Synthesis of (-)-quinocarcin by directed condensation of α-amino aldehydes

Article abstract of DOI:10.1021/ja056206n

An enantioselective synthesis of the natural antiproliferative agent quinocarcin was achieved by the directed condensation of optically active α-amino aldehyde intermediates. Condensation of the N-protected α-amino aldehyde 1, prepared in eight steps (19% yield) from (R,R)-pseudoephedrine glycinamide, with the C-protected α-amino aldehyde derivative 2, prepared in seven steps (34% yield) from (R,R)-pseudoephedrine glycinamide, afforded the corresponding imine in quantitative yield. Without isolation, direct treatment of this imine intermediate with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and hydrogen cyanide led to cleavage of the fluorenylmethoxycarbonyl (Fmoc) protective group followed by addition of cyanide (Strecker reaction) to form the bis-amino nitriles 3 as a mixture of diastereomers, in 91% yield. Treatment of the diastereomers 3 with trimethylsilyl cyanide and zinc chloride in 2,2,2-trifluoroethanol at 60 °C led to stepwise cyclization to form the tetracyclic product 4 (42% yield from 1 and 2). The latter intermediate was transformed into (-)-quinocarcin (1) in five steps (45% yield). The yield of quinocarcin was 19% from 1 and 2 (7 steps), and 4% from pseudoephedrine glycinamide (15 steps). Copyright

Full text of DOI:10.1021/ja056206n

Published on Web 11/10/2005
Synthesis of (-)-Quinocarcin by Directed Condensation of r-Amino
Aldehydes
Soojin Kwon and Andrew G. Myers*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received September 9, 2005; E-mail: myers@chemistry.harvard.edu
Scheme 1
(-)-Quinocarcin is a pentacyclic alkaloid with antiproliferative
effects.1,2 It is structurally similar to the saframycins3 and ectein-
ascidins4 in the A-, B-, and C-rings, but differs from these molecules
in the D-ring, which is five-membered rather than six-membered.
We sought to extend to the synthesis of quinocarcin an approach
we had earlier used to prepare (-)-saframycin A, involving the
directed condensation of C- and N-protected R-amino aldehyde
derivatives.5 To achieve this it was necessary to devise chemistry
to synthesize the five-membered D-ring of quinocarcin that was
compatible with the planned condensation-based approach, and to
determine an effective sequence for its implementation. We describe
here the realization of these objectives in a synthetic route to (-)-
quinocarcin.6 The major bond formations were achieved using
simple condensation reactions of R-amino aldehyde derivatives.
The synthetic sequence to (-)-quinocarcin developed is il-
lustrated in Scheme 1 and employs as starting materials the
N-protected R-amino aldehyde component 1, comprising the A-
and B-rings of the target and synthesized in eight steps from (R,R)-
pseudoephedrine glycinamide7 (19% yield, see Supporting Informa-
tion), and the C-protected R-amino aldehyde component 2, also
synthesized from (R,R)-pseudoephedrine glycinamide (seven steps,
34% yield, see Supporting Information).8 Condensation of 1 and 2
in dichloromethane in the presence of sodium sulfate afforded the
corresponding imine. Without isolation, the imine intermediate was
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.1 equiv),
cleaving the fluorenylmethoxycarbonyl (Fmoc) protective group,
and to the resulting product was added methanolic hydrogen cyanide
(prepared in situ), leading to Strecker addition. This sequence,
sample of the natural product, as determined by 1H NMR and HPLC
analysis, and by optical rotation measurements. The entire sequence
from 1 and 2 proceeds in 19% yield (7 steps); the yield from
pseudoephedrine glycinamide is approximately 4% (15 steps).
By conducting the key cyclization reaction of the bis-amino
nitriles 3 at 23 °C (1 h, ZnCl2, TMSCN, TFE) rather than at 60
°C, it was possible to isolate and characterize three of the four
possible diastereomeric tricyclic bis-amino nitrile intermediates 7
(7a, 44%; 7b, 15%; 7c, 12%, Scheme 2), as well as a small amount
of the bicyclization product 4 (18%) that predominates at higher
temperature. The fourth diastereomer (7d) could also be isolated,
after longer treatment at 23 °C (12 h, 19%, see Scheme 2). Each
of the individual diastereomeric tricyclic amino nitriles 7a-d was
transformed into the tetracyclic product 4 upon subjection to the
cyclization medium for 19 h at 61 °C, albeit at different rates and
with different efficiencies (see Scheme 3). These experiments leave
little doubt that the sequence of bicyclization to form product 4
involves initial formation of the C-ring followed by formation of
the D-ring. This proves to be critical to achieving proper stereo-
chemistry of the D-ring; in one alternative sequence that we
investigated, where D-ring formation preceded C-ring formation,
the allyl silane-imine addition reaction did not provide the necessary
stereochemistry for synthesis of quinocarcin.11
conducted as one operation, afforded the bis-amino nitriles 3 as a
mixture of diastereomers, as indicated, in 91% yield after flash-
column chromatography.
In the key transformation of the synthetic route, the mixture of
diastereomers 3 was warmed in 2,2,2-trifluoroethanol (TFE) in the
presence of trimethylsilyl cyanide (3.6 equiv) and zinc chloride
(3.3 equiv) at 60 °C for 15 h, forming the tetracyclic ring system
of quinocarcin in the form of the cyanopiperazine intermediate 4
(46% from 3).9 This process, which forms two of the four rings of
the target and three of its six stereocenters, proceeds by initial
cyclization of the C-ring in an intramolecular amino nitrile exchange
and then by closure of the D-ring in an allyl silane-imine addition
reaction,9 steps discussed in greater detail below. To complete the
synthesis of quinocarcin, the tetracyclic cyanopiperazine intermedi-
ate 4 was bis-methylated and the olefinic side-chain of the resulting
product was subjected to oxidative cleavage. The aldehyde formed
was then oxidized with Jones reagent in acetone to furnish the
intermediate 5 (64% over the three steps).10 Debenzylation of 5
with boron trichloride (5 equiv) produced quinocarcin and a small
amount of its noncyclized precursor 6, also known as DX-52-1.
By treating the crude mixture with silver nitrate in aqueous
methanol, complete conversion to quinocarcin was achieved (70%
yield, two steps). The synthetic material was identical to an authentic
9
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10.1021/ja056206n CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
appendage in both diastereomeric morpholino nitrile series (see
structures 9 and 10, Scheme 4). In brief, when each of the four
pairs of diastereomeric starting materials was subjected to cycliza-
tion conditions (40-60 °C, ∼15 h) the tetracycle 4 was formed as
the major product, but the substrate 9, containing a cis-allyl silane
appendage and an S-configured morpholino nitrile group, formed
4 most efficiently (53% yield). In both the cis- and trans-substrate
series the S-morpholino nitrile stereochemistry correlated with a
slightly greater efficiency of product formation (Scheme 4).
Acknowledgment. Financial support from the National Institutes
of Health is gratefully acknowledged. S.K. acknowledges a pre-
doctoral fellowship from Eli Lilly. We thank Dr. Richard Staples
for the X-ray analyses, and Kyowa Hakko Kogyo Co., Ltd. for an
authentic sample of quinocarcin.
Scheme 3
Supporting Information Available: Detailed experimental pro-
cedures and tabulated spectroscopic data (1H and 13C NMR, FT-IR and
HRMS) for all new compounds, and the X-ray analysis of the aldehyde
intermediate referred to in reference 10. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Scheme 4
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(10) The intermediate aldehyde could be crystallized from benzene. The
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(11) Kwon, S. Ph.D. Thesis, Harvard University, Cambridge, MA, 2005. In
no case have we observed diastereomers of product 4 in any of the
cyclization reactions described.
We investigated the influence of modification of the stereo-
chemistry of the morpholino nitrile group upon the key cyclization
reaction (using as starting material the diastereomer produced in
the synthesis of the C-protected R-amino aldehyde derivative 2;
see structure 8, Scheme 4, and the Supporting Information) as well
as the influence of modification of the geometry of the allyl silane
JA056206N
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