COMMUNICATION
The novel and efficient direct synthesis of N,O-acetal compounds using
a hypervalent iodine(III) reagent: an improved synthetic method for a
key intermediate of discorhabdins
Yu Harayama, Masako Yoshida, Daigo Kamimura and Yasuyuki Kita*
Received (in Cambridge, UK) 7th December 2004, Accepted 19th January 2005
First published as an Advance Article on the web 4th February 2005
DOI: 10.1039/b418212j
hypervalent iodine chemistry, we have already reported various
oxidation reactions of carbonyl, alkynyl, phenol and phenyl ether
derivatives6 using phenyliodine(III) bis(trifluoroacetate) (PIFA)
and phenyliodine(III) diacetate (PIDA). We now report the novel
and efficient direct synthesis of N,O-acetal compounds via the
oxidative fragmentation reaction of a-amino acids or a-amino
alcohols using bis(trifluoroacetoxy)iodo(III) pentafluorobenzene
(C6F5I(OCOCF3)2). This reagent is very easily prepared from
pentafluoroiodobenzene and nitric acid.7 Furthermore, we suc-
ceeded in the improved synthesis of the key intermediate of
discorhabdins by using this method.
The use of hypervalent iodine(III) reagents allowed us to
develop the novel and efficient direct synthesis of N,O-acetal
compounds via the oxidative fragmentation reaction of a-amino
acids or a-amino alcohols; furthermore, we succeeded in
developing an improved synthesis of the key intermediate of
discorhabdins.
N,O-acetal compounds are important intermediates since they are
relatively stable, but readily generate unstable N-imines, which are
attacked by nucleophiles to produce functionalized and unnatural
amine or amino acid derivatives.
a-Amino acids and a-amino alcohols have recently attracted
much attention because they are easily available and versatile
building blocks and chiral auxiliaries. Therefore, the synthesis of
N,O-acetal compounds from a-amino acids or a-amino alcohols
facilitates the asymmetric synthesis of functionalized and unnatural
amine or amino acid derivatives and natural products containing a
nitrogen atom. In fact, by using this methodology, we recently
diastereoselectively accomplished the first total synthesis of the
marine anti-cancer alkaloid, (+)-discorhabdin A, but there has
remained the problem of using highly toxic lead tetraacetate
(Scheme 1).1
First, we examined the oxidation of the N-Fmoc serine methyl
ester using hypervalent iodine(III) reagents to optimize the reaction
conditions. These results are shown in Table 1. Surprisingly, the
reaction was found to smoothly proceed only by using
C6F5I(OCOCF3)2 to give N,O-acetal compounds under slightly
diluted condition, while almost no reaction occurred using other
hypervalent iodine(III) reagents (entries 6, 7) and lead tetraacetate
˚
(entries 8–10). Molecular sieves 3 A are necessary to keep the
reaction conditions anhydrous in order to prevent water insertion.
Similarly, the reactions of other N-protected-a-amino alcohols
(1) with C6F5I(OCOCF3)2 were investigated. These results are
shown in Table 2. The N,O-acetal compounds (2) were produced
in high yields (entries 1–7), and the relatively low yield of alaninol
was caused by the instability of the product (entry 4). When the
protective groups of nitrogen were changed from carbamates to
benzoyl, the yield of 2h was moderate (entry 8). The products 2a,
b, f–h are important compounds because they can be transformed
into unnatural amino acids followed by Ben-Ishai’s or Boto’s
method.8 Furthermore, we found that this reaction could be
applied to the discorhabdin intermediate having functionalized and
unstable pyrroloiminoquinone moieties (entry 9), which leads to
the improved synthetic method for the key intermediate of
discorhabdins.
Several methods have appeared for the synthesis of N,O-acetal
compounds from a-amino acids and a-amino alcohols, e.g., the
electrochemical oxidation of a-amino acids,2 the oxidation by lead
tetraacetate3 or the radical reaction4 of a-amino acids and a-amino
alcohols. However, these methods have some problems in terms of
using highly toxic reagents and complex handling. Furthermore,
most of them produced N,O-Ac-acetals because of the ligand
insertion, but this type of acetal is often quite unstable.5 Therefore,
it is advantageous to accomplish the direct synthesis of the more
stable N,O-acetals.
Over the past several years, hypervalent iodine(III) reagents have
received much attention due to their low toxicity, ready
availability, easy handling, and reactivities similar to those of
heavy metal reagents. As a continuation of our studies of
Next, we applied this method to a-amino acid derivatives (3).
These results are shown in Table 3. The N,O-acetal compounds (4)
were produced in moderate yields (entries 1–5).
A plausible reaction mechanism for the preparation of 2 or 4 via
the oxidative fragmentation reaction of 1 or 3 is shown in
Scheme 2. It is possible that the reaction proceeds via the radical
path way, but no signal was found in the ESR spectroscopic
studies. We rather propose that the reaction proceeds via the five-
membered ring intermediate as shown in Scheme 2. A similar
mechanism was proposed using lead tetraacetate.3
Scheme 1 First total synthesis of (+)-discorhabdin A
*kita@phs.osaka-u.ac.jp
A typical experimental procedure is as follows. To a stirred
solution of the amino alcohol (1) or amino acid (2) in
1764 | Chem. Commun., 2005, 1764–1766
This journal is ß The Royal Society of Chemistry 2005