Synthetic studies toward MPC1001: Preparation of a β-hydroxyl-tyrosine derivative

Article abstract of DOI:10.1016/j.tetlet.2011.11.069

A procedure for the asymmetric synthesis of a novel β-hydroxy-α- amino acid derivative to be used in the preparation of the natural product MPC1001 and analogs has been developed. The amino acid was efficiently prepared in six steps via a Mukaiyama aldol

Full text of DOI:10.1016/j.tetlet.2011.11.069

Tetrahedron Letters 53 (2012) 380–382
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies toward MPC1001: preparation of a b-hydroxyl-tyrosine
derivative
⇑
Paul T. Schuber Jr., Robert M. Williams
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A procedure for the asymmetric synthesis of a novel b-hydroxy-a-amino acid derivative to be used in the
Received 21 September 2011
Revised 11 November 2011
Accepted 14 November 2011
Available online 22 November 2011
preparation of the natural product MPC1001 and analogs has been developed. The amino acid was effi-
ciently prepared in six steps via a Mukaiyama aldol reaction via a diphenyloxazinone and 3-bromo-4-
methoxybenzaldehyde.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
MPC1001
b-Hydroxyl-a-amino acid
Mukaiyama aldol reaction
Oxazinone
Epipolythiodioxopiperazine
The epipolythiodioxopiperazine (ETP) family of natural prod-
ucts has interested the scientific community due to their unique
chemical structure and potent biological activity.1 Since the dis-
covery of Gliotoxin by Weindling and coworkers in 1932, there
have been more than fourteen distinct structural classes of these
fungal metabolites isolated to date.1 The sulfur-bridged diketopi-
perazine moiety that distinguishes the ETP family of natural prod-
ucts has been shown to be responsible for their biological activity
(Fig. 1).2
In 2004, MPC1001 and congeners were isolated from the myce-
lium of the Cladorrhnmum sp. by Hasegawa and coworkers.3 These
compounds are structurally unique because they contain an oxepin
moiety fused to the ETP core. To date, a total synthesis of MPC1001
has not been reported. However, two approaches toward the
tricyclic core have been published. In 2009, Clive and coworkers
completed the synthesis of the complex ring system from trans-
an IC50 value of 9.3 nM which is more potent than the therapeutic
agents etoposide (400 nM), mitomycin C (25 nM), and adriamycin
(20 nM). The complex structure and potent biological activity of
MPC1001 render this compound an attractive synthetic target.
Herein, we report a general method for the synthesis of a
b-hydroxy-a-amino acid derivative 15 using an asymmetric
Mukaiyama aldol reaction. The flexibility in our design provides
the opportunity for the preparation of analogs of MPC1001. Our
approach employs a commercially available aldehyde 6 and an
optically pure oxazinone 5 as our template.
We envisioned disconnecting MPC1001 to provide isovanillic
acid (1), the complex oxepin ring-containing amino acid 2, and
the b-hydroxy-a-amino acid derivative 3. Amino acid 3 could arise
from the Mukaiyama aldol reaction of 3-bromo-4-methoxybenzal-
dehyde (6) and the silyl enol ether derived from oxazinone 5
(Scheme 1).
4-hydroxyl-
L
-proline utilizing an acid-promoted ring closure of
The synthetic approach to the unnatural amino acid portion is
devised around a chiral diphenyloxazinone glycine template (5)
that allows for the synthesis of either L or D amino acid derivatives.
the primary alcohol onto a vinylogous amide.4 Recently, Bräse and
coworkers utilized a late-stage ring closing metathesis to afford
an advanced oxepin derivative that was also made from trans-4-
Lactone 5 can be easily prepared from commercially available
hydroxyl-L
-proline.5 In addition to the MPC family of natural
products, the aranotin,6 emethallicins,7 and emestrian8 classes also
contain an oxepin subunit. MPC1001 is unique because it also
O
S N
N S
O
possesses an interesting b-hydroxyl-a-amino acid moiety.
R3
R4
R1
R2
S
N
MPC1001 is especially intriguing due to its biological activity
N
Me
OH
S
against the human prostate cell cancer line DBU.3 MPC1001 displays
OH
O
O
Gliotoxin
ETP Core
⇑
Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491 3944.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
Figure 1. Structure of Gliotoxin and the ETP core.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.069

P. T. Schuber Jr., R. M. Williams / Tetrahedron Letters 53 (2012) 380–382
381
O
Unfavored
Favored
OH
Ph
Ph
MeO
O
NHMe
OH
Ph
Ph
O
OTBS
R
O
OH
HO
O
OTBS
H
O
O
N
O
H
H
S
N
+
R
S
OH
O
+
Me
O
N
NH2
H
H
N
H
LA
O
O
Cbz
LA
Br
O
OH
Cbz
OH
O
OH
OMe
MeO
T1
T2
OMe
MeO
(-) MPC1001
1
2
3
Ph
Ph
NCbz
OTBS
Figure 2. Transition state analysis for the aldol condensation.
O
H
Ph
O
O
Ph
O
+
NCbz
Ph
HO
Ph
Br
MeO
O
NH2
OTBS
Br
MeO
Scheme 1. Synthetic strategy.
O
OMe
5
TBAF, O o
C
MeO
NH
Pb(OAc)4
4
6
O
OTBS
CH2Cl2 : MeOH
(1:1), O oC, 79%
THF, 85%
Br
MeO
Br
10
13
(1S,2R)-(+)-2-amino-1,1-diphenylethanol in three steps in high
yield with no chromatography required.9 The diphenyloxazinone
template has been utilized in a wide range of synthetic transforma-
tions including enolate alklation, glycine electrophilic reactivity,
radical chemistry, dipolar cycloadditions, as well as homologation
at the lactone carbonyl which provides access to highly functional-
ized amino acids.10
The synthesis commenced with the formation of the silylenol
ether derivative 7 from oxazinone 5 (Scheme 2).11 Unfortunately,
utilizing conditions previously developed for the preparation of
MeO
MeO
O
NH2
OH
Br
MeO
14
Scheme 3. Synthesis and crystal structure of compound 14.
b-hydroxyl-a-amino acids via oxazinone 5 resulted in the recovery
of the starting materials.11 After some experimentation, we found
that dropwise addition of silylenol ether 7 to a mixture of aldehyde
6 and 8 mol % Cu(OTf)2 in CH2Cl2 provided compound 8 in a 99%
yield.12 Removal of the Cbz protecting group under hydrogenolysis
conditions afforded the secondary amine 4 in a 74% yield along
with the R,R-diastereomer 9. The amine 4 was deprotected without
cleaving the template or reducing the aromatic bromide. Exposure
of the free amine 4 to ZnCl2 in a 2:1 methanol/THF mixture in a
sealed tube for 24 h provided the methyl ester 10 in a 90% yield.
The newly formed amino ester 10 was then immediately methyl-
ated under reductive amination conditions to afford tertiary amine
11 in an 88% yield. Final removal of the oxazinone template with
Pb(OAc)4 at 0 °C gave the N-methyl amine 12 in a 73% yield.
The stereochemical rationalization for the diastereoselectivity
of the Mukaiyama aldol reaction is described by an open transition
state (Fig. 2). Given that Lewis acids prefer the anti preferences,13
there are two main contributing transition states that can dictate
the outcome of the reaction. T1 is unfavored due to the steric inter-
actions between the Lewis acid and the lactone ring, as well as the
silyl protection group and the aromatic portion of the aldehyde.
Therefore, the less sterically hindered transition state, T2, is fa-
vored resulting in the anti-product.
A corroborating X-ray crystal structure analysis was obtained of
the amino acid methyl ester 14 as shown in Scheme 3. Removal of
the oxazinone template from 10 yielded 13 in good yield followed
by deprotection of the silyl ether with TBAF, which gave the crys-
talline amino ester 14. X-ray crystallography analysis of this spe-
cies confirmed the relative stereochemistry (Scheme 3).
In summary, N-methyl amino acid 12 was synthesized in six
steps from oxazinone 5 employing a diastereoselective Mukaiyama
aldol with commercially available 3-bromo-4-methoxybenzalde-
hyde 6. The amino acid derivative 12 is currently under investiga-
tion for use in the synthesis of (ent)-MPC1001.
Ph
O
Ph
Ph
Ph
O
NaHMDS, TBSCl
8 mol % Cu(OTf)2
NCbz
NCbz
THF, -78 oC to rt.
86%
6, CH2Cl2, rt,
1 h, 99%
TBSO
O
5
7
Ph
Ph
Ph
Ph
H2 (1 atm)
O
O
NCbz
OTBS
ZnCl2
O
O
NH
(R)
10 mol % Pd/C,
EtOAc, 7h
(S)
MeOH : THF (2:1)
80 oC, 24h, 90%
OTBS
Br
MeO
Br
MeO
8
4 - 74 % - (S),(R)
9 - 14% - (R),(R)
Ph
Ph
Ph
Ph
HCHO ( 37% in H2O )
HO
MeO
HO
MeO
NH
OTBS
NaBH4CN, HOAc
THF : MeCN (1:1), 88%
NMe
OTBS
11
O
O
Br
MeO
Br
MeO
10
MeO
O
NHMe
OTBS
Pb(OAc)4
Br
MeO
Acknowledgment
CH2Cl2 : MeCN
(1:1), O oC, 73%
12
Scheme 2. Synthesis of N-methyl amino ester 12.
This work was supported by the National Institutes of Health
(Grant RO1GM068011).

382
P. T. Schuber Jr., R. M. Williams / Tetrahedron Letters 53 (2012) 380–382
Brannon, D. R.; Cline, J. C.; DeLong, D. C.; Gorman, M.; Huckstep, L. L.; Lively, D.
Supplementary data
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1968, 90, 6518; (f) Cosulich, D. B.; Nelson, N. R.; van den Hende, J. H. J. Am.
Chem. Soc. 1968, 90, 6519.
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.069.
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