Accelerating spirocyclic polyketide synthesis using flow chemistry

Article abstract of DOI:10.1002/anie.201402056

Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction.

Full text of DOI:10.1002/anie.201402056

Angewandte
Chemie
DOI: 10.1002/anie.201402056
Natural Product Synthesis Very Important Paper
Accelerating Spirocyclic Polyketide Synthesis using Flow Chemistry**
Sean Newton, Catherine F. Carter, Colin M. Pearson, Leandro de C. Alves, Heiko Lange,
Praew Thansandote, and Steven V. Ley*
Abstract: Over the past decade, the integration of synthetic
chemistry with flow processing has resulted in a powerful
platform for molecular assembly that is making an impact
throughout the chemical community. Herein, we demonstrate
the extension of these tools to encompass complex natural
product synthesis. We have developed a number of novel flow-
through processes for reactions commonly encountered in
natural product synthesis programs to achieve the first total
synthesis of spirodienal A and the preparation of spirangien A
methyl ester. Highlights of the synthetic route include an
iridium-catalyzed hydrogenation, iterative Roush crotylations,
gold-catalyzed spiroketalization and a late-stage cis-selective
reduction.
through the use of inline analytical tools for seamless reaction
analysis,[5] polymer-supported reagents to minimize down-
stream processing[6] and computational software to facilitate
multistep sequences.[7] Here we describe how the application
of these methods expedited the syntheses of two related
spirocyclic polyketide natural products, spirangien A methyl
ester (2) and spirodienal A (3) (Figure 1).[8]
Natural products provide constant inspiration for the
academic community with their fascinating structures and
potent biological activities.[1] Many effective batch-mode
techniques for their preparation exist, however, a successful
total synthesis programme still requires monumental research
effort. Each synthetic step requires intensive optimization
and repetitive experimentation. Today, given the plethora of
synthetic methods at our disposal, the challenges go beyond
one of molecular complexity to encompass more convergent,
atom/step efficient and sustainable processes.[2] These princi-
pals are important in any synthetic endeavour but in our
resource limited environment, the management of our labour
intensive, energy and solvent inefficient practices need to
change. As flow chemistry[3] continues to advance through the
on-going development of equipment and software, it is our
view that the next step is to expand the scope of flow
protocols to encompass the sensitive and asymmetric trans-
formations required to make natural products. Flow chemis-
try could streamline natural product synthesis, addressing
some of the issues encountered in batch-mode.[4] At the same
time, the challenging structures of natural products could be
used to elevate flow chemistry to a new level of discovery.
In recent times, our group has focused on developing flow
technologies and procedures to facilitate chemical processes
Figure 1. Spirocyclic polyketides isolated from Sorangium cellulosum.
Spirangien A (1) was isolated by Hçfle in 2005 from the
myxobacterium Sorangium cellulosum So ce90.[9] In 2008,
Paterson et al. reported the first total synthesis of 1 together
with its structurally more stable methyl ester 2, confirming the
structure and absolute stereochemistry.[10] This was followed
by a number of fragment-based syntheses which focused on
the spiroketal motif.[11] In 2009, Ahn isolated a related natural
product from Sorangium cellulosum KM0141, spirodienal A
(3),[12] the absolute configuration of which was unknown until
this work.
The synthesis began with 2,3-butane diacetal protected
aldehyde 4, the flow synthesis of which we have previously
described.[13] A functionalized triphenylphosphine mono-
lith[14] was then used to perform a Wittig reaction in flow.
The resultant triphenylphosphine oxide was immobilized on
the monolith, delivering a,b-unsaturated methyl ester 5
without further purification (Scheme 1) which was then
subjected to an asymmetric hydrogenation reaction in flow
using Pfaltzꢀs catalyst (R,R)-6[15] and a bespoke tube-in-tube
reactor to facilitate gas–liquid contact.[16] This reactor enables
pressurized gases to be used safely in the laboratory and
significantly reduces the volume of gas required relative to
batch-mode hydrogenations. A protecting group switch was
then performed on the vicinal diol to prepare acetonide 8.
Polymer-supported benzylamine (QP-BZA) and basic alumi-
nium oxide scavenged the acetic acid and ferric chloride
respectively so that solvent removal was the only necessary
manual handling required to isolate the product.
[*] Dr. S. Newton, Dr. C. F. Carter, Dr. C. M. Pearson, L. de C. Alves,
Dr. H. Lange, Dr. P. Thansandote, Prof. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: svl1000@cam.ac.uk
[**] We gratefully acknowledge EPSRC (S.N. and C.M.P.), AstraZeneca
(C.F.C.), CNPq SWB (L.de C.A.), Humboldt fellowship (H.L.),
NSERC (P.T.) and the BP 1702 Professorship endowment (S.V.L.) for
funding. We thank Prof. Ahn (Korea Maritime University) for kindly
providing spectroscopic data of spirodienal A and Johnson-Matthey
for their assistance with the hydrogenation step.
A telescoped reduction–crotylation protocol was then
used to convert methyl ester 8 directly into homoallylic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402056.
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Scheme 1. Flow synthesis of homoallylic alcohol 10. M=monolith; QP=QuadraPure; BZA=benzylamine; psi=pounds per square inch;
VBPR=variable back pressure regulator; DIBALH=diisobutylaluminium hydride; Bn=benzyl; Cy=cyclohexyl; BArF =tetrakis(pentafluorophenyl)-
borate.
alcohol 10.[17] Taking advantage of the superior temperature
control in flow, methyl ester 8 was selectively and reprodu-
cibly reduced to the aldehyde. In real time, the concentration
of the aldehyde intermediate was measured using a FlowIR
cell.[18] This data was exported and converted into a flow rate
for a third pump that dispensed crotylating reagent (S,S)-9.
This reagent is therefore automatically dispensed as a function
of the concentration of the aldehyde intermediate, maintain-
ing stoichiometry along a flowing stream of varying concen-
tration.
Homoallylic alcohol 10 was used to prepare two advanced
fragments, aldehyde 22 (Scheme 2) and bis-alkyne 31
(Scheme 3), which contain the same three contiguous stereo-
centers. This high yielding four step flow sequence from
readily available aldehyde 4 enabled useful quantities of this
key olefin to be prepared repeatedly on demand, which was
essential to support the synthesis in its latter stages.
The preparation of aldehyde fragment 22 from homo-
allylic alcohol 10 commenced with a telescoped silylation-
ozonolysis sequence. Olefin 10 was firstly reacted with
a stream of TESOTf and DIPEA (Scheme 2). The reaction
was complete in 30 seconds, taking advantage of the enhanced
mixing in the 1 mL chip. The output was then diluted with
methanol and subjected to a rapid flow of ozone.[19] The
resulting ozonide was collected in a flask containing polymer-
supported triphenylphosphine to generate aldehyde 11. This
setup avoids significant ozonide build up as it is instanta-
neously quenched. The fast flow rates used for this sequence
established a high throughput of 12 mmolhꢀ1 of aldehyde 11
from olefin 10.
The next two stereocenters were also installed using
a flow-Roush crotylation, this time with (R,R)-9. Chain
elongation reactions are key to natural product assembly
and the development of this flow protocol has been described
elsewhere.[17] In this sterically demanding case, boron tri-
fluoride was required to improve the conversion and diaste-
reoselectivity of the reaction. Advanced olefin 12 was then
dissolved in acetone and passed through a column containing
polymer-supported sulfonic acid (QP-SA) to concomitantly
cleave the silyl ether and protect the 1,3-diol as an acetonide
13. This was then subjected to a second ozonolysis in flow to
afford primary alcohol 14 following a reductive workup. The
same silyl protection procedure was then used, this time with
TBSOTf. However, in this case, the output from the 1 mL chip
was mixed with a stream of aqueous ammonium chloride
solution and directed through a commercially available flow
liquid-liquid extractor (FLLEX)[20] to remove the salts in situ
and furnish silyl ether 15. The FLLEX unit offers an
alternative to polymer-supported reagents for inline work-
up procedures.
A two step batch-mode sequence was required to
synthesize aldehyde 16. Selective cleavage of the external
acetonide to furnish the vicinal diol[21] was followed by
oxidative cleavage under standard conditions. These steps
required long reaction times and were not suitable for a flow
protocol. Aldehyde 16 was converted into alkyne 17 in flow
using the Ohira–Bestmann reagent.[22]
With alkyne 17 in hand, we then investigated methods to
install the two methyl groups of the terminal trisubstituted
double bond. This was eventually achieved through a silylcup-
ration reaction wherein the transient vinyl cuprate species
was quenched with iodomethane to generate vinylsilane 18
with the required syn relationship.[23] Vinyl iodide 19 was
prepared in flow by combining vinyl silane 18 with a solution
of N-iodosuccinimide. Excess reagent was efficiently removed
inline by washing with an aqueous thiosulfate solution. The
final methyl group of the trisubstituted double bond was
installed through a Negishi cross-coupling reaction between
vinyl iodide 19 and dimethylzinc in batch-mode (Scheme 2).
The last two steps to provide the advanced aldehyde fragment
22 were a silyl deprotection in flow, using an elevated reaction
temperature to reduce the reaction time from 16 h to 1 h,
2
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Scheme 2. Flow synthesis of aldehyde 22. Reagents and conditions a) TMSOTf, DIPEA, CH2Cl2, 08C!RT, 89%; b) NaIO4, THF-H2O (1:1), RT,
95%; c) CuCN, PhMe2SiLi, THF, 08C, then MeI, 08C, 90%; d) PdCl2(PPh3)2 (20 mol%), Me2Zn, THF, RT, 82%. TESOTf=triethylsilyl
trifluoromethanesulfonate; DIPEA=N,N-diisopropylethylamine; PS=polymer-supported; SA=sulfonic acid; TBS=tert-butyldimethylsilyl;
FLLEX=flow liquid-liquid extractor; CMP=cross membrane pressure; NIS=N-iodosuccinimide; TBAF=tetrabutylammonium fluoride;
BAIB=bis(acetoxy)iodobenzene; TEMPO=2,2,6,6-tetramethylpiperidine 1-oxyl.
followed by a TEMPO-mediated oxidation, again in flow.[24] It
was found that a plug of silica gel was sufficient to separate
any trace of unreacted alcohol 21 from the desired product
whereas the iodine by-products were removed with a poly-
mer-supported thiosulfate.
The second advanced fragment bis-alkyne 31 was also
prepared from homoallylic alcohol 10. As with the previous
fragment, the synthesis began with a telescoped silylation–
ozonolysis protocol (Scheme 3). However, in this case,
homoallylic alcohol 10 was treated with an excess of
TESOTf to both protect the secondary alcohol and open
the acetonide ring, preparing the primary silyl ether and
secondary enol ether in situ.[21] The output stream was then
diluted with methanol and subjected to a stream of ozone to
oxidatively cleave the enol ether and terminal olefin. This
single flow operation carries out three protecting group
manipulations and two oxidations, resulting in the prepara-
tion of aldehyde 23 for the subsequent chain elongation step.
The stereogenic relationship from C14–C16 was realized
following the method developed by Marshall et al., using
propargylic mesylate (R)-24 to generate a chiral allenylzinc
reagent in situ which reacts with aldehyde 23 through an SE2’
mechanism.[25] This furnished bis-silyl ether 25 in high yield
and reasonable diastereoselectivity which was then passed
through a column containing QP-SA held at low temperature
to perform the silyl deprotection and 1,3-diol protection in
a single step. The low temperature was necessary to avoid 1,2-
acyl migration of the secondary acetate group, a major
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Scheme 3. Flow synthesis of bis-alkyne 31. Reagents and conditions a) (R)-24, Pd(OAc)2 (10 mol%), PPh3, Et2Zn, THF, 08C!ꢀ788C!ꢀ208C!
RT, 95%. Ms=methanesulfonate; TMS=trimethylsilyl.
impurity formed during the corresponding batch protocol.[26]
Primary alcohol 26 was oxidized to aldehyde 27 in flow using
TEMPO, following the same procedure described above.
Dibromoolefin 28 was then synthesized using a previously
reported protocol from our group to effect the Ramirez
olefination in flow using a monolithic ylid.[27]
of complexity, aldehyde 22 and bis-alkyne 31 are among the
most advanced substrates prepared in flow to date.
Previous approaches prepared the spiroketal fragment via
conventional acid-catalyzed spiroketalization in which the
linear precursor was prepared from an aldol reaction.[29] Our
approach involved a highly ambitious gold catalyzed spiroke-
talization from an internal alkyne and so the fragments were
coupled by reacting the lithium acetylide of bis-alkyne 31 with
aldehyde 22 to furnish ynol 32 as an inseparable epimeric
mixture (d.r. = 2.7:1) at the C23 position (Scheme 4). This was
subsequently oxidized to the ynone and reduced using the
Corey–Bakshi–Shibata reagent (S)-33 to give a single diaste-
reoisomer[30] which was characterized via Mosherꢀs method
(see Supporting Information). The ynol was then methylated
and the linear precursor globally deprotected to afford pentol
34 in preparation for the key spiroketalization step.
In recent years, gold-catalyzed reactions have been used
in total synthesis programs to promote selective spiroketal-
ization reactions.[31] After extensive screening, it was found
that gold(I) chloride would promote the desired spiroketal-
ization event and afford the key spiroketal intermediate 35 in
moderate yield. Other spiroketal frameworks were isolated
including a minor amount of a [4.6]-spiroketal generated by
Attempts to generate the bis-alkyne from dibromoolefin
28 failed, presumably due to the lability of the acetate
protecting group. To progress the synthesis, the acetate group
was cleaved by combining dibromoolefin 28 with a stream of
DIBALH. The reaction was purified inline using a polyol
resin (IRA-743), which effectively chelates aluminium resi-
dues, to afford secondary alcohol 29, which was then
reprotected using the previously described silylation proce-
dure. Finally, bis-alkyne 31 was prepared through a Corey–
Fuchs reaction in flow. The excess base was quenched inline
using a stream of aqueous ammonium chloride solution.
In summary, synthesis of advanced aldehyde fragment 22
was completed in 13 steps (9 in flow and 4 in batch) and
11.6% overall yield from homoallylic alcohol 10
(Scheme 2).[28] The second advanced fragment, bis-alkyne
31, was prepared in 8 steps (7 in flow and 1 in batch) and in
22% overall yield, also from homoallylic alcohol 10. In terms
4
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Scheme 4. Reagents and conditions a) 31, nBuLi, THF, ꢀ788C, then 22, ꢀ788C!RT, 87% (>99% brsm); b) MnO2, CH2Cl2, RT, 97%; c) (S)-33,
BH3·Me2S, THF, ꢀ308C, 91%; d) NaH, MeI, THF, 08C!RT, 99%; e) TBAF, THF, RT, >99%; f) QP-SA, MeOH, RT, >99%; g) AuCl (10 mol%),
PPTS, CH2Cl2, ꢀ208C!RT, 30%. PPTS=pyridinium p-toluenesulfonate.
spiroketalization onto the C22 position, and an unsaturated
spiroketal compound formed through elimination of the C23
methoxy group. However, the desired spiroketal 35 was
isolated and the configuration confirmed via nOe analysis and
proton-proton coupling constants.[9]
With spiroketal 35 in hand, the endgame strategies for
both natural products were explored (Scheme 5). Spirodie-
nal A (3) was prepared from alkyne 35 in a three step
sequence. Firstly, a Sonogashira reaction with vinyl iodide
36,[32] followed by a mixed-metal cis-selective reduction[33] of
the C12–C13 internal alkyne and lastly an allylic oxidation to
afford the dienal motif. The data for synthetic spirodienal A
(3) matched the isolated natural product and signified a first
total synthesis, confirming the absolute structure and stereo-
chemistry of the natural product.
The synthesis of spirangien A methyl ester (2) required
silyl protection of the hydroxy groups followed by iodination
of the terminal alkyne. Following diimide reduction of the
iodoalkyne and global desilylation, vinyl iodide 37 was
prepared which represented a formal total synthesis.[10]
Appendage of the stannane tetraene 38 reported by Paterson
et al. then furnished spirangien A methyl ester (2). The
spectroscopic data matched those previously reported.[10]
In conclusion, we have synthesized spirangien A methyl
ester (2) and spirodienal A (3) with a divergent and concep-
tually new approach that integrates batch and flow chemistry.
Our approach also gives access to other members of this
family of natural products.[34] Both syntheses share a common
building block, homoallylic alcohol 10, which was readily
available in multigram quantities via a short flow sequence.
The highlight of this work is the significant use of flow
technologies to prepare the two complex coupling fragments,
aldehyde 22 and bis-alkyne 31. Completing these syntheses in
flow required the development of a number of new methods
including automated reagent addition, silylations, crotyla-
tions, ozonolysis, olefinations and oxidations in flow all of
which were used iteratively and dramatically accelerated the
parallel synthesis of these two fragments.
Scheme 5. Reagents and conditions a) 36, [Pd(PPh3)4] (5 mol%), CuI
(10 mol%), Et3N, PhH, RT, 90%; b) Zn(Cu/Ag), MeOH-H2O-THF
(1:1:1), 408C, 59%; c) MnO2, CH2Cl2, RT, 84%; d) TESOTf, 2,6-lutidine,
CH2Cl2, ꢀ788C!08C, 59%; e) NIS, AgNO3, acetone-DMF (5:1), RT,
49%; f) NBSH, Et3N, iPrOH-THF (1:1), RT, 93%; g) CSA, MeOH, RT,
91%; h) 38, [Pd2(dba)3] (10 mol%), AsPh3 (26 mol%), DMF-THF (4:1),
RT, 43%. NBSH=2-nitrobenzenesulfonylhydrazide; CSA=(ꢁ)-cam-
phor-10-sulfonic acid; dba=dibenzylideneacetone.
Whilst complex and sensitive reactions using a flow based
approach is certainly challenging, this work shows that once
general protocols are in place the benefits are soon realized.
In every case, the transformations developed in flow display
an advantage over the corresponding batch reactions, whether
it is a higher yield, an improved safety profile or simply
a faster and more efficient process. As flow technologies
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Received: February 3, 2014
Published online: && &&, &&&&
Keywords: flow chemistry · natural products · spirangien A ·
.
spirodienal A · total synthesis
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6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Natural Product Synthesis
S. Newton, C. F. Carter, C. M. Pearson,
L. de C. Alves, H. Lange, P. Thansandote,
S. V. Ley*
&&&& — &&&&
Accelerating Spirocyclic Polyketide
Synthesis using Flow Chemistry
Rise of the machines: The syntheses of
two spirocyclic polyketides, spirangien A
methyl ester and spirodienal A, are de-
scribed. This machine-assisted approach
extends the application of flow chemistry
to complex natural product synthesis and
includes several flow-through processes
of transformations commonly encoun-
tered in total synthesis.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!