COMMUNICATION
Synthetic studies on (2)-lemonomycin: stereocontrolled construction of
the 3,8-diazabicyclo[3.2.1] skeleton
Kentaro Rikimaru, Kazuki Mori, Toshiyuki Kan and Tohru Fukuyama*
Received (in Cambridge, UK) 30th September 2004, Accepted 1st November 2004
First published as an Advance Article on the web 8th December 2004
DOI: 10.1039/b415030a
accomplished by the Ugi 4-CC reaction with p-methoxyphenyl
isocyanide and acetaldehyde to access easily the corresponding
diketopiperazine. However, we found that the Ugi 4-CC reaction
of the isocyanide 8 and glyoxyaldehyde dimethylacetal 7 in
trifluoroethanol11 was more suitable for an efficient preparation of
13. Thus, after conversion to the dipeptide 9, the transformation to
the cyclic enamide 10 was performed by treatment with CSA (10-
camphorsulfonic acid) and quinoline. Although cleavage of the
amide bond derived from the isocyanide of the Ugi adducts often
requires harsh conditions, we discovered recently that the amide
bond derived from the phenyl carbonate-type isocyanide was
readily converted via the corresponding N-acyloxazolidinone
derivatives.12 Thus, upon treatment of the amidocarbonate 10
with t-BuOK, the oxazolidinone formation proceeded smoothly to
provide 11 with release of phenol. The imide 11 was readily
converted to the hydroxymethyl derivative 12 by simple reduction
with NaBH4. Changing the protecting group from TIPS to Ac
proceeded smoothly in one step to provide 13 in high yield. For the
crucial construction of the bicyclo[3.2.1] system, we found that an
acyliminium ion-mediated cyclization was more suitable to obtain
the desired stereochemistry.13 The elaboration of the cyclization
precursor 15 was achieved by a cross-metathesis of 13 and
allyltrimethylsilane in the presence of 2 mol% of the Grubbs 2nd
generation catalyst (14).14,15 Upon treatment of 15 with BF3?Et2O,
generation of the conjugate acyliminium cation 16 and subsequent
cyclization of the allylsilane moiety proceeded immediately to
Stereoselective synthesis of the pentacyclic key intermediate 22
for (2)-lemonomycin (1) has been accomplished using the Ugi
4-CC reaction with our novel isocyanide 8, a cross-metathesis
of 13 and allylsilane and a subsequent intramolecular Hosomi–
Sakurai type reaction.
(2)-Lemonomycin (1) is
a
tetrahydroisoquinoline alkaloid1
isolated from Streptomyces candidus (LL-AP191).2 Although the
isolation of 1 was achieved in 1964, the structure determination
was not reported until 2000 by researchers at Wyeth-Ayerst.3 It
was also discovered that the compound possessed interesting
antibiotic activity against methicillin-resistant Staphylococcus
aureus (MRSA) and vancomycin-resistant Enterococcus faecium
(VREF), as well as cytotoxicity against a human colon tumor cell
line (HCT-116).3 Because of its potent biological activity and
challenging structure, lemonomycin has become an attractive
target for synthesis, and indeed the first total synthesis of 1 was
achieved by Stoltz and co-workers in 2003.4
During the course of our total synthesis of ecteinascidin 743,5 we
established an efficient synthetic strategy for the tetrahydroisoqui-
noline alkaloids via the Ugi four-component condensation (4-CC)6
and the intramolecular Mizoroki–Heck reaction. Furthermore, an
application of this protocol was demonstrated by the stereo-
selective construction of the highly strained 3,8-diazabicy-
clo[3.2.1]octane framework of (+)-naphthyridinomycin (2).7 In a
subsequent synthetic investigation, we developed an efficient
synthetic methodology for (2)-lemonomycin (1) and report herein
the stereocontrolled synthesis of the tetracyclic key intermediate 22
for 1.
The heart of our synthetic plan is illustrated in Scheme 1.
Incorporation of a unique amino sugar moiety and transformation
to a labile quinone and hemiaminal moiety would be carried out at
later stages of the total synthesis. Thus, the tetracyclic compound 3
was designed as a key intermediate in our total synthesis of 1.
According to our synthetic study on 2,7 the preparation of 3 from
4 would be readily achieved by hydration of the enamide of 4 and
subsequent electrophilic cyclization between an electron-rich
aromatic ring and an aldehyde. Since there is a significant
difference between 1 and 2 in the stereochemistry at the C-15
position, the stereoselective construction of the bicyclo[3.2.1]
system bearing an exo-oriented side chain in 4 would be a crucial
step for the total synthesis of 1.8
Our synthesis started from the two chiral amino acid derivatives
57,9 and 610 (see Scheme 2). In our synthetic investigation of the
related alkaloids,5,7 condensation of the amino acid derivatives was
*fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1 Structure and synthetic strategy of lemonomycin (1).
This journal is ß The Royal Society of Chemistry 2005
394 | Chem. Commun., 2005, 394–396
Rikimaru, Kentaro
