Total synthesis of (-)-reveromycin A via a hetero-Diels-Alder approach

Article abstract of DOI:10.1055/s-0030-1258308

The asymmetric total synthesis of (-)-reveromycin A is described which utilizes a Lewis acid catalyzed inverse electron demand hetero-Diels-Alder reaction followed by hydroboration/oxidation to afford the labile [6,6]-spiroketal core in a highly stereosel

Full text of DOI:10.1055/s-0030-1258308

3954
FEATURE ARTICLE
Total Synthesis of (–)-Reveromycin A via a Hetero-Diels–Alder Approach
(
–)-Reveromycin Avia
a
a
H
etero-
D
r
iels–A
l
i
der
A
p
a
School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3010 Victoria, Australia
Fax +61(3)93478396; E-mail: masr@unimelb.edu.au
Received 30 September 2010; revised 1 October 2010
IgM in B lymphoma cells could also make it a useful tool
Abstract: The asymmetric total synthesis of (–)-reveromycin A is
for studying intracellular transport of Ag.9 Several total
described which utilizes a Lewis acid catalyzed inverse electron
demand hetero-Diels–Alder reaction followed by hydroboration/
oxidation to afford the labile [6,6]-spiroketal core in a highly stereo-
syntheses of (–)-reveromycin B (4)10 have been disclosed
and two total syntheses of reveromycin A (1) have been
selective manner. An asymmetric syn-aldol reaction installed the reported11,12 along with a number of synthetic approaches
to the spiroketal fragment.13 In addition, several biologi-
stereochemistry at C4–C5 whilst a Stille cross coupling was utilized
cally active derivatives of 1 have been synthesized.14 In
to form the C21–C22 bond. The C18 hemisuccinate was formed by
high pressure acylation reaction and a final Wittig extension fol-
this feature article, we report the full details of our unique
lowed by global deprotection with tetrabutylammonium fluoride
approach to the total synthesis reveromycin A.12
gave (–)-reveromycin A.
Key words: reveromycin, [6,6]-spiroketal, hetero-Diels–Alder,
high-pressure acylation, Stille coupling
H
CO2H
5
O
4
CO2H
1
9
11
H
15
H
O
OH
O
The reveromycins A (1), B (2), C (3), and D (4) (Figure 1)
are examples of spiroketal-containing natural products,
which were isolated from a soil actinomycete belonging to
the Streptomyces genus.1 Compounds 1, 3, and 4 possess
a [6,6]-spiroketal whilst 2 has a [5,6]-spiroketal moiety.
The absolute configuration of compound 1 was deter-
mined by a combination of degradative and spectroscopic
studies.2 The reveromycins were identified as being po-
tent inhibitors of the mitogenic activity induced by the
epidermal growth factor (EGF) in mouse epidermal cells
inhibiting some element of the epidermal growth factor
receptor (EGFR) pathway with IC50 values in the order of
0.7–1.1 mg/mL for A (1), C (3), D (4), and 6.0 mg/mL for
reveromycin B (2).3 The EGFR signaling pathway con-
tributes to a number of processes important to tumor
progression including cell proliferation, apoptosis, angio-
genesis, and metastatic spread and abnormal expression
and/or mutation of the EGFR has been implicated in the
progression of some classes of solid tumors.4 Compound
1 also exhibits antiproliferative activity against human tu-
mor cell lines KB (IC50 1.9 mg/mL) and K562 (IC50 1.6 mg/
mL) as well as a strong antitumor effect against human
ovarian carcinoma BG-1.5 In addition, reveromycin A (1)
inhibits protein synthesis of mammalian cells and arrested
the cell cycle at G1 phase6 and bone resorption by induc-
ing apoptosis in osteoclasts, making it a possible agent for
the treatment of osteoporosis.7 Reveromycin A (1) has
also shown antifungal activity3 and has been identified as
a highly specific inhibitor of isoleucyl-tRNA synthetase
(IC50 1.9 ng/mL) using yeast genetics and biochemical
studies.8 The ability of compound 1 to inhibit the presen-
tation of antigen (Ag) internalized via specific surface
O18
CO2H
23
1 reveromycin A: R1 = R2 = H
3 reveromycin C: R1 = H; R2 = Me
4 reveromycin D: R1 = Me; R2 = H
R2
R1
H
O
CO2H
H
OH
O
n-Bu
CO2H
HO2C
O
2 reveromycin B
O
Figure 1 The structures of reveromycins A–D
H
1) LiOH
2) CH2N2
OAc
O
H
1
O
3) O3, MeOH
then NaBH4
4) Ac2O, py
n-Bu
[6,6]-spiroketal
OAc
OAc
5
[5,6]-spiroketal
H
H
H
H+
H+
R1
R1
R1
O
O
O
O
R2
H
H
PG = H
n-Bu
H
H
O
O
R2
I
PGO
R2
n-Bu
III
II
n-Bu
OPG
H
OH
single anomeric
isomer
double anomeric
isomer
Scheme 1 Degradation of reveromycin A (1) into the [5,6]-spiro-
ketal 5
SYNTHESIS 2010, No. 23, pp 3954–3966
x
x.
x
x
.
2
0
1
0
Advanced online publication: 21.10.2010
DOI: 10.1055/s-0030-1258308; Art ID: E28410SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
(–)-Reveromycin A via a Hetero-Diels–Alder Approach
3955
The thermodynamic instability of the reveromycin A isomers I and III close in energy. This has been observed
spiroketal was demonstrated early by a degradation of in the syntheses of the reveromycin A spiroketal that uti-
reveromycin
A
into [5,6]-spiroketal triacetate
5
lized the traditional approach16 of cyclization of a dihy-
(Scheme 1).13a Base hydrolysis and esterification re- droxy ketone precursor under thermodynamic
moved the C18 succinate ester and ozonolysis followed control.11,13a,b
by reductive work-up and acetylation provide the 5,6-
spiroketal 5. This isomerization is driven by the steric in-
teraction in the reveromycin A type [6,6]-spiroketal B I,
Our retrosynthetic analysis of reveromycin A (1) is shown
in Scheme 2. We elected to introduce the C18 succinate
ester at a late stage in the synthesis. Other disconnections
as shown lead to the key alkyne spiroketal intermediate 6.
which is alleviated by formation of the [5,6]-spiroketal
when the C18 tertiary alcohol is free (i.e. I → II).15
The introduction of the C18 and C19 stereocenters would
When the C18 alcohol is protected, isomerization to the involve a stereoselective and regioselective hydroboration
[6,6]-spiroketal single anomeric isomer (i.e. I → III) oc- of the alkene spiroketal 7 from the less hindered face as in-
curs, albeit at the loss of one anomeric stabilization. Thus, dicated. Compound 7, in turn, arises from a stereoselec-
the steric interaction in I makes the two [6,6]-spiroketal tive hetero-Diels–Alder (HDA) reaction17 between the
Biographical Sketches
Mariana El Sous graduated studies, over four years of degenerative diseases. Dr.
with a Ph.D. in synthetic or- drug discovery and drug de- El Sous then entered the
ganic chemistry in 2003 velopment experience was pharmaceutical industry and
under the supervision of acquired in the biotechnolo- has worked in all aspects of
Professor Mark Rizzacasa at gy industry focusing on the intellectual property, clini-
the University of Mel- synthesis of small mole- cal research and regulatory
bourne. After the comple- cules required for the treat- affairs.
tion of her postgraduate ment of cancer and neuro-
Danny Ganame completed spent one year with Profes- search (Melbourne) in 2008
his undergraduate and ho- sor David Soloman (Mel- where he is currently work-
nours studies at La Trobe bourne University) and one ing as a medicinal chemist
University in 1998 and year with Professor Mark in the CRC for Cancer re-
joined Professor Mark Riz- Rizzacasa as a postdoctoral search program developing
zacasa in 2002 for his Ph.D. researcher. He then moved novel anti-tumor small mol-
studies that focused on natu- to The Walter and Eliza Hall ecules.
ral product synthesis. He Institute of Medical Re-
Peter Tregloan carried out University College Dublin, Lausanne in Switzerland,
his undergraduate and post- he returned to Australia to Calgary in Canada, and
graduate studies at The Uni- The University of Mel- Erlangen in Germany. All of
versity of Adelaide. After bourne in 1974. While at these have related to his in-
postdoctoral work at the Melbourne he has held visit- terest in measuring the ef-
University of Kent at Can- ing academic positions on a fects of high pressure on the
terbury, UK, and a lecture- number of occasions at each kinetics and equilibria of re-
ship in physical chemistry at of the universities of actions in solution.
Mark Rizzacasa obtained a fessor Robert E. Ireland’s moted to full Professor in
Ph.D. in 1990 under the research group at the Uni- 2008. His interests include
guidance
of
Professor versity of Virginia. In early the total synthesis of bioac-
Melvyn Sargent at the Uni- 1993, he then returned to tive natural products and the
versity of Western Austra- Australia to begin an ap- development of synthetic
lia. He then moved on to the pointment in the School of methodologies.
USA and spent two years as Chemistry at the University
a postdoctoral fellow in Pro- of Melbourne and was pro-
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

3956
M. El Sous et al.
FEATURE ARTICLE
Table 1 Conditions for the Hetero-Diels–Alder Synthesis Spiro-
ketal 13
Entry Additive
(mol%)
Solvent
Temp
(°C)
Time Yield (%)
(d)
of 13
1
2
3
4
K2CO3 (25)
toluene
toluene
toluene
hexane
110
110
0
1
14
K2CO3 (50)
Eu(fod)3 (5)
Eu(fod)3 (5)
1
38
3
32
0
3
86
driven exo to endo isomerization of the dienophile 12
(Table 1). However, this afforded the spiroketal 13 in low
yields. We next turned to Lewis acids and found
12,19,20
Eu(fod)3
was the best at catalyzing the HDA reac-
tion between 8 and 12 with hexane the optimal solvent
giving 13 in excellent yield.
H
OTBS
O
H
O
OBn
n-Bu
OH
H
Scheme 2 Retrosynthetic analysis of reveromycin A (1)
O
OTBS
7
see Table 2
n-Bu
+
8
+
a,b-unsaturated ketone diene 8 and the optically pure
methylenepyran dienophile 9.10e The [4+2] cycloaddition
proceeds via the TS‡ shown where the diene approaches
the dienophile with the ketone oxygen atom in an axial
orientation.17 This kinetic HDA approach would deliver
the reveromycin A spiroketal 6 in a stereoselective man-
ner with all the stereochemistry of the spiroketal con-
trolled by the stereocenters present in the methylene pyran
9.10e,13c
9
H
O
OTBS
OBn
14
Scheme 4 HDA synthesis of the reveromycin A spiroketal 7
Table 2 HDA Synthesis of the Reveromcyin A Spiroketal 7
The preparation of the required diene and a model HDA
reaction is shown in Scheme 3. Lithiation of stannane 1018
followed by addition to butylacrolein afforded the allylic
alcohol 11 in good yield. Oxidation with Dess–Martin pe-
riodinane then gave the heterodiene 8. The model dieno-
phile 12 was prepared by base-induced elimination of 2-
(chloromethyl)tetrahydropyran.10e
Entry Additive (mol%) Solvent
Temp Time Yield (%)
(°C)
110
110
0
(d)
(ratio 7/14)
1
2
3
4
K2CO3 (50)
K2CO3 (50)
Eu(fod)3 (15)
Eu(fod)3 (15)
toluene
neat
1
11 (1:0)
1
26 (1:0)
MeCN
neat
2
35 (1:1.3)
59 (2:1)
0
3
Initial attempts at the HDA between 8 and 12 involved the
use of potassium carbonate as additive,10e,13c,15 which ef-
fectively reduced the amount of the thermodynamically
We next examined the HDA between diene 8 and the
known dienophile 9, utilized in our total synthesis of
reveromycin B (2)10e (Scheme 4). Again, we found that
base additives gave low yields of the spiroketal 7, howev-
er, gratifyingly, only one spiroketal stereoisomer was de-
tected (Table 2). With Eu(fod)3 as catalyst (higher loading
of 15 mol%) the spiroketal 7 was formed in low yield
along with the ene product 14 as a mixture of diastereo-
isomers with the best solvent being acetonitrile. The best
yields of spiroketal 7 were obtained when the HDA reac-
tion was conducted in the absence of solvent20 at 0 °C us-
ing 15 mol% Eu(fod)3. Although the formation of the ene
product 14 could not be suppressed, we were able to syn-
n-Bu
Dess–Martin
reagent
n-BuLi
BnO
n-Bu
SnBu3
CH2Cl2
96%
OH
10
OBn
n-Bu
CHO
83%
11
O
O
O
see Table 1
+
O
OBn
12
OBn
n-Bu
8
13
Scheme 3
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

FEATURE ARTICLE
(–)-Reveromycin A via a Hetero-Diels–Alder Approach
3957
H
H
δC 97.0
OTBS
OTBS
O
O
TBSOTf
BH3⋅THF
cat. CSA
2,6-Lutidine
7
H
H
O
O
15
CH2Cl2
97%
H2O2, NaOH
72%
97%
HO
TBSO
OBn
OR
n-Bu
n-Bu
17 R = Bn
H2
Pd(OH)2
H
H
15
δC 106.2
H
H
18 R = H; 95%
H
OTBS
1) TBAF
O
H
OAc
O
H
1) DMP
O
O
OR
H 3.84
O
O
O
2)
11
n-Bu
2) H2, Pd/C
3) Ac2O, py
n-Bu
P(OMe)2
H
OBn
OAc
δ
O
OH
TBSO
OAc
N2
75%
16
5
19
n-Bu
MeOH, K2CO3
88% for 2 steps
6 R = TBS
19 R = H; 87%
H
TBAF
THF, r.t.
Scheme 5 Conversion of HDA [6,6]-spiroketal adduct 7 into rever-
omycin A degradation product 5,6-spiroketal 5
δH 4.26
H
1) DMP
thesize multigram quantities of spiroketal 7 using this pro-
cedure.
O
2) Ph3P=C(Me)CHO
3) Ph3P=CHCO2Me
79% for 3 steps
CO2Me
H
O
Hydroboration of 7 with borane–tetrahydrofuran proceed-
ed in good yield and high stereoselectivity to afford the
double anomeric reveromycin A type [6,6]-spiroketal 15
(Scheme 5). The stereochemistry of 15 was then verified
by its conversion into the known reveromycin A (1) deg-
radation product [5,6]-spiroketal 5. When [6,6]-spiroketal
15 was treated with 10-camphorsulfonic acid, complete
isomerization to the reveromycin B type [5,6]-spiroketal
16 as expected.15 The characteristic downfield change in
the chemical shift21 of the spiro carbon in going from a
[6,6]- to a [5,6]-spiroketal confirmed that isomerization
had occurred. This supports the stereochemical assign-
ment of the HDA adduct 7 as shown as well as alcohol 15.
Removal of the tert-butyldimethylsilyl (TBS) ether in 16
followed by hydrogenolysis and acetylation afforded 5,6-
spiroketal 5, the data of which was identical to that report-
TBSO
20
n-Bu
H
Scheme 6 Synthesis of E,E-diene ester 20
Evans’ aldol reaction proved to be the best method.24
Thus, condensation of the aldehyde 21 with the tin enolate
derived from oxazolidine-2-thione 2210e afforded the ad-
duct 23 in excellent yield for the three steps. Reduction of
23 gave diol 24, which upon treatment with tetrabutylam-
monium fluoride at 50 °C in tetrahydrofuran induced re-
moval of the hindered TBS group and subsequent
protection of the 1,3-diol gave bis-TBS ether 25. We next
examined a method for the key succinylation of the tertia-
ry alcohol in 25.
29
ed:13a,b [a]D +45.6 (c 1.0, CHCl3) {Lit.13a (naturally de-
H
rived) [a]D +39.1 (c 0.13, CHCl3); Lit.13a (synthetic) [a]D
+44.3 (c 0.18, CHCl3)}. This sequence unequivocally
confirmed the stereochemistry of [6,6]-spiroketal 15.
1) DIBAL-H
2) DMP
O
CHO
20
H
O
TBSO
The introduction of the C1–C10 side chain began with
protection of the hindered tertiary alcohol in 15 to give
TBS ether 17 (Scheme 6). Careful hydrogenolysis of 17
then afforded alcohol 18 in good yield. Extended reaction
times for the hydrogenolysis resulted in some isomeriza-
tion of 18 to the corresponding single anomeric [6,6]-
spiroketal. Oxidation of 18 gave the aldehyde, which was
converted into key alkyne intermediate 6 using the one-
pot Bestmann–Ohira protocol.22 The 1H NMR signals for
H19 and H11 (reveromycin numbering) appeared at the
expected chemical shifts (see Scheme 6) when compared
to related double anomeric [6,6]-spiroketals.13b,23 Remov-
al of the primary TBS ether gave alcohol 19 which on ox-
idation and sequential Wittig reactions with stabilized
ylides gave the E,E-diene ester 20.
n-Bu
H
21
i-Pr
H
Sn(OTf)2
N-ethylpiperidine
O
N
O
S
O
H
OH
O
S
O
N
O
TBSO
23
i-Pr
n-Bu
H
22
87% for 3 steps
H
OR1
NaBH4
O
THF, H2O
OR1
24 R1 = H; R2 = TBS
25 R1 = TBS; R2 = H; 65%
H
O
89%
R2O
n-Bu
H
1) TBAF, 50 °C
2) TBSCl, imid.
Reduction of ester 20 followed by oxidation gave labile
a,b,g,d-unsaturated aldehyde 21, which was used immedi-
ately in the aldol reaction (Scheme 7). After considerable
experimentation, we found that the Nagao variant of the
Scheme 7 Installation of the C4 and C5 stereochemistry by an
asymmetric syn-aldol reaction
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

3958
M. El Sous et al.
FEATURE ARTICLE
Conventional methods for acylation failed to provide any
succinylated product, which reflected the hindered nature
of the C18 alcohol in the spiroketal. In addition, due to the
propensity of the [6,6]-spiroketal in 25 to easily isomerize
to the [5,6]-spiroketal, Lewis acid based reagents for acy-
lation of hindered alcohols, such as Sc(OTf)3,25 had to be
avoided. We next examined the use of high pressure in the
N,N¢-dicyclohexylcarbodiimide/4-(dimethylamino)pyri-
dine-mediated succinylation of tertiary alcohols as report-
ed by Shimizu and co-workers.11,26 This involves the use
of 1.5 GPa (15 kbar) pressure to form succinate esters
from tertiary alcohols and succinic acid monoesters. In or-
der to improve this approach, we elected to test the high
pressure succinylation using a simple apparatus that oper-
ates at a much lower pressure of ~0.4 GPa (4 kbar).
The apparatus utilized is shown in Figure 2. Substrate, re-
agents and solvent are placed in a Teflon sampler tube
which is then inserted into the high-pressure upper sample
chamber of the steel cylinder. The chamber is then com-
pletely filled with high-pressure oil and sealed off with the
small-bore piston while ensuring that any air bubbles are
removed. The cylinder is screwed into the base and pres-
sure is introduced manually via a hydraulic pump, which
forces fluid into the low-pressure chamber to a maximum
of 0.1 GPa (1 kbar). The pressure displaces the large-bore
piston and applies force to the small-bore piston such that
the pressure generated in the cylinder is greater than that
applied by the ratio of areas of the two pistons.27 In this
apparatus design, the pressure in the small reaction cylin-
der is increased fourfold, resulting in the generation of 0.4
GPa (4 kbar) (maximum instrument capacity) of pressure
being exerted onto the Teflon sampler. While this pres-
sure is considerably lower than that utilized by Shimizu,26
we anticipated that it would be sufficient enough to effect
succinylation.
Figure 2
chose the 2-(trimethylsilyl)ethyl (Tmse) ester28 protecting
group. This would allow for a fluoride-mediated global
deprotection to be utilized as the final step to cleave both
the ester (Tmse) and alcohol (TBS) protecting groups.
High pressure acylation of 26 using the half acid 2710e and
N,N¢-dicyclohexylcarbodiimide/4-(dimethylamino)pyri-
dine in dichloromethane at 0.4 GPa for 72 hours provided
an excellent yield of the succinate ester 28 with no detect-
able isomerization of the spiroketal. A downfield shift of
the signal for H19 in was observed the 1H NMR spectrum
supporting C19 acylation. Acylation of the more complex
spiroketal 25 with 27 at 0.4 GPa also proceeded in high
yield to afford the desired succinate ester 29. Selective re-
The high-pressure succinylation was initially tested on a
model system derived from spiroketal 6 as shown in
Scheme 8. Removal of both TBS ethers followed by se-
lective reprotection of the primary alcohol gave the tertia-
ry alcohol 26 in good yield. For the succinate residue, we
H
H
CO2Tmse
CO2H
TmseO2C
OTBS
O
OTBS
C 95.4
27
O
H
DCC, DMAP
CH2Cl2
O
O
H
RO 18
n-Bu
O
δ
O
0.4 GPa
19
n-Bu
H
28
H 4.83
Tmse = trimethylsilylethyl
92%
H
6 R = TBS
TBAF
then TBSCl
imidazole
δ
26 R = H; 93%
H
CO2Tmse
27
OR
25
O
DCC, DMAP
CH2Cl2
O
H
OTBS
O
0.4 GPa
O
96%
29 R = TBS
30 R = H; 85%
n-Bu
HF⋅pyridine
H
pyridine THF
Scheme 8 High-pressure succinylation reactions
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

FEATURE ARTICLE
(–)-Reveromycin A via a Hetero-Diels–Alder Approach
3959
H
CO2Tmse
Bu3SnH
30
OH
O
Pd(Ph3P)2Cl2
56%
O
H
H
OTBS
O
O
SnBu3
31
n-Bu
H
I
CO2Tmse
TmseO2C
32
OH
O
Pd2(dba)3, TFP
NMP, 60 °C
O
H
OTBS
CO2Tmse
O
O
22
58%
n-Bu
H
33
CO2R1
H
O
CO2R1
1) DMP
OR2
O
H
O
2) Ph3PCHCO2Tmse
88%
CO2R1
O
n-Bu
H
34 R1 = Tmse; R2 = TBS
1 R1 = R2 = H; 94%
TBAF
DMF
Scheme 9 Completion of the total synthesis of reveromycin A (1)
moval of the primary TBS group afforded alcohol 30 MeOH)}. In addition, synthetic 1 possessed an identical
ready for introduction of the C20–C25 diene. RP-HPLC retention time to that of a natural sample.
Palladium-catalyzed hydrostannylation of the alkyne 30 The total synthesis of (–)-reveromycin A (1) has been
(Scheme 9) proved somewhat difficult owing to steric achieved which utilizes a Lewis acid catalyzed inverse
hindrance. It was discovered that the slow addition of pal- electron demand hetero-Diels–Alder reaction to synthe-
ladium catalyst at two hour intervals (up to 70 mol% over size the [6,6]-spiroketal core of this complex natural prod-
9 h) as well as the addition of excess tributyltin hydride (8 uct. In addition, a modified high pressure succinylation
equiv), was required for complete consumption of the was utilized to introduce the C18 succinate ester. Other
starting alkyne 30. Under these optimized conditions, the key steps in the sequence included a stereo- and regio-
E-vinyl stannane 31 was obtained in 56% yield. A small selective hydroboration to form the C18 and C19 stereo-
amount of C19 alkene was also isolated, which was centers, a tin-mediated asymmetric syn-aldol reaction to
formed by protodestannylation29 during the reaction and introduce the C4 and C5 stereocenters and a Stille cross
not during isolation and purification. A Stille cross- coupling to form the C21–C22 bond.
coupling30 reaction between stannane 31 and vinyl iodide
3210e using modified Farina conditions31 gave the desired
1H NMR (400 MHz, 500 MHz) and proton decoupled 13C NMR
tetraene 33 along with a small amount of the C22 geomet-
ric isomer which could be removed by HPLC. Careful ox-
idation of the primary alcohol in 33 with Dess–Martin
periodinane buffered with excess pyridine followed by
Wittig extension with excess 2-(trimethylsilyl)ethyl
(triphenylphosphoranylidene)acetate32 generated fully
protected reveromycin A 34. Concomitant removal of all
the protecting groups (Tmse and TBS) was achieved by
exposure of 34 to excess tetrabutylammonium fluoride in
N,N-dimethylformamide at ambient temperature over 48
hours to afford (–)-reveromycin A (1), which was purified
by reverse-phase chromatography (C18 SPE cartridge,
900 mg) with a 40 to 60% methanol–water solvent gradi-
ent as eluent. Synthetic 1 was identical to that of natural
(–)-reveromycin A (1) in all respects (NMR, IR, UV,
HRMS) including the sign and magnitude of specific ro-
tation: [a]D22 –122.4 (c 0.16, MeOH) {Lit.1b [a]D23 –115 (c
(100 MHz, 125 MHz, and 200 MHz) were measured in CDCl3 with
residual CHCl3 as internal standard unless otherwise stated. Optical
rotations were recorded for 1 mL solns and units are deg·cm2·g–1.
Flash chromatography was carried out on silica gel 60. Analytical
TLC was conducted on aluminum-backed 2 mm thick silica gel 60
GF254 and chromatograms were visualized with 20% w/w phospho-
molybdic acid in EtOH. HRMS were obtained by ionizing samples
via electron spray ionization (ESI). Anhyd THF, Et2O, CH2Cl2 were
dried using a solvent cartridge system. Anhyd MeOH was distilled
from Mg(OMe)2. All other solvents were purified by standard meth-
ods. PE used refers to petroleum ether bp 40–60 °C. All other com-
mercially available reagents were used as received.
1-(Benzyloxy)-3-methyleneheptan-2-ol (11)
A soln of 2.1 M BuLi in hexanes (1.3 mL, 2.79 mmol) was added
dropwise to a soln of the stannane 10 (1.15 g, 2.79 mmol) in anhyd
THF (12 mL) under argon and the resulting yellow soln was stirred
at –78 °C for 15 min. A soln of butylacrolein (344 mg, 410 mL, 2.79
mmol) in anhyd THF (1 mL) was then added dropwise and the soln
turned colorless. The mixture was stirred at –78 °C for 30 min and
Et2O and H2O were then added. The organic extract was washed
with H2O, dried (MgSO4), and the solvent removed under reduced
22
0.1, MeOH); Lit.11 (synthetic) [a]D –122.4 (c 0.16,
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

3960
M. El Sous et al.
FEATURE ARTICLE
pressure. Purification by flash chromatography (10% EtOAc–PE)
provided the allylic alcohol 11 (543 mg, 83%) as a colorless oil;
TLC: Rf = 0.27 (10% EtOAc–PE).
Spiroketal 7 and Alkene 14
To a cooled (0 °C) mixture of the dienophile 910e (878 mg, 3.25
mmol) and the diene 8 (1.0 g, 4.30 mmol) was added Eu(fod)3 (570
mg, 0.549 mmol) and the resulting mixture stirred at 0 °C for 3 d.
Et2O and H2O were added to the mixture and the organic extract was
washed with 1% HCl, H2O, and brine, dried (MgSO4), filtered, and
concentrated. Purification was achieved by flash chromatography
(2.5% EtOAc–PE) to give the spiroketal adduct 7 (639 mg, 39%) as
a colorless oil. Further elution (5% EtOAc–PE) gave the alkene 14
(320 mg, 20%) as a colorless oil.
IR (thin film): 3439, 3060, 3026, 2952, 2857, 1647, 1493, 1451,
1102 cm–1.
1H NMR (300 MHz): d = 0.90 [t, J = 7.5 Hz, 3 H, (CH2)3CH3],
1.26–1.48 [m, 4 H, (CH2)2CH3], 1.91–2.12 (m, 2 H, CH2C=CH2),
2.36 (br s, 1 H, OH), 3.37–3.43 (dd, J = 9.6, 8.4 Hz, 1 H, CH2OBn),
3.57–3.61 (dd, J = 9.6, 3 Hz, 1 H, CH2OBn), 4.28–4.32 (dd, J = 8.1,
2.9 Hz, 1 H, CHOH), 4.58 (s, 2 H, CH2Ph), 4.93 (s, 1 H, C=CH2),
5.13 (s, 1 H, C=CH2), 7.30–7.37 (m, 5 H, ArH).
Spiroketal 7
TLC: Rf = 0.48 (5% EtOAc–PE).
[a]D21 +55.0 (c 0.15, CH2Cl2).
13C NMR (75.5 MHz): d = 13.9, 22.5, 30.1, 32.2, 73.3, 73.8, 110.5,
127.7, 127.8, 128.4, 137.8, 148.2.
Anal. Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.64; H,
9.47.
IR (thin film): 3032, 2956, 2931, 2860, 1462 (C=C), 1256, 1160,
1089, 982 cm–1.
1H NMR (300 MHz): d = –0.004 [s, 3 H, Si(CH3)2C(CH3)3], 0.003
[s, 3 H, Si(CH3)2C(CH3)3], 0.82 (d, J = 6.6 Hz, 3 H, CH3-12), 0.86
[s, 9 H, Si(CH3)2C(CH3)3], 0.87 (t, J = 6.6 Hz, 3 H, CH3-28), 1.20–
2.30 (m, 17 H, H10, H12–14, H16–17, H25–27), 3.41 (dt, J = 9.9,
2.1 Hz, 1 H, H9), 3.49 (dt, J = 9.6, 6 Hz, 1 H, H11), 3.71 (dt, J = 9.9,
5.1 Hz, 1 H, H9), 3.98 (ABq, J = 11.4 Hz, 2 H, CH2OBn), 4.56
(ABq, J = 12.3 Hz, 2 H, CH2Ph), 7.26–7.38 (m, 5 H, ArH).
13C NMR (75.5 MHz): d = –5.3, –5.3, 14.0, 17.7, 18.3, 21.8, 22.7,
25.9, 27.9, 31.3, 31.5, 32.0, 34.7, 34.9, 36.5, 60.7, 66.7, 71.8, 73.1,
94.6, 113.3, 127.3, 127.5, 128.2, 138.7, 141.2.
1-(Benzyloxy)-3-methyleneheptan-2-one (8)
To a soln of the alcohol 11 (802 mg, 3.42 mmol) in anhyd CH2Cl2
(10 mL) under an argon atmosphere was added Dess–Martin perio-
dinane (2.05 g, 4.78 mmol) at r.t. The mixture was stirred for 2.5 h
under argon and then Et2O, sat. aq NaHCO3 (30 mL), and aq 1.5 M
Na2S2O3 (30 mL) were added and the mixture was stirred until both
layers were clear. The organic extract was washed with a mixture of
sat. aq NaHCO3–1.5 M aq Na2S2O3 (1:1), then washed with H2O
and brine, and dried (MgSO4), and the solvent was removed under
reduced pressure. Purification by chromatography (10% EtOAc–
PE) provided the unstable ketone 8 (767 mg, 96%) as a colorless oil,
which was used immediately in the Diels–Alder reaction; TLC:
Rf = 0.36 (10% EtOAc–PE).
HRMS (ESI): m/z [M + Na]+ calcd for C30H50O4SiNa: 525.3376;
found: 525.3355.
Anal. Calcd for C30H50O4Si: C, 71.66; H, 10.02. Found: C, 71.80;
H, 10.00.
IR (thin film): 3061, 3027, 2952, 2857, 1689 (C=O), 1647, 1493,
1451 cm–1.
1H NMR (300 MHz): d = 0.90 [t, J = 7.2 Hz, 3 H, (CH2)3CH3],
1.28–1.42 [m, 4 H, (CH2)2CH3], 2.26–2.30 (t, J = 6.6 Hz, 2 H,
CH2C=CH2), 4.48 (s, 2 H, CH2OBn), 4.62 (s, 2 H, CH2Ph), 5.73 (s,
1 H, C=CH2), 5.90 (s, 1 H, C=CH2), 7.30–7.39 (m, 5 H, ArH).
13C NMR (75.5 MHz): d = 13.7, 22.3, 30.3, 30.5, 71.9, 73.2, 123.7,
127.8, 127.9, 128.4, 137.4, 147.1, 197.7.
Alkene 14
TLC: Rf = 0.36 (5% EtOAc–PE).
IR (thin film): 3528, 2957, 2930, 2859, 1682 (C=C), 1471 (C=C),
1255, 1095, 836 cm–1.
1H NMR (300 MHz): d = 0.002 [s, 6 H, Si(CH3)2C(CH3)3], 0.83 [t,
J = 3 Hz, 3 H, (CH2)3CH3], 0.84 [s, 9 H, Si(CH3)2C(CH3)3], 0.87 (d,
J = 1.5 Hz, 3 H, CH3-3), 1.08–1.96 (m, 12 H, H3, H4,
CH2CH2OTBS, (CH2)3CH3, OH), 2.21–2.42 (m, 2 H, H1¢), 3.26–
3.45 (m, 3 H, CH2OTBS, CH2OBn), 3.51 (dt, J = 8.1, 2.7 Hz, 1 H,
H2), 3.67 (m, 1 H, CH2OTBS), 4.41 (m, 1 H, H5), 4.51 (s, 2 H,
CH2Ph), 4.86 (s, 1 H, C=CH2), 5.13 (s, 1 H, C=CH2), 7.26–7.28 (m,
5 H, ArH).
13C NMR (75.5 MHz): d = –5.3, 14.1, 17.7, 18.3, 22.8, 25.9, 28.7,
29.7, 30.5, 30.6, 31.1, 35.7, 41.1, 59.6, 73.5, 75.4, 77.3, 77.6, 77.7,
98.7, 109.4, 127.5, 127.7, 128.2, 138.4, 149.8, 149.9, 151.6.
HRMS (ESI): m/z [M + Na]+ calcd for C30H50O4SiNa: 525.3376;
found: 525.3382.
Spiroketal 13
To a mixture of the diene 8 (154 mg, 0.663 mmol) in anhyd hexanes
(2 mL) was added a soln of the dienophile 12 (228 mg, 2.32 mmol)
in anhyd hexanes (3 mL). The mixture was cooled to 0 °C and
Eu(fod)3 (33 mg, 0.0321 mmol) was added and the resulting mixture
stirred at 0 °C for 3 d. Et2O and H2O were added to the mixture and
the organic extract was washed with 2% HCl, H2O, and brine, dried
(MgSO4), filtered, and concentrated. Purification was achieved by
flash chromatography (2.5% EtOAc–PE) to give the spiroketal ad-
duct 13 (188 mg, 86%) as a colorless oil; TLC: Rf = 0.65 (5%
EtOAc–PE).
IR (thin film): 2955, 2931, 2872, 2859, 1681, 1623, 1454, 1228,
1155, 1030, 981 cm–1.
1H NMR (300 MHz): d = 0.86 [t, J = 6.9 Hz, 3 H, (CH2)3CH3],
1.21–2.26 [m, 16 H, H4, H5, H9–H11, (CH2)3CH3], 3.61 (m, 1 H,
H8), 3.87 (dt, J = 11.4, 3.3 Hz, 1 H, H8), 4.04 (s, 2 H, CH2OBn),
4.57 (ABq, J = 12.3 Hz, 2 H, CH2Ph), 7.27–7.39 (m, 5 H, ArH).
13C NMR (75.5 MHz): d = 14.0, 18.5, 21.3, 22.5, 25.4, 31.2, 31.3,
32.2, 34.6, 61.4, 66.7, 71.8, 94.7, 113.3, 127.4, 127.6, 128.2, 138.7,
141.4.
Spiroketal Alcohol 15
To a stirred soln of the spiroketal 7 (370 mg, 0.746 mmol) in anhyd
THF (7 mL) cooled to 0 °C under an argon atmosphere was added
1 M borane–THF complex (2.61 mL, 2.611 mmol) dropwise. After
3 h at 0 °C, the mixture was quenched by the slow addition of aq 1
M NaOH (3.5 mL) and aq 30% H2O2 (0.57 mL) and the resulting
mixture was stirred at r.t. for 18 h. The mixture was diluted with
Et2O and H2O and the organic extract was washed with H2O and
brine, dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(15% EtOAc–PE) to give the reveromycin A spiroketal 15 (281 mg,
72%) as a colorless oil; TLC: Rf = 0.32 (10% EtOAc–PE).
HRMS (ESI): m/z [M + Na]+ calcd for C21H30O3Na: 353.2093;
found: 353.2086.
[a]D21 +34.7 (c 0.75, CH2Cl2).
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

FEATURE ARTICLE
(–)-Reveromycin A via a Hetero-Diels–Alder Approach
3961
IR (thin film): 3446 (OH), 2957, 2861, 1650 (C=C), 1459, 1253,
1086, 973 cm–1.
IR (thin film): 2958, 2934, 2874, 1744 (C=O), 1459, 1438, 1371,
1243, 1187, 1047 cm–1.
1H NMR (300 MHz): d = 0.047 [s, 6 H, Si(CH3)2C(CH3)3], 0.82 (d,
J = 6 Hz, 3 H, CH3-12), 0.88 [s, 9 H, Si(CH3)2C(CH3)3], 0.90 (t,
J = 6.6 Hz, 3 H, CH3-28), 1.20–1.88 (m, 16 H, H10, H13, H14, H16,
H17, H25–H27), 2.27–2.32 (m, 1 H, H12), 2.76 (s, 1 H, OH), 3.56–
3.73 (m, 6 H, H9, H11, H19, CH2OBn), 4.48 (ABq, J = 11.7 Hz, 2
H, CH2Ph), 7.26–7.34 (m, 5 H, ArH).
13C NMR (100 MHz): d = –5.2, –5.2, 14.1, 17.9, 18.3, 23.4, 24.5,
26.0, 27.5, 29.7, 29.8, 31.8, 33.6, 34.8, 36.3, 59.2, 70.1, 71.3, 72.3,
73.6, 76.0, 97.0, 127.8, 127.9, 128.5, 137.5.
1H NMR (300 MHz): d = 0.85 (d, J = 6.3 Hz, 3 H, CH3-12), 0.89 (t,
J = 7.2 Hz, 3 H, CH3-28), 1.18–2.00 (m, 17 H, H10, H12–H14,
H16, H17, H25–H27), 2.02 (s, 3 H, COCH3), 2.03 (s, 3 H, COCH3),
2.06 (s, 3 H, COCH3), 3.48 (dt, J = 11.1, 2.7 Hz, 1 H, H11), 4.15 (m,
1 H, H9), 4.21 (dd, J = 12.0, 9.0 Hz, 1 H, H20), 4.30 (m, 1 H, H9),
4.50 (dd, J = 12, 2.3 Hz, 1 H, H20), 5.17 (dd, J = 8.7, 2.3 Hz, 1 H,
H19).
13C NMR (75.5 MHz): d = 14.1, 17.7, 20.9, 21.0, 21.1, 23.2, 25.5,
29.0, 31.4, 32.2, 34.3, 34.5, 34.6, 38.4, 61.7, 63.9, 73.6, 76.5, 86.2,
106.9, 170.3, 171.1.
HRMS (ESI): m/z [M + Na]+ calcd for C30H52O5SiNa: 543.3482;
found: 543.3464.
Anal. Calcd for C23H38O8: C, 62.42; H, 8.65. Found: C, 62.19; H,
8.36.
5,6-Spiroketal 16
To a soln of the alcohol 15 (35.9 mg, 0.069 mmol) in anhyd CH2Cl2
(4 mL) was added 6.9 mM CSA in CH2Cl2 (110 mL, 0.76 mmol) and
the soln was stirred at r.t. for 2 h. Sat. aq NaHCO3 and Et2O were
added and the organic extract was separated and washed with sat. aq
NaHCO3, H2O, and brine, dried (MgSO4), filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (10% EtOAc–PE) to give the reveromycin B
spiroketal 16 (34.9 mg, 97%) as a colorless oil; TLC: Rf = 0.66 (10%
EtOAc–PE).
Spiroketal 17
To a soln of the alcohol 15 (378 mg, 0.727 mmol) in CH2Cl2 (6 mL)
at 0 °C under argon was added 2,6-lutidine (467 mg, 508 mL, 4.36
mmol) and TBSOTf (961 mg, 636 mL, 3.63 mmol) and the resulting
mixture was stirred at r.t. for 15 h. Sat. aq NaHCO3 and Et2O were
added and the mixture was stirred vigorously for 30 min. The aque-
ous phase was extracted with Et2O and the combined organic ex-
tracts were washed with H2O, sat. aq CuSO4, sat. aq NaHCO3, H2O,
and brine, dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification of the crude product by flash chromatography
(2.5–5% EtOAc–PE) gave the TBS ether 17 (450 mg, 97%) as a col-
orless oil; TLC: Rf = 0.61 (5% EtOAc–PE).
[a]D23 +26.9 (c 1.09, CH2Cl2).
IR (thin film): 3446 (OH), 2957, 2861, 1650, 1459, 1253, 1086,
1033 cm–1.
[a]D20 –5.2 (c 1.24, CH2Cl2).
1H NMR (300 MHz): d = 0.048 [s, 3 H, Si(CH3)2C(CH3)3], 0.053 [s,
3 H, Si(CH3)2C(CH3)3], 0.84 (d, J = 6 Hz, 3 H, CH3-12), 0.88 (t,
J = 7.8 Hz, 3 H, CH3-28), 0.89 [s, 9 H, Si(CH3)2C(CH3)3], 1.23–
2.01 (m, 17 H, H10, H12–H14, H16, H17, H25–H27), 2.28–2.39
(m, 1 H, OH), 3.43–3.50 (m, 2 H, H9, H11), 3.59–3.63 (dd, J = 9.9,
3.3 Hz, 1 H, H20), 3.66–3.79 (m, 2 H, H9, H20), 3.81–3.84 (dd,
J = 6.6, 3.3 Hz, 1 H, H19), 4.57 (s, 2 H, CH2Ph), 7.32–7.34 (m, 5 H,
ArH).
13C NMR (75.5 MHz): d = –5.2, 14.1, 17.8, 18.3, 23.3, 25.5, 26.0,
29.0, 29.2, 34.0, 34.9, 36.0, 36.4, 39.3, 59.7, 71.2, 73.3, 74.0, 75.0,
89.7, 106.2, 127.4, 127.6, 128.3, 138.4.
HRMS (ESI): m/z [M + Na]+ calcd for C30H52O5SiNa: 543.34817;
found: 543.34983.
IR (thin film): 2956, 2929, 2858, 1472, 1463, 1361, 1256, 1088,
835, 774 cm–1.
1H NMR (300 MHz): d = 0.012 [s, 6 H, Si(CH3)2C(CH3)3], 0.003 [s,
3 H, Si(CH3)2C(CH3)3], 0.031 [s, 3 H, Si(CH3)2C(CH3)3], 0.75–0.82
[m, 24 H, 2 Si(CH3)2C(CH3)3, CH3-12, CH3-28], 1.01–1.87 (m, 16
H, H10, H13, H14, H16, H17, H25–H27), 2.25 (td, J = 13.8, 3.0 Hz,
1 H, H12), 3.35–3.41 (m, 2 H, H19, H20), 3.59–3.78 (m, 4 H, H9,
H11, H20), 4.50 (ABq, J = 12.3, Hz, 2 H, CH2Ph), 7.17–7.27 (m, 5
H, ArH).
13C NMR (75.5 MHz): d = –5.2, –5.1, –1.8, –1.7, 14.2, 17.9, 18.3,
18.4, 23.3, 24.9, 25.8, 26.1, 27.2, 29.0, 31.2, 32.2, 34.4, 35.1, 36.6,
59.4, 69.9, 72.8, 73.3, 74.3, 80.1, 96.6, 127.2, 127.4, 128.2, 139.0.
HRMS (ESI): m/z [M + Na]+ calcd for C36H66O5Si2Na: 657.4346;
Triacetate 5
found: 657.4330.
To a cooled (0 °C) soln of the alcohol 16 (34.9 mg, 0.067 mmol) in
anhyd THF (2 mL) was added TBAF (136 mg, 0.430 mmol) and the
yellow soln was stirred at r.t. for 18 h. Et2O and H2O were added and
the organic extract was washed with H2O and brine, dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (5% EtOAc–PE) to give
the diol (25.6 mg, 94%) as a colorless oil. To a soln of the diol (23.0
mg, 0.057 mmol) in anhyd MeOH (4 mL) was added Pd(OH)2 (12
mg) and the resulting suspension was stirred for 2 h under an atmo-
sphere of H2 gas. The catalyst was removed by filtration through
Celite and the filter cake was washed with EtOAc. The filtrate was
concentrated under reduced pressure to give the crude triol as an oil
which was dissolved in anhyd pyridine (1 mL) and Ac2O (0.5 mL),
and DMAP (5 mg) was then added. The resulting mixture was
stirred for 18 h under argon at r.t. and the solvents were removed un-
der reduced pressure. The brown residue was purified by flash chro-
matography (15% EtOAc–PE) to afford the triacetate 5 (20 mg,
80%) as a low melting colorless solid; mp 58–59 °C; TLC: Rf = 0.28
(15% EtOAc–PE).
Spiroketal Alcohol 18
To a soln of the benzyl ether 17 (374 mg, 0.589 mmol) in anhyd
MeOH (10 mL) was added Pd(OH)2 (50 mg) and the resulting sus-
pension was stirred for 20 h under an atmosphere of H2 gas. The cat-
alyst was removed by filtration through Celite and the filter cake
was washed with EtOAc. The filtrate was concentrated under re-
duced pressure to give the crude alcohol as a colorless oil. Purifica-
tion by flash chromatography (5% EtOAc–PE) gave the alcohol 18
(304 mg, 95%) as an oil; TLC: Rf = 0.44 (5% EtOAc–PE).
[a]D32 +12.8 (c 1.35, CH2Cl2).
IR (thin film): 3436 (OH), 2956, 2930, 2859, 1472, 1463, 1256,
1086, 835 cm–1.
1H NMR (300 MHz): d = 0.062 [s, 3 H, Si(CH3)2C(CH3)3], 0.072 [s,
3 H, Si(CH3)2C(CH3)3], 0.099 [s, 3 H, Si(CH3)2C(CH3)3], 0.12 [s, 3
H, Si(CH3)2C(CH3)3], 0.80–0.93 (m, 6 H, CH3-12, CH3-28), 0.86 [s,
9 H, Si(CH3)2C(CH3)3], 0.90 [s, 9 H, Si(CH3)2C(CH3)3], 1.25–1.92
(m, 16 H, H10, H13, H14, H16, H17, H25–H27), 2.24 (m, 1 H,
H12), 2.33 (br s, 1 H, OH), 3.45 (dd, J = 7.5, 3.3 Hz, 1 H, H19),
3.65–3.77 (m, 5 H, H9, H11, H20).
[a]D29 +45.6 (c 1.0, CHCl3) {Lit.13a (naturally derived) [a]D +39.1 (c
0.13, CHCl3); Lit.13a (synthetic) [a]D +44.3 (c 0.18, CHCl3); Lit.13b
(synthetic) [a]D25 +37.5 (c 1.0, CHCl3)}.
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

3962
M. El Sous et al.
FEATURE ARTICLE
13C NMR (75.5 MHz): d = 5.3, –5.2, –1.9, –1.8, 14.1, 17.9, 18.3,
23.2, 24.8, 25.8, 26.0, 27.6, 30.1, 30.9, 33.2, 34.1, 34.8, 36.3, 59.2,
61.9, 72.9, 74.6, 80.1, 96.6.
HRMS (ESI): m/z [M + Na]+ calcd for C24H44O4SiNa: 447.2907;
found: 447.2901.
Diene Ester 20
HRMS (ESI): m/z [M + Na]+ calcd for C29H60O5Si2Na: 567.3877;
To a soln of the alcohol 19 (79 mg, 0.186 mmol) in CH2Cl2 (1.8 mL)
was added Dess–Martin periodinane (157 mg, 0.372 mmol) and the
resulting soln was stirred at r.t. for 30 min. The mixture was diluted
with Et2O and washed with sat. aq NaHCO3–aq 1.5 M Na2S2O3
(1:1) until two clear layers formed. The aqueous phase was extract-
ed with Et2O and the combined organic extracts were washed with
H2O and brine, dried (MgSO4), filtered, and concentrated to give the
crude aldehyde (77.5 mg) as a yellow oil, which was dissolved in
toluene (6.5 mL). Ph3P=C(Me)CHO (232 mg, 0.728 mmol) was
added and the resulting mixture was heated to reflux under argon for
16 h. The solvent was removed under reduced pressure and the
crude product was filtered through a plug of silica gel (5% EtOAc–
PE) to give the dienal (80 mg) which was dissolved in toluene (12
mL) and methyl (triphenylphosphoranylidene)acetate (242 mg,
0.726 mmol) was added and the resulting soln was heated to reflux
under argon for 22 h. The solvent was removed under reduced pres-
sure and the residue was purified by flash chromatography (5%
EtOAc–PE) to give the diene ester 20 (76 mg, 79%) as a colorless
oil; TLC: Rf = 0.58 (10% EtOAc–PE).
found: 567.3879.
Spiroketal Alkyne 6
To a soln of the alcohol 18 (123 mg, 0.231 mmol) in CH2Cl2 (2.3
mL) under argon at 0 °C was added Dess–Martin periodinane (147
mg, 0.347 mmol) and the resulting mixture was stirred at r.t. for 1
h. The mixture was diluted with Et2O and stirred with sat. aq
NaHCO3–aq 1.5 M Na2S2O3 (1:1) until two clear layers formed. The
aqueous phase was extracted with Et2O and the combined organic
extracts were washed with H2O and brine, dried (MgSO4), filtered,
and concentrated under reduced pressure to give the crude aldehyde
(119 mg, 97%) as a yellow viscous oil, which was used immediately
in the next reaction. To a soln of the crude aldehyde (368 mg, 0.677
mmol) in MeOH (19 mL) was added dimethyl 1-diazo-2-
oxopropylphosphonate22 (260 mg, 1.35 mmol) and anhyd K2CO3
(281 mg, 2.03 mmol) and the resulting mixture was stirred at r.t. for
60 h. The solvent was removed and Et2O and H2O were added. The
aqueous phase was extracted with Et2O and the combined organic
extracts were washed with H2O and brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. Purification of the crude
product by flash chromatography (2.5% EtOAc–PE) gave the
alkyne 6 (330 mg, 90%) as a colorless oil; TLC: Rf = 0.78 (5%
EtOAc–PE).
[a]D19 –5.2 (c 1.04, CH2Cl2).
IR (thin film): 3307, 2956, 2931, 2859, 1720 (C=O), 1622, 1463,
1435, 1258, 1170 cm–1.
1H NMR (300 MHz): d = 0.093 [s, 6 H, Si(CH3)2C(CH3)3], 0.82 (d,
J = 6.6 Hz, 3 H, CH3-12), 0.89 [s, 9 H, Si(CH3)2C(CH3)3], 0.90 (t,
J = 6.6 Hz, 3 H, CH3-28), 1.25–2.08 (m, 14 H, H13, H14, H16, H17,
H25–H27), 1.77 (s, 3 H, CH3-8), 1.83–2.55 (m, 3 H, H10, H12),
2.27 (d, J = 2.1 Hz, 1 H, C≡CH), 3.75 (s, 3 H, OCH3), 3.84 (m, 1 H,
H11), 4.29 (s, 1 H, H19), 5.76 (d, J = 15.9 Hz, 1 H, H7), 6.15 (t,
J = 6.3 Hz, 1 H, H9), 7.36 (d, J = 15.6 Hz, 1 H, H6).
13C NMR (75.5 MHz): d = –2.6, –2.3, 12.3, 14.1, 17.7, 18.6, 23.2,
24.2, 25.9, 27.4, 27.7, 31.5, 31.9, 33.8, 38.9, 51.4, 70.0, 72.7, 74.5,
74.6, 83.1, 95.8, 114.6, 133.2, 139.3, 150.1, 168.1.
[a]D19 +12.9 (c 0.954, CH2Cl2).
IR (thin film): 3434, 2958, 2931, 2859, 2097 (C≡C), 1641, 1256,
1088 cm–1.
1H NMR (300 MHz): d = 0.052 [s, 6 H, Si(CH3)2C(CH3)3], 0.088 [s,
6 H, Si(CH3)2C(CH3)3], 0.85 [d, J = 6.6 Hz, 3 H, CH3-12), 0.88 [s,
9 H, Si(CH3)2C(CH3)3], 0.89 [s, 9 H, Si(CH3)2C(CH3)3], 0.90 (t,
J = 6.6 Hz, 3 H, CH3-28), 1.25–2.04 (m, 17 H, H10, H12, H13, H14,
H16, H17, H25–H27), 2.31 (d, J = 2.7 Hz, 1 H, C≡CH), 3.64–3.84
(m, 3 H, H9, H11), 4.26 (br s, 1 H, H19).
13C NMR (75.5 MHz): d = –5.2, –2.5, –2.3, 14.1, 17.9, 18.4, 18.6,
23.2, 24.3, 25.9, 26.0, 27.7, 27.8, 31.9, 34.0, 35.5, 35.9, 38.5, 59.8,
70.2, 72.9, 73.2, 74.6, 82.9, 95.7.
HRMS (ESI): m/z [M + Na]+ calcd for C30H50O5SiNa: 541.3325;
found: 541.3346.
Aldol Adduct 23
HRMS (ESI): m/z [M + Na]+ calcd for C30H58O4Si2Na: 561.3771;
To a soln of the methyl ester 20 (75 mg, 0.153 mmol) in CH2Cl2 (2.7
mL) under argon at 0 °C was added dropwise 1 M DIBAL-H in
CH2Cl2 (720 mL, 0.720 mmol), and the resulting mixture was stirred
at 0 °C for 30 min and then warmed to r.t. EtOAc (1 mL), CH2Cl2
(4 mL) and 0.5 M sodium tartrate (5 mL) were added and the mix-
ture was stirred for 30 min. Et2O and H2O were added and the aque-
ous phase was extracted with Et2O. The combined organic extracts
were washed with H2O and brine, dried (MgSO4), filtered, and con-
centrated under reduced pressure to give the crude allylic alcohol
(70 mg), which was dissolved in CH2Cl2 (2 mL). Pyridine (72 mL,
0.892 mmol) and Dess–Martin periodinane (126 mg, 0.297 mmol)
were added and the resulting soln was stirred at r.t. under argon for
1 h. The mixture was diluted with Et2O and washed with sat. aq
NaHCO3–aq 1.5 M Na2S2O3 until two clear layers formed. The
aqueous phase was extracted with Et2O and the combined organic
extracts were washed with H2O, sat. aq CuSO4, sat. aq NaHCO3,
H2O, and brine, dried (MgSO4), filtered, and concentrated to give
the crude aldehyde 21 (67 mg) as a yellow oil. To a suspension of
Et2O-washed Sn(OTf)2 (279 mg, 0.671 mmol) in CH2Cl2 (2 mL) un-
der argon at –55 °C, was added N-ethylpiperidine (144 mg, 119 mL,
0.872 mmol). A soln of oxazolidine-2-thione 2210e (134 mg, 0.671
mmol) in CH2Cl2 (2 mL) was added via cannula and the mixture
was stirred at –55 °C for 1 h then cooled to –78 °C. A soln of the
crude aldehyde 21 in CH2Cl2 (2 mL) at –78 °C was then added via
cannula and the resulting mixture was stirred at –78 °C for 30 min.
found: 561.3772.
Spiroketal Alcohol 19
To a soln of the TBS ether 6 (200 mg, 0.371 mmol) in THF (7.6 mL)
under argon was added TBAF·3H2O (291 mg, 1.11 mmol) and the
resulting soln was stirred at r.t. for 5.5 h. Et2O and H2O were added
and the aqueous phase was extracted with Et2O. The combined or-
ganic extracts were washed with H2O and brine, dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. Purification of the
crude product by flash chromatography (20% EtOAc–PE) gave the
alcohol 19 (137 mg, 87%) as a colorless oil; TLC: Rf = 0.30 (15%
EtOAc–PE).
[a]D18 +24.8 (c 1.20, CH2Cl2).
IR (thin film): 3448 (OH), 3309, 2958, 2931, 2860, 2110 (C≡C),
1739, 1644, 1463, 1374, 1256, 1091, 981 cm–1.
1H NMR (300 MHz): d = 0.089 [s, 6 H, Si(CH3)2C(CH3)3], 0.84 (d,
J = 6.0 Hz, 3 H, CH3-12), 0.88 [s, 9 H, Si(CH3)2C(CH3)3], 0.90 (t,
J = 6.0 Hz, 3 H, CH3-28), 1.23–2.04 (m, 17 H, H10, H12–H14,
H16, H17, H25–H27), 2.41 (d, J = 2.4 Hz, 1 H, C≡CH), 3.17 (br s,
1 H, OH), 3.78–3.97 (m, 3 H, H9, H11), 4.30 (s, 1 H, H19).
13C NMR (75.5 MHz): d = –2.6, –2.3, 14.1, 17.9, 18.6, 23.1, 24.2,
25.9, 27.3, 31.6, 33.7, 33.8, 36.1, 38.8, 60.7, 70.1, 73.4, 74.5, 82.5,
95.8.
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

FEATURE ARTICLE
(–)-Reveromycin A via a Hetero-Diels–Alder Approach
3963
The mixture was poured into pH 7 buffer and stirred for 30 min and
the emulsion was filtered through Celite, and then extracted with
CH2Cl2. The combined organic extracts were washed with brine,
dried (Na2SO4), filtered, and concentrated under reduced pressure.
Purification of the crude product by flash chromatography (10–15%
EtOAc–PE) gave the aldol adduct 23 (86 mg, 87%) as a gum; TLC:
Rf = 0.28 (15% EtOAc–PE).
cation of the crude product by flash chromatography (50% EtOAc–
PE) gave the triol (43 mg, 86%) as a colorless oil. To a soln of the
triol (21.5 mg, 49 mmol) in DMF (890 mL) under argon was added
imidazole (20 mg, 0.296 mmol) and TBSCl (29 mg, 0.197 mmol)
and the mixture was stirred at r.t. for 20 h. Et2O and H2O were add-
ed, and the aqueous phase was extracted with Et2O. The combined
organic extracts were washed with H2O and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purification of
the crude product by flash chromatography (10% EtOAc–PE) gave
the bis-TBS ether 25 (24.9 mg, 76%) as a colorless oil; TLC: Rf =
0.55 (15% EtOAc–PE).
[a]D19 +64.7 (c 0.78, CH2Cl2).
IR (thin film): 3453 (OH), 3307, 2958, 2932, 2859, 2113, 1703,
1650, 1462, 1365, 1327, 1264, 1090 cm–1.
1H NMR (300 MHz): d = 0.088 [s, 6 H, Si(CH3)2C(CH3)3], 0.80 (d,
J = 6.3 Hz, 3 H, CH3-12), 0.85–0.93 [m, 9 H, CH(CH3)2, CH3-28],
0.88 [s, 9 H, Si(CH3)2C(CH3)3], 1.16–1.50 (m, 6 H, H25–H27), 1.20
(d, J = 6.9 Hz, 3 H, CH3-4), 1.56–2.49 [m, 12 H, H10, H12–H14,
H16, H17, CH(CH3)2], 1.73 (s, 3 H, CH3-8), 2.29 (d, J = 2.4 Hz, 1
H, C≡CH), 2.57 (br s, 1 H, OH), 3.77 (m, 1 H, H11), 4.27 (s, 1 H,
H19), 4.37 (d, J = 5.7 Hz, 2 H, CH2OCS), 4.64 (t, J = 5.4 Hz, 1 H,
H5), 4.75 (dd, J = 9.3, 5.4 Hz, 1 H, H4), 5.05 (m, 1 H, NCH), 5.57
(dd, J = 15.9, 6.6 Hz, 1 H, H6), 5.72 (t, J = 6.9 Hz, 1 H, H9), 6.36
(d, J = 15.9 Hz, 1 H, H7).
13C NMR (75.5 MHz): d = –2.6, –2.3, 11.5, 12.6, 14.1, 14.8, 17.7,
18.2, 18.6, 23.2, 24.2, 25.9, 27.4, 27.8, 29.0, 29.7, 31.3, 33.6, 35.9,
38.9, 42.8, 63.3, 67.3, 70.0, 72.7, 73.8, 74.7, 83.0, 95.8, 124.7,
130.5, 133.2, 137.3, 176.7, 186.1.
[a]D24 +8.4 (c 1.33, CH2Cl2).
IR (film): 3400, 3309, 2950, 2858, 1647, 1461 cm–1.
1H NMR (400 MHz): d = –0.01 (s, 3 H, SiCH3), 0.02 [s, 6 H,
Si(CH3)2], 0.03 (s, 3 H, SiCH3), 0.85 (t, J = 6.6 Hz, 3 H, CH3-28),
0.88 [s, 9 H, SiC(CH3)3], 0.89 [s, 9 H, SiC(CH3)3], 0.89–0.93 (m, 6
H, CH3-4, CH3-12), 1.30–1.69 (m, 14 H, H12, H13, H14, H16, 1 ×
H17, H25–H27), 1.71 (s, 3 H, CH3-8), 1.79 (dt, J = 13.6, 4.8 Hz, 1
H, H17), 2.10–2.15 (m, 2 H, H4, 1 × H10), 2.25–2.32 (m, 1 H, OH),
2.30 (d, J = 2.4 Hz, 1 H, H21), 2.48 (ddd, J = 15.4, 6.8, 4.2 Hz, 1 H,
H10), 3.39 (dd, J = 10.0, 6.4 Hz, 1 H, 1 H3), 3.57 (dd, J = 9.6, 6.4
Hz, 1 H, 1 H3), 3.74–3.79 (m, 1 H, H11), 4.24 (dd, J = 6.8, 4.4 Hz,
1 H, H5), 4.27 (t, J = 2.0 Hz, 1 H, H19), 5.49 (dd, J = 15.6, 6.8 Hz,
1 H, H6), 5.60 (t, J = 7.0 Hz, 1 H, H9), 6.11 (d, J = 15.6 Hz, 1 H,
H7).
13C NMR (100 MHz): d = –5.35, –5.32, –4.9, –4.0, 11.3, 12.7, 14.0,
17.7, 18.23, 18.26, 23.1, 24.0, 25.9, 26.9, 27.7, 31.5, 31.6, 33.8,
36.2, 38.2, 43.0, 65.0, 69.8, 71.2, 73.4, 73.7, 75.2, 81.8, 96.0, 128.2,
128.7, 133.5, 134.7.
HRMS (ESI): m/z [M + Na]+ calcd for C38H70O5Si2Na: 685.4659;
found: 685.4661.
HRMS (ESI): m/z [M + Na]+ calcd for C38H63NO6SSiNa: 712.4043;
found: 712.4028.
Diol 24
To a soln of the aldol adduct 23 (123 mg, 0.178 mmol) in THF (3.5
mL) and H2O (230 mL) at 0 °C was added NaBH4 (20 mg, 0.534
mmol) and the resulting mixture was stirred at r.t. for 1 h. The sol-
vent was removed and Et2O and H2O were added to the residue and
the soln was stirred vigorously for 30 min. The aqueous phase was
extracted with Et2O and the combined organic extracts were washed
with 1 M NaOH, H2O, brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification of the crude product by
flash chromatography (40% EtOAc–PE) gave the diol 24 (87 mg,
89%) as a pale yellow oil; TLC: Rf = 0.35 (30% EtOAc–PE).
Spiroketal Alcohol 26
To a stirred soln of the bis-TBS ether 6 (70 mg, 0.133 mmol) in THF
(2.6 mL) under argon was added TBAF·3H2O (209 mg, 0.800
mmol) and the mixture was heated at reflux for 24 h. Et2O and H2O
were added, and the aqueous phase was extracted with Et2O. The
combined organic extracts were washed with H2O and brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. Purifi-
cation of the crude product by flash chromatography (30% EtOAc–
PE) gave the diol (39 mg, 95%) as a colorless oil. To a soln of the
diol (36 mg, 0.115 mmol) in DMF (1.1 mL) under argon was added
imidazole (15 mg, 0.231 mmol) and TBSCl (29 mg, 0.197 mmol)
and the mixture was stirred at r.t. for 1.5 h. Et2O and H2O were add-
ed, and the aqueous phase was extracted with Et2O. The combined
organic extracts were washed with H2O and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purification of
the crude product by flash chromatography (10% EtOAc–PE) gave
the spiroketal alcohol 26 (48 mg, 98%) as a colorless oil; TLC: Rf =
0.56 (15% EtOAc–PE).
[a]D15 –8.9 (c 0.40, CH2Cl2).
IR (thin film): 3403 (OH), 3309, 2959, 2933, 2861, 2113, 1649,
1461, 1384 cm–1.
1H NMR (300 MHz): d = 0.09 [s, 6 H, Si(CH3)2C(CH3)3], 0.81 (d,
J = 6 Hz, 3 H, CH3-12), 0.84–0.92 (m, 6 H, CH3-4, CH3-28), 0.88
[s, 9 H, Si(CH3)2C(CH3)3], 1.25–1.68 (m, 6 H, H25–H27), 1.75 (s,
3 H, CH3-8), 1.80–2.44 (m, 14 H, H4, H10, H12–H14, H16, H17, 2
OH), 2.28 (d, J = 2.4 Hz, 1 H, C≡CH), 3.62–3.72 (m, 2 H, H3), 3.77
(dd, J = 14.1, 5.1 Hz, 1 H, H11), 4.28 (s, 1 H, H19), 4.34 (dd,
J = 6.9, 3.9 Hz, 1 H, H5), 5.60 (dd, J = 15.9, 6.9 Hz, 1 H, H6), 5.71
(t, J = 6.9 Hz, 1 H, H9), 6.29 (d, J = 15.6 Hz, 1 H, H7).
[a]D16 +31.8 (c 0.18, CH2Cl2).
IR (film): 3440, 3309, 2954, 2927, 2858, 1461 cm–1.
1H NMR (400 MHz): d = 0.05 [s, 6 H, Si(CH3)2], 0.86–0.93 (m, 6
H, CH3-12, CH3-28), 0.89 [s, 9 H, SiC(CH3)3], 1.29–1.91 (m, 15 H,
H10, H12–H14, 1 × H16, 1 × H17, H25–27), 2.09–2.10 (m, 2 H,
H16, H17), 2.35 (d, J = 2.8 Hz, 1 H, H21), 3.66–3.82 (m, 3 H, H9,
H11), 4.26 (t, J = 2.2 Hz, 1 H, H19).
13C NMR (75.5 MHz): d = –2.5, –2.3, 11.7, 12.7, 14.1, 17.7, 18.6,
23.2, 24.2, 25.9, 27.5, 27.8, 29.6, 31.3, 31.6, 33.6, 35.9, 38.9, 40.2,
66.4, 70.0, 72.7, 74.7, 83.0, 95.9, 125.6, 130.2, 133.2, 137.0.
HRMS (ESI): m/z [M + Na]+ calcd for C32H56O5SiNa: 571.3795;
found: 571.3804.
Bis-TBS Ether 25
To a stirred soln of the TBS ether 24 (64 mg, 0.116 mmol) in THF
(2 mL) under argon was added TBAF·3H2O (182 mg, 0.699 mmol)
and the mixture was heated at reflux for 21 h. Et2O and H2O were
added, and the aqueous phase was extracted with Et2O. The com-
bined organic extracts were washed with H2O, brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. Purifi-
13C NMR (100 MHz): d = –5.19, –5.17, 14.0, 17.8, 18.3, 23.1, 24.0,
25.91, 25.99, 27.0, 27.7, 31.8, 33.6, 35.4, 36.0, 37.9, 59.6, 69.8,
71.2, 73.3, 73.5, 81.8, 95.8.
HRMS (ESI): m/z [M + Na]+ calcd for C24H44O4SiNa: 447.2906;
found: 447.2892.
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

3964
M. El Sous et al.
FEATURE ARTICLE
Succinate Ester 28
Alcohol 30
To a soln of the alcohol 26 (18 mg, 42 mmol) in CH2Cl2 (1.5 mL) in
a Teflon tube was added the acid 2710e (37 mg, 0.169 mmol), DMAP
(0.58 mg, 4.8 mmol) and DCC (26 mg, 0.127 mmol) and capped
(with most of the air removed). The tube was placed in a pressure
oil apparatus and pressurized to 0.4 GPa at r.t. for 72 h. Et2O and
H2O were added, the suspension was filtered through Celite, and the
aqueous phase was extracted with Et2O. The combined organic ex-
tracts were washed with 1 M HCl, sat. aq NaHCO3, H2O, and brine,
dried (MgSO4), filtered, and concentrated under reduced pressure.
Purification of the crude product by flash chromatography (2.5–5%
EtOAc–PE) gave the ester 28 (24 mg, 92%) as a colorless oil; TLC:
Rf = 0.30 (5% EtOAc–PE).
To ester 29 (31 mg, 35 mmol) was added a cold (0 °C) freshly pre-
pared soln of HF–pyridine (72 mg, 1.79 mmol) and pyridine (102
mL, 1.29 mmol) in THF (730 mL) and the mixture was stirred for
12.5 h. Et2O was added and the mixture was slowly quenched with
sat. aq NaHCO3. The aqueous phase was extracted with Et2O and
the combined organic extracts were washed with H2O and brine,
dried (Na2SO4), filtered, and concentrated under reduced pressure.
Purification of the crude product by flash chromatography (10–15%
EtOAc–PE) gave the alcohol 30 (22 mg, 85%) as a colorless oil;
TLC: Rf = 0.42 (15% EtOAc–PE).
[a]D18 +10.8 (c 1.10, CH2Cl2).
IR (film): 3450, 3309, 2929, 2859, 1732, 1631 cm–1.
[a]D15 +11.7 (c 1.20, CH2Cl2).
IR (film): 3309, 2954, 2929, 2858, 1732, 1461 cm–1.
1H NMR (400 MHz): d = 0.021 (s, 3 H, SiCH3), 0.028 [s, 9 H,
Si(CH3)3], 0.06 (s, 3 H, SiCH3), 0.78 (d, J = 7.2 Hz, 3 H, CH3-12),
0.82–0.89 (m, 6 H, CH3-4, CH3-28), 0.89 [s, 9 H, SiC(CH3)3], 0.97
[t, J = 8.6 Hz, 2 H, OCH2CH2Si(CH3)3], 1.18–1.69 (m, 14 H, H12–
14, H16, 1 × H17, H25–H27), 1.72 (s, 3 H, CH3-8), 1.98–2.16 (m,
2 H, H10, H17), 2.27 (d, J = 2.4 Hz, 1 H, H21), 2.29–2.31 (m, 1 H,
H4), 2.48–2.51 (m, 1 H, H10), 2.53–2.64 (m, 4 H, H2¢, H3¢), 2.99
(d, J = 4.4 Hz, 1 H, OH), 3.44–3.50 (m, 1 H, H3), 3.65 (t, J = 9.8
Hz, 1 H, H3), 3.73–3.78 (m, 1 H, H11), 4.16 [t, J = 8.6 Hz, 2 H,
OCH2CH2Si(CH3)3], 4.29 (dd, J = 7.0, 3.8 Hz, 1 H, H5), 4.84 (t,
J = 2.0 Hz, 1 H, H19), 5.54 (dd, J = 15.8, 7.0 Hz, 1 H, H6), 5.66 (t,
J = 7.0 Hz, 1 H, H9), 6.17 (d, J = 16.0 Hz, 1 H, H7).
1H NMR (400 MHz): d = 0.03 [s, 9 H, Si(CH3)3], 0.04 [s, 6 H,
Si(CH3)2], 0.85–0.90 (m, 6 H, CH3-12, CH3-28), 0.89 [s, 9 H,
SiC(CH3)3], 0.97 [t, J = 8.6 Hz, 2 H, OCH2CH2Si(CH3)3], 1.19–
2.14 (m, 16 H, H10, H12–H14, H16, 1 × H17, H25–H27), 2.23 (d,
J = 13.6 Hz, 1 H, H17), 2.34 (d, J = 2.8 Hz, 1 H, H21), 2.53–2.64
(m, 4 H, H2¢, H3¢), 3.64–3.70 (m, 1 H, H11), 3.73 (dd, J = 9.8, 5.4
Hz, 1 H, H9), 3.80 (dt, J = 9.8, 6.0 Hz, 1 H, H9), 4.16 [t, J = 8.6 Hz,
2 H, OCH2CH2Si(CH3)3], 4.83 (t, J = 2.0 Hz, 1 H, H19).
13C NMR (100 MHz): d = –5.15, –5.18, –1.5, 13.9, 17.2, 17.9, 18.3,
22.7, 24.0, 24.2, 26.0, 27.7, 29.3, 30.0, 31.5, 33.72, 33.77, 35.6,
36.4, 59.7, 62.9, 66.4, 66.5, 73.4, 81.4, 83.1, 95.4, 171.2, 172.2.
HRMS (ESI): m/z [M + Na]+ calcd for C33H60O7Si2Na: 647.3775;
found: 647.3765.
13C NMR (100 MHz): d = –5.0, –4.2, –1.5, 12.5, 12.6, 13.8, 17.2,
17.7, 18.0, 22.7, 24.0, 24.1, 25.7, 25.8, 27.7, 29.3, 30.0, 31.4, 31.5,
33.7, 33.9, 36.3, 41.2, 62.8, 65.9, 66.5, 73.5, 75.0, 77.9, 81.3, 83.0,
95.6, 125.3, 129.4, 133.1, 136.4, 171.2, 172.2.
Succinate Ester 29
HRMS (ESI): m/z [M + Na]+ calcd for C41H72O8Si2Na: 771.4663;
found: 771.4648.
To a soln of the alcohol 25 (24 mg, 36 mmol) in CH2Cl2 (1.5 mL) in
a Teflon tube was added the acid 27 (31 mg, 0.144 mmol), DMAP
(0.85 mg, 4.1 mmol), and DCC (22 mg, 0.108 mmol) and capped
(with most of the air removed). The tube was placed in a pressure
oil apparatus and pressurized to 0.4 GPa at r.t. for 72 h. Et2O and
H2O were added, the suspension was filtered through Celite, and the
aqueous phase was extracted with Et2O. The combined organic ex-
tracts were washed with 1 M HCl, sat. aq NaHCO3, H2O, and brine,
dried (MgSO4), filtered, and concentrated under reduced pressure.
Purification of the crude product by flash chromatography (5%
EtOAc–PE) gave the ester 29 (30 mg, 96%) as a colorless oil; TLC:
Rf = 0.68 (15% EtOAc–PE).
Stannane 31
To a soln of the alkyne 30 (35 mg, 46 mmol) in CH2Cl2 (2.2 mL) at
0 °C under argon was added Pd(PPh3)2Cl2 (3.2 mg, 4.6 mmol) and
the mixture was stirred for 10 min. Bu3SnH (50 mL, 0.186 mmol)
was added dropwise and stirring was continued at 0 °C for 1 h. Extra
amounts of Pd(PPh3)2Cl2 (19.6 mg, 28 mmol) and Bu3SnH (100 mL,
0.373 mmol) were both added in portions every hour over a period
of 8 h while stirring at 0 °C. The solvent was removed under re-
duced pressure and purification of the crude product by flash col-
umn chromatography (5% EtOAc–PE, containing 1% Et3N) gave
the vinyl stannane 31 (27 mg, 56%) as a yellow oil which was used
immediately in the next reaction.
1H NMR (300 MHz): d = 0.03 [s, 9 H, Si(CH3)3], 0.07 [s, 6 H,
Si(CH3)2], 0.75–0.92 {m, 18 H, Sn[(CH2)3(CH3)]3, CH3-4, CH3-12,
CH3-28}, 0.89 [s, 9 H, SiC(CH3)3], 0.98 [t, J = 11.2 Hz, 2 H,
OCH2CH2Si(CH3)3], 1.16–2.4 {m, 35 H, Sn[(CH2)3(CH3)]3, H10,
H12–14, H16, H17, H25–H27}, 1.74 (s, 3 H, CH3-8), 2.55–2.66 (m,
4 H, H2¢, H3¢), 3.03 (dd, J = 10.0, 4.0 Hz, 1 H, OH), 3.45–3.58 (m,
2 H, H3), 3.67 (dt, J = 13.0, 4.0 Hz, 1 H, H11), 4.16 [t, J = 11.4 Hz,
2 H, OCH2CH2Si(CH3)3], 4.28 (dd, J = 15.2, 9.8 Hz, 1 H, H5), 4.38
(d, J = 8.4 Hz, 1 H, H19), 5.52–5.60 (m, 2 H, H6, H9), 6.20 (d,
J = 15.4 Hz, 1 H, H7), 6.28–6.31 (m, 2 H, H20, H21).
[a]D21 +6.7 (c 1.73, CH2Cl2).
IR (film): 3309, 3269, 2929, 2858, 1735, 1461 cm–1.
1H NMR (400 MHz): d = –0.01 (s, 3 H, SiCH3), 0.021 [s, 6 H,
Si(CH3)2], 0.026 (s, 3 H, SiCH3), 0.03 [s, 9 H, Si(CH3)3], 0.83–0.90
(m, 9 H, CH3-4, CH3-12, CH3-28), 0.88 [s, 9 H, SiC(CH3)3], 0.89 [s,
9 H, SiC(CH3)3], 0.98 [t, J = 8.6 Hz, 2 H, OCH2CH2Si(CH3)3],
1.25–1.68 (m, 14 H, H12–14, H16, 1 × H17, H25–H27), 1.71 (s, 3
H, CH3-8), 1.98–2.18 (m, 2 H, H4, H17), 2.22 (m, 1 H, H10), 2.28
(d, J = 2.4 Hz, 1 H, H21), 2.44–2.52 (m, 1 H, H10), 2.54–2.66 (m,
4 H, H2¢, H3¢), 3.38 (dd, J = 10.0, 6.4 Hz, 1 H, H3], 3.57 (dd,
J = 9.6, 6.4 Hz, 1 H, H3), 3.72–3.77 (m, 1 H, H11), 4.17 [t, J = 8.6
Hz, 2 H, OCH2CH2Si(CH3)3], 4.24 (dd, J = 6.6, 4.2 Hz, 1 H, H5),
4.84 (br s, 1 H, H19), 5.49 (dd, J = 15.6, 6.8 Hz, 1 H, H6), 5.61 (t,
J = 7.0 Hz, 1 H, H9), 6.11 (d, J = 15.6 Hz, 1 H, H7).
13C NMR (100 MHz): d = –5.35, –5.32, –4.9, –3.9, –1.5, 11.3, 12.6,
13.9, 17.2, 17.8, 18.23, 18.26, 22.7, 24.0, 24.1, 25.8, 25.9, 27.7,
29.3, 30.0, 31.4, 33.7, 34.0, 36.3, 43.0, 62.9, 65.0, 66.5, 73.6, 73.7,
75.1, 81.3, 83.1, 95.6, 128.3, 128.7, 133.4, 134.7, 171.2, 172.3.
HRMS (ESI): m/z [M + Na]+ calcd for C47H86O8Si3Na: 885.5528;
found: 885.5522.
Bis-Tmse Ester 33
To a soln of the vinyl stannane 31 (12 mg, 11 mmol) in NMP (550
mL) was added iodide 32 (7 mg, 23 mmol) and the mixture was
freeze–thaw–degassed (3 ×). TFP (0.53 mg, 2.3 mmol) and
Pd2(dba)3 (0.53 mg, 0.5 mmol) were added and the soln was stirred
at 60 °C under argon for 5 h. Et2O and H2O were added, and the
aqueous phase was extracted with Et2O. The combined organic ex-
tracts were washed with H2O and brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. Purification of the crude
product by flash chromatography (10% EtOAc–PE) gave 8.5 mg of
Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

FEATURE ARTICLE
(–)-Reveromycin A via a Hetero-Diels–Alder Approach
3965
a yellow oil containing impurities (1H NMR spectroscopic analy-
sis). Further purification was achieved using preparative normal
phase HPLC (C18 5 mm, 250 × 10 mm, 10–15% EtOAc–PE, flow
rate: 2 mL·min–1). This gave the bis-Tmse ester 33 (6 mg, 58%) as
a colorless oil; TLC: Rf = 0.37 (15% EtOAc–PE).
[a]D23 –105.8 (c 0.31, CH2Cl2).
IR (film): 3450, 2956, 2858, 1710, 1612, 1458 cm–1.
1H NMR (400 MHz): d = 0.02 (s, 3 H, SiCH3), 0.03 [s, 9 H,
Si(CH3)3], 0.04 [s, 9 H, Si(CH3)3], 0.07 (s, 3 H, SiCH3), 0.76–0.84
(m, 9 H, CH3-4, CH3-12, CH3-28), 0.89 [s, 9 H, SiC(CH3)3], 0.96–
1.04 [m, 4 H, 2 OCH2CH2Si(CH3)3], 1.17–1.76 (m, 14 H, H12–H14,
H16, 1 × H17, H25–H27), 1.73 (s, 3 H, CH3-8), 1.98–2.05 (m, 2 H,
H4, 1 × H10), 2.26 (s, 3 H, CH3-22), 2.29–2.41 (m, 2 H, H10, H17),
2.54–2.66 (m, 4 H, H2¢, H3¢), 3.01 (d, J = 4.4 Hz, 1 H, OH), 3.39–
3.51 (m, 2 H, H3), 3.67 (t, J = 9.0 Hz, 1 H, H11), 4.15–4.23 [m, 4
H, 2 OCH2CH2Si(CH3)3], 4.29 (dd, J = 6.8, 4.4 Hz, 1 H, H5), 4.60
(d, J = 7.6 Hz, 1 H, H19), 5.54–5.59 (m, 2 H, H6, H9), 5.79 (br s, 1
H, H23), 6.18 (d, J = 16.0 Hz, 1 H, H7), 6.32–6.34 (m, 2 H, H20,
H21).
13C NMR (100 MHz): d = –5.0, –4.1, –1.5, –1.4, 12.5, 12.8, 13.9,
14.2, 17.2, 17.3, 17.6, 18.0, 22.7, 24.0, 24.5, 25.8, 27.4, 29.3, 30.0,
31.7, 33.3, 34.0, 35.7, 41.2, 62.0, 62.9, 65.9, 74.5, 78.0, 78.3, 83.0,
95.6, 120.4, 125.7, 127.9, 132.8, 134.2, 136.2, 137.9, 151.0, 167.1,
171.4, 172.3.
HRMS (ESI): m/z [M + Na]+ calcd for C57H102O11Si4Na: 1097.6396;
found: 1097.6386.
Reveromycin A (1)
To a soln of the triester 34 (6.4 mg, 5.9 mmol) in DMF (1 mL) under
argon was added TBAF·3H2O (15 mg, 59 mmol) and the soln was
stirred at r.t. for 24 h. Further TBAF·3H2O (15 mg, 59 mmol) was
added and stirring was continued for a total of 48 h. The mixture
was partitioned between EtOAc and sat. aq NH4Cl, and the aqueous
phase was acidified with 10% HCl until pH 3 was obtained. The or-
ganic extract was washed with H2O and brine, dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. Purification was
carried out by reverse phase chromatography (C18 spherex, 900
mg, 60–40% H2O–MeOH) to give (–)-reveromycin A (1) (3.7 mg,
94%) as colorless powder; TLC: Rf = 0.38 (15% MeOH–CH2Cl2).
22
23
[a]D –122.4 (c 0.16, MeOH) {Lit.1b (natural) [a]D –115 (c 0.1,
MeOH); Lit.11 (synthetic) [a]D22 –122.4 (c 0.16, MeOH)}.
IR (film): 3450, 2940, 2852, 1693, 1610, 1480 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.77 (d, J = 6.0 Hz, 3 H, CH3-
12), 0.83 (t, J = 6.0 Hz, 3 H, CH3-28), 1.07 (d, J = 6.8 Hz, 3 H, CH3-
4), 1.17–1.72 (m, 15 H, H12–H14, H16, H17, H25–H27), 1.74 (s, 3
H, CH3-8), 1.83 (dt, J = 13.2, 3.9 Hz, 1 H, H10), 2.01 (dt, J = 12.6,
4.4 Hz, 1 H, H4), 2.25 (s, 3 H, CH3-22), 2.26–2.40 (m, 1 H, H10),
2.48–2.60 (m, 4 H, H2¢, H3¢), 3.41–3.48 (m, 1 H, H11), 4.03–4.07
(m, 1 H, H5), 4.61 (d, J = 7.6 Hz, 1 H, H19), 5.51 (dd, J = 16.0, 7.2
Hz, 1 H, H6), 5.58 (t, J = 7.0 Hz, 1 H, H9), 5.80 (d, J = 16.0 Hz, 1
H, H2), 5.87 (br s, 1 H, H23), 6.24 (d, J = 16.0 Hz, 1 H, H7), 6.42–
6.44 (m, 2 H, H20, H21), 6.97 (dd, J = 15.6, 7.6 Hz, 1 H, H3).
13C NMR (100 MHz, CD3OD): d = 13.1, 14.3, 14.7, 15.3, 18.1, 23.9,
25.2, 25.5, 28.8, 30.0, 31.2, 32.9, 33.1, 34.9, 35.3, 37.0, 44.3, 76.4,
77.0, 79.8, 84.3, 97.1, 121.8, 122.7, 128.0, 129.6, 134.3, 135.6,
137.9, 139.4, 152.6, 152.9, 170.3, 170.3, 173.5, 176.0.
HRMS (ESI): m/z [M + Na]+ calcd for C50H90O10Si3Na: 957.5739;
found: 957.5730.
Reveromycin A Tris-Tmse Ester 34
To a soln of the alcohol 33 (6.5 mg, 6.9 mmol) in CH2Cl2 (1 mL) was
added pyridine (5 mL, 62 mmol) and Dess–Martin periodinane (8.8
mg, 20 mmol) and the resulting soln was stirred at r.t. for 2 h. The
mixture was diluted with Et2O and washed with sat. aq NaHCO3–aq
1.5 M Na2S2O3 (1:1) until two clear layers formed. The aqueous
phase was extracted with Et2O and the combined organic extracts
were washed with H2O, sat. aq CuSO4, sat. aq NaHCO3, H2O, and
brine, dried (MgSO4), filtered, and concentrated to give the crude
aldehyde (6.48 mg) as a yellow oil. The crude aldehyde was dis-
solved in CH2Cl2 (1 mL) and 2-(trimethylsilyl)ethyl (triphenylphos-
phoranylidene)acetate27 (31 mg, 68 mmol) was added and the soln
was stirred at r.t. for 22 h. Evaporation of the solvent and purifica-
tion of the crude product by flash chromatography (5% EtOAc–PE)
gave the tris-Tmse ester 34 (6.4 mg, 88%) as a colorless oil; TLC:
Rf = 0.66 (15% EtOAc–PE).
HRMS (ESI): m/z [M + Na]+ calcd for C36H52O11Na: 683.3407;
found: 683.3406.
UV-vis (MeOH): lmax (e, M–1 cm–1) = 238 nm (36513).
Acknowledgment
We are indebted to Dr. Hiroyuki Osada (RIKEN Institute, Japan)
for an authentic sample of reveromycin A (1) as well as copies of
the NMR spectra. We also thank Professor Rob Capon (University
of Queensland) for the HPLC comparisons. This work was financi-
ally supported by the Australian Research Council.
[a]D31 –69.6 (c 0.21, CH2Cl2).
IR (film): 2957, 2931, 2860, 1733, 1654, 1460 cm–1.
References
1H NMR (400 MHz): d = –0.01 (s, 3 H, SiCH3), 0.031 (s, 3 H,
SiCH3), 0.039 [s, 9 H, Si(CH3)3], 0.04 [s, 9 H, Si(CH3)3], 0.05 [s, 9
H, Si(CH3)3], 0.76 (d, J = 6.4 Hz, 3 H, CH3-12), 0.80–0.84 (m, 6 H,
CH3-4, CH3-28), 0.88 [s, 9 H, SiC(CH3)3], 0.96–1.04 [m, 6 H, 3
OCH2CH2Si(CH3)3], 1.10–1.80 (m, 14 H, H12–H14, H16, 1 × H17,
H25–H27), 1.70 (s, 3 H, CH3-8), 1.95 (dt, J = 13.6, 4.0 Hz, 1 H,
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Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York

3966
M. El Sous et al.
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Synthesis 2010, No. 23, 3954–3966 © Thieme Stuttgart · New York