Synthesis of the tetrahydroisoquinoline alkaloid (±)-renieramycin G and a (zb)-lemonomycinone analogue from a common intermediate

Article abstract of DOI:10.1021/ja0535817

The total synthesis of tetrahydroisoquinoline alkaloids (±)-renieramycin G (4) and a lemonomycinone analogue (7) is described. A general strategy to synthesize both the mono- and bistetrahydroisoquinoline alkaloids from a common advanced intermediate, 17, is presented. Copyright

Full text of DOI:10.1021/ja0535817

Published on Web 07/29/2005
Synthesis of the Tetrahydroisoquinoline Alkaloid (()-Renieramycin G and a
(()-Lemonomycinone Analogue from a Common Intermediate
Philip Magnus* and Kenneth S. Matthews
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received June 1, 2005; E-mail: p.magnus@utexas.edu
Recently, we reported a new strategy to construct the tetrahy-
droisoquinoline core structure common to a number of antitumor
antibiotics, and it is exemplified by the conversion of 1 into 3 via
2 with complete control of the relative stereochemistry at C1 and
C3 (Scheme 1).1 Here, we report the application of this strategy to
the synthesis of (()-renieramycin G (4)2 and the (()-lemonomy-
cinone congener 7 (Figure 1) from the same intermediate 17
(Scheme 2).
The tetrahydroisoquinoline alkaloids represented by saframycins,
ecteinascidins, renieramycins, naphthyridinomycin, safracins,
quinocarcins, tetrazomine, and lemonomycin have generated wide
chemical and biological interest because of their potent antitumor
and antimicrobial activity.3 The renieramycins (A-S)4 are isolated
from various marine sponges and have the same core bisisoquinoline
structure as the saframycins, except the C22 nitrogen atom of the
saframycins is an oxygen atom in the renieramycins and frequently
acylated as its (Z)-2-methylbut-2-enoic acid ester (angelic acid
ester). Fukuyama and Danishefsky have reported total syntheses
of renieramycins.5 Lemonomycin (5) is a broad-spectrum antibiotic
isolated from the fermentation broth of Streptomyces candidus (LL-
AP191) in 1964.6 The structure was elucidated in 2000,7 and the
only total synthesis was reported by Stoltz in 2003;8 apart from
the unusual presence of the aldehyde hydrate, it is the first member
of this large class of compounds to have a carbohydrate appendage.
Our synthesis starts from the formation of the electron-rich
isoquinoline 10 (Scheme 2), from a modification of the Larock
isoquinoline synthesis,9 by coupling o-iodoimine 81 and acetylene
9 using room temperature Castro conditions,10 followed by a copper-
catalyzed ring closure. Treatment of isoquinoline 10 with benzyl-
oxymethyllithium11 followed by quenching with methyl chlorofor-
mate gave the 1,2-dihydroisoquinoline 11. Attempted reduction of
enecarbamate 11 directly to amino alcohol 13 was complicated by
elimination products derived from the electron-rich isoquinoline.12
Instead, amino alcohol 13 was obtained by first converting silyl
ether 11 to oxazolidinone 12 by treatment with TBAF, then
stereoselective reduction of the 3,4-olefin by ionic hydrogenation
cleanly gave the 1,3-cis-substituted tetrahydroisoquinoline; hy-
drazinolysis then yielded amino alcohol 13 (X-ray). Silyl-activated
amide coupling conditions were used to simultaneously protect the
alcohol and activate the amine toward coupling with the mixed
anhydride 14, giving solely the amide-coupled product 15 upon
acidic workup.13 Swern oxidation gave hemiaminal 16 as a mixture
of diastereomers (3:2),14 which was converted to thioaminal 17 as
a single diastereomer (X-ray).
Figure 1. Tetrahydroisoquinoline alkaloids.
Scheme 1. General Approach to Isoquinoline Alkaloids
Scheme 2. Common Intermediate
19 gave a single diastereomer, 20, which upon diastereoselective
reprotonation by treatment with tert-butyllithium and quenching
with BHT gave complete inversion at the C13 stereocenter with
minimal degradation.15 Alcohol 21 was isolated after TIPS removal.
Subsequent Swern oxidation and silyl enol ether formation gave
cyclization precursor 22. The N-acyliminium cyclization was
promoted with thiophile AgBF4, providing aldehyde 23 as a single
diastereomer at C15. The relative stereochemistry was assigned by
X-ray analysis of the oxime derivative 24.16 The selectivity is
attributed to the steric bulk of the C1 substituent, which exists in
an axial orientation, as seen by X-ray analysis of 17, 18, and 24.
Hydrogenolysis of dibenzyl ether 22 formed diol 25 as the
unhydrated aldehyde. Removal of the Boc group led to amine 26,
In our initial approach to (()-lemonomycinone amide (7),
alkylation of amide 17 with allyl bromide gave product 18 as a
single diastereomer (Scheme 3). The relative stereochemistry was
assigned by X-ray analysis, revealing that the alkylation occurred
from the least hindered face, giving the undesired stereochemistry
at the C13 stereocenter. Elaboration of product 18 to alcohol 21
proved unsuccessful. However, alkylation of amide 17 with iodide
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10.1021/ja0535817 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. (()-Lemonomycinone Amide
diastereomers were best separated after trityl deprotection to give
phenol 31. The cyclization was promoted by treatment with AgBF4
as before; however, cyclization was complete within 10 min along
with rapid loss of the Boc group, presumably due to the generation
of HBF4. Subsequent reductive methylation gave N-methylamine
33. Hydrogenolysis was followed by oxidation with CAN to give
bisisoquinolinequinone 35. Incomplete hydrogenolysis gave the
monobenzylated product 34 (X-ray).17 Completion of the synthesis
was achieved by treating alcohol 35 with excess angeloyl chloride
3618 to give (()-renieramycin G (4).19,20
In conclusion, a general approach to both mono- and bistetrahy-
droisoquinoline alkaloids from a common advanced intermediate
has been described. The common intermediate 17 was synthesized
from imine 8 in 10 steps and 32% yield. From 17, (()-
lemonomycinone amide (7) was synthesized in nine steps and 16%
yield, while (()-renieramycin G (4) was synthesized in eight steps
and 18% yield.21
Acknowledgment. The National Institutes of Health (GM
32721), the Welch Chair (F-0018), and Merck Research laboratories
are thanked for their support of this research.
Supporting Information Available: Detailed experimental pro-
cedures and spectroscopic data (1H and 13C NMR, FT-IR, and HRMS)
for new compounds, and X-ray analysis data (cif). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
Scheme 4. (()-Renieramycin G
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A., Ed.; Academic Press: San Diego, 2000; Vol. 53, p 120.
(4) Isolation and characterization: Saito, N.; Tanaka, C.; Koizumi, Y.;
Suwanborirux, K.; Amnuoypol, S.; Pummangura, S.; Kubo, A. Tetrahe-
dron 2004, 60, 3873-3881 and references therein.
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Tetrahedron Lett. 1990, 31, 5989-5992. (b) Cribrostatin 4 (renieramycin
H): Danishefsky, S. J.; Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.;
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(12) For potential side reactions during ionic hydrogenation of electron-rich
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(13) Without TMS protection of the alcohol, only the ester-coupled product is
obtained when 1 equiv of mixed anhydride 14 is used.
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(16) Oxime 24 from 23 (HONH3Cl, KOAc, EtOH/H2O, 85% yield, X-ray)
gave a 1:1 mixture of cis:trans isomers, crystallizing as a 4:1 mixture.
(17) Phenol 34 from 33 (Pd(OH)2, MeOH, 1 atm H2, 1 h, 85% yield, X-ray).
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which exists entirely in the hydrated aldehyde form. Oxidation of
phenol 26 with CAN8a gave (()-lemonomycinone amide (7).
The synthesis of (()-renieramycin G (4) (Scheme 4) started with
the addition of KHMDS to a mixture of amide 17 and benzyl
chloride 29 in the presence of 18-crown-6 to give very efficient
conversion to product 30 as a single diastereomer. The previous
conditions for diastereoselective reprotonation were employed;
however, complete inversion was not observed, and instead, a 6:1
ratio of the desired isomer to starting material was obtained. These
(20) An authentic sample of renieramycin G was not available for comparison,
but spectral data were consistent with published data (ref 2).
(21) We are grateful to Prof. R. M. Williams for sending us a preprint of their
manuscript describing the synthesis of (-)-renieramycin G.
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