A practical synthesis of the ansa chain of benzenic ansamycin antibiotics: Total synthesis of an ansatrienol derivative

Article abstract of DOI:10.1055/s-2006-958967

A practical and stereocontrolled synthetic approach towards the ansa chain of the benzenic ansamycins (mycotrienins) is described, which can be scaled up to multigram quantities. Key features of the synthesis are the formation of the Z-configured tri-subs

Full text of DOI:10.1055/s-2006-958967

304
FEATURE ARTICLE
A Practical Synthesis of the Ansa Chain of Benzenic Ansamycin Antibiotics:
Total Synthesis of an Ansatrienol Derivative
Total
S
ynthesis of
m
A
nsatrienol itry Kashin, Axel Meyer, Rüdiger Wittenberg,1 Kai-Uwe Schöning,1 Stefan Kamlage,1 Andreas Kirschning*
Institut für Organische Chemie, Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
E-mail: andreas.kirschning@oci.uni-hannover.de
Received 30 March 2006; revised 13 April 2006
Ansatrienin A (mycotrienin I, 1a) and ansatrienin B (my-
Abstract: A practical and stereocontrolled synthetic approach to-
wards the ansa chain of the benzenic ansamycins (mycotrienins) is
described, which can be scaled up to multigram quantities. Key fea-
tures of the synthesis are the formation of the Z-configured tri-
cotrienin II, 2a) were isolated from the fermentation broth
of Streptomyces collinus by Zähner, Zeeck, and co-work-
ers in 1981.3 Independently, Japanese scientists isolated
substituted double bond by
a
one-pot esterification of 1a and 2a after fermentation of Streptomyces rishiriensis.4
Later, trienomycin (3a),5 cytotrienin (1b),6 as well as the
highly active thiazinotrienomycin (4a)7 were reported; all
are structurally closely related to the ansatrienins. All
members of this group have an identical ansa chain that
includes features such as the stereotriad from C11 to C13,
the all-trans-configured triene unit, and the Z-configured
trisubstituted alkene at C14/C15.
allyl(diisopropoxy)borane and ring-closing metathesis, formation
of the b-keto ester via ethyl diazoacetate addition to an aldehyde,
and use of the Duthaler–Hafner acetate aldol reaction for the intro-
duction of the stereocenter at C3. The practicality of this synthesis
is demonstrated by the preparation of an ansatrienol derivative,
representing a formal total synthesis of the ansatrienins.
Key words: aldol reaction, ansamycin antibiotics, macrolactamiza-
tion, ring-closing metathesis, total synthesis
nucleophilic
substitution
HO
macrolactamization
NH
1
Introduction
The ansamycins (mycotrienins) are an important class of
macrolactam antibiotics from microbial sources of which
rifamycin, geldanamycin, and ansamitocin are well-
known examples. This class of secondary metabolites is
characterized by a cyclic structure in which an aliphatic
ansa chain forms a bridge between two nonadjacent posi-
tions of a cyclic p-system. Many exhibit antibacterial, an-
tifungal, or antitumor activity.2 The ansatrienins 1a and 2a
are benzenic ansamycins with 17 carbon atoms in the ali-
phatic chain (Figure 1).
HO
HO
HO
O
OMe
5
Still–Gennari or
RCM
Duthaler–Hafner
aldol
X
8
I
O
OEt
X
O
O
PGO
PGO
O
OMe
O
P
O
H
6
CO2Et
N
EtO
EtO
X
a R =
b R =
HWE olefination
OMe
17
Me
HO
NH
O
1
13
9
O
CH3
H
N
O
11
3
OMe
RO
PhSO2
O
NHTBS
O
OMe
OH
O
OH
NH
7
S
Scheme 1 Retrosynthetic analysis.
X=
O
OH
OH
The first total syntheses of the benzenic ansamycins
trienomycin A (3a), ansatrienin A (1a), and thiazino-
trienomycin E (4a) were described by the groups of Smith
and Panek.8–10 From the knowledge accumulated on these
natural products, it is evident that the biological activity is
strongly dependent on the type of aromatic or quinoidic
central structure as well as the side chain. In contrast, the
ansa chain is a highly preserved structural element for all
the ansamycins depicted in Figure 1. Therefore, we initi-
1
2
3
4
Figure 1 Benzenic ansamycin antibiotics 1–4; the ansa chain is
marked with bold backbone bonds.
SYNTHESIS 2007, No. 2, pp 0304–0319
Advanced online publication: 10.01.2007
DOI: 10.1055/s-2006-958967; Art ID: Z06406SS
x
x
.
x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Total Synthesis of an Ansatrienol Derivative
305
Dmitry Kashin was born in group of Prof. A. Kirschning schweig) where he worked on
Perm (Russia) in 1975. He and worked on the total syn- epothilones. Currently, he
studied chemistry at the Uni- thesis of ansatrienin B. After works as a research assistant
versität Perm and received his finishing his PhD at the end of in the group of A. Kirschning.
Master-Degree in 1999. For 2003 he did a postdoc with
his PhD thesis he joined the Prof. Höfle (GBF, Braun-
Axel Meyer was born in his studies of chemistry at the doctoral degree on the topic of
Kronberg/Taunus (Germany) University of Hannover and Hybrid Ansamycin Antibiot-
in 1975. From 1995 to 1998 he received his Diploma under ics and is currently finishing
worked as a laboratory techni- the direction of Prof. A. Kir- his studies.
cian at Synthopol Chemie in schning in 2003. He then start-
Buxtehude. In 1998 he started ed working towards his
Rüdiger Wittenberg was sis. In 2000 he moved to Han- joined Prof. Liebeskind’s
born in Karlsruhe (Germany) nover University, where he group at Emory University,
in 1973. He studied chemistry obtained his PhD in 2002 with Atlanta (USA) working on Pd-
at the Technical University a thesis about synthetic routes catalyzed Cu-mediated cross-
Clausthal and the Universidad towards macrocyclic natural coupling reactions of thioor-
de Sevilla (Spain) and joined products, namely ansatrienin ganics. Since 2004 he is work-
Prof. Kirschning’s group in and the novel diterpene to- ing for ALTANA Chemie’s
1998 starting his diploma the- nantzitlolone. In 2002 he subsidiary DS Chemie.
Kai-Uwe Schöning, born in group of Prof. A. Eschenmoser polymer light stabilization.
1970, studied chemistry at the as a postdoctoral research fel- Further areas of research dur-
Technical
University
of low both, at the ETH Zurich ing his time with Ciba SC
Clausthal. He received his and the Scripps Research Insti- comprised the synthesis of ac-
PhD in the group of Prof. A. tute, La Jolla. In the year 2000 tive pharmaceutically interme-
Kirschning, working on the to- he joined Ciba Specialty diates and enzyme-catalyzed
tal synthesis of Ansatrienol in Chemicals in Basel where he reactions.
1998. Subsequently, he spent currently holds a position as a
one and a half year in the project manager in the area of
Stefan Kamlage studied (1999) at the University of sity of Berlin in the group of
chemistry at the Technical Potsdam under the supervision Prof. R. Haag. His current re-
University of Clausthal where of Prof. M. G. Peter. After a search interest focusses on the
he obtained his Diploma under break of laboratory work for synthesis of chiral glycerol-
the guidance of Prof. Kir- six years, he is now a postdoc- based dendrons and dendritic
schning. He obtained his PhD toral fellow at the Free Univer- architectures.
Andreas Kirschning was USA) with Prof. H. G. Floss, versity of Hannover and be-
born in 1960 in Hamburg. He he started his independent re- came director of the institute
studied chemistry at the Uni- search at the Technical Uni- of organic chemistry. His re-
versity of Hamburg and versity of Clausthal in 1991, search interests cover the total
Southampton
University where he finished his habilita- synthesis and mutasynthesis of
(UK). In Hamburg, he joined tion in 1996. In 1997, he held a natural products, glycochemis-
the group of Prof. E. Schau- position as guest professor at try and synthetic technology
mann and received his PhD in the Humboldt-University in (solid-phase-assisted synthe-
1989 working in the field of Berlin and in 1998 as a visiting sis, microreactors, enabling
organosilicon chemistry. After professor at the University of technologies).
a postdoctoral stay at the Uni- Wisconsin in Madison (USA).
versity of Washington (Seattle, In 2000 he moved to the Uni-
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

306
D. Kashin et al.
FEATURE ARTICLE
ated a synthetic program to develop a practical and effi- As an alternative, we constructed the trisubstituted double
cient synthesis of the ansa chain 6 in multigram quantities. bond by following a protocol developed by Schreiber et
This polyketide-type fragment then may serve as a start- al.14 It is based on the in situ esterification of allyl(diiso-
ing point for several new ansatrienins that differ in the bi- propoxy)borane (20) with an allylic hydroxy group fol-
ologically important aromatic moiety.11
lowed by ring-closing alkene metathesis (Scheme 3). The
known Evans aldol product 1515,16 was expected to be the
best point during the synthesis to apply this method. Allyl
alcohol 15 afforded cyclic boronate 16 that was trans-
formed into diol 18 in only moderate yield, even after ex-
tensive optimization. Furthermore, the ring-closing
metathesis required substantial amounts (12 mol%) of
second-generation Grubbs catalyst 19 which is unaccept-
able in the early stages of a total synthesis.
Here, we describe the large-scale synthesis of the ansa
chain 6 and show the utility of this fragment in the prepa-
ration of ansatrienol 5, which resembles a formal total
synthesis of the ansatrienins. Our convergent synthetic
plan, based on building blocks 7–9,9b,11 is outlined in
Scheme 1. These building blocks will be combined by
ring-closing metathesis (RCM) or Still–Gennari alkena-
tion to generate the Z-configured double bond at C14/
C15, Horner–Wadsworth–Emmons alkenation (HWE),
and the rarely employed Duthaler–Hafner acetate aldol re-
action. Insertion of benzyl sulfone into the termini of the
ansa chain 6 according to Smith’s concept should yield
lactam macrocycles as exemplified for ansatrienol 5.
OH
b or
c or d HO
B
HO
O
Bn
Bn
O
N
O
N
a
18
O
O
O
O
16
2
The Stereotriad and Z-Configured Trisub-
O
OH
Oi-Pr
B
N Mes
N
stituted Alkene
Mes
Cl
X
H
i-PrO
Ru
Cl
Ph
One synthetic key issue of the ansa chain that we had to
address was the practical construction of the trisubstituted
Z-configured double bond at C14/C15. We approached it
by Still–Gennari alkenation and alternatively by ring-
closing metathesis with an allylboronic acid (Scheme 2).
The former approach utilizes aldehyde 1012 and methyl-
branched phosphonate 1113 which were coupled under
Horner–Wadsworth–Emmons conditions affording the Z-
configured aldehyde 12 (the E-isomer was not detected by
NMR spectroscopy) after reduction and allylic oxidation.
The aldol reaction according to the Evans protocol yielded
aldol product 13 (dr 95:5) in moderate yield. However,
this route had to be abandoned because the aldol reaction
sequence could not be efficiently scaled up (>200 mg).
15 X = oxazolidinone
17 X = N(Me)OMe
PCy3
e
20
19
f–i
O
O
OH
O
OH OH
j
EtO
EtO
22
21
a,d (10%)
a (85%)
B
OH
OH
O
O
O
O
O
EtO
EtO
23
24
Scheme 3 Ring-closing metathesis strategy towards the Z-config-
ured trisubstituted alkene. Reagents and conditions: (a) allyl(diiso-
propoxy)borane (20, 2 equiv), 19 (12 mol%), CH2Cl2, 40 °C, 2 h, 69%
for 16; (b) 1 M NaOH, THF, 35% H2O2, 0 °C to r.t., decomposition;
(c) Na2BO2·H2O2·3 H2O, r.t., 1.5 h, 42%; (d) buffered 35% H2O2
O
OTBS
H
a–c
d
10
(pH 8.8), dioxane–H2O,
0
°C to r.t., 1.5 h, 42%; (e)
O
OTBS
Me
Me(OMe)NH·HCl, 2 M Me3Al in heptane, THF, –15 °C to r.t., 24 h;
(f) Et3SiCl, imidazole, DMF, 0 °C, 2 h, 61% for two steps; (g)
DIBAL-H, THF, –78 °C, 2 h; (h) N2CH2CO2Et, SnCl2, CH2Cl2, r.t.,
24 h, 81% for two steps; (i) AcOH, H2O, THF, r.t., 1 h, 99%; (j)
Me4NBH(OAc)3, MeCN, AcOH, –40 °C, 2 d, 90% (dr 30:1).
H
F3CCH2O
F3CCH2O P
O
OMe
12
O
11
OTBS
O
O
O
O
OH
When the corresponding Weinreb amide 17 was subjected
to the ring-closing metathesis conditions no product was
formed and 17 was reisolated in only 50% yield.
O
N
O
N
Bn 14
Bn
13
Therefore, we first elongated the Weinreb amide 17 with
ethyl diazoacetate after two standard steps (O-silylation
and reductive formation of the aldehyde).17 The resulting
b-keto ester was deprotected18 to afford b-hydroxy ketone
21. The following 1,3-anti-selective reduction protocol
yielded diol 22 and this reaction proceeded with very
good diastereocontrol (dr 30:1).19 Allyl alcohols 21 and
Scheme 2 Still–Gennari strategy towards the Z-configured trisub-
stituted alkene. Reagents and conditions: (a) KHMDS, 18-crown-6,
THF, –78 °C, 2 h, 71%; (b) DIBAL-H, THF, –78 °C, 1 h, 70%; (c)
MnO2, CH2Cl2, r.t., 0.5 h, 89%; (d) 14, Bu2BOTf, Et3N, THF, –78 °C
to r.t., 1.5 h; then –78 °C and addition of 12, 17 h, 66%.
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
307
O
OH
a–c
ref. 24–26
P
EtO
CO2Et
O
CO2Et
EtO
c, d
OPiv
a, b
HO
15
HO
H
9
30
CO2Et
OPiv
25
26
O
OTBDPS
i–l
OTBDPS
e–h
TESO
29
O
O
H
OEt
e
d
O
OEt
O
30
O
ref. 27
H
O
O
27
31
CO2Et
28
O
Scheme 4 Synthesis of ester 28. Reagents and conditions: (a)
LiBH4, THF, 0 °C, 2 h; then H2O2, MeOH, H2O, 90%; (b) PivCl, py,
CH2Cl2, –20 °C, 2 h, 96%; (c) allyl(diisopropoxy)borane (20, 2
equiv), 19 (3 mol%), CH2Cl2, reflux, 20 h; then H2O; (d) buffered
35% H2O2 (pH 8.8), –5 °C to 0 °C, 1 h, 81% for 2 steps; (e) TBDPSCl,
imidazole, DMAP, CH2Cl2, –5 °C, 10 h, 99%; (f) Et3SiOTf, Et3N,
DMF, r.t., 1 h, 99%; (g) DIBAL-H, CH2Cl2, –78 °C, 1 h, 98%; (h)
Dess–Martin periodinane, CH2Cl2, r.t., 2 h; (i) N2CHCO2Et, SnCl2,
CH2Cl2, r.t., 16 h, 85% for 2 steps; (j) TsOH, THF, H2O, r.t., 24 h,
95%; (k) Me4NBH(OAc)3, MeCN, AcOH, –40 °C, 2 d, 90%
(dr 30:1); (l) Me2C(OMe)2, TsOH, r.t., 2 h, 97%.
Scheme 5 Synthetic routes towards phosphonate 9. Reagents and
conditions: (a) NaBH4, EtOH, r.t., 2 h, 99%; (b) PBr3, Et2O, reflux, 1
h; (c) P(OEt)3, 120 °C, 1 h, 91% for two steps; (d) N2CHCO2Et,
Rh2(OAc)4, 25 °C, r.t., 18 h; (e) I2, CH2Cl2, r.t., 6 h, 40% for two steps.
4
The Aromatic Building Block
OMe
OMe
OH
OMe
a–c
d–f
Br
22 were transformed into allyl alcohol 23 and boronate 24,
respectively. The poor yield of b-keto ester 21 was most
likely due to the presence of its enol form, which could
also react with the allyl(diisopropoxy)borane (20). Sup-
port for this hypothesis came from the isolation of cyclic
boronate 24 as the main product from diol 22.
NO2
NO2
NHTBS
OMe
33
O
PhO2S
OMe
32
7
Scheme 6 Synthesis of aromatic building block 7. Reagents and
conditions: (a) MeI, Ag2O, CH2Cl2, 40 °C, 3 h, 73%; (b) NaBH4,
MeOH, 0 °C, 1 h, 92%; (c) Ph3P, CBr4, Et2O, 0 °C, 1 h then r.t., 2 h,
86%; (d) PhSO2Na, DMF, 50 °C, 14 h, 85%; (e) Pd/C, H2, MeOH, r.t.;
(f) TBSOTf, Et3N, DMF, r.t., 99% for two steps.
Finally, we found that allyl alcohol 25, which can be made
available from oxazolidinone 15, was an ideal precursor
for the ring-closing metathesis strategy in every respect
(Scheme 4). The method gave diol 26 in high yield with a
minimum amount (3 mol%) of catalyst 19 required, and
was scaled up starting with 25 g of 25.20 Aldehyde 27 was
obtained after applying a set of standard reactions (se-
quential protection,21 removal of the pivaloate group22 and
Dess–Martin oxidation23). Utilizing the b-keto ester se-
quence described in Scheme 3 allowed the preparation of
fully protected ester 28.
The synthesis of the aromatic moiety 7 was based on re-
lated work on ansatrienol A (mycotrienol I) published by
Panek and co-workers (Scheme 4).9 Methylation of phe-
nol 32, reduction of the aldehyde group, and finally bro-
mination of the resulting benzylic alcohol yielded
bromide 33. The phenylsulfonyl group was introduced by
nucleophilic substitution using sodium benzenesulfinate.
Hydrogenation of the nitro group followed by N-silylation
of the amino group afforded aromatic building block 7
(Scheme 6).
3
The Triene Unit
Phosphonate 9 was made available from furan 29 follow-
ing two different routes (Scheme 5). Tetramethoxybutene
was prepared by oxidative cleavage of furan with bromine
in methanol.24 Subsequent partial hydrolysis to the
monoaldehyde,25 Horner–Wadsworth–Emmons elonga-
tion by two carbon atoms and subsequent hydrolysis of
the remaining acetal group provided aldehyde 30. Reduc-
tion, bromination of the resulting hydroxy group26 and fi-
nally Michaelis–Arbuzov reaction led to the desired
phosphonate 9. Alternatively, intermediate 30 could be
accessed in a shorter approach which was initiated by car-
bene addition of ethyl diazoacetate to furan 29.27 The re-
sulting (E,Z)-dienal 31 was isomerized to (E,E)-dienal 30
in the presence of a catalytic amount of iodine.
5
Assembly of the Ansa Chain and Synthesis of
Ansatrienol
It should be pointed out that the synthetic routes described
so far allow access to all three building blocks 7, 9, and 28
in multigram amounts (>10 g). In the following, we as-
sembled the macrocycle after formation of aldehyde 34
(from ester 28) (Scheme 7). Horner–Wadsworth–Em-
mons alkenation with phosphonate 9 yielded triene ester
[(E,E)/(Z,E) 6:1] that was transformed via a reduction–
oxidation sequence28 into the corresponding aldehyde 35,
which then was subjected to Duthaler–Hafner acetate al-
dol reaction conditions.29 Thus, in situ formation of eno-
late 36 and reaction with aldehyde 35 yielded aldol
product 37. Here, separation of the minor Z,E-isomer
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

308
D. Kashin et al.
FEATURE ARTICLE
MeO
NHR
OMe
OTBDPS
OTBDPS
a–e
b–d
40
O
a
X
O
H
OH
O
O
O
O
28 X = OEt
34 X = H
O
O
35
O
OMe
OTBDPS
Ot-Bu
e
f–j
41 R = alloc
42 R = H
f
O
O
O
OH
MeO
37
X
OPiv
NH
g, h
MeO
O
O
HO
HO
Ti
O
L
L
O
OMe
OMe
38 X = Cl
39 X = I
43
k
Ot-Bu
36
Scheme 8 End game towards ansatrienol 43. Reagents and conditi-
ons: (a) polytriphenylphosphonium bromide, MeOH, r.t., 1 h; (b) allyl
chloroformate, acetone, 5 M K2CO3, r.t., 1 h, 92% for two steps; (c)
LiOH, r.t., 5 d, 86%; (d) TPAP, NMO, acetone, r.t., 1 h, 78%; (e)
NaClO2, NaH2PO4·H2O, t-BuOH, H2O, 2-methylbut-2-ene, r.t., 82%;
(f) Pd(PPh3)4 (20 mol%), THF, morpholine, r.t., 12 h; (g) 2-chloro-1-
methylpyridinium iodide, Et3N, toluene, r.t., 26% for two steps; (h)
10-camphorsulfonic acid, MeOH, r.t., 2 h, 91%.
O
l, m
O
O
O
H
MeO
NHTBS
OMe
L =
O
O
OPiv
O
O
OMe
40
group, the aniline derivative 40 was collected in excellent
yield (77% for three steps). Aniline derivative 40 contains
the entire carbon backbone of the ansatrienins.
Scheme 7 Coupling of building blocks 7, 9, and 34. Reagents and
conditions: (a) DIBAL-H, CH2Cl2, –78 °C, 2 h, 99%; (b) 9, LiHMDS,
THF; then 34, –78 °C to –10 °C, 10 h, 96%; (c) DIBAL-H, THF, –78
°C, 2 h, 96%; (d) NMO, TPAP, CH2Cl2, MS 4 Å, r.t., 2 h, 72%; (e)
CpTiCl3, diacetone-D-glucose (L-H), LDA, t-BuOAc, Et2O, –78 °C to
–65 °C, 12 h, 93%; (f) MeI, Ag2O, CH2Cl2, r.t., 2 d, 88%; (g) LiAlH4,
Et2O, 0 °C to r.t., 3 h, 93%; (h) PivCl, py, CH2Cl2, 0 °C to r.t., 1 h,
98%; (i) TBAF, THF, r.t., 2 h, 94%; (j) LiCl, 2,6-lutidine, MsCl,
DMF, r.t., 1 h, 79%; (k) NaI, 2,6-di-tert-butylpyridine, acetone, r.t., 1
h; (l) 7, NaHMDS (2 equiv), THF, –78 °C, 1 h; (m) 5% Na(Hg),
Na2HPO4, MeOH, –10 °C, 1 h, 77% for three steps.
Before the macrolactamization could take place
(Scheme 8), we had to exchange the labile N-silyl protect-
ing group (it was commonly cleaved upon attempted lib-
eration of the carboxylic acid at C1) for the N-
allyloxycarbonyl (alloc) group. Polytriphenylphosphoni-
um bromide served as a mild proton source for tert-bu-
tyldimethylsilyl cleavage.30 Hydrolysis of the pivaloate
ester with lithium hydroxide into the corresponding
alcohol31 and subsequent oxidation of the primary alcohol
led to carboxylic acid 41. Liberation of the free amino
group32 was followed by Mukaiyama macrolactamization
of amino acid 42.33 Finally, deprotection of the acetonide
at C11 and C1334 yielded ansatrienol 43, thereby complet-
ing the formal total synthesis of several ansatrienins.9b
(formed during Horner–Wadsworth–Emmons alkenation)
from the E,E-isomer by chromatography became possi-
ble.
Standard functional group manipulations (O-methylation,
ester reduction and protection, removal of silyl protection,
mesylation followed by chloride substitution, and Finkel-
stein iodination) yielded allyl iodide 39 which represents
the complete ansa chain (Scheme 7). The rationale for this
synthetic sequence is as follows: While envisaging the
coupling between the sulfone-stabilized carbanion and the
allyl iodide 39 according to Smith’s protocol, we had to
face the facile elimination of methanol at C2/C3 and for-
mation of the corresponding tetraene. Indeed, this prob-
lem turned up at all stages of the synthesis when a
carbonyl group was still present at C1. Therefore, we first
had to reduce the tert-butyl ester. Only by eliminating the
electron-withdrawing properties of the carbonyl group at
C1 it became possible to couple the dianion derived from
7 with iodide 39. After reductive removal of the sulfone
In conclusion, we have developed a practical, high yield-
ing, and very stereocontrolled synthesis of the benzenic
ansamycin antibiotic ansa chain (22 linear steps from ox-
azolidinone 15 to allyl chloride 38 in 17.2% overall yield).
Synthetic key steps were the one-pot formation of the Z-
configured trisubstituted alkene at C14/C15 by ring-clos-
ing metathesis and the rarely employed Duthaler–Hafner
acetate aldol reaction, which proceeded with excellent ste-
reocontrol. We demonstrated that the synthetic approach
is well suited for the preparation of ansatrienol 43, a
known precursor of the ansatrienins. Currently, we are ex-
ploiting this synthetic route to generate hybrid antibiotics
that are composed of the ansatrienin ansa chain and aro-
matic moieties known from other ansamycin antibiotics
such as geldanamycin and ansamitocin.
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
309
NMR spectra were recorded with a Bruker DPX-400 spectrometer
at 400 MHz (1H NMR) and at 100 MHz (13C NMR) and measured
in CDCl3, C6D6, or CD3OD. Chemical shifts were recorded in ppm
relative to internal standard CDCl3 (1H d = 7.25, 13C d = 77.0),
CD3OD (1H d = 4.78, 13C d = 49.3), C6D6. MS spectra were obtained
on a Micromass LCT with Lock-Spray using the electrospray ion-
ization (ESI) mode. Optical rotations were collected on a JASCO
P-1020 polarimeter. Melting points were determined in open glass
capillaries with a Gellenkamp apparatus and are uncorrected. All re-
actions were carried out in oven-dried glassware under an N2 atmo-
sphere. All solvents were distilled immediately before use: Et2O
and THF (Na, benzophenone), CH2Cl2 (CaH2). Commercially
available reagents and anhydrous solvents (toluene, DMF, MeCN)
were used as received. Analytical TLC was performed using pre-
coated silica gel 60 F254 plates (Merck, Darmstadt). Spots were vi-
sualized with UV light at 254 nm or by staining with H2SO4/
4-methoxybenzaldehyde in EtOH. Flash column chromatography
was performed on Merck silica gel 60 (230–400 mesh). The prepa-
ration of the following compounds can be found in references: 10,12
12,35 14,15 15,16 17,10,36 20,37 30.27
cooled to 0 °C. 35% H2O2 (10 mL) was added and the mixture was
stirred at 0 °C for 0.5 h and then r.t. for 1 h. Then 37% aq NaHSO3
soln (100 mL) was added. The aqueous layer was washed with brine
and extracted with Et2O (3 × 500 mL). The combined organic phas-
es were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography (hexane–EtOAc,
1:1) to yield the title compound 18 (1.89 g, 42%) as colorless crys-
tals; mp 130–131 °C.
1H NMR (400 MHz, CD3OD): d = 7.18 (m, 5 H, Ph), 5.32 (t, 1 H,
10-H), 4.65 (m, 1 H, 4-H), 4.53 (d, J = 9.4 Hz, 1 H, 8-H), 4.16 (m,
3 H, 3-H, 11-H, 11-H¢), 4.05 (dq, J = 9.4, 6.8 Hz, 1 H, 7-H), 3.98
(ddd, J = 13.2, 5.8, 1.2 Hz, 1 H, 3-H¢), 3.00 (dd, J = 13.5, 3.2 Hz, 1
H, Bn), 2.86 (dd, J = 13.5, 8.0, 1 H, Bn), 1.62 (s, 3 H, 9-CH3), 1.26
(d, J = 6.8 Hz, 3 H, 7-CH3).
13C NMR (100 MHz, CD3OD): d = 176.9, 155.2, 139.3, 137.0,
131.0, 130.0, 129.1, 128.5, 72.2, 67.9, 59.3, 56.8, 43.2, 38.5, 18.7,
15.5.
HRMS (EI): m/z [M+ + Na] calcd for C18H23NNaO5: 356.1471;
found: 356.1488.
(4R)-4-Benzyl-3-[(Z,2R,3R)-6-(tert-butyldimethylsiloxy)-3-hy-
droxy-2,4-dimethylhex-4-enoyl]oxazolidin-2-one (13)
(2R,3R)-3-Hydroxy-2,4-dimethylpent-4-enoic Acid N-Methoxy-
N-methylamide (17)
Oxazolidinone 14 (82 mg, 0.35 mmol) was diluted in anhyd THF (5
mL) and cooled to –78 °C. Et3N (60 mL, 0.43 mmol) and 1 M
Bu2BOTf in THF (0.43 mL, 0.43 mmol) were added and the soln
was warmed to r.t. After 1.5 h, the soln was cooled to –78 °C and a
soln of aldehyde 12 (88 mg, 0.41 mmol) in anhyd THF (3 mL) was
added. The resulting soln was stirred for 17 h at this temperature.
Then, the reaction was terminated by addition of phosphate buffer
soln (pH 7, 5 mL). The aqueous phase was extracted with Et2O
(3 × 10 mL) and the combined organic phases were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by flash chromatography (hexane–EtOAc,
1:1) to yield the title compound 13 (123 mg, 66%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 7.35–7.19 (m, 5 H, Ph), 5.46 (m,
1 H, 10-H), 4.65 (m, 3 H, 4-H, 3-H, 3-H¢), 4.33 (dd, J = 8.0, 1.0 Hz,
1 H, 8-H), 4.23–4.14 (m, 3 H, 7-H, 11-H, 11-H¢), 3.25 (dd, J = 13.3,
3.3 Hz, 1 H, CH2Ph), 2.89 (s, 1 H, OH), 2.76 (dd, J = 13.3, 9.6 Hz,
1 H, CH2Ph), 1.74 (s, 3 H, 9-CH3), 1.34 (d, 3 H, 7-CH3), 0.90 (s, 9
H, Si-t-Bu), 0.08 [s, 6 H, Si(CH3)2].
Me(OMe)NH·HCl (18.3 g, 188 mmol, 3 equiv) was dissolved in an-
hyd THF (100 mL), cooled to 0 °C and treated with 2 M Me3Al in
THF (94 mL, 188 mmol) over a period of 10 min. Stirring was con-
tinued at r.t. for a further 30 min. The temperature was lowered to
–15 °C and a soln of oxazolidinone 15 (19 g, 62.6 mmol) in anhyd
THF (160 mL) was added. The soln was allowed to warm to r.t. and
was stirred for 24 h after which time the soln was poured into a
cooled mixture (0 °C) of CH2Cl2 (450 mL) and 0.5 M HCl (450
mL). The mixture was vigorously stirred at r.t. for 1 h. The aqueous
layer was extracted with CH2Cl2 (3 × 400 mL) and the resulting or-
ganic phases were washed with brine, dried (MgSO4) and concen-
trated under reduced pressure. Co-distillation with toluene (3 ×)
afforded a dry crude product 17 that was directly used for the next
reaction; mp 76–77 °C (Lit.36 76–78 °C).
1H NMR (200 MHz, CDCl3): d = 5.17 (m, 1 H, 5-H), 4.99 (m, 1 H,
5-H¢), 4.33 (m, 1 H, 3-H), 3.73 (s, 3 H, N-OCH3), 3.22 (s, 3 H, N-
CH3), 3.07 (m, 1 H, 2-H), 1.72 (s, 3 H, 4-CH3), 1.11 (d, J = 6.8 Hz,
3 H, 2-CH3).
13C NMR (100 MHz, CDCl3): d = 175.7, 152.9, 137.0, 135.1, 129.4,
128.9, 128.5, 127.4, 72.0, 66.1, 59.5, 55.2, 41.7, 37.7, 26.0, 19.6,
18.3, 13.1, –5.2.
13C NMR (50 MHz, CDCl3): d = 143.0, 111.9, 74.0, 72.4, 61.5, 36.4,
19.6, 9.8.
HRMS (ESI): m/z (M + Na+ + MeCN) calcd for C11H20N2NaO3:
251.1372; found: 251.1378.
(4R)-4-Benzyl-3-{(2R)-2-[(6R)-2-hydroxy-5-methyl-3,6-dihy-
dro-2H-1,2-oxaborinin-6-yl]oxazolidin-2-one (16)
(2R,3R)-2,4-Dimethyl-3-(triethylsiloxy)pent-4-enoic Acid
N-Methoxy-N-methylamide
To a soln of allylboronic ester 20 (6.72 g, 39.6 mmol) in anhyd
CH2Cl2 (100 mL) were added oxazolidinone 15 (6.0 g, 19.8 mmol)
and Grubbs catalyst 19 (2.0 g, 2.37 mmol). The soln was heated un-
der reflux for 2 h and then washed with brine. The organic layer was
dried (Na2SO4) and concentrated under reduced pressure. The resi-
due was purified by flash chromatography (hexane–EtOAc, 2:1) to
yield the title compound 16 (4.69 g, 69%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 7.28 (m, 5 H, Ph), 5.65 (s, 1 H, 10-
H), 4.90, 4.85 (m, 1 H, 8-H), 4.68 (m, 1 H, 4-H), 4.20 (m, 2 H, 3-H,
3-H¢), 4.09 (dq, J = 6.9, 2.4 Hz, 1 H, 7-H), 3.37 (dd, J = 13.2, 3.1
Hz, 1 H, Bn), 2.78 (dd, J = 13.2, 9.8 Hz, 1 H, Bn), 1.70 (s, 3 H, 9-
CH3), 1.42 (m, 2 H, 11-H, 11-H¢), 1.06 (d, J = 6.9 Hz, 3 H, 7-CH3).
The resulting amide 17 was dissolved in anhyd DMF (30 mL), treat-
ed with imidazole (6.40 g, 94 mmol) and cooled to 0 °C. Et3SiCl
(15.8 mL, 94 mmol) was added and the soln was stirred for 2 h. Et2O
(30 mL) and sat. aq NaHCO3 were added, the aqueous phase was
extracted with Et2O (3 × 30 mL), and the combined organic phases
were washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (hexane–EtOAc, 7:1) to yield the title compound (11.5 g,
61% for 2 steps) as a colorless oil.
[a]D20 9.3 (c 0.9, CHCl3).
1H NMR (200 MHz, CDCl3): d = 4.88 (m, 1 H, 5-H), 4.77 (m, 1 H,
5-H¢), 4.25 (d, J = 8.8 Hz, 1 H, 3-H), 3.66 (s, 3 H, N-OCH3), 3.13
(s, 3 H, N-CH3), 3.11 (m, 1 H, 2-H), 1.71 (br s, 3 H, 4-CH3), 1.19
(d, J = 6.8 Hz, 3 H, 2-CH3), 0.94 [m, 9 H, Si(CH2CH3)3], 0.60 [m, 6
H, Si(CH2CH3)3].
13C NMR (50 MHz, CDCl3): d = 175.0, 146.0, 112.7, 78.2, 61.4,
40.5, 32.0, 17.1, 14.5, 6.9, 4.8.
HRMS (EI): m/z [M+] calcd for C18H22BNO5: 343.1591; found:
343.1592.
(4R)-4-Benzyl-3-[(Z,2R,3R)-3,6-dihydroxy-2,4-dimethylhex-4-
enoyl]oxazolidin-2-one (18)
Cyclic boronate 16 (4.69 g, 13.7 mmol) was diluted in a buffer
[KCl, B(OH)3, NaOH, dioxane–H2O (1:1), 750 mL; pH 8.8) and
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

310
D. Kashin et al.
FEATURE ARTICLE
HRMS (ESI): m/z [M + Na+ + MeCN] calcd for C17H33N2NaO3Si:
HRMS (ESI): m/z [M + Na+ + MeCN] calcd for C13H21NNaO4:
365.2236; found: 365.2237.
278.1368; found: 278.1375.
(2R,3R)-2,4-Dimethyl-3-(triethylsiloxy)pent-4-enal
Ethyl (3S,4S,5R)-3,5-Dihydroxy-4,6-dimethylhept-6-enoate
(22)
The resulting Weinreb amide (11.5 g, 38.1 mmol) was dissolved in
anhyd THF (170 mL) and cooled to –78 °C. 1.2 M DIBAL-H in tol-
uene (44.5 mL, 53.4 mmol) was added dropwise. After 2 h, the tem-
perature was raised to –50 °C and the reaction was terminated by
addition of MeOH. This mixture was poured into sat. aq potassium
sodium tartrate and stirred for 1 h. The aqueous phase was extracted
with EtOAc (3 × 150 mL) and the combined organic phases were
dried (Na2SO4) and concentrated under reduced pressure. Co-distil-
lation with toluene (3 ×) afforded the dry crude product and which
could be used directly in the next step.
1H NMR (200 MHz, CDCl3): d = 9.70 (d, J = 1.8 Hz, 1 H, 1-H), 4.98
(m, 1 H, 5-H), 4.91 (m, 1 H, 5-H¢), 4.37 (d, J = 5.0 Hz, 1 H, 3-H),
2.56–2.41 (m, 1 H, 2-H), 1.69 (s, 3 H, 4-CH3), 0.98 (d, J = 6.8 Hz,
3 H, 2-CH3), 0.86 [t, J = 7.7 Hz, 9 H, Si(CH2CH3)3], 0.63–0.49 [m,
6 H, Si(CH2CH3)3].
Me4NBH(OAc)3 (64.1 g, 243 mmol) was dissolved in anhyd MeCN
(150 mL) and glacial AcOH (150 mL) was added and the mixture
was stirred at r.t. for 0.5 h. The soln was cooled to –40 °C and a soln
of b-keto ester 21 (6.52 g, 30.4 mmol) dissolved in anhyd MeCN
(60 mL) was added. The soln was stirred at –40 °C for 48 h and
treated with sat. aq potassium sodium tartrate and stirred at r.t. for 1
h. The mixture was diluted with CH2Cl2 and the organic phase was
washed with sat. NaHCO3. The aqueous phase was extracted with
CH2Cl2 (4 ×). The combined organic phases were dried (Na2SO4)
and concentrated under reduced pressure to yield the title compound
22 as a colorless oil which was directly used in the following reac-
tion.
[a]D20 –60.4 (c 0.8, CHCl3).
1H NMR (200 MHz, CDCl3): d = 5.06 (m, 1 H, 7-H), 4.94 (m, 1 H,
7-H¢), 4.44 (br s, 1 H, 5-H), 4.16 (q, J = 7.2 Hz, 2 H, OCH2CH3),
4.12 (m, 1 H, 3-H), 3.57 (br s, 1 H, OH), 2.84 (br s, 1 H, OH), 2.60
(d, J = 6.3 Hz, 2 H, 2-H, 2-H¢), 1.76 (m, 1 H, 4-H), 1.69 (s, 3 H, 6-
CH3), 1.29 (t, 3 H, OCH2CH3), 0.88 (d, J = 7.0 Hz, 3 H, 4-CH3).
13C NMR (50 MHz, CDCl3): d = 173.1, 145.6, 110.4, 73.7, 71.2,
60.8, 39.6, 39.4, 19.7, 14.1, 9.7.
13C NMR (50 MHz, CDCl3): d = 204.6, 144.8, 112.7, 75.7, 50.4,
18.3, 8.2, 6.8, 4.7.
Ethyl (4R,5R)-4,6-Dimethyl-3-oxo-5-(triethylsiloxy)hept-6-
enoate
A suspension of SnCl2 (1.45 g, 7.63 mmol) in anhyd CH2Cl2 (170
mL) was treated with ethyl diazoacetate (8.02 mL, 76.3 mmol). The
resulting aldehyde described above was dissolved in anhyd CH2Cl2
(30 mL) and added to the tin(II) soln. The resulting mixture was
stirred at r.t. for 24 h. The aqueous phase was extracted with
CH2Cl2, the combined organic phases were washed with sat.
NaHCO3, dried (Na2SO4), and concentrated under reduced pressure.
The crude product was purified by flash chromatography (hexane–
EtOAc, 25:1) to yield the title compound (10.2 g, 81%) as a color-
less oil.
HRMS (ESI): m/z [M + Na+ + MeCN] calcd for C13H23NNaO4:
280.1525; found: 280.1519.
Ethyl [(4S,5S,6R)-2-Allyl-6-isopropenyl-5-methyl-1,3,2-dioxa-
borinan-4-yl]acetate (24)
Diol 22 (50 mg, 0.23 mmol) was dissolved in anhyd CH2Cl2 (8 mL)
and treated with allyl(diisopropoxy)borane (20, 145 mL, 0.69
mmol). After 0.5 h the soln was concentrated under reduced pres-
sure and purified by flash chromatography (hexane–EtOAc, 10:1)
to yield the title compound 24 (52 mg, 85%) as a colorless oil.
1H NMR (200 MHz, CDCl3): d = 5.87 (dddd, J = 17.2, 9.8, 7.5, 7.5
Hz, 1 H, CH2CH=CH2), 5.07, 4.98, 4.89, 4.84 (m, 4 H,
CH2CH=CH2, 7-H, 7-H¢), 4.41 (m, 1 H, 5-H), 4.26 (ddd, J = 7.3,
6.6, 3.1 Hz, 1 H, 3-H), 4.17 (q, J = 7.1 Hz, 2 H, OCH2CH3), 2.67
(dd, J = 14.9, 7.3 Hz, 1 H, 2-H), 2.54 (dd, J = 14.9, 6.6 Hz, 1 H, 2-
H¢), 2.06–1.92 (m, 1 H, 4-H), 1.70 (s, 2 H, CH2CH=CH2), 1.66 (s, 3
H, 6-CH3), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.85 (d, J = 7.2 Hz,
3 H, 4-CH3).
[a]D20 +43.7 (c 0.94, CHCl3).
IR (film): 2958, 2932, 2858, 1741, 1712, 1651, 1265, 909, 735 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.06 (s, enol-OH), 4.97 (s, 2-H,
enol), 4.93, 4.89, 4.87, 4.83 (4 m, 7-H und 7-H¢, keto + enol), 4.23
(m, 1 H, 5-H, keto + enol), 4.19 (q, J = 7.0 Hz, OCH2CH3, enol),
4.18 (q, J = 7.2 Hz, OCH2CH3, keto), 3.47 (s, 2-H, keto), 2.84
(pseudo quint, J = 6.8 Hz, 4-H, keto + enol), 1.69 (br s, 6-CH3, keto
+ enol), 1.28 (t, J = 7.0 Hz, OCH2CH3, enol), 1.27 (t, J = 7.0 Hz,
OCH2CH3, keto), 1.12 (d, J = 6.8 Hz, 4-CH3, keto), 1.09 (d, J = 6.8
Hz, 4-CH3, enol), 0.94 (m, SiCH2CH3, keto), 0.92 (m, SiCH2CH3,
enol), 0.60 (m, SiCH2CH3, keto), 0.58 (m, SiCH2CH3, enol).
Ethyl (Z,4R,5R)-5,8-Dihydroxy-4,6-dimethyl-3-oxooct-6-enoate
(23)
13C NMR (50 MHz, CDCl3): d = 205.4, 180.1, 145.0, 113.4, 89.6,
61.2, 51.1, 49.5, 17.6, 14.1, 6.8, 4.7.
Ethyl ester 21 (50 mg, 0.23 mmol) was dissolved in anhyd CH2Cl2
and treated with allyl(diisopropoxy)borane (20, 0.12 mL, 0.58
mmol). After 10 min Grubbs catalyst 19 (23 mg, 28 mmol) was add-
ed and the soln was heated under reflux for 2 h. The reaction was
terminated by addition of brine (10 mL) and the aqueous phase was
extracted with CH2Cl2. The combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude ma-
terial was purified by flash chromatography (hexane–EtOAc, 4:1).
The resulting material was immediately dissolved in a buffer [KCl,
B(OH)3, NaOH, dioxane–H2O, 1:1), 5 mL; pH 8.8], cooled to 0 °C
and treated with 35% H2O2 (50 mL). After completion of the reac-
tion 38% aq NaHSO3 soln (1 mL) was added. The aqueous phase
was extracted with Et2O (3 × 5 mL) and the combined organic phas-
es were dried (Na2SO4) and concentrated under reduced pressure.
Flash chromatography (hexane–EtOAc, 1:1) yielded the title com-
pound 23 (5.4 mg, 10% for 2 steps) as a colorless oil.
Ethyl (4R,5R)-5-Hydroxy-4,6-dimethyl-3-oxohept-6-enoate (21)
The resulting b-keto ester (10 g, 30.4 mmol) was dissolved in anhyd
THF (30 mL) and treated with H2O (90 mL) and glacial AcOH (180
mL) to cleave the silyl protecting group. The mixture was stirred for
1 h and the soln was concentrated to ~15 mL under reduced pressure
and filtered through a pad of silica gel (hexane–EtOAc, 4:1). Con-
centration of the filtrate under reduced pressure yielded the title
compound 21 (6.52 g, 99%) as a yellow oil.
1H NMR (200 MHz, CDCl3): d = 5.08 (m, 1 H, 7-H), 4.97 (m, 1 H,
7-H¢), 4.47 (br s, 1 H, 5 H), 4.21 (q, J = 7.2 Hz, 2 H, OCH2CH3),
3.57 (br s, 2 H, 2-H), 2.87 (dq, J = 7.2, 3.4 Hz, 1 H, 4-H), 2.48 (s, 1
H, OH), 1.70 (s, 3 H, 6-CH3), 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3),
1.10 (d, J = 7.2 Hz, 3 H, 4-CH3).
13C NMR (50 MHz, CDCl3): d = 206.8, 182.4, 143.7, 112.0, 73.6,
61.5, 48.6, 48.1, 19.3, 14.1, 9.1.
1H NMR (200 MHz, CDCl3): d = 12.18 (s, enol-OH), 5.61 (m, 1 H,
7-H, keto + enol), 4.99 (s, 2-H, enol), 4.72 (d, J = 6.9 Hz, 5-H, keto),
4.64 (d, J = 7.8 Hz, 5-H, enol), 4.25–4.19 (m, 8-H, keto + enol,
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
311
OCH2CH3, enol), 4.13 (q, J = 7.1 Hz, OCH2CH3, keto), 4.08 (dd,
J = 13.1, 7.3 Hz, 1 H, 8-H¢, keto), 3.50 (s, 2-H, keto), 2.98 (pseudo
quint, J = 7.0 Hz, 4-H, keto), 2.54–2.40 (m, 4-H, enol), 2.40 (m, 5-
OH, keto + enol), 1.75 (s, 6-CH3, keto + enol), 1.28 (m, OCH2CH3,
4-CH3, keto + enol).
mL) and the aqueous phase was extracted with CH2Cl2 (2 × 500
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. Purification was achieved by
flash chromatography (hexane–EtOAc, 8:1) to afford the cyclic bo-
ronate (8.52 g, 33.5 mmol) as colorless oil. This residue was taken
up in a pre-cooled (–5 °C to 0 °C) phosphate buffer [KCl, B(OH)3,
NaOH, dioxane–H2O, 1:1), 1.5 L; pH 8.8] and 30% H2O2 (12 mL)
was added dropwise over a period of 2 h. Stirring was continued for
1 h at this temperature and the reaction was terminated by addition
of 38% aq NaHSO3 soln (100 mL). The aqueous layer was extracted
with t-BuOMe (3 × 500 mL) and the combined organic extracts
were dried (Na2SO4) and concentrated under reduced pressure. Pu-
rification was achieved by flash chromatography (hexane–EtOAc,
2:1) to afford the title compound 26 (6.67 g, 81% for two steps) as
a colorless oil.
(2S,3R)-2,4-Dimethylpent-4-ene-1,3-diol
To a soln of oxazolidinone 15 (19.7 g, 64.9 mmol) in anhyd THF
(250 mL) was added LiBH4 (4.95 g, 227 mmol) at 0 °C over a period
of 10 min. After 2 h the reaction was terminated by addition of sat.
potassium sodium tartrate soln (300 mL) and the mixture was
stirred for 1.5 h. The aqueous phase was extracted with t-BuOMe
(3 × 300 mL) and the combined organic phases were concentrated
under reduced pressure. The residual oil crude oil was dissolved in
MeOH–H2O (1:1) and 30% H2O2 (20 mL) was added at 0 °C. The
mixture was stirred at r.t. for 30 min and the excess of H2O2 was re-
duced at 0 °C by careful addition of 38% aq NaHSO3 soln (60 mL).
The aqueous layer was extracted with t-BuOMe (4 × 300 mL). The
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated under reduced pressure. Addition of t-BuOMe dis-
solved the product while the oxazolidinone could be filtered and
washed with t-BuOMe. The combined organic phases were concen-
trated under reduced pressure. The residue was purified by flash
chromatography (hexane–t-BuOMe, 1:1) to yield the title com-
pound (7.61 g, 90%) as a colorless oil.
[a]D20 –16.4 (c 1.03, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.57 (m, 1 H, 5-H), 4.31 (d, J = 7.7
Hz, 1 H, 3-H), 4.18 (dd, J = 12.4, 8.2 Hz, 1 H, 6-H), 4.09 (dd,
J = 11.0, 5.8 Hz, 1 H, 1-H), 4.06 (dd, J = 12.4, 6.5 Hz, 1 H, 6-H¢),
3.73 (dd, J = 11.0, 5.6 Hz, 1 H, 1-H¢), 2.64 (br s, 2 H, 2 OH), 2.02
(m, 1 H, 2-H), 1.75 (m, 3 H, 4-CH3), 1.20 (s, 9 H, t-Bu), 1.05 (d,
J = 6.8 Hz, 3 H, 2-CH3).
13C NMR (100 MHz, CDCl3): d = 178.9, 139.8, 127.2, 71.6, 66.2,
58.0, 38.9, 36.6, 27.2, 19.1, 12.7.
[a]D20 +18.7 (c 1.04, CHCl3).
HRMS: m/z [M+ + Na + MeCN] calcd for C15H27NNaO4: 308.1838;
1H NMR (400 MHz, CDCl3): d = 4.99 (m, 1 H, 5-H), 4.92 (m, 1 H,
5-H¢), 4.23 (d, J = 3.5 Hz, 1 H, 3-H), 3.70 (dd, J = 10.7, 4.5 Hz, 1
H, 1-H), 3.66 (dd, J = 10.7, 5.8 Hz, 1 H, 1-H¢), 2.54 (br s, 2 H, 2
OH), 1.92–1.83 (m, 1 H, 2-H), 1.70 (s, 3 H, 4-CH3), 0.86 (d, J = 7.0,
3 H, 2-CH3).
13C NMR (100 MHz, CDCl3): d = 146.2 (q, C4), 110.5 (s, C5), 76.9
(t, C3), 66.7 (s, C1), 37.2 (t, C2), 19.2 (p, 4-CH3), 9.7 (p, 2-CH3);
found: 308.1824.
(Z,2S,3R)-6-(tert-Butyldiphenylsiloxy)-3-hydroxy-2,4-dimethyl-
hex-4-enyl 2,2-Dimethylpropanoate
To a cooled soln (–5 °C) of 26 (12.7 g, 51.9 mmol) in anhyd CH2Cl2
(400 mL) were added imidazole (5.3 g, 78 mmol), DMAP (0.64 g,
5.2 mmol), and, over a period of 1 h dropwise, TBDPSCl (14 mL,
54.6 mmol). The mixture was stirred for 10 h at this temperature and
terminated by addition of sat. aq NaHCO3 (250 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 300 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure. The product was purified by flash chromatography (hex-
ane–EtOAc, 10:1) afforded the title compound (24.9 g, 99%) as a
colorless oil.
HRMS: m/z [M+] calcd for C7H14O2: 130.0991; found: 130.0991.
(2S,3R)-3-Hydroxy-2,4-dimethylpent-4-enyl 2,2-Dimethylpro-
panoate (25)
A soln of the diol described above (15 g, 115 mmol) in anhyd pyri-
dine–CH2Cl2 (1:1, 500 mL) was treated dropwise with PivCl (14.5
mL, 118 mmol) at –20 °C. The soln was stirred at –20 °C for 2 h
followed by hydrolysis with sat. aq NaHCO3 (250 mL). The aque-
ous layer was extracted with CH2Cl2 (3 × 150 mL) and the com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy (hexane–EtOAc, 15:1) to afford the title compound 25 (23.7 g,
96%) as a highly hygroscopic, colorless crystals.
[a]D20 +1.4 (c 1.01, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.70–7.67 (m, 4 H, Ph), 7.46–7-
36 (m, 6 H, Ph), 5.52 (m, 1 H, 5-H), 4.28 (dd, J = 12.7, 8.0 Hz, 1 H,
6-H), 4.17–4.12 (m, 1 H, 6-H¢), 4.03 (dd, J = 7.6, 3.6 Hz, 1 H, 3-H),
3.99 (dd, J = 11.0, 5.8 Hz, 1 H, 1-H), 3.58 (dd, J = 11.0, 5.8 Hz, 1
H, 1-H¢), 1.89 (pseudo sept, J = 6.7 Hz, 1 H, 2-H), 1.70 (m, 3 H, 4-
CH3), 1.51 (d, J = 3.6 Hz, 1 H, 3-OH), 1.10 (s, 9 H, t-Bu in Piv),
1.04 (s, 9 H, t-Bu in TBDPS), 0.94 (d, J = 6.7 Hz, 3 H, 2-CH3).
13C NMR (100 MHz, CDCl3): d = 178.5, 137.8, 135.7, 135.6, 133.8,
133.6, 129.8, 129.7, 127.9, 127.7, 127.6, 71.4, 66.1, 59.8, 38.7,
36.6, 27.1, 26.8, 19.1, 18.6, 12.7.
[a]D20 –3.3 (c 1.04, CHCl3).
1H NMR (400 MHz, CDCl3): d = (m, 1 H, 5-H), 4.92 (m, 1 H, 5-H¢),
4.13 (dd, J = 11.0, 7.0 Hz, 1 H, 1-H), 4.03 (d, J = 4.8 Hz, 1 H, 3-H),
3.90 (dd, J = 11.0, 5.9 Hz, 1 H, 1-H¢), 2.06–1.97 (m, 1 H, 2-H),
1.87 (br s, 1 H, OH), 1.70 (s, 3 H, 4-CH3), 1.20 (s, 9 H, t-Bu), 0.90
(d, J = 6.9 Hz, 3 H, 2-CH3).
13C NMR (100 MHz, CDCl3): d = 178.7, 145.6, 111.5, 75.2, 66.6,
38.8, 35.4, 27.2, 18.6, 10.5.
HRMS: m/z [M+ + Na] calcd for C29H42NaO4Si: 505.2750; found:
505.2757.
(Z,2S,3R)-6-(tert-Butyldiphenylsiloxy)-2,4-dimethyl-3-(triethyl-
siloxy)hex-4-enyl 2,2-Dimethylpropanoate
HRMS: m/z [M+] calcd for C12H22O3: 214.1569; found: 214.1576.
To a soln of the ester (40 g, 82.8 mmol) described above in anhyd
DMF (500 mL) was added Et3N (23 mL, 166 mmol). The mixture
was cooled to 0 °C and Et3SiOTf (22.5 mL, 99.4 mmol) was added
dropwise over a period of 40 min. Stirring was continued at r.t. for
1 h before hydrolysis was achieved by addition of sat. aq NaHCO3
(300 mL). The aqueous layer was extracted with hexane (3 × 400
mL) and the combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. Purification of the crude product
(Z,2S,3R)-3,6-Dihydroxy-2,4-dimethylhex-4-enyl 2,2-Dimethyl-
propanoate (26)
A soln of alcohol 25 (7.2 g, 33.6 mmol) in anhyd CH2Cl2 (500 mL)
was treated with allyl(diisopropoxy)borane (20, 14 mL, 67.2 mmol)
and the mixture was stirred at r.t. for 10 min. Then, Grubbs catalyst
19 (0.86 g, 1.01 mmol; 3 mol%) was added in small portions over a
period of 3 to 5 min. The mixture was heated under reflux for 20 h.
The reaction was terminated by addition of sat. aq NaHCO3 (250
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

312
D. Kashin et al.
FEATURE ARTICLE
was achieved by flash chromatography (hexane–EtOAc, 20:1) af-
forded the title compound (49 g, 99%) as a colorless oil.
[a]D20 –9.2 (c 1.01, CHCl3).
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified by flash chromatography (hexane–EtOAc–
Et3N, 30:1:1) to yield the title compound (1.89 g, 85% for 2 steps)
as a colorless oil. The NMR spectra revealed a 2:1 mixture of the
keto and enol tautomers.
1H NMR (400 MHz, CDCl3): d = 7.68–7.67 (m, 4 H, Ph), 7.44–7.35
(m, 6 H, Ph), 5.47–5.44 (m, 1 H, 5-H), 4.36 (dd, J = 12.5, 8.2 Hz, 1
H, 6-H), 4.21 (d, J = 7.5 Hz, 1 H, 3-H), 4.09–4.04 (m, 1 H, 6-H¢),
3.94 (dd, J = 11.0, 5.6 Hz, 1 H, 1-H), 3.58 (dd, J = 11.0, 5.6 Hz, 1
H, 1-H¢), 1.90–1.81 (m, 1 H, 2-H), 1.71 (m, 3 H, 4-CH3), 1.06 (s, 9
H, t-Bu in Piv), 1.04 (s, 9 H, t-Bu in TBDPS), 0.94–0.90 [m, 12 H,
2-CH3, Si(CH2CH3)3], 0.58–0.52 [m, 6 H, Si(CH2CH3)3].
13C NMR (100 MHz, CDCl3): d = 178.3, 137.9, 135.6, 133.8, 133.7,
129.6, 129.5, 127.6, 127.5, 127.3, 71.6, 66.0, 59.9, 38.7, 37.8, 27.1,
26.8, 19.1, 18.6, 13.1, 6.8, 4.7.
[a]D20 +2.5 (c 1.09, CHCl3).
1H NMR (400 MHz, CDCl3): d = 11.85 (s, enol), 7.69–7.66 (m, 4 H,
keto + enol), 7.45–7.36 (m, 6 H, keto + enol), 5.44–5.39 (m, 1 H,
keto + enol), 4.85 (s, 1 H, enol), 4.40 (d, J = 8.5 Hz, 1 H, enol), 4.36
(d, J = 8.2 Hz, 1 H, keto), 4.33 (dd, J = 13.1, 8.2 Hz, 1 H, keto +
enol), 4.11 (q, J = 7.1 Hz, OCH2CH3, enol), 4.10 (q, J = 7.1 Hz,
OCH2CH3, keto), 3.38 (d, J = 15.7 Hz, 1 H, keto), 3.33 (d, J = 15.7
Hz, 1 H, keto), 2.90 (dq, J = 8.3, 6.9 Hz, 1 H, keto), 2.36–2.29 (m,
1 H, enol), 1.71 (s, 3 H, keto), 1.68 (s, 3 H, enol), 1.24 (t, J = 7.1 Hz,
OCH2CH3, enol), 1.20 (t, J = 7.1 Hz, OCH2CH3, keto), 1.16 (d,
J = 6.8 Hz, 3 H, keto), 1.08 (d, J = 6.8 Hz, 3 H, enol), 1.04 (s, 9 H,
t-Bu, keto + enol), 0.91 [t, J = 7.9 Hz, 9 H, Si(CH2CH3)3, keto +
enol], 0.55 [q, J = 7.9 Hz, 6 H, Si(CH2CH3)3, keto + enol].
13C NMR (100 MHz, CDCl3): d = 205.0 (keto), 179.4 (enol), 172.6
(enol), 167.0 (keto), 136.8 (enol), 136.4 (keto), 135.6 (enol), 135.5
(keto), 134.0 (enol), 133.9 (enol), 133.8 (keto), 133.7 (keto), 129.5
(keto + enol), 128.1 (keto + enol), 127.6 (keto + enol), 89.3 (enol),
72.1 (enol), 71.9 (keto), 61.2 (keto), 60.1 (enol), 59.9 (keto), 59.8
(enol), 51.1 (keto), 50.2 (keto), 45.1 (enol), 26.8 (keto + enol), 19.2
(keto + enol), 18.3 (keto), 18.1 (enol), 14.7 (enol), 14.2 (enol), 14.0
(keto), 13.8 (keto), 6.8, 4.8;
HRMS: m/z [M+ + Na] calcd for C35H56NaO4Si2: 619.3615; found:
619.3622.
(Z,2S,3R)-6-(tert-Butyldiphenylsiloxy)-2,4-dimethyl-3-(triethyl-
siloxy)hex-4-en-1-ol
To a soln of the ester (24.7 g, 41.3 mmol) described above in anhyd
CH2Cl2 (500 mL) was added 1.2 M DIBAL-H in toluene (86 mL,
0.103 mol, 2.5 equiv) dropwise at –78 °C over a period of 1 h. The
reaction was terminated by addition of MeOH at –78 °C. This mix-
ture was poured into sat. aq potassium sodium tartrate soln and
stirred for 1 h. The aqueous layer was extracted with CH2Cl2
(3 × 300 mL) and the combined organic layers were dried (Na2SO4)
and concentrated under reduced pressure. Purification of the crude
product was achieved by flash chromatography (hexane–EtOAc,
15:1) to yield the title compound (20.8 g, 98%) as a colorless oil.
HRMS: m/z [M+ + Na] calcd for C34H52NaO5Si2: 619.3251; found:
619.3249.
[a]D20 –57.5 (c 1.05, CHCl3).
Ethyl (Z,4R,5R)-8-(tert-Butyldiphenylsiloxy)-5-hydroxy-4,6-
dimethyl-3-oxooct-6-enoate
1H NMR (400 MHz, CDCl3): d = 7.73–7.69 (m, 4 H, Ph), 7.47–7.38
(m, 6 H, Ph), 5.43 (m, 1 H, 5-H), 4.42 (d, J = 8.5 Hz, 1 H, 3-H), 4.29
(dd, J = 12.0, 8.3 Hz, 1 H, 6-H), 4.29 (dd, J = 12.0, 6.8 Hz, 1 H, 6-
H¢), 3.52 (dd, J = 11.3, 6.2, 3.8 Hz, 1 H, 1-H), 3.43 (dd, J = 11.3,
6.2, 4.8 Hz, 1 H, 1-H¢), 2.78 (t, J = 6.2 Hz, 1 H, OH), 1.81–1.72 (m,
1 H, 2-H), 1.81 (m, 3 H, 4-CH3), 1.05 (m, 12 H, 2-CH3, t-Bu in TB-
DPS), 0.90 [t, J = 7.8 Hz, 9 H, Si(CH2CH3)3], 0.52 [q, J = 7.8 Hz, 6
H, Si(CH2CH3)3].
13C NMR (100 MHz, CDCl3): d = 141.5, 135.7, 135.6, 133.4, 133.3,
129.8, 129.7, 127.8, 127.7, 125.3, 72.4, 64.7, 59.6, 40.3, 26.7, 19.1,
18.4, 13.8, 6.8, 4.8.
HRMS: m/z [M+ + Na] calcd for C30H48NaO3Si2: 535.3040; found:
535.3066.
To a soln of the b-keto ester (35.6 g, 59.6 mmol) mentioned above
in H2O–THF (2:1, 600 mL) was added TsOH (1.13 g, 5.96 mmol).
The mixture was stirred at r.t. for 24 h, then hydrolyzed with sat. aq
NaHCO3 (200 mL). The aqueous phase was extracted with t-
BuOMe (3 × 200 mL) and the combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexane–EtOAc, 8:1) to
yield the title compound (27.4 g, 95%) as a colorless oil. The NMR
spectra reveal a 4:1 mixture of the keto and enol tautomers.
[a]D20 +13.6 (c 1.06, CHCl3).
1H NMR (400 MHz, CDCl3): d = 70–7.66 (m, 4 H, Ph, keto + enol),
7.47–7.37 (m, 6 H, Ph, keto + enol), 5.51–5.43 (m, 1 H, 7-H, keto +
enol), 4.86 (s, 2-H, enol), 4.36 (d, J = 6.4, 3.0 Hz, 5-H, keto), 4.27
(dd, J = 13.2, 7.8 Hz, 1 H, 8-H, keto), 4.33–4.18 (m, 5-H, 8-H,
enol), 4.13 (dq, J = 7.1, 1.9 Hz, OCH2CH3, keto), 4.18–4.09 (m, 8-
H¢, keto + enol, OCH2CH3, enol), 3.39 (d, J = 15.7 Hz, 2-H, keto),
3.35 (d, J = 15.7 Hz, 2-H¢, keto), 2.78 (pseudo quint, J = 6.8 Hz, 4-
H, keto), 2.35–2.28 (m, 4-H, enol), 2.02–2.01 (m, 5-OH, keto +
enol), 1.68 (s, 6-CH3, keto), 1.65 (s, 6-CH3, enol), 1.27 (t, J = 7.1
Hz, OCH2CH3, enol), 1.23 (t, J = 7.1 Hz, OCH2CH3, keto), 1.15 (d,
J = 6.9 Hz, 4-CH3, enol), 1.10 (d, J = 7.0 Hz, 4-CH3, enol), 1.04 (s,
9 H, t-Bu, keto + enol).
13C NMR (100 MHz, CDCl3): d = 205.4 (keto, enol), 172.6 (enol),
167.0 (keto), 136.8 (enol), 135.8 (keto), 135.7 (keto + enol), 135.6
(keto + enol), 133.9 (enol), 133.8 (keto), 133.7 (enol), 133.6 (keto),
129.7 (keto), 129.6 (enol), 128.1 (enol), 127.9 (keto), 127.7 (keto),
127.6 (enol), 127.6 (keto), 127.5 (enol), 89.2 (enol), 71.7 (enol),
71.0 (keto), 61.3 (keto + enol), 60.0 (enol), 59.9 (keto), 50.2 (keto),
48.6 (keto), 43.6 (enol), 26.8 (keto + enol), 19.2 (keto + enol), 19.1
(keto), 18.2 (enol), 14.3 (enol), 14.2 (enol), 14.1 (keto), 11.8 (keto).
(Z,2R,3R)-6-(tert-Butyldiphenylsiloxy)-2,4-dimethyl-3-(trieth-
ylsiloxy)hex-4-enal (27)
To a cooled soln (0 °C) of the alcohol (1.92 g, 3.73 mmol) described
above in anhyd CH2Cl2 (22 mL) was added portionwise Dess–Mar-
tin periodinane (2.37 g, 5.96 mmol). The mixture was stirred at r.t.
for 2 h and then hydrolyzed with a mixture of sat. aq NaHCO3 (25
mL) and sat. aq NaS2O3 (15 mL). The organic phase was washed
with this mixture (40 mL) again and the combined aqueous extracts
were washed CH2Cl2 (40 mL). The combined organic phases were
dried (Na2SO4) and concentrated under reduced pressure. The crude
product 27 was employed in the next step without further purifica-
tion.
Ethyl (Z,4R,5R)-8-(tert-Butyldiphenylsiloxy)-4,6-dimethyl-3-
oxo-5-(triethylsiloxy)oct-6-enoate
To a suspension of SnCl2 (141 mg, 0.75 mmol) in anhyd CH2Cl2 (20
mL) were added N2CHCO2Et (0.77 mL, 7.46 mmol) and freshly
prepared aldehyde 27 (1.91 g, 3.7 mmol) dissolved in anhyd CH2Cl2
(8 mL). The mixture was stirred at r.t. for 16 h and hydrolyzed with
sat. aq K2CO3 (2 mL) and filtered through a pad of silica gel. The
combined organic phases were washed with sat. NaHCO3, dried
HRMS: m/z [M+ + Na] calcd for C28H38NaO5Si: 505.2386; found:
505.2379.
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
313
Ethyl (Z,3S,4S,5R)-8-(tert-Butyldiphenylsiloxy)-3,5-dihydroxy-
4,6-dimethyloct-6-enoate
trated under reduced pressure. The resulting dienol (780 mg, 99%)
was immediately used in the next step.
A soln of Me4NBH(OAc)3 (54 g, 204 mmol) in anhyd AcOH (200
mL) and anhyd MeCN (200 mL) was stirred at r.t. for 0.5 h. The
mixture was cooled to –40 °C and the resulting b-keto ester (12.3 g,
25.5 mmol) mentioned above dissolved in anhyd MeCN (125 mL)
was added. The soln was stirred at this temperature for 48 h after
which time another portion of Me4NBH(OAc)3 (54 g, 204 mmol)
was added. After 5 d the reaction was hydrolyzed with sat. aq potas-
sium sodium tartrate (200 mL). The mixture was allowed to warm
to r.t. and diluted with CH2Cl2. The organic phase was washed with
sat. aq NaHCO3. The aqueous phase was extracted with CH2Cl2
(4 × 200 mL) and the combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexane–EtOAc, 5:1) to
yield the title compound (11.2 g, 90%) as a colorless solid; mp 89–
90 °C.
1H NMR (400 MHz, CDCl3): d = 7.29 (dd, J = 15.6, 10.8 Hz, 1 H,
4-H), 6.41 (dd, J = 15.2, 10.8 Hz, 1 H, 3-H), 6.23 (m, 1 H, 2-H),
5.88 (d, J = 15.6 Hz, 1 H, 5-H), 4.29 (m, 2 H, 1-H, 1-H¢), 4.20 (q,
J = 7.2 Hz, 2 H, OCH2CH3), 1.29 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (100 MHz, CDCl3): d = 167, 143.7, 141.0, 127.7, 121.4,
62.6, 60.4, 14.2.
Ethyl (2E,4E)-6-Bromohexa-2,4-dienoate
To a soln of the resulting alcohol (0.78 g, 4.99 mmol) in anhyd Et2O
(10 mL) was added dropwise PBr3 (0.55 mL, 5.8 mmol) at r.t. The
soln was heated under reflux conditions for 1 h, cooled to r.t. and
poured into cold H2O (20 mL). The aqueous phase was extracted
with Et2O (3 × 20 mL) and the combined organic phases were
washed with brine, dried (Na2SO4), and concentrated under reduced
pressure. The resulting bromide was immediately used in the next
reaction.
[a]D20 –17.6 (c 1.09, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.70–7.67 (m, 4 H, Ph in TBDPS),
7.45–7.36 (m, 6 H, Ph in TBDPS), 5.49 (m, 1 H, 7-H), 4.48 (m, 1 H,
5-H), 4.27–4.19 (m, 2 H, 8-H, 8-H¢), 4.14 (dq, J = 7.2, 2.2 Hz, 2 H,
OCH2CH3), 3.98–3.92 (m, 1 H, 3-H), 3.46 (d, J = 4.4 Hz, 1 H, 5-
OH), 2.84 (d, J = 3.1, 1 H, 3-OH), 2.44 (dd, J = 16.1, 9.6 Hz, 1 H,
2-H), 2.34 (dd, J = 16.1, 3.1 Hz, 1 H, 2-H¢), 1.72 (s, 3 H, 6-CH3),
1.64–1.60 (m, 1 H, 4-H), 1.26 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.04
(s, 9 H, t-Bu in TBDPS), 0.92 (d, J = 7.0 Hz, 3 H, 4-CH3).
1H NMR (200 MHz, C6H6): d = 7.26 (dd, J = 15.2, 10.4 Hz, 1 H, 3-
H), 5.87 (d, J = 15.2 Hz, 1 H, 2-H), 5.69 (m, 2 H, 4-H, 5-H), 4.13
(q, J = 7.2 Hz, 2 H, OCH2CH3), 3.43 (m, 2 H, 6-H, 6-H¢), 1.09 (t,
J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (50 MHz, C6H6): d = 166.0, 142.7, 136.6, 132.7, 123.4,
60.3, 31.2, 14.3.
Ethyl (2E,4E)-6-(Diethoxyphosphoryl)hexa-2,4-dienoate (9)
The above mentioned crude product was heated at 120 °C for 1 h
with P(OEt)3 (6.3 mL, 36.7 mmol) and the mixture was directly
passed through a column of silica gel (hexane–EtOAc, 10:1) to
yield phosphonate 9 (1.26 g, 91% for two steps) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 173.0, 139.1, 135.7, 135.6, 133.6,
129.67, 129.65, 127.7, 127.6, 126.3, 71.9, 71.3, 60.7, 60.1, 41.8,
39.2, 26.8, 20.4, 19.1, 14.1, 11.1.
HRMS: m/z [M+ + Na] calcd for C28H40NaO5Si: 507.2543; found:
507.2558.
1H NMR (200 MHz, CDCl3): d = 7.23 (ddd, J = 15.4, 8.8, 1.4 Hz, 1
H, 3-H), 6.30 (ddd, J = 15.2, 8.8, 4.8 Hz, 1 H, 4-H), 6.06 (dddd,
J = 15.2, 15.2, 15.2, 7.4 Hz, 1 H, 5-H), 5.84 (dd, J = 15.4, 2.2 Hz, 1
H, 2-H), 4.14 [m, 4 H, P(OCH2CH3)2], 4.10 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 2.70 (dd, J = 23.2, 7.4 Hz, 2 H, 6-H, 6-H¢), 1.30 [m, 9
H, P(OCH2CH3)2, OCH2CH3].
Ethyl {(4S,5S,6R)-6-[(Z)-3-(tert-Butyldiphenylsiloxy)-1-methyl-
prop-1-enyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}acetate (28)
To a soln of the resulting diol (6.21 g, 12.8 mmol) in 2,2-dimeth-
oxypropane (50 mL) was added TsOH (300 mg). The mixture was
stirred at r.t. for 2 h, diluted with Et2O and washed with sat. aq
NaHCO3. The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (hexane–EtOAc, 20:1) to yield the title compound
28 (6.52 g, 97%) as a colorless oil.
13C NMR (50 MHz, CDCl3): d = 167.3, 143.9, 133.2, 131.9, 121.6,
62.5, 60.8, 31.6, 16.8, 14.7.
2,5-Dimethoxy-3-nitrobenzaldehyde
To a soln of phenol 32 (9.76 g, 49.5 mmol) in anhyd CH2Cl2 (50
mL) was added MeI (15.6 mL, 250 mmol). The mixture was heated
under refluxing conditions for 2 h during which time freshly pre-
pared Ag2O (11.6 g, 50 mmol) was added in small portions. Heating
was continued for a further 1 h before the mixture was cooled to r.t.
After filtration the silver salts were washed with CH2Cl2. The com-
bined organic phases were concentrated under reduced pressure.
The crude product was purified by flash chromatography (hexane–
EtOAc, 10:1) to yield the title compound (7.68 g, 73%) as a yellow
solid; mp 112–114 °C.
1H NMR (400 MHz, CDCl3): d = 10.36 (s, 1 H, CHO), 7.62 (d,
J = 3.3 Hz, 1 H, Ar), 7.57 (d, J = 3.3 Hz, 1 H, Ar), 4.03 (s, 3 H,
OCH3), 3.88 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 187.4, 155.5, 150.0, 131.8, 117.1,
116.8, 65.7, 56.3.
[a]D20 +18.6 (c 1.03, CHCl3).
1H NMR (400 MHz, CDCl3): d = 70–7.66 (m, 4 H, Ph in TBDPS),
7.44–7.36 (m, 6 H, Ph in TBDPS), 5.49 (m, 1 H, 7-H), 4.48 (d,
J = 5.8 Hz, 1 H, 5-H), 4.29 (dd, J = 13.1, 6.5 Hz, 1 H, 8-H), 4.21
(dd, J = 13.1, 4.5 Hz, 1 H, 8-H¢), 4.13 (dq, J = 7.1, 2.8 Hz, 2 H,
OCH2CH3), 3.73 (ddd, J = 9.4, 9.0, 3.5 Hz, 1 H, 3-H), 2.43 (dd,
J = 15.4, 3.5 Hz, 1 H, 2-H), 2.36 (dd, J = 15.4, 9.4 Hz, 1 H, 2-H¢),
1.69 (s, 3 H, 6-CH3), 1.65–1.60 (m, 1 H, 4-H), 1.25 (s, 3 H, CCH3),
1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.22 (s, 3 H, CCH3), 1.04 (s, 9
H, t-Bu in TBDPS), 0.75 (d, J = 6.9 Hz, 3 H, 4-CH3).
13C NMR (100 MHz, CDCl3): d = 171.2, 135.5, 134.5, 134.0, 133.9,
129.5, 127.6, 126.6, 100.8, 71.3, 69.9, 60.6, 60.4, 40.3, 39.5, 26.8,
24.2, 23.7, 20.8, 19.2, 14.2, 12.1.
HRMS: m/z [M+ + Na] calcd for C31H44NaO5Si: 547.2856; found:
547.2868.
HRMS (EI): m/z [M+] calcd for C9H9NO5: 211.0481; found:
211.0472.
Ethyl (2E,4E)-6-Hydroxyhexa-2,4-dienoate
The aldehyde 30 (0.77 g, 5.0 mmol) was dissolved in anhyd EtOH
(20 mL) and treated with NaBH4 (0.1 g, 2.5 mmol) at 0 °C and
stirred at r.t. for 2 h. The soln was concentrated under reduced pres-
sure and the crude product was dissolved in 2% aq HCl (10 mL).
The aqueous phase was extracted with EtOAc and the combined or-
ganic phases were washed with brine, dried (Na2SO4), and concen-
(2,5-Dimethoxy-3-nitrophenyl)methanol
A suspension of the resulting aldehyde (7.68 g, 36.3 mmol) in
MeOH (150 mL) was cooled to 0 °C and NaBH4 (0.51 g, 13.48
mmol, 0.37 equiv) was added. The mixture was stirred at this tem-
perature for 1 h and then hydrolyzed with 0.5 M aq HCl. The aque-
ous phase was extracted with Et2O (3 × 150 mL). The combined
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

314
D. Kashin et al.
FEATURE ARTICLE
organic phases were dried (Na2SO4) and concentrated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (hexane–EtOAc, 4:1 to 1:1) affording the title compound
(7.12 g, 92%) as a yellow solid; mp 50–52 °C.
1H NMR (400 MHz, CDCl3): d = 7.27 (d, J = 3.3 Hz, 1 H, Ar), 7.24
(d, J = 3.3 Hz, 1 H, Ar), 4.76 (s, 2 H, CH2OH), 3.87 (s, 3 H, OCH3),
3.83 (s, 3 H, OCH3), 2.17 (s, 1 H, OH).
3:1:2) to yield the title compound 7 (63 mg, 99% for two steps) as a
colorless crystals; mp 89–91 °C.
1H NMR (400 MHz, C6D6): d = 7.77–7.76 (m, 2 H, PhSO2), 6.96–
6.92 (m, 1 H, PhSO2), 6.88–6.85 (m, 2 H, PhSO2), 6.64 (d, J = 2.9
Hz, 1 H, Ar), 6.23 (d, J = 2.9 Hz, 1 H, Ar), 4.31 (s, 2 H, CH2SO2Ph),
3.92 (s, 1 H, NH), 3.45 (s, 3 H, OCH3), 3.37 (s, 3 H, OCH3), 0.88 (s,
9 H, t-Bu), 0.13 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 155.4, 144.8, 138.2, 119.6, 108.6,
62.9, 60.1, 56.0.
13C NMR (100 MHz, C6D6): d = 156.6, 142.7, 142.2, 140.1, 132.6,
129.0, 128.7, 122.3, 104.0, 103.8, 60.4, 57.0, 54.9, 26.3, 17.9, –4.4.
HRMS (EI): m/z [M+] calcd for C9H11NO5: 213.0637; found:
HRMS (EI): m/z [M+] calcd for C21H31NO4SSi: 421.1743; found:
213.0638.
421.1737.
1-(Bromomethyl)-2,5-dimethoxy-3-nitrobenzene (33)
2-{(4S,5S,6R)-6-[(Z)-3-(tert-Butyldiphenylsiloxy)-1-methyl-
prop-1-enyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}ethanal (34)
A soln of ester 28 (3.10 g, 5.91 mmol) in anhyd CH2Cl2 (45 mL) was
cooled to –78 °C and 1.2 M DIBAL-H in toluene (7.5 mL, 9 mmol,
1.5 equiv) was added. The mixture was stirred at this temperature
for 2 h, hydrolyzed with MeOH, poured into sat. aq potassium sodi-
um tartrate and stirred for a further 1 h. The aqueous phase was ex-
tracted with CH2Cl2 (3 × 30 mL) and the combined organic phases
were dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography (hexane–
EtOAc, 15:1) to yield the title compound 34 (2.81 g, 99%) as a col-
orless oil. The resulting aldehyde was immediately used in the next
reaction.
A soln of the resulting benzyl alcohol (7.11 g, 33.3 mmol) in anhyd
Et2O (300 mL) was cooled to 0 °C. Ph3P (13.1 g, 50 mmol) and CBr4
(16.6 g, 50 mmol) were added and the mixture was stirred at 0 °C
for 1 h and at r.t. for 2 h. After addition of brine the organic phase
was separated, dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(hexane–EtOAc, 3:1) to yield the title compound 33 (7.89 g, 86%)
as a yellow solid; mp 99.5–100.5 °C.
1H NMR (400 MHz, CDCl3): d = 7.32 (d, J = 3.1 Hz, 1 H, Ar), 7.18
(d, J = 3.1 Hz, 1 H, Ar), 4.53 (s, 2 H, CH2), 3.97 (s, 3 H, OCH3),
3.84 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 155.1, 145.5, 135.4, 121.9, 110.3,
63.2, 56.1, 26.0.
[a]D20 +16.6 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 9.70 (dd, J = 2.6, 1.8 Hz, 1 H, 1-
H), 7.70–7.66 (m, 4 H, Ph in TBDPS), 7.45–7.36 (m, 6 H, Ph in TB-
DPS), 5.51 (tq, J = 5.3, 1.4 Hz, 1 H, 7-H), 4.52 (d, J = 5.9 Hz, 1 H,
5-H), 4.29 (dd, J = 13.3, 6.8 Hz, 1 H, 8-H), 4.22 (dd, J = 13.3, 5.3
Hz, 1 H, 8-H¢), 3.78 (dt, J = 8.8, 3.5 Hz, 1 H, 3-H), 2.49 (ddd,
J = 16.3, 9.1, 2.6 Hz, 1 H, 2-H), 2.42 (ddd, J = 16.3, 3.5, 1.8 Hz, 1
H, 2-H¢), 1.70 (m, 3 H, 6-CH3), 1.70–1.62 (m, 1 H, 4-H), 1.26 (s, 3
H, CCH3), 1.23 (s, 3 H, CCH3), 1.04 (s, 9 H, t-Bu in TBDPS), 0.75
(d, J = 7.0 Hz, 3 H, 4-CH3).
13C NMR (100 MHz, CDCl3): d = 201.2, 135.5, 134.3, 133.9, 133.8,
129.6, 127.6, 126.7, 100.9, 69.9, 69.8, 60.5, 47.4, 40.5, 26.8, 24.2,
23.8, 20.8, 19.2, 12.1.
HRMS (ESI): m/z [M+ + Na] calcd for C29H40NaO4Si: 503.2594;
found: 503.2607.
HRMS (EI): m/z [M+] calcd for C9H10BrNO4: 274.9793; found:
274.9890.
2,5-Dimethoxy-3-nitro-1-[(phenylsulfonyl)methyl]benzene
To a soln of bromide 33 (7.89 g, 28.6 mmol) in anhyd DMF (250
mL) was added PhSO2Na (9.39 g, 57.2 mmol). The mixture was
stirred at 50 °C for 14 h, diluted with Et2O (400 mL) and washed
with brine. The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (hexane–EtOAc, 4:1 to 1:1) to yield the title com-
pound (8.19 g, 85%) as a yellow solid; mp 110–112 °C.
1H NMR (400 MHz, CDCl3): d = 7.76 (m, 2 H, PhSO2), 7.65 (m, 1
H, PhSO2), 7.53 (m, 2 H, PhSO2), 7.33 (d, J = 3.3 Hz, 1 H, Ar), 7.10
(d, J = 3.3 Hz, 1 H, Ar), 4.43 (s, 2 H, CH2SO2Ph), 3.79 (s, 3 H,
OCH3), 3.67 (s, 3 H, OCH3).
Ethyl (2E,4E,6E)-8-{(4S,5S,6R)-6-[(Z)-3-(tert-Butyldiphenylsi-
loxy)-1-methylprop-1-enyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}oc-
ta-2,4,6-trienoate
13C NMR (100 MHz, CDCl3): d = 154.6, 146.3, 143.5, 138.4, 134.1,
129.2, 128.4, 125.4, 122.5, 111.2, 63.1, 56.0, 55.8.
HRMS (EI): m/z [M+] calcd for C15H15NO6S: 337.0620; found:
337.0620.
A soln of LiHMDS (4.16 g, 4.68 mmol) in anhyd THF (100 mL)
was cooled to –78 °C and phosphonate 9 (1.29 g, 4.68 mmol) in an-
hyd THF (10 mL) was added dropwise in the dark and stirring was
continued at –78 °C for 30 min. Then, a soln of aldehyde 34 (1.0 g,
2.08 mmol) dissolved in anhyd THF (10 mL) was slowly added
over a period of 30 min. After 2 h at –78 °C the temperature was
raised to –10 °C and after additional 10 h the reaction was hydro-
lyzed with sat. aq NH4Cl (50 mL). The aqueous phase was extracted
with Et2O (3 × 50 mL). The combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexane–EtOAc, 20:1) to
yield the title compound (1.20 g, 96%) as a colorless oil.
2,5-Dimethoxy-3-[(phenylsulfonyl)methyl]aniline
To a suspension of the resulting sulfone (50 mg, 0.15 mmol) de-
scribed above in anhyd MeOH (4 mL) was added Pd/C (10%, 5 mg).
The mixture was stirred under a H2 atmosphere for 1 h and filtered
through a pad of Celite. The Celite was washed with EtOAc and the
combined organic phases were concentrated under reduced pres-
sure. The resulting aniline was immediately used in the next reac-
tion.
N-(tert-Butyldimethylsilyl)-2,5-dimethoxy-3-[(phenylsulfo-
nyl)methyl]aniline (7)
[a]D20 +8.2 (c 1.06, CHCl3).
To a soln of the freshly prepared aniline (46 mg, 0.15 mmol) de-
scribed above in anhyd DMF (2 mL) were added anhyd Et3N (0.16
mL, 1.13 mmol) followed by TBSOTf (0.17 mL, 0.75 mmol). The
mixture was stirred for 20 min, hydrolyzed with brine and extracted
with Et2O (3 × 5 mL). The combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexane–EtOAc–Et3N,
1H NMR (400 MHz, CDCl3): d = 7.70–7.66 (m, 4 H, Ph in TBDPS),
7.42–7.36 (m, 6 H, Ph in TBDPS), 7.28 (dd, J = 15.3, 11.3 Hz, 1 H,
3-H), 6.49 (dd, J = 14.9, 10.7 Hz, 1 H, 5-H), 6.19 (dd, J = 14.9, 10.7
Hz, 1 H, 4-H), 6.15 (dd, J = 15.3, 10.7 Hz, 1 H, 6-H), 5.89 (dt,
J = 15.3, 7.4 Hz, 1 H, 7-H), 5.84 (d, J = 15.3 Hz, 1 H, 2-H), 5.48 (m,
1 H, 13-H), 4.48 (d, J = 5.5 Hz, 1 H, 11-H), 4.32–4.27 (m, 1 H, 14-
H), 4.25–4.21 (m, 1 H, 14-H¢), 4.20 (q, J = 7.1 Hz, 2 H, OCH2CH3),
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
315
3.29 (dt, J = 7.9, 4.3 Hz, 1 H, 9-H), 2.34–2.20 (m, 2 H, 8-H, 8-H¢),
1.68 (m, 3 H, 12-CH3), 1.64–1.58 (m, 1 H, 10-H), 1.30 (t, J = 7.1
Hz, 3 H, OCH2CH3), 1.24 (s, 3 H, OCCH3), 1.23 (s, 3 H, OCCH3),
1.04 (s, 9 H, t-Bu in TBDPS), 0.73 (d, J = 6.9 Hz, 3 H, 10-CH3).
13C NMR (100 MHz, CDCl3): d = 167.1, 144.6, 140.8, 136.1, 135.5,
134.6, 134.0, 133.9, 131.6, 129.5, 128.3, 127.6, 126.5, 120.4, 100.6,
74.1, 70.1, 60.6, 60.2, 40.4, 37.7, 26.8, 24.6, 23.9, 20.9, 19.2, 14.3,
12.4.
(m, 1 H, 10-H), 1.25 (s, 3 H, OCCH3), 1.23 (s, 3 H, OCCH3), 1.04
(s, 9 H, t-Bu in TBDPS), 0.74 (d, J = 6.9 Hz, 3 H, 10-CH3).
13C NMR (100 MHz, CDCl3): d = 193.5, 152.1, 142.8, 138.2, 135.5,
134.6, 134.0, 133.9, 131.5, 130.9, 129.5, 128.3, 127.6, 126.5, 100.6,
74.0, 70.0, 60.6, 40.4, 37.7, 26.8, 24.5, 23.9, 20.9, 19.2, 12.4.
Duthaler–Hafner Aldol Reaction and Formation of tert-Butyl
Ester 37
To a soln of CpTiCl3 (1.26 g, 5.86 mmol) in anhyd Et2O (40 mL)
was added dropwise a soln of diacetone-D-glucose (3.05 g, 11.7
mmol) and anhyd Et3N (2.4 mL, 16.7 mmol) in anhyd Et2O (10
mL). The mixture was stirred at r.t. for 15 h and the precipitate was
removed by filtration under an argon atmosphere. The filtrate was
collected for the next reaction.
HRMS (EI): m/z [M+ + Na] calcd for C37H50NaO5Si: 625.3325;
found: 625.3354.
(2E,4E,6E)-8-{(4S,5S,6R)-6-[(Z)-3-(tert-Butyldiphenylsiloxy)-1-
methylprop-1-enyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}octa-2,4,6-
trien-1-ol
A soln of the resulting ester (1.66 g, 2.74 mmol) in anhyd THF (25
mL) was cooled to –78 °C and 1.2 M DIBAL-H in toluene (9.1 mL,
11 mmol) was added dropwise. The mixture was stirred at this tem-
perature for 2 h, hydrolyzed with MeOH and poured into sat. aq po-
tassium sodium tartrate soln. The mixture was stirred for a further 1
h. The aqueous phase was extracted with Et2O (3 × 25 mL). The
combined organic phases were dried (Na2SO4) and concentrated un-
der reduced pressure. The crude product was purified by flash chro-
matography (hexane–EtOAc, 3:1) to yield the title compound (1.47
g, 96%) as a colorless oil.
To a soln of 2 M LDA in THF–n-heptane (2.7 mL, 5.4 mmol) in an-
hyd Et2O (20 mL) was added dropwise a soln of anhyd t-BuOAc
(0.71 mL, 5.3 mmol) in anhyd Et2O (5 mL) at –78 °C. After 0.5 h
the titanium reagent containing soln described above was added
dropwise via a cannula to the mixture and stirring was continued at
–78 °C for 0.5 h. Within 0.5 h the temperature was raised to –30 °C.
The soln was kept at this temperature for a further 0.5 h and later
cooled to –78 °C. Aldehyde 35 (1.24 g, 2.22 mmol) dissolved in an-
hyd Et2O (14 mL) was added and the mixture was allowed to warm
to –65 °C. The mixture was stirred at this temperature overnight and
hydrolyzed with THF–H2O (1:1; 60 mL). After 1 h the solid titani-
um salts were filtered through a short pad of Celite. The filtrate was
washed with brine and the combined aqueous phases were extracted
with Et2O (2 × 30 mL). The combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexane–EtOAc, 8:1) to
yield the title compound 37 (1.39 g, 93%) as a colorless oil.
[a]D20 +7.6 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.69–7.66 (m, 4 H, Ph in TBDPS),
7.44–7.35 (m, 6 H, Ph in TBDPS), 6.28–6.05 (m, 4 H, 3-H, 4-H, 5-
H, 6-H), 5.81 (dt, J = 15.1, 6.0 Hz, 1 H, 2-H), 5.70 (dt, J = 14.9, 7.2
Hz, 1 H, 7-H), 5.47 (m, 1 H, 13-H), 4.48 (d, J = 5.5 Hz, 1 H, 11-H),
4.48 (dd, J = 12.9, 6.5 Hz, 1 H, 14-H), 4.25–4.19 (m, 3 H, 14-H¢, 1-
H, 1-H¢), 3.29 (dt, J = 7.7, 4.9 Hz, 1 H, 9-H), 2.29–2.17 (m, 2 H, 8-
H, 8-H¢), 1.68 (m, 3 H, 12-CH3), 1.65–1.57 (m, 1 H, 10-H), 1.24 (s,
3 H, OCCH3), 1.22 (s, 3 H, OCCH3), 1.04 (s, 9 H, t-Bu in TBDPS),
0.73 (d, J = 6.9 Hz, 3 H, 10-CH3).
[a]D20 +13.4 (c 0.97, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.69–7.66 (m, 4 H, Ph in TBDPS),
7.44–7.35 (m, 6 H, Ph in TBDPS), 6.28 (dd, J = 15.1, 10.4 Hz, 1 H,
triene), 6.18 (dd, J = 14.6, 10.4 Hz, 1 H, triene), 6.15–6.04 (m, 2 H,
triene), 5.69 (dt, J = 15.1, 7.2 Hz, 1 H, 9-H), 5.66 (dd, J = 15.1, 6.1
Hz, 1 H, 4-H), 5.47 (m, 1 H, 15-H), 4.54 (m, 1 H, 3-H), 4.47 (d,
J = 5.4 Hz, 1 H, 13-H), 4.30 (dd, J = 13.0, 6.5 Hz, 1 H, 16-H), 4.23
(dd, J = 13.0, 4.8 Hz, 1 H, 16-H¢), 3.27 (dt, J = 7.7, 4.8 Hz, 1 H, 11-
H), 3.09 (t, J = 4.1 Hz, 1 H, 3-OH), 2.52–2.41 (m, 2 H, 2-H, 2-H¢),
2.28–2.19 (m, 2 H, 10-H, 10-H¢), 1.68 (m, 3 H, 14-CH3), 1.60 (m, 1
H, 12-H), 1.49 (s, 9 H, t-Bu), 1.23 (s, 3 H, OCCH3), 1.22 (s, 3 H,
OCCH3), 1.04 (s, 9 H, t-Bu in TBDPS), 0.72 (d, J = 6.9 Hz, 3 H, 12-
CH3).
13C NMR (100 MHz, CDCl3): d = 171.7, 135.5, 134.6, 134.0, 133.9,
133.6, 133.0, 131.9, 131.7, 130.9, 130.0, 129.5, 127.6, 126.4, 100.5,
81.5, 74.4, 70.1, 68.7, 60.6, 42.4, 40.3, 37.7, 28.1, 26.8, 24.6, 23.9,
20.9, 19.2, 12.4.
HRMS (ESI): m/z [M+ + Na] calcd for C41H58O6NaSi: 697.3900;
found: 697.3912.
13C NMR (100 MHz, CDCl3): d = 135.6, 134.6, 134.1, 134.0, 133.4,
131.9, 131.7, 131.4, 130.1, 129.5, 127.6, 126.5, 100.5, 74.4, 70.1,
63.5, 60.7, 40.3, 37.7, 26.9, 24.6, 23.9, 20.9, 19.2, 12.4.
MS (ES): m/z (%) = 77 (52), 83 (50), 91 (42), 95 (50), 97 (42), 107
(43), 121 (50), 135 (57), 139 (96), 149 (42), 175 (43), 199 (100),
200 (49), 203 (44), 281 (64).
(2E,4E,6E)-8-{(4S,5S,6R)-6-[(Z)-3-(tert-Butyldiphenylsiloxy)-1-
methylprop-1-enyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}octa-2,4,6-
trienal (35)
To a soln of the resulting alcohol (1.74 g, 3.10 mmol) described
above in anhyd CH2Cl2 (20 mL) were added NMO (0.54 g, 4.65
mmol), powdered 4 Å molecular sieves (1.55 g; 500 mg/mmol) and
tetrapropylammonium perruthenate (TPAP) (54 mg, 0.15 mmol).
The mixture was stirred at r.t. for 2 h and filtered through a pad of
silica gel. This pad was washed with EtOAc and the combined or-
ganic phases were concentrated under reduced pressure. The crude
product was purified by flash chromatography (hexane–EtOAc,
20:1) to yield the title compound 35 (1.24 g, 72%) as a colorless oil.
The resulting aldehyde was immediately used for the next step.
O-Methylation of Alcohol 37
To a soln of the resulting alcohol 37 (1.39 g, 2.06 mmol) in anhyd
CH2Cl2 (20 mL) were added MeI (2.6 mL, 41.2 mmol) and freshly
prepared Ag2O (8.59, 37.1 mmol). The mixture was stirred at r.t. for
48 h and was purified without concentration by flash chromatogra-
phy (cyclohexane–EtOAc, 15:1) to yield the title compound (1.25
g, 88%) as a colorless oil.
[a]D20 +9.2 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 9.55 (d, J = 8.0 Hz, 1 H, 1-H),
7.70–7.66 (m, 4 H, Ph in TBDPS), 7.44–7.36 (m, 6 H, Ph in TB-
DPS), 7.09 (dd, J = 15.1, 11.1 Hz, 1 H, 3-H), 6.61 (dd, J = 14.5,
10.7 Hz, 1 H, 5-H), 6.32 (dd, J = 14.5, 11.1 Hz, 1 H, 4-H), 6.20 (dd,
J = 15.0, 10.7 Hz, 1 H, 6-H), 6.13 (dd, J = 15.1, 7.0 Hz, 1 H, 2-H),
5.84 (dt, J = 15.0, 7.3 Hz, 1 H, 7-H), 5.49 (m, 1 H, 13-H), 4.49 (d,
J = 5.5 Hz, 1 H, 11-H), 4.30 (dd, J = 13.3, 7.2 Hz, 1 H, 14-H), 4.22
(dd, J = 13.3, 5.3 Hz, 1 H, 14-H¢), 3.29 (dt, J = 8.0, 4.1 Hz, 1 H, 9-
H), 2.37–2.23 (m, 2 H, 8-H, 8-H¢), 1.69 (m, 3 H, 12-CH3), 1.67–1.60
[a]D20 +9.0 (c 0.97, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.69–7.66 (m, 4 H, Ph), 7.44–7.35
(m, 6 H, Ph), 6.24 (dd, J = 15.1, 10.4 Hz, 1 H, triene), 6.19 (dd,
J = 14.4, 10.1 Hz, 1 H, triene), 6.09 (dd, J = 14.4, 10.4 Hz, 1 H,
triene), 6.08 (dd, J = 15.1, 10.1 Hz, 1 H, triene), 5.71 (dt, J = 15.1,
7.2 Hz, 1 H, 9-H), 5.50 (dd, J = 15.1, 8.0 Hz, 1 H, 4-H), 5.47 (m, 1
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

316
D. Kashin et al.
FEATURE ARTICLE
H, 15-H), 4.47 (d, J = 5.7 Hz, 1 H, 13-H), 4.30 (dd, J = 13.0, 6.6 Hz,
1 H, 16-H), 4.22 (dd, J = 13.0, 4.7 Hz, 1 H, 16-H¢), 4.01 (dt, J = 7.7,
5.7 Hz, 1 H, 3-H), 3.26 (d, J = 1.0 Hz, 3 H, OCH3), 3.27–3.25 (m, 1
H, 11-H), 2.53 (dd, J = 14.9, 8.0 Hz, 1 H, 2-H), 2.36 (dd, J = 14.9,
5.8 Hz, 1 H, 2-H¢), 2.25–2.21 (m, 2 H, 10-H, 10-H¢), 1.67 (m, 3 H,
14-CH3), 1.65–1.59 (m, 1 H, 12-H), 1.43 (s, 9 H, t-Bu), 1.23 (s, 3 H,
CCH3), 1.21 (s, 3 H, CCH3), 1.04 (s, 9 H, t-Bu in TBDPS), 0.72 (d,
J = 6.9 Hz, 3 H, 12-CH3).
13C NMR (100 MHz, CDCl3): d = 170.1, 135.5, 134.6, 134.0, 133.9,
133.7, 133.2, 131.9, 131.8, 131.4, 129.8, 129.5, 127.6, 126.4, 100.5,
81.5, 78.8, 74.4, 70.1, 60.6, 56.4, 42.4, 40.3, 37.7, 28.1, 26.8, 24.6,
23.9, 20.9, 19.2, 12.4.
13C NMR (100 MHz, CDCl3): d = 178.4, 135.5, 134.6, 134.0, 133.9,
133.6, 133.1, 132.4, 131.9, 131.8, 129.9, 129.5, 127.6, 126.4, 100.5,
79.0, 74.4, 70.1, 61.0, 60.6, 56.2, 40.3, 38.7, 37.7, 34.8, 27.2, 26.8,
24.6, 23.9, 20.9, 19.2, 12.4.
HRMS (ESI): m/z [M+ + Na] calcd for C43H62NaO6Si: 725.4213;
found: 725.4210.
Desilylation
To a soln of the resulting silyl ether (264 mg, 0.376 mmol) de-
scribed above in anhyd THF (7 mL) was added TBAF·3 H2O (237
mg, 0.752 mmol). The mixture was stirred at r.t. for 2 h and filtered
through a pad of silica gel. The filtrate was concentrated under re-
duced pressure and the crude product was purified by flash chroma-
tography (hexane–EtOAc, 3:1) to yield the title compound (164 mg,
94%) as a colorless oil.
Reduction of the tert-Butyl Ester
A soln of the resulting ester (288 mg, 0.418 mmol) in Et2O (10 mL)
was cooled to 0 °C and LiAlH4 (32 mg, 0.836 mmol) was added.
The mixture was stirred at 0 °C for 0.5 h and at r.t. for 3 h. Hydrol-
ysis was achieved by addition of sat. aq potassium sodium tartrate.
After 1 h the aqueous phase was extracted with Et2O (3 × 10 mL)
and the combined organic phases were dried (Na2SO4) and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (hexane–EtOAc, 3:1) to yield the title com-
pound (241 mg, 93%) as a colorless oil.
[a]D20 –7.2 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.25–6.10 (m, 4 H, triene), 5.76
(dt, J = 15.1, 7.4 Hz, 1 H, 9-H), 5.57 (m, 1 H, 15-H), 5.49 (dd,
J = 15.1, 8.0 Hz, 1 H, 4-H), 4.52 (d, J = 5.3 Hz, 1 H, 13-H), 4.18–
4.03 (m, 4 H, 1-H, 1-H¢, 16-H, 16-H¢), 3.68 (dt, J = 8.0, 5.8 Hz, 1 H,
3-H), 3.39 (dt, J = 7.4, 4.9 Hz, 1 H, 11-H), 3.25 (s, 3 H, OCH3),
2.40–2.28 (m, 2 H, 10-H, 10-H¢), 1.95–1.87 (m, 1 H, 2-H), 1.84–
1.75 (m, 2 H, 2-H¢, 12-H), 1.66 (m, 3 H, 14-CH3), 1.36 (s, 3 H,
CCH3), 1.35 (s, 3 H, CCH3), 1.19 (s, 9 H, t-Bu in Piv), 0.81 (d,
J = 6.9 Hz, 3 H, 12-CH3).
13C NMR (100 MHz, CDCl3): d = 178.4, 136.8, 133.4, 133.1, 132.5,
132.1, 131.5, 130.1, 126.2, 100.1, 79.1, 74.5, 71.9, 60.1, 58.7, 56.3,
39.4, 38.7, 37.8, 34.8, 27.2, 24.8, 23.8, 21.7, 12.5.
HRMS (ESI): m/z [M+ + Na] calcd for C27H44NaO6: 487.3036;
found: 487.3043.
[a]D20 +19.7 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.69–7.66 (m, 4 H, Ph), 7.44–7.35
(m, 6 H, Ph), 6.24–6.05 (m, 4 H, triene), 5.71 (dt, J = 14.8, 7.4 Hz,
1 H, 9-H), 5.53 (dd, J = 15.4, 8.0 Hz, 1 H, 4-H), 5.47 (m, 1 H, 15-
H), 4.48 (d, J = 5.3 Hz, 1 H, 13-H), 4.30 (dd, J = 13.4, 6.5 Hz, 1 H,
16-H), 4.23 (dd, J = 13.4, 5.3 Hz, 1 H, 16-H¢), 3.76 (dt, J = 8.0, 4.4
Hz, 1 H, 3-H), 3.76 (m, 2 H, 1-H, 1-H¢), 3.25 (s, 3 H, OCH3), 3.27
(m, 1 H, 11-H), 2.51 (br s, 1 H, OH), 2.32–2.18 (m, 2 H, 10-H, 10-
H¢), 1.89–1.72 (m, 2 H, 2-H, 2-H¢), 1.68 (m, 3 H, 14-CH3), 1.65–
1.56 (m, 1 H, 12-H), 1.24 (s, 3 H, CCH3), 1.22 (s, 3 H, CCH3), 1.04
(s, 9 H, t-Bu in TBDPS), 0.73 (d, J = 6.9 Hz, 3 H, 12-CH3).
13C NMR (100 MHz, CDCl3): d = 135.5, 134.6, 134.0, 133.9, 133.7,
133.0, 132.2, 132.0, 131.8, 129.8, 129.5, 127.6, 126.4, 100.5, 82.0,
74.4, 70.1, 60.9, 60.6, 56.2, 40.3, 37.9, 37.7, 26.8, 24.6, 23.9, 20.9,
19.2, 12.4.
Allyl Chloride 38
To a soln of the resulting alcohol (390 mg, 0.84 mmol) described
above in anhyd DMF (10 mL) was added LiCl (178 mg, 4.2 mmol).
The suspension was vigorously stirred and 2,6-lutidine (0.39 mL,
3.36 mmol) was added followed by MsCl (0.13 mL, 1.68 mmol).
The mixture was stirred at r.t. for 1 h and then cooled to 0 °C and
hydrolyzed with sat. aq NaHCO3 (10 mL). The aqueous phase was
extracted with hexane (3 × 10 mL) and the combined organic phas-
es were dried (Na2SO4) and concentrated under reduced pressure.
The crude product was purified by flash chromatography (hexane–
EtOAc, 20:1) to yield the title compound 38 (320 mg, 79%) as a col-
orless oil.
HRMS (ESI): m/z [M+ + Na] calcd for C38H54O5NaSi: 641.3638;
found: 641.3621.
Pivaloylation of the Primary Alcohol
To a soln of the resulting alcohol (241 mg, 0.389 mmol) in anhyd
pyridine–CH2Cl2 (1:1; 10 mL) was added PivCl (0.1 mL, 0.778
mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min and at r.t.
for 1 h. Hydrolysis was achieved by addition of sat. aq NaHCO3 (5
mL) and the aqueous phase was extracted with hexane (3 × 10 mL).
The combined organic phases were dried (Na2SO4) and concentrat-
ed under reduced pressure. The crude product was purified by flash
chromatography (hexane–EtOAc, 15:1) to yield the title compound
(268 mg, 98%) as a colorless oil.
[a]D20 +11.5 (c 1.0, CHCl3).
1H NMR (400 MHz, C6D6): d = 6.26–6.09 (m, 4 H), 5.88 (dt,
J = 14.6, 7.3 Hz, 1 H), 5.49 (dd, J = 14.5, 8.0 Hz, 1 H), 5.39 (t pseu-
do quint, J = 8.0, 1.4 Hz, 1 H), 4.52 (d, J = 5.5 Hz, 1 H), 4.30 (ddd,
J = 10.9, 6.9, 6.7 Hz, 1 H), 4.23 (dt, J = 10.9, 6.3 Hz, 1 H), 4.14 (dd,
J = 11.4, 8.2 Hz, 1 H), 4.07 (dd, J = 11.4, 7.7 Hz, 1 H), 3.62 (dt,
J = 8.0, 5.3 Hz, 1 H), 3.39 (dt, J = 7.4, 4.8 Hz, 1 H), 3.14 (d, J = 1.4
Hz, 3 H), 2.33–2.29 (m, 2 H), 1.93 (dddd, J = 13.9, 13.9, 6.2, 1.0
Hz, 1 H), 1.83–1.75 (m, 2 H), 1.59 (m, 3 H), 1.35 (s, 3 H), 1.33 (s,
3 H), 1.22 (d, J = 0.9 Hz, 9 H), 0.81 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, C6D6): d = 177.6, 139.1, 133.6, 133.5, 133.1,
132.8, 131.6, 130.7, 123.2, 101.0, 79.3, 74.7, 71.0, 61.2, 56.1, 40.7,
40.6, 38.7, 38.1, 35.4, 27.3 24.8, 23.9, 21.4, 12.6.
HRMS (ESI): m/z [M+ + Na] calcd for C27H43ClNaO5: 505.2697;
found: 505.2679.
[a]D20 –4.9 (c 1.04, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.70–7.66 (m, 4 H, Ph), 7.44–7.35
(m, 6 H, Ph), 6.22–6.05 (m, 4 H, triene), 5.71 (dt, J = 15.1, 7.5 Hz,
1 H, 9-H), 5.49 (dd, J = 15.1, 8.0 Hz, 1 H, 4-H), 5.47 (m, 1 H, 15-
H), 4.48 (d, J = 5.5 Hz, 1 H, 13-H), 4.30 (dd, J = 13.5, 6.8 Hz, 1 H,
16-H), 4.23 (dd, J = 13.5, 5.4 Hz, 1 H, 16-H¢), 4.16 (ddd, J = 11.0,
7.2, 6.2 Hz, 1 H, 1-H), 4.09 (ddd, J = 11.0, 6.2, 6.2 Hz, 1 H, 1-H¢),
3.68 (dt, J = 8.0, 5.7 Hz, 1 H, 3-H), 3.25 (d, J = 1.0 Hz, 3 H, OCH3),
3.29–3.24 (m, 1 H, 11-H), 2.30–2.18 (m, 2 H, 10-H, 10-H¢), 1.96–
1.88 (m, 1 H, 2-H), 1.84–1.75 (m, 1 H, 2-H¢), 1.68 (m, 3 H, 14-CH3),
1.65–1.58 (m, 1 H, 12-H), 1.24 (s, 3 H, CCH3), 1.22 (s, 3 H, CCH3),
1.20 (s, 9 H, t-Bu in Piv), 1.04 (s, 9 H, t-Bu in TBDPS), 0.73 (d,
J = 6.8 Hz, 3 H, 12-CH3).
Allyl Iodide 39
To a soln of allyl chloride 38 (320 mg, 0.66 mmol) in acetone (10
mL) were added 2,6-di-tert-butylpyridine (13 mg, 0.066 mmol) and
NaI (148 mg, 0.99 mmol). The mixture was stirred at r.t. for 1 h and
then filtered through a pad of neutral alumina. The solid residue was
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
317
washed with acetone and the combined organic phases were re-
moved in vacuo. The crude product 39 was dried in vacuo for 1 h
and directly employed in the next step.
1H NMR (400 MHz, CDCl3): d = 7.60 (br s, 1 H, Ar), 7.20 (br s, 1
H, NH), 6.40 (d, J = 3.0 Hz, 1 H, Ar), 6.26–6.06 (m, 4 H, triene),
5.98 (dddd, J = 11.5, 11.5, 10.5, 5.7 Hz, 1 H, OCH2CH=CH2), 5.76
(dt, J = 14.8, 7.4 Hz, 1 H, 9-H), 5.48 (dd, J = 15.1, 8.0 Hz, 1 H, 4-
H), 5.37 (dq, J = 17.2, 1.3 Hz, 1 H, OCH2CH=CHH), 5.27 (dq,
J = 10.5, 1.3 Hz, 1 H, OCH2CH=CHH), 5.27–5.24 (m, 1 H, 15-H),
4.69–4.67 (m, 3 H, 13-H, OCH2CH=CH2), 4.18–4.05 (m, 2 H, 1-H,
1-H¢), 3.77 (s, 3 H, OCH3, Ar), 3.69 (s, 3 H, OCH3, Ar), 3.69 (m, 1
H, 3-H), 3.37-3.32 (m, 1 H, 11-H), 3.24 (s, 3 H, OCH3), 2.68–2.54
(m, 2 H, 17-H, 17-H¢), 2.36–2.22 (m, 4 H, 16-H, 16-H¢, 10-H, 10-
H¢), 1.95–1.87 (m, 1 H, 2-H), 1.83–1.74 (m, 1 H, 2-H¢), 1.74–1.65
(m, 1 H, 12-H), 1.68 (s, 3 H, 14-CH3), 1.32 [s, 6 H, C(CH3)2], 1.19
(s, 9 H, t-Bu), 0.77 (d, J = 6.9 Hz, 3 H, 12-CH3).
13C NMR (100 MHz, CDCl3): d = 178.3, 156.1, 153.1, 140.4, 135.1,
134.7, 133.6, 133.1, 132.5, 132.4, 132.0, 131.9, 131.8, 129.8, 125.3,
118.2, 109.8, 101.9, 100.6, 79.1, 74.4, 69.4, 65.8, 61.1, 61.0, 56.2,
55.5, 40.7, 38.7, 37.7, 34.8, 30.0, 28.6, 27.1, 24.6, 24.1, 20.1, 12.5.
HRMS (ESI): m/z [M+ + Na] calcd for C40H59NNaO9: 720.4088;
found: 720.4053.
Coupling of Allyl Iodide 39 and Sulfone 7
To a soln of sulfone 7 (362 mg, 0.86 mmol) in anhyd THF (12 mL)
was added 2 M NaHMDS in THF (0.9 mL, 1.8 mmol) at –78 °C. Af-
ter 15 min a soln of freshly prepared 39 (380 mg, 0.66 mmol) in an-
hyd THF (5 mL) was added and stirring was continued at –78 °C for
1 h. The reaction was terminated by addition of MeOH followed by
brine (10 mL). The aqueous phase was extracted with Et2O (3 × 10
mL). The combined organic phases were dried (Na2SO4) and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (hexane–EtOAc–Et3N, 10:1:2) to yield
the title compound (608 mg) which still contained impurities of
starting sulfone 7.
Pivaloate 40
The resulting crude sulfone (608 mg, 0.66 mmol) was taken up in
Na2HPO4 (936 mg, 6.6 mmol) and anhyd MeOH (20 mL) and
cooled to –10 °C. Na(Hg) (1.42 g) was added and the mixture was
stirred at –10 °C for 1 h, filtered through a pad of silica gel (2%
Et3N–EtOAc). After concentration under reduced pressure, the
crude product was dissolved in EtOAc and washed with H2O and
brine. The organic phase was dried (Na2SO4) and concentrated un-
der reduced pressure. The crude product was purified by flash chro-
matography (hexane–EtOAc–Et3N, 10:1:2) to yield the title
compound 40 (396 mg, 77% for three steps) as a colorless oil.
Saponification of the Pivaloyl Ester
The resulting carbamate (81 mg, 0.116 mmol) was treated with
LiOH (2 g) and the mixture was stirred for 5 d. The crude product
was filtered through a pad of silica gel and the solid was washed
with Et2O. The combined organic extracts were concentrated under
reduced pressure. Purification of the crude product by flash chroma-
tography (hexane–EtOAc, 1:1) yielded the title compound (61 mg,
86%) as a colorless oil.
[a]D20 +19.3 (c 0.88, CHCl3).
[a]D20 +18.2 (c 0.91, CHCl3).
1H NMR (400 MHz, C6D6): d = 6.60 (d, J = 2.9 Hz, 1 H, Ar), 6.31
(d, J = 2.9 Hz, 1 H, Ar), 6.26–6.07 (m, 4 H, triene), 5.97–5.87 (m, 1
H, 9-H), 5.43 (dd, J = 14.3, 8.0 Hz, 1 H, 4-H), 5.46–5.41 (m, 1 H,
15-H), 5.04 (d, J = 5.5 Hz, 1 H, 13-H), 4.33–4.21 (m, 2 H, 1-H, 1-
H¢), 4.21 (s, 1 H, NH), 3.62 (dt, J = 7.8, 5.2 Hz, 1 H, 3-H), 3.55 (s,
3 H, OCH3, Ar), 3.50 (s, 3 H, OCH3, Ar) 3.50 (m, 1 H, 11-H), 3.14
(d, J = 1.9 Hz, 3 H, OCH3), 2.83–2.69 (m, 2 H, 17-H, 17-H¢), 2.59–
2.46 (m, 2 H, 16-H, 16-H¢), 2.42–2.29 (m, 2 H, 10-H, 10-H¢), 1.98–
1.86 (m, 5 H, 2-H, 12-H, 14-CH3), 1.84–1.73 (m, 1 H, 2-H¢), 1.43
(s, 3 H, CCH3), 1.42 (s, 3 H, CCH3), 1.22 (s, 9 H, t-Bu in Piv), 0.96
(s, 9 H, t-Bu in TBS), 0.91 (d, J = 6.9 Hz, 3 H, 12-CH3), 0.22 [s, 6
H, Si(CH3)2].
13C NMR (100 MHz, C6D6): d = 177.6, 157.1, 142.0, 141.6, 135.2,
134.9, 133.9, 133.2, 133.1, 132.5, 132.3, 130.4, 126.1, 103.4, 100.9,
100.8, 79.3, 74.9, 69.7, 61.3, 59.8, 56.0, 54.9, 41.2, 38.7, 38.3, 35.4,
31.1, 29.6, 27.3, 26.5, 24.9, 24.3, 21.3, 17.9, 12.8.
HRMS (ESI): m/z [M+ – TBS + Na] calcd for C36H55NNaO7:
636.3876; found: 636.3781.
1H NMR (400 MHz, C6D6): d = 8.24 (br s, 1 H, Ar), 7.28 (s, 1 H,
NH), 6.59 (d, J = 3.1 Hz, 1 H, Ar), 6.27–6.07 (m, 4 H, triene), 5.94
(dt, J = 14.4, 7.2 Hz, 1 H, 9-H), 5.80 (dddd, J = 11.5, 11.5, 10.3, 5.7
Hz, 1 H, OCH2CH=CH2), 5.46 (dd, J = 14.4, 8.0 Hz, 1 H, 4-H), 5.32
(m, 1 H, 15-H), 5.12 (dq, J = 17.2, 1.3 Hz, 1 H, OCH2CH=CHH),
5.01 (dq, J = 10.4, 1.3 Hz, 1 H, OCH2CH=CHH), 4.98 (d, J = 5.5
Hz, 1 H, 13-H), 4.56 (dt, J = 5.7, 1.4 Hz, 2 H, OCH2CH=CH2),
3.79–3.64 (m, 3 H, 3-H, 1-H, 1-H¢), 3.50 (s, 3 H, OCH3, Ar), 3.50–
3.46 (m, 1 H, 11-H), 3.24 (s, 3 H, OCH3, Ar), 3.09 (s, 3 H, OCH3),
2.69–2.55 (m, 2 H, 17-H, 17-H¢), 2.52–2.35 (m, 4 H, 16-H, 16-H¢,
10-H, 10-H¢), 2.14 (br s, 1 H, OH), 1.90 (m, 3 H, 14-CH3), 1.88–
1.81 (m, 2 H, 2-H, 12-H), 1.69–1.61 (m, 1 H, 2-H¢), 1.43 (s, 3 H,
CCH3), 1.42 (s, 3 H, CCH3), 0.87 (d, J = 6.9 Hz, 3 H, 12-CH3).
13C NMR (100 MHz, C6D6): d = 157.0, 153.1, 140.8, 135.3, 135.1,
133.7, 133.4, 133.0, 132.9, 132.8, 132.7, 132.0, 130.6, 125.7, 118.0,
110.3, 102.4, 100.9, 81.4, 74.8, 69.7, 65.9, 60.6, 60.3, 56.0, 55.1,
41.0, 38.7, 38.2, 30.5, 29.2, 24.8, 24.2, 21.3, 12.8.
HRMS (ESI): m/z [M+ + Na] calcd for C35H51NNaO8: 636.3512;
found: 636.3510.
Desilylation of Pivaloate 40
To a soln of the ester 40 (69.7 mg, 93 mmol) in anhyd MeOH (5 mL)
was added polytriphenylphosphonium bromide30 (3 mg). The mix-
ture was stirred for 1 h, neutralized with Amberlite-21 and filtered.
The combined organic phases were removed under reduced pres-
sure and the crude product was directly employed in the next step.
Oxidation at C1 and Formation of Aldehyde
The resulting alcohol (83.5 mg, 136 mmol) was dissolved in acetone
(5 mL) and NMO was added (48 mg, 408 mmol) followed by TPAP
(5 mg, 13.6 mmol) were added. The mixture was stirred for 1 h at r.t.
and filtered through a pad of silica gel. The pad was washed with
EtOAc and the combined organic phases were concentrated under
reduced pressure. The crude product was purified by flash chroma-
tography (hexane–EtOAc, 3:1) to yield the title compound (65 mg,
78%) as a colorless oil. The aldehyde is prone to facile elimination
of MeOH and must be directly employed for the next oxidation
step!
Allyloxycarbonyl Protection of Aniline
The resulting amine was dissolved in acetone (4 mL) and 5 M aq
K2CO3 (0.56 mL) as well as allyl chloroformate (0.1 mL, 0.93
mmol) were added. The mixture was stirred at r.t. for 1 h and
washed with brine. The aqueous phase was extracted with EtOAc
(3 × 5 mL) and the combined organic phases were dried (Na2SO4)
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (hexane–EtOAc, 5:1) to yield the
title compound (60 mg, 92% for two steps) as a colorless oil.
Carboxylic Acid 41
The resulting aldehyde was dissolved in t-BuOH (5 mL) and
2-methylprop-2-ene (5 mL), NaH2PO4⋅H2O (110 mg, 800 mmol) in
H2O (5 mL) and NaClO2 (96 mg, 1.06 mmol) were added. The mix-
[a]D20 +17.1 (c 0.93, CHCl3).
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

318
D. Kashin et al.
FEATURE ARTICLE
ture was stirred at r.t. for 1 h, hydrolyzed with brine and extracted
with EtOAc (3 × 5 mL). The combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexane–EtOAc, 30:1) to
yield the title compound 41 (56 mg, 84%) as a colorless oil.
flash chromatography (hexane–EtOAc) to yield ansatrienol 43 (10
mg, 91%) as a single isomer.
[a]D20 +90.2 (c 0.60, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 3.0 Hz, 1 H), 7.87 (s,
1 H), 6.39 (d, J = 3.0 Hz, 1 H), 6.18 (dd, J = 15.6, 9.9 H, 1 H), 6.04–
5.88 (m, 3 H), 5.68–5.60 (m, 1 H), 5.57 (dd, J = 15.6, 6.9 Hz, 1 H),
5.28–5.24 (m, 1 H), 4.82 (m, 1 H), 4.15–4.11 (m, 1 H), 3.78–3.69
(m, 1 H), 3.78 (s, 3 H), 3.63 (s, 3 H), 3.39 (s, 3 H), 2.81 (dd, J = 13.2,
3.3 Hz, 1 H), 2.77–2.71 (m, 1 H), 2.54 (dd, J = 13.2, 9.3 Hz, 1 H),
2.52–2.34 (m, 5 H), 1.90 (m, 3 H), 1.70 (dt, J = 7.1, 4.1 Hz, 1 H),
0.92 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.2, 155.8, 140.5, 137.6, 134.9,
134.0, 133.6, 132.6, 132.0, 130.7, 130.2, 129.1, 125.5, 110.5, 103.1,
78.9, 73.2, 69.9, 61.2, 56.7, 55.5, 44.8, 40.0, 36.5, 31.0, 29.0, 20.2,
10.8.
1H NMR (400 MHz, CDCl3): d = 60 (br s, 1 H, Ar), 7.22 (br s, 1 H,
NH), 6.41 (d, J = 3.0 Hz, 1 H, Ar), 6.31–6.22 (m, 2 H, triene), 6.16–
6.07 (m, 2 H, triene), 5.99 (dddd, J = 11.5, 11.5, 10.4, 5.7 Hz, 1 H,
OCH2CH=CH2), 5.79 (dt, J = 14.5, 7.1 Hz, 1 H, 9-H), 5.50 (dd,
J = 15.3, 8.0 Hz, 1 H, 4-H), 5.38 (dq, J = 17.2, 1.3 Hz, 1 H,
OCH2CH=CHH), 5.28 (dq, J = 10.4, 1.3 Hz, 1 H, OCH2CH=CHH),
5.28–5.24 (m, 1 H, 15-H), 4.68 (dd, J = 5.7, 2.8 Hz, 2 H,
OCH2CH=CH2), 4.68 (d, J = 5.6 Hz, 1 H, 13-H), 4.09–4.04 (m, 1 H,
3-H), 3.78 (s, 3 H, OCH3, Ar), 3.69 (s, 3 H, OCH3, Ar), 3.41–3.35
(m, 2 H, 11-H, OH), 3.30 (s, 3 H, OCH3), 2.68–2.50 (m, 4 H, 17-H,
17-H¢, 2-H, 2-H¢), 2.36–2.20 (m, 4 H, 16-H, 16-H¢, 10-H, 10-H¢),
1.75–1.65 (m, 4 H, 12-H, 14-CH3), 1.32 [s, 6 H, C(CH3)2], 0.77 (d,
J = 6.9 Hz, 3 H, 12-CH3).
HRMS (ESI): m/z [M+ + Na] calcd for C28H39NNaO6: 508.2675;
found: 508.2662.
HRMS (ESI): m/z [M+ + Na] calcd for C35H49NNaO9: 650.3305;
found: 650.3330.
Acknowledgment
Amino Acid 42
Support was kindly made possible with graduate fellowships provi-
ded by the state of Lower Saxony for R.W. and D.K. We thank the
Deutsche Forschungsgemeinschaft (grant Ki 397/7-1) and the
Fonds der Chemischen Industrie for financial support. We are gra-
teful to Solvay Pharmaceutical Research Laboratories for the dona-
tion of chemicals.
To a soln of carboxylic acid 41 (56 mg, 89 mmol) in THF (10 mL)
were added morpholine (77 mg, 890 mmol) and Pd(PPh3)4 (21 mg,
18 mmol). The mixture was stirred at r.t. for 12 h and hydrolyzed
with 10% aq NaH2PO4. The aqueous phase was extracted with
EtOAc (3 × 10 mL) and the combined organic phases were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (CH2Cl2–MeOH, 20:1) to
yield aniline 42 (34 mg, 71%) as a colorless oil. The product was di-
rectly employed in the next step.
References
(1) Rüdiger Wittenberg, current address: DS-Chemie GmbH,
Straubinger Straße 12, 28219 Bremen, Germany; Kai-Uwe
Schöning, current address: Ciba Speciality Chemicals Inc.,
R-1059.4.04, 4002 Basel, Switzerland; Stefan Kamlage,
current address: Institut für Organische Chemie, Freie
Universität Berlin, Takustraße 3, 14195 Berlin, Germany.
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A. Zbl. Bakt. Hyg., I. Abt. Orig. C2 1981, 122. (b) Zeeck,
A.; Damberg, M.; Russ, P. Tetrahedron Lett. 1982, 23, 59.
(4) (a) Sugita, M.; Furihata, K.; Seto, H.; Otake, N.; Sasaki, T.
Agric. Biol. Chem. 1982, 46, 1111. (b) Sugita, M.; Sasaki,
T.; Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1982, 35,
1467. (c) Sugita, M.; Natori, Y.; Sueda, N.; Furihata, K.;
Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1474. (d) Sugita,
M.; Hiramato, S.; Ando, C.; Sasaki, T.; Furihata, K.; Seto,
H.; Otake, N. J. Antibiot. 1985, 38, 799.
(5) (a) Umezawa, I.; Funayama, S.; Okada, K.; Iwasaki, K.;
Satoh, J.; Masuda, K.; Komiyama, K. J. Antibiot. 1985, 38,
699. (b) Funayama, S.; Okada, K.; Komiyama, K.;
Umezawa, I. J. Antibiot. 1985, 38, 1107. (c) Funayama, S.;
Okada, K.; Iwasaki, K.; Komiyama, K.; Umezawa, I. J.
Antibiot. 1985, 38, 1677. (d) Nomoto, H.; Katsumata, S.;
Takahashi, K.; Funayama, S.; Komiyama, K.; Umezawa, I.;
Omura, S. J. Antibiot. 1989, 42, 479.
Macrolactamization
The resulting aniline (34 mg, 63 mmol) was slowly added via a can-
nula to a soln which was prepared from the Mukaiyama salt (2-chlo-
ro-1-methylpyridinium iodide; 161 mg, 630 mmol) and anhyd Et3N
(0.18 mL, 1.26 mmol) in anhyd toluene (35 mL). The mixture was
stirred at r.t. for 4 h and concentrated under reduced pressure. The
crude product was purified by flash chromatography (hexane–
EtOAc) to yield the macrocyclic title compound (12 mg, 26% for
two steps) as a mixture of isomers. The NMR data are given for the
major isomer.
1H NMR (400 MHz, C6D6): d = 8.38 (d, J = 3.0 Hz, 1 H, Ar), 7.32
(s, 1 H, NH), 6.05 (d, J = 3.0 Hz, 1 H, Ar), 6.05 (dd, J = 15.4, 10.8
Hz, 1 H, triene), 5.90–5.73 (m, 3 H, triene), 5.44–5.38 (m, 1 H, 9-
H), 5.39 (dd, J = 15.2, 8.5 Hz, 1 H, 4-H), 5.29 (m, 1 H, 15-H), 4.99
(dd, J = 6.3 Hz, 1 H, 13-H), 4.24 (m, 1 H, 3-H), 3.61–3.55 (m, 1 H,
11-H), 3.43 (s, 3 H, OCH3, Ar), 3.42 (s, 3 H, OCH3, Ar), 3.12 (s, 3
H, OCH3), 3.09–2.99 (m, 1 H, 2-H), 2.95 (dd, J = 13.2, 3.3 Hz, 1 H,
2-H), 2.59–2.22 (m, 6 H, 10-H, 10-H¢, 16-H, 16-H¢, 17-H, 17-H¢),
2.12–2.05 (m, 1 H, 12-H), 2.05 (m, 3 H, 14-CH3), 1.34 (s, 3 H,
OCCH3), 1.33 (s, 3 H, OCCH3), 0.89 (d, J = 7.0 Hz, 3 H, 12-CH3).
13C NMR (100 MHz, C6D6): d = 167.6, 158.8, 141.8, 135.6, 135.2,
133.9, 133.7, 133.6, 133.5, 132.4, 131.5, 130.6, 125.8, 111.5, 105.9,
101.0, 80.2, 73.4, 69.5, 62.1, 56.0, 55.2, 45.9, 37.2, 36.2, 31.4, 30.5,
24.3, 24.2, 20.5, 12.4.
HRMS (ESI): m/z [M+ + Na] calcd for C31H43NNaO6: 548.2988;
found: 548.2998.
(6) Zhang, H.-P.; Kakeya, H.; Osada, H. Tetrahedron Lett.
1997, 38, 1789.
(7) Hosokawa, N.; Naganawa, H.; Iinuma, H.; Hamada, M.;
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(8) Smith, A. B. III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am.
Chem. Soc. 1996, 118, 8316.
(9) (a) Panek, J. S.; Masse, C. E. J. Org. Chem. 1997, 62, 8290.
(b) Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. J. Am.
Chem. Soc. 1998, 120, 4123.
Ansatrienol Derivative 43
The resulting macrocycle (12 mg, 23 mmol) was dissolved in MeOH
(2 mL) and 1-camphorsulfonic acid (1.5 mg) was added. The mix-
ture was stirred for 2 h, hydrolyzed with Et3N (0.1 mL) and concen-
trated under reduced pressure. The crude product was purified by
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of an Ansatrienol Derivative
319
(10) (a) Smith, A. B. III; Wan, Z. Org. Lett. 1999, 1, 1491.
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(b) Schöning, K.-U.; Wittenberg, R.; Kirschning, A. Synlett
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(12) Aldehyde 10 was prepared by ozonolysis of TBS-protected
(Z)-but-2-ene-1,4-diol, see: Keck, G. E.; Wager, C. A.;
Wager, T. T.; Savin, K. A.; Covel, J. A.; McLaws, M. D.;
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(13) Phosphonate 11 was prepared from dichloroethyl
phosphonate (Scheme 9): Patois, C.; Savignec, P. Synth.
Commun. 1991, 21, 2391.
a) CF3CH2OH,
Et3N, THF (99%)
b) LDA, MeOC(O)Cl,
THF, –78 °C
c) HCl/H2O
(69% for two steps)
Me
Me
F3CCH2O
F3CCH2O P
O
Cl
Cl
OMe
P
O
(28) Among many different oxidation procedures tested, TPAP
(cat.)/NMO was best suited for the oxidation of the highly
unsaturated alcohol: Ley, S. V.; Normann, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639.
O
11
Scheme 9
(29) (a) Riediker, M.; Duthaler, R. O. Angew. Chem., Int. Ed.
Engl. 1989, 28, 494. (b) Duthaler, R. O.; Herold, P.;
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(20) One major problem that arose during the oxidative cleavage
of the boronic ester was the formation of furan 45 which may
have originated from over oxidation of diol 26 and formation
of the aldehyde 44 (Scheme 10). Lactol formation and
elimination yields 45. This side reaction was fully
suppressed, if H2O2 was slowly added to a well cooled
solution of the boronate
(31) When other alcohols than allyl alcohol were employed we
observed exchange of allyl in the alloc group by these
alcohols.
(32) Friedrich-Bochnitschek, S.; Waldmann, H.; Kunz, H. J. Org.
Chem. 1989, 54, 751.
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(37) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem.
O
PivO
PivO
OH
O
1990, 55, 1868.
OH
O
PivO
44
45
Scheme 10
Synthesis 2007, No. 2, 304–319 © Thieme Stuttgart · New York