A concise total synthesis of (-)-quinocarcin via aryne annulation

Full text of DOI:10.1021/ja808112y

Published on Web 11/26/2008
A Concise Total Synthesis of (-)-Quinocarcin via Aryne Annulation
Kevin M. Allan and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received October 14, 2008; E-mail: stoltz@caltech.edu
Scheme 2
The tetrahydroisoquinoline antitumor antibiotics have received
considerable attention over the past several decades owing to their
intricate polycyclic architectures and potent broad-spectrum cytotoxicity
(e.g., 1-5, Figure 1).1 An archetypal member of the 3,8-diaza-
Drawing from our previous total synthesis of the related tetrahy-
droisoquinoline lemonomycin (3),7 we chose to build the bridged
bicycle using an auxiliary-controlled diastereoselective dipolar cy-
cloaddition between an oxidopyrazinium betaine and a chiral dipo-
larophile (Scheme 3).14 Deprotonation of oxidopyrazinium bromide
Figure 1. Tetrahydroisoquinline antitumor antibiotics.
Scheme 3
bicyclo[3.2.1]octane subclass, quinocarcin (1), has shown remarkable
antiproliferative activity against lymphocytic leukemia.2 Further in vitro
studies involving the more stable citrate salt of 13 (KW2152) and the
aminonitrile DX-52-14 (2) revealed similar inhibition of non-small cell
lung cancer and adenocarcinoma. Certain members of this family are
currently in advanced human clinical trials in the U.S. as anticancer
treatments, notably Ecteinascidin 7435 (Yondelis, 4) and the jorumycin
analogue PM00104/506 (Zalypsis, 5). As part of our ongoing studies
directed toward this class of molecules,7 we report an 11-step
asymmetric total synthesis of (-)-quinocarcin. This represents the
shortest synthesis to date and features a key aryne annulation reaction
developed in our laboratories to assemble the heterocyclic framework.8,9
Intriguing structural and biological features of quinocarcin have led
to the pursuit of its total synthesis.10-12 To date, the Pictet-Spengler
condensation has been the most popular procedure used to close the
namesake tetrahydroisoquinoline ring system,10,11d,e while alternate
strategies centered on the reduction of isoquinolines are noticeably
less common.11c We have recently reported a method for the
construction of a broad array of substituted isoquinolines 8 that employs
a fluoride-induced annulation reaction between arynes derived from
silylaryl triflates13 6 and N-acyl enamines 7 (Scheme 1).8 Isoquinoline
1315 to form the putative active dipole in situ followed by subsequent
addition of the acrylamide of Oppolzer’s sultam (14) produced an 11:1
mixture of separable diastereomeric cycloadducts.7,11a,b Purification
of the major diastereomer and removal of the auxiliary via basic
methanolysis provided methyl ester 12 in 74% yield and 99% ee.
Acylation with benzyloxyacetyl chloride (15) then afforded imide 16.
To advance this intermediate to enamine 11, regioselective metha-
nolysis at the lactam carbonyl was required. An extensive screening
of additives revealed that several metal triflate salts are capable of
inducing this selectivity,16 and yttrium(III) triflate was eventually found
to provide the optimum yield of 11.
Scheme 1
With N-acyl enamine 11 in hand, we focused our attention on the key
aryne annulation. Using optimized conditions,8 enamine 11 and 3-meth-
oxy-2-(trimethylsilyl)phenyl triflate17 (17) were combined in the presence
of tetra-n-butylammonium difluorotriphenylsilicate (TBAT) at 40 °C to
generate isoquinoline 9, an intermediate comprising the core carbon atoms
of quinocarcin (Scheme 4).18 Having thus assembled the molecular
scaffold, our next challenge lay in a diastereoselective reduction of the
isoquinoline ring system to introduce the stereocenters at C(5) and C(11a).
After exploring several one-step methods to accomplish this transforma-
tion,19 we opted for a two-step sequence beginning with hydrogenation
9 was retrosynthetically targeted, for construction through the union
of aryne 10 and N-acyl enamine 11 (Scheme 2). We ultimately
envisioned enamine 11 to arise through functionalization of diazabi-
cycle 12, the stereoselective formation of which would impart
asymmetry upon our forward route.
9
17270 J. AM. CHEM. SOC. 2008, 130, 17270–17271
10.1021/ja808112y CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
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(9) Shortly after our report, Blackburn and Ramtohul disclosed a preparation of
both isoquinolines and benzocyclobutanes using CsF as the fluoride source;
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Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1993, 115, 10742–10753. (c) Katoh,
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over Pd on C that afforded a 3.3:1 mixture of unstable diastereomeric
dihydroisoquinolines (18a and 18b).20 Treatment of this mixture with
sodium cyanoborohydride resulted in a completely stereoselective reduction
to produce an equivalent ratio of separable tetrahydroisoquinolines (19a
and 19b), the major diastereomer of which corresponds to the stereo-
chemistry of the target alkaloid.21 Upon heating, the newly formed
secondary amine selectively condensed with one of the two neighboring
esters to form lactam 20 in 99% yield. In light of the slow benzyl group
hydrogenolysis implicit in the success of the previous heterogeneous
reduction, the more active Pearlman’s catalyst was required to remove
the two protecting groups and subsequently methylate the unmasked
amine, providing tetracycle 21. In the final two steps, saponification of
the methyl ester was followed by a partial reduction of the lactam under
dissolving metal conditions.11a,b,e,22 Treatment of the resulting hemiaminal
with 1 N HCl resulted in closure of the oxazolidine ring and completion
of (-)-quinocarcin (1).
In summary, we successfully completed a short asymmetric total
synthesis of (-)-quinocarcin (1) in 10% overall yield via a longest linear
sequence of 11 steps from known compounds (13 steps from commercially
available materials). By applying our aryne annulation technology toward
the construction of key isoquinoline intermediate 9, we are able to assemble
the core of the molecule in only five steps and advance this material to the
natural product target along the shortest synthetic route reported to date.
We are currently investigating the application of this methodology toward
the synthesis of additional members of the tetrahydroisoquinoline antitumor
antibiotic family and will report these efforts in due course.
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K.; Minami, J.; Terashima, S. Tetrahedron 1994, 50, 6221–6238. (h) Katoh,
T.; Kirihara, M.; Yoshino, T.; Tamura, O.; Ikeuchi, F.; Nakatani, K.; Matsuda,
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(13) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211–1214.
(14) The reaction protocol for this dipolar cycloaddition is based on the pioneering work
of Joule; see: (a) Kiss, M.; Russell-Maynard, J.; Joule, J. A. Tetrahedron Lett.
1987, 28, 2187–2190. (b) Yates, N. D.; Peters, D. A.; Allway, P. A.; Beddoes,
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(15) Oxidopyrazinium bromide 13 is prepared in two steps from commercially
available pyruvaldehyde and glycinamide hydrochloride; see: Karmas, G.;
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(16) Additional metal triflate salts examined include Zn(OTf)2, Sc(OTf)3, and
Sm(OTf)3. However, none provided enamine 11 in greater than 40% yield.
(17) 3-Methoxy-2-(trimethylsilyl)phenyl triflate (17) is prepared in three steps from
3-methoxyphenol; see: Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am.
Chem. Soc. 1999, 121, 5827–5828.
(18) Attempts to employ the N-methyl analogue of the tertiary amine in 11 resulted
in decomposition of the corresponding isoquinoline product, presumably
through reaction of this less hindered amine with aryne 10.
(19) Under the best one-step conditions, the reduction of isoquinoline 9 with sodium
cyanoborohydride in 1:50 HCl/MeOH at 23 °C led to a 1.6:1 mixture of
diastereomeric tetrahydroisoquinolines (19a and b) in 46% yield. For a similar
procedure, see ref 11c.
Acknowledgment. The authors thank Abbott, Amgen, Boehringer-
Ingelheim, Bristol-Myers Squibb, Merck, Sigma-Aldrich, and Caltech for
generous funding. Special thanks to Dr. Scott C. Virgil of the Caltech
Center for Catalysis and Chemical Synthesis for helpful discussions.
(20) The diastereomeric ratio was determined by 1H NMR. Remarkably little
hydrogenolysis of the benzyl protecting groups was observed within the first
6 h of this reaction.
(21) Reduction of either dihydroisoquinoline diastereomer (18a or b) is observed
to be completely stereoselective for the formation of the syn-5,11a-tetrahy-
droisoquinoline (19a and b) following installation of the stereocenter at C(5).
For a similar example of asymmetric induction, see: Ishida, A.; Fujii, H.;
Nakamura, T.; Oh-ishi, T.; Aoe, K.; Nishibata, Y.; Kinumaki, A. Chem. Pharm.
Bull. 1986, 34, 1994–2006.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(22) Evans, D. A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986, 108, 2478–2479.
(1) For a comprehensive review of the chemistry and biology of the tetrahydroiso-
quinoline alkaloids, see: Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102,
1669–1730.
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