Tetrahedron Letters
Multigram synthesis of 1-O-acetyl-3-O-(4-methoxybenzyl)-4-N-(9-
fluorenylmethoxycarbonyl)-4-N-methyl-L-pyrrolosamine
⇑
Matthew Burk, Nolan Wilson, Seth B. Herzon
Department of Chemistry, Yale University, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1-O-acetyl-3-O-(4-methoxybenzyl)-4-N-(9-fluorenylmethoxycarbonyl)-4-N-methyl-L-
Received 26 November 2014
Revised 11 December 2014
Accepted 12 December 2014
Available online xxxx
pyrrolosamine (7), which constitutes a protected form of the N,N-dimethyl-L-pyrrolosamine residues
found within the antiproliferative bacterial metabolites (À)-lomaiviticins A and B (1 and 2, respectively),
is reported. The synthetic route to 7 proceeds in eight steps and 13% overall yield from (E)-crotyl alcohol.
The protected carbohydrate 7 is envisioned to be a useful derivative for syntheses of 1 and 2.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Lomaiviticin
Natural products
Carbohydrate
Synthesis
(À)-Lomaiviticins A (1) and B (2, Fig. 1) are complex bacterial
metabolites that were first isolated in 2001 from a strain of Salin-
ispora pacifica.1 (À)-Lomaiviticin A (1) is a potent inhibitor of cul-
tured human cancer cell proliferation, with half-maximal
inhibitory potencies in the low nanomolar–picomolar range.1a
The cytotoxic effects of 1 derive from induction of double-strand
breaks in DNA.2
revealed1b that both carbohydrate residues of 1 are of the
This calls for implementation of the Shi ketone derived from the
unnatural sugar -Fructose itself was
-fructose to obtain ent-4.7
synthesized from
-sorbose by a multistep sequence.8 Second,
although the Shi epoxidation was singularly effective in accessing
4 and ent-4, 0.3 equiv of the chiral ketone was required to achieve
high conversions, rendering the process impractical on large
scales. Third, we have observed that the dialkylamino and O-allyl
substituents of 5 are incompatible with certain steps in our syn-
thesis of the diazofluorene function of the targets. To address these
issues, we have developed the synthesis of 1-O-acetyl-3-O-(4-
methoxybenzyl)-4-N-(9-fluorenylmethoxycarbonyl)-4-N-methyl-
L-form.
L
L
L
(À)-Lomaiviticins A (1) and B (2) possess dimeric C2-symmetric
structures, each of which contain two diazofluorene functional
groups.3 They are related to the natural monomeric diazofluorenes
known as the kinamycins (not shown), which have been isolated
from various strains of Streptomyces.4 (À)-Lomaiviticin A (1) con-
tains two
L
-oleandrose residues and two N,N-dimethyl-
L-pyrrolos-
L-pyrrolosamine (7), which constitutes
a protected form of
amine residues. Several groups have initiated synthetic studies
toward 1 and 2.5 Our laboratory reported a synthesis of (À)-lomai-
viticin aglycon (3).5i We also reported a strategy to prepare N,N-
N,N-dimethyl- -pyrrolosamine. The route to 7 proceeds in eight
steps, 13% overall yield, and readily provides multigram quantities
of product.
L
dimethyl-O-allyl-
D
-pyrrolosamine (5) and O-allyl-
L
-oleandrose (6)
As an alternative to the Shi protocol, we applied a sequence
comprising Sharpless epoxidation of (E)-crotyl alcohol,9 followed
by oxidation and in situ chain extension (Scheme 2).10 Decagram
quantities of ent-4 were readily obtained in 48% yield and 86% ee
by this two-step sequence.
With large quantities of ent-4 in hand, we explored its opening
with protected dialkylamine nucleophiles (Scheme 3). After some
experimentation, the use of (3,4-dimethoxybenzyl)methylamine
was determined to be optimal for the epoxide opening and
subsequent steps. Heating solutions of ent-4 and (3,4-dimethoxy-
benzyl)methylamine in ethanol at 55 °C formed the aminoalcohol
9 in 60% yield on a 19 g scale. Attempts to directly convert the
ester 9 to the corresponding aldehyde 11 by treatment with
in three steps from ethyl (2E,4R,5R)-4,5-epoxy-2-hexenoate (4)
and ethyl (2E,4S,5S)-4,5-epoxy-2-hexenoate (ent-4), respectively
(Scheme 1).5e The epoxides 4 and ent-4 were prepared in 41% yield
and 96% ee by Shi epoxidation of ethyl sorbate, as previously
described.6 Distinct strategies to prepare protected forms of the
aminosugar residues of 1 and 2 have also been reported by the
Shair laboratory.5c,h
Several issues render our route to 5 and 6 inadequate for
syntheses of (À)-lomaiviticins A and B (1 and 2). First, it was
⇑
Corresponding author.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.