Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones

Article abstract of DOI:10.1016/j.tet.2008.06.017

N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound 1 has been prepared employing a convergent strategy

Full text of DOI:10.1016/j.tet.2008.06.017

Tetrahedron 64 (2008) 7920–7928
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones
y
z
*
Fabian Feyen , Andrea Jantsch , Kurt Hauenstein, Bernhard Pfeiffer, Karl-Heinz Altmann
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Z u¨ rich, HCI H405, Wolfgang-Pauli-Str. 10, CH-8093 Z u¨ rich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2008
Received in revised form 4 June 2008
Accepted 6 June 2008
Available online 10 June 2008
N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and
represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound
1
has been prepared employing a convergent strategy that is based on the consecutive assembly of
building blocks 3, 4, and 19 into diene 20 and subsequent RCM-mediated macrocycle formation. The
aldol reaction between aldehyde 3 and ketone 4 delivered the required 6R,7S diastereoisomer 5 with
good selectivity and provided a reliable entry into the stereoselective synthesis of carboxylic acid 12.
RCM with diene 20 was highly E-selective, thus giving efficient access to (E)-9,10-dehydro-1 (2). The
latter is a key analog in SAR studies with 1.
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
The corresponding natural products epothilones A/B (Fig. 1) are
microtubule-stabilizing agents with pronounced in vitro and in
10
Natural products are a unique source of lead structures for drug
discovery and development, and a substantial part of modern
pharmacotherapy is based on compounds that are either natural
vivo antitumor activity and have served as successful lead
structures for the development of a series of clinical candidates for
11
cancer chemotherapy .
1
products themselves or derived from natural product leads. Tra-
Following the discovery of 1, we have also investigated a (lim-
ited) number of structural variants with alternative carbamoyl- or
ditionally, the organic chemistry of natural product-based drug
discovery, for reasons of technical feasibility, has mainly focused on
the preparation of semisynthetic derivatives as potential new drug
12 9
acyl-substituents on N
; however, while some of these analogs
retained significant antiproliferative activity, all of them were less
2
candidates, while de novo total synthesis has generally been more
potent than lead structure 1. In addition to the exploration of dif-
12
important for the resolution of structural and stereochemical
questions.3 In cases of severely limited availability of a natural
product, a problem particularly notorious with compounds of
marine origin, total synthesis has also been a means of providing
material for extended biological testing and, in particular, of ana-
ferent N -substituents, our initial structure–activity relationship
(SAR) studies with 1 were focused on structural modifications that
had been demonstrated for natural epothilones to lead to enhanced
antiproliferative activity. Based on work by Danishefsky and co-
workers this includes the incorporation of a E double bond between
4
9
10 12,13
logs for initial SAR studies. More recently, however, a number of
C and C
,
thus resulting in azathilone 2 (Fig.1) as an important
total synthesis-based concepts have been developed that directly
aim at the discovery of new drug leads that are not genuine natural
products, but (still) exhibit natural product-like structural features.
This includes the preparation of screening libraries either by di-
target structure for synthesis. Access to 2, however, was not
5
6
versity- or biology-oriented synthesis (DOS or BIOS, respectively),
O
O
7
but also the design and synthesis of natural product hybrids or
R
O
1
2
8
N
O
S
S
‘
non-natural’ natural products. In this context, we have recently
12
reported on the potent antiproliferative activity of 12-aza-epothi-
10
Y
9
N
X
N
8
b,9
15
O
lone (‘azathilone’) 1 (Fig. 1),
which is an epothilone-derived
HO
7
6
O
HO
O
non-natural natural product that inhibits human cancer cell growth
in vitro with sub-100 nM IC50 values.
1
O
OH
O
OH
*
Corresponding author. Tel.: þ41 44 633 73 90; fax: þ41 44 633 13 69.
E-mail address: karl-heinz.altmann@pharma.ethz.ch (K.-H. Altmann).
Present address: Carbogen-Amcis AG, CH-5502 Hunzenschwil, Switzerland.
Present address: Lonza AG, CH-3930 Visp, Switzerland.
R = H: Epo A
X-Y = CH -CH : 1
2 2
X-Y = CH=CH: 2
R = CH : Epo B
3
y
z
Figure 1.
0
040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.017

F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
7921
possible based on our first generation strategy for the synthesis of
consistently reported to show good to excellent selectivity in favor
of the formation of the desired 6R,7S isomer.
9
,13
15a,b,17b,18
1
,
which did not proceed through an appropriate unsaturated
intermediate (or even a precursor with a masked double bond
As shown in Scheme 2, our expectations on the stereochemical
outcome of the critical aldol step were borne out by the experi-
mental results, such that the reaction between aldehyde 3 and the
Li-enolate derived from ketone 4 produced a 8/1 mixture of 6,7-syn
diastereoisomers. While the respective absolute configurations of
these isomers could not be rigorously established, due to a lack of
crystalline intermediates for the entire sequence leading from 3/4
to the target structures 2/1, prior experience in our own labo-
9
10
between C and C ). As a consequence, we had to establish a new,
independent route to 2; as the reduction of 2 directly leads to 1, this
approach would simultaneously constitute a new route to azathi-
lone 1. In this paper we now disclose full experimental details for
14
the synthesis of 2, which is based on a highly stereoselective
ring-closing olefin metathesis (RCM) reaction, and its subsequent
conversion to 1 by diimide reduction.
8
a,15a
ratory
as well as a significant amount of literature precedence
1
5b,17b,18,19
for aldol reactions with 4
clearly suggest that the major
2
. Results and discussion
product must be compound 5 with the desired 6R,7S configuration.
As illustrated in Scheme 1, our retrosynthesis of 2 involved the
RCM-based ring closure of a diene precursor I-2 as the ultimate key
disconnection. Compound 1 would then be obtained through se-
lective reduction of the 9/10-double bond in 2 or an appropriately
protected precursor thereof (I-3). Although the stereoselectivity of
the ring-closure reaction was difficult to predict a priori, based on
previous studies by Danishefsky and co-workers on related (N-free)
systems the E-configured macrocyclic alkene was expected to be
formed preferentially, although perhaps not with complete selec-
OPMB
OPMB
3
OPMB
O
HO
RO
c)
a)
b)
+
O
O
O
O
OR OR
5
12b–e
tivity.
Diene I-2 was envisioned to be derived from alcohol 19
R = H: 6
R = TBS: 7
O
O
O
and a protected carboxylic acid I-1 by simple esterification. Building
block 19 was planned to be elaborated from the known alcohol
4
1
5,22
OH
X
1
5,
while intermediate I-1 was assumed to be accessible from
15c,16
15a,17
aldehyde 3
and the Schinzer ketone 4,
as aldol reactions
TBSO
TBSO
d)
e)
between 4 and
a
-chiral aldehydes related to 3 have been
O
OTBS OTBS
O
OTBS OTBS
8
X = O: 9
O
O
f)
X = CH : 10
2
N
O
RCM
RO
S
1
N
TBSO
TBSO
g)
h)
O
OH
OH
I-3 (R = H: 2)
O
OTBS
O
OTBS O
O
OR
11
12
Scheme 2. (a) 4, LDA, ꢀ78 ꢁC, 5 h, then addition of 3, ꢀ90 ꢁC, 75 min, 76%, dr¼8/1; (b)
ꢁ
PPTS, MeOH, rt, 20 h, 86%; (c) (i) TBSOTf, 2,6-lutidine, ꢀ78 C/rt, 1.5 h; (ii) flash
O
O
chromatography, 76% (single isomer); (d) H
2
/Pd–C, MeOH, rt, 20 h, 86%; (e) TPAP, NMO,
Br, LiHMDS, THF, 0 C, 1.5 h, 76% (two steps); (g) CSA
/MeOH 1/1, 0 C, 1 h, 87%; (h) PDC (11 equiv), DMF, rt, 64 h, 85%.
ꢁ
4
Å MS, CH
2
Cl
2
, rt, 1 h; (f) MePPh
3
ꢁ
N
S
(1.0 equiv), CH
2
Cl
2
N
RO
O
O
As a possible alternative entry into the synthesis of building
block I-1 we have also investigated the aldol reaction between
I-2
2
0
aldehyde 3 and the Ti-enolate of
already incorporates the required carboxylate oxidation state at C1
epothilone numbering, see Fig. 1). Unfortunately, the desired aldol
g-keto imide 13 (Fig. 2), which
Esterification
O
S
OR
(
product was obtained only with variable selectivities and in vari-
able and low yields (10–30%; dr¼1:1–4:1) and this approach was
not further pursued.
O
O
RO
N
+
OH
Aldol
N
O
OR
I-1
O
OH
S
O
19
TBSO
S
N
O
O
O
OTBSO
O
OTBS
PMBO
N
13
14
+
O
O
O
Figure 2.
O
HO
OTBS 15
3
4
While the separation of the mixture of isomers produced in the
reaction between 3 and 4 was possible at the stage of the imme-
diate aldol products, it was more conveniently performed after
Scheme 1. Retrosynthesis of target structures 1 and 2. R¼protecting group or H.
Protecting groups can vary independently.

7922
F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
conversion of this product mixture to fully protected tetrol 7 via
acetal cleavage with PPTS, to produce 6, and subsequent persily-
lation with TBSOTf (Scheme 2). After flash chromatography com-
pound 7 was isolated as a single isomer in 48% overall yield for the
three-step sequence from aldehyde 3. Catalytic hydrogenation of 7
provided the partially protected tetrol 8 in excellent yield (86%) and
O
O
N
O
S
a)
b)
12
+
19
N
21
this was further converted to aldehyde 9 by TPAP oxidation.
TBSO
O
þ ꢀ
Subsequent Wittig reaction with [Ph PCH ] I gave olefin 10 in 76%
3 3
20
yield (based on 8). The elaboration of 10 into the desired carboxylic
acid 12 (¼I-1 with R¼TBS; Scheme 1) was then achieved in excel-
lent overall yield (74%) through selective cleavage of the primary
TBS ether followed by oxidation of the resulting free alcohol 11 with
an excess of PDC in DMF. Alternatively, 12 could also be obtained
from 11 in a two-step sequence that involved Swern oxidation to
aldehyde 14 (Fig. 2) followed by further oxidation of the crude
O
OTBS
O
O
O
O
N
N
O
S
S
t
22
aldehyde with NaClO
in similar overall yield as for the one-step approach with PDC.
2
, 2-methyl-2-butene, BuOH, and NaH
2
PO
4
N
N
2
3
RO
O
O
HO
O
15,22
d)
The synthesis of building block 19 from protected alcohol 15
1
2
2
(
Scheme 3) involved conversion of the latter to iodide 16 through
treatment with I , Ph P, and imidazole and subsequent reaction of
6 with an excess of allylamine to provide O-TBS-protected amino
O
OR
O
OH
2
3
1
R = TBS: 21
R = H: 2
c)
alcohol 17 in high yield (79%).
ꢁ
Scheme 4. (a) DCC (1.3 equiv), DMAP (0.3 equiv), CH
2
Cl
2
, 0 C, 15 min, rt, 15 h, 77%; (b)
HO
I
S
S
2nd generation Grubbs catalyst (0.15 equiv, incremental addition), CH
0%; (c) HF$Pyr, pyridine, THF, 4.5 h, rt, 65%; (d) KO C-N]N-CO K (excess), AcOH,
CH Cl , 52%.
2 2
Cl , refl, 18 h,
7
2
2
a)
N
b)
N
2
2
OTBS
OTBS
O
15
16
converted to the corresponding cycloalkene in good yield in the
2
6
presence of the second generation catalyst.
In contrast to the transformation 20/21 (Scheme 4), however,
the cyclization of 22 was completely non-selective, i.e., the product
R
N
O
S
2
6
was obtained as a 1/1 mixture of double bond isomers. Com-
pletely E-selective RCM reactions mediated by second generation
Grubbs catalyst have been reported by Danishefsky and co-workers
for dienes 23a/b, but the yields of the desired cyclization products
were severely compromised by the fact that the major reaction
pathway for these substrates involves RCM between the double
N
S
N
d)
OTBS
N
R = H: 17
OH
19
c)
R = BOC: 18
0
0
0
9
ꢁ
10
10
16
17
10
10
9
Scheme 3. (a)
I
2
,
Ph
(11 equiv), Et
C, 5 h, 92%; (d) TBAF, aq THF, rt, 2 h, 81%.
3
2
P, imidazole, Et O/CH
3
CN 3/1,
0
C/rt, 30 min, 79%; (b)
O, Et N, DMAP (cat), THF,
bonds C –C and C –C (rather than C –C and C –C ; epo-
CH
0
2
]CHCH
2
NH
2
2
O, refl, 20 h, 79%; (c) BOC
2
3
12b,27
thilone numbering, Fig. 1).
Interestingly, none of the corre-
ꢁ
sponding alternative cyclization product was isolated from RCM
reactions with diene 20. The cyclization of 20, however, was con-
sistently accompanied by the formation of a minor by-product,
which we initially assumed to be the 9,10-Z isomer of 21. In order to
investigate the biological activity of this purported Z isomer, the
compound was isolated from one of our larger scale (ca. 900 mg of
diene 20) RCM reactions in 3.5% yield and ca. 90% purity. After
deprotection and HPLC purification spectral analysis clearly in-
dicated the resulting product to be an isomer of 2, but, quite
surprisingly, it also suggested the presence of an E rather than a Z
2
Carbamoylation of the allylic amino group with BOC O then
gave N/O-bis-protected derivative 18, whose treatment with TBAF
furnished the desired free alcohol 19 in 46% overall yield for the
four-step sequence from 15.
Initial attempts at the esterification of alcohol 19 and acid 12
with either DCC or EDC and DMAP gave the desired ester 20 only in
moderate and somewhat variable yields of 25–57%. A significant
improvement in the efficiency of the reaction could be realized,
however, through rigorous drying of both starting materials
3
double bond as part of the macrocycle (based on J¼15.5 Hz and the
(
co-evaporation with toluene immediately before use) and the use
of a 20% excess of alcohol 19 over acid 12. Thus, under optimized
conditions (dried starting materials, 1.0 equiv 12, 1.2 equiv 19,
absence of a NOE between the two alkene protons). As this was
outside of the scope of our study, we have made no further at-
tempts to ascertain the identity of the side product formed in RCM
reactions with 20, but it should be noted that Zeng et al. have re-
1
.3 equiv DCC, 0.3 equiv DMAP) ester 20 was consistently obtained
in yields between 76 and 82% (Scheme 4).
cently reported the epimerization of the stereocenter
a
to the
With diene 20 in hand, our first attempt at ring closure involved
2 2
the use of first generation Grubbs catalyst in boiling CH Cl as the
2
4
O
R
O
solvent, but no macrocycle formation was observed under these
conditions (only recovered starting material was isolated). In con-
trast, the use of second generation Grubbs catalyst led to efficient
and highly stereoselective macrocyclization, thus furnishing the
desired 9,10-E-configured cycloalkene 21 in 70% isolated yield.
1
0
S
10'
9'
S
N
1
6
N
9
TBSO
O
O
17
TBSO
O
2
3a: R = CH
3
3
These findings mirror previous observations by Danishefsky and
22
23b: R = CF
co-workers25 as well as Sun and Sinha26 on RCM-based macro-
O
OTBS
O
OTES
cyclizations with the related diene 22 (Fig. 3), which did not
undergo RCM with first generation Grubbs catalyst, whereas it was
Figure 3.

F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
7923
double bond in a vinyl cyclopropane in the course of an RCM re-
action.28 Whether or not the minor product obtained in the RCM-
based cyclization of diene 20 may be the result of an analogous
epimerization at C8 (epothilone numbering; Fig. 1) remains to be
elucidated.
As we have reported earlier,8,14 the antiproliferative activity of
9,10-dehydro analog 2 is at least 30-fold lower than for the satu-
rated parent compound 1, which stands in stark contrast to the
effects associated with the incorporation of a 9,10-E double bond in
natural epothilones. While the molecular origin of this discrepancy
is not understood at this point, it may be speculated that the data
are indicative of differences in the bioactive conformation between
the polyketide-based natural products and the azamacrolide-based
azathilones. NMR-based structural studies are currently in progress
to address this question as is the synthesis of additional azathilone
analogs for more extensive SAR studies.
In summary, we have achieved the synthesis of the desatured
azathilone 2, which is a key derivative in the elucidation of the SAR
of this new class of tubulin modulators. We have also demon-
strated that 2 can be converted to 1 in good yield, although the
reaction conditions for this transformation still require further
optimization. Both 2 and 1 may serve as key intermediates for the
preparation of additional azathilones for more extensive future
SAR studies.
The conversion of the fully protected cycloalkene 21 to our
major target structure 2 then required the selective removal of the
3
7
TBS protecting groups on O and O without concomitant loss of the
12
crucial BOC moiety on N . This transformation could be achieved
in good yield (65%) by treatment of 21 with HF$pyridine in THF
under carefully controlled conditions. Continuous reaction moni-
toring proved to be absolutely mandatory in this case, as different
batches of HF$pyridine (or even the same batch used at different
times) can lead to different reaction kinetics and, thus, highly var-
iable yields for otherwise identical reaction conditions. While
cycloalkene 2 was our primary synthetic target, we have also in-
vestigated the possible conversion of this analog or its protected
precursor 21 to the saturated azathilone 1. Obviously, the reduction
of the 9/10-double bond in 2/21 is complicated by the presence of
a second alkene functionality in the C15 side chain; it was, there-
fore, not surprising that catalytic hydrogenation methods mostly
gave mixtures of mono- and bis-hydrogenated products (in addi-
tion to unchanged starting material; according to MS-analysis of
3. Experimental section
3.1. General
crude reaction mixtures). The use of H
not give any conversion. Interestingly, hydrogenation of 21 in the
presence of Wilkinson’s catalyst, Rh(I)-(PPh Cl, in EtOH for 2 h
resulted in selective reduction of the trisubstituted side-chain
double bond, providing analog 25 (Fig. 4) in 70% isolated yield.
2
/Ra-Ni with 2 in EtOH did
All solvents used for reactions were purchased as anhydrous
grade from Fluka and used without further processing. Solvents for
extractions, column chromatography and TLC were of commercial
grade and distilled before use. TLC was performed on Merck TLC
aluminum sheets (silica gel 60 F254). Spots were visualized with UV
3 3
)
light (
or KMnO
using Fluka silica gel 60 for preparative column chromatography
40–63 m), unless specifically noted otherwise. NMR spectra were
recorded on a Bruker AV-400 (400 MHz) and a Bruker DRX-500
500 MHz) spectrometer at 298 K or the temperature specifically
indicated with the analytical data. Infrared spectra (IR) were
recorded on a Jasco FT/IR-6200 instrument. Optical rotations
were measured on a Jasco P-1020 polarimeter. RP-HPLC analyses
l
¼254 nm) or through staining with phosphomolybdic acid
4
. Flash column chromatography (FC) was performed
O
O
(
m
N
O
S
(
N
TBSO
O
25
were carried out on a Waters Symmetry column (C18, 3.5 mm,
O
OTBS
Figure 4.
4.6ꢂ100 mm) at a detection wavelength of 254 nm. Compounds
3
were eluted with water (A)/CH CN (B) 50/50 for 2 min followed by
a gradient A/B 50/50/A/B 10/90 from 2 to 9 min. Preparative
In light of these difficulties we finally resorted to the use of in
situ generated diimide as the reducing agent,29 which had been
successfully employed by Danishefsky and co-workers for the
RP-HPLC was carried out using a Waters Symmetry column (C18,
5
m
m, 19ꢂ100 mm) using the same solvent system as above. Elution
was performed with A/B 50/50 for 2 min followed by a gradient of
conversion of various 9,10-dehydroepothilones to the saturated
A/B 50/50/A/B 30/70 from 2 to 9 min.
parent compounds.1
2b–d
More recently, we have also employed this
methodology in the synthesis of a new 12,13-trans-cyclopropane-
3.1.1. (4R,5S,6S)-7-(4-Methoxybenzyloxy)-2-((S)-2,2-dimethyl-1,3-
dioxan-4-yl)-5-hydroxy-2,4,6-trimethylheptan-3-one (5)
based Epo A analog.30 After initial unsuccessful attempts with
31
mesitylenesulfonyl hydrazine as a diimide source, the desired
transformation could finally be achieved with dipotassium diazo-
A solution of ketone 4 (4.02 g, 18.75 mmol) in 10 ml of THF was
added to a solution of LDA (freshly prepared from 11.2 ml of 1.6 M
n-BuLi in hexane (17.90 mmol) and 2.53 ml (17.90 mmol) of diiso-
3
2
dicarboxylate (PADA)/AcOH
2 2
in boiling CH Cl , although the
ꢁ
reaction proved to be extremely slow. Thus, treatment of 2 with
a total of 164 equiv of PADA (prepared according to Ref. 33) and
propylamine in 20 ml of THF) at ꢀ78 C and the mixture was stirred
ꢁ
at this temperature for 5 h. It was then cooled to ꢀ90 C and al-
3
28 equiv of AcOH for 4 h gave the desired azathilone 1 in 15%
dehyde 3 (crude; prepared through Swern oxidation of 3.25 g
15c
isolated yield after HPLC purification together with 50% of
recovered starting material. Purification of the target compound by
RP-HPLC was indispensable, as no separation of 2 and 1 was
achievable by conventional silica gel flash chromatography. When
the reaction time was extended to 8 days and the total amount of
PADA/AcOH was increased to ca. 680/1360 equiv (added in 11
separate portions) the total yield could be increased to 52% (after
HPLC purification). The conversion of 2 to 1 is thus feasible in
acceptable yield, but, clearly, additional optimization work would
be required to establish a truly practical approach for this
transformation.
(19.0 mmol) of the corresponding alcohol ) was added in 10 ml of
ꢁ
THF. After 75 min at ꢀ90 C the reaction was quenched by addition
of MeOH (2.5 ml), the mixture was diluted with AcOEt and water,
and the phases were separated. Re-extraction of the aqueous
solution with AcOEt, drying of the combined organic extracts over
4
MgSO , and removal of the solvent under reduced pressure gave
a residue that was purified by FC (AcOEt/hexane 1/4). The aldol
product 5 was obtained as a clear oil (6.03 g, 76%) as a 8/1 mixture
of diastereoisomers that was not separated at this point.
It should be noted that the reaction has also been carried out
successfully on the same scale, when the enolate of 4 was generated

7924
F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
þ
over only 75 min and the addition of aldehyde 3 was performed at
748 ([MNa ], 100), 579 (65), 140 (13), 96 (32), 83 (43). HRMS (ESI-
ꢁ
ꢁ
þ þ
ꢀ
78 C rather than ꢀ90 C.
pos) (C39H O Si ) calcd 747.4842 (MNa ), found 747.4865 (MNa ).
76 6 3
1
H NMR (400 MHz, CDCl
3
):
d
7.22 (d, J¼8.8 Hz, 2H); 6.85 (d,
J¼8.7 Hz, 2H); 4.42 (s, 2H); 4.03 (dd, J¼11.8, 2.5 Hz, 1H); 3.97–3.88
m, 1H); 3.86–3.80 (m, 1H); 3.78 (s, 3H); 3.63–3.55 (m, 2H); 3.52–
.40 (m, 2H); 3.40 (br s, 1H); 3.23–3.15 (m, 1H); 2.17 (s, 3H); 1.85–
3.1.4. (2S,3S,4R,7S)-3,7,9-Tri-tert-butyldimethylsilyloxy-1-hydroxy-
2,4,6,6-tetramethylnonan-5-one (8)
Protected tetrol 7 (2.25 g, 3.09 mmol) was hydrogenated over
10%-Pd/C (0.7 g) at rt and atmospheric pressure in 60 ml of EtOH for
2 h. The catalyst was then removed by filtration and subsequently
(
3
1
.75 (m, 1H); 1.70–1.50 (m, 1H); 1.35 (s, 3H); 1.28 (s, 3H); 1.21 (s,
13
3
H); 1.08 (s, 3H); 1.04 (d, J¼7.0 Hz, 3H); 0.96 (d, J¼6.9 Hz, 3H).
): 217.0, 159.1, 130.7, 129.2, 113.7, 98.4, 74.8,
2.9, 72.6, 72.5, 60.0, 55.2, 51.4, 41.8, 36.1, 29.7, 25.1, 21.7, 19.0, 18.5,
4.2, 10.0. IR (film): 3489 (br), 2962, 2937, 2876, 1687, 1609, 1513,
369, 1244, 1097, 1033, 972, 850, 819. MS (ESI) m/z (rel intensity)
C
ꢁ
NMR (100 MHz, CDCl
7
1
1
3
d
extracted with 300 ml of warm (60 C) AcOEt. The combined fil-
trates and extracts were evaporated under reduced pressure and
the residue was purified by FC (hexane/AcOEt 30/1) to provide
1.60 g (86%) of the title compound 8 as a viscous oil.
þ
20
1
4
45 ([MNa ], 88), 405 (18), 223 (6), 140 (3), 83 (7). HRMS (ESI)
[
a
]
D
ꢀ17.1 (c 0.93, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 3.98–
þ
þ
(
C
H
24 38
O
6
) calcd 445.2561 (MNa ), found 445.2565 (MNa ). NMR
3.88 (m, 2H); 3.72–3.50 (m, 4H); 3.30–3.20 (m, 1H); 2.25 (br s, 1H);
signals for major diastereoisomer.
1.65–1.45 (m, 3H); 1.17 (s, 3H); 1.12 (d, J¼6.3 Hz, 3H); 1.05 (s, 3H);
1
.00 (d, J¼7.1 Hz, 3H); 0.92 (s, 9H); 0.88 (s, 9H); 0.85 (s, 9H); 0.12 (s,
3
2
.1.2. (2S,3S,4R,7S)-1-(4-Methoxybenzyloxy)-3,7,9-trihydroxy-
,4,6,6-tetramethylnonan-5-one (6)
3H); 0.08 (s, 3H); 0.08 (s, 3H); 0.07 (s, 3H); 0.04 (s, 3H); 0.02 (s, 3H).
13
3
C NMR: (100 MHz, CDCl ): d 218.5, 73.9, 64.8, 61.0, 53.8, 53.0, 46.7,
To a solution of the aldol product 5 (4.0 g, 9.47 mmol) in 150 ml
38.1, 37.5, 26.4, 26.2, 26.1, 26.0, 19.1, 18.4, 18.4, 18.3, 15.8, 15.4, ꢀ3.6,
of MeOH was added pyridinium-p-toluene sulfonate (1.98 g,
0.41 mmol) and the mixture was stirred at rt for 20 h. Satd aq
NaHCO was then added and the solution was extracted with AcOEt
4ꢂ100 ml). The combined organic extracts were dried over MgSO
the solvent was evaporated in vacuo, and the residue purified by FC
ꢀ3.7, ꢀ3.8, ꢀ3.9, ꢀ5.2, ꢀ5.3. IR (film): 2948, 2930, 2851, 1688, 1509,
þ
1
1469, 1252, 1091, 983, 836, 768. MS (ESI): m/z¼627.16 [MþNa ].
þ
3
HRMS (MALDI) (C31
627.4258 (MNa ).
H
68
O
5
Si
3
)
calcd 627.4267 (MNa ), found
þ
(
4
,
(
(
AcOEt/hexane 2/1) to provide 3.11 g (86%) of the title compound 6
3.1.5. (2R,3S,4R,7S)-3,7,9-Tris(tert-butyldimethylsilyloxy)-2,4,6,6-
tetramethyl-5-oxononanal (9)
To a stirred mixture of alcohol 8 (1.6 g, 2.64 mmol) and dried,
2 2
powdered 4 Å molecular sieves in 80 ml of CH Cl were added
mixture of diastereoisomers).
1
H NMR (400 MHz, CDCl
3
):
d
7.23 (d, J¼8.6 Hz, 2H); 6.85 (d,
J¼8.6 Hz, 2H); 4.42 (s, 2H); 4.05 (m, 1H); 3.88–3.80 (m, 1H); 3.78 (s,
H); 3.67–3.60 (dd, J¼8.7, 1.5 Hz, 1H); 3.60–3.52 (m, 1H); 3.51–3.43
m,1H); 3.30–3.00 (br m, 4H); 1.90–1.80 (m,1H); 1.65–1.50 (m, 2H);
3
(
1
3
1
1
1
3
4
0.81 g (6.02 mmol) of N-methylmorpholine-N-oxide (NMO) fol-
lowed by tetra-n-propylammonium perruthenate (TPAP) (49 mg,
0.14 mmol). The mixture was stirred at rt for 1 h followed by
filtration through a short plug of silica, washing with AcOEt, and
evaporation of the filtrate to give 1.66 g of crude aldehyde 9 (quant),
which was directly used in the next step.
.19 (s, 3H); 1.10 (s, 3H); 1.08 (d, J¼7.0 Hz, 3H); 0.96 (d, J¼6.9 Hz,
13
3
H). C NMR: (100 MHz, CDCl ): d 217.0, 159.1, 130.3, 129.3, 113.7,
00.8, 76.2, 73.1, 72.9, 61.8, 55.2, 52.6, 41.8, 36.0, 32.5, 21.7, 18.5, 14.1,
0.4. IR (film): 3445 (br), 2966, 2360, 1688, 1613, 1513, 1248, 1076,
þ
20
1
037, 733, 704. MS (MALDI) m/z (rel intensity) 405 ([MNa ], 100),
[
a
]
D
ꢀ43.4 (c 1.30, CH
2 2 3
Cl ). H NMR (400 MHz, CDCl ): d 9.71 (d,
31 (7), 235 (7), 202 (5), 72 (3). HRMS (MALDI) (C21
05.2248 (MNa ), found 405.2255 (MNa ).
H
34
O
6
) calcd
J¼2.1 Hz, 1H); 4.06 (dd, J¼8.0 Hz, 2.2 Hz, 1H); 3.88 (dd, J¼7.5 Hz,
2.8 Hz, 1H); 3.64 (m, 1H); 3.57 (m, 1H); 3.22 (qi, J¼7.0 Hz, 1H); 2.30
þ
þ
(
m, 1H); 1.60–1.53 (m, 1H); 1.52–1.42 (m, 1H); 1.21 (s, 3H); 1.12 (d,
3
.1.3. (2R,3R,4S,7S)-1-(4-Methoxybenzyloxy)-3,7,9-tris(tert-
J¼7.0 Hz, 3H); 1.09 (d, J¼7.0 Hz, 3H); 1.03 (s, 3H); 0.87 (s, 9H); 0.87
butyldimethylsilyloxy)-2,4,6,6-tetramethylnonan-5-one (7)
To a solution of compound 6 (1.51 g, 3.92 mmol) and 3.49 g
19.5 mmol) of 2,6-lutidine in 30 ml of CH Cl was added a solution
of TBSOTf (5.65 g, 19.5 mmol) in 10 ml of CH Cl dropwise at
78 C. After 15 min at ꢀ78 C and 1.5 h at rt, the reaction was
quenched by addition of aq NaHCO followed by extractive work-up
with AcOEt. Purification of the residue obtained after drying of the
extracts and evaporation of solvent by FC (Et O/hexane 1/25) gave
.167 g (76%) of the fully protected tetrol as single
diastereoisomer.
(s, 9H); 0.86 (s, 9H); 0.09 (s, 3H); 0.07 (s, 3H); 0.07 (s, 3H); 0.04 (s,
13
3
3H); 0.01 (s, 6H). C NMR (100 MHz, CDCl ): d 217.9, 204.2, 76.2,
(
2
2
73.8, 60.9, 53.8, 50.8, 46.5, 38.1, 26.1, 26.0, 25.9, 24.5, 19.2, 18.3, 18.3,
þ
2
2
15.5, 12.4, ꢀ3.7, ꢀ3.9, ꢀ5.2, ꢀ5.3. MS (ESI): m/z¼625.27 [MþNa]
ꢁ
ꢁ
þ
ꢀ
and 641.26 [MþK] . HRMS (ESI-pos) (C31
66 5 3
H O Si ) calcd 625.41103
þ þ
3
(MNa ), found 625.41046 (MNa ).
2
3.1.6. (3S,6S,7R,8R)-1,3,7-Tris(tert-butyldimethylsilyloxy)-4,4,6,8-
tetramethyldec-9-en-5-one (10)
2
7
a
LiHMDS (3.40 ml of a 1 M solution in THF) was added dropwise
2
0
1
ꢁ
[a
]
D
ꢀ13.1 (c 1.78, CHCl
m, 2H); 6.83–6.77 (m, 2H); 4.40–4.31 (m, 2H); 4.21 (dd, J¼7.7,
.7 Hz, 1H); 4.12 (dd, J¼7.0, 2.5 Hz, 1H); 3.80–3.73 (m, 2H); 3.67 (dd,
J¼9.2, 6.3 Hz, 1H); 3.48–3.40 (m, 1H); 3.31 (s, 3H); 3.28 (dd, J¼9.1,
.6 Hz, 1H); 2.10–1.97 (m, 1H); 1.85–1.74 (m, 1H); 1.70–1.60 (m, 1H);
.20 (s, 3H); 1.19 (s, 3H); 1.15 (d, J¼7.0, 3H); 1.07 (d, J¼7.1 Hz, 3H);
.01 (s, 9H); 1.00 (s, 9H); 0.98 (s, 9H); 0.15 (s, 3H); 0.13 (s, 3H); 0.11
3
). H NMR (400 MHz, C
6
D
6
):
d
7.25–7.19
to a solution of Ph
3
PCH
3
I (1.25 g, 3.5 mmol) in 20 ml of THF at 0 C
(
2
and the mixture was stirred at this temperature for 30 min. Solu-
tion (30 ml) of the above crude aldehyde 9 in THF were then added
ꢁ
dropwise via syringe and stirring at 0 C was continued for 45 min.
6
1
1
Satd aq NH
Et O (100 ml) and the phases were separated. The aqueous solution
was re-extracted with Et
O (2ꢂ100 ml), the combined organic ex-
tracts were dried over MgSO and the solvent was removed by
evaporation. Purification of the residue by FC (Et O/hexane 1/
4
Cl (30 ml) was added followed by water (30 ml) and
2
2
1
(
s, 3H); 0.10 (s, 3H); 0.08 (s, 3H); 0.07 (s, 3H). H NMR (400 MHz,
4
CDCl ): 7.25–7.21 (m, 2H); 6.88–6.83 (m, 2H); 4.39 (s, 2H); 3.87
3
d
2
(
3
1
3
0
1
3
ꢀ
dd, J¼7.6, 2.8 Hz, 1H); 3.83 (dd, J¼7.4, 2.3 Hz, 1H); 3.80 (s, 3H);
100/1/50) gave 1.20 g of olefin 10 as a colorless oil (76% over two
.70–3.52 (m, 3H); 3.33–3.24 (m, 1H); 3.18 (dd, J¼9.2, 7.5 Hz, 1H);
steps).
2
0
1
.78–1.67 (m, 1H); 1.59–1.42 (m, 2H); 1.14 (s, 3H); 1.02 (d, J¼5.9 Hz,
[
a
]
D
ꢀ23.1 (c 3.66, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 5.99–
H); 1.00 (s, 3H); 0.96 (d, J¼7.1 Hz, 3H); 0.90 (s, 9H); 0.89 (s, 9H);
5.88 (m, 1H); 5.07–4.97 (m, 2H); 3.92 (dd, J¼7.5, 2.9 Hz, 1H); 3.88
(dd, J¼7.0, 2.1 Hz, 1H); 3.71–3.62 (m, 1H); 3.61–3.53 (m, 1H); 3.10–
3.02 (m, 1H); 2.16–2.08 (m, 1H); 1.61–1.45 (m, 2H); 1.19 (s, 3H);
1.05–1.00 (m, 9H); 0.92 (s, 9H); 0.89 (s, 9H); 0.87 (s, 9H); 0.10 (s,
3H); 0.09 (s, 3H); 0.08 (s, 3H); 0.06 (s, 3H); 0.04 (s, 3H); 0.03 (s, 3H).
13
3
.88 (s, 9H); 0.11–0.01 (m, 18H). C NMR (100 MHz, CDCl ): d 218.5,
59.1, 130.8, 129.3, 113.7, 76.4, 74.0, 72.9, 71.6, 61.1, 55.2, 53.7, 45.9,
8.8, 38.1, 26.2, 26.1, 26.0, 24.6, 18.6, 18.5, 18.3, 18.3, 16.7, 15.2, ꢀ3.6,
3.7, ꢀ3.7, ꢀ3.9, ꢀ5.2, ꢀ5.3. MS (ESI) m/z (rel intensity) 785 (85),

F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
7925
13C NMR (100 MHz, CDCl
3.7, 45.9, 43.5, 38.1, 26.2, 26.1, 26.0, 24.9, 18.8, 18.7, 18.5, 18.4, 18.3,
5.0, ꢀ3.5, ꢀ3.7, ꢀ3.8, ꢀ3.9, ꢀ5.2, ꢀ5.3. IR (film): 2954, 2930, 2858,
691,1469,1254,1092, 984, 837, 766. MS (MALDI) m/z (rel intensity)
):
d
218.5, 140.0, 115.3, 76.2, 73.8, 61.0,
3
2 4
NaH PO (143 mg, 1.03 mmol) in water (5 ml) and the mixture was
5
1
1
6
stirred at rt for 3 h. It was then concentrated in vacuo and the
residue was partitioned between AcOEt and brine. The phases were
separated and the aqueous solution was extracted with AcOEt. The
þ
þ
23 ([MNa ], 100), 601 ([MH ], 4), 509 (12), 506 (22), 481 (17), 456
4
combined organic extracts were then dried over MgSO , the solvent
(
(
9), 345 (14), 303 (29), 301 (15), 279 (29), 235 (26), 199 (11), 183
was evaporated and the resulting mixture was purified by FC
(hexane/AcOEt 20/1/10/1/4/1) to yield (after two columns)
230 mg (94%) of acid 12 as a yellow oil.
þ
14),140 (14). HRMS (MALDI) (C32
H
68
O
4
Si
3
) calcd 623.4321 (MNa ),
þ
found 623.4330 (MNa ).
Procedure B: To solution of alcohol 11 (1.15 g, 2.4 mmol) in 70 ml
of DMF was added pyridinium dichromate (PDC) and the resulting
solution was stirred at rt for 64 h. It was then poured into 150 ml of
brine, 50 ml of water were added, and the solution was extracted
with AcOEt (7ꢂ100 ml). The combined organic extracts were dried
3
4
.1.7. (3S,6S,7R,8R)-3,7-Bis(tert-butyldimethylsilyloxy)-1-hydroxy-
,4,6,8-tetramethyl-dec-9-en-5-one (11)
Camphorsulfonic acid was added to a solution of olefin 10
ꢁ
(
1.64 g, 2.73 mmol) in 50 ml of CH
2
Cl
mixture was stirred at 0 C for 1 h. Aq NaHCO
phases were separated, and the aqueous solution was re-extracted
with CH Cl
(4ꢂ50 ml). The combined organic extracts were
washed with brine and dried over MgSO . Subsequent evaporation
2
/MeOH 1/1 at 0 C and the
ꢁ
3
was then added, the
4
over MgSO and the solvent was evaporated under reduced pres-
sure. Purification of the resulting residue by FC (AcOEt/hexane 1/
6/1/2 (þ5% MeOH)) gave 1.0 g (85%) of acid 12 as a light-yellow oil
that could be converted to a white solid by co-evaporation with
toluene.
2
2
4
of the solvent gave 1.15 g (87%) of a colorless oil that was homo-
genous by TLC and was directly used in the next step. Analytical
data are for material from a different experiment that was sub-
mitted to FC (AcOEt/hexane 1/9).
2
0
1
[a
]
D
ꢀ21.0 (c 0.82, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 10.98
(br s, 1H); 5.99–5.88 (m, 1H); 5.08–4.98 (m, 2H); 4.40 (dd, J¼6.7,
3.0 Hz, 1H); 3.87 (dd, J¼7.5, 1.8 Hz, 1H); 3.08–3.01 (m, 1H); 2.49
(dd, J¼16.4, 3.0 Hz, 1H); 2.31 (dd, J¼16.4, 6.7 Hz, 1H); 2.13–2.06
(m, 1H); 1.19 (s, 3H); 1.10 (s, 3H); 1.05 (d, J¼7.0 Hz, 3H); 1.02 (d,
J¼7.0 Hz, 3H); 0.91 (s, 9H), 0.87 (s, 9H); 0.08 (s, 3H); 0.07 (s, 3H);
2
0
). 1H NMR (400 MHz, CDCl
[
a]
D
ꢀ9.3 (c 0.71, CHCl
.88 (m, 1H); 5.08–4.97 (m, 2H); 4.07 (dd, J¼6.7, 3.7 Hz, 1H); 3.89
dd, J¼7.5, 1.8 Hz, 1H); 3.64 (t, J¼6.0 Hz, 2H); 3.08–3.01 (m, 1H);
.13–2.06 (m, 1H); 1.82 (br s, 1H); 1.62–1.50 (m, 2H); 1.19 (s, 3H);
.10 (s, 3H); 1.05 (d, J¼7.0 Hz, 3H); 1.03 (d, J¼7.0 Hz, 3H); 0.92 (s,
H), 0.90 (s, 9H); 0.12 (s, 3H); 0.10 (s, 3H); 0.09 (s, 3H); 0.08 (s,
3
3
): d 5.99–
5
(
2
1
9
3
6
13
3
0.07 (s, 3H); 0.04 (s, 3H). C NMR (100 MHz, CDCl ): d 218.4,
177.5, 139.8, 115.5, 76.3, 73.3, 53.6, 46.2, 43.4, 40.1, 26.2, 26.0, 24.1,
19.0, 18.7, 18.5, 18.2, 15.5, ꢀ3.5, ꢀ3.8, ꢀ4.3, ꢀ4.6. IR (film): 2956,
2930, 2858, 1714, 1681, 1386, 1254, 1087, 998, 837, 775, 707, 671.
13
H). C NMR (100 MHz, CDCl
0.2, 53.9, 46.1, 43.3, 38.3, 26.0, 25.8, 25.2, 19.0, 18.5, 18.3, 17.4,
5.5, ꢀ3.5, ꢀ3.6, ꢀ3.8, ꢀ3.9. IR (film): 2955, 2930, 2858, 1702,
3
): d 219.7, 139.8, 115.5, 76.3, 73.0,
þ
þ
MS (MALDI) m/z (rel intensity) 523 ([MNa ], 100), 501 ([MH ], 3),
1
456 (6), 345 (11), 303 (5), 285 (6), 235 (14), 140 (11). HRMS
þ
1473, 1252, 1087, 983, 829, 775. MS (MALDI) m/z (rel intensity)
(MALDI) (C26
(MNa ).
H
52
O
5
Si
2
) calcd 523.3246 (MNa ), found 523.3255
þ
þ
5
09 ([MNa ], 100), 345 (14), 301 (6), 235 (12), 184 (18), 162 (14),
þ
140 (7). HRMS (MALDI) (C26
54
H O
4
Si
2
) calcd 509.3453 (MNa ),
þ
found 509.3463 (MNa ).
3.1.10. 4-[(1E,3S)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-iodo-
15c
2
-methyl-1-pentenyl]-2-methylthiazole (16)
To a solution of 10.0 g (30.35 mmol) of alcohol 15 in 180 ml of
3
a 3/1 mixture of Et O and CH CN were successively added Ph P
3
4
.1.8. (3S,6R,7S,8S)-3,7-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
,4,6,8-tetramethyl-5-oxodec-9-enal (14)
2
3
To a solution of alcohol 11 (270 mg, 0.55 mmol) in CH
12 ml) were added NaHCO (121 mg, 1.44 mmol), H O (13
and DMP (611 mg, 1.44 mmol, as a 15% (w/v) solution in CH
2
Cl
2
(12.0 g, 45.79 mmol), imidazole (6.24 g, 91.4 mmol) and iodine
(11.6 g, 45.8 mmol) at 0 C. The mixture was stirred at rt for 30 min
ꢁ
(
3
2
ml),
2
Cl
2
).
followed by the addition of 35 ml of satd aq Na
Et O. The layers were separated and the organic solution was
washed with 35 ml of brine, dried over Na SO , and the solvent was
removed under reduced pressure. The residue was purified by FC
2 2 3
S O and 400 ml of
The suspension was stirred for 1.5 h, when TLC (hexane/AcOEt
0/1) indicated complete conversion. The mixture was diluted
with Et O and then washed with satd aq NaHCO . The phases
were separated and the aqueous solution was re-extracted with
Et O. The combined organic extracts were then dried over
MgSO , the solution was concentrated in vacuo, and the resulting
2
1
2
4
2
3
(15% Et
oil.
2
O/hexane) to provide 10.6 g (79%) of iodide 5 as a colorless
2
1H NMR (400 MHz, CDCl
): d 6.92 (s, 1H); 6.52 (s, 1H); 4.22 (dd,
4
3
semi-solid residue was purified by FC (hexane/AcOEt 50/1) to
provide 243 mg (91%) of the target aldehyde 14 as a slightly
yellow oil.
J¼7.5, 3.4 Hz, 1H); 3.20 (dd, J¼7.4, 6.5 Hz, 2H); 2.70 (s, 3H); 2.15–
2.00 (m, 2H), 2.00 (s, 3H); 0.91 (s, 9H); 0.11 (d, J¼2.9 Hz, 3H); 0.04
13
(d, J¼3.0 Hz, 3H). C NMR (100 MHz, CDCl
3
): d 164.6, 152.9, 141.1,
20
1
[
a
]
D
ꢀ43.4 (c 1.30, CH
J¼2.1 Hz, 1H); 4.06 (dd, J¼8.0 Hz, 2.2 Hz, 1H); 3.88 (dd, J¼7.5 Hz,
.8 Hz, 1H); 3.64 (m, 1H); 3.57 (m, 1H); 3.22 (qi, J¼7.0 Hz, 1H); 2.30
m, 1H); 1.60–1.53 (m, 1H); 1.52–1.42 (m, 1H); 1.21 (s, 3H); 1.12 (d,
J¼7.0 Hz, 3H); 1.09 (d, J¼7.0 Hz, 3H); 1.03 (s, 3H); 0.87 (s, 9H); 0.87
s, 9H); 0.86 (s, 9H); 0.09 (s, 3H); 0.07 (s, 3H); 0.07 (s, 3H); 0.04 (s,
2
Cl
2
). H NMR (400 MHz, CDCl
3
):
d
9.71 (d,
119.4, 115.5, 78.2, 40.4, 25.9, 19.2, 18.2, 14.0, 3.1, ꢀ4.5, ꢀ4.9.
2
(
3.1.11. (S,E)-N-Allyl-3-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-
methylthiazol-4-yl)-pent-4-en-1-amine (17)
To a solution of iodide 16 (4.0 g, 9.14 mmol) in 60 ml of Et O was
2
added allylamine (6.10 g, 100.7 mmol) with a syringe and the
mixture was refluxed for 20 h. After cooling to rt 20 ml of satd aq
(
3
7
1
H); 0.01 (s, 6H). 13C NMR (100 MHz, CDCl
3.8, 60.9, 53.8, 50.8, 46.5, 38.1, 26.1, 26.0, 25.9, 24.5, 19.2, 18.3, 18.3,
3
): d 217.9, 204.2, 76.2,
NaHCO
solution was extracted with AcOEt. The combined organic extracts
were then dried over Na SO and the solvent was removed under
reduced pressure. Purification of the residue by FC (AcOEt/MeOH/
Et N 100/3/1) gave 2.73 g (81%) of the title compound as honey-
yellow oil.
3
were added, the phases were separated, and the aqueous
þ
5.5, 12.4, ꢀ3.7, ꢀ3.9, ꢀ5.2, ꢀ5.3. MS (ESI): m/z¼625.27 [MþNa]
þ
and 641.26 [MþK] . HRMS (ESI-pos) (C31
H
66
O
5
Si
3
) calcd 625.41103
2
4
þ þ
MNa ), found: 625.41046 (MNa ).
(
3
3.1.9. (3S,6S,7R,8R)-3,7-Bis(tert-butyldimethylsilyloxy)-4,4,6,8-
2
0
1
tetramethyl-5-oxodec-9-enoic acid (12)
[a
]
D
ꢀ9.3 (c 1.33, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 6.82 (s,
Procedure A: To a solution of aldehyde 14 (240 mg, 0.49 mmol) in
1H); 6.41 (s, 1H); 5.80–5.70 (m, 1H); 5.02 (dd, J¼17.1, 1.6 Hz, 1H);
4.92 (dd, J¼10.2, 1.3 Hz, 1H); 4.11 (dd, J¼7.4, 5.0 Hz, 1H); 3.09 (d,
J¼6.0 Hz, 3H); 2.58–2.47 (m, 1H); 2.54 (s, 3H); 1.88 (d, J¼0.9 Hz,
t
a mixture of THF (13 ml), BuOH (23 ml), and 2-methyl-2-butene
(
2
18.4 ml, 36.8 mmol) were added NaClO (173 mg, 1.53 mmol) and

7926
F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
2
0
1
3
H); 1.75–1.50 (m, 2H); 1.23 (br s, 1H); 0.77 (s, 9H); 0.00 (s, 3H);
0.11 (s, 3H). 13C NMR (100 MHz, CDCl
): 164.1, 153.1, 142.1, 136.9,
18.5, 115.5, 115.0, 77.6, 52.5, 46.0, 36.6, 25.8, 19.1, 18.1, 13.9, ꢀ4.7,
5.2. IR (film): 2951, 2922, 2861,1463,1252,1076, 836, 768, 288. MS
[
a
]
D
ꢀ25.3 (c 0.63, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 6.94 (s,
ꢀ
3
d
1H); 6.46 (s, 1H); 5.95–5.86 (m, 1H); 5.80–5.70 (m, 1H); 5.20 (dd,
J¼6.2, 3.5 Hz, 1H); 5.13–4.95 (m, 4H); 4.35 (dd, J¼6.2, 3.4 Hz, 1H);
3.85–3.72 (m, 3H); 3.20–3.08 (m, 2H); 3.07–3.01 (m, 1H); 2.67 (s,
3H); 2.50 (dd, J¼17.0, 3.4 Hz, 1H); 2.27 (dd, J¼17.0, 5.9 Hz, 1H);
2.12–2.08 (m, 1H); 2.09 (s, 3H); 2.00–1.90 (m, 2H); 1.42 (s, 9H);
1.20 (s, 3H); 1.08 (s, 3H); 1.05 (d, J¼7.0 Hz, 3H); 1.02 (d, J¼7.0 Hz,
1
ꢀ
þ
þ
(
ESI) m/z (rel intensity) 389 ([MNa ], 62), 367 ([MH ], 100), 235
11). HRMS (ESI-pos) (C19
(
34
H N
2
OSSi) calcd 367.2234 (MþH), found
3
67.2240 (MþH).
3
H); 0.90 (s, 9H); 0.86 (s, 9H); 0.10 (s, 3H); 0.03 (s, 3H); 0.02 (s,
13
3.1.12. (S,E)-tert-Butyl-allyl-(3-(tert-butyldimethylsilyloxy)-4-
3
3H); 0.01 (s, 3H). C NMR (100 MHz, CDCl ): d 217.9, 171.2, 164.6,
methyl-5-(2-methylthiazol-4-yl)-pent-4-enyl)-carbamate (18)
155.3, 152.4, 139.9, 136.5, 134.2, 120.9, 116.5, 116.3, 115.4, 79.6,
77.5, 76.2, 73.8, 53.4, 49.7, 46.1, 43.7, 43.5, 40.3, 31.6, 28.4, 26.2,
26.1, 23.6, 19.8, 19.2, 18.8, 18.5, 18.2, 15.1, 14.4, ꢀ3.5, ꢀ3.9, ꢀ4.2,
ꢀ4.7. IR (film): 2958, 2933, 2858, 1739, 1695, 1466, 1409, 1366,
1252, 1169, 986, 836, 779. MS (MALDI) m/z (rel intensity) 857
To a solution of amine 17 (1.50 g, 4.09 mmol) and Et N (1.71 ml,
2
2.72 mmol) in 40 ml of THF was added BOC O (938 mg,
3
1
ꢁ
4
38 mmol) at 0 C. After 5 min 30 mg (0.25 mmol) of DMAP were
ꢁ
added and the mixture was stirred at 0 C for 5 h. Aq satd NH
4
Cl
þ
(
25 ml) was then added, the phases were separated, and the
aqueous solution was extracted with AcOEt. The combined organic
extracts were washed with water and brine and dried over Na SO
([MNa ], 100), 523 (38), 429 (5), 357 (7), 335 (9), 279 (14), 235
78 2 7 2
(24), 166 (4). HRMS (MALDI) (C44H N O SSi ) calcd 857.4961
þ þ
(MNa ), found 857.4941 (MNa ).
2
4
.
Removal of the solvent under reduced pressure and purification of
the residue by FC (AcOEt/hexane 1/10) gave 1.764 g (92%) of the
title compound as a colorless oil.
3.1.15. (E)-(2S,9S,10S,11R,14S)-10,14-Bis-(tert-butyldimethyl-
silanoxy)-9,11,13,13-tetramethyl-2-[(E)-1-methyl-2-(2-methyl-
thiazol-4-yl)-vinyl]-12,16-dioxo-1-oxa-5-aza-cyclohexadec-
7-ene-5-carboxylic acid tert-butylester (21)
Grubbs second generation catalyst ([1,3-bis(2,4,6-trimethyl-
phenyl)-2-imidazolidinylidene]dichloro(phenyl-methylene)-
(tricyclohexylphosphine)-ruthenium; 9 mg, 0.16 mmol) was
added to a solution of diene 20 (96.0 mg, 0.114 mmol) in 48 ml of
2
0
1
[
a
]
D
ꢀ0.7 (c 0.74, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 6.82 (s,
1
1
1
H); 6.38 (s, 1H); 5.81–5.70 (m, 1H); 5.10–5.00 (m, 2H); 4.10 (br s,
H); 3.80 (br s, 2H); 3.22 (br m, 2H); 2.68 (s, 3H); 1.99 (s, 3H); 1.87–
.70 (m, 2H); 1.43 (s, 9H); 0.88 (s, 9H); 0.05 (s, 3H); 0.00 (s, 3H).
1
3
C
3
NMR (100 MHz, CDCl ): d 164.3,155.1,152.9,141.7,134.1,118.7,116.2,
1
15.1, 79.3, 76.6, 49.7, 43.9, 34.8, 28.4, 25.8, 19.1, 18.1, 13.9, ꢀ4.7,
ꢀ
5.2. IR (film): 2955, 2926, 2855, 1688, 1465,1405,1248,1166,1065,
2 2
CH Cl and the mixture was refluxed for 16 h. At this point ad-
þ
8
36, 771. MS (ESI) m/z (rel intensity) 489 ([MNa ], 100), 467
ditional catalyst was added (6 mg) and refluxing was continued
for 2 more hours. The mixture was then filtered through Celite
and the filtrate was concentrated under reduced pressure. Puri-
þ
(
(
(
[MH ], 10), 280 (10), 279 (49), 235 (21), 96 (16), 83 (20). HRMS
ESI-pos) (C24
MNa ).
þ
42
H N
2
O
3
SSi) calcd 489.2578 (MNa ), found 489.2585
þ
fication of the residue by FC (hexane/Et
5–40 m, low pressure) gave 64.8 mg (70%) of fully protected
cycloalkene 21.
2
O 5/3, 20 g of silica gel
1
m
3.1.13. (S,E)-tert-Butyl-allyl(3-hydroxy-4-methyl-5-(2-
2
0
1
methylthiazol-4-yl)pent-4-enyl)-carbamate (19)
A 1 M solution of TBAF in 5% aq THF (5.2 ml) was added drop-
wise to a solution of fully protected amino alcohol 18 (1.30 g,
[
a
]
D
þ3.2 (c 1.03, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 6.93 (s,
1H); 6.56 (s, 1H); 5.40 (d, J¼9.9 Hz, 1H); 5.35–5.20 (m, 2H); 4.41–
4.25 (m, 2H); 4.00 (m, 1H); 3.60–3.50 (m, 1H); 3.30–3.18 (m, 1H);
3.10 (t, J¼11.7 Hz, 1H); 3.02–2.94 (m, 1H); 2.70 (s, 3H); 2.60 (dd,
J¼16.6, 6.4 Hz, 1H); 2.52–2.40 (m, 2H); 2.12 (s, 3H); 2.11–2.00 (m,
1H); 1.98–1.87 (m, 1H); 1.42 (s, 9H); 1.23 (s, 3H); 1.16 (s, 3H); 1.13 (d,
J¼6.8 Hz, 3H); 1.07 (d, J¼7.0 Hz, 3H); 0.89 (s, 9H); 0.87 (s, 9H); 0.15
2
.78 mmol) in 30 ml of THF over a period of 10 min at rt. The
mixture was then stirred at rt for 2 h, when TLC indicated complete
consumption of starting material. After addition of 25 ml of satd aq
NH
with AcOEt. The combined organic extracts were washed with
water and brine (50 ml each), dried over Na SO , and the solvent
4
Cl and phase separation the aqueous solution was extracted
13
(s, 3H); 0.12 (s, 3H); 0.05 (s, 3H); 0.05 (s, 3H). C NMR (100 MHz,
2
4
3
CDCl ): d 216.0, 170.4, 164.6, 155.6, 152.5, 137.3, 134.3, 124.4, 120.4,
was removed in vacuo. Purification of the residue by FC (AcOEt/
hexane 1/1) gave 793 mg (81%) of alcohol 19 as a colorless oil.
116.5, 79.5, 77.1, 76.8, 73.1, 54.3, 48.0, 43.7, 42.9, 42.4, 32.1, 29.1, 26.0,
25.9, 23.7, 22.6, 19.2, 19.0, 18.4, 18.2, 15.1, 14.1, 12.6, ꢀ3.6, ꢀ4.3, ꢀ4.4,
ꢀ5.0. IR (film): 2952, 2926, 2858, 1691, 1743, 1248, 1169, 1076, 986,
2
0
1
[
a
]
D
þ7.7 (c 1.43, CHCl
3 3
). H NMR (400 MHz, CDCl ): d 6.75 (s,
þ
1
1
2
(
1
H); 6.39 (s, 1H); 5.68–5.55 (m, 1H); 5.00–4.90 (m, 2H); 4.41 (br s,
H); 4.10–4.00 (br s, 1H); 3.76–3.38 (br m, 3H); 3.10–2.95 (m, 1H);
829, 771, 733. MS (MALDI) m/z (rel intensity) 829 ([MNa ], 60), 807
þ
([MH ], 3), 773 (28), 707 (100), 575 (11), 542 (13), 523 (6), 414 (4),
13
.51 (s, 3H); 1.85 (s, 3H); 1.78–1.50 (m, 2H); 1.30 (s, 9H). C NMR
): 164.2, 156.8, 152.9, 142.0, 134.0, 118.1, 116.2,
15.1, 79.7, 73.7, 50.0, 43.7, 34.0, 28.2, 18.9, 14.5. IR (film): 3428 (br),
972, 2930, 1691, 1469, 1412, 1364, 1254, 1168, 920, 873, 779. MS
74 2 7 2
354 (5), 178 (23). HRMS (MALDI) (C42H N O SSi ) calcd 829.4648
þ þ
(MNa ), found 829.4632 (MNa ).
100 MHz, CDCl
3
d
1
3.1.16. (E)-(2S,9S,10S,11R,14S)-10,14-Bis-(tert-butyldimethyl-
silanoxy)-9,11,13,13-tetramethyl-2-[(E)-1-methyl-2-(2-methyl-
thiazol-4-yl)-vinyl]-12,16-dioxo-1-oxa-5-aza-cyclohexadec-
7-ene-5-carboxylic acid tert-butylester (2)
þ
þ
(
(
(
ESI) m/z (rel intensity) 375 ([MNa ], 100), 353 ([MH ], 28), 279
16), 257 (4), 188 (5), 177 (5), 96 (4), 82 (5). HRMS (ESI-pos)
þ
þ
C
18
H
28
N
2
O
3
S) calcd 375.1713 (MNa ), found 375.1720 (MNa ).
ꢁ
To a cooled (0 C) solution of the protected cylcoalkene 21
3
.1.14. (3S,6R,7S,8S)-((S,E)-5-(tert-Butoxycarbonyl)-2-methyl-1-(2-
(32.0 mg, 0.039 mmol) in 3 ml of THF was added pyridine (0.5 ml)
followed by slow dropwise addition of HF$Pyr (0.6 ml). The mixture
was stirred at rt for 2 h at which point additional HF$Pyr (0.6 ml)
methylthiazol-4-yl)-pent-1-en-3-yl)-3,7-bis(tert-butyldimethyl-
silyloxy)-4,4,6,8-tetramethyl-5-oxodec-9-enoate (20)
ꢁ
A solution of DCC (402 mg, 1.95 mmol) in 2 ml of CH
2
Cl
2
was
was added (after cooling to 0 C) and stirring was continued for
added dropwise to a solution of alcohol 19 (633 mg, 1.80 mmol),
carboxylic acid 12 (750 mg, 1.50 mmol) (both dried by co-evapo-
ration with toluene), and DMAP (55 mg, 0.45 mmol) in 8 ml of
additional 2.5 h (rt). The mixture was then carefully (dropwise)
3
added to 30 ml of ice-cold satd aq NaHCO (CAUTION: strong
foaming) and the aqueous solution was extracted with AcOEt
ꢁ
ꢁ
CH
mixture was evaporated and the residue was purified by FC
hexane/AcOEt 9/1) to provide 968 mg (77%) of ester 20 as a
colorless oil.
2
Cl
2
at 0 C. After stirring at 0 C for 30 min and 6 h at rt, the
(6ꢂ20 ml). The combined organic extracts were dried over MgSO
4
and the solvent was removed by evaporation. Purification of the
resulting residue by FC (hexane/AcOEt 1/1) gave 14.8 mg (65%) of
the target compound 2.
(

F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
7927
2
0
1
þ
[
a
]
D
ꢀ83.8 (c 0.47, CHCl
7.29 (s, 1H); 6.49 (s, 1H); 5.92 (dd, J¼15.5, 4.8 Hz, 1H); 5.38–5.30
m, 1H); 5.13 (dd, J¼7.6, 2.6 Hz, 1H); 5.08 (d, J¼6.1 Hz, 1H); 4.54 (d,
J¼6.2 Hz, 1H); 4.44–4.37 (m, 1H); 3.97 (dd, J¼14.3, 6.2 Hz, 1H); 3.71
3
). H NMR (DMSO-d
6
, 500 MHz, 318 K):
HRMS (ESI) (C30
603.3075 (MNa ).
H
48
N
2
O
7
S) calcd 603.3074 (MNa ), found
þ
d
(
Acknowledgements
(
dd, J¼14.8, 7.7 Hz, 1H); 3.54–3.48 (m, 1H); 3.27–3.17 (m, 2H);
3
2
9
.16–3.08 (m, 1H); 2.65 (s, 3H); 2.41–2.33 (m, 2H); 2.07 (s, 3H);
.11–2.03 (m, 1H); 2.03–1.93 (m, 1H); 1.85–1.76 (m, 1H); 1.40 (s,
H); 1.16 (s, 3H); 1.08 (d, J¼6.7 Hz, 3H); 1.02 (d, J¼6.9 Hz, 3H); 0.90
The excellent support by the mass spectrometry facility at the
Laboratory of Organic Chemistry of the ETH Z u¨ rich is gratefully
acknowledged.
(
s, 3H). 13C NMR (100 MHz, CDCl
3
): d 219.9, 170.4,165.6, 155.6, 151.3,
1
37.8, 124.9, 120.4, 117.5, 115.2, 79.7, 77.2, 74.2, 71.0, 54.7, 49.5, 42.9,
Supplementary data
4
3
1
1.3, 39.9, 38.1, 33.8, 29.7, 28.5, 21.7, 18.7, 16.1, 13.7, 10.9; IR (film):
460 (br), 1977, 2926, 2360, 2332, 1735, 1688, 1466, 1413, 1366,
283, 1248, 1166, 986, 746. MS (MALDI) m/z (rel intensity) 601
1H NMR spectra of compounds 1 and 2. Analytical RP-HPLC
traces of compounds 1 and 2 and the FC-purified mixture of 1 and 2
obtained after diimide reduction of 2. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.06.017.
þ
þ
(
4
[MNa ], 75), 579 ([MH ], 5), 567 (17), 545 (49), 523 (21), 506 (18),
79 (100), 457 (20), 413 (19), 391 (27), 314 (20), 235 (15), 178 (31).
þ
HRMS (ESI) (C30
H
46
N
2
O
7
S) calcd 601.2918 (MNa ), found 601.2919
þ
(
MNa ).
References and notes
3.1.17. (E)-(2S,9S,10S,11R,14S)-10,14-Dihydroxy-9,11,13,13-
tetramethyl-2-[(E)-1-methyl-2-(2-methylthiazol-4-yl)-vinyl]-12,16-
dioxo-1-oxa-5-aza-cyclohexadecane-5-carboxylic acid tert-
butylester (1)
1
. (a) Cragg, G. M.; Newman, D. J. Pure Appl. Chem. 2005, 77, 7–24; (b) Anticancer
Agents from Natural Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.;
CRC: Boca Raton, FL, 2005; (c) Cragg, G. M.; Newman, D. J.; Snader, K. M. Nat.
Prod. Rep. 2000, 17, 215–234.
. Selected reviews: (a) Butler, M. S. J. Nat. Prod. 2004, 67, 2141–2153; (b) Hamann,
M. T. Curr. Pharm. Des. 2003, 9, 879–889.
To a solution of cycloalkene 2 (24 mg, 0.046 mmol) in CH
2 2
Cl
2
(
10 ml) were added 500 mg (2.58 mmol) of dipotassium diazo-
33
dicarboxylate (PADA) followed by AcOH (100
Two additional aliquots of AcOH (100 l each) were added after
0 min and 60 min, respectively (5.16 mmol of AcOH in total), and
the mixture was stirred at rt. This procedure was repeated after
8 h, 21 h, and 24 h. The progress of the reaction was monitored
ml, 1.72 mmol).
3. For an example where total synthesis has served to provide material of
a complex natural product (discodermolide) for Phase I clinical studies see:
Mickel, S. J. Curr. Opin. Drug Discov. Dev. 2004, 7, 869–881.
4. For examples from the area of microtubule-stabilizing natural products see:
Altmann, K.-H.; Gertsch, J. Nat. Prod. Rep. 2007, 24, 327–357.
m
4
5
6
. Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58.
. N o¨ ren-M u¨ ller, A.; Reis-Corr eˆ a, I., Jr.; Prinz, H.; Rosenbaum, C.; Saxena, K.;
Schwalbe, H. J.; Vestweber, D.; Cagna, G.; Schunk, S.; Schwarz, O.; Schiewe, H.;
Waldmann, H. Proc. Natl. Acad. Sci. U.S.A. 2005, 103, 10606–10611.
1
by ESI-MS (MþK peaks at m/z 617 and 619 for 2 and 1, re-
Ò
spectively). After 40 h the mixture was filtered through HYFLO
7. Tietze, L. F.; Bell, H. P.; Chandrasekar, S. Angew. Chem., Int. Ed. 2003, 42, 3996–
and the filter was washed with three 5 ml portions of CH
combined filtrates were evaporated, the residue was redissolved
in CH Cl (10 ml) and PADA and AcOH were added in the same
2 2
Cl . The
4028.
8
. (a) Feyen, F.; Cachoux, F.; Gertsch, J.; Wartmann, M.; Altmann, K.-H. Acc. Chem.
Res. 2008, 41, 21–31; (b) Feyen, F.; Gertsch, J.; Wartmann, M.; Altmann, K.-H.
Angew. Chem., Int. Ed. 2006, 45, 5880–5885.
2
2
amounts and by the same procedure as described above, with
additional PADA and AcOH being added after 56 h, 60 h, and 64 h
9
. Altmann, K.-H.; Fl o¨ rsheimer, A.; Bold, G.; Caravatti, G.; Wartmann, M. Chimia
2004, 58, 686–690.
(
total reaction time). After 80 h the mixture was worked up as for
the 40 h time point, the product mixture was redissolved in 10 ml
of CH Cl and PADA and AcOH were added as before. Additional
10. For recent reviews on the chemistry, biology, and clinical applications of
epothilones see: (a) Altmann, K.-H.; Pfeiffer, B.; Arseniyadis, S.; Pratt, B. A.;
Nicolaou, K. C. ChemMedChem 2007, 2, 396–423; (b) H o¨ fle, G.; Reichenbach, H.
In Anticancer Agents from Natural Products; Cragg, G. M., Kingston, D. G. I.,
Newman, D. J., Eds.; CRC: Boca Raton, FL, 2005; pp 413–450.
2
2
aliquots of PADA/AcOH were added after 170 h and 174 h,
bringing the total amount of PADA/AcOH added in the course of
the reaction to 28.38 mmol/56.76 mmol. After 190 h the mixture
was worked up by filtration through HYFLO ; the filter was
washed with CH
evaporated. The residue was submitted to FC in AcOEt/hexane
providing 21.8 mg (91%) of a 4/1 mixture of 1 and 2 (according to
analytical RP-HPLC). Purification of this material by preparative
RP-HPLC gave 7.6 mg of pure 1 together with 1.0 mg (4%) of
starting material 2. A second chomatographic run with mixed
fractions from the first separation gave additional 4.8 mg of 1
bringing the total yield to 12.4 mg (52%).
11. Larkin, J. M. G.; Kaye, S. B. Expert Opin. Invest. Drugs 2006, 15, 691–702.
12. (a) Chou, T. C.; Dong, H. J.; Zhang, X. G.; Tong, W. P.; Danishefsky, S. J. Cancer Res.
2005, 65, 9445–9454; (b) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.;
Ò
Chou, T. C.; Dong, H. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 10913–
10922; (c) Yoshimura, F.; Rivkin, A.; Gabarda, A. E.; Chou, T. C.; Dong, H. J.;
Sukenick, G.; Morel, F. F.; Taylor, R. E.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2
Cl
2
(3ꢂ5 ml) and the combined filtrates were
2003, 42, 2518–2521; (d) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Chou, T. C.;
Dong, H. J.; Tong, W. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 2899–
2901; (e) Chou, T. C.; Dong, H. J.; Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho,
Y. S.; Tong, W. P.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 4761–4767.
13. For a side-chain-modified analog of 1 with enhanced antiproliferative activity
cf. Ref. 8b.
14. A preliminary account of this work has appeared as a short conference report:
Feyen, F.; Gertsch, J.; Wartmann, M.; Altmann, K.-H. Chimia 2007, 61, 143–146.
15. (a) Altmann, K.-H.; Bold, G.; Caravatti, G.; Denni, D.; Fl o¨ rsheimer, A.; Schmidt,
A.; Rihs, G.; Wartmann, M. Helv. Chim. Acta 2002, 85, 4086–4110; (b) Schinzer,
D.; Bauer, A.; Schieber, J. Chem.dEur. J. 1999, 5, 2492–2500; (c) Mulzer, J.;
Mantoulidis, A.; Oehler, E. J. Org. Chem. 2000, 65, 7456–7467.
2
0
). 1H NMR (500 MHz, 318 K, CDCl
3 3
):
[
a]
D
ꢀ4.3 (c 0.98, CHCl
d
7.01 (s, 1H); 6.64 (s, 1H); 5.18 (d, J¼9.7 Hz, 1H); 4.38 (d,
J¼9.7 Hz, 1H); 3.72 (dd, J¼7.2, 3.0 Hz, 1H); 3.63–3.45 (br m, 1H);
16. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc.
3
2
2
1
9
.38–3.30 (m, 1H); 3.30–3.12 (m, 2H); 3.10–2.94 (br m, 1H);
.93–2.86 (m, 1H); 2.78 (s, 3H); 2.50 (dd, J¼14.4, 11.2 Hz, 1H);
.40 (dd, J¼14.3, 2.1 Hz, 1H); 2.30–2.10 (br m, 1H); 2.07 (s, 3H);
2001, 123, 5407–5413.
17. (a) Klar, U.; R o¨ hr, B.; Kuczynski, F.; Schwede, W.; Berger, M.; Skuballa, W.;
Buchmann, B. Synthesis 2005, 301–305; (b) F u¨ rstner, A.; Mathes, C.; Lehmann,
C. W. Chem.dEur. J. 2001, 7, 5299–5317; (c) Taylor, R. E.; Galvin, G. M.; Hilfiker,
K. A.; Chen, Y. J. Org. Chem. 1998, 63, 9580–9583; (d) Schinzer, D.; Limberg, A.;
B o¨ hm, O. Chem.dEur. J. 1996, 2, 1477–1482.
18. (a) Klar, U.; Buchmann, B.; Schwede, W.; Skuballa, W.; Hoffmann, J.; Lichtner,
R. B. Angew. Chem., Int. Ed. 2006, 45, 7942–7948; (b) Taylor, R. E.; Chen, Y.;
Galvin, G. M.; Pabba, P. K. Org. Biomol. Chem. 2004, 2, 127–132.
.88–1.75 (m, 2H); 1.70–1.52 (m, 3H); 1.50–1.45 (m, 1H); 1.45 (s,
H); 1.42 (s, 3H); 1.40–1.30 (m, 1H); 1.14 (d, J¼6.9 Hz, 3H); 1.07
13
(
d
s, 3H); 0.97 (d, J¼7.1 Hz, 3H). C NMR (100 MHz, CDCl
219.7, 171.0, 170.2, 155.0, 151.7, 139.6, 117.5, 115.4, 79.5, 76.6,
1.7, 71.4, 53.9, 48.2, 43.6, 41.4, 39.2, 35.1, 33.8, 28.2, 27.8, 23.7,
1.4, 18.5, 17.6, 16.1, 15.7, 11.2. IR (film): 3460 (br), 2969, 2926,
3
):
7
2
2
19. (a) Schinzer, D.; Bourguet, E.; Ducki, S. Chem.dEur. J. 2004, 10, 3217–3224; (b)
Schinzer, D.; B o¨ hm, O.; Altmann, K.-H.; Wartmann, M. Synlett 2004, 1375–1378.
0. Koch, G.; Loiseleur, O.; Fuentes, D.; Jantsch, A.; Altmann, K.-H. Synlett 2004,
2
358, 2339, 1731, 1681, 1473, 1419, 1369, 1287, 1252, 1151, 976,
6
93–697.
1. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem.
Commun. 1987, 1625–1627.
þ
7
40. MS (MALDI) m/z (rel intensity) 603 ([MNa ], 57), 581
2
þ
(
[MH ], 23), 547 (18), 525 (100), 481 (73), 262 (6), 178 (9).

7928
F. Feyen et al. / Tetrahedron 64 (2008) 7920–7928
2
2. Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.;
Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974–7991.
3. The synthesis of carboxylic acid 12 has been reported previously by Sinha
and co-workers in Ref. 26. While this group has employed different starting
materials, their overall strategy to 12 is similar to ours. In particular, the
25. Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073–10092.
26. Sun, J.; Sinha, S. C. Angew. Chem., Int. Ed. 2002, 41, 1381–1383.
27. This problem was eventually overcome by the (uncomplicated and still E-se-
lective) RCM of dienes 24a/b and introduction of the side chain subsequent to
macrocyclization:
2
synthesis also proceeds through fully protected triol 10 as
a key in-
termediate. However, no experimental details or analytical data are disclosed
in Ref. 26 (including the associated Supplementary data), except for H and
1
R
1
3
C data for 12. It should also be noted that several discrepancies exist
between the 13C data reported for 12 by Sinha and co-workers and those
reported in this paper. The Supplementary data to Ref. 26 lists 22 carbon
signals for 12, which does correspond to the total number of non-equivalent
C-atoms. At the same time, however, the signal for the carboxylate carbon is
missing from the list.
O
TBSO
O
O
2
4a: R = CH
3
3
Danishefsky and co-workers have described the synthesis of carboxylic acid
24b: R = CF
1
2a, but following a strategy different from the one discussed in this paper
O
OTES
(
Refs. 12b,d):
2
8. Zeng, X.; Wei, X.; Farina, V.; Napolitano, E.; Xu, Y.; Zhang, L.; Haddad, N.; Yee, N. K.;
Grinberg, N.; Shen, S.; Senanayake, C. H. J. Org. Chem. 2007, 71, 8864–8875.
9. Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91–155.
TBSO
2
O
30. Kuzniewski, C. N.; Gertsch, J.; Wartmann, M.; Altmann, K.-H. Org. Lett. 2008, 10,
183–1186.
31. Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron 1976, 32,
157–2162.
1
O
OTES OH
2a
2
1
3
2. (a) Corey, E. J.; Mock, W. L.; Pasto, D. J. Tetrahedron Lett. 1961, 347–352; (b)
H u¨ nig, S.; M u¨ ller, H. R.; Their, W. Tetrahedron Lett. 1961, 353–357; (c) van Ta-
melen, E. E.; Dewey, R. S.; Timmons, R. J. J. Am. Chem. Soc. 1961, 83, 3725–3726.
2
4. For recent reviews on olefin metathesis cf., e.g.: (a) Grubbs, R. H. Tetrahedron
004, 60, 7117–7140; (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
8–29.
2
1
33. Beruben, D.; Marek, I.; Normant, J. F.; Platzer, N. J. Org. Chem.1995, 60, 2488–2501.