belongs to the third category. PTT is widely used in
agriculture due to its bactericidal, fungicidal, and herbicidal
properties.3 PTT is unique among naturally occurring phos-
phonates in that it has a C-P-C bond. The first C-P bond
in PTT is catalyzed by phosphoenol-pyruvate mutase, as
in the first category.3 Genetic studies suggests that a
methylcobalamin dependent protein (BcpD) catalyzes the
formation of the second C-P bond in PTT.3,16-18
Bialaphos biosynthesis in Streptomyces hygroscopicus and
Streptomyces Viridochromogenes has been investigated by
analyzing the accumulated intermediates in the blocked PTT
biosynthetic mutants.3,19-24 It was proposed that either
N-AcDMPT (1) or N-AcDMPTT (2) is the substrate for the
BcpD-catalyzed P-methylation reaction (Scheme 1).3,16-18
Figure 1
AcDMPTT.
. Retrosynthetic analysis of the N-AcDMPT and N-
oxidative elimination method from phenyl selenide 4 was
chosen and conditions were optimized to resolve issues such
as low yield and low optical purity.29 One of the other
intermediates, (S)-2-aminobutyrolactone hydrochloride (5)
can be easily scaled up to tens of grams following a “one-
pot” reaction from L-(+)-methionine.30
Scheme 1. Proposed Last Two Steps in PTT Biosynthesis
(S)-2-Aminobutyrolactone hydrochloride 5 was synthe-
sized from L-(+)-methionine over three steps, including thiol-
methylation with methyl iodide, hydrolysis in basic aqueous
solution, and ring closure mediated by 6 M hydrochloric acid
in one pot, with an overall yield of 60% (Scheme 2).30
N-AcDMPT (1) and N-AcDMPTT (2) are natural products
with a phosphinic functional group. To date, only a very
small pool of phosphinic natural products have been identi-
fied.3 In addition, BcpD activity has not been reconstituted
in vitro. To facilitate detailed mechanistic studies of this
unique P-methylation reaction, convenient chemical synthe-
ses for both N-AcDMPT (1) and N-AcDMPTT (2) are
described in this paper.
Scheme 2. Synthesis of Phenyl Selenide 4
The retrosynthetic analysis is outlined in Figure 1, in which
both N-AcDMPT (1) and N-AcDMPTT (2) were synthesized
from the same intermediate phenyl selenide 4. The C-P bond
can be constructed by coupling hypophosphite to an olefin
at room temperature via a triethylborane initiated radical
reaction.25 Several methods are present in the literature on
the synthesis of R-vinyl glycine.26-28 In this paper, the
Nucleophilic ring opening of 5 led to the formation of (S)-
2-amino-4-bromobutyric acid hydrobromide (8). After re-
crystallization, the compound 8 obtained has an optical purity
of [R]24D ) -9.6 (c ) 1.0, H2O), which is close to the value
reported in the literature29 ([R]23D ) - 6.8 (c ) 1.0, H2O)).
The carboxylate and amino groups in 8 were then protected
sequentially by methylation and acetylation to form (S)-
methyl 2-acetamido-4-bromobutanoate (9). The conversion
of bromide 9 to phenyl senelide 4 was achieved following
the standard Sharpless conditions using sodium phenylse-
lenide generated from diphenyldiselenide and sodium boro-
hydride in situ.31
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The production of R-vinyl glycine 3 from phenyl selenide
4 was the most challenging step in compound 1 synthesis.
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(28) Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K. J. Org. Chem.
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