Short stereoselective synthesis of the phytophthora universal mating hormone α1 using lithiation/borylation reactions

Article abstract of DOI:10.1002/anie.201400714

The universal mating hormone α 1 of the virulent plant pathogen Phytophthora has been synthesized in 12 steps and 28 % overall yield. Key CC bond-forming steps involved the use of two lithiation/borylation reactions to couple together enantioenriched building blocks, one of which also set up the stereochemistry of the tertiary alcohol at C11. Detailed analysis showed that the diastereomeric purity of the target molecule was >91 %, the highest obtained to date. In search of a mate: The universal mating hormone α 1 of the virulent plant pathogen Phytophthora has been synthesized in 12?steps and 28 % overall yield. Key CC bond-forming steps involved the use of two lithiation/borylation reactions to couple together enantioenriched building blocks, one of which also set up the stereochemistry of the tertiary alcohol at C11. The diastereomeric purity of the target molecule is >91 %, the highest obtained to date.

Full text of DOI:10.1002/anie.201400714

Angewandte
Chemie
DOI: 10.1002/anie.201400714
Natural Product Synthesis
Short Stereoselective Synthesis of the Phytophthora Universal Mating
Hormone a1 Using Lithiation/Borylation Reactions**
Alexander P. Pulis, Philipp Fackler, and Varinder K. Aggarwal*
Abstract: The universal mating hormone a1 of the virulent
plant pathogen Phytophthora has been synthesized in 12 steps
All syntheses involve coupling of enantioenriched build-
ing blocks. This inevitably leads to diastereomers, which are
essentially impossible to separate because of the remoteness
of the stereogenic centers, and are therefore carried through.
Based on the enantiomeric purity of the building blocks, the
maximum isomeric purity of a1 obtained in previous total
syntheses ranges from 80–90%, with a 10–20% mixture of the
remaining isomers. If these are divided into several diaste-
reoisomers, they may not be readily apparent during analysis,
especially as some diastereoisomers are virtually identical,
thus making isomeric purity difficult to assess. Herein we
report a short, highly stereoselective, and convergent syn-
thesis of a1 using our lithiation/borylation methodology.
Our retrosynthetic analysis of 1 involves lithiation/bor-
À
and 28% overall yield. Key C C bond-forming steps involved
the use of two lithiation/borylation reactions to couple together
enantioenriched building blocks, one of which also set up the
stereochemistry of the tertiary alcohol at C11. Detailed analysis
showed that the diastereomeric purity of the target molecule
was > 91%, the highest obtained to date.
T
he fungus-like parasite, Phytophthora infestans, was respon-
sible for the Irish potato famine in the mid-19th century, and
continues to be responsible for billions of dollars worth of
crop damage annually.[1] Control of this virulent plant
pathogen is essential and is of increasing importance as
food resources for a growing population become increasingly
challenging to supply. Phytophthora reproduces by creating
sexual spores called oospores, a process triggered by the
universal hormone a1 (1; Figure 1). Although it had been
À
À
ylation disconnections between C3 C4 and C11 C12, thus
leading to three key fragments: the secondary boronic ester 2,
bis(carbamate) 3, and allylic boronic ester 4 (Scheme 1). In
Figure 1. Structure of the Phytophthora universal mating hormone a1.
proposed as early as 1929 that sexual reproduction in
Phytophthora was induced by a hormone-like compound,[2]
it was not until 2005 that the gross structure was reported after
isolation of 1.2 mg of a1 from 1830 L of a culture broth.[3]
Yajima et al. reported the first asymmetric synthesis of
a stereoisomer library of a1 and concluded that the absolute
configuration was (3R,7R,11R,15R) based upon oospore-
inducing assays.[4] A number of total syntheses of 1 have since
been reported,[5] but in particular, the detailed and thorough
analysis of all stereoisomers of 1 by Bajpai and Curran[6] is
especially noteworthy.
[*] Dr. A. P. Pulis,[+] Dr. P. Fackler,[+] Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Scheme 1. Retrosynthetic analysis of 1. PG=protecting group,
pin=pinacolato, Cb=N,N-diisopropyl carbamoyl.
Homepage: http://www.bris.ac.uk/chemistry/research/organic/
aggarwal-group
[+] These authors contributed equally to this work.
particular, we envisaged that 3 could be selectively lithiated at
the allylic carbamate first and coupled with 4, followed by
a second lithiation and coupled with 2.[7] If the fragments
could be obtained in high e.r. (ꢀ 99:1), then the diasteromeric
purity of the product would be determined in the lithiation/
borylation reaction of the allylic carbamate, a reaction which
we had found to give ꢀ 98:2 e.r.
[**] We thank the EPSRC and the European Research Council (FP7/
2007–2013, ERC grant no. 246785) for financial support. P.F. thanks
the German Academic Exchange Service (DAAD) for a fellowship.
We thank Prof. Matthew Crump for NMR assistance and Prof.
Dennis P. Curran with NMR analysis of the final compounds.
Fragment 2 could be derived from the known b-boronic
ester 5 and vinyl boronic ester 6. We anticipated that 3 could
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400714.
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be derived from the enone 7, using Noyoriꢀs ruthenium-
catalyzed asymmetric hydrogenation,[8] which itself could be
derived from citronellal. The third fragment, 4, could be
derived from the allylic alcohol 8 by palladium-catalyzed
borylation, and in turn 8 could be synthesized from the known
aldehyde 9.
Building block 2 was prepared as shown in Scheme 2. The
copper-catalyzed conjugate borylation of ethyl but-2-ynoate
and subsequent asymmetric conjugate reduction gave 5 in
high yield (98%) and with excellent e.r. (99:1).[9] Chemo-
selective reduction of the ester moiety in the presence of the
boronic ester was achieved simply with NaBH4. Finally,
protection with TBDPS gave the desired boronic ester 2 in
high yield (71%, two steps) and high e.r. (99:1).
from 7 in a one-pot operation.[12] Catalytic asymmetric
hydrogenation of the enone moiety in 10 with Noyoriꢀs
(S,S)-11 catalyst[8] gave the desired diol 12 in 90% yield, 99:1
d.r., and > 99:1 e.r. Finally, bis(carbamoylation) with N,N-
diisopropyl carbamoyl chloride gave 3 in 94% yield.
The last of the key fragments was synthesized from the
known aldehyde 9 (> 99:1 e.r.), which is available in three
steps from the Roche ester (Scheme 4).[13] Aldehyde 9 was
treated with vinyl magnesium bromide to form the corre-
sponding alcohol with 1:1 d.r., > 99:1 e.r., and 68% yield.
After formation of the carbonate 13, palladium-catalyzed
borylation with B2(pin)2 gave 4 in high yield (83%) and high
e.r. (> 99:1).
Scheme 2. Synthesis of fragment 2. BINAP=2,2’-bis(diphenylphos-
phanyl)-1,1’-binaphthyl, PMHS=polymethylhydrosiloxane,
TBDPS=tert-butyldiphenylsilyl, THF=tetrahydrofuran, Xantphos=
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
Scheme 4. Synthesis of the boronic ester 4 from the Roche ester.
dba=dibenzylideneacetone, DMSO=dimethylsulfoxide.
The synthesis of the central fragment 3 began with
a Horner–Wadsworth–Emmons reaction between citronellal
(99:1 e.r.) and dimethyl (2-oxopropyl)phosphonate under
Masamune–Roush conditions,[10] thus giving 7 in 88% yield
(Scheme 3). Selective ozonolysis of the electron-rich trisub-
stituted olefin in 7 in the presence of the enone was achieved
using pyridine as an additive.[11] In the presence of pyridine,
the chemoselectivity of the reaction was easier to control, and
since ozonides are not intermediates in the ozonolysis it is also
safer. Chemoselective reduction of the aldehyde with
LiAlH(OtBu)3 gave the desired alcohol 10 in 74% yield
With the key fragments in hand, we set about their union
using our lithiation/borylation methodology. Thus treatment
of 3 with sBuLi/TMEDA effected chemoselective lithiation at
the more acidic allylic carbamate, and addition of 4 with
subsequent warming and oxidation gave the tertiary alcohol
14 in 81% yield and 97:3 d.r. (Scheme 5).[7,14]
Hydrogenation of the alkenes in 14 initially proved
problematic as use of Pd/C led to a complex mixture of
products, including possible epimerization at C12, silyl
removal, and elimination of the tertiary alcohol. Using PtO2
instead resulted in a much cleaner reaction, thus giving the
Scheme 3. Synthesis of the bis(carbamate) 3 from citronellal.
DMAP=4-(N,N-dimethyl)pyridine.
Scheme 5. Union of 4 and 3. TES=triethylsilyl, Tf=trifluoromethane-
sulfonyl.
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corresponding tertiary alcohol in high yield (98%) and
without epimerization at C12.[15]
Protection of the tertiary alcohol with TESCl gave the
carbamate 15, our precursor for the second and final
lithiation/borylation reaction. However, under the standard
reaction conditions (Et2O, TMEDA, sBuLi, À788C, 5 h) we
obtained a complex mixture of products. We suspected that
lithiation might be the problem and so tested this part of the
process by deprotonation and trapping with Me3SnCl under
a variety of conditions (Table 1). Under standard reaction
conditions (Et2O/TMEDA; entry 1), we obtained a complex
mixture of products as before. The use of TBME as the
solvent gave significantly improved results, thus affording
Table 1: Optimization of reaction conditions for the lithiation of 15.[a]
Scheme 6. Coupling of the boronic ester 2 with the carbamate 12, and
completion of the synthesis. DMP=Dess–Martin periodinane, TBAF=
tetra-n-butylammonium fluoride.
Entry
Solvent
Diamine
Yield [%][b]
15
16
approximately 94:6, thus indicating that the C7 was 99:1
(7R/7S). Stereoisomers at C11 were approximately 98:2 (11R/
11S), and is consistent with the measured d.r. of 14. Thus,
based on analysis of the bis-Mosher’s the overall diastereo-
meric purity of a1 must be > 91%, the highest measured to
date.
In conclusion we have reported the shortest (12 steps,
longest linear sequence), highest yielding [21.3% overall
yield, (27.8% brsm)],[18] and most stereoselective synthesis
(> 91% diastereomeric purity) of the a1 hormone by
coupling together highly enantioenriched building blocks.
Key steps involved two late-stage lithiation/borylation reac-
tions to couple the building blocks together, thus giving high
diastereocontrol (97:3) at the difficult tertiary alcohol stereo-
center. Our route enables the synthesis of significant quanti-
ties of a1 (ca. 100 mg was prepared) and should thus aid the
study of Phytophthora reproduction.
1[c]
2[c]
3[c]
4
Et2O
TMEDA
TMEDA
TMCDA
(À)-sparteine
0
43
40
71
18
0
0
TBME
TBME
TBME
22
[a] Reaction conditions: (8R/S)-carbamate 15 (1 equiv), diamine
(2.1 equiv), sBuLi (2 equiv), À788C for 5 h, then ClSnMe3 (2.5 equiv).
[b] Yield of isolated product. [c] Reactions contained numerous uniden-
tified side products. TBME=tert-butylmethyl ether, TMCDA=
(rac,trans)-N,N,N’,N’-tetramethylcyclohexane-1,2-diamine, TMEDA=
N,N,N’,N’-tetramethylethylenediamine.
40% of the stannane 16 (entry 2). Alternative diamines were
then explored as they can have a major impact on the
outcome of lithiation reactions. Whilst TMCDA gave similar
results, use of the more hindered (À)-sparteine gave 16 in high
yield (71%) together with the recovered starting material 15
(22%; entries 3 and 4).[16,17]
Received: January 22, 2014
Published online: && &&, &&&&
By using these reaction conditions in the lithiation/
borylation reaction with 2 and subsequent oxidation, the
desired secondary alcohol was obtained in 72% yield,
together with the recovered carbamate 15 in 24% (94%
brsm, Scheme 6). Oxidation of the secondary alcohol with
Dess–Martin periodinane gave the known ketone,[5a] and
subsequent deprotection with TBAF in AcOH/THF, as
described by Yajima et al.,[4] gave a1 in high yield (83%).
Its characterization data was identical to that of the reported
data in every respect.
Based on the enantiomeric purity of the building blocks
the maximum isomeric purity of a1 was calculated to be 96:4,
which is considerably greater than any previous synthesis. To
measure the isomeric purity, the bis-Mosher’s ester of a1 was
prepared and analyzed according to Curranꢀs stereoisomer
method.[6] The product was determined to be 95:5 at C3
(3R/3S), thus indicating that a small degree of epimerization
at the labile C3 center had occurred during deprotection, and
99:1 at C15 (15R/15S). The anti/syn (C3/C7) ratio was
Keywords: asymmetric synthesis · boron · lithium ·
.
natural products · total synthesis
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Angewandte
Chemie
Communications
Natural Product Synthesis
A. P. Pulis, P. Fackler,
V. K. Aggarwal*
&&&& — &&&&
Short Stereoselective Synthesis of the
Phytophthora Universal Mating Hormone
a1 Using Lithiation/Borylation Reactions
In search of a mate: The universal mating
hormone a1 of the virulent plant patho-
gen Phytophthora has been synthesized in
couple together enantioenriched building
blocks, one of which also set up the
stereochemistry of the tertiary alcohol at
C11. The diastereomeric purity of the
target molecule is >91%, the highest
obtained to date.
À
12 steps and 28% overall yield. Key C C
bond-forming steps involved the use of
two lithiation/borylation reactions to
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!