, P. L. Small, A. G. Castro and J. Pedrosa, Infect. Immun., 2007,
75, 3979; (j) E. Torrado, A. G. Fraga, E. Logarinho, T. G. Martins, J.
A. Carmona, J. B. Gama, M. A. Carvalho, F. Proenc¸a, A. G. Castro
and J. Pedrosa, J. Immunol., 2010, 184, 947.
19 M. Scholl, S. Ding, W. C. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953.
20 (a) F. VanMiddlesworth, V. D. Patel, J. Donaubauer, P. Gannett and C.
J. Sih, J. Am. Chem. Soc., 1985, 107, 2996; (b) H. Nemoto, H. Kurobe,
K. Fukumoto and T. Kametani, Heterocycles, 1985, 23, 567.
21 We confirmed this assignment by combination of gCOSY and TOSCY
to assign each proton and identifying their key NOE interactions by
collection and evaluation of their ROESY spectrum. Copies of these
spectra have been provided in the ESI†.
22 R. Noyori, I. Nishida and J. Sakata, J. Am. Chem. Soc., 1983, 105,
1598.
23 (a) M. T. Crimmins and J. She, Synlett, 2004, 8, 1371; (b) M. T.
Crimmins and A. C. DeBaillie, J. Am. Chem. Soc., 2006, 128, 4936;
(c) M. T. Crimmins and D. J. Slade, Org. Lett., 2006, 8, 2191.
24 V. A. Keller, J. R. Martinelli, E. R. Streiter and S. Burke, Org. Lett.,
2002, 4, 467.
25 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
26 J. Tsuji and T. Yamakawa, Tetrahedron Lett., 1979, 20, 613.
27 W. R. Roush, A. D. Palkowitz and M. J. Palmer, J. Org. Chem., 1987,
52, 316.
7 (a) R. E. Simmonds, F. V. Lali, T. Smallie, P. L. Small and B. M. Foxwell,
J. Immunol., 2009, 182, 2194; (b) E. Coutanceau, J. Decalf, A. Martino,
A. Babon, N. Winter, S. T. Cole, M. L. Albert and C. Demangel, J. Exp.
Med., 2007, 204, 1395; (c) E. Peduzzi, C. Groeper, D. Schu¨tte, P. Zajac,
S. Rondini, E. Mensah-Quainoo, G. C. Spagnoli, G. Pluschke and C.
A. Daubenberger, J. Invest. Dermatol., 2007, 127, 638.
8 (a) M. S. Oliveira, A. G. Fraga, E. Torrado, A. G. Castro, J. P. Pereira,
A. L. Filho, F. Milanezi, F. C. Schmitt, W. M. Meyers, F. Portaels, M. T.
Silva and J. Pedrosa, Infect. Immun., 2005, 73, 6299; (b) S. Adusumilli,
A. Mve-Obiang, T. Sparer, W. Meyers, J. Hayman and P. L. Small, Cell.
Microbiol., 2005, 7, 1295.
28 (a) S. Mu¨ller, B. Liepold, G. Roth and H. J. Bestmann, Synlett, 1996,
521; (b) G. Roth, B. Liepold, S. Mu¨ller and H. J. Bestmann, Synthesis,
2004, 59.
29 (a) D. W. Hart and J. Schwartz, J. Am. Chem. Soc., 1974, 96, 8115; (b) P.
Wipf and H. Jahn, Tetrahedron, 1996, 52, 12853.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5159–5165 | 5165
©