Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction

Article abstract of DOI:10.1038/nchem.1947

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin 2-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Full text of DOI:10.1038/nchem.1947

ARTICLES
PUBLISHED ONLINE: 11 MAY 2014 | DOI: 10.1038/NCHEM.1947
Synthesis of most polyene natural product
motifs using just 12 building blocks and one
coupling reaction
Eric M. Woerly, Jahnabi Roy and Martin D. Burke
*
The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized
synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via
iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity
commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the
polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and
one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both
the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first
total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin b-D-glucopyranoside.
Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.
ost of the molecules found in living systems are prepared serving as pharmaceutical agents12, pigments for light harvesting13,
naturally via the iterative assembly of a limited number fluorescent probes14, quenchers of reactive oxygen species15 and
M
of bifunctional building blocks (Fig. 1a)1. For example, pro- transducers of solar energy into mechanical energy16. Synthesis of
teins are usually derived from just 20 amino acids, and DNA and these natural products is made challenging by their sensitivities
RNA are each made from only four nucleotides1. Capitalizing on to light, oxygen and many common reagents, including protic
this inherent modularity, generalized strategies based on building and Lewis acids, as well as by difficulties in controlling the stereo-
blocks have been developed for efficient, flexible and fully auto- chemistry of each double bond. Common methods for the synthesis
mated access to these molecules in the laboratory2–4, and the result- of polyenes include olefin-generating reactions11, such as the Wittig,
ing impacts on science, medicine and technology have been Horner–Wadsworth–Emmons and Julia olefinations, but these
transformational. In a similar vein, a recent analysis revealed that stereoselective processes often suffer from a lack of stereocontrol.
75% of all mammalian oligosaccharides comprise just 36 monosac- Reactions based on transition metals17,18 with organozinc, organos-
charide units5, and an increasingly general platform for automated tannane, organosilicon and organoboron intermediates have the
oligosaccharide synthesis is broadening access to this class of bio- important advantage of stereospecificity; that is, the stereochemistry
molecules as well6. In stark contrast, traditionally the laboratory syn- in the building blocks can be translated faithfully into the products,
thesis of small-molecule natural products has involved the but the required building blocks and/or intermediates often suffer
customized development of a unique pathway and collection of from instability and/or toxicity.
building blocks to access each target. As a result, despite many
The preparation of polyenes via cross-coupling of non-toxic orga-
important advances in accessing individual structures, small-mol- noboron intermediates has been impeded specifically by the instability
ecule synthesis remains a relatively inefficient and inflexible of polyenyl boronic acids19, yet some progress has been made, includ-
process practised almost exclusively by specialists.
ing several recent examples that involve iterative cross-coupling with
Importantly, like their peptide, oligonucleotide and oligosacchar- stable N-methyliminodiacetic acid (MIDA) boronates20–23. In this
ide counterparts, most small-molecule natural products are bio- type of synthesis, bifunctional haloboronic acid building blocks with
synthesized via iterative building block assembly (Fig. 1b)1. For all of the required functional groups preinstalled in the correct oxi-
example, polyketides are constructed from malonyl coenzyme A dation states and with the desired stereochemical relationships are
(CoA) and methylmalonyl CoA, polyterpenes from isopentenyl linked together sequentially using only the stereospecific Suzuki–
and dimethylallyl pyrophosphate, fatty acids from malonyl CoA, Miyaura cross-coupling reaction in an iterative manner. The MIDA
non-ribosomal peptides from amino acids and polyphenylpropa- ligand prevents random oligomerization via reversible attenuation of
noids from phenylpyruvic acid. This suggests that a systematic the reactivity of the borane terminus21,22, analogous to the way a 9-
approach based on building blocks should make many small mol- fluorenyl-methoxycarbonyl (FMOC) groupenablesthe precise assem-
ecules similarly attainable.
bly of amino acids. MIDA boronates are also convenient to prepare,
With this goal in mind, we aim to identify substructural motifs analyse, purify and store, and more than 170 are now commercially
that are prevalent in natural products and transform them into mini- available24. Collectively, these features have enabled the simple, effi-
mized collections of bifunctional building blocks compatible with cient and flexible synthesis of a wide range of small-molecule
iterative assembly7–10. Polyene natural products provide an excellent natural products21,23,25–30, pharmaceutical agents31–34, ligands35,36
opportunity for exploring this concept, as they are well represented and materials37 via iterative cross-coupling.
across all major biosynthetic classes (Fig. 1c)11. These molecules
Building on this momentum, we decided to ask the question,
also perform a wide range of important functions, including how many bifunctional MIDA boronate building blocks would be
Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. e-mail: burke@scs.uiuc.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
a
Oligonucleotides
b
NH2
N
Polypeptides
Polyketide
Polyterpene
O
O
O
NH2
N
O
Me
O
P
HO
HO
Co-A
O
O
P
HO
S
O
R
O
Me
O
O
O
HO
Amino acids
Methylmalonyl CoA
Nucleosides
Isopentenyl pyrophosphate
Oligosaccharides
OH
Polyphenylpropanoid
O
Fatty acid
CO2H
O
HO
Non-ribosomal peptide
HO
OH
OH
O
O
O
NH2
OH
HO
Co-A
HO
S
Phenylpyruvic
acid
Sugar units
Amino acid
Malonyl-CoA
c
O
Me
Me
Me
Me
Me
O
Me Me
Me Me
HO
O
OH
OH
O
O
O
Me
HO
Me
Me
CO2Me
Me
Me
Me
O
HO
Me
Me
N
H
HO
Epolactaene
(hybrid peptide/polyketide)
Apozeaxanthinone
(polyterpene)
Neurosporaxanthin β-D-glucopyranoside
(polyterpene)
OH
Cl
Me
O
OH
HO
Me
Me
Me Me
Me
OMe
Me
Me
Me
N
H
O
O
O
Me
Me Me
Me
Cl
Me
HO
Me
Dihydroxyagerafastin
(polyketide)
Auxarconjugatin A
(hybrid peptide/polyketide)
O
Violaxanthin
(polyterpene)
H
OMe
O
H
OH
O
OH
NHAc
O
Me
O
OH
O
CO2H
MeO
CO2H
HO2C
O
O
N
H
H
Fuligoic acid
(fatty acid)
Natamycin
(polyketide)
O
O
Me
OH
Physarigin A
(fatty acid)
HO
OH
Cl
NH2
O
O
HO
Me
Me
H2O3PO
Me
Me
O
CN
NC
Me
Me
Me
OCONH2
Me
O
OH
O
MeO
Me
O
CO2H
H
Me
Me
OH
OH
OMe
Me
Me
OH
Cl
O
HO
Asnipyrone B
(polyketide)
Enacyloxin IIa
Hemicalyculin A
(polyketide)
(hybrid peptide/polyketide)
Figure 1 | The iterative assembly of bifunctional building blocks is a versatile strategy for the preparation of small molecules. a, Nature biosynthesizes
macromolecules, including polypeptides, oligonucleotides and oligosaccharides, via the iterative coupling of building blocks. b, Nature similarly prepares small
molecules derived from a range of biosynthetic pathways via the iterative assembly of bifunctional building blocks. c, A collection of polyene natural products
from a variety of biosynthetic pathways.
required to make most of the polyene motifs found in nature? To to date (238,541 as of 15 January 2012) was used to identify all
find the answer, we devised a general retrosynthetic algorithm for known polyene natural products. Specifically, a substructure search
systematically deconstructing these motifs into the minimum total for a polyene, defined as three or more carbon–carbon double bonds
number of building blocks. This analysis generated the intriguing in conjugation, none of which are contained in a ,12-membered
hypothesis that the polyene motifs found in .75% of all polyene ring, returned 2,839 natural products. Importantly, this set includes
natural products can be prepared using just 12 MIDA boronate small molecules derived from all major biosynthetic classes:
building blocks and one coupling reaction. As described below, polyterpenes, polyketides, fatty acids, hybrid peptide/polyketides and
we have tested and confirmed this hypothesis.
polyphenylpropanoids (Fig. 1c).
To determine the minimum number of bifunctional MIDA bor-
onate building blocks that would be required to access the polyene
Results
The Dictionary of Natural Products38, a comprehensive database motifs found in most of these natural products and maximize the
of small molecules isolated from natural sources and characterized stability of the corresponding building blocks and intermediates,
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
which is then dissected into two copies of the same dienyl building
block (Fig. 2b). This dienyl substructure is also found in more than
350 additional polyene natural products, including auxarconjugatin
A, natamycin and fuligoic acid (Fig. 1c), which again reveals the
potential for a high degree of overlapping building-block utility.
In a third example, the complex polyene motif found in the poly-
terpene-derived natural product neurosporaxanthin b-D-glucopyra-
noside41 is identified as the corresponding octaene (Fig. 2c).
Following the general retrosynthetic guidelines, this motif is dis-
sected into the fewest number of building blocks of similar size,
that is, a diene and two trienes. To minimize the length, and there-
fore maximize the stability of the polyenyl borane intermediates, the
algorithm first selects coupling a diene building block followed by
two different trienes. As a result, three building blocks are identified
as being required for this synthesis. Importantly, at least one of these
building blocks is similarly identified as potentially contributory to
the synthesis of over 1,100 other polyene natural products, including
violaxanthin, enacyloxin IIa and hemicalyculin A (Fig. 1c), which
again demonstrates the potential for a high degree of redundant
building-block utilization.
a
O
O
OMe
Me
Me
Asnipyrone B
MeN
B
O
O
O
X
O
Me
Me
NHAc
O
b
MeO
CO2H
N
H
Physarigin A
Systematic manual application of this same algorithm to all 2,839
polyene natural products and filtering for a maximum overlap in
building-block utilization revealed a striking result: theoretically,
only 12 bifunctional haloalkenyl MIDA boronate building blocks
(BB1–BB12, Fig. 3a) are required to access the polyene motifs
found in .75% of polyene natural products. Efficient and stereospe-
cific syntheses of all 12 of these building blocks was accomplished
readily by taking advantage of many of the enabling features of the
MIDA boronate platform, which include compatibility of the
MIDA boronate group with many different types of reaction con-
ditions and purification by column chromatography (see
Supplementary Information), and already four of these building
blocks (BB1–BB4) are commercially available.
MeN
B
MeN
B
O
O
O
O
O
O
X
X
O
O
c
Me
Me
O
Me Me
HO
O
OH
OH
O
Me
Me
Me
Me
HO
Neurosporaxanthin β-D-glucopyranoside
Me
Me
Me
Me
When we first attempted to construct complex polyene motifs via
iteratively coupling these building blocks together, we encountered
an important limitation21. Specifically, although the polyenyl
MIDA boronate intermediates were stable, many of the deprotected
polyenyl boronic acid intermediates were not25,26, which resulted in
poor or no yields of the desired final products. Alternatively, we
found that the corresponding polyenyl boronic esters, which can
also be formed readily via transligation of MIDA boronates with
pinacol, are much more stable. The challenge with using pinacol
esters as intermediates, however, is that they generally require
aqueous basic conditions for subsequent cross-coupling42, and
MeN
B
Me
O
O
O
MeN
X
MeN
B
O
Me
B
O
O
O
O
Me
X
O
O
O
X
O
Me
Figure 2 | Three examples of applying the standardized three-step
retrosynthetic algorithm to polyene natural products not synthesized
previously. a, Asnipyrone B. b, Physarigin A. c, Neurosporaxanthin
b-D-glucopyranoside.
we developed the following systematic three-step retrosynthetic such conditions are incompatible with the aqueous base-labile
algorithm: (1) the polyene motif is identified as the polyene frame- MIDA boronate protecting group on the bifunctional building
work minus the two olefinic termini, (2) using mono-, di- and triene blocks. As an opportunity to overcome this potential impasse, it
haloalkenyl MIDA boronates, the polyene motif is dissected into was determined that when dimethylsulfoxide (DMSO) is employed
the fewest number of building blocks that are as similar in size as solvent, vinyl pinacol boronic esters can be cross-coupled under
as possible and (3) disconnections are chosen such that the length anhydrous conditions26,43. We thus envisioned a modified iterative
of the longest polyenyl borane intermediate in each pathway cross-coupling cycle that involved the initial coupling of a pinacol
is minimized.
boronic ester to a bifunctional halo MIDA boronate building
The following examples demonstrate the application of this block under anhydrous DMSO conditions followed by deprotection
general retrosynthetic algorithm to three structurally diverse and of the resulting MIDA boronate to generate a new pinacol boronic
not previously synthesized polyene natural products derived from ester suitable for the next round of coupling (Fig. 3b).
a range of biosynthetic pathways (Fig. 2). Asnipyrone B is a polyke-
With the goal to develop a maximally general platform, we
tide-derived polyene natural product isolated from Aspergillus further sought to identify common reaction conditions for coupling
niger39 (Fig. 2a). Applying the algorithm, the targeted motif is ident- polyenyl pinacol esters with haloalkenyl MIDA boronate building
ified as a simple trans-monoene, and a single bifunctional building blocks and to transform the resulting polyenyl MIDA boronates
block would be required. Importantly, this same substructure is also into the corresponding pinacol boronic esters. For the latter, we
found in more than 1,200 other polyene natural products, including found that a wide range of polyenyl MIDA boronates of varying
epolactaene, apozeaxanthione and dihydroxyagerafastin (Fig. 1c), lengths and with varying substitution patterns can all be converted
which reveals that the same bifunctional building block could con- into the corresponding pinacol esters using the same conditions:
tribute to the construction of many other natural products.
pinacol and NaHCO3 in MeOH at 45 8C for three hours.
Using the same algorithm, the polyene motif of the fatty-acid- Moreover, we found that polyenyl pinacol esters of varying
derived natural product physarigin A40 is identified as a tetraene, length, stereochemistry and methyl-substitution patterns can all
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
a
MeN
B
b
X
O
O
O
MeN
MeN
B
O
O
O
O
B
O
O
O
I
Br
O
O
C
BB5
BB1
Cross-coupling
Me
Me
Me
Me
MeN
B
O
O
B
O
O
O
O
MeN
MeN
B
Me
Br
B
O
O
O
O
O
I
O
O
O
Me
Me
Me
Me
Pinacol
D
Me
HO
HO
N
BB6
BB2
Deprotection
HO2C
CO2H
MIDA
MeN
MeN
B
MeN
B
MeN
B
Me
Me
B
O
O
O
O
O
O
O
O
O
O
O
O
Br
I
I
Br
O
O
O
O
Me
BB9
Me
Me
BB11
BB3
BB7
MeN
MeN
MeN
B
MeN
B
Me
Br
B
O
O
O
B
O
O
O
O
O
O
O
O
O
I
I
I
O
O
O
O
Me
Me
Me
BB10
BB12
BB8
BB4
Figure 3 | A general platform for making polyene motifs via iterative cross-coupling. a, A collection of 12 bifunctional MIDA boronate building blocks
BB1–BB12 can be used to synthesize the polyene motifs found in .75% of all polyene natural products. b, An iterative cross-coupling strategy that involves
the coupling (C in circle) of a pinacol boronic ester to a bifunctional halo MIDA boronate building block followed by deprotection (D in circle) of the
resulting MIDA boronate to generate a new pinacol boronic ester suitable for the next round of coupling. Trapezoids represent building blocks.
be coupled to mono-, di- and trienyl bromide and iodide bifunc- highly complex decaene 15. The yields for the deprotection steps
tional MIDA boronate building blocks using the same set of were generally outstanding, even with very long and complex
cross-coupling conditions: XPhos (dicyclohexyl(2′,4′,6′-triisopro- polyene intermediates. Importantly, although the yields for the
pyl-2-biphenylyl)phosphine) palladacycle precatalyst44, Cs2CO3 cross-couplings tended to decrease somewhat as the length of the
and DMSO. Further, it was determined that final couplings polyene intermediates grew larger, the predictability of this trend
between a polyenyl MIDA boronate intermediate and capping enabled us to begin each sequence with the appropriate amounts
vinyl-halide building block can be best achieved using a common of the required building blocks and thereby produce milligram
set of aqueous basic conditions (XPhos palladacycle precatalyst, quantities of the targeted final products in every case. Successful
.
NaOH and THF H2O) to promote the in situ release of an unstable, syntheses of these targets demonstrates a general approach to the
but also highly reactive, polyenyl boronic acid directly from the cor- polyene motifs found in .75% of all the polyene natural products
responding stable polyenyl MIDA boronate45.
isolated to date.
With these building blocks and the general reaction conditions in
Encouraged by the broad applicability of this platform, we
hand, we sought to test the hypothesis that, collectively, they can further targeted its application to complete the first total syntheses
enable the preparation of most of the polyenes found in nature. of a series of polyene natural products that represent a range of
To enable such an experiment, we identified a collection of biosynthetic pathways, namely the polyketide asnipyrone B
polyene motifs that represent the corresponding chemical space (natural product 1 (NP1)), the fatty-acid physarigin A (NP2) and
occupied by .75% of all polyene natural products (A–O, Fig. 4). the polyterpene neurosporaxanthin b-D-glucopyranoside (NP3)
This collection includes both trans- and cis-olefins, various (Fig. 5), using the same retrosynthetic algorithm, collection of
methyl-substitution patterns and a wide range of chain lengths bifunctional building blocks and common reaction conditions.
(from three to ten double bonds), and thus represents a substantial Therefore, applying this approach to each of these total syntheses
challenge for the development of a common synthesis platform.
only required the preparation of the corresponding capping
Utilizing only the aforementioned general retrosynthetic algor- elements. Thus, relative to the traditional design of an indi-
ithm, the same 12 MIDA boronate building blocks and common vidualized synthesis route to each natural product, preparation of
deprotection and cross-coupling conditions, we attempted to syn- all the corresponding customized building blocks and ad hoc
thesize all of the targeted polyene motifs 1–15, with MIDA optimization of all the reaction conditions required to couple
boronate 16 and vinyl iodide 17 serving as representative natural- those building blocks together, this systematized approach has
product-like capping groups. Without any ad hoc optimization of major advantages. Moreover, as described below, more than 75%
the platform, all of the targeted polyene motifs were prepared suc- of the capping elements represented in the complete collection of
cessfully (Table 1).
polyene natural products fall into just 20 general structural cate-
These syntheses ranged from a single round of iterative cross- gories for which common synthetic routes exist or can be
coupling to generate triene 1 to four iterations to generate the readily envisioned.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
A
B
Me
Me
Me
C
Me
Me
Me
Me
D
A
B
C
D
E
F
Me
Me
Me
G
H
I
Me
E
F
G
H
I
Me
Me
J
Me
Me
Me
K
L
J
K
L
M
N
O
Me
Me
Me
Me
Me
Me
M
N
O
0
100
200
300
400
500
600
700
800
900
1,000
Number of natural products
Figure 4 | A collection of polyene motifs collectively found in >75% of all polyene natural products.
After facile preparation of the required capping elements
Discussion
(Supplementary Information)46,47, preparation of asnipyrone B Herein we demonstrate explicitly the synthesis of the polyene motifs
(NP1) commenced with a standardized deprotection of MIDA bor- found in .75% of all known polyene natural products. These
onate 18 and coupling with commercially available halo MIDA bor- natural products represent much of the diversity found in the com-
onate BB3 to provide diene 19 (Fig. 5a). This sterically encumbered plete collection. Further, it is encouraging that accessing .90% of
1,3-methyl-substituted motif was prepared readily without modifi- this chemical space would require only 25 building blocks, .95%
cation of the general reaction conditions. Application of the would require a total of 50 and the motifs found in all polyene
general in situ deprotection/coupling conditions with capping natural products could be accessed with only 75 building blocks
building block 20 completed a very efficient and fully stereocon- (Supplementary Information).
trolled first total synthesis of this natural product.
Completing the total syntheses via this approach also requires
Physarigin A (NP2) similarly only required preparation of the access to the terminal capping elements. Importantly, similar to
capping building blocks 21 and 22. The latter is a variant of a the high level of structural redundancy found in the polyene
known building block48, and preparation of the former was facili- motifs, a systematic analysis of the capping elements has also
tated greatly by using another commercially available MIDA boro- revealed a substantial level of structural overlap (for the complete
nate (Supplementary Information) (Fig. 5b)49. In the event, analysis, see the Supplementary Information). For example, if a
deprotection of 21 and cross-coupling to BB5 using our standar- unique pair of building blocks was found in each of the 2,839
dized conditions provided the triene 23 in good yield. Another targets, 5,678 capping elements would be necessary. However, the
round of deprotection and coupling with the same bifunctional high level of structural redundancy reduces this number to 1,942
building block established the structure of the targeted pentaene unique building blocks, and just 604 of these building blocks
intermediate 24. A final cross-coupling with halide 22 completed would be needed to access 75% of all the caps found in polyene
the first total synthesis of physarigin A.
natural products. Moreover, these 604 building blocks can be
Finally, we questioned whether this platform could enable the subdivided into just 20 common structural classes (for example,
total synthesis of the complex polyene natural product neurosporax- a/b-unsaturated esters, allylic alcohols and styrenes), in which
anthin b-D-glucopyranoside (NP3) (Fig. 5c). Again, the corre- most members of each class can probably be accessed using
sponding capping elements were accessed readily (Supplementary small variations of a common synthetic route. Syntheses of
Information), and the synthesis commenced via deprotection of many of these building blocks can be facilitated further by using
MIDA boronate 25 and subsequent cross-coupling of the resulting commercial MIDA boronates that are already available, including
pinacol boronic ester with diene BB6 to provide tetraene 26. A BB1–BB4, just as the capping element 18 in the synthesis of
second, third and fourth iteration of couplings with building asnipyrone B was prepared in a single step from BB3. Finally,
blocks BB11, BB9 and 27, respectively, without any ad hoc optim- alkenyl MIDA boronates can be converted directly into alkenyl
ization of our previously established standard conditions, followed halides27, which allows for the rapid preparation of many halide
by removal of the protecting groups, readily provided the first syn- capping elements from the corresponding readily accessible
thetic access to this highly complex polyene natural product.
All of these results collectively support the conclusion that most
MIDA boronates.
The 2,839 natural products included in this study represent
polyene natural product motifs can now be prepared using just 12 more than 1% of all the natural products isolated to date. It is
building blocks and one coupling reaction.
stimulating to consider how many building blocks would be
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
Table 1 | The synthesis of polyene motifs present in >75% of all known polyene natural products.
MeN
Me
Me
MeN
MeN
B
X
B
O
O
O
O
B
Me
Me
O
B
O
O
O
O
O
O
D
O
C
O
O
16
MeN
MeN
B
MeN
MeN
B
X
B
O
O
O
X
O
O
O
B
O
O
O
O
O
O
O
O
O
O
D
C
D
C
Deprotection
Pinacol,
Coupling
C
Deprotection/coupling
2nd generation XPhos 2nd generation XPhos
I
OH
17
DC
D
NaHCO3, MeOH
Cs CO , DMSO NaOH, THF·H O
Pd cycle,
Pd cycle,
2
3
2
OH
DC
Trapezoids represent building blocks
Polyene MIDA boronates
Polyene product
Polyene MIDA boronates
Polyene product
motif
coupled
motif
coupled
Me
Me
97
(CH2)3OH
Cy
A
N
BB6, BB6
BB1
(CH2)3OH
1
Cy
D
:
:
:
95
D
C
Isolated
yields (%)
9
52
65
:
95
Isolated
yields (%)
DC
:
:
C
74
74
DC
52
E
BB2
(CH2)3OH
L
BB5, BB8
Cy
(CH2)3OH
Cy
D
2
10
:
95
43
D
:
95
78
98
60
C:
:
:
C
73
DC:
DC
45
(CH2)3OH
Me
Cy
F
BB3
O
BB6, BB10
Me
(CH2)3OH
Cy
D
3
:
95
56
D
Me
Me
11
C:
:
95
74
97
48
66
DC:
:
:
C
Me
DC
29
M
BB4
Me
Cy
(CH2)3OH
H
BB7, BB9
(CH2)3OH
Cy
D
4
:
:
:
95
50
D
Me
12
C
:
95
75
91
18
74
DC
:
:
C
DC
60
(CH2)3OH
D
BB5
Cy
D:
Me
5
C
BB12, BB10
95
78
(CH2)3OH
Cy
D
:
:
C
Me
Me
31
DC
13
:
95
32
96
31
Me
:
:
C
(CH2)3OH
DC
29
Cy
:
I
BB6
6
Me
Me
95
74
D
B
BB6, BB6, BB10
:
:
(CH2)3OH
C
DC
Cy
D
55
Me
Me
14
:
95
74
97
74
97
52
(CH2)3OH
:
:
C
Cy
G
BB8
BB9
DC
36
7
8
:
95
81
D
C:
Me
Me
44
DC:
(CH2)3OH
J
BB6, BB11, BB9
Cy
D
Me
Me
(CH2)3OH
15
Cy
K
:
95
74
97
51
99
38
Me
:
:
C
:
95
50
D
DC
48
C:
DC
88
:
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
a
MeN
B
MeN
b
BB5
NHAc
NHAc
MeN
B
MeN
B
BB3
MeO
MeO
O
O
O
B
O
O
O
D
C
O
O
O
O
O
O
D
C
O
O
O
O
Me
19
Me
Me
99%
85%
21
23
MeN
85%
59%
18
BB5
NHAc
O
MeO
B
O
O
D
C
O
O
O
99%
55%
24
Br
OMe
O
20
CO2H
Asnipyrone B
Br
N
DC
H
NP1
22
Physarigin A
72%
DC
NP2
10%
c
MeN
B
MeN
Me Me
Me
Me Me
BB6
BB11
B
O
O
O
O
O
O
D
C
D
C
O
O
Me
Me
99%
66%
99%
52%
26
25
MeN
B
Me
Me
Me Me
MeN
BB9
Me
Me Me
Me
O
O
O
B
O
O
O
D
C
O
O
Me
Me
Me
Me
29
Me
99%
30%
28
O
OSiEt3
O
OSiEt3
OSiEt3
Br
O
Me
Me
O
Me Me
RO
Me
27
DC
73%
OR
OR
OSiEt3
O
O
Me
Me
Me
Me
RO
30, R = SiEt3
Neurosporaxanthin β-D-glucopyranoside NP3, R = H
HF pyridine
THF
39%
Figure 5 | The total synthesis of three polyene natural products using bifunctional MIDA boronate building blocks and one set of reaction conditions in
an iterative fashion. a, The total synthesis of asnipyrone B (NP1). b, The total synthesis of physarigin A (NP2). c, The total synthesis of neurosporaxanthin
b-D-glucopyranoside (NP3). C in circle represents coupling; D in circle represents deprotection; DC in circle represents deprotection/coupling.
required to access most of the remaining 99%. Although the However, unlike their peptide, oligonucleotide and oligosaccharide
answer to this is not yet known, the strategy demonstrated counterparts, small molecules do not inherently possess a common
herein, that is, systematically identifying common motifs and functional-group handle that can be used for attachment to a solid
transforming them into bifunctional building blocks compatible support. Thus, the generalized automation of small molecule syn-
with iterative coupling, provides
a roadmap for pursuing thesis represents an exceptional problem that will require a
this problem. For example, we have identified 12 additional distinct solution.
common structural motifs that are collectively present in more
Finally, although we focus herein on a generalized approach to
than 100,000 natural products (Supplementary Information). make known polyene natural products, the combinatorial assembly
Half of these motifs have already been transformed into bi- of the building blocks derived from this analysis could provide
functional halo MIDA boronates that are now commercially access to many new polyene natural product-like compounds.
available. To achieve the same goal with some of the others Expanding this same concept to include building blocks algorithmi-
will require solutions to frontier methodological problems, cally derived from all known natural products could provide practi-
which include new chemistry to make and stereospecifically cal access to large collections of natural product-like compounds for
cross-couple Csp3 boronates. In this vein, it is highly encouraging functional screening.
that there have been many recent advances in methods to
prepare and stereoretentively cross-couple Csp3 boronic acids building block-based approach for small-molecule synthesis would
and/or their derivatives50.
substantially expedite and broaden access to the extraordinary
In summary, the development of a more general and systematic
With at least the conceptual framework for a more-generalized functional potential that these molecules possess. The results
approach to small-molecule synthesis in hand, the prospective presented herein demonstrate an actionable roadmap to pursue
impact of fully automating the building-block assembly process is this objective.
increasingly clear. The achievement of such automation with pep-
tides2, oligonucleotides3 and, increasingly, oligosaccharides4 has
had a transformative impact on the respective areas of molecular
science. The key to automating iterative synthesis is to find a way
Methods
Full experimental details, procedures and characterization for new compounds are
included in the Supplementary Information.
to purify the intermediates automatically, and in all of these previous Received 30 January 2014; accepted 4 April 2014;
cases, this goal has been achieved via solid-phase synthesis2–4
.
published online 11 May 2014
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7

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1947
ARTICLES
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Acknowledgements
We gratefully acknowledge A. Hill for helping to complete the synthesis of physarigin A and
S. O’Hara and S. Fujii for building-block synthesis, as well as the National Institutes of
Health (GM080436 and GM090153) and Howard Hughes Medical Institute (HHMI) for
funding. M.D.B. is an HHMI Early Career Scientist and E.M.W. was a Natural Science
Foundation Predoctoral Fellow.
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Author contributions
E.M.W. and M.D.B. conceived the project. E.M.W., J.R. and M.D.B. designed and executed
the experiments. E.M.W. and M.D.B. wrote the paper.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to M.D.B.
30. Fujita, K., Matsui, R., Suzuki, T. & Kobayashi, S. Concise total synthesis of (2)-
myxalamide A. Angew. Chem. Int. Ed. 51, 7271–7274 (2012).
Competing financial interests
The authors declare no competing financial interests.
8
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