Scalable and efficient synthesis of the mycolactone core

Article abstract of DOI:10.1016/j.tet.2010.02.010

A highly efficient, scalable, and stereoselective synthesis of the mycolactone core is reported. The synthesis consists of 14 longest linear steps, with 19% overall yield.

Full text of DOI:10.1016/j.tet.2010.02.010

Tetrahedron 66 (2010) 2263–2272
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Scalable and efficient synthesis of the mycolactone core
*
Katrina L. Jackson, Wenju Li, Chi-Li Chen, Yoshito Kishi
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient, scalable, and stereoselective synthesis of the mycolactone core is reported. The syn-
thesis consists of 14 longest linear steps, with 19% overall yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 December 2009
Received in revised form
28 January 2010
Accepted 1 February 2010
Available online 4 February 2010
1. Introduction
(Xenopus laevis and Xenopus tropicalis), leading to the isolation of the
tetraene-containing mycolactone E from Mycobacterium liflandii.8
Buruli ulcer is a devastating, but neglected disease of the skin and
soft tissue caused by Mycobacterium ulcerans, the third most com-
mon mycobacterial pathogen of humans after Mycobacterium
tuberculosis and Mycobacterium leprae.1 The disease is characterized
by the formation of necrotic lesions that are usually painless and can
extend to over15% ofa patient’s skinsurfaceif left untreated. In1999,
Smalland co-workersisolatedtwo equilibratingtoxins, mycolactone
A and B, from West African strains of M. ulcerans and later demon-
strated with animal tests that these toxins are responsible for the
observed pathology of the disease.2 The gross structures of myco-
lactone A and B were elucidated primarily through 2-D NMR ex-
periments,3 and their stereochemistry was subsequently predicted
via the NMR database approach and confirmed by total synthesis.4 In
addition, several other groups have described syntheses of the
mycolactone core or unsaturated fatty acid side chain.5 Because
mycolactone A and B exist as an equilibrium mixture of geometric
isomers, they are referred to as mycolactone A/B in this paper.
Since the structure of mycolactone A/B was reported, five more
structurally distinct mycolactones have been described from dif-
ferent strains of M. ulcerans, and close relatives from fish and frogs
(Fig. 1). All of the mycolactones described to date are composed of
a common and conserved 12-membered macrolactone core and
a highly unsaturated fatty acid side chain that differs amongst the
members of this class of natural products. Mycolactone C, which
lacks a C120 hydroxyl group, was identified as the major toxin in
Australian strains of M. ulcerans in 2003.6 Later, in 2005, a toxin
bearing methyl substitution at the C20 position, mycolactone D, was
proposed as the major metabolite in Chinese strains of M. ulcerans.7
Mycobacteriosis was then discovered in African clawed frogs
Me Me
20
Me
15
10
OH OH
Me
O
O
Me
1
5
Me
O
Mycolactone Core
Mycolactone Unsaturated Fatty Acid Side Chains
Isolated from human
pathogen M. ulcerans
R
Me Me
Me
X
16'
Me
mycolactone A/B: X=OH; R=H
mycolactone C: X=H; R=H
mycolactone D: X=OH; R=Me
1'
12'
O
OH OH
Isolated from frog
Me Me
Me
Me
pathogen M. liflandii
1'
15'
Me
mycolactone E
OH
O
OH
Isolated from fish
Me Me
pathogen M. marinum
14'
Me
1'
saltwater fish
mycolactone F
O
OH
OH
OH
Me Me Me
14'
Me
freshwater fish
1'
mycolactone dia-F
O
OH
Figure 1. Structures of the mycolactones.
Most recently, mycolactone F has been isolated from mycobac-
terial pathogens infecting saltwater fish,9 and mycolactone dia-F
has been isolated from pathogens of freshwater fish.10
While much has been learned about Buruli ulcer throughout the
last decade, many questions still remain unanswered. For example,
many researchers have wondered whether it would be feasible to
* Corresponding author. Tel.: þ1 617 495 4679; fax: þ1 617 495 5150.
E-mail address: kishi@chemistry.harvard.edu (Y. Kishi).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.010

2264
K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
develop a diagnostic method for the early detection of Buruli ulcer
that relies on recognition of mycolactone toxins in human skin.1a
Other highly important research areas are centered on the study
of the trafficking and cellular actions of mycolactones,11 as well as
the identification of the cellular target of these toxins. In order for
research into these, and other, fields of study to be practically
conducted, we feel it is necessary to have reliable and scalable
methods for the production of mycolactones of high purity.1e This is
particularly important considering that the mycolactones isolated
from laboratory-scale cultivation of these slow-growing mycobac-
teria are often scant in quantity (typically microgram) and difficult
to isolate cleanly given that mycolactones of varying side chain
structures are often present in the crude lipid extracts from the
cultured mycobacteria.1e
treatment of 2 with p-methoxybenzyl trichloroacetimidate in the
presence of a catalytic amount of scandium(III) triflate, we were
able to obtain 3 in 81% yield without observing a significant
quantity of the d-lactone. Using standard conditions (OsO4/NMO
followed by Pb(OAc)4), alkene 3 was oxidatively cleaved to fur-
nish the aldehyde, which was reduced to alcohol 4 with NaBH4 in
good overall yield (71% for three steps). Lastly, 4 was converted to
the corresponding alkyl iodide 5, providing the desired C1–C7
fragment as a 93:7 mixture with its corresponding enantiomer,
ent-5.
2.2. Synthesis of the C8–C13 fragment
Next we focused on a new synthesis of the C8–C13 segment
(Scheme 2). Subjection of readily available allylic alcohol 7, pre-
pared from 6 by the protocol of Jamison,14 to Sharpless asymmetric
epoxidation15 provided the expected epoxide 8. The optical purity
of 8 thus obtained was found to be 80% ee.16 Fortunately, we were
able to crystallize and recrystallize 8 from acetone/hexanes (10:1)
or toluene/hexanes (1:1) to obtain the optically pure 8 (>99% ee) in
70% yield.
2. Results and discussion
Based on the knowledge accumulated through our first- and
second-generation total syntheses,4 we recognized the need for
improvements in two areas. First, we wished to develop shorter,
more efficient, and easily scalable syntheses of the fragments used
to assemble the mycolactone core. Second, we wished to prepare
the mycolactone core with a high level of stereochemical homo-
geneity, i.e., no contamination of minor stereoisomers.
Me
Me
a. LiAlH4
OH
OH
ref. 13
7
6
2.1. Synthesis of the C1–C7 fragment
b. Ti(Oi-Pr)4, TBHP
(-)-DET, 4A MS
Me
c. MeLi, CuCN
O
OH
We began our synthesis of the mycolactone core by turning our
attention to the C1–C7 fragment (Scheme 1). Starting from known
aldehyde 1,12 the C5 and C6 stereocenters were installed using
Brown crotylboration13 in 86% ee as determined by (R)- and (S)-
Mosher’s ester analysis. Given that we wished to prepare the
mycolactone core in optically pure form, it was important to be
mindful of the minor enantiomer present in 2, as downstream
products resulting from this contaminant would need to be re-
moved at some later stage in the synthesis. Notably, we mentioned
8
Me
OH
d. cyclopentanone
p-TsOH
Me
O
O
O
OH
Me
Me
10
9
e. Cp2Zr(H)Cl
O
O
I
O
8
+
I
13
then I2
in our previous synthesis that a significant amount of the d-lactone
Me
Me
Me
Me
was often formed during the Brown crotylboration to convert 1–
24d; however, in this work we found that shortened reaction times
during the oxidative workup step allowed us to avoid this
byproduct altogether.
22 : 1
11
12
Scheme 2. Reagents and conditions: (a) LiAlH4, Et2O, rt, 98%; (b) Ti(O-i-Pr)4, TBHP,
(ꢁ)-DET, 4 Å MS, CH2Cl2, ꢁ25 ꢀC, 70%; then recrystallization from 10:1 hexanes/ace-
tone, ꢁ24 ꢀC (c) MeLi, CuCN, THF, ꢁ20 ꢀC, 79%; (d) p-TsOH, cyclopentanone, rt, 89%;
(e) Cp2Zr(H)Cl, THF, 50 ꢀC, then I2, THF, 0 ꢀC, 68%. TBHP¼tert-butyl hydroperoxide,
DET¼diethyl tartrate, MS¼molecular sieves, p-TsOH¼para-toluenesulfonic acid.
a. (+)-Ipc2-Z-crotyl-
borane
MeO
H
MeO
Me
then NaOH, H2O2
O
O
O
OH
As in examples previously reported,17 optically pure 8 was
treated with the higher-order cuprate prepared from CuCN and
MeLi to furnish 1,3-diol 9 exclusively. Upon treatment with p-TsOH
and cyclopentanone, 9 was uneventfully converted to cyclo-
pentylidene acetal 10.
1
2
b. PMB-trichloroacet-
c. i. OsO4, NMO
MeO
imidate, Sc(OTf)3
ii. Pb(OAc)4
Me
OPMB
O
iii. NaBH4
3
The last step required for the synthesis of the C8–C13 fragment
was the conversion of alkyne 10 to vinyl iodide 11. We examined
several protocols for this transformation, all of which relied on the
use of the Schwartz hydrozirconation reagent, [Cp2Zr(H)Cl].18 First,
we attempted hydrozirconation using Cp2Zr(H)Cl prepared in situ
from DIBAL-H and Cp2ZrCl2,19 but found that this reagent gave
poor regioselectivity (1:1.3 11/12 at room temperature and 6:1 11/
12 at 50 ꢀC) as well as multiple byproducts. We eventually found
that the Schwartz reagent, prepared from Red-Al and Cp2ZrCl2
following the reported protocol,18c gave improved regioselectivity
as well as attenuated levels of byproduct formation. After opti-
mization of temperature, reagent equivalents, and reaction dura-
tion, we were consistently able to obtain close to 70% yield of 11 as
a 22:1 mixture with 12. It is noteworthy that 8 was obtained in
optically pure form and therefore 11 was free from any enantio-
meric contaminants.
OH
Me
I
7
d. Ph3P, I2,
imidazole
1
MeO
MeO
Me
OPMB
O
OPMB
O
4
5 (93 : 7 with ent-5)
Scheme 1. Reagents and conditions: (a) Z-2-Butene, t-BuOK, n-BuLi, (þ)-(Ipc)2BOMe,
BF3$OEt2, THF, ꢁ78 ꢀC; then NaOH, H2O2, 1 h, 78%, 86% ee; (b) PMB-
trichloroacetimidate, Sc(OTf)3, PhMe, 0 ꢀC, 81%; (c) (i) OsO4, NMO, 3:1 acetone-H2O;
(ii) Pb(OAc)4, PhH, rt; (iii) NaBH4, MeOH, 0 ꢀC, 71% for three steps; (d) Ph3P, imidazole,
I2, CH2Cl2, rt, 92%. PMB¼para-methoxybenzyl, THF¼tetrahydrofuran, Tf¼trifluoro-
methane-sulfonate, NMO¼N-methylmorpholine N-oxide, Ac¼acetyl.
To continue with the synthesis, we wished to convert alcohol
2 to the corresponding p-methoxybenzyl (PMB) ether. Under the
majority of conditions examined, however, mixtures of the de-
sired product 3 and the d-lactone were observed. Fortunately, on

K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
2265
2.3. Synthesis of the C14–C20 fragment
2.4. Assembly of the mycolactone core
Having completed syntheses of the C1–C7 and C8–C13 frag-
ments, we set out to prepare the remaining C14–C20 segment re-
quired for the synthesis of the mycolactone core (Scheme 3). The
synthesis commenced with (R)-propylene oxide 13 (Alfa Aesar,
>99% optical purity), which was opened with the lithium anion of
ethynyltrimethylsilane. The resultant secondary alcohol was pro-
tected as a TBS ether to furnish 14. Upon treatment with NIS and
AgNO3, 14 was converted to the alkynyl iodide, which underwent
subsequent hydroboration with Cy2BH to provide 15 after
quenching with acetic acid. The overall yield for these four steps
was 95%.
With scalable and efficient routes established for the requisite
fragments, we turned our attention to their assembly to construct
the mycolactone core. The first two fragments coupled were 5 and
11, and this was accomplished using
a Negishi coupling
(Scheme 4).23 Notably, we chose to prepare the alkylzinc iodide
species via zinc insertion using an active Zn–Cu couple24 rather
than by transmetallation from Li to Zn due to the electrophilic ester
present in 5. In the event, the coupling proceeded smoothly in the
presence of eight equivalents of LiCl in N-methylpyrrolidinone
(freshly distilled) to furnish 22 in excellent yield (95%). Notably, we
were able to detect minor diastereoisomers in the 1H NMR of 22.
These minor products resulted from coupling of alkyl iodide 5,
which was obtained as a 93:7 mixture of enantiomers (Scheme 1),
with vinyl iodide 11, which was synthesized in enantiomerically
pure form but contained a small amount of regioisomer 12 (Scheme
2). We were unable to estimate the exact ratio of the components in
the mixture by 1H NMR, as the signals overlapped significantly.
However, if we assume the rates of formation of the various
products are similar, statistically 22, 23, 24, and 25 should be
present in a ratio of 89:6.7:4:0.3. In accordance with this, it was
possible to detect 22, 23, and 24 by 1H NMR, although we were
unable to observe 25 as it was present in such low quantity.
a. i. n-BuLi, ethynyl-
trimethylsilane
Me
b. i. NIS, AgNO3
BF3⋅OEt2
Me
13
O
I
TMS
Me
OTBS
ii. Cy2BH,
ii. TBSCl,
imidazole
then AcOH
14
Me
c. propyne,
d. Ti(O-i-Pr)4
17, H2O2
PdCl2(PPh3)2,
16
19
Me
OTBS
Me
Me
CuI, Et2NH
O
OTBS
OTBS
18
15
16
Me
Me
O
e. LiAlMe4,
BF3⋅OEt2
f. TBSCl
Me
Me
Me
imidazole
5
13
a. Zn, Cu(OAc)2,
O
Me
Pd(PPh3)4, LiCl
93:7 with ent-5
Me
OH OTBS
Me
TBSO
OTBS
1
MeO
19
20
Me
OPMB
11
O
22
17
22:1 with 12
Me Me
20
Me
g. Cp2Zr(H)Cl
major
NH HN
OH HO
14
I
(from 5 11)
+
then I2
TBSO
OTBS
Me
Me
O
O
21
MeO
OMe
O
O
O
O
Me
Me
Me
+
+
Me
Scheme 3. Reagents and conditions: (a) (i) n-BuLi, ethynyltrimethyl-silane, BF3$OEt2,
Et2O, ꢁ78 ꢀC; (ii) TBSCl, imidazole, DMF, rt; (b) (i) NIS, AgNO3, DMF, rt; (ii) Cy2BH, THF,
O
O
O
Me
OPMB
Me
OPMB
Me
OPMB
0
ꢀC, then AcOH, 95% for four steps; (c) propyne, PdCl2(PPh3)2, CuI, Et2NH, rt, 96%;
(d) Ti(O-i-Pr)4, 17, 4,40-thiobis(6-t-butyl-m-cresol), H2O2, phosphate buffer, CH2Cl2,
40 ꢀC, 91%, ꢂ50:1 dr; (e) LiAlMe4, BF3$OEt2, CH2Cl2, ꢁ78 ꢀC, 87%; (f) TBSCl, imidazole,
DMF, rt, 99%; (g) Cp2Zr(H)Cl, THF, 50 ꢀC, then I2, THF, 0 ꢀC, 68%. TBS¼tert-butyldime-
thylsilyl, DMF¼N,N-dimethylformamide, NIS¼N-iodosuccinimide, Cy¼cyclohexyl.
OMe
OMe
OMe
23
24
25
minor
(from ent-5 + 11)
minor
(from 5 + 12)
trace/undetectable
(from ent-5 + 12)
Scheme 4. Reagents and conditions: (a) Zn, Cu(OAc)2, Pd(PPh3)4, LiCl, NMP, 55 ꢀC, 95%
(for mixture of 23, 24, and 25). NMP¼N-methyl-2-pyrrolidinone.
To continue the synthesis of the C14–C20 fragment, vinyl iodide
15 was coupled with propyne under Sonogashira conditions20 to
produce enyne 16. At this stage we wished to oxidize the cis-olefin
in 16 in a stereoselective manner. We hoped that an enantiose-
lective epoxidation could override the pre-existing stereocenter at
C19, thereby allowing us to introduce the C–O bond at C16 ster-
eoselectively. A literature search revealed ample precedent for
enyne epoxidation,21 and we felt that ligand 17 recently reported by
Katsuki and co-workers could meet our need.21b Indeed, on treat-
ment with Ti(O-i-Pr)4 and H2O2 in the presence of 17, cis-olefin 16
was smoothly converted to propargylic epoxide 18 in excellent
yield with outstanding selectivity (ꢂ50:1 dr, as estimated by 1H
NMR). Satisfied with this result, we proceeded forward with the
synthesis of the C14–C20 fragment.
Upon treatment with LiAlMe4, a highly regio- and stereospecific
opening of the propargylic epoxide 18 was observed to furnish
homopropargylic alcohol 19.22 To complete the synthesis, alcohol
19 was protected as the TBS ether 20, and subsequent hydro-
zirconation–iodination under the same conditions optimized for
the conversion of 10/11 provided vinyl iodide 21, this time with
complete regioselectivity.
At this point, we began to search for a point at which the minor
contaminants could be removed (Scheme 5). Fortunately, once the
cyclopentylidene acetal had been cleaved under acidic conditions
to form 26, we were readily able to chromatographically separate
1,3-diol 28, derived from 24. However, at this stage, it was not
practical to separate the minor diastereoisomer 27 resulting from
23. Despite this, we carried on with the synthesis with the hope
that the remaining diastereoisomeric contaminant could be re-
moved at a later stage.
Accordingly, we proceeded to convert 26 to seco-acid 29 in
a two-step sequence consisting of primary alcohol protection and
saponification of the methyl ester (Scheme 6). In our previous
study,4d selective protection of the primary alcohol was cleanly
achieved under standard conditions (TIPSCl, imidazole, DMF). In
this study, however, we observed mixtures of the primary- and
secondary-protected alcohols in varying ratios. The reason for the
discrepancy in these studies is not clear at this time. Nevertheless,
we were eventually able to selectively protect the primary position
using triisopropylsilyl triflate and 2,6-lutidine at ꢁ78 ꢀC. After

2266
K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
OH
I
13
OH
O
a. TFA,
wet CH2Cl2
Me
Me
O
a. HF⋅pyr,
Me
O
b. Ph3P, I2
pyr
22 + 23 + 24
HO
Me
O
imidazole
Me
31
Me
1
MeO
Me
OPMB
Me
OPMB
34
Me
OPMB
O
33
26
(major)
Me Me
20
Me
OH
Me
c. Zn, Cu(OAc)2,
21, Pd(PPh3)4,
LiCl
HO
O
OTBS
TBS
Me
O
Me
+
HO
Me
O
+
HO
Me
Me
1
MeO
O
MeO
Me
OPMB
Me
OPMB
Me
OPMB
O
35
27
28
Scheme 7. Reagents and conditions: (a) HF$pyr, pyr, CH3CN, 0 ꢀC, 92%; (b) Ph3P, I2,
imidazole, CH2Cl2, rt, 99%; (c) Zn, Cu(OAc)2, 20, Pd(PPh3)4, LiCl, NMP, 60 ꢀC, 88%.
pyr¼pyridine.
(minor)
(minor)
chromatographically
separated at this stage
Scheme 5. Regents and conditions: (a) 1:4:16 TFA/H2O/CH2Cl2, 91%. (for mixture of 27
and 28). TFA¼trifluoroacetic acid.
fragment in optically pure form and removing the minor contam-
inants chromatographically, we can be confident that the material
produced through this sequence is >99% optically pure.
hydrolysis of the methyl ester to form 29, the stage was set for
macrolactonization. On exposure to standard Yamaguchi condi-
tions,25 seco-acid 29 was converted to macrolactone 31. To our
delight, the remaining minor diastereoisomeric lactone, 32, was
readily removed chromatographically at this stage to afford 31 in
optically pure form (>99% ee).
3. Conclusion
A third synthesis of the mycolactone core has been described.
While our first and second syntheses allowed us to unambiguously
confirm the relative and absolute stereochemistry of the myco-
lactones and optimize protecting group strategy, respectively, the
synthetic efforts described herein have resulted in a scalable and
efficient route to the mycolactone core, which has allowed for the
preparation of multi-gram quantities in high purity. We feel that
this material will be useful for research efforts aimed at addressing
some of the many unsolved questions still surrounding Buruli ulcer.
OTIPS
OTIPS
a. i. TIPSOTf,
Me
Me
2,6-lutidine
26 + 27
HO
Me
HO
Me
+
ii. LiOH
HO
HO
Me
Me
OPMB
O
OPMB
O
29
(major)
30
(minor)
4. Experimental
OTIPS
OTIPS
13
4.1. General procedures and methods
b. Cl3C6H2COCl,
i-Pr2NEt,
Me
O
Me
O
DMAP
NMR spectra were recorded on Varian Inova 500 MHz or
600 MHz spectrometers. Chemical shifts are reported in parts per
million (ppm). For 1H NMR spectra (CDCl3 or C6D6), the residual
solvent peak was used as the internal reference (7.26 ppm in CDCl3;
7.15 ppm in C6D6). For 13C NMR spectra, the central solvent peak
was used as the internal reference (77.0 ppm in CDCl3; 128.0 ppm
in C6D6). Mass spectrometry was performed on an Agilent 6210
Time-of-Flight mass spectrometer with an electrospray ionization
source. Analytical thin layer chromatography (TLC) was performed
with E. Merck pre-coated TLC plates, silica gel 60F-254, layer
thickness 0.25 mm. Flash chromatography separations were per-
formed on E. Merck Kieselgel 60 (230–400) mesh silica gel. Re-
agents and solvents are of commercial grade and were used as
supplied. All reactions were conducted under an inert atmosphere.
Reaction vessels were flame-dried or oven-dried and allowed to
cool to rt under inert atmosphere.
O
O
+
Me
Me
1
Me
Me
OPMB
OPMB
31
(major)
32
(minor)
chromatographically
separated at this stage
Scheme 6. Reagents and conditions: (a) (i) TIPSOTf, 2,6-lutidine, CH2Cl2, ꢁ78 ꢀC; (ii)
LiOH, 1:1:4H2O/MeOH/THF, 88% for two steps (as mixture of 29 and 30); (b)
Cl3C6H2COCl, i-Pr2NEt, benzene, then DMAP, benzene, 74% (for single compound, 31).
TIPS¼triisopropylsilyl, DMAP¼4-(dimethylamino)pyridine.
To complete the synthesis of the mycolactone core, the triiso-
propyl ether of 31 was cleaved,26 and the resultant primary alcohol,
33, was converted to alkyl iodide 34 (Scheme 7). Under the same
Negishi coupling conditions optimized for the case of 5þ11/22,
alkyl iodide 34 was coupled with 21 (1.5 equiv) to provide 35 in 88%
yield.
4.2. Synthesis outlined in Scheme 1
To summarize, the synthesis of the mycolactone core described
herein proceeds in 14 linear steps and 19% overall yield. This syn-
thesis features scalable and efficient methods for the preparation of
the C1–C7, C8–C13, and C14–C20 fragments, and has allowed for
the preparation of 6.0 grams of protected mycolactone core 35 with
relative ease. Furthermore, we anticipate that it should be
straightforward to prepare even larger quantities of this material
should the need arise. Importantly, by synthesizing the C8–C13
4.2.1. Preparation of 2. To a solution of potassium tert-butoxide
(13.45 g,120 mmol) in THF (60 mL) at ꢁ78 ꢀC was added condensed
cis-2-butene (42 mL, 461 mmol) followed by n-BuLi in hexanes
(1.6 M in hexanes, 75 mL,120 mmol) dropwise. The resultant bright
yellow suspension was stirred for 10 min at ꢁ78 ꢀC, 20 min at
ꢁ50 ꢀC, and 10 min at ꢁ78 ꢀC. A solution of (þ)-Ipc2-BOMe
(43.80 g, 151 mmol) in Et2O (100 mL) was added dropwise via

K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
2267
cannula. The colorless solution was stirred at ꢁ78 ꢀC for 40 min,
and then BF3$OEt2 (19.2 mL, 151 mmol) was added dropwise.
Aldehyde 111 (12.0 g, 92.2 mmol) was then added dropwise as
a solution in THF (90 mL). The resultant mixture was stirred a fur-
ther 3 h at ꢁ78 ꢀC before being quenched with 3 M aqueous NaOH
(73.2 mL) and diluted with EtOAc (500 mL). 30% H2O2 (35.4 mL)
was added carefully, the cold bath was removed, and the resultant
mixture was stirred for 1 h. The layers were separated, and the
aqueous extracted with EtOAc (3ꢃ200 mL). The combined organics
were washed with saturated aqueous NaCl, dried (MgSO4), and
concentrated in vacuo. The crude residue was purified by flash
column chromatography in a solvent gradient (SiO2, 5%/10%/
30% EtOAc/hexanes) to provide 2 (13.38 g, 78% yield, 86% ee as
combined organic phase was washed with brine, dried (Na2SO4),
and concentrated in vacuo. The crude residue was purified by flash
column chromatography (SiO2, 25% EtOAc/hexanes) to provide al-
23
cohol 4 (6.51 g, 71% over three steps) as a colorless oil: [
a]
þ0.8 (c
D
1.77, CHCl3); 1H NMR (500 MHz, CDCl3)
d
0.87 (3H, d, J¼7.0 Hz),
1.45–1.56 (1H, m), 1.56–1.67 (2H, m), 1.71–1.82 (1H, m), 2.05–2.14
(1H, m), 2.25–2.37 (2H, m), 3.47–3.52 (1H, m), 3.54 (1H, dd, J¼5.0,
11.0 Hz), 3.665 (1H, apparent dd, J¼8.0, 11.0 Hz), 3.67 (3H, s), 3.80
(3H, s), 4.49 (2H, AB quartet, J¼11.0, 26.5 Hz), 6.85–6.90 (2H, m),
7.24–7.28 (2H, m). 13C NMR (100 MHz, CDCl3)
d 173.9, 159.2, 130.3,
129.5 (2C), 113.8 (2C), 81.4, 71.4, 65.8, 55.2, 51.5, 36.7, 33.9, 29.3,
21.6, 11.9 LRMS (ES) calculated for [MþH]þ (C17H27O5) requires m/z
311, found 311.
determined by conversion to the corresponding (R)- and (S)-
27
Mosher’s esters) as a colorless oil. [
(500 MHz, CDCl3)
a
]
D
ꢁ25.4 (c 1.0, CHCl3); 1H NMR
4.2.4. Preparation of 5. To a solution of alcohol 4 (0.217 g,
d
1.04 (3H, d, J¼7.0 Hz), 1.36–1.45 (1H, m), 1.51–
0.699 mmol) in CH2Cl2 (8 mL) was added imidazole (0.143 g,
2.10 mmol), PPh3 (0.385 g, 1.47 mmol), and iodine (0.373 g,
1.47 mmol). The resultant brown reaction mixture was stirred at rt
for 1 h. The reaction was diluted with EtOAc and poured into sat-
urated aqueous Na2S2O3. The aqueous layer was separated and
extracted with EtOAc (3ꢃ20 mL). The combined organics were
washed with saturated aqueous NaHCO3 and brine, dried (MgSO4),
and concentrated in vacuo. The crude material was purified by flash
1.60 (2H, m), 1.64–1.75 (1H, m), 1.80–1.90 (1H, m), 2.25–2.33 (1H,
m), 2.37 (2H, t, J¼7.5 Hz), 3.47–3.54 (1H, m), 3.69 (3H, s), 5.07–5.13
(2H, m), 5.75–5.83 (1H, m); 13C NMR (125 MHz, CDCl3)
d 14.16,
21.41, 33.32, 33.83, 43.51, 51.50, 74.23, 115.40, 140.77, 174.17; HRMS
(ESI) exact mass calculated for [MþNa]þ (C10H18O3Na) requires m/z
209.1148, found 209.1141.
4.2.2. Preparation of 3. Alcohol 2 (0.90 g, 4.83 mmol) and PMB-
column chromatography (SiO2,10% EtOAc/hexanes) to provide alkyl
26
trichloroacetimidate (2.44 g, 9.66 mmol) were dissolved in PhMe
iodide 5 (0.269 mg, 92% yield) as a colorless oil: [
a
]
þ18.2 (c 1.0,
D
(48 mL)
and
cooled
to
0 ꢀC.
Scandium(III)
tri-
CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.04 (3H, d, J¼6.5 Hz),1.45–1.54
fluoromethanesulfonate (0.12 g, 0.24 mmol) was added portion-
wise over 2 min. Stirring at 0 ꢀC was continued for a further 15 min.
The reaction was diluted with hexanes and filtered over Celite. The
filtrate was concentrated in vacuo, and the crude residue was pu-
(1H, m), 1.54–1.78 (3H, m), 1.89–1.98 (1H, m), 2.27–2.39 (2H, m),
3.09 (1H, dd, J¼7.6, 9.6 Hz), 3.37 (1H, dd, J¼6.0, 9.6 Hz), 3.42–3.48
(1H, m), 3.68 (3H, s), 3.82 (3H, s), 4.48 (2H, AB quartet, J¼11.5,
21.0 Hz), 6.87–6.92 (2H, m), 7.25–7.29 (2H, m); 13C NMR (125 MHz,
rified by flash column chromatography (SiO2, 7.5% EtOAc/hexanes)
CDCl3) d 12.17, 15.40, 20.90, 29.96, 33.74, 38.88, 51.34, 55.09, 71.70,
27
to provide 3 (1.20 g, 81% yield) as a colorless oil: [
a
]
ꢁ25.4 (c 1.0,
80.57, 113.62, 129.15, 130.53, 159.02, 173.60; HRMS (ESI) exact mass
calculated for [MþNa]þ (C17H25IO4Na) requires m/z 443.0690,
found 443.0659.
D
CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.05 (3H, d, J¼7.0 Hz),1.43–1.59
(2H, m), 1.60–1.72 (1H, m), 1.75–1.86 (1H, m), 2.24–2.36 (2H, m),
2.51 (1H, apparent sextet, J¼6.5 Hz), 3.23–3.29 (1H, m), 3.68 (3H, s),
3.81 (3H, s), 4.48 (2H, AB quartet, J¼11.5 Hz, 33.0 Hz), 5.01–5.09
(2H, m), 5.80–5.89 (1H, m), 6.86–6.92 (2H, m), 7.26–7.31 (2H, m);
4.3. Synthesis outlined in Scheme 2
13C NMR (125 MHz, CDCl3)
d
15.63, 21.00, 30.40, 34.04, 40.60, 51.42,
4.3.1. Preparation of 7. To a 0 ꢀC solution of LiAlH4 (1 M in Et2O
from Aldrich, 179 mL, 179 mmol) was added diynol 613 (19.34 g,
179 mmol) in Et2O (200 mL) dropwise. The resultant mixture was
heated to a gentle reflux and stirred for 9 h. The reaction was di-
luted with Et2O (310 mL) and treated, in sequence, with H2O
(6.5 mL), 2 N NaOH (6.5 mL) and H2O (6.5 mL). After stirring for
a further 15 min, the mixture was filtered through Celite, dried
(MgSO4), and concentrated in vacuo to provide pure 7 (19.37 g, 98%
yield) as a colorless oil whose 1H NMR was identical to that pub-
lished previously.14
55.25, 71.36, 82.11, 113.71, 114.45, 129.35, 130.89, 140.75, 159.09,
174.06; HRMS (ESI) exact mass calculated for [MþNa]þ
(C18H26O4Na) requires m/z 329.1723, found 329.1730.
4.2.3. Preparation of 4. To a solution of 3 (9.00 g, 29.4 mmol) in 3:1
acetone/H2O (488 mL) was added 4-methylmorpholine N-oxi-
de$H2O (7.94 g, 58.8 mmol) and OsO4 (0.1 M in H2O, 5.9 mL,
0.59 mmol). The resultant solution was stirred at rt for 14 h. Satu-
rated aqueous Na2S2O3 (300 mL) and EtOAc (300 mL) were added,
and the mixture was stirred for 1 h. The phases were separated, and
the aqueous extracted with EtOAc (3ꢃ200 mL). The combined or-
ganic phase was washed with H2O and brine, dried (Na2SO4), and
concentrated in vacuo to yield an inconsequential 3:1 mixture of
diol diastereoisomers, which was carried on to the following step
without further purification.
To a solution of the diol from the above step in benzene (185 mL)
was added Pb(OAc)4 (20.6 g, 46.4 mmol). The resultant mixture was
stirred at rt for 20 min. Saturated aqueous NaHCO3 was added until
the aqueous phase reached pH 7.0, and the mixture was extracted
with EtOAc (3ꢃ200 mL). The combined organic phase was washed
with brine, dried (MgSO4), and concentrated in vacuo to provide
the crude aldehyde, which was used in the following step without
further purification.
4.3.2. Preparation of 8. To a suspension of activated 4 Å molecular
sieves (30.0 g, powdered) in anhydrous CH2Cl2 (430 mL) at ꢁ10 ꢀC
were added (ꢁ)-diethyl
D-tartrate (3.21 mL, 18.8 mmol) and tita-
nium tetraisopropoxide (4.40 mL, 15.0 mmol). The resultant mix-
ture was cooled to ꢁ25 ꢀC and treated with tert-butyl
hydroperoxide (78.6 mL, 5.5 M solution in decane, 432 mmol). Af-
ter 20 min, a solution of alcohol 714 (20.7 g, 188 mmol) in anhy-
drous CH2Cl2 (110 mL) was added dropwise via cannula over
30 min. The resultant mixture was stirred 4 h at ꢁ25 ꢀC, then
warmed to rt over 2 h. After 30 min at rt, H2O (52 mL) and 4 M
aqueous NaOH (26 mL) were added. The resultant mixture was
stirred for 30 min, and the cloudy suspension was filtered through
Celite. After diluting with CH2Cl2 (300 mL), the organic phase was
washed with 10% Na2SO3. The layers were separated, and the
aqueous phase extracted with CH2Cl2 (2ꢃ300 mL). The combined
organic phase was washed with brine, dried (Na2SO4), and con-
centrated in vacuo. The crude residue was purified by flash column
chromatography (SiO2, 15% acetone/hexanes) to afford 8 (19.8 g,
The crude aldehyde from the preceding step was dissolved in
MeOH (300 mL) and cooled to 0 ꢀC. NaBH4 (2.22 g, 58.8 mmol) was
added portionwise over 5 min, and the solution was stirred at 0 ꢀC
for 1 h. Saturated aqueous NH4Cl was added to quench the reaction,
and the mixture was extracted with EtOAc (3ꢃ200 mL). The

2268
K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
83%) as white solid. It was determined by conversion of 9 (for
preparation of 9, see the following step) to the corresponding (R)-
and (S)-Mosher esters that the Sharpless asymmetric epoxidation
had proceeded in 80% ee. Optically pure 8 (16.5 g, 70%, >99% ee)
was obtained by recrystallization from hexanes/acetone (10/1) or
(100 mL). The biphasic mixture was stirred vigorously for 10 min,
then the layers were separated and the aqueous extracted with
EtOAc (3ꢃ100 mL). The combined organics were washed with
brine, dried (MgSO4), and concentrated in vacuo. The crude residue
was purified by flash column chromatography (SiO2, 1% EtOAc/
hexanes) to provide vinyl iodide 11 as an inseparable 22:1 mixture
toluene/hexanes (1/1) in a ꢁ20 ꢀC freezer: Rf 0.35 (hexanes/ace-
20
tone, 4/1); [
d
a]
þ18.7 (c 0.4, CHCl3); 1H NMR (600 MHz, CDCl3)
with the undesired regioisomer 12 as a clear oil (5.57 g, 68% yield).
D
26
1.75 (1H, dd, J¼5.4, 7.8 Hz), 1.83 (3H, t, J¼1.8 Hz), 2.48–2.65 (2H,
Spectroscopic data for the major regioisomer: [
a
]
þ10.9 (c 1.0,
D
m), 3.14–3.20 (2H, m), 3.67–3.75 (1H, m), 3.95–4.05 (1H, m); 13C
CHCl3); 1H NMR (500 MHz, C6D6)
d
0.28 (3H, d, J¼6.7 Hz), 1.42–1.56
NMR (125 MHz, CDCl3)
d
3.44, 21.63, 53.50, 57.80, 61.16, 73.08,
(5H, m), 1.56–1.64 (1H, m), 1.66–1.73 (1H, m), 1.85–1.96 (3H, m),
1.96–2.03 (1H, m), 2.12 (3H, d, J¼1.5 Hz), 3.05 (1H, ddd, J¼3.5, 8.0,
11.0 Hz), 3.09 (1H, apparent t, J¼11.5 Hz), 3.51 (1H, dd, J¼5.0,
11.5 Hz), 6.33 (1H, dt, J¼1.7, 7.2 Hz); 13C NMR (125 MHz, C6D6)
78.15; HRMS (ESI) exact mass calculated for [MþNa]þ (C7H10O2Na)
requires m/z 149.0573, found 149.0576.
4.3.3. Preparation of 9. To a suspension of CuCN (34.6 g, 387 mmol)
in anhydrous THF (560 mL) was added MeLi (1.6 M in ether, 524 mL,
838 mmol) dropwise at ꢁ20 ꢀC under argon. The mixture was
stirred until it became clear, then epoxide 8 (16.2 g, 129 mmol) was
added as a solution in anhydrous Et2O (250 mL) via cannula over
30 min. The resultant mixture was stirred at ꢁ20 ꢀC overnight, then
warmed to 0 ꢀC. The reaction was diluted with Et2O (500 mL) and
saturated aqueous NH4Cl (115 mL) and stirred vigorously for
10 min. The precipitate was removed by filtration through Celite,
then the organic layer was separated, washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was dissolved in
acetone (40 mL) and H2O (50 mL), and was treated with NaIO4
(6.10 g, 28.5 mmol). After 2 h, the mixture was quenched by the
addition of Na2SO3 (7.2 g, 57.0 mmol), diluted with Et2O, and fil-
tered through Celite. The organic phase was separated, washed
with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography in a solvent gradient
d 137.51, 110.21, 94.84, 76.00, 67.21, 40.33, 34.14, 33.70, 30.72, 27.72,
24.55, 22.73, 12.28; HRMS (ESI) exact mass calculated for [MþNa]þ
(C13H21IO2Na) requires m/z 359.0478, found 359.0470.
4.4. Synthesis outlined in Scheme 3
4.4.1. Preparation of 14. A solution of n-BuLi (91.5 mL of a 1.87 M
solution in hexanes,171 mmol) was added dropwise to a solution of
ethynyltrimethylsilane (32.0 mL, 214 mmol) in Et2O (950 mL) at
ꢁ78 ꢀC. Once addition was complete, the reaction mixture was
warmed to 0 ꢀC for 40 min, then recooled to ꢁ78 ꢀC. (R)-2-Meth-
yloxirane 13 (Alfa Aesar, >99% optical purity, 10.0 mL, 143 mmol)
was added via syringe, and the resultant solution was stirred for
10 min. A solution of BF3$OEt2 (freshly distilled, 21.5 mL, 171 mmol)
in Et2O (21.5 mL) was added dropwise over 3 min. The mixture was
stirred at ꢁ78 ꢀC for 1 h, then quenched with saturated aqueous
NaHCO3 (100 mL). The layers were separated, and aqueous was
extracted with Et2O (3ꢃ100 mL). The combined organic phase was
dried (MgSO4), and the solvent was removed by distillation through
a Vigreux column (10 cm height, 55 ꢀC oil bath) until 200 mL of
solution remained. The crude residue, whose 1H and 13C NMR
spectral data were consistent with those reported,27 was used for
the next step without purification.
(SiO2, 33% EtOAc/hexanes/50% EtOAc/hexanes) to give pure diol 9
20
(19.4 g, 79%): Rf 0.25 (50% EtOAc/hexanes); [
a
]
þ17.6 (c 0.4,
D
CHCl3); 1H NMR (600 MHz, CDCl3)
d
0.92 (3H, d, J¼7.2 Hz), 1.85 (3H,
t, J¼3.0 Hz), 1.85–1.93 (1H, m), 2.36–2.40 (1H, m), 2.50–2.54 (1H,
m), 2.77–3.83 (2H, m), 3.63–3.67 (1H, m), 3.68–3.72 (1H, m), 3.73–
3.78 (1H, m); 13C NMR (125 MHz, CDCl3)
d 3.39, 13.54, 25.81, 38.94,
67.00, 74.84, 75.06, 78.31; HRMS (ESI) exact mass calculated for
To a solution of crude alcohol (143 mmol) and imidazole (19.4 g,
285 mmol) in DMF (150 mL) was added TBSCl (30.1 g, 200 mmol).
The resultant solution was stirred at rt for 48 h. The mixture was
diluted with Et2O (1.5 L) and washed with brine (2ꢃ250 mL), H2O
(2ꢃ250 mL), and brine (250 mL). The organic phase was dried
(MgSO4), and gently concentrated in vacuo until 100 mL of solution
remained. The crude residue of 14, whose 1H and 13C NMR spectral
data were consistent with those reported,28 was used for the next
step without purification.
[MþNa]þ (C8H14O2Na) requires m/z 165.0886, found 165.0884.
4.3.4. Preparation of 10. To a solution of diol 9 (18.7 g, 131 mmol) in
cyclopentanone (200 mL) was added p-TsOH (monohydrate, 2.50 g,
13.1 mmol). The mixture was stirred 12 h at rt, then treated with
Et3N (3.64 mL, 26.3 mmol). The mixture was concentrated in vacuo,
and the residue purified by flash column chromatography (SiO2,
10% EtOAc/hexanes/50% EtOAc/hexanes) to provide 10 (22.3 g,
89% based on consumed diol) along with recovered diol 9 (1.63 g,
20
5%): Rf 0.40 (10% EtOAc/hexanes); [
(500 MHz, C6D6)
a]
ꢁ4.1 (c 0.3, CHCl3); 1H NMR
4.4.2. Preparation of 15. To a solution of crude alkyne 14
D
d
0.42 (3H, d, J¼6.5 Hz),1.54 (3H, t, J¼2.5 Hz),1.50–
(143 mmol) and NIS (43.3 g,192 mmol) in DMF (475 mL) was added
AgNO3 (3.63 g, 21.4 mmol). The resultant mixture was stirred for
5 h at rt. The mixture was quenched with brine (150 mL), filtered
over Celite, and diluted with hexanes/Et2O (1:1, 2 L). The separated
organic phase was washed with brine (2ꢃ1 L) and H2O (3ꢃ1 L),
dried (MgSO4), and gently concentrated in vacuo until 100 mL of
solution remained. The crude residue was unstable and used for the
next step immediately without purification.
1.63 (4H, m), 1.69–1.82 (2H, m), 1.85–1.95 (1H, m), 2.04–2.13 (2H,
m), 2.28–2.43 (2H, m), 3.17 (1H, t, J¼11 Hz), 3.24–3.30 (1H, m), 3.58
(1H, dd, J¼11.5, 5.0 Hz); 13C NMR (125 MHz, C6D6)
d 3.51, 12.30,
22.84, 24.23, 24.66, 30.85, 33.69, 40.43, 67.21, 75.89, 76.95, 110.41,
127.69; HRMS (ESI) exact mass calculated for [MþNa]þ
(C13H20O2Na) requires m/z 231.1356, found 231.1357.
4.3.5. Preparation of 11. Schwartz reagent (w70% pure homemade
reagent,18c 13.5 g, 36.6 mmol) was transferred to a round bottom
flask under inert atmosphere, then treated with a solution of alkyne
10 (5.08 g, 24.4 mmol) in THF (150 mL). The resultant suspension
was heated to 50 ꢀC and stirred for 30 min. The reaction was cooled
to rt, then to 0 ꢀC. A solution of iodine (9.28 g, 36.6 mmol) in THF
(122 mL) was added dropwise to the 0 ꢀC suspension until a brown
color just persisted. At this point the addition of iodine/THF was
ceased, and the remaining iodine/THF solution was discarded. The
reaction was quenched after 5 min by dilution with 1:1 saturated
aqueous NaHCO3/saturated aqueous Na2S2O3 (200 mL) and EtOAc
THF (715 mL) was bubbled with Ar for 15 min at 0 ꢀC, then
cyclohexene (37.5 mL, 371 mmol) was added. To the resultant so-
lution was cautiously added BH3$S(CH3)2 (17.6 mL, 185 mmol)
dropwise over 20 min. The reaction was stirred for 2 h at 0 ꢀC and
1 h at rt with constant bubbling of Ar through the solution. The
resultant Cy2BH solution was cooled to 0 ꢀC, and the crude alkynyl
iodide from the preceding step was added dropwise over 10 min.
The reaction was stirred 3 h at rt, then quenched by addition of
AcOH (32.6 mL, 570 mmol) at 0 ꢀC over 5 min. After stirring at rt for
30 min, the reaction was allowed to stand at 5 ꢀC for 12 h. The
mixture was gently concentrated in vacuo to 200 mL, then K2CO3

K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
2269
(95 g in 300 mL water) was added to neutralize the mixture. Fol-
lowing dilution with hexanes (1.5 L), the organics were washed
with saturated aqueous NaHCO3 (3ꢃ400 mL) and brine (400 mL),
dried (MgSO4), and concentrated in vacuo. The crude residue was
purified by flash chromatography (SiO2, 100% hexanes/5% CH2Cl2/
hexanes) to provide vinyl iodide 15 (44.1 g, 95% over four steps) as
a colorless oil, whose 1H and 13C NMR spectral data were consistent
with those reported.29
separated, and aqueous extracted with Et2O (3ꢃ250 mL). The
combined organic phase was dried (MgSO4), concentrated in vacuo,
and purified by flash chromatography (SiO2, 33% CH2Cl2/hexanes/
50% CH2Cl2/hexanes/10% Et2O/hexanes) to afford alcohol 19
25
(18.3 g, 87%) as a colorless oil; [
a
]
ꢁ8.5 (c 1.13, CHCl3); 1H NMR
D
(600 MHz, CDCl3)
d
0.09 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 1.14 (3H, d,
J¼4.8 Hz), 1.19 (3H, d, J¼6.0 Hz), 1.55 (1H, dt, J¼14.4, 9.6 Hz), 1.78
(3H, d, J¼1.8 Hz), 1.83 (1H, ddd, J¼14.4, 3.6, 1.8 Hz), 2.47–2.40 (1H,
m), 3.57–3.53 (1H, m), 3.58 (1H, d, J¼1.8 Hz), 4.11–4.06 (1H, m); 13C
4.4.3. Preparation of 16. Propyne was bubbled (via a balloon)
through a solution of vinyl iodide 15 (44.1 mL, 135 mmol) in Et2NH
(0.9 L) for 10 min at 0 ꢀC. PdCl2(PPh3)2 (4.12 g, 5.4 mmol) and CuI
(2.06 g, 10.8 mmol) were added. Propyne was continually bubbled
into the resultant solution as the reaction stirred for 3 h at rt. The
mixture was diluted with pentane (4 L) and washed with saturated
aqueous NH4Cl (3ꢃ2 L), H2O (2ꢃ2 L) and brine (2 L). The organic
phase was dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash chromatography (SiO2, 100% pentane/5%
Et22O5/pentane) to afford enyne 16 (30.5 g, 96%) as a colorless oil;
NMR (125 MHz, CDCl3)
d
ꢁ4.79, ꢁ3.93, 3.57, 17.07, 17.88, 24.53,
25.82, 33.05, 42.75, 70.13, 74.68, 77.36, 81.00; HRMS (ESI) exact
mass calculated for [MþNa]þ (C15H30O2SiNa) requires m/z
293.1913, found 293.1907.
4.4.6. Preparation of 20. TBSCl (14.3 g, 94.9 mmol) was added to
a solution of alcohol 19 (18.3 g, 67.8 mmol) and imidazole (13.8 g,
203 mmol) in DMF (225 mL), and the reaction was stirred at rt for
48 h. The mixture was diluted with Et2O/hexanes (1:1, 1.4 L). The
organic layer was washed with brine (2ꢃ500 mL), H2O
(2ꢃ500 mL), and brine (500 mL), dried (MgSO4), and concen-
trated. The residue was purified by flash chromatography (SiO2,
[
a
]
þ4.9 (c 1.51, CHCl3); 1H NMR (600 MHz, CDCl3)
d 0.04 (3H, s),
D
0.04 (3H, s), 0.87 (9H, s),1.13 (3H, d, J¼6.0 Hz),1.95 (3H, d, J¼2.4 Hz),
2.46–2.35 (2H, m), 3.87 (1H, dq, J¼6.0, 6.0 Hz), 5.49–5.44 (1H, m),
100% hexanes/9% CH2Cl2/hexanes) to afford alkyne 20 (25.9 g,
5.85 (1H, dt, J¼10.2, 7.5 Hz); 13C NMR (125 MHz)
d
ꢁ4.78, ꢁ4.61,
99%) as a colorless oil: [
a
]
þ10.8 (c 1.28, CHCl3); 1H NMR
23
D
4.36, 18.15, 23.49, 25.86, 40.11, 68.22, 76.61, 89.83, 110.89, 138.74;
HRMS (ESI) exact mass calculated for [MþH]þ (C14H27OSi) requires
m/z 239.1831, found 239.1826.
(500 MHz, CDCl3) d 0.057 (3H, s), 0.061 (3H, s), 0.07 (3H, s), 0.08
(3H, s), 0.90 (18H, overlapped two singlets), 1.07 (3H, J¼6.0 Hz),
1.14 (3H, d, J¼6.0 Hz), 1.54 (1H, ddd, J¼6.0, 6.0, 13.5 Hz), 1.77 (3H, d,
J¼2.5 Hz), 1.82 (1H, ddd, J¼6.0, 6.0, 13.5 Hz), 2.46–2.54 (1H, m),
3.68 (1H, apparent q, J¼6.0 Hz), 3.98 (1H, apparent sextet,
J¼6.0 Hz); HRMS (ESI) exact mass calculated for [MþH]þ
(C21H44O2Si2) requires m/z 385.2958, found 385.2954.
4.4.4. Preparation of 18. To a solution of ligand 1721b (5.02 g,
9.38 mmol) in CH2Cl2 (200 mL) was added Ti(O-i-Pr)4 (2.54 mL,
8.53 mmol). The reaction was stirred for 1 h at rt. Enyne 16 (20.0 g,
85.3 mmol), 4,40-thiobis(6-tert-butyl-m-cresol) (Sumitomo Chem-
ical, 2.0 g, 5.58 mmol), H2O2 (30% solution in H2O, 20 mL,
176 mmol), and phosphate buffer (pH 7.4, 67 mM, 10 mL) were
added. The resultant reaction mixture was stirred at 40 ꢀC for 4 h,
then H2O2 (30% solution in H2O, 20 mL, 196 mmol) was added
(repeated twice more, stirring 4 h between each H2O2 addition).
The reaction was stirred at 40 ꢀC for another 18 h until all of the
enyne was converted to the epoxide. Solid NH4Cl (30 g) was added,
and the resultant mixture was diluted with hexanes (2 L) and fil-
tered over Celite. The filtrate was washed with saturated NH4Cl
solution (3ꢃ400 mL), dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash chromatography in a solvent
gradient (SiO2, 3% CH2Cl2/hexanes/10% CH2Cl2/hexanes/10%
4.4.7. Preparation of 21. Schwartz reagent (w70% pure homemade
reagent,18c 1.44 g, 3.90 mmol) was transferred to a round bottom
flask under inert atmosphere, then treated with a solution of al-
kyne 20 (1.00 g, 2.60 mmol) in THF (4.3 mL). The resultant sus-
pension was heated to 50 ꢀC and stirred for 1 h. The reaction was
cooled to rt, then to 0 ꢀC. A solution of iodine (0.99 g, 3.90 mmol)
in THF (4.3 mL) was added dropwise to the 0 ꢀC suspension until
a brown color just persisted. At this point the addition of iodine/
THF was ceased, and the remaining iodine/THF solution was dis-
carded. The reaction was quenched by dilution with 1:1 saturated
aqueous NaHCO3/saturated aqueous Na2S2O3 (10 mL) and EtOAc
(10 mL). The biphasic mixture was stirred vigorously for 10 min,
then the layers were separated. The aqueous phase was extracted
with EtOAc (3ꢃ10 mL). The combined organics were washed with
brine, dried (MgSO4), filtered, and concentrated. The crude resi-
due was purified by flash column chromatography (SiO2, 1%
Et2O/hexanes) to afford epoxide 18 (19.8 g, 91%, ꢂ50:1 dr as de-
25
termined by 1H NMR) as a colorless oil; [
a
]
D
ꢁ11.9 (c 1.80, CHCl3);
1H NMR (600 MHz, CDCl3)
d 0.04 (3H, s), 0.05 (3H, s), 0.87 (9H, s),
1.22 (3H, d, J¼6.0 Hz), 1.75 (1H, dt, J¼14.1, 6.0 Hz), 1.84 (3H, d,
J¼1.8 Hz), 1.86 (1H, dt, J¼14.1, 6.0 Hz), 3.12 (1H, dt, J¼6.0, 1.8 Hz),
3.38–3.35 (1H, m), 4.05 (1H, dq, J¼6.0, 6.0 Hz); 13C NMR (125 MHz,
EtOAc/hexanes) to provide vinyl iodide 21 as a clear oil (0.88 g,
27
60% yield): [
a
]
þ10.9 (c 1.0, CHCl3); 1H NMR (500 MHz)
d 0.05–
D
CDCl3)
d
ꢁ4.89, ꢁ4.53, 3.65, 18.04, 23.85, 25.79, 38.92, 44.85, 55.26,
0.09 (12H, m), 0.90 (9H, s), 0.91 (9H, s), 0.93 (3H, d, J¼6.5 Hz), 1.15
(3H, d, J¼6.3 Hz), 1.54–1.67 (2H, m), 2.40 (3H, d, J¼1.5 Hz), 2.49–
2.58 (1H, m), 3.65–3.70 (1H, m), 3.89 (1H, apparent sextet,
J¼6.0 Hz), 6.15 (1H, dd, J¼1.5, 10.3 Hz); 13C NMR (125 MHz)
66.37, 74.25, 82.13; HRMS (ESI) exact mass calculated for [MþNa]þ
(C14H26O2SiNa) requires m/z 277.1600, found 277.1592.
4.4.5. Preparation of 19. To a solution of epoxide 18 (19.8 mL,
78.0 mmol) in CH2Cl2 (780 mL) at ꢁ78 ꢀC was added AlMe3 (2 M
solution in PhMe, Aldrich, 78.0 mL, 156 mmol) dropwise. After
stirring for 10 min, MeLi (1.6 M solution in Et2O, Aldrich, 98 mL,
156 mmol) was added dropwise. The reaction was stirred a further
20 min, then treated with a solution of BF3$OEt2 (freshly distilled,
19.8 mL, 156 mmol) in Et2O (19.8 mL). After 1 h at ꢁ78 ꢀC, the re-
action mixture was carefully quenched by dropwise addition of
MeOH (100 mL) over 30 min while still stirring at ꢁ78 ꢀC. The re-
sultant mixture was warmed to rt, saturated aqueous NH4Cl
(100 mL) was added, and stirring was continued for 30 min. The
mixture was then treated with saturated aqueous sodium potas-
sium tartrate (150 mL) and stirred for 2 h. The phases were
d
ꢁ4.66, ꢁ4.55, ꢁ4.18, 14.10, 18.06, 24.06, 25.86, 25.91, 25.96,
27.89, 40.32. 44.90, 65.85, 71.87, 93.09, 145.04; HRMS (ESI) exact
mass calculated for [MþNa]þ (C21H45IO2Si2Na) requires m/z
535.1895, found 535.1889.
4.5. Synthesis outlined in Scheme 4
4.5.1. Preparation of 22. To prepare active Zn–Cu couple, Cu(OAc)2
(87.3 mg, 0.437 mmol) was suspended in glacial AcOH (20 mL). To
this was added Zn dust (1.43 g, 21.9 mmol), and the resultant sus-
pension was heated to reflux for one minute or until all of the
copper had deposited onto the zinc (disappearance of blue color in
the supernatant). Stirring was stopped, and the reddish-gray silt

2270
K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
was allowed to settle. The AcOH was removed by pipette, then
another portion of AcOH (20 mL) was added and the suspension
was heated to reflux for one minute. The AcOH was removed again
by pipette, and this process was repeated once more. Finally, the
Zn–Cu couple was rinsed with Et2O (3ꢃ20 mL), with each rinse
being removed by pipette. The resultant active couple was dried
under vacuum for 30 min.
138.05, 159.03, 174.00; HRMS (ESI) exact mass calculated for
[MþH]þ (C25H41O6) requires m/z 437.2903, found 437.2879.
4.7. Synthesis outlined in Scheme 6
4.7.1. Preparation of 29. To a stirred ꢁ78 ꢀC solution of diol 26
(9.70 g, 22.2 mmol) in CH2Cl2 (222 mL) was added 2,6-lutidine
(6.20 mL, 53.3 mmol), followed by TIPSOTf (6.57 mL, 24.4 mL)
dropwise. The resultant solution was stirred at ꢁ78 ꢀC for 20 min,
then poured into saturated aqueous NH4Cl. The layers were sepa-
rated, and the aqueous phase extracted with EtOAc (3ꢃ200 mL).
The combined organics were washed with 1 M HCl, saturated
aqueous NaHCO3, and brine, then dried (MgSO4) and concentrated
in vacuo. The crude residue was carried on to the following step
without further purification.
To the crude ester from the preceding step dissolved in 4:1:1
THF/MeOH/H2O (1.11 L) was added 1 M LiOH (193 mL). The re-
sultant solution was stirred at rt for 1.5 h. The reaction was cau-
tiously and slowly poured into 1 M HCl, then the mixture was
extracted with EtOAc (4ꢃ500 mL). The combined organics were
washed with H2O (2ꢃ500 mL) and brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified by flash
column chromatography (SiO2, 25%/50% methyl t-butyl ether/
Alkyl iodide 5 (1.84 g, 4.37 mmol) dissolved in anhydrous 15:1
PhH/DMF (17.5 mL) was cannulated into to the active Zn–Cu
couple, and the resultant suspension was heated at 55 ꢀC for 1 h.
Meanwhile, LiCl (1.11 g, 26.2 mmol, dried over flame/vacuum) and
Pd(PPh3)4 (361 mg, 0.312 mmol) were combined and purged with
argon. Freshly distilled anhydrous NMP (12.5 mL) was added,
followed by the vinyl iodide 11 (1.05 g, 3.12 mmol) in NMP (4.1 mL,
plus a little more to aid in transfer). Then the colorless alkylzinc
iodide solution was added via cannula (the excess settled Zn was
left behind in the original flask as much as possible). The reaction
mixture was degassed with one freeze-pump-thaw cycle, and the
mixture was heated to 55 ꢀC for 35 min. The reaction was cooled to
rt, diluted with EtOAc, and poured into saturated aqueous
NaHCO3. The layers were separated, and the aqueous extracted
with EtOAc (3ꢃ50 mL). The combined organics were washed with
H2O (3ꢃ100 mL) and brine (100 mL), dried (Na2SO4) and con-
centrated in vacuo. The crude residue was purified by flash col-
umn chromatography in a solvent gradient (SiO2, 5%/10% EtOAc/
hexanes) to provide 22 (1.50 g, 95%) as a colorless oil, which
hexanes) to provide seco-acid 29 (14.85 g, 88% over two steps,
26
contaminated with w6% of 30) as a colorless oil: [
a
]
D
þ1.1 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3)
d
0.85 (3H, d, J¼6.5 Hz), 0.91 (3H,
contained small amounts of the diastereomeric products 23 and
d, J¼7.0 Hz), 1.05–1.18 (21H, m), 1.50–1.62 (3H, m),1.62 (3H, s), 1.62–
1.72 (1H, m), 1.72–1.82 (2H, m), 1.82 (1H, dd, J¼8.5, 13.0 Hz), 1.88–
1.98 (1H, m), 2.22–2.30 (3H, m), 2.35 (2H, t, J¼7.3 Hz), 3.26–3.32
(1H, m), 3.63 (1H, apparent dt, J¼5.0, 7.0 Hz), 3.71 (1H, dd, J¼7.3,
9.8 Hz), 3.81 (3H, s), 3.91 (1H, dd, J¼3.9, 9.8 Hz), 4.47 (2H, AB
quartet, J¼11.5, 18.0 Hz), 5.25 (1H, apparent t, J¼6.5 Hz), 6.86–6.90
26
24. Spectral data is reported only for the major product, 22: [a]
D
þ5.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.75 (3H, d,
J¼6.8 Hz), 0.83 (3H, d, J¼6.8 Hz), 1.44–1.55 (2H, m), 1.55–1.70 (5H,
m), 1.70–1.87 (6H, m), 1.87–1.96 (2H, m), 2.08–2.18 (1H, m), 2.24
(1H, dd, J¼4.6, 12.9 Hz), 2.28–2.39 (3H, m), 3.26 (1H, ddd, J¼3.5,
3.5, 7.0 Hz), 3.33–3.39 (1H, m), 3.40 (1H, t, J¼11.0 Hz), 3.68 (3H, s),
3.73 (1H, dd, J¼4.5, 11.0 Hz), 3.81 (3H, s), 4.46 (2H, AB quartet,
J¼11.0, 25.5 Hz), 5.27 (1H, dd, J¼6.0, 7.0 Hz), 6.86–6.91 (2H, m),
(2H, m), 7.26–7.31 (2H, m); 13C NMR (125 MHz)
d 11.73, 13.73, 14.83,
16.17, 17.94, 21.32, 29.68, 29.97, 33.33, 33.75, 33.99, 39.27, 42.97,
55.25, 68.42, 71.42, 76.53, 81.80, 113.71, 122.37, 129.28, 131.15,
135.70, 159.03, 178.22; HRMS (ESI) exact mass calculated for
[MþH]þ (C33H59O6Si) requires m/z 579.4075, found 579.4043.
7.25–7.31 (2H, m); 13C NMR (125 MHz)
d 12.60, 14.46, 15.99, 21.47,
22.47, 24.24, 30.01, 30.53, 31.52, 33.29, 33.83, 34.02, 40.13, 42.67,
51.34, 55.13, 67.41, 71.34, 77.16, 81.89, 110.04, 113.60, 122.14,
129.09, 131.13, 134.89, 158.93, 173.93; HRMS (ESI) m/z exact mass
calculated for [MþH]þ (C30H47O6) requires m/z 503.3372, found
503.3372.
4.7.2. Preparation of 31. To a solution of seco-acid 29 (14.9 g,
25.7 mmol) in PhMe (260 mL) was added i-Pr2NEt (26.8 mL,
153.9 mmol) and 2,4,6-trichlorobenzoyl chloride (12.1 mL,
77.0 mmol). The resultant solution was stirred for 1.5 h at rt. In
a separate flask, DMAP (9.41 g, 77.0 mmol) was dissolved in PhMe
(1.3 L). To this solution was added the anhydride solution dropwise
via cannula over 4 h, and the resultant cloudy suspension was
stirred a further 12 h at rt. The reaction mixture was poured into
1 M HCl, and the layers were separated. The aqueous phase was
extracted with EtOAc (3ꢃ150 mL), and the combined organics were
washed with saturated aqueous NaHCO3, H2O, and brine. After
drying (MgSO4), the organic phase was concentrated in vacuo. The
crude residue was purified by flash column chromatography in
a solvent gradient (SiO2, 100% hexanes/2% EtOAc/hexanes) to
provide macrolactone 31 (10.61 g, 74%) in pure form as a white
4.6. Synthesis outlined in Scheme 5
4.6.1. Preparation of 26. A mixture of CH2Cl2 (663 mL), H2O
(166 mL), and TFA (41 mL) was shaken vigorously in a separatory
funnel. The lower organic layer was drained into a round bottom
flask containing 22 (6.29 g, 12.5 mmol). The resultant solution was
stirred at rt for 3.5 h. The reaction solution was cautiously and
slowly poured into ice-cold saturated aqueous NaHCO3. The layers
were separated, and the aqueous extracted with EtOAc (3ꢃ250 mL).
The combined organics were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The crude residue was purified by flash
column chromatography in a solvent gradient (SiO2, 25%/50%
EtOAc/hexanes) to provide 1,3-diol 26 (4.97 g, 91%, contaminated
with w6% of 27) as a white waxy solid. During this chromato-
waxy solid. During this chromatography, 32 (0.86 g, 6%) was re-
27
moved. Data for the 31: [
(500 MHz, CDCl3)
a]
ꢁ17.9 (c .84, CHCl3); 1H NMR
D
d
0.99 (3H, d, J¼6.8 Hz), 1.04 (3H, d, J¼7.0 Hz).
graphic separation, it was possible to remove minor contaminant
1.04–1.14 (21H, m),1.40–1.52 (1H, m),1.57–1.67 (1H, m),1.66 (3H, s),
1.67–1.84 (3H, m), 1.85–1.92 (2H, m), 1.92–2.00 (1H, apparent
septet, J¼6.5 Hz), 2.06–2.13 (1H, m), 2.07 (1H, dt, J¼3.5, 12.0 Hz),
2.42–2.53 (2H, m), 3.10–3.16 (1H, m), 3.54 (1H, dd, J¼7.0, 10.0 Hz),
3.68 (1H, dd, J¼5.5, 10.0 Hz), 3.81 (3H, s), 4.42 (2H, AB quartet,
J¼11.5, 97.0 Hz), 4.98–5.04 (1H, br d, J¼10.0 Hz), 5.08 (1H, ddd,
J¼3.4, 6.1, 12.0 Hz), 6.87–6.90 (2H, m), 7.25–7.30 (2H, m); 13C NMR
28. Data for 26: [
d
a
]
þ1.9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
27
D
0.82 (3H, d, J¼6.8 Hz), 0.89 (3H, d, J¼7.2 Hz), 1.40–1.80 (8H, m),
1.63 (3H, s), 1.84 (1H, dd, J¼9.0, 13.2 Hz), 2.16–2.34 (5H, m), 3.19–
3.26 (1H, m), 3.50 (1H, dt, J¼4.0, 8.0 Hz), 3.63 (1H, dd, J¼7.6,
10.8 Hz), 3.67 (3H, s), 3.70 (1H, dd, J¼3.2, 10.8 Hz), 3.80 (3H, s), 4.43
(2H, AB quartet, J¼11.4, 23.4 Hz), 5.13 (1H, apparent t, J¼7.2 Hz),
6.84–6.90 (2H, m), 7.22–7.29 (2H, m); 13C NMR (125 MHz)
d
13.82,
(125 MHz) d 11.90, 12.80, 15.64, 17.66, 17.97, 19.28, 20.51, 28.99,
15.39, 16.08, 21.51, 29.41, 32.86, 33.91, 34.20, 39.62, 42.89, 51.39,
55.17, 67.66, 71.35, 77.05, 82.26, 113.63, 121.35, 129.36, 130.77,
30.59, 32.63, 35.84, 40.42, 45.68, 55.17, 65.17, 70.82, 73.62, 83.10,
113.63, 121.91, 129.34, 131.07, 137.10, 159.01, 173.39; HRMS (ESI)

K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
2271
exact mass calculated for [MþH]þ (C33H57O5Si) requires m/z
being removed by pipette. The resultant active couple was dried
under vacuum for 30 min.
561.3975, found 561.3985.
Alkyl iodide 34 (1.00 g, 1.95 mmol) dissolved in anhydrous 15:1
PhH/DMF (7.0 mL) was cannulated into to the active Zn–Cu couple,
and the resultant suspension was heated at 50 ꢀC for 1 h. Mean-
while, LiCl (494 mg, 11.7 mmol, dried over flame/vacuum) and
Pd(PPh3)4 (337 mg, 0.292 mmol) were combined and purged with
argon. Freshly distilled anhydrous NMP (8.0 mL) was added, fol-
lowed by vinyl iodide 21 (1.5 g, 2.92 mmol) in NMP (3.7 mL, plus
a little more to aid in transfer). Then the colorless alkylzinc iodide
solution was added via cannula (the excess settled Zn was left be-
hind in the original flask as much as possible). The reaction mixture
was degassed with one freeze-pump-thaw cycle, and the mixture
was heated to 60 ꢀC for 17.5 h. The reaction was cooled to rt, diluted
with EtOAc, and poured into saturated aqueous NaHCO3. The layers
were separated, and the aqueous extracted with EtOAc (3ꢃ50 mL).
The combined organics were washed with H2O (3ꢃ100 mL) and
brine (100 mL), dried (Na2SO4) and concentrated in vacuo. The
crude residue was purified by flash column chromatography in
4.8. Synthesis outlined in Scheme 7
4.8.1. Preparation of 33. To a stirred 0 ꢀC solution of 31 (4.00 g,
7.13 mmol) in CH3CN (300 mL) in a Teflon bottle was added pyri-
dine (20.1 mL, 249.6 mmol). After 10 min, HF$pyridine (70%,
20.1 mL) was added. Stirring was continued at 0 ꢀC for 72 h. Using
extreme caution, the reaction was quenched slowly by repeatedly
pipetting w20 mL aliquots of the reaction mixture onto ice-cold
saturated aqueous NaHCO3. After all of the reaction mixture was
transferred, the resultant biphasic mixture was stirred for 30 min,
then the layers were separated. The aqueous phase was extracted
with EtOAc (3ꢃ200 mL), and the combined organics were washed
with 1 M HCl and brine, dried (MgSO4), and concentrated in vacuo.
The crude residue was purified by flash column chromatography
(25% EtOAc/hexanes) to provide alcohol 33 (2.66 g, 92%) as a white
25
solid: [
a]
ꢁ42.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d 1.04
D
(3H, d, J¼6.5 Hz), 1.06 (3H, d, J¼7.0 Hz), 1.43–1.54 (1H, m), 1.55–1.65
(2H, m), 1.67 (3H, s), 1.67–1.77 (3H, m), 1.77–1.85 (1H, m), 1.85–1.96
(2H, m), 2.11 (1H, td, J¼3.4, 12.5 Hz), 2.19 (1H, br d, J¼12.5 Hz), 2.41
(1H, dt, J¼11.0, 14.0 Hz), 2.54 (1H, dt, J¼4.4, 12.7 Hz), 3.09–3.14 (1H,
m), 3.45 (1H, dd, J¼3.4, 11.7), 3.58 (1H, dd, J¼3.9, 11.7), 3.81 (3H, s),
4.40 (2H, AB quartet, J¼11.0, 98.5 Hz), 4.85 (1H, ddd, J¼2.9, 8.8,
11.7 Hz), 4.99 (1H, br d, J¼11.0 Hz), 6.85–6.90 (2H, m), 7.24–7.29
a solvent gradient (SiO2, 1%/2%/3% EtOAc/hexanes) to provide
ꢁ8.2 (c 1.0, CHCl3); 1H NMR
25
35 (1.318 g, 88%) as a colorless oil: [
(500 MHz, CDCl3)
a
]
D
d
0.02–0.07 (12H, m), 0.84 (3H, d, J¼7.0 Hz), 0.88
(3H, d, J¼6.5 Hz), 0.88 (9H, s), 0.90 (9H, s),1.03 (3H, d, J¼6.5 Hz),1.14
(3H, d, J¼6.5 Hz), 1.40–1.52 (1H, m), 1.52–1.83 (9H, m), 1.59 (3H, d,
J¼1.0 Hz), 1.66 (3H, s), 1.83–1.95 (2H, m), 2.02–2.08 (1H, m), 2.09
(1H, dd, J¼3.5, 12.5 Hz), 2.14 (1H, dd, J¼3.5, 13.5 Hz), 2.37–2.52 (3H,
m), 3.10–3.15 (1H, m), 3.81 (3H, s), 3.90 (1H, apparent sextet,
J¼6.5 Hz), 4.31 (1H, d, J¼11.0 Hz), 4.51 (1H, d, J¼11.0 Hz), 4.84–4.91
(1H, m), 5.00 (1H, m), 5.12 (1H, d, J¼9.5 Hz), 6.85–6.90 (2H, m),
(2H, m); 13C NMR (125 MHz)
d 13.70, 15.69, 19.00, 20.65, 28.84,
31.58, 32.44, 35.88, 40.20, 45.67, 55.23, 63.97, 70.76, 74.31, 83.16,
113.68, 121.71, 129.36, 130.95, 137.45, 159.06, 175.07; HRMS (ESI)
exact mass calculated for [MþH]þ (C24H37O5) requires m/z
405.2641, found 405.2640.
7.25–7.30 (2H, m); 13C NMR (125 MHz)
d
ꢁ4.70, ꢁ4.39, ꢁ4.34,
ꢁ4.05, 14.47, 15.66, 15.74, 16.01, 18.07, 18.10, 19.26, 20.61, 23.96,
25.89, 25.96, 28.97, 30.25, 32.61, 35.19, 35.67, 37.61, 43.03, 45.03,
45.74, 55.24, 66.00, 70.82, 73.14, 76.04, 83.21, 113.68, 121.89, 129.39,
130.46, 131.09, 131.60, 137.12, 159.05, 173.59; HRMS (ESI) exact mass
calculated for [MþH]þ (C45H81O6Si2) requires m/z 773.5572, found
773.5577.
4.8.2. Preparation of 34. To a solution of alcohol 33 (1.67 g,
4.12 mmol) in CH2Cl2 (82 mL) was added imidazole (841 mg,
12.4 mmol), triphenylphosphine (2.27 g, 8.65 mmol), and iodine
(2.20 g, 8.65 mmol). The resultant mixture was stirred at rt for 12 h.
The reaction was quenched by dilution with 1:1 saturated aqueous
NaHCO3/saturated aqueous Na2S2O3 and EtOAc. The layers were
separated, and the aqueous phase was extracted with EtOAc
(3ꢃ100 mL). The combined organics were washed with brine, dried
(MgSO4), and concentrated in vacuo. The crude residue was puri-
Acknowledgements
We are grateful to the National Institutes of Health (C.A. 22215)
and to the Eisai Research Institute for generous financial support.
K.L. J. gratefully acknowledges a Mary Fieser postdoctoral fellow-
ship from Harvard University.
fied by flash column chromatography (SiO2, 5% EtOAc/hexanes) to
provide 34 (2.10 g, 99%) as a clear oil: [
25
a
]
ꢁ8.2 (c 1.0, CHCl3); 1H
D
NMR (500 MHz, CDCl3)
d
1.04 (3H, d, J¼7.0 Hz), 1.11 (3H, d,
J¼7.0 Hz), 1.37–1.49 (1H, m), 1.52–1.68 (1H, m), 1.65 (3H, s), 1.68–
1.84 (3H, m), 1.84–1.96 (3H, m), 2.04–2.18 (2H, m), 2.37–2.47 (1H,
m), 2.47–2.53 (1H, m), 3.01 (1H, td, J¼1.0, 9.8 Hz), 3.10–3.14 (1H, m),
3.31 (1H, dd, J¼3.9, 9.8 Hz), 3.82 (3H, s), 4.32 (1H, d, J¼11.0 Hz), 4.52
(1H, d, J¼11.0 Hz), 4.91–5.02 (2H, m), 6.86–6.91 (2H, m), 7.25–7.30
References and notes
1. For reviews on Buruli ulcer, see: (a) Asiedu, K.; Scherpbier, R. In Buruli Ulcer:
Mycobacterium Ulcerans Infection; Ravinglione, M., Ed.; World Health Organi-
zation: Geneva, Switzerland, 2000; (b) Rohr, J. Angew. Chem. Int. Ed. 2000, 39,
2847; (c) Johnson, P. D. R.; Stinear, T.; Small, P. L. C.; Pluschke, G.; Merritt, R. W.;
Portaels, F.; Huygen, K.; Hayman, J. A.; Asiedu, K. PLoS Med. 2005, 2, e108; (d)
Van der Werf, T. S.; Stienstra, Y.; Johnson, C.; Phillips, R.; Adjei, O.; Fleischer, B.;
Wansbrough-Jones, M. H.; Johnson, P. D. R.; Portaels, F.; van der Graaf, W. T. A.;
Asiedu, K. Bull. World Health Organ. 2005, 83, 785; (e) Hong, H.; Demangel, C.;
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(2H, m); 13C NMR (125 MHz)
d 10.55, 15.69, 17.16, 19.19, 20.67, 28.81,
31.21, 32.56, 35.79, 40.34, 45.58, 55.26, 70.81, 74.45, 83.12, 113.68,
120.89, 129.39, 131.00, 137.85, 159.05, 173.38; HRMS (ESI) exact
mass calculated for [MþNa]þ (C24H35IO4Na) requires m/z 537.1472,
found 537.1434.
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rahedron 2007, 63, 5739.
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4.8.3. Preparation of 35. To prepare active Zn–Cu couple, Cu(OAc)2
(39 mg, 0.194 mmol) was suspended in glacial AcOH (10 mL). To
this was added Zn dust (636 mg, 9.72 mmol), and the resultant
suspension was heated to reflux for one minute or until all of the
copper had deposited onto the zinc (disappearance of blue color in
the supernatant). Stirring was stopped, and the reddish-gray silt
was allowed to settle. The AcOH was removed by pipette, then
another portion of AcOH (10 mL) was added, and the suspension
was heated to reflux for one minute. The AcOH was removed again
by pipette, and this process was repeated once more. Finally, the
Zn–Cu couple was rinsed with Et2O (3ꢃ10 mL), with each rinse

2272
K.L. Jackson et al. / Tetrahedron 66 (2010) 2263–2272
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total synthesis, see: Judd, T. C.; Bischoff, A.; Kishi, Y.; Adusumilli, S.; Small, P. L. C.
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26. We also examined this transformation on a mixture of primary (14-membered)
and secondary (12-membered) macrolactones. On exposure of a 65:35 mixture
of TIPS-protected macrolactones to these deprotection conditions (HF$pyr, pyr,
CH3CN, 0 ꢀC), we obtained solely the 12-membered deprotected macrolactone
product.
OTIPS
OH
Me
Me
TIPSO
a. i. LiOH
ii. CCl3C6H2COCl
Me
OPMB
HO
+
10. Kim, H.-J.; Jackson, K. L.; Kishi, Y.; Williamson, H. R.; Mosi, L.; Small, P. L. C.
Chem. Commun. 2009, 7402.
Me
Me
MeO
MeO
i-Pr2NEt, DMAP
Me
OPMB
11. (a) Pahlevan, A. A.; Wright, D. J. M.; Andrews, C.; George, K. M.; Small, P. L. C.;
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Hamada, H.; Small, P. L. C. Infect. Immun. 2008, 76, 2002.
O
O
65 : 35
OTIPS
Me
OTIPS
Me
O
12. Marples, B. A.; Saint, C. G.; Traynor, J. R. J. Chem. Soc., Perkin Trans. 1 1986, 567.
13. (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919; (b) Brown, H. C.;
Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570.
b. HF pyr, pyr
+
O
O
O
Me
Me
14. Langille, N. F.; Jamison, T. F. Org. Lett. 2006, 8, 3761.
Me
OPMB
Me
OPMB
15. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
16. The optical purity was estimated from 1H NMR analysis of (R)- and (S)-Mosher
esters prepared from 9.
65 : 35
Me
OH
OH
17. Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4343; LiCu(Me)2
was originally used for this reaction. It was later found that the higher order
cuprate reported by Lipshutz ( Lipshutz, B. H.; Kozlowski, J.; Wilhelm, R. S. J. Am.
Chem. Soc. 1982, 104, 2305 ) gives better regioseletivity for some substrates.
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Angew. Chem. 1976, 88, 402.
Me
O
only 12-membered
lactone observed
O
O
O
+
Me
Me
Me
Me
OPMB
OH
89%
9%
19. Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675.
Reagents and conditions: (i) 1 M LiOH, 4:1:1 THF/MeOH/H2O, rt;CCl3C6H2COCl,
i-Pr2NEt, DMAP, benzene, rt, 86%, two steps;HF$pyr, pyr, CH3CN, 0 ꢀC, 38 h, 89%
(þ9% loss of PMB product).
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Saito, B.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 45, 3478; (d) Shimada, Y.;
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