One-Step Homologation for the Catalytic Asymmetric Synthesis of Deoxypropionates

Article abstract of DOI:10.1002/chem.201604478

A one-step homologation protocol for the synthesis of natural products containing deoxypropionate motif is described by the combination of Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)-Pd-catalyzed vinylation and ZACA–oxidation reaction. In contrast to most other synthetic strategies used to date that typically require three steps per deoxypropionate unit due to the functional-group interconversions, our one-step homologation strategy promises to provide a general and more efficient synthetic route toward deoxypropionate natural products as exemplified by significant improvements in the syntheses of intermediates and/or final products of mycolipenic acid 1 and its analogue 2, (?)-rasfonin, and syn- and anti-dicarboxylic acids 5 and 6.

Full text of DOI:10.1002/chem.201604478

A Journal of
Accepted Article
Title: One-step Homologation for the Catalytic Asymmetric Synthesis of
Deoxypropionates
Authors: Ei-ichi Negishi, Shiqing Xu, Haijun Li, Masato Komiyama, and
Akimichi Oda
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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To be cited as: Chem. Eur. J. 10.1002/chem.201604478
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One-step Homologation for the Catalytic Asymmetric Synthesis
of Deoxypropionates
†
†
Shiqing Xu, Haijun Li, Masato Komiyama, Akimichi Oda and Ei-ichi Negishi*
Dedicated to the memory of Professor Jean F. Normant
Abstract: A one-step homologation protocol for the synthesis of
natural products containing deoxypropionate motif is described by
the combination of ZACA–Pd-catalyzed vinylation and ZACA–
oxidation reaction. Contrastive to most other synthetic strategies
used to date that typically require 3 steps per deoxypropionate unit
due to the functional-group interconversions, our one-step
homologation strategy promises to provide a general and more
efficient synthetic route toward deoxypropionate natural products as
exemplified by significant improvements in the syntheses of
intermediates and/or final products of mycolipenic acid 1 and its
analogue 2, (‒)-rasfonin, syn- and anti-dicarboxylic acids 5 and 6.
Introduction
Deoxypropionate units, alternately methylated alkyl chain
containing multiple stereogenic centers, are ubiquitous structural
motifs found in a broad range of naturally occurring compounds
1
derived from polyketide pathways. Single deoxypropionate unit
Figure 1. Representative examples of natural products and bioactive
molecules containing deoxypropionate units.
(
1,3-dimethyl subunit) can be represented by two stereoarrays
corresponding to syn- and anti-orientations of the methyl groups
Figure 1). A wide range of fascinating biological activities and
(
pharmacological properties are associated with these structures,
Ir(I)-catalyzed asymmetric hydrogenation of enantio-enriched
and stereodefined trisubstituted allylic alcohols and derivatives.12
Recently, Aggarwal developed an assembly-line synthesis of
deoxypropionates via iterative homologation of boronic esters
with chiral lithiated benzoate esters and chloromethyllithium
2
e.g., neutral sphingomyelinase inhibitor (+)-scyphostatin, potent
3
squalene synthase inhibitor zaragozic acid A, antibiotics TMC-
5
1
51 A,4 pheromones (+)-4,6,8,10,16,18-hexamethyldocosane
6
7
and (‒)-lardolure , glycolipids of Mycobacterium tuberculosis, as
well as apoptosis inducer (‒)-rasfonin.8
(
Scheme 1d).13 Despite the tremendous progress, the majority of
In the light of the broad biological activities and abundance of
this motif found in natural products, substantial efforts have been
made to develop synthetic methods for the stereoselective
reported methods have to install temporary directing groups or
chiral auxiliaries to assist asymmetric C–C bond or C–H bond
formation that are to be removed later. Thus, these methods
suffer from long synthetic sequences and low efficiency requiring
several functional-group interconversions between chain-
growing steps (3–6 steps per unit) (Scheme 1a-c). Recently,
convergent strategies for the synthesis of the long-chain
9
construction of deoxypropionates. The most common methods
used to date are chiral auxiliary-controlled (aza)-enolate
alkylations and conjugate additions, as well as substrate-
controlled conjugate additions and allylic alkylations.10 In
addition to these stoichiometric approaches, catalytic
enantioselective methods have also been introduced. Minnaard
and Feringa reported an iterative catalytic route to
deoxypropionate subunits by Cu-catalyzed asymmetric
conjugate addition of Grignard reagents to α,β-unsaturated
thioesters.11 Burgess developed an iterative route based on
1
4
polydeoxypropionate motif have been reported. Most recently,
Nozaki developed
deoxypropionate
a
motif
novel one-step construction of
by stereo-controlled propylene
oligomerization.15 However, Nozaki’s elegant methodology
suffers from scope limitation (only all-syn deoxypropionate), and
difficulty of chain length control leading to multiple oligomers
mixtures with different number of deoxypropionate units.
Therefore, strategies for highly efficient and stereoselective
synthesis of deoxypropionate motif are still highly desirable.
[
a]
Dr. S. Xu, Dr. H. Li, M. Komiyama, A. Oda, Prof. Dr. E. Negishi
Herbert C. Brown Laboratories of Chemistry, Purdue University
560 Oval Drive, West Lafayette, Indiana 47907-2084, USA
Recently, we reported
a
highly convergent and
Fax: (+1) 765-494-0239
enantioselective route to polydeoxypropionates exemplified as
phthioceranic acid.14d Zr-catalyzed asymmetric carboalumination
of alkenes (ZACA) –Pd-catalyzed vinylation was used to
E-mail: negishi@purdue.edu
†
These authors contributed equally to this work
1
6
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
prepare smaller deoxypropionate fragments, and then two key
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oxidation with O
2
); (iii) use of alkene substances of one-point-
binding without requiring any directing groups (ability to repeat
ZACA reaction after one-pot ZACA–Pd-catalyzed vinylation to
realize one-step homologation synthesis of deoxypropionate
motif). In this paper we show that mycolipenic acid 1 and its
analogue 2, (‒)-rasfonin key intermediate 4, and syn- and anti-
dicarboxylic acids 5 and 6 (Figure 1) can be synthesized with
high efficiency and stereoselectivity by using our one-step
homologation protocol.
Results and Discussion
Our first two targets were mycolipenic acid 1 (side chain of
2
pentaacyltrehalose) and its analogue 2 (side chain of an Ac SGL
analogue).
sulfoglycolipid Ac
Pentaacyltrehalose
(PAT),17
diacylated
SGL,18 and polyacylated sulfoglycolipid SL-1
19
2
are three representative examples of cell-wall lipids exclusively
found in virulent strains of Mycobacterium tuberculosis.
Substantial studies revealed that these lipids can not only
potentially be used as biomarkers, but also are promising
candidates for new tuberculosis vaccines.1
7-20
The common
structural feature of these lipids is encompassing a trehalose as
a central carbohydrate, which is acylated with various long-chain
fatty acids, typically polymethylated chiral deoxypropionate
chains (Figure 1). However, low availability of these lipids limited
their further development as potential tuberculosis vaccines. The
main challenge in total synthesis of these lipids is highly efficient
and stereoselective synthesis of deoxypropionate side-chains.
Mycolipenic acid 1, the major acyl residue found in
pentaacyltrehalose, has been shown to be a potent inhibitor of
leukocyte migration in vitro.17,20 Mycolipenic acid 1 was first
synthesized and characterized by Polgar et al. in 1958 by a
lengthy route comprising a kinetic resolution.21 Minnikin and co-
workers synthesized 1 as a racemate in 1992.22 Recently,
Minnaard and Feringa reported a catalytic asymmetric synthesis
of mycolipenic acid
1 by using an iterative three-step
homologation procedure involving Cu-catalyzed asymmetric
conjugate addition of MeMgBr to α,β-unsaturated thioesters
Scheme 1. Strategies of the synthesis of deoxypropionate units.
(
Scheme 1a), which required 14 longest linear steps in 3%
overall yield from glycol.23
Our synthesis of mycolipenic acid 1 began with the ZACA
reaction of 1-eicocene. It has been reported that water as an
3
3
sequential Cu-catalyzed stereocontrolled sp –sp cross-coupling
reactions allowed convergent assembly of smaller building
blocks to build-up long polydeoxypropionate chains with
excellent stereoselectivity. In continuation of our efforts in the
development of efficient methods for the construction of
deoxypropionates, we report herein a one-step homologation
protocol (one step per deoxypropionate unit, Scheme 1e) for
additive significantly affects reaction rate, enantioselectivity, and
yield of ZACA reaction.14d,24 We decided to survey different
25
additives to optimize ZACA reaction. Consistent with previous
results,14d ZACA reaction of 1-eicocene did not occur in the
absence of an additive (Table 1, entry 1). After addition of
2
mol% of water, ZACA reaction proceeded smoothly and
provided desired (S)-2-methyl-1-eicosanol 7 of 77% ee in 71%
yield after in situ oxidation with O (entry 2). Similar to water, the
addition of MAO (methylaluminoxane) and IBAO
isobutylaluminoxane) produced 7 of 75% ee in 72% yield, and
highly
concise
and
enantioselective
synthesis
of
deoxypropionate natural products by the combination of ZACA–
Pd-catalyzed vinylation and ZACA–oxidation reaction, which is
contrastive to most other synthetic methods that require 3–6
steps per unit. This one-step homologation protocol heavily
relies on three key features of ZACA reaction: (i) catalytic
asymmetric C–C bond formation to introduce stereogenic carbon
centers; (ii) many potential transformations of the initially formed
alkylalane intermediates (i.e. in situ Pd-catalyzed vinylation, and
2
(
74% ee in 68% yield, respectively (entries 3 and 5). EAO
(
ethylaluminoxane) provided product 7 in 70% yield, but with a
decreased enantiopurity of 69% ee (entry 4). To our delight, the
use of 5 mol% TIBAO (tetraisobutyldialuminoxane) provided the
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desired alcohol 7 in 78% yield and 85% ee (entry 6). The
increased amount of TIBAO (10 mol%) led to
a lower
enantiopurity of 77% ee (entry 7). The exact mechanistic role of
water and aluminoxanes remain unclear. Presumably,
aluminoxanes can act as Lewis acid activators or co-activators
to assist the formation of the active cationic zirconium complex.
Table 1. Additive effect on the ZACA reaction of 1-eicocene.
Entry
Additive
none
Additive
Yield [%]a
ee [%]b
Scheme 2. Synthesis of mycolipenic acid 1. Reaction conditions: [a] (+)-
o
(
NMI)
Zn(OTf)
vinylbromide (6 equiv). [c] i) Et
2
ZrCl
2
(1 mol%), AlMe
3
(1.5 equiv), TIBAO (5 mol%), DCM, 0 C. [b] i)
1
2
3
4
5
6
7
none
0
NA
77
75
69
74
85
77
2
(1.2 equiv), DMF; ii) PdCl
2
(DPEPhos) (3 mol%), DIBAL-H (6 mol%),
H
2
O
2 mol%
5 mol%
5 mol%
5 mol%
5 mol%
10 mol%
71
72
70
68
78
79
o
3
SiCLi(Me)CH=NCy (1.3 equiv), ‒20 C; ii)
MAOc
EAOd
IBAOe
TIBAOf
TIBAOf
COOH (2 equiv), 0 oC; iii) H
O, 0 oC. [d] NaClO
CF
3
2
2
(1.4 equiv), NaH
2
PO
4
·H
2
O
t
o
(1.1 equiv), 2-methyl-2-butene (10 equiv), H
2
O/ BuOH, 23 C.
to carboxylic acid by Pinnick oxidation29 under very mild
conditions completed the total synthesis of mycolipenic acid 1 in
a
Isolated yield. b Determined by 1H NMR of Mosher ester analysis of
2
8% overall yield over 5 steps from 1-eicocene. There was no
sign of epimerization throughout these steps. Its spectral data as
well as [α] 26 = + 17.79o (c = 2.08, CHCl
) are in good
agreement with those reported previously.23
c
d
alcohol
e
7.
Methylaluminoxane.
Ethylaluminoxane.
Isobutylaluminoxane. f Tetraisobutyldialuminoxane.
D
3
With the optimized reaction conditions in hand, we began the
total synthesis of mycolipenic acid 1 as shown in Scheme 2.
The key intermediate 9 was synthesized by ZACA-based one-
step homologation strategy. 1-Eicocene was subjected to ZACA
To further demonstrate the utility of our ZACA-based one-step
homologation strategy for the synthesis of deoxypropionates, we
executed the synthesis of trimethyl-branched 2 as summarized
in Scheme 3. (+)-(4S,6S,8S,E)-2,4,6,8-Tetramethyltetracos-2-
reaction in the presence of (+)-(NMI)
2
ZrCl
2
(1 mol%),26 Me
3
Al
enoic acid 2 is the key side-chain of an Ac
2
SGL analogue 3
(
1.5 equiv), and TIBAO (5 mol%), providing a chiral isoalkylalane
which showed the most promising T-lymphocyte-activation
3
0
intermediate. This isoalkyldimethylalane, generated by ZACA
reaction, was directly used for Pd-catalyzed Negishi coupling
activity among a series of analogues (Figure 1). The chain
length has been shown to be of utmost importance for high
antigenicities. The previously reported synthesis of 2 used an
iterative hydrazone lithioenamine (azaenolate) alkylation of four-
step homologation protocol (Scheme 1b).30 Its major drawback
is the use of stoichiometric amounts of the expensive chiral
auxiliary three times as well as long synthetic sequences. In our
synthesis, the preparation of the key trimethyl-branched
intermediate 14 was achieved only in three steps from 1-
octadecene as shown in Scheme 3. 1-Octadecene was
subjected to two rounds of (+)-ZACA‒Pd-catalyzed vinylation
followed by a third (+)-ZACA reaction and in situ oxidation with
with vinyl bromide in the presence of Zn(OTf)
Pd(DPEphos)Cl /i-Bu AlH with DMF as the solvent. This one-pot
ZACA‒Pd-catalyzed vinylation process produced alkene (S)-8 in
0% GC yield after fast flash chromatography with hexane.
Without further purification, crude alkene 8 was subjected to a
second (+)-ZACA reaction followed by in situ oxidation with O to
2
and catalytic
2
2
7
2
afford the desired alcohol 9 (d.r. = 5.2/1) in 49% isolated yield.
After purification by ordinary silica gel column chromatography,
(
obtained in 34% yield over 2 steps from 1-eicocene (Scheme 2).
It should be noted that the previous synthesis of 9 required 11
longest linear steps (11% overall yield) from glycol.23
Swern oxidation27 of 9 produced aldehyde 10 in almost
quantitative yield. The crudely obtained aldehyde 10 was
2S,4S)-2,4-dimethyl-1-docosanol 9 (d.r. > 50/1, 97% ee) was
2
O . The crude alcohol 14 was thus obtained in 35% yield over
three steps from 1-octadecene containing minor amounts of
other diastereomers (d.r. = 18.6/1.6/2/1). This crude alcohol 14
could be purified by ordinary column chromatography to give a
pure 14 (>99% ee, d.r. > 40/1) in 15% yield from 1-octadecene.
After Swern oxidation, Corey-Peterson olefination, and Pinnick
2
8
subjected
Et
to
Corey-Peterson
olefination
with
3
SiCLi(Me)CH=NCy (in situ generated by treating N-
s
cyclohexyl(2-triethylsilylpropylidene)imine with BuLi at ‒78 °C).
oxidation, trimethyl-branched deoxypropionate 2 was thus
After treatment with CF
3
CO
2
H, the desired aldehyde 11 of >98%
synthesized in 12% yield over six steps from 1-octadecene.
In order to explore the scope of our ZACA-based one-step
homologation strategy, a key intermediate 4 in recently reported
syntheses of (‒)-rasfonin31 was chosen. (‒)-Rasfonin was
isolated from the fermented mycelium of Taleromyces species
E was obtained in 90% yield. In the previously reported
synthesis of mycolipenic acid 1, aldehyde 10 was converted to
the corresponding enoate ester by Wittig reaction with the
formation of 10% Z-isomer.23 Finally, conversion of aldehyde 11
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To further demonstrate its synthetic utility, one-step
homologation strategy was applied to the synthesis of syn- and
anti-dicarboxylic acids 5 and 6, identified as the metabolites in
human blood and urine,35 and the fatty components of Pollen
Typhae (a traditional Chinese herbal medicine widely used to
treat the hemorrhagic diseases both by external and oral
3
6
application) . The synthesis of syn- and anti-dicarboxylic acids
and 6 was summarized in Scheme 5. The (+)-ZACA reaction
5
of styrene proceeded smoothly with the addition of 1 equivalent
of water, followed by Pd-catalyzed vinylation, providing alkene
(
S)-19. Alkene (S)-19 was subjected to (‒)-ZACA and (+)-ZACA
reaction by using different enantiomer of (NMI) ZrCl catalyst,
producing anti-pamplefleur 20 (d.r = 11.4/1) and syn-pamplefleur
0 (d.r. = 3.6/1) in 47% and 43% yield from styrene, respectively.
2
2
2
Both crude anti- and syn-pamplefleur 20 can be purified by
ordinary column chromatography to remove the minor
diastereomer. It should be noted that the odor response of
pamplefleur isomers 20 is rather unusual in the realm of chiral
fragrances.37 All the four stereoisomers of pamplefleur 20 were
synthesized by using lipase-catalyzed kinetic resolution of
racemic primary alcohols from 2-phenyl-1-propanol in 6‒8 steps
and extremely low overall yield (<1%) due to the poor
enantioselectivity of the kinetic resolutions.37
Scheme 3. Synthesis of mycolipenic acid analogue 2. Reaction conditions
(a d) are the same as described in Scheme 2.
3
565-A1.31 Recent studies have indicated that (‒)-rasfonin is an
active apoptosis inducer in ras dependent cells, having potential
use for the development of novel cancer chemotherapeutics.32,33
Compound 4 was synthesized as an intermediate for the total
synthesis of (‒)-rasfonin in 2006 by Boeckman based on the use
of camphor lactam chiral auxiliaries in 12 steps (longest linear
sequence) from (‒)-camphoric acid,31a and in 2012 by Minnaard
in 12 steps from glycol,31b respectively. Our synthesis of 4 is very
simple as summarized in Scheme 4. Carbozirconation reaction
of 2-butyne with ZrCp
treatment with allylic ether, provided 1,4-diene 17 in 68% yield.
2 2
Cl and EtMgBr, followed by in situ
3
4
The ZACA reaction of 1-alkene 17 containing a proximal π-bond
was slower compared to those of alkenes without any other
functional groups, such as 1-eicocene and 1-octadecene. Such
difficulty was solved by the use of promotor MAO (5 mol%),
2 2
increased amount of (+)-(NMI) ZrCl catalyst (3 mol%), and
higher temperature (23 °C). Then after in situ Pd-cataylzed
vinylation, alkene 18 was subjected to a second (+)-ZACA
reaction followed by oxidation providing 4 (d.r = 4.2/1) in 85%
yield. The undesired diastereomer of 4 was removed by ordinary
column chromatography. Thus, 4 (d.r > 50) was synthesized in
22% yield over just 3 steps from 2-butyne.
Scheme 5. Synthesis of syn- and anti- dicarboxylic acids 5 and 6. Reaction
conditions: [a] i) Zn(OTf)
DIBAL-H (6 mol%), vinylbromide (6 equiv). [b] (‒)-(NMI)
(1.5 equiv), TIBAO (5 mol%), DCM. [c] (+)-(NMI)
equiv), TIBAO (5 mol%), DCM.
2
(1.2 equiv), DMF; ii) PdCl
2
(DPEPhos) (3 mol%),
ZrCl (2 mol%), AlMe
(2 mol%), AlMe (1.5
Scheme 4. Synthesis of (‒)-rasfonin key intermediate 4. Reaction conditions:
a] (+)-(NMI) ZrCl (3 mol%), AlMe
(1.5 equiv), MAO (5 mol%), DCM, 23 oC,
6 h. [b] i) Zn(OTf) (1.2 equiv), DMF; ii) PdCl (DPEPhos) (3 mol%), DIBAL-H
6 mol%), vinylbromide (6 equiv).
2
2
3
[
2
2
3
2
ZrCl
2
3
1
2
2
(
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Chemistry - A European Journal
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Anti- and syn-pamplefleur 20 were converted to their
corresponding iodide 21. Anti-21 was treated with 2.1
equivalents of BuLi followed by the addition of dry ice providing
can be constructed by altering different enantiomer of
(NMI) ZrCl catalyst. Our one-step homologation strategy heavily
2 2
t
relies on three key features of ZACA reaction: (i) catalytic
asymmetric C–C bond formation, (ii) many potential
transformations of the initially formed alkylalane intermediates
and, (iii) use of alkene substances of one-point-binding without
requiring any directing groups. Although there is room for further
improvements, especially of the modest enantioselectivity of
ZACA reaction which would limit the yields of isomerically pure
products. The one-step homologation protocol presented herein
promises to provide a general, efficient, and satisfactory route to
deoxypropionates as exemplified by significant improvements in
the syntheses of intermediates and/or final products of
mycolipenic acid 1 and its analogue 2, (‒)-rasfonin, and syn- and
anti-dicarboxylic acids 5 and 6.
carboxylic acid anti-22 in 81% yield, which was further converted
to dicarboxylic acid anti-5 by oxidative cleavage of phenyl group
3 4
/NaIO
.38 The synthesis of anti-6 was achieved by
with RuCl
CuI-catalyzed allylation of iodide anti-21 with allylmagnesium
chloride to produce alkene anti-23 in 92% yield. RuCl -catalyzed
3
oxidation of both phenyl ring and terminal double bond of 23 to
the carboxylic acid groups completed the synthesis of anti-6.
The dicarboxylic acids syn-5 and syn-6 were efficiently
synthesized in the similar route from iodide syn-21. Through the
comparison of the NMR spectra of anti- and syn-5, as well as
anti- and syn-6, no epimerization was observed during the
transformations.
A comparison of current and previous syntheses of natural
products containing deoxypropionate motif was summarized in
Table 2, which clearly indicates the substantial improvements Experimental Section
accomplished in our synthesis by using ZACA-based one-step
homologation protocol. Thus, this one-step homologation
strategy promises to provide a facile general and more efficient
synthetic route toward natural products containing the
deoxypropionate motif.
General information: All reactions were run under a dry Argon
atmosphere. Reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25-mm Merck silica gel plates (60F-254) or by GC
analysis of reaction aliquots. Flash chromatographic separations were
carried out on 230-400 mesh silica gel. 1H and 13C NMR spectra were
recorded on Varian-Inova-300, Bruker-ARX-400 or Bruker Avance-III-800.
Optical rotations were measured on an Autopol III automatic polarimeter.
THF and ether was dried by distillation under argon from
Table 2. Comparison of current and previous syntheses of deoxypropionates.
sodium/benzophenone. CH
2 2
Cl was dried by distillation under argon from
26
CaH . (–)-(NMI) ZrCl and (+)-(NMI)
2
2
2
2
ZrCl
2
were prepared as reported in
the literature. Other commercially available solvents and reagents were
of reagent grade and used without further purification.
(
4S)-4-Methyl-docos-1-ene (8). To a solution of (+)-(NMI)
2
ZrCl (268 mg,
2
0.4 mmol, 1 mol%) in CH
2
Cl
2
(120 mL) at 23 °C were added Me Al (6 mL,
3
60 mmol, 1.5 equiv) under argon. Then the resultant solution was cooled
to 0 °C, and tetraisobutyldialuminoxane solution (TIBAO) (10 wt. % in
toluene, 6.9 mL, 2 mmol, 5 mol%) was added dropwise at 0 °C. The
reaction mixture was stirred at 0°C for 15 min, and 1-eicosene (11.6 g,
1
0
3.7 mL, 40 mmol) was added dropwise. After the mixture was stirred at
°C for 24 h, the solvent as well as excess Me Al were evaporated in
(17.5 g, 48 mmol, 1.2 equiv) in 120
mL of DMF was added dropwise at 0 °C, and the mixture was stirred for
h at 70 °C. In another flask, Pd(DPEphos)Cl (0.86 g, 1.2 mmol, 3
3
vacuo. Then flamed-dried Zn(OTf)
2
2
2
mol%) was dissolved in THF (20 mL) followed by dropwise addition of a
solution of DIBAL-H in hexanes (1 M, 2.4 mL, 2.4 mmol, 6 mol%). After
10 min, vinyl bromide (16.9 mL, 240 mmol, 6.0 equiv) was added to the
above the Pd catalyst solution under 0 °C, which then was transferred to
the above DMF solution at 0 °C. After stirring for 12 h at 0 °C and another
2
h under room temperature, the reaction was quenched with 2N HCl,
filtered through celite, extracted with hexanes, washed with saturated
aqueous NaHCO solution and Brine, dried over anhydrous Na SO
3
2
4
,
concentrated, and purified by column chromatography (silica gel,
hexanes as eluent) to afford the crude title product without further
purification (70% yield).
Conclusions
(2S,4S)-2, 4-Dimethyl-docosan-1-ol (9). To a solution of (+)-(NMI)
201 mg, 0.3 mmol) in CH Cl (100 mL) at 23 °C were added Me Al (4.5
mL, 45 mmol) under argon. Then the resultant solution was cooled to
°C, and TIBAO (10 wt. % in toluene, 5.2 mL, 1.5 mmol) was added
dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and
2 2
ZrCl
(
2
2
3
In summary, a general approach to deoxypropionate natural
products through ZACA-based one-step homologation protocol
is described by the combination of ZACA–Pd-catalyzed
vinylation and ZACA–oxidation reaction. Both syn- and anti-
deoxypropionate motif, found in a number of natural products,
0
(
4S)-4-methyl-docos-1-ene
8
(crude product from 40 mmol of 1-
eicosene) in 20 mL of CH
2
Cl was added dropwise. After stirring at 0 °C
2
for 24 h, the reaction mixture was treated with a vigorous stream of O
2
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Chemistry - A European Journal
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bubbled through a needle at 0 °C for 4 h. The reaction was then
give the title compound (1/10 EtOAc/hexane) in 92% isolated yield (376
26.6
= +17.79o (c = 2.08, CHCl ). 1H NMR (300 MHz, CDCl
quenched with 2N HCl, extracted with Et
2
O, washed with saturated
mg). [α]
D
3
3
): δ
aqueous NaHCO solution and Brine, dried over anhydrous Na
3
2
SO
4
,
0.87 (d, J = 4.4 Hz, 3 H), 0.92 (t, J = 4.8 Hz, 3 H), 1.03 (d, J = 4.4 Hz, 3
H), 1.11–1.16 (m, 1 H), 1.17–1.21 (m, 1 H), 1.28–1.36 (m, 34 H), 1.38–
1.43 (m, 1 H), 1.89 (s, 3 H), 2.65–2.70 (m, 1 H), 6.70 (d, J = 6.8 Hz, 1 H),
concentrated, and purified by column chromatography (silica gel, 9/1 of
hexanes/ethyl acetate) to afford the title product (6.9 g, 49% from 1-
eicosene, d.r. = 5.2/1). The product was further purified by column
chromatography (silica gel, 0 to 2% gradient ethyl acetate in hexanes) to
give the title product (4.8 g, 34% from 1-eicosene, d.r. > 50/1, 97% ee).
12.36 (bs, 1 H); 13C NMR (101 MHz, CDCl
3
) δ 11.9, 14.0, 19.5, 20.3,
22.6, 26.8, 29.3, 29.7, 29.9, 30.7, 31.0, 31.9, 37.5, 44.4, 125.4, 150.9,
+
174.1. HRMS calcd for C27
H
52
O
2
Na [M+Na] : 431.3865, found 431.3850.
26.4
= ‒7.71o (c = 1.40, CHCl ). 1H NMR (300 MHz, CDCl
[
α]
D
3
3
): δ 0.86–
(
2S,4S,6S)-2,4,6-Trimethyldocosan-1-ol (14). To a solution of (+)-
(NMI) ZrCl (152 mg, 0.23 mmol, 1 mol%) in CH Cl (100 mL) at 23 °C
were added Me Al (3.4 mL, 34.2 mmol) under argon. Then the resultant
0
.93 (m, 9 H), 1.00–1.10 (m, 1 H), 1.12–1.40 (m, 35 H), 1.40–1.57 (m, 1
H), 1.63–1.80 (m, 1 H), 3.35–3.55 (m, 2 H); 13C NMR (101 MHz, CDCl
2
2
2
2
3
)
3
δ 14.08, 17.30, 20.33, 22.68, 26.90, 29.38, 29.72, 30.05, 31.93, 33.10,
+
solution was cooled to 0 °C, TIBAO (10 wt. % in toluene, 3.93 mL, 1.14
mmol) was added dropwise at 0 °C. The reaction mixture was stirred at
3
6.68, 41.11, 68.27. HRMS calcd for C24
H
50ONa [M+Na] : 377.3759,
found 377.3745.
0
°C for 15 min, and crude (4R,6S)-4,6-dimethyldocos-1-ene 13 (product
from 30.8 mmol of (S)-4-methylicos-1-ene 12) in 20 mL of CH Cl was
added dropwise. After stirring at 0 °C for 24 h, the reaction mixture was
treated with a vigorous stream of O bubbled through a needle for 4 h at
0 °C. The reaction was then quenched with 2N HCl, extracted with Et O,
washed with saturated aqueous NaHCO solution and Brine, dried over
anhydrous Na SO concentrated, and purified by column
(
2S,4S)-2,4-Dimethyldocosanal (10). To a stirred solution of oxalyl
2
2
chloride (0.35 mL, 4.0 mmol) in 10 mL of CH Cl
2
2
at ‒78 oC was added
dropwise DMSO (0.43 mL, 6.0 mmol) in 5 mL of CH
After 30 min stirring at ‒78 C, (2S,4S)-2,4-dimethyl-docosan-1-ol 9 (709
2
Cl
2
via cannula.
2
o
2
mg, 2.0 mmol) in 20 mL of CH
resulting white heterogeneous mixture was stirred at ‒78 C for 2 h, and
2
Cl
2
was added slowly and dropwise. The
3
o
2
4
,
o
Et
3
N (1.12 mL, 8.0 mmol) was added. After 30 min at –78 C, the mixture
chromatography (silica gel, 9/1 of hexanes/ethyl acetate) to afford the
title product (5.16 g, 35% from 1-eicosene, d.r. = 18.6/1.6/2/1). The crude
product was further purified by column chromatography (silica gel, 0 to
1 % gradient ethyl acetate in hexanes) to give the title product (2.2 g,
o
was warmed to 23 C for 4 h and 10 mL of H
2
O was added. The aqueous
O three times. The combined organic extracts
were washed with brine, dried over Na SO , and concentrated under
layer was extracted with Et
2
2
4
26.4
= ‒12.12o (c =
reduced pressure. The title product was obtained as orange oil (699 mg,
15% from 1-octadecene, d.r. > 40/1, ee >99%). [α]
1.60, CHCl ): δ 0.83–0.94 (m, 12 H), 0.97–
).1H NMR (300 MHz, CDCl
D
1
99%) and used directly to the next reaction without further purification. H
3
3
NMR (300 MHz, CDCl
3
): δ 0.83–0.87 (m, 6 H), 1.05 (d, J = 6.8 Hz, 3 H),
.08–1.36 (m, 36 H), 1.65–1.72 (m, 1 H), 2.36–2.45 (m, 1 H), 9.55 (d, J =
.4 Hz, 1 H); 13C NMR (101 MHz, CDCl
) δ 13.9, 14.0, 19.7, 22.6, 26.7,
1.02 (m, 1 H), 1.18–1.32 (m, 33 H), 1.47–1.50 (m, 1 H), 1.55–1.60 (m, 1
H), 1.69–1.76 (m, 1 H), 3.33–3.38 (m, 1 H), 3.51–3.55 (m, 1 H); 13C NMR
(101 MHz, CDCl ) δ 14.0, 17.5, 20.4, 20.8, 22.6, 26.8, 27.5, 29.3, 29.6,
3
1
2
2
3
9.3, 29.6, 29.8, 30.3, 31.8, 36.6, 38.2, 44.0, 205.0. HRMS calcd for
29.9, 30.0, 31.8, 33.0, 36.4, 41.2, 45.1, 68.1. HRMS calcd for C25
[M+Na] : 391.3916, found 391.3902.
H52ONa
+
+
24
C H48ONa [M+Na] : 375.3603, found 375.3591.
s
(
4S,6S,E)-2,4,6-Trimethyltetracos-2-enal (11). BuLi (1.85 mL, 1.4 M in
(4S,6S,8S,E)-2,4,6,8-Tetramethyltetracos-2-enoic acid (2). A solution
2
of 80% chemically pure NaClO (79.2 mg, 0.7 mmol) and NaH PO ·H 0
cyclohexane, 2.6 mmol) was added dropwise to solution of 2-
a
2
2
4
triethylsilylpropionaldehyde-N-cyclohexylimine (0.76 g, 3.0 mmol) in 20
mL of THF at –78 oC. After stirring at –78 oC for 1 h, (2S,4S)-2,4-
dimethyldocosanal 10 (699 mg, 1.98 mmol) in THF (20 mL) was added
(77.5 mg, 0.55 mmol) in water (3 mL) was added dropwise to a rapidly
stirred solution of aldehyde 16 (204 mg, 0.5 mmol) and 2-methyl-2-
butene (0.54 mL, 5 mmol) in tert-butanol (3 mL) at room temperature.
The resultant solution was stirred for 12 h at room temperature, then it
was quenched with 2N HCl and extracted four times with ether. The
o
dropwise. The solution was immediately warmed to –20 C, maintained at
this temperature for 4 h, quenched with H
with Et O. The combined organic extracts were washed with brine, dried
over Na SO , and concentrated under reduced pressure. The oil thus
obtained was dissolved in 20 mL of dry THF and cooled to 0 oC, where
2
O, and extracted three times
2
2 4
extracts were washed with brine and water, dried over Na SO ,
2
4
concentrated and purified by flash silica gel column chromatography to
give the desired compound (1/10 EtOAc/hexane) in 92% isolated yield
26.7
= +21.80o (c = 2.00, CHCl ). 1H NMR (300 MHz,
upon CF
3
CO
2
H (0.31 mL, 4.0 mmol) was added slowly with stirring. The
(196 mg). [α]
D
3
o
reaction mixture was stirred at 0 C for 2 h, quenched with 10 mL of H
maintained at 0 C for 12 h, and poured into saturated aqueous NaHCO
2
O,
CDCl ): δ 0.85 (d, J = 4.4 Hz, 3 H), 0.87 (d, J = 4.0 Hz, 3 H), 0.92 (t, J =
3
o
3
4.8 Hz, 3 H), 1.03 (d, J = 4.4 Hz, 3 H), 1.10–1.15 (m, 1 H), 1.18–1.35 (m,
33 H), 1.39–1.45 (m, 1 H), 1.49–1.52 (m, 1 H), 1.90 (s, 3 H), 2.65–2.74
solution. The aqueous layer was extracted with Et
2
O. The combined
organic extracts were washed with brine, dried over Na
2
SO4, and
(m, 1 H), 6.70 (d, J = 6.8 Hz, 1 H); 13C NMR ( 101 MHz, CDCl
3
) δ 12.1,
concentrated. The residue was purified by flash chromatography (1/20
EtOAc/hexane) to provide the title product (710 mg, 90% yield over 2
14.1, 20.0, 20.4, 20.5, 22.7, 27.0, 28.2, 29.4, 29.7, 29.9, 30.0, 31.1, 31.9,
37.1, 44.2, 45.6, 125.5, 151.0, 174.1. HRMS calcd for C28
54 2
H O Na
steps from 9). [α] 26.7
= +2.61o (c = 1.69, CHCl
). 1H NMR (300 MHz,
[M+Na] : 445.4022, found 445.4004.
+
D
3
CDCl
3
): δ 0.88 (d, J = 4.4 Hz, 3 H), 0.92 (t, J = 4.8 Hz, 3 H), 1.08 (d, J =
(
2S,4R,E)-2,4,6-Trimethyloct-6-en-1-ol (4). To
(NMI) ZrCl (64 mg, 0.095 mmol) in CH Cl (7.9 mL) at 23 °C were
added Me Al (0.46 mL, 4.77 mmol) under argon. After 5 min, the
resultant solution was cooled to 0 °C, and the crude 18 (3.18 mmol) in
CH Cl (7.9 mL) was added dropwise. The reaction mixture was allowed
a solution of (+)-
4
2
.4 Hz, 3 H), 1.22–1.34 (m, 36 H), 1.42–1.45 (m, 1 H), 1.80 (s, 3 H),
.81–2.89 (m, 1 H), 6.25 (d, J = 6.4 Hz, 1 H), 9.43 (s, 1 H); 13C NMR (101
2
2
2
2
3
MHz, CDCl
3
) δ 9.1, 13.9, 19.4, 20.2, 22.6, 26.8, 29.3, 29.6, 29.8, 30.7,
31.0, 31.8, 37.4, 44.3, 137.7, 160.1, 194.9. HRMS calcd for C27H52ONa
+
2
2
[M+Na] : 415.3916, found 415.3900.
to warm up to 23 °C and stirred for 24 h. Then 10% methylaluminoxane
in toluene (0.11 mL, 0.16 mmol) was added at 0 °C. The resultant
mixture was warmed up to 23 °C and stirred for additional 18 h. The
Mycolipenic acid (1). A solution of 80% chemically pure NaClO
mg, 1.4 mmol) and NaH PO ·H O (155 mg, 1.1 mmol) in H O (5 mL) was
2
(158
2
4
2
2
added dropwise to a rapidly stirred solution of aldehyde 11 (392 mg, 1.0
mmol) and 2-methyl-2-butene (1.07 mL, 10 mmol) in tert-butanol (5 mL)
at 23 oC. The resultant solution was stirred for 12 h at 23 oC. Then the
reaction mixture was quenched with 2N HCl and extracted four times with
reaction mixture was treated with a vigorous stream of O
through a needle for 3 h at 0 °C. The reaction was then quenched with
2 N HCl, extracted with CH Cl , washed with saturated aqueous NaHCO
solution and Brine, dried over MgSO , concentrated, and purified by
2
bubbled
2
2
3
4
ether. The extracts were washed with brine and water, dried over Na
concentrated and purified by flash silica gel column chromatography to
2
SO
4
,
column chromatography (silica gel, 8 % ethyl acetate in hexanes) to
afford the title product (460 mg, 85% yield, d.r. = 4.2/1) as a colorless oil.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201604478
FULL PAPER
The product was further purified by column chromatography (silica gel, 0
to 8 % gradient ethyl acetate in hexanes) to give the title product (265 mg,
mL) to adjust the pH to 1 at 0 °C. The aqueous layer was extracted with
EtOAc (10 mL) four times. The combined organic layer was dried over
23
1
d.r. > 50/1, 95% ee). [α]
CDCl ) δ 0.82 (d, J = 6.2 Hz, 3 H), 0.90–0.96 (m, 4 H), 1.24–1.30 (m, 2
H), 1.56 (s, 3 H), 1.58 (d, J = 6.7 Hz, 3 H), 1.63–1.70 (m, 2 H), 1.70–1.78
m, 1H), 2.01 (q, J = 9.6 Hz, 1 H), 3.35–3.42 (m, 1 H), 3.49–3.57 (m, 1 H),
D
= –8.82° (c 0.23, CH
2
Cl
2
). H NMR (800 MHz,
MgSO
4
, concentrated, and purified by column chromatography (silica gel,
3
30 to 70 % gradient EtOAc with 1% AcOH in hexanes) to afford the title
24
2 2
= +2.4° (c 2.8, CH Cl H
). 1
product (61 mg, 71%) as a white solid. [α]
D
(
5
1
NMR (800 MHz, CDCl ) δ 0.99 (d, J = 6.7 Hz, 3 H), 1.19 (d, J = 7.0 Hz, 3
3
.18 (qd, J = 6.7, 1.2 Hz, 1 H). 13C NMR (201 MHz, CDCl
H), 1.41–1.49 (m, 1 H), 1.61–1.70 (m, 1 H), 2.01–2.12 (m, 1 H), 2.22 (dd,
J = 15.3, 7.8 Hz, 1 H), 2.39 (dd, J = 15.4, 5.9 Hz, 1 H), 2.50–2.59 (m, 1
3
) δ 13.36,
5.56, 17.44, 20.21, 28.13, 33.17, 40.94, 47.60, 68.30, 119.87, 134.58.
+
H), 11.45 (s, 2 H). 13C NMR (201 MHz, CDCl
7.07, 39.92, 41.39, 179.53, 183.47. HRMS calcd for
HRMS calcd for C11
H
23O [M+H] : 171.1749, found 171.1743.
3
) δ 16.71, 19.33, 27.85,
3
8 14 4
C H O Na
(
(
2R,4R)-2-Methyl-4-phenylpentan-1-ol (anti-20). To a solution of (‒)-
NMI) ZrCl (230 mg, 0.34 mmol, 2 mol%) in CH Cl (24 mL) at 23 °C
Al (2.47 mL, 25.8 mmol) under argon. After 5 min, the
resultant solution was cooled to 0 °C, and to the solution was added
tetraisobutylaluminoxane (0.86 mmol) in CH Cl (6.9 mL). The reaction
mixture was stirred for 10 min, and (R)-pent-4-en-2-ylbenzene 19 (17.2
mmol) in CH Cl (3.4 mL) was added dropwise. After stirring at 0 °C for
0 h, the reaction mixture was treated with a vigorous stream of oxygen
bubbled through a needle for 3 h at 0 °C. The reaction was then
quenched with 2N HCl, extracted with CH Cl , washed with saturated
aqueous NaHCO solution and brine, dried over MgSO , concentrated,
+
[M+Na] :197.0790, found 197.0786.
2
2
2
2
was added Me
3
2
2
Acknowledgements
2
2
We thank the Negishi-Brown Institute, Purdue University and
Teijin Limited for the support of this research.
2
2
2
3
4
Keywords: asymmetric catalysis • natural product synthesis •
deoxypropionates • cross-coupling • ZACA reaction
and purified by column chromatography (silica gel, 8 % ethyl acetate in
hexanes) to afford the title product (2.67 g, 87%, d.r. = 11.4/1) as a
colorless oil. The product was further purified by column chromatography
[
[
1]
2]
a) L. Katz, Chem. Rev. 1997, 97, 2557–2576; b) C. Khosla, Chem. Rev.
997, 97, 2577–2590; c) C. Khosla, R. S. Gokhale, J. R. Jacobsen, D.
(
silica gel, 0 to 8 % gradient ethyl acetate in hexanes) to give the title
1
23
product (1.79 g, 58%, d.r. > 30/1, e.r. > 98/2) as colorless oil. [α]
D
=
E. Cane, Annu. Rev. Biochem. 1999, 68, 219–253.
1
‒
3
1
0.42° (c 2.9, CH
2
Cl
2
). H NMR (800 MHz, CDCl
3
) δ 0.90 (d, J = 6.7 Hz,
a) M. Tanaka, F. Nara, K. Suzuki-Konagai, T. Hosoya, T. Ogita, J. Am.
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H), 1.22 (d, J = 6.9 Hz, 3 H), 1.31 (s, 1 H), 1.39–1.46 (m, 1 H), 1.57–
.67 (m, 2 H), 2.78–2.85 (m, 1 H), 3.42 (dd, J = 10.5, 6.2 Hz, 1 H), 3.50
(
dd, J = 10.5, 5.1 Hz, 1 H), 7.14–7.22 (m, 3 H), 7.26–7.31 (m, 2 H).13
C
[
[
3]
4]
NMR (201 MHz, CDCl3) δ 16.95, 22.23, 33.52, 37.18, 41.97, 68.15,
25.93, 126.91, 128.42, 147.92.
9115–9125.
1
J. Kohno, M. Nishio, M. Sakurai, K. Kawano, H. Hiramatsu, N. Kameda,
N. Kishi, T. Yamashita, T. Okuda, S. Komatsubara, Tetrahedron 1999,
(
(
3R,5R)-3-Methyl-5-phenylhexanoic acid (anti-22). To a solution of
(2R,4R)-5-iodo-4-methylpentan-2-yl)benzene anti-21 (173 mg, 0.60
55, 7771–7786.
[
5]
M. T. Fletcher, S. Chow, L. K. Lambert, O. P. Gallagher, B. W. Cribb, P.
G. Allsopp, C. J. Moore, W. Kitching, Org. Lett. 2003, 5, 5083–5086.
K. Mori, S. Kuwahara, Tetrahedron 1986, 42, 5545–5550.
mmol) in Pentane / Et
pentane (0.74 mL, 1.26 mmol) under argon. After 5 min, the resultant
solution was transferred into dry ice (132 mg, 3 mmol) in pentane / Et
3 / 2 (3.0 mL) at ‒78 °C, followed by quickly adding the same amount
2
O = 3/2 (3 mL) at ‒78 °C was added 1.7 M tBuLi in
[
[
6]
7]
2
O
M. Daffé, F. Papa, A. Laszlo, H. L. David, J. Gen. Microbiol. 1989, 135,
=
2
759–2766.
of dry ice (132 mg, 3 mmol). The reaction mixture was allowed to warm
up to 23 °C, stirred for 1 h, and quenched through the addition of half
[
[
[
8]
a) T. Tomikawa, K. Shin-Ya, K. Furihato, T. Kinoshita, A.Miyajima, H.
Seto, Y. Hayakawa, J. Antibiot. 2000, 53, 848–850; b) K. Akiyama, S.
Kawamoto, H. Fujimoto, M. Ishibashi, Tetrahedron Lett. 2003, 44,
saturated NaHCO
layer was separated, and the organic layer was extracted with half
saturated NaHCO aq. twice. The combined aqueous layer was acidified
with 6N HCl dropwise at 0 °C, extracted with EtOAc three times. The
combined organic layer was washed with brine, dried over MgSO
concentrated, and used in the next step without further purification (101
3
aq. until the aqueous pH around 8. The aqueous
8427–8431.
3
9]
For review articles, see: a) S. Hanessian, S. Giroux, V. Mascitti,
Synthesis 2006, 1057–1076; b) B. ter Horst, B. L. Feringa, A. J.
Minnaard, Chem. Commun. 2010, 46, 2535–2547; c) F. Schmid, A.
Baro, S. Laschat, Synthesis 2016, DOI: 10.1055/s-0035-1562540.
4
,
24
). 1H NMR (800 MHz, CDCl
mg, 81%). [α]
D
= +4.9° (c 3.4, CDCl ) δ
3
3
10] a) W. Oppolzer, R. Moretti, G. Bernardinelli, Tetrahedron Lett. 1986, 27,
713–4716; b) D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs, R.
0.96 (d, J = 6.7 Hz, 3 H), 1.23 (d, J = 6.9 Hz, 3 H), 1.48–1.53 (m, 1 H),
1.53–1.60 (m, 1 H), 1.91–1.97 (m, 1 H), 2.15 (dd, J = 15.1, 8.3 Hz, 1 H),
2.37 (dd, J = 15.1, 5.5 Hz, 1 H), 2.73–2.82 (m, 1 H), 7.15–7.20 (m, 3 H),
7.26–7.30 (m, 2 H), 11.58 (s, 1 H).
4
Zahler, J. Am. Chem. Soc. 1990, 112, 5290–5313; c) A. K. Ghosh, C.
Liu, Org. Lett. 2001, 3, 635–638; d) M. O. Duffey, A. LeTiran, J. P.
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Yang, S. Giroux, V. Mascitti, J. Ma, F. Raeppel, J. Am. Chem. Soc.
(
(
(
2R,4R)-2,4-dimethylhexanedioic acid (anti-5). To
3R,5R)-3-methyl-5-phenylhexanoic acid anti-22 (0.49 mmol) in MeCN
2.5 mL), CCl (2.5 mL), and water (5.0 mL) at 0 °C were added sodium
a solution of
2
003, 127, 13784–13792; f) B. Breit, C. Herber, Angew. Chem. Int. Ed.
004, 43, 3790–3792; Angew. Chem. 2004, 116, 3878–3880; g) C.
4
2
periodate (1.57 g, 7.32 mmol) and Ruthenium(III) chloride hydrate (25 mg,
.10 mmol) under argon. After vigorously stirring at 0 °C for 6 h and 8 °C
for 14 h, the resulting mixture was filtered through a sheet of filter paper,
and washed with water (2.5 mL) and CH Cl (10 mL). The aqueous layer
was extracted with EtOAc (10 mL) three times. To the combined organic
layer was added sat. NaHCO aq. (1.9 mL) and H O (1.9 mL) to adjust
Herber, B. Breit, Angew. Chem. Int. Ed. 2005, 44, 5267–5269; Angew.
Chem. 2005, 117, 5401–5403; h) G. J. Brand, C. Studte, B. Breit, Org.
Lett. 2009, 11, 4668–4670.
0
2
2
[
[
[
11] R. D. Mazery, M. Pullez, F. Lopez, S. R. Harutyunyan, A. J. Minnaard,
B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 9966–9967.
12] J. Zhou, K. Burgess, Angew. Chem. Int. Ed. 2007, 46, 1129–1131;
Angew. Chem. 2007, 119, 1147–1149.
3
2
the pH to 8. After vigorously stirring for 15 min, the mixture was filtered
through celite pad, and washed with water (7.5 mL). The organic layer
13] S. Balieu, G. E. Hallett, M. Burns, T. Bootwicha, J. Studley, V. K.
Aggarwal, J. Am. Chem. Soc. 2015, 137, 4398–4403.
was extracted with mixture of sat. NaHCO
3 2
aq. (0.94 mL) and H O (8.4
mL) twice. To the combined aqueous layer was added 6N HCl aq. (0.81
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201604478
FULL PAPER
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14] a) P. S. Diez, G. C. Micalizio, Angew. Chem. Int. Ed. 2012, 51, 5152–
156; Angew. Chem. 2012, 124, 5242–5246; b) M. C. Pischl, C. F.
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[26] a) G. Erker, M. Aulbach, M. Knickmeier, D. Wingbermühle, C. Kürger,
M. Nolte, S. Werner, J. Am. Chem. Soc. 1993, 115, 4590–4601; b) (+)–
2
Rasappan, V. K. Aggarwal, Nature Chem. 2014, 6, 810–814; d) S. Xu,
A. Oda, T. Bobinski, H. Li, Y. Matsueda, E. Negishi, Angew. Chem. Int.
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2 2 2 2
(NMI) ZrCl (CAS number: 641627-68-1) and (–)–(NMI) ZrCl (CAS
number: 148347-88-0) are available from Sigma-Aldrich and Wako
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This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201604478
FULL PAPER
FULL PAPER
Shiqing
Xu,
Haijun
Li,
Masato
Komiyama, Akimichi Oda and Ei-ichi
Negishi*
Page No. – Page No.
One-step Homologation for the
Catalytic Asymmetric Synthesis of
Deoxypropionates
A one-step homologation strategy for the construction of deoxypropionate motif is
described via the combination of ZACA–Pd-catalyzed vinylation and ZACA–
oxidation reaction. The power of this one-step homologation protocol has been
demonstrated by the highly efficient synthesis of intermediates and/or final products
of mycolipenic acid 1 and its analogue 2, (‒)-rasfonin, and syn- and anti-
dicarboxylic acids 5 and 6.
This article is protected by copyright. All rights reserved.