Improved synthesis of the polyhydroxylated central part of phoslactomycin B

Article abstract of DOI:10.1016/j.tetlet.2007.06.058

A new approach to the C(7)-C(13) intermediate for the synthesis of phoslactomycin B was investigated. Asymmetric dihydroxylation of the β,γ-unsaturated ester proceeded cleanly to afford the β-hydroxyl-γ-lactone with 97.6% ee, which upon protection as the

Full text of DOI:10.1016/j.tetlet.2007.06.058

Tetrahedron Letters 48 (2007) 5601–5604
Improved synthesis of the polyhydroxylated central part
of phoslactomycin B
Hisato Nonaka, Noriaki Maeda and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259,
Midori-ku, Yokohama 226-8501, Japan
Received 28 May 2007; revised 11 June 2007; accepted 15 June 2007
Available online 17 June 2007
Dedicated to the late Professor Yoshihiko Ito, Kyoto University
Abstract—A new approach to the C(7)–C(13) intermediate for the synthesis of phoslactomycin B was investigated. Asymmetric
dihydroxylation of the b,c-unsaturated ester proceeded cleanly to afford the b-hydroxyl-c-lactone with 97.6% ee, which upon pro-
tection as the PMB ether followed by hydride reduction furnished a diol. After selective protection of the prim-OH, oxidation of the
sec-OH and chelation-controlled addition of CH2@CHMgBr afforded the C(7)–C(11) segment. Later on, the C(11) stereocentre was
constructed by the asymmetric transfer hydrogenation using the Noyori catalyst.
Ó 2007 Elsevier Ltd. All rights reserved.
Phoslactomycin B (1) is one of the phoslactomycin
family that shows a selective PP2A inhibitory activity.1
The common structure of 1 and the other members is
drawn in Figure 1, while each member of the family pos-
sesses a specific substituent on the cyclohexane ring. The
same structural unit is also seen in leustroducsins.2 To
study the biological profile at molecular level with struc-
tural analogues and compounds possessing a specific
function, synthesis of these compounds should be
established. Synthesis of leustroducsin B (R = 6-methyl-
octanoic acid moiety) has been published first by Fuku-
yama and co-workers3 and quite recently by Imanishi
and co-workers.4 Although the syntheses are elegant,
the long sequences of reactions and the low-yielding
steps seem to be improved in order to apply the methods
to synthesis of analogues for the biological study.
On the other hand, we reported a synthesis of 1.5 The
synthesis features the chelation-controlled addition of
CH2@CHMgBr to the a-PMB-oxy ketone 5 to produce
the key intermediate 6 that covers the most congested
part of the molecule (Scheme 1). The addition was
highly stereoselective (5!6), and the strategy will be
applicable to synthesis of other phoslactomycins. How-
ever, the method suffers from that the Sharpless asym-
metric epoxidation6 (Sharpless AE) does not exceed
50% yield in theory.
O=P(OH)2
Herein, taking advantage of the chelation-controlled
addition in mind, we retrosynthesized the key intermedi-
ate 6 to a keto aldehyde 7 as delineated in Scheme 2. The
first approach to a real compound 8 of type 7 involves
asymmetric dihydroxylation7 (AD reaction) of olefin 9
to hydroxyl lactone 8 through lactonization of the ini-
tially formed diol.8 Alternatively, we conceived stereo-
selective addition of an acetate anion (MCH2CO2R) to
an aldehyde derivative 10 of L-malic acid.
O
OH
9
8
O
O
OH
R
H2N
R = H, Phoslactomycin B (1)
R = OC(O)CnH2n+1, Phoslactomycins, Leustroducsins
Figure 1. Phoslactomycins and leustroducsins.
Olefin 9, the substrate for the AD reaction in the first
approach (Scheme 3), was prepared from butane-1,4-
diol (11) in 77% yield with a modification9 of the method
of Lee and co-workers,10 who submitted the olefin to
Keywords: Phoslactomycin B; Chelation-controlled addition; Asym-
metric dihydroxylation; Asymmetric transfer hydrogenation.
*
Corresponding author. Tel./fax: +81 45 924 5789; e-mail:
ykobayas@bio.titech.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.058

5602
H. Nonaka et al. / Tetrahedron Letters 48 (2007) 5601–5604
OH
14 with p-methoxybenzyl trichloroacetimidate (PMB-
LiCH2CO2Et
96%
kinetic resolution
CHO
OH
CO2Et
Im) in the presence of BF3ÆOEt2 (3 mol %), while CSA
(10 mol %), one of the standard acids for PMB protec-
tion,11 assisted the reaction incompletely.
via Sharpless AE
44%
2
rac-3
PMB
O
6 steps
8 steps
OH
O
Addition of CH2@CHMgBr was first attempted with a
ketone 16, which was prepared in 51% yield from 8
through hydrolysis of the lactone 14, Jones oxidation,
and condensation with Me(MeO)NHÆHCl/DCC.12
While the addition in THF at ꢀ78 °C produced a mix-
ture of products, that in CH2Cl2/THF (12:1) gave 17,
but as a diastereomeric mixture in a 4:1 ratio. Thus, con-
version of the amide to the corresponding ketone with
TMSC„CLi was not investigated.
CO2Et
64.3%
4
(R)-3
Yadav's
method
1) O3
2) LiCH2CO2Et
then H–
PMB
O
PMB
MgBr
2 steps
OTBS
O
OTBS
OTES
TBDPSO
O
H
H
TBDPSO
5
6
A synthetic route we investigated next was hydride
reduction of 14 to diol 18. Although LiAlH4, LiB(H)Et3
and DIBAL each in THF produced a mixture of 18 and
unidentified less polar product(s), LiBH4 in aqueous
Et2O13 produced diol 18, which was converted to TES
ether 19 in 69% yield from 8 (three steps). Oxidation
of the secondary hydroxyl group of 19 gave ketone 20,
which was submitted to reaction with CH2@CHMgBr
at ꢀ78 °C in THF to furnish alcohol 21 exclusively.14
Protection of the newly formed hydroxyl group as a
TES group gave 22 in 82% yield, which upon Swern oxi-
dation15 furnished aldehyde 23 as the sole product.
40.5% from 4
1
Scheme 1. Summary of the previous synthesis of phoslactomycin B (1)
through 6. PMB: p-MeOC6H4CH2, TBS: SiMe2Bu-t, TBDPS:
SiPh2Bu-t, TES: SiEt3.
PMB
O
OTBS
9
OTES
H
TBDPSO
Addition of the lithium anion derived from TMSC„CH
and n-BuLi produced a 3:1 diastereomeric mixture of
24a and 24b (desired product) by H NMR spectros-
6
1
copy.16 Although the mixture was separable, oxidation
with SO3Æpy and DMSO was carried out without separa-
tion to afford ketone 25 cleanly. Subsequently, asym-
metric transfer hydrogenation17 using the Noyori
catalyst furnished 24a and 24b in a 1:17 ratio, which
was separated easily by chromatography on silica gel.
Finally, protection of the newly formed hydroxyl group
with TBSOTf and subsequent removal of the TMS
group at the acetylenic carbon produced the intermedi-
ate 6 in good yield. The total yield of 6 from diol 11
was 23.1% in 16 steps, while that in the original method5
was 11.0% from crotonaldehyde (2) in 18 steps. In addi-
tion to the improved yield and steps, the present synthe-
sis has another advantage of easy operation of the
reactions involved in the synthesis.
PMB
O
Li
CHO
+
+
MgBr
TMS
RO
O
7
OH
CHO
OR2
or
R1O
O
TBDPSO
O
8
10
We also examined the chiral pool strategy using L-
malic acid, which was converted efficiently to aldehyde
27 of type 10 (in Scheme 2) by the literature method
(Scheme 4).18 Addition of an anion derived from
EtOAc and LDA at ꢀ78 °C in THF produced a
85:15 mixture of 28 and 29 in 81% yield.19,20 Although
28 is the none-chelation product, addition of HMPA as
a co-solvent did not improve the selectivity (82% dr).
The mixture was transformed into 30 in two steps of
PMB protection of the hydroxyl group and the PMP
acetal cleavage. Unfortunately, mobility of 30 and the
diastereomer on TLC was close, and we did not inves-
tigate this approach.
9
9
CO2H
HO2C
TBDPSO
CO2Me
OH
L-malic acid
9
Scheme 2. Retrosynthesis of the key intermediate 6.
AD reaction with AD-mix-a to afford the hydroxyl
lactone (enantiomer of 8) with somewhat low 86% ee.
Instead, we used AD-mix-b, which provided 8 with
97.6% ee (determined by chiral HPLC analysis of the
derived benzoate). Although a reason for the difference
in the observed enantiomeric purities was not clear,
the high level in our side was reproducibly attained.
The hydroxyl group of 8 was protected to PMB ether
In summary, we developed an alternative approach to
the key intermediate 6 for synthesis of phoslactomycin

H. Nonaka et al. / Tetrahedron Letters 48 (2007) 5601–5604
5603
CO2Me
1) TBDPSCl
NaH/THF
OH
AD-mix-β
CO2H
CHO
OTBDPS
OH
9
2) SO3·py, DMSO
then Et3N
90 ˚C,
overnight
80%
MeSO2NH2
89%
HO
TBDPSO
OH CO2Me
11
12
13
96%
OR
OPMB
CO-X
OPMB
CON(OMe)Me
CH2=CHMgBr
1) NaOH, MeOH
2) CrO3, H2SO4
+
diastereomer
OH
TBDPSO
O
O
TBDPSO
CH2Cl2 / THF
–40 to –20 ˚C
O
OTBDPS
15: X = OH
16: X = N(OMe)Me
51% from 8
4
: 1
Me(MeO)NH•HCl
DCC, Et3N, DMAP
8: R = H (97.6% ee)
14: R = PMB
PMB-Im
BF3·OEt2
17
LiBH4
Et2O, H2O
OPMB
OR
SO3·py, DMSO
then Et3N
(COCl)2, DMSO
then Et3N
OPMB
OPMB
CH2=CHMgBr
OTES
OR2
OTES
O
(Swern Oxidn)
TBDPSO
TESCl, Im
OR1
TBDPSO
OTBDPS
21: R = H
22: R = TES
82% from 19
18: R1 = R2 = H
19: R1 = H, R2 = TES
69% from 8
20
TESOTf
2,6-lutidine
PMBO
OH
OPMB
CHO
PMBO
O
SO3·py, DMSO
then Et3N
HC C-TMS
n-BuLi
OTES
OTES
OTBDPS
23
OTES
TMS
TMS
91%
OTBDPS
24a (α-OH)
24b (β-OH)
OTBDPS
82%
from 22
(24a / 24b = 3 : 1)
25
PMBO
OR1
K2CO3
95%
(TsDPEN)Ru(p-cymene)
6
OTES
R2
i-PrOH
87%
OTBDPS
24b: R1 = H, R2 = TMS
26: R1 = TBS, R2 = TMS
TBSOTf
2,6-lutidine
97%
Scheme 3. Synthesis of the key intermediate 6.
CHO
1) BH3•SMe2
L-malic acid
Acknowledgement
O
O
2) p-MeOC6H4CH(OMe)2
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
3) SO3•Py, DMSO, Et3N
62%
PMP
27
OH
OH
EtOAc, LDA
81%
+
O
O
CO2Et
28
CO2Et
29
PMP
References and notes
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OPMB
28 + 29
CON(OMe)Me
2)
O
p-MeOC6H4CH(OMe)2
TBDPSO
OH
PMP
O
PMP
O
i
O
+
Me(MeO)NH•HCl
-PrMgCl
CON(OMe)Me
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ii
OH
i
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vii
iii
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