Studies on C18-C20 aldol couplings of rhizopodin

Article abstract of DOI:10.1055/s-0033-1338493

The aldol addition of an enol(ate) to a carbonyl compound is one of the most powerful and versatile C-C bond forming reactions. In complex target synthesis the coupling of two chiral partners may complicate the stereochemical outcome by multiple stereoinductions. Here, we report studies on pivotal aldol couplings employed in the rhizopodin synthesis, detailing the various directing effects exerted by the stereogenic centers present in this sterically hindered connection. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338493

PAPER
▌2305
paper
Studies on C18–C20 Aldol Couplings of Rhizopodin
C18–C20 Aldol Couplings of Rhizopodin
Michael Dieckmann,a Sven Rudolph,b Carolin Lang,c Wiebke Ahlbrecht,c Dirk Menche*a
a
Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax +49(228)735813; E-mail: dirk.menche@uni-bonn.de
b
ASM Research Chemicals, 30938 Burgwedel, Germany
c
Universität Heidelberg, Institut für Organische Chemie, INF 270, 69120 Heidelberg, Germany
Received: 09.04.2013; Accepted after revision: 17.05.2013
gent access to this key fragment, our synthetic plan relied
on pivotal aldol reactions10 to set the C18–C20 segment,
either by a coupling along the C19–C20 bond (aldol cou-
pling 1) or along the C18–C19 bond (aldol coupling 2), by
Abstract: The aldol addition of an enol(ate) to a carbonyl com-
pound is one of the most powerful and versatile C–C bond forming
reactions. In complex target synthesis the coupling of two chiral
partners may complicate the stereochemical outcome by multiple
stereoinductions. Here, we report studies on pivotal aldol couplings union of aldehyde 5 with ketones 3/4 or ketone 8 with al-
employed in the rhizopodin synthesis, detailing the various direct-
ing effects exerted by the stereogenic centers present in this sterical-
ly hindered connection.
dehydes 6/7, respectively. Herein, we report in detail the
subtle stereoselective contributions of the various stereo-
genic centers of the methyl ketones and aldehydes in these
pivotal aldol reactions under various enolization condi-
Key words: natural products, aldol reaction, asymmetric synthesis,
methyl ketone, Felkin product
tions with different protective groups. This fundamental
study enabled high-yielding access to the central C8–C22
fragment 2 of rhizopodin.
Myxobacteria are an extremely proliferative source of
novel polyketides and an impressive number of structural-
Me
N
OMe
O
22'
O
ly unique and biosynthetically diverse representatives
have been reported from these soil-living organisms,
in particular by the pioneering work of Höfle and
Reichenbach.1 In 1993 they reported rhizopodin as the
main metabolite from Myxococcus stipitatus (strain Mx
f164).2,3 Being originally considered to be monomeric, the
structure was more recently revised to be a C2-symmetric
dimer (1), as shown in Scheme 1.4 The full configuration
was independently assigned in our group by extensive
NMR studies in combination with modeling and chemical
derivatization5 and in the group of Schubert by an X-ray
structure analysis of actin-bound rhizopodin.6 The unique
architecture of rhizopodin is characterized by a 38-mem-
bered macrolide ring with two conjugated diene systems
and two disubstituted oxazole systems in combination
with two enamide side chains and contains in total 18 ste-
reogenic centers.
OMe
OMe OH
O
OMe
O
17'
8
O
N
HO
OH
N
O
8'
17
O
MeO
O
O
OH OMe
OMe
OMe
N
O
22
Me
rhizopodin (1)
OMe
TBS
8
O
OH OMe
N
22
17
OPG
O
2)
1)
2a/2b
Rhizopodin presents a highly potent antiproliferative
agent that inhibits the growth of various cancer cell lines
in low nanomolar concentrations.2 This potency has been
attributed to its ability to disrupt actin cytoskeleton forma-
tion by binding specifically to a few critical sites of G-ac-
tin.7 The important biological properties and its natural
scarcity, coupled with its intriguing molecular architec-
ture have attracted high interest from the synthetic
community8 and so far two total syntheses have been ac-
complished by our group and by Paterson et al.9 A concise
preparative approach to the central C8–C22 subunit 2
proved to be particularly challenging. To enable conver-
aldol 1)
aldol 2)
TBS
TBS
O
O
O
OPG
O
O
H
O
OPG
R
R
+
+
H
3/4
5a/5b
6/7
8a/8b
R
a: PG = PMB
b: PG = TBS
3, 6
4, 7
OMe
N
PG: protective group
O
Scheme 1 Pivotal C18–C20 aldol couplings in the synthesis of
rhizopodin
SYNTHESIS 2013, 45, 2305–2315
Advanced online publication: 12.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338493; Art ID: SS-2013-T0198-OP
© Georg Thieme Verlag Stuttgart · New York

2306
M. Dieckmann et al.
PAPER
As shown in Scheme 2, a joint synthesis of the required served with bulky silyl groups and, in one case, a high 1,5-
ketones (3 and 4) and aldehydes (6 and 7) was effected by syn selectivity which would also be required here was re-
a late-stage diversification strategy starting from readily ported for a substrate with a β-OTBS-substituent.16 Con-
available aldehyde 9.11,12 Brown allylation13 and protec- sequently, a TBS protective group was chosen for the β-
tion of the newly generated alcohol as a TBS ether gave alkoxy-substituent of the methyl ketones studied herein
homoallylic ether 10, which was further derivatized to ei- (3/4).
ther primary alcohol 11 by deprotection of the PMB group
or acid 12 by oxidative cleavage of the double bond. Oxi-
R
Nu:
Me
Me
4
dation of 11 then gave the target aldehyde 6, which was
transformed into methyl ketone 3 through a two-step se-
quence (addition of MeMgBr and oxidation). Acid 12, in
turn, was condensed with serine methyl ester to oxazole
13, which was then transformed into aldehyde 7 in a five-
step sequence, involving reduction of the terminal ester to
the aldehyde, asymmetric Brown allylation, methylation
of the newly generated alcohol, PMB deprotection, and
subsequent oxidation of the terminal alcohol. The corre-
sponding methyl ketone 4 was obtained in an analogous
sequence as before.
H
H
Me
O
β
PO
α
H
M
H
O
1
MLn
O
H
RL
1
R'
H
14
15
1,5-anti induction
1,2'-syn Felkin–Anh induction
17
16
Figure 1 Transitions states for aldol couplings of type 1
As shown in Table 1 for selected examples, a variety of
reaction conditions with various metal counter ions and
bases were evaluated. However, in all cases, either the un-
desired isomer 17 was obtained preferentially or no selec-
tivity was observed. This unfavorable facial bias could
also not be overturned by the use of chiral Ipc ligands (en-
tries 4 and 5) or by using Mukaiyama type conditions.17
Similar results were obtained with the simplified ketone 3
as well as with the more elaborate analogue 4. In addition,
yields remained low in all cases, presumably due to the
high steric hindrance exerted by the neopentylic center of
the methyl ketone.
1. (–)-Ipc2BAllyl
2. TBSOTf
O
OPMB
TBSO
OPMB
H
64%
(2 steps)
10
9
1. O3; Ph3P
2. NaClO2
DDQ
98%
76%
(2 steps)
TBSO
O
TBSO
OH
TBSO
OPMB
DMP
88%
HO2C
R
11
12
6: R = H
1. MeMgBr
2. DMP
3: R = Me
1. Serin-OMe ester, IBC
2. DBU, Cl3CBr
3. DAST
Faced with these unpromising results, we turned our at-
tention to an inversion of the coupling partners and stud-
ied the coupling of aldehydes 6/7 with methyl ketones
8a/8b, giving the two possible aldol products 18 and 19.
As shown in Table 2 for selected reactions with simplified
aldehyde 6,18 a strong facial bias towards the undesired
product 19 was again observed. This preference could
again not be overturned by the use of chiral Ipc ligands
(entries 4 and 5). Only Mukaiyama type aldol couplings
enabled preferential formation of the desired epimer 18
(entry 6). However, very low conversion was observed,
which could not be further increased. In general, the ob-
served yields remained initially moderate under conven-
tional conditions, again presumably due to the high steric
hindrance exerted by the geminal dimethyl-substituents of
the aldehyde. However, in contrast to the studies de-
scribed above, higher degrees of conversion could be ob-
tained by modification of the reaction conditions (entry
7), which could be further optimized (Table 4).
72%
(3 steps)
78% (2 steps)
OMe
TBS
TBS
O
1. DIBAL-H
2. (–)-Ipc2Ballyl
3. Ag2O, MeI
MeO2C
O
O
OPMB
N
N
R
O
O
4. DDQ
5. DMP
13
37%
(5 steps)
7: R = H
4: R = Me
1. MeMgBr
2. DMP
92% (2 steps)
Scheme 2 Joint synthesis of required ketones 3 and 4 and aldehydes
6 and 7
Having established an efficient route to the required build-
ing blocks, we first turned our attention to aldol coupling
of type 1 and studied the union of methyl ketones 3/4 with
aldehydes 5a/5b bearing different protective groups (Ta-
ble 1). As shown in Figure 1, a Felkin–Anh induction ex-
erted by the aldehyde was expected to favor the desired
1,2′-syn product 16. In contrast, high 1,5-anti inductions
in the coupling of methyl ketones have been observed in
boron and alkali-metal-mediated aldol couplings.14 Ac-
cording to a model developed by Goodman,15 this selec-
tivity may be rationalized by a boat-type transition state
involving an H-bond between the formyl-H of the alde-
hyde and the β-alkoxy substituent of the ketone. In agree-
ment with this model, substituents favoring such a
coordination (e.g., PMB, Bn, MOM) led to high selectiv-
ities, while only a moderate or no selectivity has been ob-
As shown in Figure 2, this inherent facial bias towards 19
may be explained by a 1,4-syn induction exerted by the
methyl ketone. In analogy to the model developed by
Goodman,14 this selectivity may result from either forma-
tion of a hydrogen bond between the β-alkoxy-substituent
and the formyl hydrogen in a similar fashion to that de-
scribed above, or a coordination of the metal center with
this β-substituent, as schematically shown for structures
20 and 21. This facial bias could not be reversed by using
Synthesis 2013, 45, 2305–2315
© Georg Thieme Verlag Stuttgart · New York

PAPER
C18–C20 Aldol Couplings of Rhizopodin
2307
a voluminous non-coordinating β-alkoxy substituent (Ta-
ble 2, entry 7), which may favor an alternative, more open
transition state of type 22 and then give the desired 1,4-
anti product 18, based on minimization of allylic strain.
The β-alkoxy substituent of the aldehyde was, in turn, ex-
pected to exert a 1,3-anti induction, which may be ex-
plained by either the polar Evans model (23)19 or the
Reetz–Cram model (24),20 leading to the desired epimer
18 (Figure 2). Based on the results shown in Table 2, this
influence appeared to be overturned by the strong stereo-
chemical influence exerted by the ketone.
Table 1 Aldol Couplings of Ketones 3/4 with Aldehydes 6a/6b
TBSO
O
O
OPG
TBSO
5
O
OH OPG
R
R
2'
1
+
H
base
5a/5b
3/4
16
3: R =
TBSO
5
O
OH OPG
a: PG = PMB
b: PG = TBS
OMe
2'
1
R
N
4: R =
17
O
Entry Ketone PG
Conditions
Solvent dr 16/17 Yield
(%)
1
2
3
4
3
3
3
3
PMB LiHMDS, –78 °C THF
PMB NaHMDS, –78 °C THF
PMB KHMDS, –78 °C THF
1:1.6
1:1.6
1:1.6
1.1.7
36
17
19
23
H
H
RL
4
H
O
Me
H
R2
α
Me
H
H
Me
4
β
β
H
4
OP
α
H
1
H
H
or
vs.
O
MLn
LnM
LnM
O
O
H
O
O
H
H
1
1
O
R
R'
R
H
H
H
20
21
TBS (+)-Ipc2BCl, Et3N, Et2O
–78 to –20 °C
22
1,4-syn induction
1,4-anti induction
OR2
TBSO
R1
OH
1
O
OR2
TBSO
OH
1
O
5
3
TBS (–)-Ipc2BCl, Et3N, THF
–78 to –20 °C
1:1.2
12
R1
4
4
3'
3'
6
7
8
4
4
4
PMB LiHMDS, –78 °C THF
PMB NaHMDS, –40 °C THF
1:2.0
1:1.3
1:2.6
25
33
5
19
18
1,3'-anti 1,4-anti
1,3'-syn 1,4-syn
1,3'-anti-induction
TBS (+)-Ipc2BCl, Et3N, Et2O
–78 to –20 °C
Nu:
Rβ
RO
Me
1
Me
H
Me
O
3'
C
H
M
1
M
O
9
4
4
PMB TMS-OTf, Et3N, CH2Cl2 1:1
BF3, –78 °C
23
6
H
3'
C
Rβ
Me
H
RO
23
:Nu
24
10
PMB TBS-OTf, Et3N,
BF3, –78 °C
CH2Cl2 1:1
Figure 2 Possible transitions states for aldol couplings given in
Table 2
To further analyze the respective contributions induced by
the α-stereogenic center of the methyl ketone as well as
the geminal dimethyl groups of the chiral aldehyde on the
stereochemical outcome of this reaction, the coupling of
methyl ketones 8a/8b with simplified aldehydes 25 and 28
was studied (Scheme 3, Table 3). Comparison of the re-
spective couplings presented in Table 2, entries 4 and 5
with the corresponding results in Scheme 3 suggest that
the geminal dimethyl center decreases the inherent 1,3′-
anti induction of the aldehyde. Furthermore, inversion of
the stereochemistry at the β-center of the aldehyde led to
increased diastereoselectivity towards 30 (Table 3, entry
1) based on a matched stereoinduction of the methyl ke-
tone and the aldehyde, in agreement with our stereochem-
ical model (Figure 2). The 1,3′-anti induction was
confirmed in an analogous addition of a methyl ketone
lacking the α-stereogenic center (entries 5 and 6).
Table 2 Aldol Couplings of Ketones 8a/8b with Aldehyde 6
TBSO
O
O
OPG
TBSO
OH
O
OPG
+
H
base
18a/18b
OH
6
8a/8b
TBSO
O
OPG
a: PG = PMB
b: PG = TBS
19a/19b
Entry PG
Conditions
Solvent dr 18/19 Yield
(%)
1
2
3
4
PMB LiHMDS, –78 °C
PMB NaHMDS, –78 °C
PMB KHMDS, –78 °C
THF
THF
THF
Et2O
1:2.4
1:2.4
1:2.6
1:5.8
83
58
43
81
PMB (+)-Ipc2BCl, Et3N,
–78 to –20 °C
In summary, these results suggest that the stereochemical
outcome of the aldol coupling of type 2 is mainly gov-
erned by a 1,4-syn induction exerted by the ketone, and
overrides an opposing stereochemical influence of the al-
dehyde from the β-substituent. Notably, the observed 1,4-
syn selectivity could not be overcome by suitable choice
of protective groups on either the aldehyde or ketone or by
suitable enolization conditions. We therefore decided to
5
6
7
PMB (–)-Ipc2BCl, Et3N,
–78 to –20 °C
Et2O
1:2.4
59
5
PMB TMS-OTf, Et3N, BF3, CH2Cl2 2.2:1
–78 °C
TBS
LiHMDS, –78 °C
THF
1:1
45
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2305–2315

2308
M. Dieckmann et al.
PAPER
TBS
O
PMB
O
PMB
TBS
O
Table 4 Aldol Couplings of Ketones 8a with Aldehyde 7
OH
O
O
O
O
O
TBSO
O
OPMB
TBSO
OH
O
OPMB
O
+
7
R
R
+
H
Ipc2BCl, Et3N
Et2O, –78 °C
H
26
base
7
8a
TBS
O
PMB
O
31
OH
25
8a
OH
OMe
R =
TBSO
O
OPMB
(+)-Ipc: dr (26/27) = 1:3 (82%)
(–)-Ipc: dr (26/27) = 1:1 (49%)
7
R
N
27
O
32
Scheme 3 Coupling of ketone 8a with simplified aldehyde 25
Entry 8a
Conditions
Solvent
dr 31/32 Yield
(equiv)
(%)
1
2
3
4
5
6
7
8
1.3
(+)Ipc2BCl, Et3N,
–78 to –20 °C, 20 h
Et2O
Et2O
THF
THF
THF
THF
DMF
1:4.0
1:4.8
1:2.5
1:1.7
1:2.1
1:1.7
1:1.1
17
95a
60
66
50
95
16
19
Table 3 Aldol Couplings of Ketones 8a/34 with Simplified Alde-
hydes 28a/28b
1.3
1.7
1.7
2.5
1.3
1.7
1.7
(+)Ipc2BCl, Et3N,
–78 to 25 °C, 20 h
OPG OH
O
OPMB
7
O
OPMB
PGO
O
Ipc2BCl, Et3N
Et2O, –78 °C
LiHMDS, –78 °C,
30 min
R
29a/29b
+
H
R
OPG OH
7
O
OPMB
LiHMDS, –40 °C,
30 min
28a: PG = TBS
28b: PG = Bn
8a (R = Me)
34 (R = H)
30a/30b
R
LiHMDS, –30 °C,
30 min
Entry
PG
R
Ipc
dr 29/30
Yield (%)a
LiHMDS, –40 °C,
40 min
1
2
3
4
5
6
TBS
TBS
Bn
Me
Me
Me
Me
H
(+)-Ipc
(–)-Ipc
(+)-Ipc
(–)-Ipc
(+)-Ipc
(–)-Ipc
1:10
1:2.5
1:19
1:6
85
43
95
95
68
66
LiHMDS, –40 °C,
30 min
Bn
LiHMDS, –78 °C,
40 min
DMF–THF 1:1.1
(3:1)
TBS
TBS
1:3
a The intermediate aldol product 32 was converted into the corre-
sponding 1,3-anti diol under these conditions. See also Dieckmann
and Menche.8h
H
1:2
a Yields estimated from the corresponding domino aldol/reduction
process. See also Dieckmann and Menche.8h
reaction temperatures as well as the use of an excess of
base lead to decreased yields. Very good yields could only
be reproducibly obtained with a slight excess of methyl
ketone and base (1.3 equivalents each) and a prolonged re-
action time of 40 minutes (entry 6).
optimize the chemical yield of aldol coupling of type 2
and correct the stereochemistry of the undesired epimer at
a subsequent stage of the synthesis (see below). Notably,
the resulting aldol products could be readily separated by
HPLC.
Due to the excellent yields and the relatively facile sepa-
ration of the two diastereomers, this aldol coupling was
selected for the synthesis of the desired C8–C22 fragment
2. The reaction proved to be easily scalable and several
grams of both isomers 31 and 32 were readily available af-
ter separation. For conversion of aldol product 31 into
building block 2a, the β-hydroxy-ketone was stereoselec-
tively reduced in a 1,3-anti fashion with NMe4HB(OAc)3
in acetonitrile/THF/acetic acid according to the Evans–
Carreira protocol (dr > 19:1),21 whereas a similar alterna-
tive using the Evans–Tishchenko protocol22 proved to be
less reliable. The resulting diol could then be regioselec-
tively methylated with sodium hydride and methyl io-
dide.23 Minor amounts of the regioisomeric C18–OMe
ether could be readily removed by chromatography. Se-
lectivity could be controlled by the reaction temperature
and time, and optimum results were obtained at 10 °C
(80%, selectivity 8:1).24
Based on previous results, boron and lithium mediated al-
dol couplings were studied in more detail, as shown in Ta-
ble 4. As shown, longer reaction times in the evaluated
lithium-aldol reactions led to increased yields (entry 3)
and only very low degrees of retro-aldol or elimination
processes were observed. In detail, methyl ketone 8a was
treated at –78 °C in THF with equimolar amounts of
LiHMDS and, after two hours, aldehyde 7 was added. It
was shown that the ratio of the two resulting epimers
could be influenced by the type of solvent and the reaction
temperature. Improved selectivities were obtained in N,N-
dimethylformamide (DMF; entries 7 and 8), resulting in a
1:1.1 diastereomeric ratio, albeit in only low yields which
could not be further increased by using an excess of meth-
yl ketone (entry 5). In a similar fashion, modified selectiv-
ities were also observed in THF by increasing the reaction
temperature to –40 °C (entries 3 and 4), whereas higher
Synthesis 2013, 45, 2305–2315
© Georg Thieme Verlag Stuttgart · New York

PAPER
C18–C20 Aldol Couplings of Rhizopodin
2309
OMe
mediated reaction. Both epimeric aldol products could be
effectively transformed into the desired C8–C22 building
block of rhizopodin in a diastereoconvergent fashion.
These results add to a more general understanding of the
subtle stereoselective effects in complex aldol reactions
and will be beneficial for the applicability and predictabil-
ity of such couplings in elaborate target synthesis.
TBS
O
OH
O
O
OPMB
OPMB
N
LiHMDS
O
7
–40 °C, THF
1. NMe4
BH(OAc)3
2. NaH, MeI
+
+
31
95%
(dr = 1:1.7)
OMe
8a
TBS
O
OH
N
76%
(2 steps)
1. Cy2BCl
LiBH4
O
2. NaH, MeI
3. PCC
82%
NMR spectra were recorded in CDCl3 with a Bruker AM 300, AM
400 or DMX-600 spectrometer. Chemical shifts are reported in
parts per million (ppm, δ) with the residual non-deuterated solvent
as internal standard. Thin-layer chromatography (TLC) was per-
formed on precoated silica gel 60 F254 (Merck) analytical plates and
visualized by fluorescence quenching under UV light. Mass spectra
were obtained with a Finnigan MAT 95 spectrometer, high-resolu-
tion data were acquired using peak matching (M/DM = 10000).
32
(3 steps)
OMe
TBS
(see table)
O
O
OMe OPMB
N
2a
O
18
33
'H-'
yield (dr 2a:18-epi-2a)
n.c.
n.c.
n.c.
NaBH4, r.t.
DIBAl-H, –78 °C
R-Me-CBS, BH3, 0 °C to r.t.
LAH, –20 °C
(S)-tert-Butyl[1-(4-methoxybenzyloxy)-2,2-dimethylhex-5-en-3-
yloxy]dimethylsilane (10)
Allylmagnesium bromide (1.0 M in Et2O, 10.7 g, 74.4 mL, 74.4
mmol, 1.9 equiv) was added dropwise to a stirred solution of
(–)-(ipc)2BOMe (24.8 g, 78.0 mmol, 2.0 equiv) in Et2O (72 mL) at
0 °C and stirred for 10 min at this temperature. The mixture was
then stirred for 1 h at r.t., the suspension was centrifuged under ar-
gon and the solution was separated from the settled magnesium
salts. The residue was washed with pentane. The combined organic
phase was concentrated, dissolved in Et2O (10 mL) and cooled to
–98 °C (liq. N2/MeOH). To this cooled solution of the allylborane,
a solution of the corresponding aldehyde 9 (8.70 g, 39.0 mmol) in
Et2O (10 mL) was added dropwise and the mixture was stirred for
3 h at –98 °C. The reaction mixture was warmed to r.t., treated with
3 M NaOH (24 mL) and 30% H2O2 (48 mL) then stirred at r.t. for
90 min, then sat. aq NaHCO3 (50 mL) was added and the phases
were separated. The aqueous phase was extracted with Et2O
(2 × 150 mL), tert-butyl methyl ether (2 × 100 mL), and EtOAc
(2 × 50 mL). The combined organic phases were dried over MgSO4,
filtered and concentrated. The residue was purified by column chro-
matography on silica gel (hexanes–EtOAc, 9:1) to give the desired
homoallylic alcohol as a colorless oil (7.33 g, 32.8 mmol, 71%).
50% (1.3:1)
80% (8.0:1)
10% (1:2.5)
LAH, –90 °C
Red-Al, –78 °C
n.c.: no conversion
Scheme 4
Conversion of the epimeric aldol product 32 into 2a was,
in turn, effected by an oxidation/reduction sequence.25
The conversion was initiated by a 1,3-syn reduction of ste-
rically hindered β-hydroxy-ketone, which was efficiently
effected by initial chelation with dicyclohexylboron chlo-
ride/Et3N and subsequent treatment with LiBH4 at –78 °C,
resulting in high selectivities (dr > 19:1). To obtain high
yields (95%) it was crucial to treat the crude product with
3 M NaOH/H2O2 for prolonged times (1.5 h) to secure
complete cleavage of the intermediate boronate. Selective
methylation was again effected by treatment with
NaH/MeI under slightly modified conditions. Consider-
able efforts were then necessary to enable efficient con-
Rf = 0.25 (hexanes–EtOAc, 9:1); ee = 92% (Mosher ester analysis);
[α]D20 –14.4 (c = 0.42, CHCl3).
version into ketone 33. After several low-yielding 1H NMR (300 MHz, CDCl3): δ = 0.90 (d, J = 3.96, 6 H), 2.02–2.05
attempts with various oxidizing agents (e.g., 2-iodoxy-
benzoic acid, Swern), it was found that high conversion
could be achieved with PCC in dichloromethane heated to
reflux. To obtain high yields (97%) it proved beneficial to
directly purify the reaction mixture after absorption on
Celite by silica gel chromatography. As shown in Scheme
4, strong reducing agents (LAH, Red-Al) were then re-
(m, 1 H), 2.24–2.26 (m, 1 H), 3.25 (d, J = 8.9 Hz, 1 H), 3.35 (d, J =
8.9 Hz, 1 H), 3.50 (dd, J = 10.3, 2.5 Hz, 1 H), 3.80 (s, 3 H), 4.43 (s,
2 H), 5.02–5.07 (m, J = 10.2, 1.5 Hz, 1 H), 5.10 (dq, J = 10.2,
1.5 Hz, 1 H), 5.91 (ddt, J = 18.0, 9.0, 6.2 Hz, 1 H), 6.86 (d, J =
8.9 Hz, 2 H), 7.2 (d, J = 8.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 19.7, 22.7, 36.6, 38.4, 55.3,
73.27, 79.4, 113.85, 116.56, 129.19, 130.1, 136.87, 159.26.
HRMS (ESI+): m/z calcd for C16H24O3Na: 287.1623; found:
287.1621.
quired to effect the required stereoselective reduction of
sterically hindered ketone 33 to 2a. High selectivities and
yields were obtained with LAH at –90 °C (dr = 8:1, 80%).
A solution of homoallylic alcohol obtained as described above (1.30
g, 4.92 mmol, 1.0 equiv) in CH2Cl2 (13 mL) under an argon atmo-
This sequence allowed the conversion of 32 into 2a in
62% yield over these four steps. Together with the conver-
sion of 31, the aldol products could be converted into the
desired fragment 2a in 68% overall yield. In combination
with the high yield in the aldol coupling, these results
demonstrate the usefulness of this approach.
sphere was cooled to 0 °C and 2,6-lutidine (1.16 g, 1.26 mL, 10.8
mmol, 2.2 equiv) was added. After stirring for 5 min, TBSOTf
(1.93 g, 1.69 mL, 7.30 mmol, 1.5 equiv) was added dropwise. The
mixture was stirred for 30 min at this temperature and at r.t. for 1 h,
then sat. aq NaHCO3 (10 mL) was added and the phases were sepa-
rated. The aqueous phase was extracted with tert-butyl methyl ether
(3 × 15 mL) and the combined organic phase was dried over
MgSO4, filtrated and the solvent was removed in vacuo. The residue
was purified by column chromatography on silica gel (hexanes–
EtOAc, 19:1) to give TBS-ether 10 as a colorless oil (1.67 g,
4.40 mmol, 90%).
In summary, we have presented a detailed analysis of the
subtle stereoselective contributions in sterically hindered
C18–C20 aldol reactions of rhizopodin. Based on this fun-
damental study, a high-yielding aldol coupling along the
C18–C19 bond could be effected by use of a lithium-
Rf = 0.61 (hexanes–EtOAc, 19:1); [α]D20 –0.4 (c = 0.79, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2305–2315

2310
M. Dieckmann et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 0.00–0.04 (m, 6 H), 0.86–0.90 (m,
15 H), 2.13–2.15 (m, 1 H), 2.33–2.36 (m, 1 H), 3.10 (d, J = 8.7 Hz,
1 H), 3.22 (d, J = 8.7 Hz, 1 H), 3.66–3–38 (m, 1 H), 3.80 (s, 3 H),
4.31–4.33 (m, 1 H), 4.41–4.43 (m, 1 H), 4.94–4.96 (m, 1 H), 4.99–
5.03 (m, 1 H), 5.85–5.89 (m, 1 H), 6.86 (d, J = 9.2 Hz, 2 H), 7.23–
7.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = –2.91, –3.31, 21.17, 21.66, 25.73,
26.13, 38.04, 40.35, 55.29, 72.77, 75.86, 113.67, 115.56, 129.00,
131.10, 137.62, 159.00.
separated and the aqueous phase was extracted with Et2O (2 × 20
mL). The combined organic layers were dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The obtained
alcohol (380 mg, 1.40 mmol) was directly used for the next step.
The alcohol (380 mg, 1.40 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (18 mL), and DMP (1.37 g, 3.22 mmol, 2.3 equiv) was add-
ed at 0 °C. After stirring for 2 h, the solvent was removed in vacuo
and the crude product was purified by column chromatography on
silica gel (hexane–EtOAc, 40:1). The desired methylketone 3 (300
mg, 1.10 mmol, 78%) was obtained as a colorless oil.
HRMS (ESI+): m/z calcd for C22H39O3Si: 379.2668; found:
379.2663.
Rf = 0.51 (hexane–EtOAc, 10:1); [α]D20 +14.6 (c = 0.9, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.08 (s, 3 H), 0.89
(s, 9 H), 1.10 (s, 3 H), 1.11 (s, 3 H), 2.15 (s, 3 H), 2.18–2.20 (m,
2 H), 3.95 (dd, J = 6.2, 4.9 Hz, 1 H), 5.01–5.05 (m, 2 H), 5.79
(dddd, J = 17.1, 10.1, 7.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = –4.4, –3.6, 18.2, 20.3, 22.2, 26.0,
39.0, 53.2, 76.7, 116.8, 136.1, 213.7.
(S)-3-(tert-Butyldimethylsilanyloxy)-2,2-dimethylhex-5-en-1-ol
(11)
PMB-ether 10 (200 mg, 0.53 mmol, 1.0 equiv) was dissolved in a
mixture of CH2Cl2 and pH 7 phosphate buffer (10:1, 22.0 mL).
DDQ (0.26 g, 1.16 mmol, 2.2 equiv) was added and the reaction
mixture was stirred for 40 min at 0 °C. After stirring for an addition-
al 1 h at r.t., the reaction mixture became dark-red. The reaction was
quenched by adding sat. aq NaHCO3 (20 mL), the layers were sep-
arated and the aqueous layer was extracted with CH2Cl2 (3 × 30
mL). The recombined organic layers were washed with brine
(20 mL), dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography (silica gel; hexanes–EtOAc, 10:1) to give alcohol
11 (132 mg, 0.51 mmol, 98% yield) as a yellowish oil.
HRMS (ESI+): m/z calcd for C15H30O2Si: 256.1756; found:
256.1759.
(S)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-4,4-
dimethylpentanoic Acid (12)
The corresponding terminal alkene 10 (221 mg, 0.58 mmol, 1.0
equiv) was dissolved in CH2Cl2 (4.0 mL) and cooled to –78 °C. A
stream of ozone was transmitted through this solution for ca. 2 min,
then oxygen was transmitted through this solution for a few min-
utes, before Ph3P (280 mg, 1.06 mmol, 1.8 equiv) was added. The
resulting mixture was stirred for 2 h at r.t., before the solvent was
removed in vacuo. The residue was purified by column chromatog-
raphy on silica gel (hexanes–EtOAc, 9:1) to give the desired alde-
hyde (173 mg, 0.458 mmol, 78%) as a light-yellow oil.
Rf = 0.58 (hexanes–EtOAc, 4:1); [α]D20 –9.2 (c = 9.90, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.09 (s, 3 H), 0.81
(s, 3 H), 0.90 (s, 9 H), 1.03 (s, 3 H), 2.26–2.33 (m, 1 H), 2.43–2.53
(m, 1 H), 2.71 (s, 1 H), 3.18 (d, J = 10.8 Hz, 1 H), 3.65 (d, J =
10.8 Hz, 1 H), 3.60–3.63 (m, 1 H), 5.00–5.05 (m, 1 H), 5.09–5.10
(m, 1 H), 5.90 (dddd, J = 17.0, 10.0, 7.0, 7.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = –4.5, –3.6, 18.1, 21.7, 23.7, 26.0,
38.2, 39.7, 70.2, 79.9, 116.4, 136.5.
Rf = 0.37 (hexanes–EtOAc, 9:1).
1H NMR (300 MHz, CDCl3): δ = 0.01 (s, 3 H), 0.06 (s, 3 H), 0.84
(s, 3 H), 0.86 (s, 9 H), 0.90 (s, 3 H), 2.45 (ddd, J = 16.7, 5.2, 2.8 Hz,
1 H), 2.66 (ddd, J = 16.7, 5.5, 1.9 Hz, 1 H), 3.11 (d, J = 8.9 Hz,
1 H), 3.20 (d, J = 8.9 Hz, 1 H), 3.22 (s, 3 H), 4.20 (t, J = 5.3 Hz,
1 H), 4.30 (d, J = 11.7 Hz, 1 H), 4.38 (d, J = 11.7 Hz, 1 H), 6.86 (d,
J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 9.76 (t, J = 1.9 Hz, 1 H).
HRMS (ESI+): m/z calcd for C14H30NaO2Si: 281.1913; found:
281.1907.
(S)-3-(tert-Butyldimethylsilanyloxy)-2,2-dimethylhex-5-en-1-al
(6)
13C NMR (100 MHz, CDCl3): δ = –4.7, –3.9, 18.2, 21.1, 21.6, 26.0,
39.9, 48.2, 55.3, 71.5, 72.7, 76.3, 113.7, 129.1, 130.7, 159.1, 202.3.
Alcohol 11 (570 mg, 2.19 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (25 mL) and DMP (3.64 g, 8.58 mmol, 3.9 equiv) was add-
ed at r.t. After stirring for 3 h, the solvent was removed in vacuo and
the crude product was purified by column chromatography on silica
gel (hexane–EtOAc, 10:1). The desired aldehyde 6 (490 mg, 1.93
mmol, 88%) was obtained as a yellowish liquid.
The aldehyde derived from ozonolysis (620 mg, 1.63 mmol, 1.0
equiv) was dissolved in tert-butanol (120 mL) and H2O (30 mL). 2-
Methyl-2-butene (13 mL, 130 mmol, 80 equiv), sodium dihydrogen
phosphate (586 mg, 4.89 mmol, 6 equiv) and sodium chlorite (884
mg, 9.77 mmol, 3 equiv) were added and the mixture was stirred for
1.5 h at r.t. under an argon atmosphere. The solvent was removed in
vacuo and the residue was dissolved in EtOAc (200 mL) and
washed with brine (100 mL). The aqueous phase was extracted with
EtOAc (3 × 100 mL), dried (MgSO4), filtered and the solvent was
removed in vacuo. The crude product was purified by column chro-
matography on silica gel (hexanes–EtOAc, 4:1) to give the desired
acid 12 (635 mg, 1.60 mmol, 98%).
Rf = 0.70 (hexanes–EtOAc, 10:1); [α]D20 +12.1 (c = 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.06 (s, 3 H), 0.08 (s, 3 H), 0.89
(s, 9 H), 1.04 (s, 3 H), 1.07 (s, 3 H), 2.29–2.31 (m, 2 H), 3.85–3.87
(m, 1 H), 5.06–5.10 (m, 2 H), 5.74–5.79 (m, 1 H), 9.60 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = –5.0, –4.0, 17.7, 18.9, 25.5, 38.0,
51.0, 75.7, 117.2, 134.8, 205.9.
HRMS (ESI+): m/z calcd for C14H28O2Si: 256.1756; found:
256.1759.
Rf = 0.3 (hexanes–EtOAc, 4:1); [α]D20 –8.1 (c = 1.11, CHCl3).
(S)-4-(tert-Butyldimethylsilyloxy)-3,3-dimethylhept-6-en-2-one
(3)
1H NMR (300 MHz, CDCl3): δ = 0.06 (m, 6 H), 0.87 (m, 9 H), 0.9
(s, 6 H), 2.41 (m, 1 H), 2.67 (dd, J = 4.7, 16.4 Hz, 1 H), 3.17 (m,
2 H), 3.79 (s, 3 H), 4.11 (m, 1 H), 4.38 (m, 2 H), 6.59 (d, J = 8.7,
2 H), 7.23 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = –4.2, –4.9, 18.2, 21.1, 21.4, 26.0,
38.3, 40.0, 55.3, 72.8, 73.6, 76.3, 113.7, 128.6, 129.1, 130.7, 159.1,
176.0.
A solution of aldehyde 6 (360 mg, 1.40 mmol, 1.0 equiv) was dis-
solved in Et2O (20 mL) under an argon atmosphere and cooled to
–78 °C before a solution of methylmagnesiumbromide (3 M in
Et2O, 335 mg, 0.9 mL, 2.81 mmol, 2 equiv) was slowly dropped
into the solution. The mixture was stirred for 30 min at this temper-
ature, then the reaction was quenched by addition of sat. aq ammo-
nium chloride (12 mL). After warming to r.t., the mixture was
diluted with Et2O (10 mL) and H2O (10 mL). The organic phase was
HRMS (ESI+): m/z calcd for C21H35O5Si: 395.2254; found:
395.2245.
Synthesis 2013, 45, 2305–2315
© Georg Thieme Verlag Stuttgart · New York

PAPER
C18–C20 Aldol Couplings of Rhizopodin
2311
(S)-Methyl 2-[2-(tert-Butyldimethylsilyloxy)-4-(4-methoxyben-
zyloxy)-3,3-dimethylbutyl]oxazole-4-carboxylate (13)
(S)-3-(tert-Butyldimethylsilyloxy)-4-{4-[(S)-1-methoxybut-3-
enyl]oxazol-2-yl}-2,2-dimethylbutanal (7)
A solution of carboxylic acid 12 (40.4 mg, 0.10 mmol, 1.0 equiv) in
THF (25 mL) under an argon atmosphere was cooled to –30 °C, and
treated with NMM (24.6 mg, 24 μL, 0.21 mol, 2.1 equiv) and IBC
(15.0 mg, 15 μL, 0.11 mmol, 1.1 equiv). The resulting mixture was
stirred at this temperature for 30 min, before L-serine methyl ester
hydrochloride (17.4 mg, 0.11 mmol, 1.1 equiv) was added as a sol-
id. The reaction mixture was warmed to r.t. and stirred overnight,
then the solvent was removed in vacuo, the residue was dissolved in
EtOAc (50 mL), filtered and washed exhaustively with EtOAc, be-
fore the solution was dried (MgSO4), filtered and the solvent was
evaporated. The obtained crude product (50.6 mg, 0.10 mmol,
99%) was used without further purification for the next step.
Methyl ester 13 (180 mg, 0.38 mmol, 1.0 equiv) was diluted in
CH2Cl2 (5 mL) under an argon atmosphere and cooled to –78 °C.
DIBAL-H (133 mg, 0.94 mL, 0.94 mmol, 2.5 equiv) was added and
the resulting reaction mixture was stirred for 2 h at –78 °C. The re-
action was quenched by successive addition of MeOH (1 mL),
EtOAc (10 mL), and sat. aq NH4Cl (5 mL). The biphasic mixture
was warmed to r.t., then 1 M aqueous tartaric acid (10 mL) was add-
ed. The organic layer was separated and the aqueous phase was ex-
tracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried over MgSO4, filtrated, and the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
on silica gel (hexanes–EtOAc, 4:1) to give the desired aldehyde
(169 mg, 0.38 mmol, quantitative).
The obtained amide (50.6 mg, 0.10 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (1.5 mL) under an argon atmosphere. The resulting solu-
tion was cooled to –78 °C before DAST (24.2 mg, 20 μL,
0.15 mmol, 1.5 equiv) was added slowly over 15 min. This mixture
was stirred at –78 °C for 1.5 h, before being slowly poured into sat.
aq NaHCO3 (5 mL). The organic layer was separated and the aque-
ous phase was extracted with CH2Cl2 (2 × 10 mL). After drying the
combined organic layer with MgSO4 and filtering, the solvent was
removed in vacuo and the residue was purified by column chroma-
tography on silica gel (hexanes–EtOAc, 2:1) to give the oxazoline
(36.0 mg, 73.0 μmol, 73%) as a light-yellow oil.
Rf = 0.53 (hexanes–EtOAc, 4:1); [α]D20 –12.5 (c = 0.61, CH3Cl3).
1H NMR (400 MHz, CDCl3): δ = –0.29 (s, 3 H), 0.04 (s, 3 H), 0.86
(s, 9 H), 0.90 (s, 3 H), 0.95 (s, 3 H), 2.91 (dd, J = 15.3, 7.1 Hz, 1 H),
3.15 (dd, J = 15.5, 4.3 Hz, 1 H), 3.20 (d, J = 8.7 Hz, 1 H), 3.25 (d,
J = 8.7 Hz, 1 H), 3.83 (s, 3 H), 4.29–4.31 (m, 1 H), 4.32 (d,
J = 11.7 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 6.88 (d, J = 8.7 Hz,
2 H), 7.24 (d, J = 8.7 Hz, 2 H), 8.15 (s, 1 H), 9.91 (s, 1 H).
13C (100 MHz, CDCl3): δ = –4.8, –4.6, 18.2, 21.1, 21.3, 26.0, 32.9,
40.2, 55.3, 72.8, 74.7, 76.3, 113.7, 129.0, 130.8, 141.1, 144.1,
159.1, 165.5, 189.1.
Rf = 0.41 (hexanes–EtOAc, 2:1); [α]D20 +24.4 (c = 0.18, CHCl3).
HRMS (ESI+): m/z calcd for C24H37NO5SiNa: 470.2339; found:
470.2326.
1H NMR (400 MHz, CDCl3): δ = 0.03 (s, 3 H), 0.06 (s, 3 H), 0.85
(s, 9 H), 0.86 (s, 3 H), 0.90 (s, 3 H), 1.39 (t, J = 7.2 Hz, 1 H), 2.34
(ddd, J = 15.5, 6.1, 0.9 Hz, 1 H), 2.72 (ddd, J = 15.6, 5.1, 1.3 Hz,
1 H), 3.16 (d, J = 8.9 Hz, 1 H), 3.20 (d, J = 8.9 Hz, 1 H), 3.76 (s,
3 H), 3.80 (s, 3 H), 4.37–4.39 (m, 4 H), 4.67 (dd, J = 10.7, 8.1 Hz,
1 H), 6.85 (d, J = 8.9 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H).
13C (100 MHz, CDCl3): δ = –4.7, –4.3, 1.1, 18.2, 21.2, 26.0, 33.1,
40.3, 52.6, 55.3, 68.2, 69.0, 72.7, 73.8, 76.5, 113.7, 128.9, 131.0,
159.0, 169.7, 171.7.
A solution of (–)-(Ipc)2BOMe (229 mg, 0.72 mmol, 2 equiv) in
Et2O (1.0 mL) under argon was cooled to –78 °C and treated slowly
with allylmagnesiumbromide (1 M in Et2O, 100 mg, 0.68 mL,
0.69 mmol, 1.9 equiv). After stirring for 15 min at this temperature,
the solution was warmed to r.t. and stirred for 1 h, then the precipi-
tate was forced to settle by centrifugation. The solution was decant-
ed into another flask under argon and the residue was washed twice
with pentane. The combined solution was then concentrated and the
residue was dissolved in Et2O (1.0 mL) before the resulting solution
was cooled to –100 °C (MeOH/liq. N2). A solution the correspond-
ing aldehyde (162 mg, 0.36 mmol, 1 equiv) in Et2O (1.0 mL) was
then added and the reaction mixture was stirred at –100 °C for 2 h.
The reaction was warmed to r.t. and treated with 3 M aqueous NaOH
(0.8 mL) and H2O2 (30% solution, 0.4 mL). The biphasic mixture
was stirred for 1 h at r.t., then the organic layer was separated, the
aqueous phase was extracted with Et2O (3 × 5 mL) and the com-
bined organic layer was washed with H2O (15 mL) and brine (15
mL). After drying (MgSO4), filtering and evaporating, the crude
product was purified by column chromatography on silica gel
(hexanes–EtOAc, 4:1) to give the corresponding homoallylic alco-
hol (116 mg, 0.24 mmol, 67%) as a colorless oil.
HRMS (ESI+): m/z calcd for C25H41NO6SiNa: 502.2601; found:
502.2604.
The obtained oxazoline (31.0 mg, 65.0 μmol, 1.0 equiv) was dis-
solved in CH2Cl2 (0.5 mL) under an argon atmosphere. This solu-
tion was cooled to 0 °C, then DBU (19.8 mg, 20 μL, 130 μmol,
2 equiv) and BrCCl3 (14.1 mg, 7 μL, 71.0 μmol, 1.1 equiv) were
added successively. The resulting mixture was stirred without fur-
ther cooling for 20 h. The resulting dark-brown solution was
quenched with sat. aq NH4Cl (2 mL). The organic layer was sepa-
rated and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL).
The combined organic extracts were dried (MgSO4), filtered and the
solvent was removed in vacuo. The obtained crude product was pu-
rified by column chromatography on silica gel (hexanes–EtOAc,
4:1) to give the desired oxazole (22.1 mg, 46.0 μmol, 71%) as a col-
orless oil.
Rf = 0.28 (hexanes–EtOAc, 4:1); [α]D20 –16.4 (c = 0.33, CHCl3).
1H NMR (400 MHz, CDCl3): δ = –0.30 (s, 3 H), 0.00 (s, 3 H), 0.83
(s, 9 H), 0.87 (s, 3 H), 0.91 (s, 3 H), 2.20 (br s, 1 H), 2.57–2.61 (m,
2 H), 2.80 (dd, J = 15.4, 7.6 Hz, 1 H), 3.02 (dd, J = 15.3, 4.0 Hz,
1 H), 3.15 (d, J = 8.9 Hz, 1 H), 3.23 (d, J = 8.9 Hz, 1 H), 3.79 (s,
3 H), 4.19 (dd, J = 7.5, 3.8 Hz, 1 H), 4.32 (d, J = 11.9 Hz, 1 H), 4.42
(d, J = 11.9 Hz, 1 H), 4.67 (dd, J = 7.3, 5.2 Hz, 1 H), 5.11–5.16 (m,
1 H), 5.17–5.22 (m, 1 H), 5.83 (ddd, J = 17.2, 10.2, 7.1 Hz, 1 H),
6.85 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.42 (s, 1 H).
Rf = 0.37 (hexanes–EtOAc, 4:1); [α]D20 –11.6 (c = 0.57, CHCl3).
1H NMR (300 MHz, CDCl3): δ = –0.38 (s, 3 H), 0.00 (s, 3 H), 0.82
(s, 9 H), 0.86 (s, 3 H), 0.90 (s, 3 H), 2.88 (dd, J = 15.3, 7.4 Hz, 1 H),
3.10 (dd, J = 15.3, 4.1 Hz, 1 H), 3.16 (d, J = 8.9 Hz, 1 H), 3.21 (d,
J = 8.9 Hz, 1 H), 3.79 (s, 3 H), 3.89 (s, 3 H), 4.20 (dd, J = 7.4,
4.1 Hz, 1 H), 4.29 (d, J = 11.9 Hz, 1 H), 4.39 (d, J = 11.9 Hz, 1 H),
6.85 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.25 (s, 1 H).
13C (100 MHz, CDCl3): δ = –4.9, –4.6, 18.2, 21.0, 21.3, 26.0, 32.8,
40.1, 52.1, 55.3, 72.8, 74.6, 76.3, 113.7, 129.0, 130.8, 133.3, 143.6,
159.0, 161.8, 164.8.
13C (75 MHz, CDCl3): δ = –4.9, –4.7, 18.2, 20.8, 21.5, 26.1, 32.9,
40.1, 41.0, 55.3, 66.6, 72.8, 74.8, 76.5, 113.7, 118.7, 129.0, 131.0,
133.7, 134.0, 143.1, 159.0, 163.9.
HRMS (ESI+): m/z calcd for C27H43NO5SiNa: 512.2808; found:
512.2817.
HRMS (ESI+): m/z calcd for C25H39NO6SiNa: 500.2444; found:
500.2468.
To a solution of the homoallylic alcohol obtained as described
above (0.27 g, 0.55 mmol, 1 equiv) in Et2O (20 mL), was added 4 Å
molecular sieves, methyliodide (7.82 g, 3.4 mL, 55.1 mmol,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2305–2315

2312
M. Dieckmann et al.
PAPER
100 equiv) and silver(I) oxide (1.28 g, 5.51 mmol, 10 equiv). The
suspension was stirred for 18 h at r.t. without light, then the mixture
was filtered through cotton/silica gel and washed with Et2O. The
solvent was removed in vacuo and the crude product was purified
by silica gel chromatography (hexane–EtOAc, 7:1) to give the
methyl ether (0.25 g, 0.50 mmol, 92%) as a colorless oil.
(S)-4-(tert-Butyldimethylsilyloxy)-5-{4-[(S)-1-methoxybut-3-
enyl]oxazol-2-yl}-3,3-dimethylpentan-2-one (4)
A solution of the aldehyde 7 (83 mg, 0.22 mmol, 1.0 equiv) was dis-
solved in Et2O (10 mL) under an argon atmosphere and cooled to
–78 °C, then a solution of methylmagnesiumbromide (3 M in Et2O,
52 mg, 150 μL, 0.44 mmol, 2 equiv) was added. The resulting mix-
ture was stirred for a further 30 min at this temperature and
quenched by addition of sat. aq NH4Cl (2 mL). After warming to
r.t., the mixture was diluted with Et2O (10 mL) and H2O (10 mL).
The organic layer was separated and the aqueous phase was extract-
ed with Et2O (2 × 10 mL). The combined organic layer was dried
(MgSO4), filtered and the solvent was removed in vacuo to give the
secondary alcohol (82.0 mg, 0.21 mmol) as the crude product,
which was directly used for the next step.
Rf = 0.72 (hexanes–EtOAc, 2:1); [α]D20 –31.7 (c = 0.90, CHCl3).
1H NMR (400 MHz, CDCl3): δ = –0.32 (s, 3 H), 0.00 (s, 3 H), 0.83
(s, 9 H), 0.86 (s, 3 H), 0.90 (s, 3 H), 2.56 (app t, J = 6.4 Hz, 2 H),
2.82 (dd, J = 15.3, 7.6 Hz, 1 H), 3.03 (dd, J = 15.5, 3.8 Hz, 1 H),
3.15 (d, J = 8.7 Hz, 1 H), 3.24 (d, J = 8.7 Hz, 1 H), 3.31 (s, 3 H),
3.79 (s, 3 H), 4.18–4.20 (m, 1 H), 4.32 (d, J = 11.7 Hz, 1 H), 4.42
(d, J = 11.7 Hz, 1 H), 5.02–5.06 (m, 1 H), 5.07–5.12 (m, 1 H), 5.80
(ddd, J = 17.2, 10.2, 7.0 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.23 (d,
J = 8.7 Hz, 2 H), 7.44 (s, 1 H).
The secondary alcohol (82.0 mg, 0.21 mmol, 1.0 equiv) was dis-
solved in CH2Cl2 (5 mL) under an argon atmosphere and treated
with Dess–Martin periodinane (123 mg, 0.29 mmol, 1.4 equiv) at
0 °C. The reaction mixture was stirred for 30 min at this tempera-
ture, then warmed to r.t. The solvent was removed under reduced
pressure and the crude product was purified by column chromatog-
raphy (hexanes–EtOAc, 1:1), to give the desired ketone 4 (78.0 mg,
0.20 mmol, 92% over two steps) as a colorless liquid.
13C (75 MHz, CDCl3): δ = –4.40, –4.41, 18.6, 21.1, 21.9, 26.4, 33.4,
39.6, 40.5, 55.7, 57.3, 73.2, 75.1, 76.7, 76.9, 113.7, 117.2, 129.0,
131.0, 134.4, 135.0, 140.8, 159.0, 164.0.
HRMS: m/z calcd for C28H45NO5SiNa: 526.2965; found: 526.2998.
The PMB-ether obtained from above (30.0 mg, 59.4 μmol,
1.0 equiv) was dissolved in CH2Cl2–H2O (10:1, 1.8 mL/0.18 mL)
under an argon atmosphere, then DDQ (30.0 mg, 131 μmol,
2.2 equiv) was added at r.t. and the resulting suspension was stirred
for 25 min. The reaction was quenched by addition of sat. aq
NaHCO3 (3 mL), then the organic layer was separated and the aque-
ous phase was extracted with CH2Cl2 (3 × 5 mL), dried over
MgSO4, filtered, and the solvent was removed under reduced pres-
sure, before the crude product was purified by flash chromatogra-
phy on silica gel (hexane–EtOAc, 7:1 → 2:1) to give the desired
alcohol (14 mg, 37.5 μmol, 63%) as a colorless liquid.
Rf = 0.67 (hexanes–EtOAc, 2:1); [α]D20 –42.9 (c = 0.6, CH3Cl3).
1H NMR (400 MHz, CDCl3): δ = –0.25 (s, 3 H), 0.01 (s, 3 H), 0.82
(s, 9 H), 1.08 (s, 3 H), 1.14 (s, 3 H), 2.17 (s, 3 H), 2.53–2.57 (m,
2 H), 2.79 (dd, J = 15.8, 7.2 Hz, 1 H), 2.86 (dd, J = 15.3, 4.1 Hz,
1 H), 3.30 (s, 3 H), 4.17 (t, J = 6.4 Hz, 1 H), 4.53 (dd, J = 7.1,
4.6 Hz, 1 H), 5.03 (dd, J = 10.2, 1.5 Hz, 1 H), 5.08 (dd, J = 17.3,
1.5 Hz, 1 H), 5.79 (ddt, J = 17.2, 10.3, 6.9 Hz, 1 H), 7.45 (s, 1 H).
13C (100 MHz, CDCl3): δ = –4.8, –4.8, 18.1, 20.2, 21.3, 25.9, 26.9,
33.5, 39.2, 53.0, 56.9, 74.9, 76.2, 117.3, 134.2, 135.3, 140.9, 162.7,
212.7.
Rf = 0.45 (hexanes–EtOAc, 1:2); [α]D20 –41.7 (c = 0.75, CHCl3).
1H NMR (400 MHz, CDCl3): δ = –0.18 (s, 3 H), –0.06 (s, 3 H), 0.86
(s, 9 H), 0.87 (s, 3 H), 0.94 (s, 3 H), 2.56 (app. t, J = 6.6 Hz, 2 H),
2.87 (dd, J = 16.0, 5.7 Hz, 1 H), 3.04 (br s, 1 H), 3.12 (dd, J = 16.6,
5.5 Hz, 1 H), 3.31 (d, J = 11.3 Hz, 1 H), 3.31 (s, 3 H), 3.56 (d,
J = 11.3 Hz, 1 H), 4.16–4.18 (m, 1 H), 5.05–5.10 (m, 2 H), 5.77
(ddd, J = 17.1, 10.2, 7.0 Hz, 1 H), 7.45 (s, 1 H).
HRMS (ESI+): m/z calcd for C21H37NO4SiNa: 418.2390; found:
418.2549.
(2S,5S,7S)-7-[(tert-Butyldimethylsilyl)oxy]-5-hydroxy-1-[(4-
methoxybenzyl)oxy]-8-{4-[(S)-1-methoxybut-3-en-1-yl]oxazol-
2-yl}-2,6,6-trimethyloctan-3-one (31) and (2S,5R,7S)-7-[(tert-
Butyldimethylsilyl)oxy]-5-hydroxy-1-[(4-methoxybenzyl)oxy]-
8-{4-[(S)-1-methoxybut-3-en-1-yl]oxazol-2-yl}-2,6,6-trimethyl-
octan-3-one (32)
13C (75 MHz, CDCl3): δ = –4.82, 18.0, 21.6, 25.9, 33.0, 39.0, 40.1,
56.9, 69.4, 76.1, 77.3, 117.4, 134.1, 135.2, 140.8, 163.6.
To a cooled (–78 °C) solution of methylketone 8a (375 mg,
1.68 mmol, 1.3 equiv) in anhydrous THF (3.0 mL) was added a so-
lution of LiHMDS (1 M in THF, 281 mg, 1.68 mL, 1.68 mmol,
1.3 equiv). The mixture was stirred at –78 °C for 2 h, then warmed
to –40 °C, then aldehyde 7 (495 mg, 1.30 mmol, 1.0 equiv) was
added as a solution in THF (2.0 mL) and the mixture was stirred at
this temperature for 40 min. Sat. aq NH4Cl (6 mL) was added and
the solution was allowed to warm to r.t., then Et2O (30 mL) was
added and the solution was washed with sat. aq NaCl (25 mL). The
aqueous layer was extracted with Et2O (4 × 25 mL), dried over
MgSO4 and concentrated in vacuo. Purification by silica column
HRMS (ESI+): m/z calcd for C20H37NO4Na: 406.2390; found:
406.2382.
The obtained primary alcohol (15.0 mg, 0.04 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (0.5 mL) under an argon atmosphere, then a so-
lution of DMP (23.2 mg, 0.06 mmol, 1.4 equiv) in CH2Cl2 (1.5 mL)
was added and the resulting mixture was stirred at r.t. for 1 h. Sat.
aq NaHCO3 (2 mL) was added, the organic layer was separated and
the aqueous phase was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic layer was dried (MgSO4), filtered and the solvent was
removed in vacuo. The resulting crude product was purified by col-
umn chromatography on silica gel (hexanes–EtOAc, 1:2) to give al-
dehyde 7 (14.0 mg, 94%) as a colorless oil.
chromatography
(40 g
SiO2;
petroleum
ether–EtOAc,
80:20 → 50:50) gave a mixture (1:1.7) of aldol products 31 and 32
(747 mg, 1.24 mmol, 95%) as a light-yellow oil. Both diastereoiso-
mers could be separated by reverse-phase HPLC [Machery-Nagel;
Nucleodur-C18; MeCN–H2O, 95:5; 35 mL/min; tR = 4.5 (31),
5.0 min (32)].
Rf = 0.64 (hexanes–EtOAc, 1:2); [α]D20 –18.0 (c = 0.1, CH3Cl3).
1H NMR (400 MHz, CDCl3): δ = –0.24 (s, 3 H), –0.02 (s, 3 H), 0.81
(s, 9 H), 1.00 (s, 3 H), 1.09 (s, 3 H), 2.53–2.57 (m, 2 H), 2.86 (dd,
J = 15.3, 7.1 Hz, 1 H), 2.95 (dd, J = 15.2, 7.1 Hz, 1 H), 3.30 (s,
3 H), 4.17 (t, J = 6.5 Hz, 1 H), 4.45 (dd, J = 7.1, 4.8 Hz, 1 H), 5.04–
5.08 (m, 2 H), 5.76–5.80 (m, 1 H), 7.45 (s, 1 H), 9.49 (s, 1 H).
13C (100 MHz, CDCl3): δ = –4.8, –4.7, 17.3, 18.6, 25.8, 33.0, 39.1,
51.3, 56.9, 74.2, 76.1, 117.3, 134.2, 135.3, 141.0, 162.2, 204.9.
Aldol Product 31
Rf = 0.10 (petrol ether–EtOAc, 80:20); [α]D20 –24.1 (c = 0.63 in
CHCl3).
1H NMR (600 MHz, CDCl3): δ = –0.26 (s, 3 H), 0.09 (s, 3 H), 0.76
(s, 3 H), 0.85 (s, 9 H), 0.92 (s, 3 H), 1.10 (d, J = 7.0 Hz, 3 H), 2.51
(d, J = 16.2 Hz, 1 H), 2.57 (ddd, J = 13.9, 13.9, 7.2 Hz, 2 H), 2.63
(dd, J = 16.9, 9.9 Hz, 1 H), 2.91–2.95 (m, 1 H), 2.93–2.97 (m, 1 H),
3.11 (dd, J = 15.6, 3.6 Hz, 1 H), 3.33 (s, 3 H), 3.46 (dd,
J = 9.2, 5.5 Hz, 1 H), 3.62 (dd, J = 8.8, 8.0 Hz, 1 H), 3.67 (s, 1 H),
HRMS: m/z [M + Na]+ calcd for C20H35NO4SiNa+: 404.2228;
found: 404.2226.
Synthesis 2013, 45, 2305–2315
© Georg Thieme Verlag Stuttgart · New York

PAPER
C18–C20 Aldol Couplings of Rhizopodin
2313
3.80 (s, 3 H), 4.20 (t, J = 6.3 Hz, 1 H), 4.20 (t, J = 6.3 Hz, 1 H), 4.26
(d, J = 9.9 Hz, 1 H), 4.33 (dd, J = 7.0, 3.4 Hz, 1 H), 4.40 (d,
J = 11.6 Hz, 1 H), 4.44 (d, J = 11.6 Hz, 1 H), 5.09 (dd, J = 29.2,
13.9 Hz, 2 H), 5.79–5.83 (m, J = 24.0, 17.2, 7.0 Hz, 1 H), 6.87 (d,
J = 6.3 Hz, 2 H), 7.23 (d, J = 8.2 Hz, 2 H), 7.47 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = –5.1, –4.8, 13.4, 18.1, 19.1, 20.6,
25.9, 32.8, 39.1, 41.3, 44.1, 47.0, 55.2, 56.8, 70.7, 71.8, 72.9, 77.6,
77.6, 113.7, 117.3, 129.3, 130.1, 134.2, 135.1, 140.8, 159.2, 163.4,
213.8.
HRMS (ESI+): m/z [M + H]+ calcd for C33H56NO7Si+: 606.3826;
found: 606.3818.
To a stirred solution of the 1,3-anti diol obtained above (49.0 mg,
80.9 μmol, 1.0 equiv) in anhydrous THF (1.0 mL) was added NaH
(60% dispersion in oil, 32.2 mg, 809 μmol, 10.0 equiv) at 0 °C. The
mixture was stirred for 10 min at 0 °C, then iodomethane (150 μL)
was added and the solution was stirred at +10 °C for 65 min before
the addition of sat. aq NH4Cl (2 mL). The mixture was warmed to
r.t., Et2O (10 mL) was added and the mixture was washed with sat.
aq NaCl (5 mL), the aqueous layer was extracted with Et2O
(4 × 10 mL), the combined organic layers were dried over MgSO4
and concentrated in vacuo. Purification by column chromatography
(10 g SiO2; pentane–EtOAc, 3:1) gave C20-monomethylated 2a
(40.1 mg, 64.7 μmol, 80%) in addition to C18-monomethylated
sideproduct (3.1 mg, 5.1 μmol, 6%, both isomers could be separated
by column chromatography) as a colorless oil.
HRMS (ESI+): m/z [M + Na]+ calcd for C33H53NO7SiNa: 626.3489;
found: 626.3494.
Aldol Product 32
Rf = 0.13 (petrol ether–EtOAc, 80:20); [α]D20 +0.4 (c = 0.61 in
CHCl3).
1H NMR (600 MHz, CDCl3): δ = –0.23 (s, 3 H), 0.03 (s, 3 H), 0.79
(s, 3 H), 0.88 (s, 9 H), 0.94 (s, 3 H), 1.05 (d, J = 7.0 Hz, 3 H), 2.56
(t, J = 6.6 Hz, 2 H), 2.61–2.64 (m, 2 H), 2.80 (dd, J = 21.9, 5.8 Hz,
1 H), 2.89–2.92 (m, 1 H), 3.17 (dd, J = 16.1, 4.7 Hz, 1 H), 3.33 (s,
3 H), 3.44 (dd, J = 8.9, 5.4 Hz, 1 H), 3.58 (t, J = 8.5 Hz, 1 H), 3.72
(d, J = 3.0 Hz, 1 H), 3.81 (s, 3 H), 4.01 (d, J = 9.7 Hz, 1 H), 4.21 (t,
J = 6.5 Hz, 1 H), 4.25 (t, J = 5.2 Hz, 1 H), 4.40 (d, J = 11.6 Hz,
1 H), 4.43 (d, J = 11.7 Hz, 1 H), 5.07 (dd, J = 28.1, 13.7 Hz, 2 H),
5.77–5.82 (m, 1 H), 6.87 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz,
2 H), 7.47 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = –4.8, 13.2, 15.3, 18.1, 18.5, 19.5,
26.0, 33.0, 39.1, 42.5, 44.5, 47.1, 55.2, 56.9, 70.6, 71.9, 72.9, 75.1,
76.1, 113.8, 117.3, 129.3, 130.0, 134.2, 135.1, 140.6, 159.2, 164.0,
214.3.
Rf = 0.55 (pentane–EtOAc, 2:1); [α]D20 –34.3 (c = 0.81 in CHCl3).
1H NMR (600 MHz, CDCl3): δ = –0.30 (s, 3 H), 0.06 (s, 3 H), 0.75
(s, 3 H), 0.83 (s, 9 H), 0.94 (d, J = 6.8 Hz, 1 H), 0.94 (s, 3 H), 1.38–
1.40 (m, 2 H), 1.94–2.02 (m, 1 H), 1.99 (qddd, J = 7.2, 7.0, 4.7,
4.4 Hz, 1 H), 2.50–2.60 (m, 2 H), 2.97 (dd, J = 15.7, 7.6 Hz, 1 H),
3.14 (dd, J = 15.8, 3.4 Hz, 1 H), 3.27 (dd, J = 16.1, 5.8 Hz, 1 H),
3.30 (s, 3 H), 3.41 (s, 3 H), 3.46 (dd, J = 16.0, 4.7 Hz, 1 H), 3.54
(ddd, J = 7.7, 4.4, 4.4 Hz, 1 H), 3.78 (s, 3 H), 3.93 (dd, J = 5.6,
5.5 Hz, 1 H), 4.16–4.20 (m, 2 H), 4.39 (d, J = 11.5 Hz, 2 H), 4.43
(d, J = 11.5 Hz, 2 H), 5.03 (d, J = 10.1 Hz, 1 H), 5.08 (dd, J = 17.2,
1.3 Hz, 1 H), 5.78 (dddd, J = 17.1, 10.0, 6.9, 6.9 Hz, 1 H), 6.85 (d,
J = 8.6 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.45 (s, 1 H).
13C NMR (150.90 MHz, CDCl3): δ = –5.2, –4.7, 12.7, 18.0, 19.8,
22.4, 25.9, 32.7, 34.0, 37.4, 39.1, 41.0, 55.3, 56.9, 59.2, 71.4, 72.4,
72.7, 76.1, 79.1, 80.6, 113.7, 117.3, 129.1, 129.2, 130.8, 134.2,
135.1, 140.9, 159.0, 163.3.
HRMS (ESI+): m/z [M + Na]+ calcd for C33H53NO7SiNa+:
626.3489; found: 626.3494.
(2S,4S,6S,7S)-2-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-8-[(4-
methoxybenzyl)oxy]-1-{4-[(S)-1-methoxybut-3-en-1-yl]oxazol-
2-yl}-3,3,7-trimethyloctan-4-ol (2a from 31)
HRMS (ESI+): m/z [M + Na]+ calcd for C34H57NO7SiNa+:
642.3802; found: 642.3810.
NMe4HB(OAc)3 (160 mg, 606 µmol, 4.7 equiv) was added to a
mixture of MeCN–acetic acid (1:1, 1.0 mL) at r.t. and stirred for
30 min. This solution was added to a solution of β-hydroxy-ketone
31 (78.0 mg, 129 μmol, 1.0 equiv) in THF–MeCN (1:1, 1.5 mL) at
–30 °C. The mixture was warmed to –20 °C, stirred for 3.5 h at this
temperature and kept in a freezer overnight (–20 °C, 12 h). An
aqueous solution of Na/K-tartrate (20%, 3.0 mL) was added at
–20 °C and the mixture was allowed to warm to r.t., then CH2Cl2
(25 mL) was added and the solution was washed with Na/K-tartrate
solution (20%, 10 mL). The aqueous layer was extracted with
CH2Cl2 (4 × 15 mL), and the combined organic layers were dried
over MgSO4 and concentrated in vacuo. Silica column chromatog-
raphy (7 g SiO2; pentane–EtOAc, 80:20 → 50:50) gave the corre-
sponding 1,3-anti-diol product (74.0 mg, 123 μmol, 95%) as a
colorless oil.
(2S,6S,7S)-2-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-8-[(4-
methoxybenzyl)oxy]-1-{4-[(S)-1-methoxybut-3-en-1-yl]oxazol-
2-yl}-3,3,7-trimethyloctan-4-one (33)
Aldol product 32 (930 mg, 1.54 mmol, 1.0 equiv) was dissolved in
Et2O (9.0 mL) and cooled to –30 °C, then anhydrous Et3N (322 μL,
2.31 mmol, 1.5 equiv), and Cy2BCl (1 M in THF, 2.31 mL,
2.31 mmol, 1.5 equiv) were added and the white mixture was stirred
for 90 min. The solution was cooled to –78 °C and LiBH4 (2 M in
THF, 3.85 mL, 7.70 mmol, 5.0 equiv) was added and the mixture
was stirred at this temperature for 90 min. Sat. aq NH4Cl (10 mL)
was added slowly and the mixture was allowed to warm to r.t., then
Et2O (20 mL) and sat. aq NH4Cl (10 mL) were added. The solution
was washed, the aqueous layer was extracted with Et2O (4 × 20 mL)
and the combined organic layers were concentrated in vacuo. The
colorless residue was dissolved in MeOH (6.0 mL) and cooled to
0 °C. The solution was stirred and aq NaOH (3 M, 3.0 mL) and
H2O2 (30%, 3.0 mL) were added and the mixture was stirred for 2 h
at r.t. The solution was diluted with CH2Cl2 (10 mL) and H2O
(10 mL) and, after washing and separation of the phases, the aque-
ous layer was extracted with CH2Cl2 (4 × 20 mL), the combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (90 g SiO2; petrol ether–
EtOAc, 3:1 → 1:1) gave the corresponding 1,3-syn-diol (886 mg,
1.46 mmol, 95%) as a colorless oil.
Rf = 0.11 (pentane–EtOAc, 2:1); [α]D20 –29.3 (c = 1.50 in CHCl3).
1H NMR (600 MHz, CDCl3): δ = –0.27 (s, 3 H), 0.09 (s, 3 H), 0.78
(s, 3 H), 0.86 (s, 9 H), 0.99 (d, J = 7.0 Hz, 3 H), 1.02 (s, 3 H), 1.39
(dd, J = 12.9, 11.0 Hz, 1 H), 1.49 (dd, J = 12.7, 10.6 Hz, 1 H), 1.87
(br s, 1 H), 2.58 (m, 2 H), 3.01 (dd, J = 15.8, 7.4 Hz, 1 H), 3.17 (dd,
J = 15.7, 2.2 Hz, 1 H), 3.32 (s, 3 H), 3.49 (dd, J = 8.9, 5.5 Hz, 1 H),
3.55 (dd, J = 9.0, 4.2 Hz, 1 H), 3.80 (s, 3 H), 4.07–4.09 (m, 1 H),
4.11–4.13 (m, 1 H), 4.16–4.18 (m, 1 H), 4.19–4.21 (m, 1 H), 4.41
(d, J = 11.6 Hz, 1 H), 4.46 (d, J = 11.3 Hz, 1 H), 4.46 (d,
J = 11.3 Hz, 1 H), 5.06 (d, J = 10.2 Hz, 1 H), 5.12 (d, J = 17.3 Hz,
1 H), 5.78–5.83 (m, 1 H), 6.86 (d, J = 8.1 Hz, 2 H), 7.24 (d,
J = 8.0 Hz, 2 H), 7.47 (s, 1 H).
Rf = 0.18 (pentane–EtOAc, 3:1); [α]D20 –29.3 (c = 1.50 in CHCl3).
1H NMR (400 MHz, CDCl3): δ = –0.16 (s, 3 H), 0.07 (s, 3 H), 0.82
(s, 3 H), 0.92 (s, 9 H), 0.97 (d, J = 7.2 Hz, 3 H), 0.99 (s, 3 H), 1.51–
1.73 (m, 2 H), 1.89 (qddd, J = 7.2, 6.9, 5.0, 1.5 Hz, 1 H), 2.60 (t, J =
6.7 Hz, 2 H), 2.84 (dd, J = 16.5, 5.0 Hz, 1 H), 3.22 (dd, J = 16.6,
5.4 Hz, 1 H), 3.36 (s, 3 H), 3.48 (dd, J = 9.0, 5.0 Hz, 1 H), 3.54 (dd,
J = 8.8, 6.9 Hz, 1 H), 3.68–3.75 (m, 2 H), 3.85 (s, 3 H), 3.96 (dt, J =
9.2, 2.5 Hz, 1 H), 4.15 (d, J = 5.8 Hz, 1 H), 4.24 (t, J = 6.5 Hz, 1 H),
13C NMR (150 MHz, CDCl3): δ = –5.2, –4.7, 11.3, 18.0, 20.1, 22.9,
25.9, 32.6, 35.7, 38.5, 39.1, 40.8, 55.3, 56.7, 60.4, 70.6, 71.5, 73.1,
74.9, 76.1, 81.7, 113.8, 117.3, 129.2, 130.2, 134.2, 135.1, 140.9,
159.2, 163.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2305–2315

2314
M. Dieckmann et al.
PAPER
4.29 (t, J = 5.1 Hz, 1 H), 4.47 (s, 2 H), 5.08 (d, J = 11.6 Hz, 1 H),
5.15 (d, J = 17.2 Hz, 1 H), 5.82 (dddd, J = 17.1, 10.0, 6.9, 6.9 Hz,
1 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.51 (s,
1 H).
13C NMR (100 MHz, CDCl3): δ = –4.8, –4.7, 11.3, 17.4, 18.0, 19.2,
25.9, 32.9, 33.9, 38.9, 39.0, 43.2, 55.3, 56.9, 73.0, 73.7, 74.8, 76.0,
76.6, 77.2, 113.8, 117.4, 129.3, 134.0, 135.2, 142.0, 158.9, 164.2.
HRMS (ESI+): m/z [M + Na]+ calcd for C34H55NO7SiNa+:
640.3645; found: 640.3642.
(2S,4S,6S,7S)-2-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-8-[(4-
methoxybenzyl)oxy]-1-{4-[(S)-1-methoxybut-3-en-1-yl]oxazol-
2-yl}-3,3,7-trimethyloctan-4-ol (2a from 32)
To a stirred solution of the ketone 33 (264 mg, 427 μmol, 1.0 equiv)
in THF (10.0 mL) under argon at –90 °C was added a precooled so-
lution of LiAlH4 (2 M in THF, 65.0 mg, 855 μL, 1.71 mmol,
4.0 equiv). The mixture was stirred at –90 °C for 45 min, and H2O
(0.6 mL) and a solution of NaOH (3 M, 1.8 mL) were added. The
mixture was warmed to r.t., Et2O (20 mL) and H2O (15 mL) were
added and the aqueous phase was separated and extracted with Et2O
(4 × 20 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. Purification by column chromatography
(25 g SiO2; pentane–EtOAc, 3:1 → 1:1) gave alcohol 2a (211 mg,
341 μmol, 80%, dr = 8.0:1) as a colorless oil.
HRMS (ESI+): m/z [M + H]+ calcd for C33H56NO7Si+: 606.3826;
found: 606.3835.
To a stirred solution of the 1,3-syn-diol obtained above (15.0 mg,
24.8 μmol, 1.0 equiv) in anhydrous THF (0.5 mL) was added NaH
(60% dispersion in oil, 5.0 mg, 124 μmol, 5.0 equiv) at 0 °C. The
mixture was stirred for 10 min at 0 °C, then iodomethane (100 μL)
was added and the solution was stirred at 0 °C for 40 min before the
addition of sat. aq NH4Cl (1 mL). The mixture was warmed to r.t.,
Et2O (10 mL) was added, and the mixture was washed with sat. aq
NaCl (5 mL), the aqueous layer was extracted with Et2O (4 × 10
mL), and the combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by silica column chromatogra-
phy (5 g SiO2; pentane–EtOAc, 3:1→1:1) gave the corresponding
C20-monomethylated product (10.0 mg, 16.1 μmol, 65%, 89%
brsm) besides recovered starting material (4.0 mg, 6.60 μmol, 27%)
as a colorless oil.
Rf = 0.55 (pentane–EtOAc, 2:1); [α]D20 –34.3 (c = 0.81 in CHCl3).
1H NMR (600 MHz, CDCl3): δ = –0.30 (s, 3 H), 0.06 (s, 3 H), 0.75
(s, 3 H), 0.83 (s, 9 H), 0.94 (d, J = 6.8 Hz, 1 H), 0.94 (s, 3 H), 1.38–
1.40 (m, 2 H), 1.94–2.02 (m, 1 H), 1.99 (qddd, J = 7.2, 7.0, 4.7,
4.4 Hz, 1 H), 2.50–2.60 (m, 2 H), 2.97 (dd, J = 15.7, 7.6 Hz, 1 H),
3.14 (dd, J = 15.8, 3.4 Hz, 1 H), 3.27 (dd, J = 16.1, 5.8 Hz, 1 H),
3.30 (s, 3 H), 3.41 (s, 3 H), 3.46 (dd, J = 16.0, 4.7 Hz, 1 H), 3.54
(ddd, J = 7.7, 4.4, 4.4 Hz, 1 H), 3.78 (s, 3 H), 3.93 (dd, J = 5.6,
5.5 Hz, 1 H), 4.16–4.20 (m, 2 H), 4.39 (d, J = 11.5 Hz, 2 H), 4.43
(d, J = 11.5 Hz, 2 H), 5.03 (d, J = 10.1 Hz, 1 H), 5.08 (dd, J = 17.2,
1.3 Hz, 1 H), 5.78 (dddd, J = 17.1, 10.0, 6.9, 6.9 Hz, 1 H), 6.85 (d,
J = 8.6 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.45 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = –5.2, –4.7, 12.7, 18.0, 19.8, 22.4,
25.9, 32.7, 34.0, 37.4, 39.1, 41.0, 55.3, 56.9, 59.2, 71.4, 72.4, 72.7,
76.1, 79.1, 80.6, 113.7, 117.3, 129.1, 129.2, 130.8, 134.2, 135.1,
140.9, 159.0, 163.3.
HRMS (ESI+): m/z [M + Na]+ calcd for C34H57NO7SiNa+:
642.3802; found: 642.3810.
Rf = 0.27 (pentane–EtOAc, 3:1); [α]D20 –27.5 (c = 1.59 in CHCl3).
1H NMR (400 MHz, CDCl3): δ = –0.27 (s, 3 H), 0.02 (s, 3 H), 0.78
(s, 3 H), 0.87 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.93 (s, 3 H), 1.39–
1.63 (m, 2 H), 1.97–2.18 (m, 1 H), 2.56 (t, J = 6.6 Hz, 2 H), 2.83
(dd, J = 15.8, 6.6 Hz, 1 H), 3.18 (dd, J = 15.9, 4.1 Hz, 1 H), 3.28–
3.35 (m, 1 H), 3.33 (s, 3 H), 3.37 (s, 3 H), 3.42–3.56 (m, 2 H), 3.62
(d, J = 9.4 Hz, 1 H), 3.81 (s, 3 H), 3.99 (d, J = 1.8 Hz, 1 H), 4.20 (t,
J = 6.1 Hz, 1 H), 4.26 (dd, J = 6.4, 4.1 Hz, 1 H), 4.43 (s, 4 H), 5.05
(d, J = 10.7 Hz, 1 H), 5.15 (s, 1 H), 5.81 (ddd, J = 17.1, 10.0, 6.9,
6.9 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H),
7.46 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = –4.7, –4.7, 12.6, 17.6, 18.1, 19.5,
26.0, 29.7, 32.1, 32.8, 36.0, 39.1, 42.9, 55.3, 56.9, 57.6, 71.9, 72.8,
75.1, 75.2, 76.2, 83.9, 113.7, 117.2, 129.2, 130.5, 134.2, 135.0,
140.6, 159.1, 164.1.
Acknowledgment
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (Me 2756/4-1).
HRMS (ESI+): m/z [M + Na]+ calcd for C34H57NO7SiNa+:
642.3802; found: 642.3829.
To a stirred solution of the alcohol prepared above (290 mg,
469 μmol, 1.0 equiv) in CH2Cl2 (7.0 mL) was added PCC (506 mg,
2.35 mmol, 5.0 equiv) at r.t. The mixture was heated at reflux for
90 min, cooled to r.t., filtered over Celite, which was rinsed with
CH2Cl2 (50 mL), and concentrated in vacuo. Purification by silica
column chromatography (20 g SiO2; pentane–EtOAc, 3:1) gave the
corresponding ketone 33 (281 mg, 455 μmol, 97%) as a colorless
oil.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2013, 45, 2305–2315