Concise synthesis of complicated polypropionates through one-pot dissymmetrical two-directional chain elongation

Article abstract of DOI:10.1002/chem.201003264

Herein, a major breakthrough in a sulfur dioxide-mediated oxyallylation cascade reaction is reported that allows the preparation of complex long-chain polyketide fragments with more than ten stereogenic centers through a carefully designed desymmetrization process. An allylbissilane is combined, under the appropriate reaction conditions, with two different 1,3-dioxy-1,3-dienes permitting the construction of a 13-membered polypropionate precursor in one pot. Four stereocenters are selectively created during this process. The so-obtained pseudo-C₂- or -C_S-symmetric products are desymmetrized through selective deprotection and can be selectively elongated in both directions using aldol chemistry. Copyright

Full text of DOI:10.1002/chem.201003264

DOI: 10.1002/chem.201003264
Concise Synthesis of Complicated Polypropionates through One-Pot
Dissymmetrical Two-Directional Chain Elongation
Claudia J. Exner,[a] Maris Turks,[b] Freddy Fonquerne,[c] and Pierre Vogel*[a]
Dedicated to Professor Horst Prinzbach on the occasion of his 80th birthday
Abstract: Herein,
a
major break-
ate reaction conditions, with two differ-
ent 1,3-dioxy-1,3-dienes permitting the
construction of a 13-membered poly-
propionate precursor in one pot. Four
stereocenters are selectively created
during this process. The so-obtained
pseudo-C2- or -CS-symmetric products
are desymmetrized through selective
deprotection and can be selectively
elongated in both directions using aldol
chemistry.
through in a sulfur dioxide-mediated
oxyallylation cascade reaction is re-
ported that allows the preparation of
complex long-chain polyketide frag-
ments with more than ten stereogenic
centers through a carefully designed
desymmetrization process. An allylbis-
silane is combined, under the appropri-
Keywords: aldol reaction
silanes asymmetric synthesis
polyketides sulfur dioxide
tandem reactions
· allyl-
A
·
·
·
A
·
AHCTUNGTRENNUNG
Introduction
be applied to these fragments to generate multifunctional
compounds diastereoselectively.[4]
Polypropionates are characterized by their alternating
methyl–hydroxyl-substituted alkyl chains. They are found in
diverse classes of natural products with biological and me-
dicinal interest,[1] and many applied synthetic approaches to
polypropionates have been reviewed recently.[2,3] All the
synthetic methods are multistep processes involving func-
tional group construction, selective protection steps, and in-
stallation of the stereogenic centers. For practical as well as
environmental and economic reasons, the number of chemi-
cal operations should clearly be reduced to a minimum. Em-
ploying one-step, two-directional chain-extension strategies
provides simple access to longer chain fragments. For rea-
sons of stereodiversity, an easy desymmetrization step has to
We have reported the one-pot synthesis of stereotriads 7
using an oxyallylation reaction cascade that combines elec-
tron-rich dienes 1 and carbon nucleophiles 4, such as enoxy-
silanes, through SO2-umpolung (Scheme 1).[5,6,7] Dienes 1,
containing a 1-arylethyl chiral auxiliary,[8] undergo hetero-
Diels–Alder (HDA) addition with SO2 to generate six-mem-
bered sultine 2, which is subsequently broken down to the
zwitterionic species 3 by Lewis acid assisted heterolysis. Nu-
[a] Dr. C. J. Exner, Prof. P. Vogel
Laboratoire de Glycochimie
et de Synthꢀse asymꢁtrique
ꢂcole Polytechnique Fꢁdꢁrale de Lausanne
1015 Lausanne (Switzerland)
Fax : (+41)21-69-39-375
E-mail: pierre.vogel@epfl.ch
[b] Prof. M. Turks
Faculty of Material Science
and Applied Chemistry
Riga Technical University
1658 Riga (Latvia)
[c] Dr. F. Fonquerne
Givaudan Suisse SA
Chemin de la Parfumerie 5
1214 Vernier (Switzerland)
Scheme 1. One-pot synthesis of stereotriads 7 through SO2-induced oxy-
allylation of C-nucleophiles 4. A=acid catalyst; R=alkyl; R1 =H, Me;
R2 =alkyl, phenyl; for Z=O: R3, R4 =H, Me, alkyl; for Z=CH2: R3 =
CH2TMS, CH2OAc, R4 =H. The opposite enantiomers are obtained
using the (R)- instead of the (S)-arylethoxy moiety in 1.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003264. It contains the prep-
aration and complete characterization of (+)-28, 29, (+)-30, (+)-31,
(R)-32, (S)-32, (À)-34, (+)-35, (+)-36, and (À)-37.
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Chem. Eur. J. 2011, 17, 4246 – 4253

FULL PAPER
cleophilic attack by alkene 4 leads to the formation of a new
À
C C bond and yields intermediate silyl sulfinate 5, which is
converted into the corresponding sulfinic acid 6 in situ
either through Pd-catalyzed[9] or buffer-mediated[10] desilyla-
tion. Sulfinic acid 6 then undergoes a highly stereoselective
retro-ene reaction with concomitant desulfinylation into
stereotriad 7. Using our method, we have developed access
to 4,5-anti-5,6-syn[7] and 4,5-anti-5,6-anti-stereotriads.[11] Ster-
eotriads 7 contain two structural motifs for further chain
elongation in both directions: 1) the ketone moiety on one
side can be used directly in aldol condensations, and 2) the
enol ester on the other side can be transformed into an eno-
late for use in stereoselective aldol reactions. In this way,
dissymmetric two-directional chain elongation can be ach-
ieved.
More recently, we communicated an extension of this
methodology to include the application of allylsilanes as C-
nucleophiles.[10,12,13] In addition, we have described the se-
quential chain elongation of products 7 to symmetrical and
nonsymmetrical polypropionate fragments through conver-
sion of compounds 7 into advanced C-nucleophiles (enoxy-
or allylsilanes) and their use in a second SO2-oxyallylation
cascade reaction.[6,10]
Scheme 2. Stepwise bidirectional chain elongation for the preparation of
11. Reagents and conditions: a) i) Tf2NTMS, SO2, CH2Cl2/toluene,
À788C; ii) Et3N, TMSOTf, MeOH, À78 to À508C, 65%;
b) (PhMe2Si)2Cu(CN)Li2, THF, À788C, quant. (based on recovered start-
ing material); c) Tf2NTMS, SO2, CH2Cl2/toluene, À788C; ii) Pd
ACHTUNGTRENNUNG(OAc)2,
PPh3, K2CO3, iPrOH, MeCN, reflux, 84%; 55% over three steps; Ar=p-
C6H4CF3.
Results and Discussion
To obtain product 11 in a one-pot procedure, we envisioned
the use of allylbissilanes 12, which should undergo two con-
secutive SO2-mediated oxyallylation reactions (Scheme 3).
After the first SO2-oxyallylation of allylbissilane 12 and
diene 1, the obtained intermediate 13 should then be
trapped with a second (different) diene 1’, which is added
later to the reaction mixture, giving the nonsymmetrical
product 15. However, the envisioned reaction contained sev-
eral anticipated difficulties that needed to be addressed.
First, the reaction of bissilane 12 and diene 1 must be com-
plete before the second diene 1’ is added, otherwise the two
dienes 1 and 1’ will compete for intermediate 13 in the
second oxyallylation. Secondly, intermediate 13 should be
stable and should not be so reactive that it undergoes
double oxyallylation with the same diene 1 to form symmet-
rical products; however, it should be reactive enough to un-
dergo oxyallylation with diene 1’ to form pseudo-symmetri-
cal products.
Pursuing the idea of a one-pot, double-chain-extension
strategy with subsequent desymmetrization, we used the
methodology described above to prepare pseudo-symmetri-
cal products, diverging from complete symmetry only in one
substituent at the chiral auxiliary. We intended to desymme-
trize these products through selective deprotection of the
chiral 1-arylethyl group. Introduction of an electron-releas-
ing or electron-withdrawing substituent in the para-position
of the phenyl ring of the chiral auxiliary of the diene should
change the electronic but not the steric situation of the aryl
ring and thus the reactivity of the benzylic center towards a
deprotecting reagent. To this end, we have prepared a series
of substituted 2-methyl-1,3-dioxy-1,3-dienes 1 (R1 =Me).[8]
Screening of these dienes under our reaction conditions in-
dicated a higher configurational stability of the chiral center
in the 1-arylethyl chiral moiety containing electron-with-
drawing substituents in the para-position of the aryl ring.
Hence, we identified diene 1b as being suitable for our pur-
poses (Scheme 2). The synthesis of pseudo-symmetrical
product 11 following our previously reported procedure
thus involved an oxyallylation cascade with diene (S)-1a
and allylsilane 8, transformation of the obtained allylacetate
9 into an advanced allylsilane 10, and a second oxyallylation
cascade with diene (R)-1b (Scheme 2).
We now report an improvement of this methodology to
include a one-pot procedure for bidirectional chain elonga-
tion, which can lead to symmetrical and pseudosymmetrical
or nonsymmetrical polypropionate precursors. The latter
two may be desymmetrized and further elongated either si-
multaneously or stepwise.
Scheme 3. Anticipated reaction mode of one-pot, two-directional chain
elongation towards nonsymmetrical propionate fragments. R=alkyl;
R1 =H, Me; R2 =alkyl, phenyl; R*=1-arylethyl chiral auxiliary.
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P. Vogel et al.
To investigate the most suitable reagents and conditions
for our purposes, we carried out a number of SO2-induced
oxyallylation reactions with different allylbissilanes 12 and a
single diene 1 (Table 1). Scheme 4 illustrates the different
reaction pathways that these bissilanes may undergo to give
diverse products. Bissilane 12 may undergo, in the first
stage, rapid SO2-oxyallylation to give the desired intermedi-
ate silyl sulfinate 13. The nucleophilicity of its allylsilane
moiety is expected to be significantly reduced compared
with the starting bissilane 12.[14] Thus, 13 may react in a
second, slower, SO2-cascade with 1 to give bis(silyl sulfi-
nates) 16, leading to symmetrical products 17 after double
chain elongation on retro-ene work up. Hydrolysis of the
silyl sulfinate moiety in 13 and subsequent retro-ene reac-
tion yields allylsilane 18. Due to the loss of reactivity in 13,
sila-ene reaction of its second allylsilane equivalent with
SO2 to give intermediate bis(silyl sulfinate) 20 becomes a
competing pathway that leads to 21 after desilylation and
desulfinylation. Furthermore, the high reactivity of 12 also
makes it very prone to undergoing sila-ene reaction with
SO2, giving silyl sulfinate 19. The second allylsilyl moiety of
19 can still serve as a C-nucleophile in an oxyallylation cas-
cade reaction to yield intermediate 20, again giving 21 after
hydrolysis. On the other hand, 19 can undergo a second sila-
ene reaction to give bis(silyl sulfinate) 22, leading to isobu-
tylene after workup. It is noteworthy that two pathways lead
to product 21, whereas only one generates structures 17 and
18. To obtain the product of interest, the reaction may thus
be tuned accordingly (Table 1).
Employing allylbissilane 12a in our cascade reaction
yielded a 1:3.2 mixture of compounds 18 and 21 as major
products (Table 1, entry 1). Changing the retro-ene reaction
conditions to a more acidic buffer system led to the isolation
of 21 as the only product (Table 1, entry 2).[15,16] Products of
Table 1. Results of the bidirectional SO2-oxyallylation cascade reaction of achiral or chiral dienes 1 and allylbissilanes 12 to give symmetrical products
17.
Entry
Diene 1
X
R1
R2
Bissilane 12
Y
Ratio 1/12
Cat.
Solvent
“H+”
17 [%]
18 [%]
21 [%]
1
2
3
4
5
6
1c
(S)-1a
1d
(R)-1e
(S)-1 f
(R)-1e
H
Me
H
Me
Me
Me
Me
Me
Me
H
Me
H
Ph
Ph
Me
Ph
iPr
Ph
12a
12a
12b
12c
12c
12c
SiMe3
SiMe3
SiBu3
SiMe2Ph
SiMe2Ph
SiMe2Ph
1:3
1:3
1:3
1:1
1:3
2.5:1
TMSOTf
TMSOTf
TMSOTf
Tf2NTMS
TMSOTf
Tf2NTMS
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
A
B
A
B
A
B
<5
–
traces
–
19 (rac)[b]
61 (rac)[b]
–
74[a,b]
44 (rac)[b]
–
–
13
55 (ent)[c,d]
37
–
–
34 (ent)[c]
<5 (ent)[c]
[a] This result has been previously published, see Turks et al.[10] [b] A racemic mixture of the two enantiomers of this compound was obtained. [c] The
opposite enantiomer than the one shown was obtained. [d] This result has been previously published, see Vogel et al.[7]
Scheme 4. Possible reaction pathways for a SO2-induced one-pot, two-directional oxyallylation cascade. R=alkyl; R1 =H, Me; R2 =alkyl, phenyl; R*=1-
arylethyl chiral auxiliary.
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Concise Synthesis of Polypropionates
FULL PAPER
a bidirectional SO2-induced oxyallylation were only ob-
served in trace amounts, indicating that rapid consumption
of allylsilane intermediate 13 occurred through sila-ene re-
action with SO2 (Scheme 2). We anticipated that silyl groups
larger than trimethylsilyl might retard these sila-ene reac-
tions and found that with larger silyl groups, such as tri-n-
butylsilyl (12b) and dimethylphenylsilyl (12c), the isolation
of advanced allylsilyl products 18 did indeed become possi-
ble (Table 1, entries 3 and 4). Subsequently, with bissilane
12c, two successive oxyallylation reactions were also viable,
giving C2-symmetric compounds 17 as the major products
(Table 1, entries 5 and 6). We observed that an excess of bis-
silane was generally needed for 2-methyl-substituted 1,3-
dioxy-1,3-dienes 1a–d and 1 f (R1 =Me) in contrast to un-
substituted 1e (R1 =H), presumably due to the lower reac-
tivity of the former.
11 was obtained in a slightly increased yield of 54%. In nei-
ther case were symmetrical products of type 17 observed
(Scheme 4).[19]
Much lower yields were observed for 11 when the order
of addition of dienes 1a and 1b was reversed. Following the
reasoning given above, these findings can be interpreted in
terms of diene 1b being more reactive than diene 1a. We at-
tribute this to the higher reactivity of the intermediate 1-
oxyallyl cationic species 3b compared with that of 3a
(Scheme 6).[5,6] Presumably, the electron-withdrawing aryl
Once good conditions for obtaining 17 and 18 were estab-
lished, we then explored the generation of nonsymmetrical
scaffolds in one-pot operations using two different dienes 1
in succession. We hypothesized that it would be advanta-
geous in this process if a less reactive diene 1 was first react-
ed with the highly reactive allylbissilane 12 to give the cor-
responding allylsilane intermediate 13 with decreased reac-
tivity. The latter compound should then react more easily
with a more reactive diene 1’. Thus, optimization of the re-
action conditions regarding the order of diene addition, the
reaction time between diene additions, the type of Lewis
acid promoter, and allylbissilane were carried out. We found
that when diene (S)-1a and allylbissilane 12c (Y=
SiMe2Ph)[17] were allowed to react first with SO2 and trime-
thylsilyl trifluoromethanesulfonate (TMSOTf) for 6 h, and
then diene (R)-1b was added and the mixture was stirred
for 18 h, the pseudo-CS-symmetrical (4R,5R,9S,10S)-config-
ured product 11 was obtained in 50% yield (Scheme 5).
When the same procedure was used with bissilane 12d (Y=
SiMePh2)[18] and diene (S)-1a, and the reaction was allowed
to proceed for 8 h before adding diene (R)-1b, compound
Scheme 6. Intermediate ion-pairs.
group in 3b makes the intermediate less stable and thus
more reactive. Hence, the more favorable process involves
reaction of less reactive diene 1a with highly reactive bissi-
lane 12 to give the corresponding intermediate 13, which
then undergoes addition to the more reactive cationic inter-
mediate 3b, generating the desired product 11.
When using dienes (R)-1a and (R)-1b, pseudo-C2-sym-
metric (4R,5R,9R,10R)-stereoisomer 23 was obtained in
38% yield (Scheme 5).[20] This result strengthens the as-
sumption that the stereochemical outcome of the SO2-in-
duced double chain elongation also follows the empirical
rule already established in many previously reported oxyal-
lylation sequences; the chiral auxiliary of each diene sepa-
rately dictates the facial selectivity of the hetero-Diels–
Alder addition of SO2 to the diene followed by a stereose-
À
lective C C bond-forming p-nucleophile attack, which sets
the two new chiral centers in one oxyallylation. After hy-
drolysis of the obtained silylsulfinate, a retro-ene reaction
through a chair-like transition state takes place that results
in a chirality transfer from the sulfinic acid-bearing chiral
center to the carbon adjacent to the carbon bearing the
chiral auxiliary. This leads to the stereochemical like-rela-
tionship (R,R or S,S configuration) between the benzylic
center of the chiral auxiliary and the adjacent carbon center
(C5 or C9) as well as the C4 and C10 stereocenters.[21]
The yields obtained for 11 and 23 by using the one-pot
process (54 and 38% for 11 and 23, respectively, Scheme 5)
are comparable to, if not even better than, the yields ob-
tained by using the stepwise procedure (55 and 30%, over
three steps, based on the recovery of starting material,
Scheme 2), and are excellent considering the complexity of
the products. In one step, scaffolds containing a 13-mem-
bered carbon chain with four newly created stereocenters
can be constructed. With this one-pot procedure, the
Scheme 5. One-pot, two-directional chain elongation for formation of
pseudo-CS- and -C2-symmetrical products 11 and 23, respectively. Re-
agents and conditions: i) (S)- or (R)-1a (2 equiv), 12c or 12d (4 equiv),
SO2, TMSOTf (0.8 equiv), toluene, À788C, 8 h; ii) (R)-1b (1 equiv),
À788C, overnight; iii) Pd
ACTHUNGTREN(NUNG OAc)2, PPh3, K2CO3, iPrOH, MeCN, reflux,
20 min. 12c: Y=SiMe2Ph, 12d: Y=SiMePh2, Ar=p-C6H4CF3.
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P. Vogel et al.
number of synthetic transformations can be reduced from
three to two, and the number of practical steps from three
to one, decreasing not only the time required for product
synthesis but also reducing the amount of waste and the
time required for purification.
With the pseudosymmetrical products in hand, we investi-
gated their desymmetrization through selective deprotection
of the chiral 1-arylethyl ethers. As expected, the SN1 heter-
olysis of the 1-phenylethoxy moiety in 11 took place faster
than that of its 4-CF3-phenylethoxy moiety. Thus, chemose-
lective monodebenzylation of 11 was achieved by treatment
with BCl3 and pentamethylbenzene[22] giving alcohol 24 in
76% yield (Scheme 7). The latter alcohol reacted with lithi-
um hexamethyldisilazide (LiHMDS) to give enolate 26
through transesterification of alcoholate 25; hydrolysis yield-
ed ketone 27.
Scheme 8. First chain elongation of 24 through chemoselective aldol reac-
tion. Reagents and conditions: a) i) LiHMDS, THF, À788C; ii) isobutyral-
dehyde, 72% (1.7:1 mixture of isomers 28 and 28’); b) i) LiHMDS, THF,
À788C; ii) TMSCl, Et3N, quant.; c) isobutyraldehyde, BF3·OEt2, CH2Cl2,
À788C, 72% (corrected yield). Ar=p-C6H4CF3.
Scheme 7. Selective deprotection of pseudo-CS-symmetrical compound 11
and its elaboration. Reagents and conditions: a) BCl3, PMB, CH2Cl2,
À788C, 76%; b) i) LiHMDS, THF, À788C; c) NH4Cl (aq.), 91%. Ar=p-
C6H4CF3, PMB=pentamethylbenzene.
Lithium enolate 26 may also be quenched with an alde-
hyde. For instance, treatment of alcohol 24 with base and
addition of isobutyraldehyde, resulted in the formation of a
1.7:1 mixture of two aldols, the major one being 28
(Scheme 8). Quenching enolate 26 with trimethylsilyl chlo-
ride gave (Z)-enoxysilane 29, which underwent stereoselec-
tive Mukaiyama aldol reaction with isobutyraldehyde, giving
aldol product 28 selectively.
Scheme 9. Confirmation of the absolute and relative stereochemical rela-
tionship at C12 and C13. Reagents and conditions: a) 1) Et2BOMe/
NaBH4, MeOH/THF, À788C; 2) NaHCO3/H2O2, MeOH, 58C, 83 % ;
b) Me2CACTHNUGTRNE(NUG OMe)2, p-TsOH, 258C, quant.; c) (R)- or (S)-MPA-OH, DCC,
Reduction of b-hydroxy ketone 28 to diol 30 under Nara-
sakaꢄs conditions[23] and subsequent acetonide formation
produced stereopentad 31, the structure of which was con-
firmed by NMR analysis (Scheme 9).[24] The six-membered
acetonide moiety of 31 was shown to be syn-configured by
the 13C NMR chemical shifts of its two methyl groups (d=
19.7 and 30.2 ppm) and of the quarternary carbon (d=
98.7 ppm). Assuming a chair-like conformation is adopted,
measurements of the coupling constants of protons H11,
H12, and H13 revealed an all syn-relationship. The absolute
configuration at C13 of aldol 28 was confirmed by the
Mosher method: careful analysis and comparison of the
1H NMR spectra of the corresponding (R)- and (S)-a-me-
thoxyphenylacetates (R)-32 and (S)-32, which were prepared
by esterification of alcohol 28 with (R)- and (S)-a-methoxy-
phenylacetic acid (MPA-OH), respectively, established the
(R)-configuration at C13.[25,26]
DMAP, CH2Cl2, 258C, 41% (S)-31, 54% (R)-31. Ar=p-C6H4CF3, DCC=
N,N’-dicyclohexylcarbodiimide,
DMAP=4-(N,N-dimethylamino)pyri-
dine.
Enol benzoate 31 was treated with MeLi·LiBr to yield the
corresponding lithium enolate, which was quenched with al-
dehyde 33[27] to give the single diastereomeric aldol product
34 (Scheme 10). Reduction of the latter under Evansꢄ condi-
tions[28] provided 4,6-anti-diol 35, which was transformed
into the corresponding 4,6-acetonide 36. 13C NMR spectro-
scopic analysis of 36 confirmed the formation of an anti-diol
(d=23.9, 24.0, 100.4 ppm). Rotating frame nuclear Over-
hauser enhancement spectroscopic (ROESY) analysis estab-
lished the 4,5-syn-5,6-anti-relationship and thus the
(4S,5R,6S)-configuration in 36.[25]
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Concise Synthesis of Polypropionates
FULL PAPER
Conclusion
The chemistry developed here shows that complex long-
chain polyketide and polypropionate fragments can be pro-
duced quickly through two consecutive SO2-promoted oxyal-
lylations of bissilanes 12c or 12d, using enantiomerically en-
riched dienes 1. In one-pot operations, C13-membered scaf-
folds containing four newly created stereogenic centers are
obtained. So far, the two enantiomers of (4R,5R,9R,10R)-
and (4R,5R,9S,10S)-stereoisomers are available. Our prod-
ucts are ready for two simultaneous or successive aldol reac-
tions, thus realizing an efficient dissymmetric, two-direction-
al chain elongation approach to the synthesis of advanced
polyketide and polypropionate fragments. The method
should allow wide chemo- and stereodiversity and thus
should produce libraries of compounds that are structurally
related to many natural compounds of biological and/or me-
dicinal interest.
Experimental Section
The general methods are described in the Supporting Information.
Compound 11: A solution of TMSOTf (0.040 mL, 0.220 mmol, 1.2 equiv.)
in toluene (0.5 mL) was cooled to À1968C with liquid nitrogen and SO2
(ca. 0.5 mL) was condensed into the mixture, which was then allowed to
Scheme 10. Second chain elongation through aldol reaction. Reagents
and conditions: a) i) MeLi·LiBr, Et2O/DME; ii) 33, 73%; b) Me4NBH-
A
ACHTUNGRTEN(NUNG OMe)2, camphorsulfonic acid
melt at À788C.
A mixture of diene (S)-1a (118 mg, 0.366 mmol,
2.1 equiv.) and allylbissilane 12c (348 mg, 0.7 mmol, 1.9 equiv) in toluene
AHCTUNGTRENNUNG
(0.2 mL) was added dropwise. The reaction mixture turned yellow and
was stirred at À788C for 6 h.
A solution of diene (R)-1b (71 mg,
0.176 mmol, 1.0 equiv) in toluene (0.1 mL) was added and the reaction
was stirred for 15 h at À788C. SO2 was evaporated for 1 h at À788C, then
the residue was evaporated to dryness by warming the reaction flask to
258C under vacuum. The residue was dissolved in MeCN (0.5 mL) and
The 2,4-syn relationship of 34, and thus the (2R,4S)-con-
figuration, was established from the corresponding 2,4-(p-
methoxybenzylidene) acetal 37 obtained by 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) mediated oxidation of
the p-methoxybenzyl (PMB) ether of 34 (Scheme 11). Anal-
ysis of the ROESY NMR spectrum revealed interactions be-
tween the protons H2 and H4 with each other as well as
with the benzylidene proton.[25]
transferred by using a cannula into a mixture containing PdACHTUNGTRENNUNG(OAc)2
(4.3 mg, 0.02 mmol, 0.1 equiv), PPh3 (4.7 mg, 0.02 mmol, 0.1 equiv.),
K2CO3 (15 mg, 0.11 mmol, 0.6 equiv.), and MeCN (0.7 mL). iPrOH
(0.5 mL) was added and the mixture was heated to reflux for 20 min.
After cooling to 258C, the reaction mixture was poured into sat. aq.
NaHCO3 (2 mL) and extracted with EtOAc (3ꢅ2 mL). The combined or-
ganic phases were again washed with sat. aq. NaHCO3 (5 mL) and brine
(5 mL), dried (MgSO4), and evaporated. The crude product was purified
by flash chromatography (PE/EtOAc) to give 11 (68 mg, 0.085 mmol,
50%) as a colorless oil.
When bissilane 12d (320 mg, 0.7 mmol) was used instead of 12c, and
diene (R)-1b (35 mg, 0.089 mmol) was added after 8 h instead of 6 h of
stirring at À788C, adduct 11 was obtained in 54% yield. Rf =0.50 (PE/
1
EtOAc, 4:1); [a]2D5 =À3 (c=0.30 in CHCl3); H NMR (400 MHz, CDCl3):
d=1.08 (t, 3J=7.1 Hz, 6H; 4-CH3, 10-CH3), 1.29, 1.31 (2ꢅd, 3J=6.8 Hz,
6H; 2’-CH3, 2’’-CH3), 1.53, 1.55 (2ꢅd, 3J=6.8 Hz, 6H; 1-CH3, 13-CH3),
1.71–1.81 (m, 2H; 6-CH2a, 8-CH2a), 1.97–2.04 (m, 2H; 6-CH2b, 8-CH2b),
2.96 (br., 2H; 4-CH, 10-CH), 3.43, 3.49 (2ꢅm, 2H; 5-CH, 9-CH), 4.37,
4.42 (2ꢅq, 3J=6.2 H, 2Hz; 1’-CH, 1’’-CH), 4.65 (d, J=7.4 Hz, 2H; =
CH2), 5.21 (q, 3J=6.5 Hz, 2H; 2-CH, 12-CH), 6.95–7.04 (m, 5H; CHPh.),
7.12 (d, 3J=8.0 Hz, 2H; o-CHAr), 7.19 (d, 3J=8.0 Hz, 2H; m-CHAr),
7.39–7.45 (m, 4H; m-CHBz), 7.61, 7.62 (2ꢅt, 2H; p-CHBz), 7.96, 7.97 ppm
(2ꢅt, 4H; o-CHBz); 13C NMR (100.6 MHz, CDCl3): d=10.9, 11.0, 11.1,
11.1 (4ꢅq, 1-CH3, 4-CCH3, 10-CCH3, 6’-CH3), 23.8, 23.9 (2ꢅq, 2’-CH3,
2’’-CH3), 36.3, 36.4 (2ꢅt, 6-CH2, 8-CH2), 38.6, 38.7 (2ꢅd, 4-CH, 10-CH),
74.1, 74.8 (2ꢅd, 1’-CH, 1’’-CH), 75.9, 76.1 (2ꢅd, 5-CH, 9-CH), 111.9,
Scheme 11. Confirmation of relative stereochemical relationship between
C(2) and C(4) in 34. Reagents and conditions: a) 1) DDQ, 4 ꢆ MS,
CH2Cl2; 2) PPTS, CH2Cl2, 23% (over two steps). Ar=p-C6H4CF3,
PMB=p-methoxybenzyl, PMP=p-methoxyphenyl, DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone, PPTS=pyridinium p-toluenesulfonate.
112.0 (2ꢅd, 2-CH, 12-CH), 114.6 (t, =CH2), 124.9 (q, JACTHNUTRGNE(NUG C,F)=3.5 Hz; m-
CHAr), 127.0, 127.2, 127.3 (3ꢅd, o-CHPh, p-CHPh, o-CHAr), 128.0 (d, m-
CHPh), 128.5, 128.6 (2ꢅd, m-CHBz), 129.6, 129.8 (2ꢅs, i-CBz), 129.9, 130.1
(2ꢅd, o-CHBz), 133.3, 133.6 (2ꢅd, p-CHBz), 143.2 (s, C-7), 145.1 (s, i-CPh),
Chem. Eur. J. 2011, 17, 4246 – 4253
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4251

P. Vogel et al.
147.6 (s, i-CAr), 150.4, 150.6 (2ꢅs, C-3, C-4’), 164.2, 164.3 ppm (2 s,
(d, o-CHAr), 128.5, 128.6 (2ꢅd, m-CHBz), 129.2, 129.4 (2ꢅs, i-CBz), 129.8,
130.1 (2ꢅd, o-CHBz), 133.5, 133.6 (2ꢅd, p-CHBz), 144.5 (s, C-7), 147.2 (s,
i-CAr), 149.5, 149.9 (2ꢅs, C-3, C-4’), 164.1, 165.0 ppm (2ꢅs, C(O)Ph), p-
CAr and CF3 could not be identified due to multiplet splitting; IR (film):
˜
C(O)Ph); IR (film): n=3063 (w, CHAr.), 2975 (m, CHaliph.), 2928 (w,
CHaliph.), 2323 (w), 1731 (s, C=O), 1601 (w, C=C), 1452 (m, CHalkyl), 1325
À
À
À
(w), 1259 (w, C-OR), 1165 (s, C F), 1124 (s, C O), 1091 (w, C O), 1067
(w, C O), 1026 (m), 972 (w), 842 (w, CHAr.1,4-subst.), 710 (w), 631 cmÀ1 (m);
n=3507 (br, OH), 3063 (w, CHAr.), 2974 (m, CHaliph.), 2921 (w, CHaliph.),
À
˜
HRMS (ESI): m/z calcd for C47H52O6F3+: 769.3711 [M+H+]; found:
1720 (s, C=O), 1601 (w, C=C), 1451 (m, CHalkyl), 1323 (s), 1249 (w, C
À
À
À
À
À
769.3729.
OR), 1162 (s, C F), 1121 (s, C O), 1089 (w, C O), 1065 (w, C O), 1025
(m), 968 (w), 841 (w, CHAr.1,4-subst.), 706 cmÀ1 (w); HRMS (ESI): m/z calcd
for C39H44O6F3+: 665.3090 [M+H+]; found: 665.3077; elemental analysis
calcd (%) for C39H43O6F3 (664.75): C 70.47, H 6.52, F 8.57, O 14.44;
found: C 70.44, H 6.60.
(2Z,4R,5R,9R,10R,11Z)-4,10-dimethyl-7-methylidene-5-[(1R)-1-phenyle-
thoxy]-9-{(1R)-1-[4-(trifluoromethyl)phenyl]ethoxy}trideca-2,11-diene-
3,11-diyl dibenzoate (23): Using the same procedure described for 11, re-
acting bissilane 12d (205 mg, 0.45 mmol) and diene (R)-1a (62 mg,
0.192 mmol), diene (R)-1b (40 mg, 0.102 mmol) was added after 7 h of
stirring at À788C. Product 23 was obtained in 38% yield. Rf =0.51 (PE/
EtOAc, 4:1); [a]2D5 =+23 (c=0.12 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.06 (d, 3J=6.8 Hz, 6H; 4-CH3, 10-CH3), 1.31, 1.34 (2ꢅd,
3J=6.5 Hz, 6H; 2’-CH3, 2’’-CH3), 1.46 (d, 3J=6.8 Hz, 6H; 1-CH3, 13-
CH3), 1.72–1.80 (2ꢅdd, 3J=3.1 Hz, 2J=7.4 Hz, 2H; 6-CH2a, 8-CH2a),
1.83–1.91 (2ꢅdd, 3J=4.3 Hz, 2J=9.2 Hz, 2H; 6-CH2b, 8-CH2b), 2.80, 2.85
(2Z,4R,5R,9S,10S)-4,10-Dimethyl-7-methylidene-11-oxo-5-{(1R)-1-[4-(tri-
fluoromethyl)phenyl]ethoxy}tridec-2-ene-3,9-diyl dibenzoate (27): Alco-
hol 24 (23 mg, 0.034 mmol) was dissolved in THF (0.3 mL) and cooled to
À788C. LiHMDS (1m in THF, 0.04 mL, 0.040 mmol, 1.1 equiv) was
added and the mixture was stirred for 35 min. The mixture was poured
into ice-cold sat. aq. NH4Cl (1 mL), the phases were separated and the
aqueous phase was extracted with Et2O (3ꢅ3 mL). The combined organ-
ics layers were dried (MgSO4) and evaporated, and the crude product
was purified by flash chromatography (PE/EtOAc) to give 27 (19 mg,
0.029 mmol, 85%) as a colorless oil. Rf =0.35 (PE/Et2O, 2:1); [a]2D5 =+14
(c=0.12 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.02 (t, 3J=7.2 Hz,
3H; 13-CH3), 1.11, 1.12 (2ꢅd, 3J=6.9 Hz, J=6.9 Hz, 6H; 10-CCH3, 3’-
3
3
3
(2ꢅm, 2H; 4-CH, 10-CH), 3.35, 3.42 (2ꢅddd, J=3.4 Hz, J=3.8 Hz, J=
9.0 Hz, 2H; 5-CH, 9-CH), 4.40, 4.44 (2ꢅq, 3J=6.2 Hz, 2H; 1’-CH, 1’’-
CH), 4.65 (s, 2H; =CH2), 5.16 (q, 3J=6.8 Hz, 2H; 2-CH, 12-CH), 7.02–
7.11 (m, 5H; CHPh.), 7.18 (d, 3J=8.0 Hz, 2H; o-CHAr), 7.28 (d, 3J=
8.3 Hz, 2H; m-CHAr), 7.41 (t, 3J=7.4 Hz, 4H; m-CHBz), 7.60 (t, 3J=
7.4 Hz, 2H; p-CHBz), 7.95 ppm (t, 3J=8.3 Hz, 4H; o-CHBz); 13C NMR
(100.6 MHz, CDCl3): d=11.0, 11.4, 11.9 (3ꢅq, 1-CH3, 4-CCH3, 10-CCH3,
13-CH3), 23.7, 23.8 (2ꢅq, 2’-CH3, 2’’-CH3), 37.0, 37.2 (2ꢅt, 6-CH2, 1’-
CH2), 39.6, 39.8 (2ꢅd, 4-CH, 3’-CH), 74.5, 74.9 (2ꢅd, 1’-CH, 1’’-CH),
75.2, 75.7 (2ꢅd, 5-CH, 9-CH), 112.0, 112.3 (2ꢅd, 2-CH, 12-CH), 114.7 (t,
3
3
CCH3), 1.31 (d, J=6.2 Hz, 3H; 2’-CH3), 1.51 (d, J=6.8 Hz, 3H; 1-CH3),
2.10–2.16 (m, 3H; 6-CH2a, 8-CH2), 2.30 (dd, AB-system, 3J=2.4 Hz, 3J=
14.8 Hz, 1H; 8-CH2b), 2.52 (dq, 4J=1.7 Hz, 3J=7.2 Hz, 2H; 12-CH2),
3
3
2.94–2.99 (m, 2H; 4-CH, 10-CH), 3.46 (td, J=3.8 Hz, J=8.2 Hz, 1H; 5-
CH), 4.44 (q, 3J=6.2 Hz, 1H; 1’-CH), 4.67, 4.76 (2ꢅs, 2H; =CH2), 5.24
(q, 3J=6.9 Hz, 1H; 2-CH), 5.45 (ddd, 3J=3.1 Hz, 3J=5.8 Hz, 3J=8.9 Hz,
1H; 9-CH), 7.14, 7.19 (2ꢅd, 3J(o-Ar,m-Ar)=8.4 Hz, 4H; CHAr), 7.38–
7.43 (m, 4H; m-CHBz), 7.54, 7.57 (2ꢅt, 3J(p-Ar,m-Ar)=7.6 Hz, 2H; p-
CHBz), 7.92, 7.97 ppm (2ꢅd, 3J(o-Ar,m-Ar)=7.2 Hz, 4H; o-CHBz);
13C NMR (100.6 MHz, CDCl3): d=7.8 (q, 13-CH3), 10.9, 11.0 (2ꢅq, 4-
CCH3, 1-CH3), 12.2 (q, 10-CCH3), 23.8 (q, 2’-CH3), 35.1 (t, 12-CH2), 36.2
(t, 6-CH2), 38.2 (t, 8-CH2), 38.6 (d, 4-CH), 49.7 (d, 10-CH), 73.7 (d, 9-
CH), 74.2 (d, 1’-CH), 76.2 (d, 5-CH), 112.5 (d, 2-CH), 115.4 (t, =CH2),
=CH2), 124.8 (q, 3J
ACHTUNGTRENNUNG(C,F)=3.6 Hz; m-CHAr), 127.0, 127.1 (2ꢅd, o-CHPh,
o-CHAr), 127.3 (p-CHPh), 127.9 (d, m-CHPh), 128.4, 128.5 (2ꢅd, m-CHBz),
129.5, 129.6 (2ꢅs, i-CBz), 129.8, 129.9 (2ꢅd, o-CHBz), 133.2, 133.4 (2ꢅd,
p-CHBz), 143.2 (s, C-7), 147.7 (s, i-CPh), 150.0, 150.3 (2ꢅs, C-3, C-4’),
164.0 ppm (s, C(O)Ph), p-CAr and CF3 could not be identified; IR (film):
n˜ =3065 (w, CHAr.), 3033 (w, CHAr.), 2974 (m, CHaliph.), 2922 (w, CHaliph.),
2322 (w), 1727 (s, C=O), 1601 (w, C=C), 1451 (m, CHalkyl), 1368 (w), 1323
À
À
À
À
(w), 1247 (w, C OR), 1162 (s, C F), 1122 (s, C O), 1086 (w, C O), 1065
À
125.0 (q, JACHTNUGTRENUNG(C,F)=3.7 Hz; m-CHAr), 127.2 (d, o-CHAr), 128.5, 128.7 (2ꢅd,
m-CHBz), 129.5 (s, i-CBz), 129.7, 129.9 (2ꢅd, o-CHBz), 130.3 (s, i-CBz),
133.1, 133.6 (2ꢅd, p-CHBz), 142.9 (s, i-CAr), 150.1 (s, C-7), 164.2, 165.7
(w, C O), 1025 (m), 971 (m), 888 (m), 841 (m, CHAr.1,4-subst.), 760 (w), 700
(w), 608 cmÀ1 (m); HRMS (ESI): m/z calcd for C47H51F3O6Na+: 791.3535
[M+Na+]; found: 791.3566; elemental analysis calcd (%) for C47H51F3O6
(768.90): C 73.42, H 6.69, F 7.41, O 12.4; found: C 73.64, H 6.62.
˜
(2ꢅs, C(O)Ph), 211.8 ppm (s, C-3); IR (film): n=3068 (w, CHAr.), 2975
(m, CHaliph.), 2928 (w, CHaliph.), 1720 (s, C=O), 1601 (w, C=C), 1451 (m,
(2Z,4R,5R,9S,10S,11Z)-11-(Benzoyloxy)-9-hydroxy-4,10-dimethyl-7-
methylidene-5-{(1R)-1-[4-(trifluoromethyl)phenyl]ethoxy}trideca-2,11-
dien-3-yl benzoate (24): Product 11 (740 mg, 0.96 mmol, 1.0 equiv) and
pentamethylbenzene (428 mg, 2.89 mmol, 3 equiv) were dissolved in
CH2Cl2 (7.4 mL) and cooled to À788C. BCl3 (1m in CH2Cl2, 1.92 mL,
1.92 mmol, 2 equiv) was added dropwise and the solution turned yellow.
The reaction was stirred for 15 min (reaction monitored by TLC), then
aq. sat. NaHCO3 (10 mL) was added and the mixture was warmed to
room temperature. The phases were separated, the aqueous phase was
extracted with CH2Cl2 (3ꢅ10 mL) and the combined organic phases were
washed with brine (10 mL), dried (MgSO4), and evaporated. The residue
was purified by flash chromatography (PE/EtOAc) to give 15 (485 mg,
76%) as a colorless oil. Rf =0.33 (PE/EtOAc, 4:1); [a]2D5 =+19 (c=0.15
in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.01 (d, 3J=7.1 Hz, 3H; 4-
À
À
À
CHalkyl), 1325 (ss), 1261 (ss, C OR), 1165 (s, C F), 1123 (s, C O), 1093
À
À
(ss, C O), 1067 (ss, C O), 1026 (m), 972 (m), 843 (m, CHAr.1,4-subst.), 779
(m), 711 cmÀ1 (m); HRMS (ESI): m/z calcd for C39H43F3O6Na+: 687.2910
[M
+
Na+]; found: 687.2870; elemental analysis calcd (%) for
C39H43F3O6 (664.75): C 70.47, H 6.52, F 8.57, O 14.44, found: C 70.05, H
6.76.
Acknowledgements
We thank the Swiss National Science Foundation (Bern) and the Roche
Research Foundation for financial support. Furthermore, we are very
grateful to M. Rey, Dr. L. Menin, and F. Sepulveda for technical support.
CH3), 1.14 (d, 3J
6.5 Hz, 3H; 2’-CH3), 1.50, 1.52 (2ꢅd, 3J=6.8 Hz, 6H; 1-CH3, 13-CH3),
1.78 (dd, 3J=9.6 Hz, 2J=14.2 Hz, 1H; 6-CH2a), 2.12 (d, 2J
(1’a,b)=
14.2 Hz, 1H; 1’-CH2b), 2.14 (d, 2J=13.9 Hz, 1H; 8-CH2a), 2.26 (dd, 3J=
ACHTUNGTRENNUNG ACHUTNGTREN(NGUN 2’,1’)=
(4-Me,4)=7.1 Hz, 3H; 10-CH3), 1.30 (d, 3J
AHCTUNGTRENNUNG
[1] For reviews on natural polypropionates, see: a) I. Paterson, G. J.
Florence, Eur. J. Org. Chem. 2003, 2193–2208; b) J. Darias, J. Cueto,
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2
3
2.8 Hz, J=13.9 Hz, 1H; 8-CH2b), 2.37 (pent, J=7.1 Hz, 1H; 4-CH), 2.96
(br., 1H, 10-CH), 3.15 (br., 1H, OH), 3.47–3.50 (m, 2H, 5-CH, 9-CH),
3
3
4.46 (q, J=6.5 Hz, 1H; 1’-CH), 4.75, 4.81 (2ꢅs, 2H; =CH2), 5.24 (q, J=
3
3
6.8 Hz, 1H; 2-CH), 5.31 (q, J=6.8 Hz, 1H; 12-CH), 7.14, 7.17 (2ꢅd, J=
8.3 Hz, 4H; CHAr), 7.42, 7.48 (2ꢅdd, 3J=7.4 Hz, 3J=8.0 Hz, 4H; m-
CHBz), 7.61, 7.62 (2ꢅdd, 3J=7.4 Hz, 3J=7.7 Hz, 2H; p-CHBz), 7.96,
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Kernen, M. Bialecki, Pure Appl. Chem. 1996, 68, 719–722; b) O.
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Meyer, N. Blanchard, M. Deffosseux, J. Cossy, Acc. Chem. Res.
8.12 ppm (2ꢅd, J=8.3 Hz, 4H; o-CHBz); 13C NMR (100.6 MHz, CDCl3):
3
d=10.9, 11.0, 11.1 (3ꢅq, 1-CH3, 4-CCH3, 13-CH3), 14.2 (q, 10-CCH3),
23.7 (q, 2’-CH3), 36.6 (t, 8-CH2), 38.5 (d, 10-CH), 40.5 (t, 6-CH2), 45.7 (d,
4-CH), 71.5 (d, 5-CH), 74.1 (d, 1’-CH), 75.9 (d, 9-CH), 112.3, 113.9 (2ꢅd,
3
2-CH, 12-CH), 114.3 (t, =CH2), 124.8 (q, J
N
4252
www.chemeurj.org
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4246 – 4253

Concise Synthesis of Polypropionates
FULL PAPER
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Received: November 12, 2010
Published online: March 8, 2011
Chem. Eur. J. 2011, 17, 4246 – 4253
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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