Total synthesis of mycolactones A and B

Article abstract of DOI:10.1016/j.tet.2007.02.057

First and second generation total syntheses of mycolactones A and B are reported. The first generation total synthesis unambiguously confirmed our earlier assignment of the relative and absolute stereochemistry of mycolactones A and B. Knowledge of the ch

Full text of DOI:10.1016/j.tet.2007.02.057

Tetrahedron 63 (2007) 5739–5753
Total synthesis of mycolactones A and B
y
z
x
*
Fengbin Song, Steve Fidanze, Andrew B. Benowitz and Yoshito Kishi
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Received 18 January 2007; revised 13 February 2007; accepted 14 February 2007
Available online 20 February 2007
Abstract—First and second generation total syntheses of mycolactones A and B are reported. The first generation total synthesis unambig-
uously confirmed our earlier assignment of the relative and absolute stereochemistry of mycolactones A and B. Knowledge of the chemical
properties of the mycolactones accumulated through the first generation total synthesis allowed us to implement several major improvements
to the original synthesis, including: (1) optimizing the choice of protecting groups, (2) eliminating the unnecessary adjustment of protecting
groups, and (3) improving the overall stereoselectivity and synthetic efficiency. The second generation total synthesis consists of 21 longest
linear steps, with 6.3% overall yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
was demonstrated that intradermal inoculation of the puri-
fied mycolactones into guinea pigs produced a lesion similar
to that of Buruli ulcer in humans.
Buruli ulcer is a severe necrotizing skin disease caused by
Mycobacterium ulcerans.1 Among the diseases caused by
mycobacteria, Buruli ulcer occurs with less frequency than
tuberculosis and leprosy. However, the occurrence of the
disease is increasing and spreading in tropical countries.
Indeed, it is noted that the incidence of Buruli ulcer may
exceed that of leprosy and tuberculosis in highly affected
areas. Infection with M. ulcerans, probably carried by
aquatic insects,2 results in progressive necrotic lesions
that, if untreated, can extend to 15% of a patient’s skin sur-
face. Unfortunately, surgical intervention is currently the
only realistic therapy for Buruli ulcer.
The gross structure of mycolactones A and B was elucidated
by Small and co-workers via spectroscopic methods, includ-
ing extensive 2D NMR experiments, to be a 12-membered
macrolide bearing a highly unsaturated side-chain.4 Through
the combined use of an NMR database and the preparation of
model compounds, we studied and established the relative
and absolute configuration of the mycolactone core,5 and
then applied the newly developed universal NMR database
concept in chiral solvents,6 to establish the complete struc-
ture of the mycolactones.7 Finally, the assigned structure
was confirmed by total synthesis.8 Through these efforts,
mycolactones A and B are now characterized as having the
stereochemistry shown below,0and as an approximately 3:2
Most pathogenic bacteria produce toxins that play an impor-
tant role(s) in disease. However, there has been no evidence
thus far to suggest toxin production by Mycobacterium
tuberculosis and Mycobacterium leprae, the two most-rec-
ognized pathogenic members of the genus Mycobacterium.
Interestingly, the possible presence of a toxin in M. ulcerans
was hypothesized for a number of years prior to the isolation
and characterization of two polyketide-derived macrolides
from this bacteria by Small and co-workers in 1999.3 These
macrolides were designated mycolactones A and B, and it
0
0
0
mixture of Z-D4 ,5 - and E-D4 ,5 -geometric isomers of the
unsaturated side-chain (Fig. 1).
Me Me
20
Me
15
OH OH
Me
O
10
O
Me
1
Keywords: Mycolactones; Total synthesis; Buruli ulcer.
* Corresponding author. Tel.: +1 617 495 4679; fax: +1 617 495 5150;
e-mail: kishi@chemistry.harvard.edu
5
Me Me Me
5'
Me OH
10'
15'
1'
O
Me
y
Present address: Johnson & Johnson PRD, 8 Clarke Drive, Cranbury,
NJ 08512, USA.
Present address: Abbott Laboratories, 100 Abbott Park Road, Abbott
Park, IL 60064-6099, USA.
Present address: GlaxoSmithKline, 1250 South Collegeville Road, Colle-
geville, PA 19426, USA.
O
OH OH
z
1: Mycolactone A: Δ4',5'=Z
2: Mycolactone B: Δ4',5'=E
x
Figure 1. Structure of mycolactones A (1) and B (2).
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.057

5740
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
Me Me
Mycolactones A and B constitute the major metabolites
produced by West African strains of M. ulcerans. However,
several mycolactone congeners, including mycolactone C,9
mycolactone D,10 and C20-methyl mycolactones A and
B,11 have recently been isolated from clinical isolates of
M. ulcerans from Africa, Malaysia, Asia, Australia, and
Mexico. In this connection, it is worthwhile noting that
clinical isolates from Asia, Mexico, and Australia are less
virulent than clinical isolates from Africa. In addition, my-
colactone congeners have also been isolated from the frog
pathogen Mycobacterium marinum12 and the fish pathogen
Mycobacterium liflandii.13
EtO
P(O)(OEt)2
O
Me OBn
5
O
Me
Reference 14
OBn OBn
6
Me Me
Me OBn
EtO
Me
OBn
O
OBn
7
Scheme 2.
acetonide in an optically active form.7 Worth noting is that
the availability of all four diastereomers was critical for the
unambiguous determination of the side-chain stereochemis-
try. However, once the stereochemistry was established, we
could focus on the synthesis of the desired tris-TBS aldehyde
12 specifically. Although the synthetic route from D-glycer-
aldehyde acetonide served well for the stereochemical study,
we wished to have a more efficient synthesis. For this reason,
we studied an alternative synthetic route (Scheme 3). Thus,
the known aldehyde 820 was subjected to Horner–
Wadsworth–Emmons olefination, then catalytic asymmetric
dihydroxylation with AD-mix-a,21 resulting in a 3.8:1 mix-
ture of diastereomers,22 with the expected and desired diol 9
as the major product. The diol was protected as its bis-TBS
ether, and the resulting compound was then subjected to a
sequence of reduction, oxidation, and Wittig olefination, to
give the corresponding a,b-unsaturated ester 10. Reduction
of 10, followed by chromatographic separation of the
diastereomers and then oxidation, gave aldehyde 12.
Mycolactones have attracted considerable attention from the
synthetic community not only for their highly potent biolog-
ical activity, but also for being the first examples of polyke-
tide macrolides to be isolated from a human pathogen.14–18
In this paper, we report first and second generation total syn-
theses of mycolactones A and B.
2. Results and discussion
2.1. First generation total synthesis19
We envisioned that an obvious synthetic route to the myco-
lactones would proceed through esterification of the C5
hydroxyl group present in the mycolactone core with the
pentaenoic acid present in the mycolactones. To demonstrate
the feasibility of this approach, we decided to utilize the
mycolactone core triol 3, previously synthesized for the pur-
poses of stereochemical assignment.5 Selective protection of
the C17/C19-1,3-diol of 3 was smoothly accomplished by
treatment with dimethoxycyclopentane and p-TsOH, to fur-
nish the suitably protected core 4 in good yield (Scheme 1).
OTBS
OH
Me
a
Me
Me
b
Me
EtO2C
OTBS
EtO2C
OHC
OH OTBS
OTBS
OTBS
Me Me
Me Me
8
9
10
Me
Me
OH OH
O
O
Me
O
Me
O
a
Me OTBS
Me
O
O
Me
OTBS
c
HO
Me
d
Me
Me
OHC
TBSO
TBSO
OTBS
Me
Me
11
OH
OH
12
3
4
Scheme 3. Reagents: (a) (1) NaH, (EtO)2P(O)CH2CO2Et, benzene, 64%;
(2) AD-mix-a, MeSO2NH2, t-BuOH/H2O (1:1), 40 h, 0 ꢀC, 70%,
d.r.¼3.8:1; (b) (1) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢀC, 99%; (2) DIBAL,
CH2Cl2, 89%; (3) SO3$py, i-Pr2NEt, CH2Cl2/DMSO (3:2); (4)
Ph3P]C(Me)CO2Et, toluene, 110 ꢀC, 83% (two steps); (c) DIBAL,
CH2Cl2, ꢁ78 ꢀC, followed by chromatographic separation of the diastereo-
mers, 57%; (d) SO3$py, i-Pr2NEt, CH2Cl2/DMSO (3:2), quant.
Scheme1. Reagents: (a) 1,1-dimethoxycyclopentane, p-TsOH, benzene,80%.
We then focused on the synthesis of a suitably protected
pentaenoic acid. Considering the anticipated instability of
the pentaenoate system, we chose to protect the side-chain
alcohols as tert-butyldimethylsilyl (TBS) ethers. Gurjar
and Cherian reported a synthesis of ethyl ester 7 of the
pentaene fatty acid via Horner–Wadsworth–Emmons olefi-
nation at C80–C90 (Scheme 2).14 Despite the differences in
the stereochemistry of the triol and the protecting groups,
this synthetic route appeared well suited to our needs, and
we chose to adopt this route for the synthesis of tris-TBS
pentaenoate 18 (see Scheme 6 for the structure 18).
Next, phosphonate (20E,40E,60E)-17 was synthesized em-
ploying a minor modification of the procedure reported by
Gurjar and Cherian.14 The allylic alcohol 14 was prepared
in four steps from allyl alcohol in 25% overall yield (Scheme
4). Oxidation, followed by Wittig olefination, gave diene es-
ter 15. Reduction, oxidation, and Wittig olefination provided
triene ester 16. Finally, a three-step sequence of deprotec-
tion, bromination, and phosphonate formation furnished
(20E,40E,60E)-17.
Our first task was the synthesis of the tris-TBS aldehyde 12.
In conjunction with the stereochemical assignment of the
mycolactone unsaturated side-chain, we previously prepared
all four diastereomers of 12 from D-glyceraldehyde
To gain insight into the chemical behavior of the anion gen-
erated from phosphonate 17, we first studied its protonation

F. Song et al. / Tetrahedron 63 (2007) 5739–5753
5741
Me
Me Me
Me Me
c
a
b
HO
OH
OTBS
d
EtO2C
OTBS
MeO C
2
P(O)(OEt)2
17
13
14
15
Me OTBS
Me
Me Me
OHC
Me Me
a
TBSO
OTBS
MeO2C
MeO2C
P(O)(OEt)2
OTBS
12
16
17
Me Me
5'
Me OTBS
TBSO
Scheme 4. Reagents: (a) (1) TBSCl, imidazole, DMF; (2) O3, CH2Cl2,
ꢁ78 ꢀC, then Ph3P; (3) Ph3P]C(Me)CO2Et, CH2Cl2; (4) DIBAL,
CH2Cl2, ꢁ78 ꢀC, 25% (four steps); (b) (1) SO3$py, i-Pr2NEt, CH2Cl2/
DMSO (3:2); (2) Ph3P]C(Me)CO2Et, benzene, 90 ꢀC, 80% (two steps);
(c) (1) DIBAL, CH2Cl2, ꢁ78 ꢀC; (2) SO3$py, i-Pr2NEt, CH2Cl2/DMSO
(3:2); (3) Ph3P]CHCO2Me, benzene, 90 ꢀC, 89% (three steps); (d) (1)
TBAF, THF, 87%; (2) PBr3, Et2O, 77%; (3) (EtO)3P, 90 ꢀC, 96%.
Me
RO2C
7'
3'
9'
OTBS
18: R=Me
19: R=H
b
Scheme 6. Reagents: (a) LDA, 12, THF, ꢁ78 ꢀC to rt, 94%; (b) LiOH, THF/
MeOH/H2O (4:1:1), quant.
Worth noting, in reference to the 1H NMR characteristics es-
tablished for the four geometric isomers of 18, we examined
the H NMR data reported for natural mycolactones A and
B, thereby revealing that the sample of natural mycolactones
contains a small amount (<5%) of a third geometric isomer
whose spectroscopic characteristics match well those of the
(20E,40Z,60Z,80E,100E)-isomer of 18.
(Scheme 5). On quenching with 2,4,6-trimethylphenol, the
anion generated from (20E,40E,60E)-17 with LDA at ꢁ78 ꢀC
yielded a 55:25:14:6 mixture23 of the geometric isomers of
17. An NOE experiment was conducted on this mixture,
yielding the results shown for the structures in Scheme 5.
Based on this NOE experiment, the geometric isomers ob-
tained from the protonation were established as (20E,40E,
60E)-17 (55%), (20E,40E,60Z)-17 (25%), (20E,40Z,60E)-17
(14%), and (20E,40Z,60Z)-17 (6%). This experiment sug-
gested that the stereochemical integrity of (20E,40E,60E)-17
would likely be lost during the subsequent Horner–
Wadsworth–Emmons olefination.
1
The pentaenoate system present in the product 18 was
expected to be prone to cis/trans-isomerization. Indeed,
on photolysis (acetone-d6, tungsten lamp), the 73:17:7:3
mixture yielded a new mixture consisting of (20E,40E,60E,
80E,100E)-18 (36%), (20E,40Z,60E,80E,100E)-18 (52%),
(20E,40E,60Z,80E,100E)-18 (4%), (20E,40Z,60Z,80E,100E)-18
(5%), and two minor isomers (3% combined).23 The two
minor isomers appeared to be (20E,40E,60E,80E,100Z)-18
and (20E,40Z,60E,80E,100Z)-18. The two major isomers were
found to be readily interconvertible, and the 3:2 ratio ap-
peared to represent the steady-state ratio for this system.4,14
Me Me
P(O)(OEt)2
MeO2C
(2'E,4'E,6'E)-17
a
The product methyl pentaenoates were found to be chro-
matographically inseparable. However, upon hydrolysis to
the corresponding acids, (20E,40E,60E,80E,100E)-19 could
be separated from (20E,40Z,60E,80E,100E)-19 by silica gel
column chromatography. Thus, it was possible to obtain
the mycolactones A and B enriched with the C40 Z geomet-
rical isomer (vide infra).
Me Me
5'
Me Me
MeO
MeO
MeO
H
PO(OEt)2
7'
7'
H
5'
H
3'
3'
O
O
H
H
O
O
H
PO(OEt)2
(2'E,4'E,6'Z)-17
(2'E,4'E,6'E)-17
(25%)
(55%)
To complete the total synthesis, 4 was coupled with 19 under
Yamaguchi esterification conditions,24 to furnish the pro-
tected mycolactones 20 in excellent yield (Scheme 7). Inter-
estingly, attempted esterification under the conditions of
EDCI/DMAP or BOP/DMAP did not give the desired
product 20.
Me
H
Me
H
MeO
5'
3'
5'
3'
H
H
H
Me
PO(OEt)2
Me
7'
7'
H
PO(OEt)2
(2'E,4'Z,6'E)-17
(2'E,4'Z,6'Z)-17
Attempted global deprotection of 20 with HF$py in MeCN
did give synthetic mycolactones A and B in 5–10% yield,
but the product was accompanied by a complex mixture of
(14%)
(6%)
Scheme 5. Reagents: (a) LDA, THF, ꢁ78 ꢀC, then 2,4,6-trimethylphenol.
1
An arrow indicates a detected, or not detected, NOE.
side-products. H NMR analysis suggested that these by-
products might be formed via sequential oxy-Michael addi-
tions of the alcohol moieties to the pentaenoate system. To
suppress these putative side-reaction(s), stepwise deprotec-
tion was then tested. In the event, treatment with tetra-n-
butylammonium fluoride (TBAF) removed the three TBS
groups, to furnish the corresponding triol in 81% yield. The
cyclopentylidene ketal was then hydrolyzed with aqueous
acetic acid in THF. Through extensive studies, the optimal
In the event, aldehyde 12 smoothly reacted with the anion
generated from (20E,40E,60E)-17, to furnish the expected
product as a 73:17:7:3 mixture (Scheme 6).23 Once again,
based on NOE experiments, the stereochemistry was as-
signed as (20E,40E,60E,80E,100E)-18 (73%), (20E,40Z,60E,
80E,100E)-18 (17%), (20E,40E,60Z,80E,100E)-18 (7%), and
(20E,40Z,60Z,80E,100E)-18 (3%).

5742
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
might be the remote diastereomers25 of the natural products.
Me Me
In order to exclude this possibility, the 1H NMR characteris-
tics in a chiral NMR solvent were studied. As shown in
Graph 1, both the synthetic and natural mycolactones A
and B exhibited the identical Dd profile in (R)- and (S)-
N,a-dimethylbenzylamines (DMBAs).6 Through these com-
parisons, we concluded that the synthetic mycolactones A
and B are indeed identical to the natural mycolactones A
and B. In addition, the synthetic mycolactones A and B
exhibited biological properties identical to those of the
natural products.26
Me
4
O
O
Me
O
a
O
Me
19
Me Me Me
Me OTBS
TBSO
O
Me
O
OTBS
20
Me Me
Me
2.2. Second generation total synthesis
OH OH
Me
O
b
O
Me
Based on the knowledge accumulated through our first gen-
eration total synthesis of the mycolactones, we recognized
that improvements could be made in two major areas. First,
the acid-promoted deprotection of the cyclopentylidene
ketal proved to be more problematic than originally antici-
pated. In contrast, mycolactones A and B appeared to be sta-
ble to TBAF-promoted TBS-deprotection conditions. These
observations immediately suggested that the cyclopentyl-
idene protecting group present in the C17/C19-diol 20
should be replaced by TBS ethers. Thus, TBAF-promoted
desilylation should allow us to accomplish a more efficient
global deprotection.
Me Me Me
5'
Me OH
O
Me
O
OH OH
4'Z : Mycolactone A (1) and 4'E : Mycolactone B (2)
Scheme 7. Reagents: (a) Cl3C6H2COCl, i-Pr2NEt, DMAP, benzene, 90%;
(b)(1)TBAF, THF, 81%;(2)AcOH/H2O/THF(2:1:2), 67%withonerecycle.
ratio of AcOH/H2O/THF was found to be 2:1:2. However,
even under the optimized conditions, by-product formation
became significant when the reaction was allowed to go to
completion. For this reason, the deprotection was quenched at
approximately 60% completion, and the recovered triol was
recycled. After one recycle, synthetic mycolactones A and B
were isolated in 67% yield as an approximately 3:2 mixture
of 40-Z (mycolactone A) and 40-E (mycolactone B) isomers.
We were interested in demonstrating the effectiveness of this
approach experimentally. For this purpose, we utilized the
cyclopentylidene protected core 4 employed in the first syn-
thesis. Thus, the protecting groups of 4 were adjusted in four
steps to obtain the requisite TBS-protected core 21 (Scheme
8). Yamaguchi esterification of 21 with 19 proceeded to
pentakis-TBS protected mycolactone. As anticipated, global
deprotection conditions (TBAF, THF, rt) furnished mycolac-
tones A and B in excellent yield.
On comparison of 1H NMR (Fig. 2), 13C NMR (Table 1), and
TLC [silica gel, CHCl3/MeOH/H2O (90:10:1)], the synthetic
mycolactones A and B were found to be superimposable on
the natural mycolactones A and B, respectively. Rigorously
speaking, however, these comparisons could not eliminate
the possibility that the synthetic mycolactones A and B
As was previously mentioned, we decided to utilize the core
triol 4 for our first generation total synthesis of the
Figure 2. 1H NMR spectrum (600 MHz, acetone-d6) of synthetic mycolactones A and B.

F. Song et al. / Tetrahedron 63 (2007) 5739–5753
5743
Table 1. 13C NMR chemical shifts observed for natural4 and synthetic
mycolactones A and B (125 MHz, acetone-d6)
The alkyne was then methylated using n-BuLi and MeI.
Hydrozirconation,29 followed by iodine quench, furnished
the bis-TBS protected vinyl iodide 25.
Carbon
Mycolactone A
Natural Synthetic
Mycolactone B
Natural Synthetic
In the interest of the overall efficiency of the synthesis, we
sought to protect the alcohol at C5 with a protecting group
orthogonal to the TBS group, and therefore employed a p-
methoxybenzyl (PMB) group. Thus, the C1–C7 alkyl iodide
with the carboxylate group at C1 was synthesized from alde-
hyde 26 using Brown crotylboration27,30 to install the C5 and
C6 stereocenters (Scheme 10).
1
2
3
4
5
6
7
8
173.3
35.9
20.8
31.4
79.3
32.8
46.4
137.2
123.8
29.3
76.3
35.4
44.3
133.9
131.2
40.5
76.9
43.8
68.9
24.6
20.5
15.9
15.0
16.2
17.1
166.9
119.6
143.1
132.1
141.8
134.7
134.8
125.1
139.9
137.2
134.6
72.4
173.3
35.9
20.7
31.5
79.3
32.7
46.3
137.3
173.3
35.9
20.8
31.4
79.3
32.8
46.4
137.2
123.8
29.3
76.3
35.4
44.3
133.9
131.2
40.5
76.9
43.8
68.9
24.6
20.5
15.9
15.0
16.2
17.1
166.9
117.4
151.1
133.2
144.3
135.3
136.1
125.1
139.9
137.2
134.6
72.4
173.3
35.9
20.7
31.5
79.3
32.7
46.3
137.3
9
123.8
123.8
a
a
The synthesis of the C8–C13 building block is outlined in
Scheme 11. Using the procedure reported by Seebach, (S)-
diethyl malate (31) was alkylated with MeI and LDA in
THF, to give alcohol 32, along with its syn diastereomer
(stereoselectivity¼8:1).31 Reduction of 32 using LiAlH4
provided the known triol 3332 in excellent yield. The triol
33 was selectively protected to give TBS ether 34 via a di-
butyltin ketal intermediate.33 The resulting diol 34 was first
converted to epoxide 35 and then coupled with propyne un-
der Yamaguchi conditions.34 Cleavage of the TBS ether and
subsequent protection of the resulting 1,3-diol gave cyclo-
pentylidene ketal 36. The alkyne moiety of 36 was then con-
verted to vinyl iodide 37 by hydrozirconation, followed by
iodine quench. The vinyl iodide thus obtained was found
to be identical to a sample synthesized by the previous
route.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
10
76.2
35.3
44.3
133.4
131.2
40.4
76.9
43.8
68.9
24.6
20.5
15.9
14.9
16.2
17.1
166.9
119.6
143.1
132.1
141.8
134.8
134.9
125.1
139.9
137.2
134.6
72.3
75.7
41.8
67.6
24.2
21.0
17.6
13.4
76.2
35.3
44.3
133.4
131.2
40.4
76.9
43.8
68.9
24.6
20.5
15.9
14.9
16.2
17.1
166.9
117.4
151.1
133.2
144.3
135.3
136.1
125.1
140.3
137.2
134.6
72.3
75.7
41.8
67.6
24.2
14.3
17.1
13.3
20
30
40
50
With the three building blocks 25, 30, and 37 in hand, we next
focused on the coupling reactions. Negishi coupling35 was
used to form the C7–C8 bond, i.e., 30+37/38. Considering
the presence of an electrophilic ester group in 30, we chose to
prepare the alkylzinc iodide species via zinc insertion by an
active Zn–Cu couple,36 instead of via transmetalation from
Li to Zn. Additionally, Pd(PPh3)4 (10 mol %) was found
the most effective catalyst for this case. In the event, the cou-
pling of 30 (1.4 equiv) and 37 proceeded smoothly in the
presence of 6–8 equiv of LiCl in N-methylpyrrolidinone
(NMP),37 to furnish 38 in 83% yield (Scheme 12).
60
70
80
90
100
110
120
130
140
150
160
170
180
190
75.7
41.9
67.7
24.2
21.0
17.6
13.3
75.7
41.9
67.7
24.2
14.3
17.1
13.3
The coupled product 38 was transformed to the seco-acid
39 in better than 70% overall yield for three steps: (1)
acid-promoted deprotection of the cyclopentylidene group,
(2) selective protection of the resultant primary alcohol as
the triisopropylsilyl (TIPS) ether, and (3) base-promoted hy-
drolysis of the methyl ester. Yamaguchi macrolactonization
of 39 then furnished the desired macrolactone 40 in 96%
yield. It is worthwhile noting that the lactone was designed
to serve as a protecting group for the C11 alcohol during
the following steps.
a
Overlapped with the solvent signals.
mycolactones, since 4 was already in hand from our previous
work on the stereochemistry assignment. However, having
identified suitable protecting groups for the alcohols at
C17 and C19, we were in a position to implement specific
improvements for the synthesis of the mycolactone core;
in particular, we were anxious to develop a shorter synthetic
route with a greater degree of selectivity and efficiency.
Deprotection of the silyl ether in 40, followed by iodination,
gave alkyl iodide 41. Under the Negishi coupling conditions
optimized for the case of the coupling of 30 with 37, alkyl
iodide 41 was coupled with 25 (1.5 equiv), to give 42 in
80% yield. The PMB group was then cleaved with DDQ,
to furnish the bis-TBS protected core 21.
Having demonstrated the feasibility of global TBAF-
promoted TBS-deprotection, we wished to implement the
TBS protecting groups from the very beginning of the syn-
thesis, thereby improving the overall efficiency of the
synthesis (Scheme 9). Thus, olefin 23 was prepared from
the known aldehyde 2220 via Brown crotylboration27 and
subsequent protection of the alcohol as the TBS ether.
Olefin 23 was then oxidatively cleaved, followed by treat-
ment with dimethyl (diazomethyl)phosphonate (DAMP) and
t-BuOK,28 to provide the terminal alkyne 24 in good yield.
As demonstrated in Scheme 8, 21 was coupled with 19 and
then subjected to the TBAF promoted global deprotection, to
furnish a 3:2 mixture of the mycolactones A and B in 72%
overall yield. Upon comparison of spectroscopic data and

5744
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
Natural Mycolactone B
Natural Mycolactone A
0.02
0.01
0
-0.01
-0.02
0.02
0.01
0
Synthetic Mycolactone A
Synthetic Mycolactone B
-0.01
-0.02
15' 13' 12' 19' 11' 9' 8' 7' 5' 3' 2' 19 17 16 10
5
15' 13' 12' 19' 11' 9' 8' 7' 5' 3' 2' 19 17 16 10
5
Graph 1. Dd-Values of 1H NMR chemical shifts in (R)- and (S)-DMBAs-d13. Each graph shows the Dd in chemical shift for natural and synthetic mycolactones
A and B, with Dd being [d(R-DMBA)ꢁd(S-DMBA)].
Me Me
Me Me
Me
Me
TBSO
H
TBSO
a
b
Me
O
O
O
O
OH
O
Me
O
Me
O
TBS TBS
26
27
O
O
a
b
Me
Me
X
Me
Me
MeO
MeO
d
c
OH
OH
21
Me
OPMB
Me
OPMB
4
O
O
28
29 X = OH
Me Me
30 X = I
Me
OH OH
Scheme 10. Reagents: (a) Z-2-butene, t-BuOK, n-BuLi, (+)-Ipc2BOMe,
BF3$OEt2, THF, ꢁ78 ꢀC, then H2O2, NaOH, 80%; (b) (1) NaH, PMBBr,
DMF, 89%; (2) TBAF, THF, 96%; (3) SO3$py, i-Pr2NEt, CH2Cl2/DMSO
(3:2), 94%; (4) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O; (5)
MeI, DBU, CH3CN, 84% for two steps; (c) (1) OsO4, NMO, acetone/H2O
(1:1), 80%; (2) Pb(OAc)4, benzene; (3) NaBH4, MeOH, 0 ꢀC, 83% (two
steps); (d) Ph3P, imidazole, I2, CH2Cl2, 92%.
Me
O
O
Me
Me Me Me
Me OH
O
Me
5'
O
OH OH
4'Z : Mycolactone A (1) and 4'E : Mycolactone B (2)
TLC, the mycolactones A and B thus synthesized were
found to be identical to the synthetic mycolactones A
and B obtained via the first route as well as to the authen-
tic natural products.
Scheme 8. Reagents: (a) (1) MeOCH2COCl, i-Pr2NEt, DMAP, CH2Cl2,
91%; (2) CH2Cl2/H2O/TFA (16:4:1), 92%; (3) TBSOTf, 2,6-lutidine,
CH2Cl2, quant.; (4) K2CO3, MeOH, 0 ꢀC, 84%; (b) (1) 19, Cl3C6H2COCl,
i-Pr2NEt, DMAP, benzene, 90%; (2) TBAF, THF, 80%.
Me
Me
Me Me
H
Me
Me
b
a
c
I
O
OTBS
TBSO
TBSO
TBSO
OTBS
22
24
25
23
Scheme 9. Reagents: (a) (1) Z-2-butene, t-BuOK, n-BuLi, (ꢁ)-Ipc2BOMe, BF3$OEt2, THF, ꢁ78 ꢀC, then H2O2, NaOH, 78%; (2) TBSCl, imidazole, DMF,
quant.; (b) (1) O3, CH2Cl2, ꢁ78 ꢀC, then Ph3P, 94%; (2) t-BuOK, DAMP, THF, 84%; (c) (1) n-BuLi, MeI, THF, ꢁ78 ꢀC to rt, 93%; (2) Cp2ZrHCl, THF,
50 ꢀC, then I2, THF, 65%.

F. Song et al. / Tetrahedron 63 (2007) 5739–5753
5745
OH
OH
OH
pentaenoic acids, obtained by silica gel column chromato-
graphy (vide ante), was coupled with 21 and then subjected
to TBAF-deprotection in the dark, to furnish a 6:1 mixture of
mycolactone A and mycolactone B (Fig. 3). Apparently, dur-
ing this synthetic operation, the stereochemical integrity of
the pentaenoic acid was compromised to some extent. We
would attribute, at least partly, the observed cis/trans-iso-
merization to the exposure of these substrates to light. If this
is the case, this experiment indicates the possibility of ob-
taining pure mycolactone A and/or B through this route. In
this connection, we specifically reference the recent work
by Negishi and co-workers, disclosing a stereoselective
synthesis of both protected (20E,40E,60E,80E,100E)- and
(20E,40Z,60E,80E,100E)-pentaenoic acids.17,38
b
a
CO2Et
Me
32
HO
d
CO2Et
EtO2C
OR
EtO2C
Me
33 R = H
31
c
34 R = TBS
O
O
O
Me
O
O
e
f
OTBS
I
Me
Me
Me
37
Me
35
36
Scheme 11. Reagents: (a) LDA, MeI, THF, ꢁ78 ꢀC, 80%, d.r.¼8:1; (b)
LiAlH4, THF, reflux; (c) (1) n-Bu2SnO, MeOH, reflux; (2) TBSCl,
CHCl3, 70% for three steps; (d) 1-(p-toluenesulfonyl)imidazole, NaH,
THF, 88%; (e) (1) n-BuLi, propyne, BF3$OEt2, THF, ꢁ78 ꢀC, 96%; (2)
TBAF, THF; (3) cyclopentanone, p-TsOH, benzene, 76%; (f) Cp2ZrHCl,
THF, 50 ꢀC, then I2, 62%.
3. Conclusion
Mycolactones A and B have been synthesized through two
different routes. Our first generation total synthesis unam-
biguously confirmed the relative and absolute stereochemis-
try predicted via an NMR database approach. Knowledge
regarding the chemical properties of the mycolactones accu-
mulated through the first generation total synthesis allowed
us to implement several major improvements to the original
synthesis, including: (1) optimizing the choice of protecting
groups, (2) eliminating the unnecessary adjustment of pro-
tecting groups, and (3) improving the overall stereoselectiv-
ity and synthetic efficiency. The second generation of total
synthesis consists of 21 steps in the longest linear sequence,
with 6.3% overall yield.
OTiPS
30
O
Me
Me
HO
Me
b
O
O
a
Me
HO
MeO
Me
OPMB
Me
OPMB
37
O
38
39
OTiPS
I
Me
O
c
d
Me
O
O
O
Me
Me
Me
OPMB
Me
OPMB
As was previously noted, several mycolactone congeners
have been isolated from various clinical isolates of M. ulcer-
ans and also from the frog pathogen M. marinum and the fish
pathogen M. liflandii. Structurally, all of these congeners ap-
pear to contain the same core structure of mycolactones A
and B, but different unsaturated side-chains. However, given
the fact that these congeners were obtained in very minute
amounts, an unambiguous structural determination is chal-
lenging. In this connection, we should specifically emphasize
that our second generation total synthesis offers an appealing
opportunity to study their structure as well as their biological
profile, particularly because of its overall efficiency and flex-
ibility. Indeed, the effectiveness of this approach has recently
been demonstrated in the case of mycolactone C.39
40
41
Me Me
Me Me
Me
Me
O
O
O
O
Me
O
e
f
Me
O
TBS TBS
TBS TBS
O
O
Me
Me
Me
Me
OPMB
OH
42
21
Scheme 12. Reagents: (a) Zn, Cu(OAc)2, Pd(PPh3)4, LiCl, NMP, 60 ꢀC,
83%; (b) (1) CH2Cl2/H2O/TFA (16:4:1), 90%; (2) TIPSCl, imidazole,
DMF, quant.; (3) LiOH, 4:1:1 THF/MeOH/H2O, 81%; (c) Cl3C6H2COCl,
i-Pr2NEt, benzene, then DMAP, benzene, 96%; (d) (1) HF$py/py/CH3CN,
90%; (2) Ph3P, imidazole, I2, CH2Cl2, 98%; (e) Zn, Cu(OAc)2, 25,
Pd(PPh3)4, LiCl, NMP, 60 ꢀC, 80%; (f) DDQ, CH2Cl2/H2O, 91%.
4. Experimental section
As was previously discussed, the pentaenoate system present
in the mycolactones is readily prone to cis/trans-isomeriza-
tion. This isomerization appeared to be facile under the
acidic conditions used for deprotection of the cyclopentyl-
idene ketal in the first generation total synthesis (Scheme
7). Interestingly, under the conditions of TBAF-promoted
global deprotection used in the second generation total syn-
thesis (Scheme 12), the cis/trans-isomerization seemed to be
controllably slow in the dark, thereby suggesting the possi-
bility that either mycolactone A free of mycolactone B, or
mycolactone B free of mycolactone A, could be obtained,
4.1. General procedures and methods
NMR spectra were recorded on Varian Inova spectrometers
(400, 500, and 600 MHz). Chemical shifts are reported in
parts per million (ppm) and coupling constants in hertz.
1
For H and 13C spectra, the central residual solvent peak
(methanol, acetone, benzene) was used as the internal refer-
ence (3.30, 2.05, 7.15 ppm, and 49.0, 29.8, 128.0 ppm, re-
spectively). Analytical thin layer chromatography (TLC)
was performed with E. Merck pre-coated TLC plates, silica
gel 60 F254, layer thickness 0.25 mm. Flash chromatography
separations were performed on E. Merck kieselgel 60 (230–
400 mesh) silica gel. Reagents and solvents are of
0
0
0
0
if pure Z-D4 ,5 or E-D4 ,5 pentaenoic acid was used. In order
0
0
0
0
to test this possibility, a 10:1 mixture of Z-D4 ,5 and E-D4 ,5

5746
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
Figure 3. 1H NMR spectrum (500 MHz, acetone-d6) of the synthetic mycolactones enriched with mycolactone A.
commercial grade and were used as supplied, with the fol-
lowing exceptions: benzene, ether, and THF were distilled
from sodium benzophenone ketyl, dichloromethane was dis-
tilled from calcium hydride, and toluene was distilled from
sodium. All reactions were conducted under an argon atmo-
sphere unless otherwise noted. Reaction vessels and appara-
tus were flame-dried or oven-dried and allowed to cool under
an inert atmosphere.
organic layers were washed with water (30 mL) and brine
(30 mL), dried over Na2SO4, and concentrated in vacuo.
Flash chromatography (4:1 hexanes/EtOAc, then 2:1
EtOAc/hexanes) provided the corresponding diol (46.0 mg,
92%).
To a stirred solution of the above diol (46.0 mg, 0.093 mmol)
in CH2Cl2 (6.0 mL) at 0 ꢀC were added 2,6-lutidine (44 mL,
0.372 mmol) and TBSOTf (87 mL, 0.372 mmol). The result-
ing solution was stirred for 90 min, then saturated aqueous
ammonium chloride (10 mL) was added. The layers were
separated, and the aqueous layer was extracted with EtOAc
(3ꢂ10 mL). The combined organic layers were washed with
water and brine, dried over Na2SO4, and concentrated
in vacuo. Flash chromatography (4:1 hexanes/EtOAc) af-
forded the methoxyacetate (67.1 mg, quant.).
4.2. First generation total synthesis
Experimental details outlined in Schemes 1–7 are given in
the Supplementary data of Refs. 5, 7, and 8.
4.3. Second generation total synthesis
4.3.1. Synthesis outlined in Scheme 8. To a stirred solution
of alcohol 4 (23.2 mg, 0.047 mmol) in CH2Cl2 (3.0 mL) at
0 ꢀC was added i-Pr2NEt (25 mL, 0.142 mmol), DMAP
(11.5 mg, 0.095 mmol), and methoxyacetyl chloride
(13 mL, 0.142 mmol). The resulting solution was stirred at
0 ꢀC for 1 h, then diluted with CH2Cl2 (10 mL) and water
(10 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3ꢂ10 mL). The combined or-
ganic extracts were washed with brine, dried over Na2SO4,
and concentrated in vacuo. Flash chromatography (4:1 hex-
anes/EtOAc) provided the methoxyacetate (24.2 mg, 91%).
To a stirred solution of the methoxyacetate (70.0 mg,
0.096 mmol) in MeOH (7.0 mL) at 0 ꢀC was added K2CO3
(35.0 mg, 0.25 mmol). The resulting solution was stirred at
0 ꢀC for 2 h, then at room temperature for 5 h. The reaction
mixture was then diluted with CH2Cl2 (15 mL) and saturated
aqueous ammonium chloride (15 mL). The layers were sep-
arated, and the aqueous layer extracted with CH2Cl2
(3ꢂ15 mL). The combined organic layers were washed
with brine (2ꢂ30 mL), dried over Na2SO4, and concentrated
in vacuo. Flash chromatography (8:1 hexanes/EtOAc)
provided 21 (52.9 mg, 84%). 1H NMR (CD3COCD3,
500 MHz,) d 5.23 (d, J¼9.0, 1H), 5.04 (d, J¼11.5, 1H),
4.91 (ddd, J¼12.5, 5.5, 2.5, 1H), 3.98 (q, J¼6.5, 1H), 3.74
(td, J¼5.5, 4.5, 1H), 3.36 (m, 1H), 2.59 (m, 1H), 2.49 (dt,
J¼14.0, 11.5, 1H), 2.31 (ddd, J¼13.5, 8.0, 3.0, 1H), 2.08–
2.18 (m, 3H), 1.91 (m, 3H), 1.76 (dd, J¼13.0, 10.0, 1H),
1.65 (s, 6H), 1.42–1.62 (m, 7H), 1.16 (d, J¼6.0, 3H), 0.96
(d, J¼6.5, 3H), 0.92 (s, 9H), 0.91 (m, 3H), 0.90 (s, 9H),
0.87 (d, J¼6.5, 3H), 0.091 (s, 3H), 0.086 (s, 3H), 0.08
(s, 6H).
Dichloromethane saturated with aqueous TFA was prepared
by shaking CH2Cl2, TFA (8 mL), and H2O (2 mL) in a sepa-
ratory funnel. The layers were allowed to separate for 30 s,
and the organic layer was used. The organic layer (5 mL)
was added to the above ester (57.2 mg, 0.102 mmol), and
the resulting solution stirred for 3.5 h. CH2Cl2 (10 mL)
and saturated aqueous sodium bicarbonate (15 mL) were
then added. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3ꢂ10 mL). The combined

F. Song et al. / Tetrahedron 63 (2007) 5739–5753
5747
4.3.1.1. Mycolactones A and B via penta-TBS protec-
tion (1 and 2). To a stirred solution of pentaene acid
19 (89.6 mg, 0.132 mmol) in benzene (1 mL) were added
i-Pr2NEt (92 mL, 0.53 mmol), Cl3C6H2COCl (42.6 mL,
0.26 mmol), and DMAP (80.8 mg, 0.66 mmol). Alcohol 21
(43.1 mg, 0.066 mmol) was then added in benzene
(1.5 mL, 0.5 mL wash). The resulting solution was stirred
for 20 h. Benzene (5 mL) and saturated aqueous sodium bi-
carbonate (5 mL) were then added. The layers were sepa-
rated, and the aqueous layer was extracted with benzene
(3ꢂ5 mL). The combined organic layers were washed with
brine (10 mL), dried over Na2SO4, and concentrated
in vacuo. Flash chromatography (20:1 hexanes/EtOAc, fol-
lowed by 4:1 hexanes/EtOAc) gave the protected mycolac-
added via cannula. The colorless solution was allowed to stir
at ꢁ78 ꢀC for 30 min, and then BF3$Et2O (9.5 mL,
75 mmol) was added followed immediately by a solution
of the known aldehyde 2220 (9.86 g, 48.7 mmol) in THF
(50 mL, 10 mL wash). The solution was stirred at ꢁ78 ꢀC
for 3 h and then quenched by addition of 3 N NaOH
(130 mL). H2O2 (30%, 65 mL) was then added carefully
with stirring, and the resulting mixture was stirred vigor-
ously at room temperature for 12 h. The mixture was then
diluted with EtOAc and washed with H2O and brine. The or-
ganic phase was then dried over anhydrous MgSO4 and con-
centrated in vacuo. Flash chromatography (39:5 hexanes/
EtOAc) gave alcohol (9.87 g, 78% yield). 1H NMR
(CDCl3, 400 MHz) d 5.78 (ddd, J¼17.6, 10.4, 7.6, 1H),
5.02 (br d, J¼17.6, 1H), 5.01 (br d, J¼10.4, 1H), 4.03
(ddq, J¼9.6, 4.0, 5.6, 1H), 3.60 (dddd, J¼9.6, 5.6, 2.0, 1.2,
1H), 3.41 (d, J¼1.2, OH), 2.21 (apparent sextet, J¼7.0,
1H), 1.59 (ddd, J¼14.4, 4.0, 2.0, 1H), 1.43 (dd, J¼14.4,
9.6, 1H), 1.16 (d, J¼6.0, 1H), 1.01 (d, J¼6.8, 1H), 0.88
(s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3,
400 MHz) d 141.0, 114.6, 74.6, 70.3, 43.7, 42.6, 25.8 (3C),
24.5, 17.8, 14.9, ꢁ4.0, ꢁ4.8.
tones (78.0 mg, 90%). These protect0ed mycolactones exist
0
as a 3:2 mixture of Z:E isomers at D4 ,5 (mycolactone num-
0
0
1
bering). H NMR (CD3COCD3, 600 MHz, Z-D4 ,5 isomer)
d 7.93 (d, J¼15.6, 1H), 6.66 (dd, J¼15.0, 11.4, 1H), 6.44
(d, J¼15.0, 1H), 6.34 (s, 1H), 6.19 (d, J¼11.4, 1H), 5.94
(d, J¼15.6, 1H), 5.66 (d, J¼9.0, 1H), 5.23 (d, J¼9.0, 1H),
5.15 (br d, J¼10.2, 1H), 4.88 (m, 1H), 4.71 (sextet, J¼4.2,
1H), 4.58 (dd, J¼9.0, 3.6, 1H), 3.96–4.06 (m, 2H), 3.76–
3.80 (m, 1H), 3.72–3.76 (m, 1H), 2.55–2.62 (m, 1H),
2.47–2.55 (m, 1H), 2.37–2.45 (m, 1H), 2.14–2.19 (m, 1H),
2.08–2.13 (m, 1H), 2.09 (s, 3H), 1.92–2.05 (m, 5H), 1.98
(s, 3H), 1.95 (s, 3H), 1.84–1.92 (m, 2H), 1.76–1.82 (m,
1H), 1.71 (s, 3H), 1.56–1.72 (m, 6H), 1.66 (s, 3H), 1.17 (d,
J¼6.0, 3H), 1.16 (d, J¼6.6, 3H), 0.92 (s, 9H), 0.91 (s,
9H), 0.86–0.91 (overlapped three singlets and three dou-
blets, 36H), 0.08–0.10 (overlapped eight singlets, 24H),
0.04 (s, 3H), 0.03 (s, 3H). 1H NMR (CD3COCD3,
To a solution of the alcohol (5.069 g, 19.65 mmol) in DMF
(100 mL) were added imidazole (3.345 g, 49.13 mmol)
and TBSCl (5.924 g, 39.30 mmol). The solution was stirred
for 15 h. Then water was added and the mixture was ex-
tracted with Et2O twice. The combined extracts were washed
with H2O, brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. Flash chromatography (49:1 hexanes/
EtOAc) gave the silyl ether 23 (7.318 g, 19.67 mmol,
0
0
600 MHz, E-D4 ,5 isomer) d 7.37 (d, J¼15.0, 1H), 6.68
(dd, J¼15.0, 11.4, 1H), 6.49 (d, J¼15.0, 1H), 6.48 (s, 1H),
6.40 (d, J¼11.4, 1H), 5.89 (d, J¼15.0, 1H), 5.67 (d,
J¼9.0, 1H), 5.23 (d, J¼9.0, 1H), 5.15 (br d, J¼10.2, 1H),
4.88 (m, 1H), 4.71 (sextet, J¼4.2, 1H), 4.58 (dd, J¼9.0,
3.6, 1H), 3.96–4.06 (m, 2H), 3.76–3.80 (m, 1H), 3.72–3.76
(m, 1H), 2.55–2.62 (m, 1H), 2.47–2.55 (m, 1H), 2.37–2.45
(m, 1H), 2.14–2.19 (m, 1H), 2.08–2.13 (m, 1H), 2.09 (s,
3H), 1.92–2.05 (m, 5H), 1.98 (s, 3H), 1.94 (s, 3H), 1.84–
1.92 (m, 2H), 1.76–1.82 (m, 1H), 1.72 (s, 3H), 1.56–1.72
(m, 6H), 1.66 (s, 3H), 1.17 (d, J¼6.0, 3H), 1.16 (d, J¼6.6,
3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.86–0.91 (overlapped three
singlets and three doublets, 36H), 0.08–0.10 (overlapped
eight singlets, 24H), 0.04 (s, 3H), 0.03 (s, 3H). MS (ES)
m/z 1332 (M+NH+4).
quant.). H NMR (CDCl3, 500 MHz) d 5.90 (ddd, J¼17.5,
1
10.5, 6.5, 1H), 5.00 (br d, J¼10.5, 1H), 4.99 (br d, J¼17.5,
1H), 3.90 (apparent sextet, J¼6.5, 1H), 3.68 (dddd, J¼6.5,
6.0, 4.0, 1H), 2.29–2.36 (m, 1H), 1.60 (ddd, J¼13.5, 6.5,
6.5, 1H), 1.48 (ddd, J¼13.5, 6.5, 6.5, 1H), 1.13 (d, J¼6.5,
1H), 0.94 (d, J¼7.0, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.05
(s, 3H), 0.044 (s, 3H), 0.039 (s, 3H), 0.035 (s, 3H); 13C
NMR (CDCl3, 400 MHz) d 141.4, 113.8, 72.9, 76.9, 43.8,
42.2, 25.9 (6C), 23.7, 18.11, 18.08, 13.7, ꢁ4.31, ꢁ4.33,
ꢁ4.4, ꢁ4.7.
A solution of 23 (7.318 g, 19.67 mmol) at ꢁ78 ꢀC in CH2Cl2
(190 mL) was saturated with ozone until a blue color per-
sisted. The solution was then purged with argon until the
blue color dissipated, and Ph3P (5.419 g, 20.66 mmol) was
added. The solution was warmed to room temperature and
stirred for 12 h, then concentrated in vacuo. Flash chromato-
graphy (39:1 hexanes/Et2O) gave the aldehyde (6.910 g,
To a stirred solution of the pentakis-TBS protected mycolac-
tone precursor (6.6 mg, 5.03 mmol) in THF (1 mL) was
added TBAF (1 M solution in THF, 75 mL, 75 mmol). The
solution was stirred at room temperature for 8 h. The reac-
tion mixture was concentrated. Flash chromatography
(100:1 EtOAc/MeOH, followed by 90:10:1 CHCl3/MeOH/
H2O) gave mycolactones (3.0 mg, 80%).
1
94% yield) as a colorless oil. H NMR (CDCl3, 500 MHz)
d 9.74 (br s, 1H), 4.37 (ddd, J¼8.4, 6.0, 3.0, 1H), 3.83 (ap-
parent sextet, J¼6.5, 1H), 2.48 (dq, J¼3.0, 6.0, 1H), 1.59–
1.71 (m, 2H), 1.16 (d, J¼6.0, 3H), 1.05 (d, J¼6.5, 3H),
0.89 (s, 9H), 0.85 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04
(s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 125 MHz)
d 205.0, 68.7, 65.6, 50.5, 44.2, 25.8 (3C), 25.7 (3C), 24.0,
18.0, 17.9, 6.9, ꢁ4.1, ꢁ4.2, ꢁ4.7, ꢁ4.8.
4.3.2. Synthesis outlined in Scheme 9.
4.3.2.1. Preparation of vinyl iodide 25. To a solution of
t-BuOK (6.56 g, 58.5 mmol) in THF (400 mL) at ꢁ78 ꢀC
was added Z-2-butene (8.2 g, 146 mmol) followed by n-
BuLi in hexanes (2.16 M, 27.1 mL, 58.5 mmol). The bright
yellow suspension was stirred at ꢁ78 ꢀC for 5 min, ꢁ45 ꢀC
for 10 min, and then ꢁ78 ꢀC for 15 min. A solution of (ꢁ)-
Ipc2BOMe (21.58 g, 68.2 mmol) in Et2O (50 mL) was then
To a solution of DAMP (2.451 g, 16.34 mmol) in THF
(90 mL) at ꢁ78 ꢀC was added t-BuOK (95%, 1.930 g,
16.34 mmol). To the resulting yellow solution was added
a solution of the aldehyde (6.112 g, 16.34 mmol) in THF
(20 mL, 5 mL wash), and the resulting solution was stirred

5748
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
at ꢁ78 ꢀC for 1 h and then warmed to 0 ꢀC for 1 h. The mix-
ture was then diluted with saturated aqueous NaHCO3 and
EtOAc. The organic phase was washed with saturated aque-
ous NaHCO3, dried over MgSO4, and concentrated in vacuo.
Flash chromatography (40:1 hexanes/EtOAc) gave the
alkyne 24 (5.083 g, 84% yield). 1H NMR (CDCl3,
500 MHz) d 3.98 (apparent sextet, J¼6.5, 1H), 3.72 (appar-
ent q, J¼5.5, 1H), 2.56–2.64 (m, 1H), 2.20 (d, J¼2.5, 1H),
1.83 (ddd, J¼13.0, 6.5, 5.5, 1H), 1.56 (ddd, J¼13.0, 6.5,
5.5, 1H), 1.13 (d, J¼5.5, 3H), 1.12 (d, J¼6.5, 3H), 0.90
(s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (three overlapped
singlets, 9H).
to stir at ꢁ78 ꢀC for 30 min, and then BF3$Et2O (9.5 mL,
75 mmol) was added followed immediately by a solution
of aldehyde 26 (9.86 g, 45.6 mmol) in THF (50 mL,
10 mL wash). The solution was stirred at ꢁ78 ꢀC for 3 h
and then quenched by addition of 3 N NaOH (130 mL).
Then, H2O2 (30%, 65 mL) was added carefully with stirring,
and the resulting mixture was stirred vigorously at room
temperature for 12 h. The mixture was then diluted with
EtOAc (1 L) and washed with H2O (500 mL) and brine
(500 mL). The organic phase was then dried over anhydrous
MgSO4 and concentrated in vacuo. Flash chromatography
(39:1 hexanes/EtOAc) gave alcohol 27 (9.87 g, 80% yield)
1
as colorless oil. H NMR (CDCl3, 400 MHz) d 5.79 (m,
To a solution of the alkyne 24 (3.653 g, 9.87 mmol) in THF
(100 mL) at ꢁ78 ꢀC were added n-BuLi (2.38 M in hexanes,
4.98 mL, 11.84 mmol) and MeI (1.0 mL, 15.99 mmol). The
solution was stirred and warmed to room temperature for
1 h. The solution was then diluted with saturated aqueous
NaHCO3 and EtOAc. The organic phase was washed with
saturated aqueous NaHCO3, brine, dried over MgSO4, and
concentrated in vacuo. Flash chromatography (20:1 hex-
anes/EtOAc) gave the methyl alkyne (3.541 g, 93% yield).
1H), 5.05–5.11 (m, 2H), 3.61 (t, J¼5.6, 2H), 3.49 (m, 1H),
2.27 (apparent sextet, J¼6.8, 1H), 1.46–1.58 (m, 4H),
1.33–1.41 (m, 2H), 1.02 (d, J¼6.8, 3H), 0.89 (s, 9H), 0.04
(s, 6H); 13C NMR (CDCl3, 100 MHz) d 141.3, 115.4, 74.9,
63.4, 43.7, 33.9, 33.0, 26.2 (3C), 22.6, 18.6, 14.3, ꢁ5.0 (2C).
To a solution of alcohol 27 (2.985 g, 10.97 mmol) in DMF
(80 mL) at 0 ꢀC was added NaH (1.317 g, 60%,
32.92 mmol). The mixture was stirred at 0 ꢀC for 30 min.
Then PMBBr (3.308 g, 16.46 mmol) was added and the
mixture was stirred at room temperature for 14 h. The
mixture was diluted with EtOAc and washed with saturated
aqueous NH4Cl. The aqueous phase was extracted with
EtOAc twice. The combined organic phase was washed
with H2O, brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. Flash chromatography (20:1 hexanes/
EtOAc) gave the PMB ether (3.818 g, 89% yield). [a]D23
ꢁ32.9 (c 1.70, CHCl3). 1H NMR (CDCl3, 400 MHz) d 7.27
(d, J¼8.4, 2H), 6.87 (d, J¼8.4, 2H), 5.85 (ddd, J¼17.2,
10.4, 7.2, 1H), 5.04 (br d, J¼17.2, 1H), 5.01 (br d, J¼10.4,
1H), 4.49 (d, J¼10.8, 1H), 4.44 (d, J¼10.8, 1H), 3.80
(s, 3H), 3.60 (t, J¼6.4, 2H), 3.21–3.27 (m, 1H), 2.47 (appar-
ent sextet, J¼7.2, 1H), 1.46–1.55 (m, 4H), 1.28–1.38
(m, 2H), 1.04 (d, J¼7.2, 3H), 0.90 (s, 9H), 0.05 (s, 6H);
13C NMR (CDCl3, 100 MHz) d 159.0, 141.1, 131.1, 129.3
(2C), 114.2, 113.7 (2C), 82.6, 71.4, 63.2, 55.2, 40.8, 33.0,
30.9, 26.0 (3H), 21.9, 18.3, 15.6, ꢁ5.3 (2C). MS (ES) 394
(M+H+).
1
[a]2D3 +10.8 (c 1.28, CHCl3). H NMR (CDCl3, 500 MHz)
d 3.98 (apparent sextet, J¼6.0, 1H), 3.68 (apparent q,
J¼6.0, 1H), 2.46–2.54 (m, 1H), 1.82 (ddd, J¼13.5, 6.0,
6.0, 1H), 1.77 (d, J¼2.5, 3H), 1.54 (ddd, J¼13.5, 6.0, 6.0,
1H), 1.14 (d, J¼6.0, 3H), 1.07 (J¼6.0, 3H), 0.90 (overlapped
two singlets, 18H), 0.08 (s, 3H), 0.07 (s, 3H), 0.061 (s, 3H),
0.057 (s, 3H). HRMS (ES) 385.2954 (M+H+), calcd
385.2958.
A solution of the methyl alkyne (1.627 g, 4.24 mmol) in
THF (10.5 mL) was added to Cp2ZrHCl (2.189 g,
8.49 mmol) via cannula. The mixture was protected from
light and stirred at 50 ꢀC for 2 h. The resulting dark red sus-
pension was cooled to room temperature. A solution of I2
(2.150 g, 8.47 mmol) in THF (7 mL) was added via cannula.
The dark brown mixture was stirred at room temperature for
30 min and then poured into a 1:1 mixture of saturated aque-
ous Na2S2O3 and saturated aqueous NaHCO3. The mixture
was diluted with EtOAc and the organic phase was separated
and washed with saturated aqueous Na2S2O3, saturated
aqueous NaHCO3, and brine. The organic solution was dried
over anhydrous MgSO4 and concentrated in vacuo. Flash
chromatography (100:1 hexanes/EtOAc) gave the vinyl io-
To a solution of the PMB ether (3.019 g, 7.70 mmol) in THF
(70 mL) was added TBAF (1 M in THF, 11.5 mL,
11.5 mmol). The solution was stirred at room temperature
for 1.5 h. The solution was concentrated in vacuo. Flash
chromatography (2:1 hexanes/EtOAc) gave the alcohol
(2.045 g, 96% yield). [a]2D3 ꢁ43.8 (c 0.55, CHCl3). 1H
NMR (CDCl3, 500 MHz) d 7.27 (d, J¼8.5, 2H), 6.87 (d,
J¼8.5, 2H), 5.85 (ddd, J¼17.5, 11.0, 8.0, 1H), 5.05 (br d,
J¼17.5, 1H), 5.02 (br d, J¼11.0, 1H), 4.50 (d, J¼11.0,
1H), 4.43 (d, J¼11.0, 1H), 3.80 (s, 3H), 3.61 (t, J¼6.0,
2H), 3.22–3.27 (m, 1H), 2.49 (apparent sextet, J¼6.5, 1H),
1.44–1.58 (m, 4H), 1.32–1.42 (m, 2H), 1.04 (d, J¼6.5,
3H); 13C NMR (CDCl3, 100 MHz) d 159.1, 140.9, 131.0,
129.4 (2C), 114.3, 113.7 (2C), 82.5, 71.5, 62.9, 55.3, 40.7,
32.8, 30.7, 21.7, 15.6. MS (ES) m/z 279 (M+H+).
1
dide 25 (1.413 g, 65% yield). H NMR (CDCl3, 500 MHz)
d 6.13 (br d, J¼9.5, 1H), 3.87 (apparent sextet, J¼6.0,
1H), 3.66 (ddd, J¼7.0, 5.5, 4.0, 1H), 2.52 (ddq, J¼9.5,
4.0, 6.5, 1H), 2.38 (d, J¼1.5, 3H), 1.53–1.64 (m, 2H), 1.13
(d, J¼6.0, 3H), 0.91 (d, J¼7.0, 3H), 0.89 (s, 9H), 0.88 (s,
9H), 0.056 (s, 3H), 0.054 (s, 3H), 0.04 (two overlapped sin-
glets, 6H); 13C NMR (CDCl3, 125 MHz) d 145.0, 93.1, 71.9,
65.8, 44.9, 40.3, 27.9, 25.90 (3C), 25.86 (3C), 24.1, 18.1
(2C), 14.1, ꢁ4.20 (2C), ꢁ4.6, ꢁ4.7.
4.3.3. Synthesis outlined in Scheme 10. To a solution of
t-BuOK (6.56 g, 58.5 mmol) in THF (400 mL) at ꢁ78 ꢀC
was added Z-2-butene (8.2 g, 146 mmol) followed by n-
BuLi in hexanes (2.16 M, 27.1 mL, 58.5 mmol). The bright
yellow suspension was stirred at ꢁ78 ꢀC for 5 min, ꢁ45 ꢀC
for 10 min, and then ꢁ78 ꢀC for 15 min. A solution of (+)-
Ipc2BOMe (21.58 g, 68.2 mmol) in Et2O (50 mL) was
then added via cannula. The colorless solution was allowed
To a solution of the alcohol (1.539 g, 5.53 mmol) in CH2Cl2
(78 mL) and DMSO (39 mL) were added i-PrN2Et (6.3 mL,
36.17 mmol) and sulfur trioxide pyridine complex (3.940 g,
24.75 mmol). The solution was stirred at room temperature
for 1 h. The solution was diluted with Et2O and washed

F. Song et al. / Tetrahedron 63 (2007) 5739–5753
5749
with water, brine, dried over MgSO4, and concentrated
in vacuo. Flash chromatography (4:1 hexanes/EtOAc) gave
the aldehyde (1.436 g, 94% yield). 1H NMR (CDCl3,
500 MHz) d 9.73 (d, J¼2.0, 1H), 7.27 (d, J¼8.5, 2H), 6.87
(d, J¼8.5, 2H), 5.83 (ddd, J¼17.5, 10.5, 6.7, 1H), 5.04 (br
d, J¼17.5, 1H), 5.03 (br d, J¼10.5, 1H), 4.52 (d, J¼11.0,
1H), 4.42 (d, J¼11.0, 1H), 3.80 (s, 3H), 3.25 (ddd, J¼8.7,
6.7, 4.7, 1H), 2.51 (apparent sextet, J¼6.7, 1H), 2.39 (t,
J¼7.5, 2H), 1.74–1.84 (m, 1H), 1.58–1.68 (m, 1H), 1.42–
1.55 (m, 2H), 1.04 (d, J¼6.7, 3H); 13C NMR (CDCl3,
125 MHz) d 202.6, 159.1, 140.5, 130.8, 129.4 (2C), 114.6,
113.7 (2C), 82.1, 71.4, 55.2, 43.9, 40.5, 30.3, 18.2, 15.7.
MS (ES) m/z 277 (M+H+).
with EtOAc three times. The combined organic phase was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude aldehyde was reduced directly without fur-
ther purification.
To a solution of the crude aldehyde in MeOH (15 mL) at
0 ꢀC was added NaBH4 (0.147 g, 3.89 mmol). The solution
was stirred at 0 ꢀC for 1 h. Saturated aqueous NH4Cl was
added and the mixture was extracted with EtOAc three
times. The combined organic phase was washed with brine,
dried over Na2SO4, and concentrated in vacuo. Flash chro-
matography (3:1 hexanes/EtOAc) gave the alcohol 29
(0.662 g, 83% yield for two steps). [a]2D3 +0.8 (c 1.77,
1
CHCl3). H NMR (CDCl3, 500 MHz) d 7.26 (d, J¼9.0,
To a solution of the aldehyde (1.044 g, 3.78 mmol) in t-
BuOH (80 mL) was added 2-methyl-2-butene (19 mL).
Then NaClO2 (3.152 g) and NaH2PO4 (3.152 g) in H2O
(32 mL) were added during 10 min. The mixture was stirred
at room temperature for 30 min. The volatile component was
evaporated under vacuum. The residue was diluted with H2O
and extracted with EtOAc twice. The aqueous phase was
acidified to pH¼3 with 1 N HCl. The acidified aqueous
phase was extracted with EtOAc three times. The combined
organic phase was washed with water, brine, dried over
MgSO4, and concentrated. The residue was used directly
for the next step without further purification.
2H), 6.87 (d, J¼9.0, 2H), 4.52 (d, J¼11.0, 1H), 4.47 (d,
J¼11.0, 1H), 3.79 (s, 3H), 3.66 (s, 3H), 3.63–3.67 (m,
1H), 3.57 (dd, J¼10.5, 5.0, 1H), 3.49 (ddd, J¼7.0, 5.0,
4.0, 1H), 2.24–2.37 (m, 2H), 2.04–2.12 (m, 1H), 1.71–1.80
(m, 1H), 1.57–1.67 (m, 2H), 1.47–1.55 (m, 1H), 0.87 (d,
J¼7.0, 3H); 13C NMR (CDCl3, 100 MHz) 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. MS (ES) m/z 311 (M+H+).
To a solution of the alcohol 29 (1.999 g, 6.448 mmol)
in CH2Cl2 (70 mL) were added imidazole (1.317 g,
19.35 mmol), Ph3P (3.551 g, 13.54 mmol), and I2 (3.436 g,
13.54 mmol). The solution was stirred at room temperature
for 2 h. The solution was diluted with EtOAc and washed
with saturated aqueous Na2S2O3, saturated aqueous
NaHCO3, and brine. The organic phase was dried over
MgSO4 and concentrated in vacuo. Flash chromatography
(9:1 hexanes/EtOAc) gave the alkyl iodide 30 (2.481 g,
To a solution of the crude acid in CH3CN (10 mL) was added
DBU (0.57 mL, 3.81 mmol) with good stirring. Then MeI
(0.26 mL, 4.18 mmol) was added and the solution was
stirred at room temperature for 14 h. Water was added and
the mixture was extracted with Et2O. The combined extracts
were washed with saturated aqueous Na2S2O3, H2O, and
brine. The organic phase was dried over MgSO4 and concen-
trated in vacuo. Flash chromatography (10:1 hexanes/
EtOAc) gave the methyl ester 28 (0.967 g, 84% yield for
two steps). [a]2D3 ꢁ26.3 (c 0.40, CHCl3). 1H NMR (CDCl3,
500 MHz) d 7.27 (d, J¼9.0, 2H), 6.87 (d, J¼9.0, 2H), 5.83
(ddd, J¼17.5, 11.0, 8.0, 1H), 5.04 (br d, J¼17.5, 1H), 5.02
(br d, J¼11.0, 1H), 4.50 (d, J¼11.5, 1H), 4.43 (d, J¼11.5,
1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.24 (ddd, J¼7.2, 5.6, 4.4,
1H), 2.49 (apparent sextet, J¼7.2, 1H), 2.22–2.32 (m, 2H),
1.71–1.83 (m, 1H), 1.59–1.70 (m, 1H), 1.44–1.58 (m, 2H),
1.04 (d, J¼7.2, 3H); 13C NMR (CDCl3, 125 MHz)
d 174.1, 159.1, 140.7, 130.9, 129.4 (2C), 114.5, 113.7
(2C), 82.1, 71.4, 55.3, 51.4, 40.6, 34.1, 30.4, 21.0, 15.7.
MS (ES) m/z 324 (M+NH+4).
1
92% yield). H NMR (CDCl3, 400 MHz) d 7.25 (d, J¼8.8,
2H), 6.87 (d, J¼8.8, 2H), 4.49 (d, J¼11.2, 1H), 4.44 (d,
J¼11.2, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.43 (ddd, J¼6.8,
5.2, 4.0, 1H), 3.35 (dd, J¼9.6, 6.0, 1H), 3.06 (dd, J¼9.6,
7.6, 1H), 2.28–2.34 (m, 2H), 1.87–1.97 (m, 1H), 1.43–1.77
(m, 4H), 1.02 (d, J¼6.8, 3H); 13C NMR (CDCl3,
100 MHz) d 173.8, 159.1, 130.6, 129.3 (2C), 113.8 (2C),
80.7, 71.9, 55.2, 51.5, 39.0, 33.9, 30.1, 21.0, 15.5, 12.3.
4.3.4. Synthesis outlined in Scheme 11. To a suspension of
LiAlH4 (2.765 g, 72.86 mmol) in THF (65 mL) was added
slowly a solution of an 8:1 diastereomeric mixture of
methylated diethyl (S)-malate 3231 (3.770 g, 18.48 mmol)
in THF (35 mL). The mixture was refluxed for 2 h and was
cooled to room temperature. Water (2.77 mL), 15% aqueous
NaOH (2.77 mL), and water (8.31 mL) were added slowly
with care sequentially. The mixture was filtered through
Celite and washed with Et2O (300 mL). The filtrate was con-
centrated in vacuo to give an 8:1 diastereomeric mixture of
To a solution of the methyl ester 28 in 1:1 mixture of ace-
tone/water (24 mL) was added NMO (1.133 g, 9.67 mmol)
and OsO4 (0.3 M in toluene, 1.09 mL, 3.27 mmol). The so-
lution was stirred at room temperature for 2 h. Saturated
aqueous Na2S2O3 and EtOAc were added. The mixture
was stirred for 1 h. The aqueous phase was separated and ex-
tracted with EtOAc three times. The combined organic phase
was washed with brine, dried over Na2SO4, and concentrated
in vacuo. Flash chromatography (1:1 hexanes/EtOAc) gave
the diastereomeric mixture of diol (0.881 g, 80% yield).
1
triols 33 (2.101 g). H NMR (CD3OD, 500 MHz) d 3.61–
3.69 (m, 2H), 3.50–3.55 (m, 3H), 1.74–1.82 (m, 1H), 0.95
(d, J¼6.0, 3H).
A solution of the crude triol 33 in MeOH (100 mL) was
treated with n-Bu2SnO (4.358 g, 17.51 mmol). The mixture
was refluxed overnight to give a clear solution. The solution
was concentrated in high vacuum to give white solid. The
solid in CHCl3 (100 mL) was treated with TBSCl (3.167 g,
21.01 mmol) for 20 min. Acetonitrile (100 mL) was added
and the solution was concentrated to about 30 mL. Hexanes
(100 mL) was added and then was extracted with CH3CN
To a solution of the diol (0.881 g, 2.59 mmol) in benzene
(16 mL) was added Pb(OAc)4 (1.814 g, 4.09 mmol). The
mixture was stirred at room temperature for 3 h. Saturated
aqueous NaHCO3 was added and the mixture was extracted

5750
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
(100 mLꢂ3). The combined acetonitrile extracts were
concentrated. Flash chromatography (2:1 hexanes/EtOAc)
gave an 8:1 diastereomeric mixture of 1,2-diols 34
(3.431 g, 79% yield from the diethyl ester). 1H NMR
(CDCl3, 500 MHz) d 4.10 (br s, OH), 3.74 (dd, J¼10.5,
4.0, 1H), 3.68 (br dd, J¼11.0, 2.0, 1H), 3.61 (dd, J¼10.5,
9.0, 1H), 3.54–3.64 (m, 2H), 2.49 (br s, OH), 1.82–1.92
(m, 1H), 0.90 (s, 9H), 0.85 (d, J¼7.0, 3H), 0.09 (two overlap-
ped singlets, 6H); 13C NMR (CDCl3, 100 MHz) d 76.7, 68.1,
64.9, 36.9, 25.8 (3C), 18.1, 13.3, ꢁ5.6, ꢁ5.7. MS (ES) m/z
235 (M+H+).
To a solution of the 8:1 diastereomeric mixture of diols
(4.300 g, 30.28 mmol) in benzene (160 mL) were added
cyclopentanone (40 mL, 452 mmol), p-TsOH (576 mg,
3.03 mmol), and MgSO4 (10 g). The mixture was stirred
for 72 h, filtered, and concentrated in vacuo. Flash chroma-
tography using EtOAc/hexanes (1:9) as eluent provided cy-
clopentylidene protected diol 36 (5.150 g, 76% yield). [a]D23
ꢁ5.2 (c 1.95, CHCl3). 1H NMR (400 MHz, C6D6) d 3.62 (dd,
J¼5.1, 11.4, 1H), 3.30 (ddd, J¼4.4, 5.9, 9.9, 1H), 3.20 (t,
J¼11.4, 1H), 2.31–2.46 (m, 2H), 2.05–2.16 (m, 2H), 1.88–
1.98 (m, 1H), 1.73–1.84 (m, 2H), 1.52–1.64 (m, 4H), 1.54
(t, J¼2.6, 3H), 0.45 (d, J¼6.6, 3H); 13C NMR (100 MHz,
C6D6) d 110.4, 77.0, 75.9, 75.9, 67.2, 40.4, 33.6, 30.8,
24.7, 24.2, 22.8, 12.3, 3.4. HRMS (ES) m/z 209.1544
(M+H+), calcd 209.1541.
To a solution of the 8:1 diastereomeric mixture of 1,2-diols
34 (8.009 g, 34.23 mmol) in THF (200 mL) at 0 ꢀC was
added NaH (60% in mineral oil, 0.904 g, 37.65 mmol).
The mixture was stirred at 0 ꢀC for 20 min. Then 1-(p-tolue-
nesulfonyl)imidazole (8.453 g, 37.65 mmol) was added
slowly with caution. The cooling bath was removed and
the mixture was stirred at room temperature for 14 h. The re-
action was quenched by addition of saturated aqueous
NH4Cl. The mixture was extracted with Et2O three times.
The combined organic extracts were washed with water,
brine, dried over MgSO4, and concentrated. Flash chromato-
graphy (20:1 hexanes/EtOAc) gave an 8:1 diastereomeric
mixture of epoxides 35 (6.501 g, 88% yield). 1H NMR
(C6D6, 500 MHz) d 3.55 (d, J¼6.0, 2H), 2.67 (ddd, J¼7.0,
4.0, 3.0, 1H), 2.35 (dd, J¼5.5, 4.0, 1H), 2.15 (dd, J¼5.5,
3.0, 1H), 1.28–1.40 (m, 1H), 0.95 (s, 9H), 0.84 (d, J¼7.0,
3H), 0.03 (s, 3H), 0.02 (s, 3H).
A solution of alkyne 36 (588.0 mg, 2.87 mmol) in THF
(7.2 mL) was added to Cp2ZrHCl (1.480 g, 5.74 mmol) via
cannula. The mixture was protected from light and stirred
at 50 ꢀC for 1 h. The resulting dark red suspension was
cooled to room temperature, and a solution of I2 (1.454 g,
5.73 mmol) in THF (5 mL) was added via cannula. The
dark brown mixture was stirred for 30 min and quenched
with 10% aqueous Na2S2O3 and saturated aqueous NaHCO3
(30 mL each). The mixture was diluted with EtOAc and sep-
arated. The organic phase was washed with 10% aqueous
Na2S2O3, saturated aqueous NaHCO3, and brine. The or-
ganic phase was then dried over anhydrous MgSO4 and con-
centrated in vacuo. Flash chromatography (19:1 hexanes/
1
EtOAc) gave vinyl iodide 37 (596.2 mg, 62% yield). H
To a solution of propyne (4.397 g, 109.73 mmol) in THF
(290 mL) at ꢁ78 ꢀC was added n-BuLi (2.38 M in hexanes,
39.51 mL, 94.04 mmol). The solution was stirred for
10 min. A solution of the 8:1 diastereomeric mixture of ep-
oxides 35 (6.771 g, 31.35 mmol) in THF (20 mL, 6 mL
wash) was added, followed by BF3$OEt2 (11.92 mL,
94.04 mmol). The solution was stirred at ꢁ78 ꢀC for 2 h.
The reaction was quenched by addition of saturated NH4Cl
and the mixture was extracted with EtOAc three times.
The combined organic phase was washed with saturated
NaHCO3, brine, dried over MgSO4, and concentrated. Flash
chromatography (8:1 hexanes/EtOAc) gave an 8:1 diastereo-
meric mixture of homopropargylic alcohols (7.712 g, 96%
yield). 1H NMR (C6D6, 500 MHz) d 3.69 (dd, J¼10.0, 5.0,
1H), 3.62–3.66 (m, 1H), 3.51–3.57 (m, 1H), 2.90 (d,
J¼4.5, OH), 2.41–2.47 (m, 1H), 2.33–2.41 (m, 1H), 1.85–
1.91 (m, 1H), 1.48 (t, J¼2.5, 3H), 0.91 (s, 9H), 0.85 (d,
J¼7.0, 3H), ꢁ0.00 (s, 3H), ꢁ0.01 (s, 3H).
NMR (500 MHz, C6D6) d 6.41 (ddq, J¼7.5, 7.0, 1.5, 1H),
3.56 (dd, J¼11.5, 5.0, 1H), 3.11 (apparent t, J¼11.5), 3.07
(ddd, J¼11.0, 8.0, 3.5), 2.14 (d, J¼1.5, 3H), 1.90–2.06 (m,
4H), 1.70–1.77 (m, 1H), 1.60–1.66 (m, 1H), 1.48–1.58 (m,
3H), 0.26 (d, J¼6.0, 3H).
4.3.5. Synthesis outlined in Scheme 12. Active Zn–Cu
couple was prepared from Zn (1.396 g, 21.34 mmol) and
Cu(OAc)2$H2O (85.2 mg, 0.43 mmol) following literature
procedure36 and was dried under vacuum for 30 min. Alkyl
iodide 30 (1.794 g, 4.27 mmol) in a 15:1 mixture of benzene/
DMF (15.0 mL) was added to the Zn–Cu couple. The mix-
ture was heated in a 55 ꢀC oil bath for 1 h with stirring to
give the alkylzinc iodide. Anhydrous LiCl (1.09 mg,
25.61 mmol) (dried with flame) and Pd(PPh3)4 (352.3 mg,
0.30 mmol) in a 50 mL flask were degassed for four times.
NMP (12.0 mL) was added, followed by addition of the
vinyl iodide 37 (1.025 g, 3.05 mmol) in NMP (4.0 mL).
Then the colorless alkylzinc iodide solution (the excess Zn
was removed as much as possible) was added via cannula.
The reaction mixture was degassed once and was stirred at
room temperature for 15 min and then at 55 ꢀC overnight.
The cooled reaction mixture was poured into a mixture of
saturated aqueous NaHCO3 and EtOAc. The mixture was
extracted with EtOAc four times. The combined extracts
were washed with H2O, brine, dried over Na2SO4, and con-
centrated. Flash chromatography (10:1 hexanes/EtOAc) af-
forded the coupled product 38 (1.265 g, 83% yield). [a]D23
To a solution of the 8:1 diastereomeric mixture of homopro-
pargylic alcohols (7.712 g, 30.12 mmol) in THF (150 mL)
was added TBAF (1.0 M in THF, 36.15 mL, 36.15 mmol).
Brine was added and the mixture was extracted with Et2O
three times. The combined organic phase was washed
with brine, dried over Na2SO4, and concentrated. Flash
chromatography (1:2 hexanes/EtOAc) gave an 8:1 dia-
stereomeric mixture of diols (4.107 g, 96% yield). 1H
NMR (CDCl3, 500 MHz) d 3.66–3.74 (m, 1H), 3.56–3.65
(m, 2H), 3.25 (br s, OH), 3.20 (br d, J¼4.0, OH), 2.42–
2.48 (m, 1H), 2.28–2.35 (m, 1H), 1.83 (dq, J¼4.0, 6.0,
1H), 1.79 (t, J¼2.5, 3H), 0.86 (d, J¼7.0, 3H); 13C NMR
(CDCl3, 125 MHz) d 78.6, 75.3, 74.8, 67.3, 39.1, 25.9,
13.6, 3.5.
1
+4.9 (c 0.73, CHCl3). H NMR (CDCl3, 500 MHz) d 7.27
(d, J¼9.0, 2H), 6.87 (d, J¼9.0, 2H), 5.26 (dd, J¼7.0, 6.0,
1H), 4.47 (d, J¼11.5, 1H), 4.42 (d, J¼11.5, 1H), 3.79 (s,
3H), 3.71 (dd, J¼11.0, 4.5, 1H), 3.66 (s, 3H), 3.39 (t,
J¼11.0, 1H), 3.32–3.40 (m, 1H), 3.25 (ddd, J¼7.0, 3.5,

F. Song et al. / Tetrahedron 63 (2007) 5739–5753
5751
3.5, 1H), 2.28–2.36 (m, 3H), 2.20–2.25 (m, 1H), 2.08–2.16
(m, 1H), 1.86–1.94 (m, 2H), 1.70–1.85 (m, 6H), 1.57–1.68
(m, 5H), 1.57 (s, 3H), 1.46–1.54 (m, 2H), 0.82 (d, J¼6.8,
3H), 0.74 (d, J¼6.8, 3H); 13C NMR (CDCl3, 100 MHz)
d 174.0, 159.0, 135.0, 131.2, 129.2 (2C), 122.2, 113.7
(2C), 110.1, 82.0, 77.2, 71.4, 67.5, 55.2, 51.4, 42.7, 40.2,
34.1, 33.9, 33.3, 31.6, 30.6, 30.1, 24.3, 22.5, 21.5, 16.1,
14.5, 12.7. HRMS (ES) m/z 503.3361 (M+H+), calcd
503.3372.
dried over Na2SO4, and concentrated. Flash chromatography
(1:1 hexanes/EtOAc) gave the seco-acid 39 (1.205 g, 81%
yield). H NMR (CDCl3, 500 MHz) d 7.27 (d, J¼8.5, 2H),
1
6.87 (d, J¼8.5, 2H), 5.25 (apparent t, J¼7.0, 1H), 4.48 (d,
J¼11.5, 1H), 4.43 (d, J¼11.5, 1H), 3.89 (dd, J¼10.0, 4.0,
1H), 3.79 (s, 3H), 3.69 (dd, J¼10.0, 7.0, 1H), 3.62 (apparent
dt, J¼4.5, 7.0, 1H), 3.26 (apparent dt, J¼6.5, 4.5, 1H), 2.30–
2.37 (m, 2H), 2.21–2.30 (m, 3H), 1.88–1.96 (m, 1H), 1.80
(dd, J¼12.5, 9.5, 1H), 1.71–1.82 (m, 1H), 1.47–1.68 (m,
4H), 1.60 (s, 3H), 1.06–1.16 (m, 3H), 1.05–1.09 (m, 18H),
0.90 (d, J¼7.5, 3H), 0.82 (d, J¼7.0, 3H); 13C NMR
(CDCl3, 100 MHz) d 178.7, 159.0, 135.7, 131.1, 129.3
(2C), 122.3, 113.7 (2C), 81.9, 76.5, 71.4, 68.4, 55.2, 42.9,
39.2, 34.0, 33.7, 33.3, 30.0, 21.3, 17.9 (6C), 16.1, 14.8,
13.7, 11.7 (3C).
A mixture of CH2Cl2 (200 mL), H2O (50 mL), and TFA
(12.5 mL) was shaken vigorously. The CH2Cl2 layer
(150 mL) was used to dissolve 38 (1.437 g, 2.86 mmol),
which was stirred for 5.5 h at room temperature. The solution
was poured into saturated aqueous NaHCO3 and diluted with
EtOAc. The mixture was extracted with EtOAc four times.
The combined extracts were washed with brine, dried over
Na2SO4, and concentrated. Flash chromatography (1:1 hex-
anes/EtOAc) gave the diol (1.119 g, 90% yield). [a]2D3 +2.6
To a solution of the seco-acid 39 (1.078 g, 1.86 mmol)
in benzene (19 mL) were added i-Pr2NEt (1.95 mL,
11.18 mmol) and Cl3C6H2COCl (0.90 mL, 5.59 mmol).
The solution was stirred for 50 min at room temperature
and then was added to a solution of DMAP (0.683 g,
5.59 mmol) in benzene (660 mL) via syringe pump over
10 h. The resulting solution was stirred at room temperature
for 8 h. The solution was washed with saturated aqueous
NaHCO3, brine, dried over Na2SO4, and concentrated. Flash
chromatography (10:1 hexanes/EtOAc) gave the macrolac-
tone 40 (0.999 g, 96% yield). [a]2D3 ꢁ19.8 (c 1.06, CHCl3).
1H NMR (CDCl3, 600 MHz) d 7.27 (d, J¼9.0, 2H), 6.87
(d, J¼9.0, 2H), 5.07 (ddd, J¼12.0, 6.0, 3.0, 1H), 5.00 (br
d, J¼10.2), 4.50 (d, J¼11.4, 1H), 4.31 (d, J¼11.4, 1H),
3.80 (s, 3H), 3.66 (dd, J¼9.9, 5.1, 1H), 3.54 (dd, J¼9.9,
6.3, 1H), 3.12 (ddd, J¼8.4, 4.2, 4.2, 1H), 2.43–2.51 (m,
2H), 2.03–2.11 (m, 2H), 1.90–1.95 (m, 1H), 1.85–1.91 (m,
3H), 1.67–1.81 (m, 2H), 1.65 (s, 3H), 1.58–1.64 (m, 1H),
1.40–1.48 (m, 1H), 1.03–1.13 (m, 21H), 1.03(d. J¼7.2,
3H), 0.98 (d, J¼7.2, 3H); 13C NMR (CDCl3, 100 MHz)
d 173.4, 159.0, 137.1, 131.1, 129.4 (2C), 121.9, 113.6
(2C), 83.1, 73.6, 70.8, 65.2, 55.2, 45.7, 40.4, 35.9, 32.6,
30.6, 29.0, 20.5, 19.3, 18.0 (6C), 15.7, 12.8, 11.9 (3C).
HRMS (ES) m/z 561.3985 (M+H+), calcd 561.3975.
1
(c 1.08, CHCl3). H NMR (CDCl3, 600 MHz) d 7.25 (d,
J¼9.0, 2H), 6.87 (d, J¼9.0, 2H), 5.13 (apparent t, J¼7.2,
1H), 4.46 (d, J¼11.4, 1H), 4.40 (d, J¼11.4, 1H), 3.80 (s,
3H), 3.70 (dd, J¼11.4, 3.6, 1H), 3.67 (s, 3H), 3.63 (dd,
J¼11.4, 7.2, 1H), 3.50 (apparent dt, J¼3.0, 8.4, 1H), 3.23
(ddd, J¼7.4, 3.7, 3.7, 1H), 2.18–2.32 (m, 5H), 1.97–2.03
(m, 1H), 1.84 (dd, J¼13.2, 9.0, 1H), 1.69–1.77 (m, 1H),
1.63 (s, 3H), 1.43–1.62 (m, 4H), 0.89 (d, J¼6.6, 3H), 0.82
(d, J¼6.6, 3H); 13C NMR (CDCl3, 100 MHz) d 174.0,
159.0, 137.9, 130.8, 129.3 (2C), 121.4, 113.6 (2C), 82.2,
77.0, 71.4, 67.6, 55.1, 51.4, 42.9, 39.6, 34.2, 33.9, 32.8,
29.4, 21.5, 16.0, 15.3, 13.8. HRMS (ES) m/z 437.2879
(M+H+), calcd 437.2903.
To a solution of the diol (1.119 g, 2.56 mmol) in DMF
(25 mL) were added imidazole (0.384 g, 5.64 mmol) and
TIPSCl (0.70 mL, 3.27 mmol). The solution was stirred at
room temperature for 5 h and then at 0 ꢀC for 26 h. The mix-
ture was diluted with water and was extracted with Et2O
three times. The combined extracts were washed with brine,
dried over Na2SO4, and concentrated. Flash chromatography
(3:1 hexanes/EtOAc) gave the silyl ether quantitatively.
1
[a]2D3 +5.5 (c 1.09, CHCl3). H NMR (CDCl3, 500 MHz)
To a solution of 40 (0.460 g, 0.82 mmol) in CH3CN (48 mL)
was added a mixture of CH3CN (48 mL), HF$pyridine
(2.3 mL), and pyridine (2.3 mL). The solution was stirred
at 0 ꢀC for 120 h. The solution was poured into saturated
aqueous NaHCO3 and the mixture was extracted with EtOAc
three times. The combined extracts were washed with brine,
dried over Na2SO4, and concentrated. Flash chromatography
(10:1 hexanes/EtOAc followed by 1:1 hexanes/EtOAc) gave
the alcohol (0.300 g, 90% yield). [a]2D3 ꢁ32.9 (c 1.48,
d 7.27 (d, J¼8.5, 2H), 6.87 (d, J¼8.5, 2H), 5.27 (apparent
t, J¼7.0, 1H), 4.47 (d, J¼11.0, 1H), 4.43 (d, J¼11.0, 1H),
3.88 (dd, J¼9.5, 4.0, 1H), 3.80 (s, 3H), 3.69 (dd, J¼9.5,
7.5, 1H), 3.67 (s, 3H), 3.60 (apparent dt, J¼4.5, 7.0, 1H),
3.24 (apparent dt, J¼7.0, 3.5, 1H), 2.19–2.33 (m, 5H),
1.88–1.96 (m, 1H), 1.80 (dd, J¼12.5, 9.5, 1H), 1.70–1.82
(m, 1H), 1.57–1.67 (m, 1H), 1.60 (s, 3H), 1.44–1.57 (m,
3H), 1.06–1.16 (m, 3H), 1.05–1.09 (m, 18H), 0.90 (d,
J¼6.5, 3H), 0.82 (d, J¼6.5, 3H); 13C NMR (CDCl3,
100 MHz) d 174.0, 159.0, 135.6, 131.2, 129.2 (2C), 122.3,
113.7 (2C), 82.1, 76.3, 71.4, 68.4, 55.2, 51.4, 42.8, 39.3,
34.1, 33.8, 33.3, 30.0, 21.6, 17.9 (6C), 16.1, 14.7, 13.7,
11.7 (3C). HRMS (ES) m/z 593.4230 (M+H+), calcd
593.4237.
1
CHCl3). H NMR (CDCl3, 500 MHz) d 7.27 (d, J¼9.0,
2H), 6.88 (d, J¼9.0, 2H), 4.99 (br d, J¼10.0, 1H), 4.86
(ddd, J¼12.0, 9.5, 3.0, 1H), 4.50 (d, J¼11.0, 1H), 4.30 (d,
J¼11.0, 1H), 3.80 (s, 3H), 3.56 (dd, J¼12.0, 4.0, 1H), 3.46
(br dd, J¼12.0, 2.8, 1H), 2.99–3.14 (m, 1H), 2.54 (ddd,
J¼13.0, 5.0, 3.5, 1H), 2.42 (ddd, J¼14.0, 11.5, 11.5, 1H),
2.19 (br d, J¼11.5, 1H), 2.11 (ddd, J¼13.0, 13.0, 3.5, 1H),
1.68–1.96 (m, 6H), 1.67 (s, 3H), 1.56–1.65 (m, 1H), 1.44–
1.53 (m, 1H), 1.06 (d. J¼7.3, 3H), 1.04 (d, J¼7.3, 3H);
13C NMR (CDCl3, 100 MHz) d 175.0, 159.0, 137.4, 130.9,
129.3 (2C), 121.7, 113.6 (2C), 83.1, 74.3, 70.7, 63.9, 55.2,
45.6, 40.2, 35.9, 32.4, 31.5, 28.8, 20.6, 19.0, 15.7, 13.6.
HRMS (ES) m/z 405.2640 (M+H+), calcd 405.2641.
To a solution of the silyl ether (1.6297 g, 2.75 mmol) in
a 4:1:1 mixture of THF/MeOH/H2O (144 mL) was added
aqueous solution of LiOH (1.0 M, 24 mL). The solution
was stirred at room temperature for 5 h. Saturated aqueous
NH4Cl was added and the mixture was extracted with EtOAc
three times. The combined extracts were washed with brine,

5752
F. Song et al. / Tetrahedron 63 (2007) 5739–5753
To a solution of the alcohol (0.605 g, 1.50 mmol) in CH2Cl2
(30 mL) were added imidazole (0.305 g, 4.49 mmol), Ph3P
(0.824 g, 3.14 mmol), and I2 (0.797 g, 3.14 mmol). The solu-
tion was stirred at room temperature for 30 min and diluted
with saturated aqueous Na2S2O3 solution. The mixture was
extracted with EtOAc three times. The combined extracts
were washed with brine, dried over Na2SO4, and concen-
trated. Flash chromatography (10:1 hexanes/EtOAc) gave
the alkyl iodide 41 (0.753 g, 98% yield). 1H NMR (CDCl3,
500 MHz) d 7.26 (d, J¼8.5, 2H), 6.87 (d, J¼8.5, 2H), 4.97
(br d, J¼10.5, 1H), 4.93 (ddd, J¼12.0, 7.0, 3.0, 1H), 4.50
(d, J¼11.0, 1H), 4.30 (d, J¼11.0, 1H), 3.80 (s, 3H), 3.29
(dd, J¼10.0, 4.0, 1H), 3.11 (ddd, J¼8.0, 4.0, 4.0, 1H), 3.00
(dd, J¼10.0, 8.5, 1H), 2.48 (ddd, J¼12.0, 5.0, 3.5, 1H),
2.41 (ddd, J¼14.0, 11.5, 11.5, 1H), 2.12 (br d, J¼11.5,
1H), 2.08 (ddd, J¼12.0, 12.0, 3.5, 1H), 1.84–1.93 (m, 3H),
1.68–1.81 (m, 3H), 1.63 (s, 3H), 1.56–1.63 (m, 1H), 1.37–
1.46 (m, 1H), 1.09 (d, J¼7.0, 3H), 1.02 (d, J¼7.0, 3H).
was added and the mixture was extracted with CH2Cl2 three
times. The combined extracts were washed with saturated
aqueous NaHCO3, H2O, brine and dried over Na2SO4. The
solution was concentrated. Flash chromatography (15:1 hex-
anes/EtOAc) gave the core structure alcohol 21 (46.1 mg,
91% yield). [a]D23 ꢁ29.2 (c 0.92, CHCl3). 1H NMR
(CD3COCD3, 600 MHz) d 5.23 (br d, J¼9.0, 1H), 5.04 (br
d, J¼10.8, 1H), 4.90 (ddd, J¼11.4, 3.6, 2.4, 1H), 3.98 (ap-
parent sextet, J¼6.0, 1H), 3.74 (ddd, J¼6.0, 6.0, 4.2, 1H),
3.34–3.38 (m, 1H), 3.15 (d, J¼5.4, OH), 2.55–2.61 (m,
1H), 2.49 (ddd, J¼14.4, 11.7, 11.7, 1H), 2.31 (ddd,
J¼13.2, 6.8, 3.0, 1H), 2.16 (dd, J¼13.2, 4.8, 1H), 2.06–
2.14 (m, 2H), 1.88–1.97 (m, 3H), 1.76–1.82 (m, 2H), 1.65
(s, 6H), 1.51–1.66 (m, 5H), 1.42–1.48 (m, 1H), 1.16 (d,
J¼6.0, 3H), 0.96 (d, J¼7.2, 3H), 0.92 (s, 9H), 0.90 (d,
J¼6.0, 3H), 0.896 (s, 9H), 0.87 (d, J¼6.6, 3H), 0.089 (s,
3H), 0.083 (s, 3H), 0.08 (s, 6H); 13C NMR (CD3COCD3,
100 MHz) d 173.9, 137.3, 132.3, 131.0, 123.1, 76.4, 73.5,
73.4, 66.4, 46.4, 45.7, 43.6, 37.6, 35.7, 35.6, 35.0, 34.9,
30.2, 26.1 (3C), 26.0 (3C), 24.3, 20.4, 18.7, 18.4, 18.2,
16.0, 15.7, 15.3, 14.8, ꢁ4.0, ꢁ4.3, ꢁ4.5, ꢁ4.7. MS (ES)
m/z 671 (M+NH+4).
Active Zn–Cu couple was prepared from Zn (0.462 g,
7.07 mmol) and Cu(OAc)2$H2O (0.028 g, 0.14 mmol) fol-
lowing literature procedure36 and was dried under vacuum
for 30 min. The alkyl iodide 41 (0.727 g, 1.41 mmol) in a
15:1 mixture of benzene/DMF (5.0 mL) was added to the
Zn–Cu couple. The mixture was heated in a 55 ꢀC oil bath
for 1 h with stirring to give the alkylzinc iodide. Anhydrous
LiCl (0.360 g, 8.48 mmol) (dried with flame) and Pd(PPh3)4
(0.245 g, 0.21 mmol) in a 25 mL flask were degassed for
four times. NMP (8.0 mL) was added, followed by addition
of the vinyl iodide 25 (1.085 g, 2.12 mmol). The colorless
alkylzinc iodide solution (the excess Zn was removed as
much as possible) was added via cannula. The reaction mix-
ture was degassed once and was stirred at room temperature
for 1 h 20 min and then at 50 ꢀC for 15 h. The cooled reac-
tion mixture was poured into a mixture of saturated aqueous
NaHCO3 and EtOAc. The mixture was extracted with
EtOAc three times. The combined extracts were washed
with H2O, brine, dried over Na2SO4, and concentrated.
Medium-pressure chromatography (50:1 hexanes/EtOAc,
Biotage) gave the protected core structure 42 (0.876 g, 80%
Acknowledgements
We thank Professor P. L. C. Small at the University of
Tennessee for a generous gift of natural mycolactones and
also for performing biological tests. We are grateful to the
National Institutes of Health (CA 22215) and to the Eisai
Research Institute for generous financial support. A.B.B.
gratefully acknowledges support in the form of an American
Cancer Society postdoctoral fellowship (PF-99-117-01-
CDD, partially funded by the National Fisheries Institute).
References and notes
1. For a general review on Buruli ulcer, see: (a) Buruli Ulcer:
Mycobacterium ulcerans Infection; Asiedu, K., Scherpbier,
R., Ravinglione, M., Eds.; World Health Organization:
Geneva, Switzerland, 2000; (b) Rohr, J. Angew. Chem., Int.
Ed. 2000, 39, 2847.
2. Marsollier, L.; Robert, R.; Aubry, J.; Saint Andre, J.-P.;
Kouakou, H.; Legras, P.; Manceau, A.-L.; Mahaza, C.;
Carbonnelle, B. Appl. Environ. Microbiol. 2002, 68, 4623.
3. George, K. M.; Chatterjee, D.; Gunawardana, G.; Welty, D.;
Hayman, J.; Lee, R.; Small, P. L. C. Science 1999, 283, 854.
4. Gunawardana, G.; Chatterjee, D.; George, K. M.; Brennan, P.;
Whittern, D.; Small, P. L. C. J. Am. Chem. Soc. 1999, 121,
6092.
5. Benowitz, A. B.; Fidanze, S.; Small, P. L. C.; Kishi, Y. J. Am.
Chem. Soc. 2001, 123, 5128.
6. (a) Kobayashi, Y.; Hayashi, N.; Tan, C.-H.; Kishi, Y. Org. Lett.
2001, 3, 2245; (b) Hayashi, N.; Kobayashi, Y.; Kishi, Y. Org.
Lett. 2001, 3, 2249; (c) Kobayashi, Y.; Hayashi, N.; Kishi, Y.
Org. Lett. 2001, 3, 2253.
1
yield). [a]2D3 ꢁ9.2 (c 1.08, CHCl3). H NMR (CD3COCD3,
600 MHz) d 7.28 (d, J¼9.0, 2H), 6.89 (d, J¼9.0, 2H), 5.23
(br d, J¼9.0, 1H), 5.01 (br d, J¼8.4, 1H), 4.87 (ddd,
J¼11.4, 5.4, 3.0, 1H), 4.52 (d, J¼10.8, 1H), 4.30 (d,
J¼10.8, 1H), 3.98 (apparent sextet, J¼6.0, 1H), 3.78 (s,
3H), 3.74 (ddd, J¼6.0, 6.0, 4.2, 1H), 3.15 (ddd, J¼7.8, 4.2,
3.0, 1H), 2.55–2.62 (m, 1H), 2.44–2.50 (m, 2H), 2.17 (dd,
J¼13.8, 5.4, 1H), 1.99–2.10 (m, 2H), 1.92–1.98 (m, 1H),
1.87–1.92 (m, 2H), 1.60–1.80 (m, 7H), 1.67 (s, 3H), 1.66
(s, 3H), 1.41–1.49 (m, 1H), 1.16 (d, J¼6.0, 3H), 1.00 (d,
J¼6.6, 3H), 0.92 (s, 9H), 0.92 (d, J¼6.0, 3H), 0.90 (s, 9H),
0.88 (d. J¼6.6, 3H), 0.091 (s, 3H), 0.086 (s, 3H), 0.08 (s,
6H); 13C NMR (CD3COCD3, 100 MHz) d 173.1, 159.7,
137.2, 132.3, 132.2, 131.0, 129.7, 122.9, 114.0, 82.9, 75.9,
73.5, 70.9, 66.4, 55.2, 46.1, 45.7, 43.7, 37.6, 36.1, 35.6,
33.2, 30.1, 29.8, 26.1(3C), 26.0 (3C), 24.3, 20.2, 19.7,
18.4, 18.3, 16.0, 15.6, 15.4, 14.7, ꢁ4.0, ꢁ4.3, ꢁ4.4, ꢁ4.7.
HRMS (ES) m/z 773.5577 (M+H+), calcd 773.5572.
7. Fidanze, S.; Song, F.; Szlosek-Pinaud, M.; Small, P. L. C.;
Kishi, Y. J. Am. Chem. Soc. 2001, 123, 10117.
To a solution of the protected core structure 42 (60.1 mg,
0.078 mmol) in an 18:1 mixture of CH2Cl2/H2O (19 mL)
at 0 ꢀC was added DDQ (26.5 mg, 0.117 mmol). The solu-
tion was stirred at 0 ꢀC for 2 h. Saturated aqueous NaHCO3
8. Song, F.; Fidanze, S.; Benowitz, A. B.; Kishi, Y. Org. Lett.
2002, 4, 647.
9. (a) Hong, H.; Gates, P. J.; Staunton, J.; Stinear, T.; Cole, S. T.;
Leadlay, P. F.; Spencer, J. B. Chem. Commun. 2003, 2822;

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Me
Me
MeO
Crotylboration
MeO
H
Brown
+
O
O
OH
ꢀ
€
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O
O
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ꢀ
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38. To adopt this synthesis for our purpose, it would be necessary to
adjust the C120-OH protecting group, i.e., from the MOM ether
to the TBS ether.
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