Enantio- and stereoselective route to the phoslactomycin family of antibiotics: Formal synthesis of (+)-fostriecin and (+)-phoslactomycin B

Article abstract of DOI:10.1039/b912267b

A general methodology applicable for the synthesis of the phoslactomycin family of antibiotics, potent and selective protein phosphatase inhibitors, has been developed starting from a β-isocupreidine-catalyzed asymmetric Baylis-Hillman reaction of 3-(4-me

Full text of DOI:10.1039/b912267b

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Enantio- and stereoselective route to the phoslactomycin family of
antibiotics: formal synthesis of (+)-fostriecin and (+)-phoslactomycin Bw
Shaheen M. Sarkar, Everlyne N. Wanzala, Setsuya Shibahara, Keisuke Takahashi,
Jun Ishihara and Susumi Hatakeyama*
Received (in Cambridge, UK) 22nd June 2009, Accepted 22nd July 2009
First published as an Advance Article on the web 10th August 2009
DOI: 10.1039/b912267b
A general methodology applicable for the synthesis of the
phoslactomycin family of antibiotics, potent and selective
protein phosphatase inhibitors, has been developed starting from
a b-isocupreidine-catalyzed asymmetric Baylis–Hillman reaction
of 3-(4-methoxybenzyloxy)propanal with hexafluoroisopropyl
acrylate, and thereby formal syntheses of (+)-fostriecin and
(+)-phoslactomycin B have been accomplished.
Phoslactomycins A–F and I, produced by the soil bacteria
species Streptomyces, constitute the phoslactomycin family of
antifungal and antitumor antibiotics together with phos-
phazomycins C1 and C2, leustroducsins A–C and H,
PD113,2714 and fostriecin.1 These compounds are highly
potent and selective inhibitors of protein serine/threonine
phosphatase 2 A, which is proposed to be responsible for their
antitumor activity.1,2 Due to their intriguing molecular
architectures and their potential as lead compounds for
anticancer drugs as well as their importance as biological
tools, this family of compounds has attracted much attention
in the chemical and biological communities. Thus, there have
been a number of synthetic studies including formal and total
syntheses of phoslactomycin A3 and B,4 leustroducsin B,5
fostriecin,6,7 and PD113,271 (Fig. 1).8 However, in spite of
Scheme 1
similarities, previously reported synthetic methods are not of
Recently we have demonstrated4c,9 that ynones 3 and 4
general utility to prepare the entire members of this family.
Herein, we report the formal asymmetric syntheses of
effectively served as pivotal intermediates for the synthesis of 1
(+)-fostriecin (1) and (+)-phoslactomycin B (2) from a
and 2 as well as their various isomers via Z- or E-selective
common precursor, demonstrating a general approach to the
conjugate addition of hydroiodic acid, C9-hydroxy directed
phoslactomycin family for the first time.
anti- or syn-selective reduction of the C11-carbonyl group,
Stille coupling and phosphorylation as major transformations
(Scheme 1). From the retrosynthetic perspective based on the
methodology we have previously established,4c,9 we envisioned
epoxide 6 as a common precursor of 3 and 4 by the disconnection
via ethynylation, ring closing metathesis, and asymmetric
allylation or pentenylation. We expected that either the methyl
group or the aminoethyl group on the C8-quaternary center
could be installed via nucleophilic opening of the epoxide
with a hydride or cyanide ion. To access 6 we envisaged
the approach from aldehyde 8 involving an asymmetric
Baylis–Hillman (BH) reaction10 giving 7 and diastereoselective
epoxidation. We came up with this strategy because we have
developed a highly enantioselective asymmetric BH reaction of
an aldehyde using b-isocupreidine (b-ICD) as a catalyst and
hexafluoroisopropyl acrylate (HFIPA) as an activated ester
(b-ICD–HFIPA method).11
Fig. 1
Graduate School of Biomedical Sciences, Nagasaki University,
Nagasaki 852-8521, Japan. E-mail: susumi@nagasaki-u.ac.jp;
Fax: +81-95-819-2426; Tel: +81-95-819-2426
w Electronic supplementary information (ESI) available: Experimental
details and spectral data (1H and 13C NMR, IR, HRMS, [a]D). See
DOI: 10.1039/b912267b
Our synthesis thus began with application of the
b-ICD–HFIPA method to aldehyde 94c (Scheme 2). When 9
ꢀc
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Scheme 2 Reagents and conditions. (i) b-ICD (0.1 equiv.), HFIPA
1C to rt;
Scheme 3 Reagents and conditions. (i) Method A: LiEt3BH, THF, ꢁ78
to 0 1C, method B: DIBAH, THF, ꢁ78 1C; (ii) Dess–Martin periodinane,
CH2Cl2; (iii) Brown and co-worker’s method: (+)-Ipc2BOMe,
CH2QCHCH2MgBr, THF-Et2O, ꢁ78 1C to rt, then 30% H2O2,
(1.3 equiv.), DMF, ꢁ55 1C; (ii) Et3N, MeOH,
0
(iii) t-BuMe2SiOTf, 2,6-lutidine, CH2Cl2, ꢁ78 1C; (iv) DIBAH, CH2Cl2,
ꢁ78 1C; (v) Dess–Martin periodinane, CH2Cl2; (vi) (EtO)2P(O)CH2CO2Et,
NaH, THF, ꢁ78 to 0 1C; (vii) n-Bu4NF, THF; (viii) VO(acac)2
(0.2 equiv.), t-BuOOH, CH2Cl2, ꢁ20 1C to rt; (ix) MeOCH2Cl,
i-Pr2EtN, CH2Cl2, 45 1C.
3
M
NaOH, THF, Yamamoto and co-worker’s method:
(MeO)3SiCH2CHQCH2, (R)-p-tol-BINAP (0.2 equiv.), AgF (0.2 equiv.),
MeOH, ꢁ20 1C; (iv) ClCOCH2CHQCH2, i-Pr2EtN, CH2Cl2, 0 1C;
(v) Grubbs’ 2nd (0.1 equiv.), CH2Cl2, reflux; (vi) ZrCl4 (0.8 equiv.), i-PrOH;
(vii) Et3SiOTf, 2,6-lutidine, CH2Cl2, ꢁ78 1C; (viii) DDQ, CH2Cl2,
0 1C; (ix) Dess–Martin periodinane, CH2Cl2; (x) HCCMgBr, CeCl3,
THF, ꢁ50 1C; (xi) Dess–Martin periodinane, CH2Cl2.
closing metathesis15 of the resulting acrylate using Grubbs’
second generation catalyst led to the clean formation of 21.
However, in the next deprotection of the methoxymethyl group,
we unexpectedly met with difficulty under standard acidic
conditions. After exploring various conditions, we eventually
found that ZrCl4-promoted alcoholysis16 was effective in this
particular case to give 22 in an acceptable yield. Upon silylation,
oxidative removal of the p-methoxybenzyl group and Dess–Martin
oxidation, 22 afforded 24 in good overall yield. Finally, addition of
acetylene followed by Dess–Martin oxidation converted 24 to
ynone 3 almost quantitatively, the synthesis of which constitutes
a formal synthesis of (+)-fostriecin (1).9
was reacted with 1.3 equiv. of HFIPA in the presence of
0.1 equiv. of b-ICD in DMF at ꢁ55 1C, 10 was obtained in
excellent enantiomeric purityz (99% ee) in 58% yield together
with 11 (38% ee, 14% yield). It is important to note that this
reaction can be easily carried out on a multi-gram scale. After
methanolysis of 10, methyl ester 12 was then converted to 14 in
68% overall yield by a five-step sequence involving silylation,
DIBAH reduction, Dess–Martin oxidation, Horner–Emmons
reaction and desilylation. Gratifyingly, vanadium-catalyzed
epoxidation12 of 14 turned out to proceed with complete diastereo-
selectivity to furnish 15 in excellent yield. The hydroxy group
of 15 was then protected as its methoxymethyl ether to give 16.
Having prepared our envisaged key intermediate 6 as 16 in
enantiomerically pure form, we then investigated the synthesis
of ynone 3, a precursor of fostriecin (1). The crucial reductive
opening of the epoxide of 16 was examined using LiEt3BH,
DIBAH and LiAlH4 under various conditions (Scheme 3).y It
was found that LiEt3BH was the reducing agent of choice
and the desired 18 was obtained almost quantitatively.
Interestingly, reaction of 16 with DIBAH at ꢁ78 1C allowed
the selective reduction of the ester group without affecting the
epoxy group to give 17 in 85% yield. The LiAlH4 reduction
gave a complex mixture including 17 and 18. After Dess–Martin
oxidation of 18, using Brown and co-workers’ asymmetric
allylation13 on 19 afforded 20 as a single diastereomer in good
yield. Alternatively, using Yamamoto and co-workers’
asymmetric allylation14 on 19 turned out to proceed with high
diastereoselectivity (dr = 94 : 6) to give 20 again in good
yield. It should be noted that, compared with the former, the
latter allylation was more beneficial for large scale production
of 20 due to the ease of purification in spite of its lower
diastereoselectivity. Acryloylation of 20 followed by ring
Next, we investigated the synthesis of ynone 4, a precursor
of phoslactomycin B (2) from the above-mentioned inter-
mediate 16. Since the first attempt to open the epoxide with
cyanide ion under various conditions gave us disappointing
results because of the high reactivity of the ester group, we
decided to implement asymmetric pentenylation before
cyanation (Scheme 4). Thus, by taking advantage of the
method described above, 16 was chemoselectively reduced
with DIBAH to 17 which, upon Dess–Martin oxidation,
gave 25. According to the procedure we have previously
developed,4c 25 was then subjected to asymmetric pentenylation
using the reagent prepared from (Z)-2-pentenylpotassium and
(+)-(Ipc)2BOMe to give syn-isomer 26 in excellent diastereo-
selectivity (dr = 97 : 3) in 83% yield. In this particular case,
silver-catalyzed pentenylation of 25 using trimethoxy((Z)-
pent-2-enyl)silane under Yamamoto and co-worker’s
asymmetric allylation conditions14a did not proceed at all.
ꢀc
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in the selectivity issues. The present work illustrates a new
methodology of general value for the synthesis of the entire
members of the phoslactomycin family. In addition, this work
exemplifies the synthetic utility of our b-ICD–HFIPA method.
This work was partly supported by a Grant-in-Aid for
Scientific Research of JSPS and MEXT.
Notes and references
z The absolute configuration and the enantiomeric purity of 10 and 11
were determined by chiral HPLC analysis and 1H NMR analysis of the
R- and S-Mosher’s esters after converting them to methyl ester 12,
respectively.
y Reductive opening of the epoxide of 15 failed under various
conditions and always gave a complex mixture.
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Scheme 4 Reagents and conditions. (i) DIBAH, THF, ꢁ78 1C;
(ii) Dess–Martin periodinane, CH2Cl2; (iii) (Z)-2-pentene, t-BuOK,
n-BuLi, THF, ꢁ78 1C, then (+)-(Ipc)2BOMe, BF3ꢂEt2O, THF–Et2O,
ꢁ78 to ꢁ50 1C, then 1 M NaOH; (iv) LiCNꢂacetone, THF, reflux;
(v) LiAlH4, Et2O, then Boc2O, NaHCO3, H2O–MeOH; (vi)
ClCOCH2CHQCH2, i-Pr2EtN, CH2Cl2, 0 1C; (vii) Grubbs’ 2nd
(0.1 equiv.), CH2Cl2, reflux; (viii) ZrCl4 (0.8 equiv.), i-PrOH, 50 1C;
(ix) 5 M HCl, THF, then CH2QCHCH2OCOCl, NaHCO3; (x)
Et3SiOTf, 2,6-lutidine, CH2Cl2, ꢁ78 1C; (xi) (COCl)2, DMSO,
CH2Cl2, ꢁ78 to ꢁ40 1C then Et3N, 0 1C; (xii) HCCMgBr, CeCl3,
THF, ꢁ50 1C; (xiii) Dess–Martin periodinane, CH2Cl2.
Y.
Kobayashi,
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Et2AlCN and TMSCN. However, we were pleased to find that
LiCNꢂacetone complex promoted this reaction effectively.
Thus, according to the procedure developed by Ciaccio
et al.,17 26 was reacted with LiCNꢂacetone complex at 40 1C
in THF to afford 27 in good yield. Reduction of 27 with
LiAlH4 followed by tert-butoxycarbonylation gave 28. Upon
acryloylation followed by ring closing metathesis using
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same yield as that of 21, indicating that the N-Boc-aminoethyl
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In the same manner as described above for the synthesis
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ZrCl4-promoted deprotection of the methoxymethyl group of
29 again afforded 30 cleanly, which, upon successive acidic
hydrolysis, allyloxycarbonylation and silylation, gave 31 in
good yield. Exposure of 31 to Swern oxidation conditions18
allowed the direct production of 32 via selective cleavage of the
primary triethylsilyl ether group. Finally, addition of acetylene
followed by Dess–Martin oxidation converted 32 to ynone 4.
At this stage, a formal synthesis of (+)-phoslactomycin B (2)4c
was also accomplished.
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´
18 A. Rodrıguez, M. Nomen, B. W. Spurand and J. J. Godfroid,
In conclusion, we have achieved the formal asymmetric
synthesis of 1 and 2 from the common intermediate 16. This
represents a significant improvement of our previous synthesis
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5907–5909 | 5909