Highly Efficient, Convergent, and Enantioselective Synthesis of Phthioceranic Acid

Article abstract of DOI:10.1002/anie.201503818

A new strategy for highly concise, convergent, and enantioselective access to polydeoxypropionates has been developed. ZACA-Pd-catalyzed vinylation was used to prepare smaller deoxypropionate fragments, and then two key sequential Cu-catalyzed stereocontrolled sp³-sp³ cross-coupling reactions allowed convergent assembly of smaller building blocks to build-up long polydeoxypropionate chains with excellent stereoselectivity. We employed this strategy for the synthesis of phthioceranic acid, a key constituent of the cell-wall lipid of Mycobacterium tuberculosis, in just 8 longest linear steps with full stereocontrol. A step-economical synthesis of phthioceranic acid was achieved by using a conceptually new strategy. ZACA-Pd-catalyzed vinylation was used to prepare smaller deoxypropionate building blocks. Then two Cu-catalyzed stereospecific sp³-sp³ cross-couplings linked the smaller fragments together with full inversion of configuration to assemble large polydeoxypropionates in a stereoselective manner. ZACA=Zr-catalyzed asymmetric carboalumination of alkenes.

Full text of DOI:10.1002/anie.201503818

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503818
German Edition: DOI: 10.1002/ange.201503818
Natural Product Synthesis
Highly Efficient, Convergent, and Enantioselective Synthesis of
Phthioceranic Acid**
Shiqing Xu, Akimichi Oda, Thomas Bobinski, Haijun Li, Yohei Matsueda, and Ei-ichi Negishi*
Abstract: A new strategy for highly concise, convergent, and
enantioselective access to polydeoxypropionates has been
developed. ZACA-Pd-catalyzed vinylation was used to pre-
pare smaller deoxypropionate fragments, and then two key
3
3
sequential Cu-catalyzed stereocontrolled sp –sp cross-cou-
pling reactions allowed convergent assembly of smaller build-
ing blocks to build-up long polydeoxypropionate chains with
excellent stereoselectivity. We employed this strategy for the
synthesis of phthioceranic acid, a key constituent of the cell-
wall lipid of Mycobacterium tuberculosis, in just 8 longest
linear steps with full stereocontrol.
D
eoxypropionate subunits are common structural motifs
found in a broad range of naturally occurring compounds
[
1]
derived from polyketide pathways. They represent a family
of structurally diverse compounds with a broad range of
[
2]
biological activities and pharmacological properties, e.g.,
[
3]
Figure 1. Representative examples of natural products containing
deoxypropionate subunits.
neutral sphingomyelinase inhibitor (+)-scyphostatin, cyto-
[
4]
[5]
toxic agents (À)-borrelidine and (À)-doliculide, phero-
mone (+)-4,6,8,10,16,18-hexamethyldocosane, calcium ion-
[
6]
[7]
ophore ionomycin, as well as the long-chain aliphatic
allylic alcohol cross-coupling with sequential substrate-con-
[
8]
[10]
phthioceranic acid (Figure 1).
trolled asymmetric hydrogenation was established. Pfaltz,
In view of the abundant presence of deoxypropionate-
containing natural products with diverse fascinating biolog-
ical activities, intense efforts for the development of efficient
and stereoselective methods for their synthesis have been
Schneider and their co-workers developed a convergent
synthesis of polydeoxypropionates phthioceranic acid and
hydroxyphthioceranic acid on the basis of a sequential Pd-
catalyzed Suzuki coupling/Ir-catalyzed asymmetric hydroge-
[
9]
[11]
made. Since deoxypropionates are devoid of heterofunc-
nation strategy. Aggarwal et al. reported another conver-
tional groups that could assist asymmetric CÀC or CÀH bond
gent stereoselective synthesis using lithiation–borylation
[12]
formation, most of the currently known and widely used
methods for their constructions have to install temporary
functional or chiral directing groups that are to be removed
followed by protodeboronation.
While these convergent
strategies for the syntheses of deoxypropionates are powerful
and efficient, their key steps linking fragments together are
not suitable for straightforward construction of the deoxy-
propionate unit, and thus require subsequent transformations,
such as hydrogenation where stereoselectivity is typically
substrate-dependent. Thus, it is highly desirable to develop
novel convergent strategies for the direct formation of
deoxypropionates, especially those exhibiting high stereose-
lectivity.
[
9]
later. These methods construct deoxypropionate units in
a linear-iterative fashion: one deoxypropionate unit after
another is typically attached to the growing alkyl chain, and
one iteration cycle typically requires 3–6 steps to introduce
one methyl-branched chiral center. Thus, they suffer from
long synthetic steps, low efficiency, and/or use of stoichio-
metric amount of chiral auxiliaries.
Recently, the first convergent route to smaller deoxypro-
Phthioceranic acid (1) is a component of sulfolipid-1 (SL-
1), a main constituent of the cell-wall lipid of virulent human
pionates through [ClTi(OiPr) ] (1.5 equiv)-mediated alkyne–
3
[13]
Mycobacterium tuberculosis (MTB).
Tuberculosis (TB)
remains one of the worldꢀs deadliest communicable diseases,
which caused 1.5 million people deaths in 2013 alone.
[
*] Dr. S. Xu, A. Oda, Dr. T. Bobinski, Dr. H. Li, Y. Matsueda,
Prof. Dr. E. Negishi
Herbert C. Brown Laboratories of Chemistry, Purdue University
[14]
Studies revealed that SL-1 shows significant immunomodu-
latory activities against various immune cells, and thus it has
been considered as a promising component of potential
5
60 Oval Drive, West Lafayette, IN 47907-2084 (USA)
E-mail: negishi@purdue.edu
[
15]
tuberculosis vaccines. Phthioceranic acid was first synthe-
[
**] We thank the Negishi–Brown Institute, Purdue University and Teijin
Limited for support of this research.
[16]
sized by Feringa and Minnaard in 27 longest linear steps
[
11]
from ethylene glycol, and also by Pfaltz and Schneider in 20
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503818.
longest linear steps from (S)-4-benzyl-2-oxazolidinone. Here
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we report a new strategy for a highly concise, convergent, and
enantioselective synthesis of long-chain polydeoxypropio-
nates as exemplified by phthioceranic acid (1) in 8 steps
nation of 1-octadecene was completed when water (1 equiv)
was added. However, only 45% of the desired alcohol 6 of
40% ee was obtained after in situ oxidation with O (entry 2),
2
(
longest linear sequence).
where the major side reaction was oligomerization. Impor-
tantly, we found that a decreased amount of water (2 mol%)
significantly improved both enantioselectivity and yield of the
desired product, although the reaction occurred at a lower
rate (entry 6). Interestingly, the enantioselectivities and
product yields in the ZACA reactions of styrene derivatives
and proximally heterosubstituted alkenes appeared to be
Our synthesis of phthioceranic acid (1) makes use of the
convergent assembly of three smaller building blocks 2–4
through two sequential stereospecific sp –sp cross-coupling
steps (Scheme 1), inspired by recent advances in the tran-
3
3
[19c,d,22,23]
basically unaffected by the amount of water.
The
mechanistic role of water in the ZACA reaction remains
unclear at present.
Under suitable conditions for the ZACA reaction of 1-
octadecene in hand, we then synthesized the building block
2
a as shown in Scheme 2. Compound (S)-7 was prepared by
Scheme 1. Strategy for the highly convergent synthesis of phthioceranic
acid (1).
sition metal-catalyzed CÀC cross-coupling of nonactivated
Scheme 2. Synthesis of fragment 2a by ZACA reaction.
[a] [(+)-(NMI) ZrCl ] (1 mol%), AlMe (1.5 equiv), H O (2 mol%),
secondary alkyl halides or pseudohalides with alkylmetal
2
2
3
2
[17,18]
08C. [b] i) Zn(OTf) (1.2 equiv); ii) [PdCl (DPEPhos)] (3 mol%), DIBAL-
nucleophiles.
Both fragments 2 and 3 should be readily
2
2
H (6 mol%), vinyl bromide (6 equiv).
prepared by Zr-catalyzed asymmetric carboalumination of
alkenes (ZACA)-Pd-catalyzed vinylation tandem process
[19]
from very simple terminal alkenes. The third fragment 4
should be easily derived from commercially available (2S,4S)-
(+)-ZACA reaction of 1-octadecene followed by [Pd-
(
+)-pentanediol 5, which, in turn, is preparable from catalytic
(DPEphos)Cl ]-catalyzed vinylation of the in-situ generated
2
[20]
[19c]
asymmetric hydrogenation of acetylacetone in one step.
isoalkylalane promoted by Zn(OTf)2.
(S)-7 was then
The synthesis of the fragment 2 began with the ZACA
reaction of 1-octadecene. To our surprise, the methylalumi-
nation of 1-octadecene using 1.5 equiv of trimethylaluminum
converted to alcohol 8 (d.r. = 5.4) by (+)-ZACA-oxidation,
which was readily purified by ordinary column chromatog-
raphy. Bromide 2a (d.r. > 50) was thus synthesized in 43%
yield over three steps from 1-octadecene.
[21]
and 3 mol% [(+)-(NMI) ZrCl ] in anhydrous CH Cl at
2
2
2
2
either 08C or room temperature resulted only in recovered
starting material (Table 1, entry 1). It has been shown that the
addition of water (1 equiv) greatly accelerates the methyl-
Trimethyl-branched intermediate 3a was synthesized by
[19c]
a similar strategy as shown in Scheme 3.
Alcohol 10 was
prepared from styrene by ZACA-vinylation and ZACA-
oxidation. After conversion of 10 into 11 in 88% yield by
[22]
alumination of terminal alkenes. Indeed, the methylalumi-
Table 1: Water effect on the ZACA reaction of 1-octadecene.
[
a]
[b]
[c]
Entry
[(+)-(NMI) ZrCl ]
H O
2
Yield [%]
ee [%]
2
2
1
2
3
4
5
6
3 mol%
1 mol%
1 mol%
1 mol%
1 mol%
1mol%
none
0
NA
40
52
73
77
77
100 mol%
50 mol%
5 mol%
2 mol%
2 mol%
45
66
77
60
Scheme 3. Synthesis of fragment 3a by ZACA reaction.
[
[
a] [(À)-(NMI) ZrCl ] (2 mol%), AlMe (3 equiv), H O (1 equiv), 08C.
2
2
3
2
b] i) Zn(OTf) (1.2 equiv); ii) [PdCl (DPEPhos)] (3 mol%), DIBAL-H
2 2
[
d]
82
(
6 mol%), vinyl bromide (6 equiv). [c] [(À)-(NMI) ZrCl ] (2 mol%),
2
2
1
[
a] Freshly prepared. [b] Isolated yield. [c] Determined by H NMR of
AlMe (2 equiv), H O (2 mol%), 08C. [d] i) tBuLi, ii) ZnBr , iii) [PdCl -
3
2
2
2
Mosher ester analysis of the alcohol 6. [d] Yield obtained after 24 h.
(DPEPhos)] (5 mol%), DIBAL-H (10 mol%), vinyl bromide (4 equiv).
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iodination and Negishi coupling, another ZACA-oxidation
produced 12 in 80% yield (62% after chromatographic
purification to d.r. > 50), which was further transformed to
bromide 3a.
The third key fragment 4 was synthesized from the
commercially available diol 5, which, in turn, is available in
[20]
one step from acetylacetone by asymmetric hydrogenation.
Fragment 4 was then synthesized as a single stereoisomer by
[24]
Mitsunobu reaction and tosylation (Scheme 4).
Scheme 4. Synthesis of fragment 4.
With the key fragments in hand, we were in a position to
Scheme 5. Highly convergent synthesis of phthioceranic acid (1).
3
3
test the key stereospecific sp –sp cross-coupling, inspired by
recent Cu-catalyzed cross-coupling of nonactivated secondary
[18a]
alkyl halides or tosylates by L. Liu.
By using CuI/TMEDA/
Using the modified conditions for Cu-catalyzed stereo-
specific cross-coupling, we achieved a convergent assembly of
phthioceranic acid (1). Thus, bromide 2a was converted to the
corresponding Grignard reagent 2 and coupled with fragment
LiOMe catalytic system, the desired product 13 was obtained
in modest 40% yield with complete inversion of configuration
d.r. > 50) (Table 2, entry 1). To our delight, changing
(
4
providing 14 in 58% yield (Scheme 5). After hydrolysis and
tosylation, tosylate 15 was subjected to another Cu-catalyzed
cross-coupling reaction with Grignard reagent 3 and afforded
the key intermediate 16 with excellent stereoselectivity (d.r.
Table 2: Optimization of stereospecific Cu-catalyzed cross-coupling of 4.
>
50). Finally, conversion of the phenyl moiety of 16 to the
carboxylic acid by oxidative cleavage with RuCl /NaIO
3
4
completed the synthesis of phthioceranic acid (1) in 8 steps
in longest linear sequence. With essentially full stereocontrol
of Cu-catalyzed cross-coupling, phthioceranic acid was gen-
erated as a single stereoisomer. Comparison of the proton and
[a]
Entry
Catalyst
Ligand
X
Yield [%]
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
TMEDA
TMEDA
PMDETA
HMTETA
2,2’-bipyridyl
2,2’:6’,2’’-terpyridine
1,10-phenanthroline
2,2’-bipyridyl
Br
Cl
Br
Br
Br
Br
Br
Br
Br
40
38
69
67
71
46
52
62
75
13
C NMR data with those of compounds previously synthe-
[11,16]
sized by other groups
showed a perfect match.
In summary, we have developed a highly concise, con-
vergent and enantioselective route to a long-chain polydeoxy-
propionate phthioceranic acid by an eight-step longest linear
sequence involving coupling together three smaller building
blocks. Key steps include ZACA-Pd-catalyzed vinylation, and
[
b]
[b]
CuI
2,2’-bipyridyl
3
3
two sequential Cu-catalyzed stereospecific sp –sp cross-
coupling reactions proceeding with full inversion of config-
uration. In view of the practically perfect stereocontrol
observed in the Cu-catalyzed cross-coupling, we anticipate
that the strategy described herein will provide a general and
efficient method for the straightforward construction of
enantiomerically and diastereomerically pure polydeoxypro-
pionates without resorting to very difficult late-stage purifi-
cation of the diastereomeric mixtures.
[
a] Isolated yields. [b] CuI (20 mol%) and 2,2’-bipyridyl (40 mol%) were
used. TMEDA=N,N,N’,N’-tetramethylethylenediamine,
PMDETA=N,N,N’,N’’,N’’-pentamethyldiethylenetriamine,
HMTETA=1,1,4,7,10,10-hexamethyltriethylenetetramine.
bidentate N,N,N’,N’-tetramethylethylenediamine (TMEDA)
to tridentate PMDTA (N,N,N’,N’’,N’’-pentamethyldiethyle-
netriamine) significantly improved the yield to 69% (entry 3).
Tetradentate 1,1,4,7,10,10-hexamethyltriethylenetetramine
(
HMTETA) did not further improve the reaction (entry 4).
Keywords: asymmetric synthesis · cross-coupling ·
natural product synthesis · polydeoxypropionates ·
ZACA reaction
The use of bidentate aromatic 2,2’-bipyridyl increased yield to
7
2
throline provided lower yields (entries 6 and 7). After using
CuI (20 mol%) and 2,2’-bipyridyl (40 mol%), the desired
product 13 was obtained in 75% with essentially perfect
stereocontrol (d.r. > 50).
1% (d.r. > 50) (entry 5). However, tridentate aromatic
,2’:6’,2’’-terpyridine and rigid planar bidentate 1,10-phenan-
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