Asymmetric total synthesis of (-)-quinocarcin

Article abstract of DOI:10.1021/ja800662q

(-)-Quinocarcin (1) has been synthesized in a longest linear sequence of 22 steps from 3-hydroxybenzaldehyde in 16% overall yield. The Pictet-Spengler reaction of L-tert-butyl-2-bromo-5-hydroxy phenylalanate (17), synthesized according to Corey-Lygo's enantioselective alkylation process, with benzoxyacetaldehyde (12) under mild acidic conditions afforded 1,3-cis tetrahydroisoquinoline 20 as an only isolable stereomer in 91% yield. The diazabicycle[3,2,1]-octane ring system of 28 was constructed by a silver tetrafluoroborate-promoted intramolecular Mannich reaction using amino thioether as a latent N-acyliminium species and tethered silyl enol ether as a nucleophile. Using amino thioether instead of aminal as a precursor of N-acyliminium was of high importance to the success of this otherwise disfavored 5-endo-Trig cyclization. A Hf(OTf)₄-catalyzed (0.1 equiv) transformation of aminal to amino thioether was uncovered in the course of this study, allowing the conversion of tricyclic aminal 24 to amino thioether 25 to be realized in high yield. From the bridged tetracyclic compound 28, a sequence of oxidation of aldehyde to acid, global deprotection under hydrogenolysis conditions, and one-pot partial reduction of lactam to aminal/oxazolidine formation completed the total synthesis of the pentacyclic (-)-quinocarcine.

Full text of DOI:10.1021/ja800662q

Published on Web 05/03/2008
Asymmetric Total Synthesis of (-)-Quinocarcin
Yan-Chao Wu, Me´lanie Liron, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
Received January 27, 2008; E-mail: zhu@icsn.cnrs-gif.fr
Abstract: (-)-Quinocarcin (1) has been synthesized in a longest linear sequence of 22 steps from
3-hydroxybenzaldehyde in 16% overall yield. The Pictet-Spengler reaction of L-tert-butyl-2-bromo-5-hydroxy
phenylalanate (17), synthesized according to Corey-Lygo’s enantioselective alkylation process, with
benzoxyacetaldehyde (12) under mild acidic conditions afforded 1,3-cis tetrahydroisoquinoline 20 as an
only isolable stereomer in 91% yield. The diazabicycle[3,2,1]-octane ring system of 28 was constructed by
a silver tetrafluoroborate-promoted intramolecular Mannich reaction using amino thioether as a latent
N-acyliminium species and tethered silyl enol ether as a nucleophile. Using amino thioether instead of
aminal as a precursor of N-acyliminium was of high importance to the success of this otherwise disfavored
5-endo-Trig cyclization. A Hf(OTf)4-catalyzed (0.1 equiv) transformation of aminal to amino thioether was
uncovered in the course of this study, allowing the conversion of tricyclic aminal 24 to amino thioether 25
to be realized in high yield. From the bridged tetracyclic compound 28, a sequence of oxidation of aldehyde
to acid, global deprotection under hydrogenolysis conditions, and one-pot partial reduction of lactam to
aminal/oxazolidine formation completed the total synthesis of the pentacyclic (-)-quinocarcine.
Introduction
(-)-Quinocarcin (1) is a pentacyclic tetrahydroisoquinoline
alkaloid1 that was isolated by Takahashi and Tomita in 1983
from the culture broth of Streptomyces melunoVinuceus.2 It
exhibited potent antitumor activities against a variety of tumor
cell lines and its citrate salt (KW2152) had been in clinic trials
in Japan.3,4 The DX-52-1 (2), a more stable compound resulting
from the ring opening of oxazolidine by cyanide, also has
significant antitumor activities.4 Quinocarcin underwent self-
redox disproportionation under anaerobic conditions leading to
inactive quinocarcinol (3) and quinocarcinamide (4).3d The
structurally related (-)-tetrazomine (5) displayed similar anti-
tumor antibiotic activity (see Figure 1).5 The antiproliferative
effect of (-)-quinocarcin was partly accounted for by its ability
Figure 1. Structures of (-)-quinocarcin (1) and related alkaloids.
(1) For a comprehensive review of the chemistry and biology of
tetrahydroisoquinoline alkaloids, see: Scott, J. D.; Williams, R. M.
Chem. ReV. 2002, 102, 1669–1730.
to inhibit RNA and/or DNA synthesis.3a However, it has been
suggested that (-)-quinocarcin and (-)-tetrazomine exerted their
cytotoxic activity through the expression of multiple mechanisms
including the mediation of oxidative damage to DNA via the
reduction of molecular oxygen to superoxide by the autoredox
disproportionation of the fused oxazolidine.6
The fascinating molecular architecture and important biologi-
cal profile of quinocarcin have attracted significant attention
from the synthetic community, culminating in one racemic7 and
three asymmetric synthesis of (-)-quinocarcine.8–10 Total
syntheses of more stable quinocarcinol methyl ester11 and
(2) (a) Takahashi, K.; Shimizu, K. J. Antibiot. 1983, 463–467. (b)
Takahashi, K.; Tomita, F. J. Antibiot. 1983, 468–470. (c) Tomita, F.;
Takahashi, K.; Tamaoki, T. J. Antibiot. 1984, 1268–1272.
(3) (a) Fujimoto, K.; Oka, T.; Morimoto, M. Cancer Res. 1987, 47, 1516–
1522. (b) Kanamaru, R.; Konishi, Y.; Ishioka, C.; Kakuta, H.; Sato,
T.; Ishikawa, A.; Asamura, M.; Wakui, A. Cancer Chemother.
Pharmacol. 1988, 22, 197–200. (c) Saito, H.; Hirata, T.; Kasai, M.;
Fujimoto, K.; Ashizawa, T.; Morimoto, M.; Sato, A. J. Med. Chem.
1991, 34, 1959–1966. (d) Kahsai, A. W.; Zhu, S. T.; Wardrop, D. J.;
Lane, W. S.; Fenteany, G. Chem. Biol. 2006, 13, 973–983.
(4) (a) Plowman, J.; Dykers, D. J.; Narayanan, V. L.; Abbott, B. J.; Saito,
H.; Hirata, T.; Grever, M. R. Cancer Res. 1995, 55, 862–867. (b)
Bunnell, C. A.; Supko, J. G.; Eder, J. P.; Clark, J. W.; Lynch, T. J.;
Kufe, D. W.; Shulman, L. N. Cancer Chemother. Pharmacol. 2001,
48, 347–355.
(6) (a) Williams, R. M.; Flanagan, M. E.; Tippie, T. N. Biochemistry 1994,
33, 4086–4092. (b) Williams, R. M.; Glinka, T.; Flanagan, M. E.;
Gallegos, R.; Coffman, H.; Pei, D. H. J. Am. Chem. Soc. 1992, 110,
733–740.
(5) (a) Suzuki, K.; Sato, T.; Morioka, M.; Nagai, K.; Abe, K.; Yamaguchi,
H.; Saito, T. J. Antibiot. 1991, 44, 479–485. (b) Ponzo, V. L.;
Kaufman, T. S. J. Chem. Soc., Perkin Trans. 1 1997, 3131–3133. (c)
Wipf, P.; Hopkins, C. R. J. Org. Chem. 2001, 66, 3133–3139. (d)
Scott, J. D.; Williams, R. M. Angew. Chem., Int. Ed. 2001, 40, 1463–
1465. (e) Scott, J. D.; Williams, R. M. J. Am. Chem. Soc. 2002, 124,
2951–2956.
(7) Fukuyama, T.; Nunes, J. J. J. Am. Chem. Soc. 1988, 110, 5196–5198.
(8) (a) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1992, 114,
2767–2768. (b) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc.
1993, 115, 10742–10753.
9
7148 J. AM. CHEM. SOC. 2008, 130, 7148–7152
10.1021/ja800662q CCC: $40.75
2008 American Chemical Society

Asymmetric Total Synthesis of (-)-Quinocarcin
Scheme 1. Retrosynthetic Analysis of 1a
A R T I C L E S
Scheme 2. Synthesis of Amino Ester 16a
a Cbz ) benzyloxycarbonyl; TBS ) tert-butyldimethylsilyl; Bn ) benzyl.
a TBSMSCl ) tert-butyldimethylsilyl chloride; DMF ) N,N-dimethyl-
formamide; NBS ) N-bromosuccinimide; TBAF ) tetrabutylammonium
fluoride; rt ) room temperature.
quinocarcinamide12 have also been reported in the literature.13
We report herein an efficient and practical synthesis of (-)-
quinocarcin following a retro-synthetic analysis shown in
Scheme 1.14 We planned to install the labile oxazolidine ring
at the late stage of the synthesis and to construct the strained
3,8-diazabicycle [3.2.1]-octane ring system by an intramolecular
nucleophilic attack of the tethered silyl enol ether onto the
incipient N-acyliminium intermediate. The amino alcohol 7, a
precursor of key cyclization intermediate 6, could in turn be
assembled by coupling of tetrahydroisoquinoline 8 and protected
amino acid 9. Tetrahydroisoquinoline 8 was thought to be
prepared from 3-hydroxybenzaldehyde (10) via a sequence of
enantioselective alkylation and diastereoselective Pictet-Spengler
reaction.
Following Corey’s procedure,16 the enantioselective alkylation
of N-(diphenylmethylene) glycine tert-butyl ester 11 by 14 in
the presence of Corey-Lygo’s phase transfer catalyst16,17 (15,
O-(9)-ally-N-(9′-anthracenylmethyl) cinchonidium bromide, 0.1
equiv) afforded, after chemoselective hydrolysis of the imine
function (THF–H2O–AcOH), the amino ester 16 in 87% yield.
Cleavage of the silyl ether from 16 gave amino phenol 17 in
91% yield.
The (S)-configuration of 16 was assigned, taking for granted
the Corey-Lygo’s empirical model, and was confirmed by
Trost’s method.18 Accordingly, both (R)- and (S)-O-methyl
mandelic amides 18 and 19 were prepared by coupling of amine
16 with the respective mandelic acids (Figure 2). The calculated
chemical shift differences (∆δArCH2 (19-18) ) -0.08 ppm;
∆δCO2CMe3 (19-18) ) +0.06 ppm) are in accordance with
the S configuration of amino ester 16.18 In addition, analysis of
1H NMR spectra of compounds 17 and 18 indicated that the de
of 17 and 18, and hence the ee of their precursor 16, is higher
than 95%.
Results and Discussion
Our synthesis started with the preparation of substituted
phenylalanine derivative 17 (Scheme 2). 3-Hydroxybenzalde-
hyde was converted to 2-bromo-5-tert-butyldimethylsilyloxy-
benzyl bromide (14) in 4 steps with 90% overall yield.15
(9) (a) Katoh, T.; Kirihara, M.; Nagata, Y;.; Kobayashi, Y.; Arai, K.;
Minami, J.; Terashima, S. Tetrahedron 1994, 50, 6239–6258. (b)
Katoh, T.; Terashima, S. Pure Appl. Chem. 1996, 68, 703–706.
(10) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796–16797.
(11) Danishefsky, S. J.; Harrison, P. J.; Webb II, R. R.; O’Neill, B. T.
J. Am. Chem. Soc. 1985, 107, 1421–1423.
(12) Flanagan, M. E.; Williams, R. M. J. Org. Chem. 1995, 60, 6791–
6797.
(13) (a) Saito, H.; Hirata, T. Tetrahedron Lett. 1987, 28, 4065–4068. (b)
Lessen, T. A.; Demko, D. M.; Weinreb, S. M. Tetrahedron Lett. 1990,
31, 2105–2108. (c) Allway, P. A.; Sutherland, J. K.; Joule, J. A.
Tetrahedron Lett. 1990, 31, 4781–4784. (d) McMills, M. C.; Wright,
D. L.; Zubkowski, J. D.; Valente, E. J. Tetrahedron Lett. 1996, 37,
7205–7208. (e) Wipf, P.; Hopkins, C. R. J. Org. Chem. 2001, 66,
3133–3139. (f) Koepler, O.; Laschat, S.; Baro, A.; Fischer, P.;
Miehlich, B.; Hotfilder, M.; le Viseur, C. Eur. J. Org. Chem. 2004,
3611–3614. (g) Schneider, U.; Pannecoucke, X.; Quirion, J.-C. Synlett
2005, 1853–1856.
Figure 2. Determination of the absolute configuration and the ee of amino
ester 16.
Synthesis of tetrahydroisoquinoline 8 is shown in Scheme 3.
The Pictet-Spengler reaction of amino phenol 17 with ben-
(16) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–
(14) Liron, M. Ph.D. Dissertation, University of Paris XI, 2006.
(15) For regioselective nuclear bromination of methoxybenzene, see:
Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano, A.
J. Org. Chem. 1995, 60, 5328–5331.
12415.
(17) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595–
8598. (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518–
525.
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A R T I C L E S
Wu et al.
Scheme 3. Synthesis of Tetrahydroisoquinoline 8a
Scheme 4. Synthesis of Amino Thioether 25a
a TBAF ) tetrabutylammonium fluoride; Boc ) tert-butylcarbonyl;
DIPEA ) N,N-diisopropylethylamine; TBAF ) tetrabutylammonium
fluoride.
zoxyacetaldehyde (12) under mild acidic conditions provided
tetrahydroisoquinoline 20 as a single diastereomer. A slow
addition of a dichloromethane (CH2Cl2) solution of 12 to the
reaction mixture containing 17, acetic acid (1.1 equiv), and 4
Å molecular sieves in CH2Cl2 was found to be important to
ensure a good yield of the desired tetrahydroisoquinoline 8
(91%). The 1,3-cis relative stereochemistry of 20 was deduced
from the observed NOE correlation between H1/H3 and was in
accordance with literature precedents.19 The presence of a
2-bromo substituent effectively obviated the regioselectivity
issue during the Pictet-Spengler reaction.20 Masking the
secondary amine as N-tert-butoxycarbamate followed by me-
thylation of the phenol provided compound 21 in 78% overall
yield. Transesterification of a tert-butyl ester to a methyl ester
with concurrent removal of the N-Boc function from 21 were
realized in a one-pot fashion to afford the desired tetrahydroiso-
quinoline 8 in 95% yield.
a HATU ) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
hexafluorophosphate; HOAt ) 1-hydroxy-7-azabenzotriazole.
based on conversion) without detectable epimerization. Reduc-
tion of 22 with lithium borohydride gave primary alcohol 23,
which upon Swern oxidation afforded directly hemiaminal 24
as a mixture of two diastereomers (ratio 3/2). Attempt to convert
the hemiaminal to amino ether or to aminonitrile by reacting
24 with methanol (MeOH), or trimethylsilyl cyanide (TMSCN)
in the presence of a variety of Lewis acids and Brønsted acids
led either to no reaction, or, if forcing conditions were used, to
destruction of the molecule. Fortunately, we found that hafnium
trifluoromethanesulfonate, known to be highly oxophilic,23 was
able to catalyze the reaction of 24 with ethanethiol to afford
the amino thioether 25 in 88% yield [Hf(OTf)4, 0.1 equiv].
Under these conditions, the O-TBS function was simultaneously
removed, setting the stage for the subsequent oxidation step.
The use of EtSH as trapping agent is important because 24 was
converted to cyclic amino ether 26 in 71% yield when
benzenethiol (PhSH) was employed as a nucelophile under
otherwise identical conditions. It is reasonable to assume that
both reactions went through the N-acyliminium intermediate (A).
In the presence of a strong external nucleophile (EtSH),
intermolecular trapping occurred to afford 25. However, with
Acylation of 1,3-cis-disubsituted tetrahydroisoquinoline was
known to be difficult.21 After much experimentation, coupling
of bulky amine 8 with amino acid 9, synthesized from glutamic
aicd following literature procedure (see Supporting Informa-
tion),22 was realized by aminolysis of the in situ generated
activated ester of 9 (Scheme 4). Thus, reaction of 9 with
1-hydroxy-7-azabenzotriazol (HOAt, HATU, DIPEA, DMF,
0 °C) afforded the corresponding HOAt ester. By raising the
temperature to room temperature, the subsequent amidation with
8 took place smoothly to provide amide 22 in 71% yield (86%
(18) (a) Ott, R.; Sauber, K. Tetrahedron Lett. 1972, 3873–3878. (b) Trost,
B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59, 4202–
4205.
(19) For 1,3-cis selective Pictet-Spengler reactions, see: (a) (b) Massiot,
G.; Mulamba, T. J. Chem. Soc., Chem. Commun. 1983, 1147–1149.
(c) Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.; Morgan, K.;
Palmer, S. J.; Prince, S. N.; Reynolds, C. D.; Wood, S. D. J. Chem.
Soc., Perkin Trans. 1, 1993, 431–439. (d) Myers, A. G.; Kung, D. W.;
Zhong, B.; Movassaghi, M.; Kwon, S. J. Am. Chem. Soc. 1999, 121,
8401–8402. (e) Myers, A. G.; Kung, D. W. J. Am. Chem. Soc. 1999,
121, 10828–10829. (f) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J.
J. Am. Chem. Soc. 2006, 128, 87–89.
(20) In the absence of a 2-bromo substituent, the Pictet-Spengler reaction
afforded the wrong regioisomer as a major product, see ref 10.
(21) Lane, J. W.; Chen, Y.; Williams, R. M. J. Am. Chem. Soc. 2005, 127,
12684–12690.
(23) (a) Kobayashi, S.; Ogawa, C.; Kawamura, M.; Sugiura, M. Synlett
2001, 983–985. (b) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima,
H.; Ishii, K. J. Org. Chem. 2003, 68, 9340–9347. (c) Sakai, N.; Asano,
J.; Shimano, Y.; Konakahara, T. Synlett 2007, 2675–2678.
(22) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.; Martin, V. S.
J. Org. Chem. 1998, 63, 3741–3744.
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Asymmetric Total Synthesis of (-)-Quinocarcin
A R T I C L E S
Scheme 5. Construction of Tetracyclic Ring of Quinocarcina
Scheme 6. Synthesis of Thiohemiaminal 34a
a TIPSOTf ) triisopropylsilyl trifluoromethanesulfonate.
a weaker nucleophile such as PhSH, nucleophile attack of
tethered alcohol prevailed over intermolecular process leading
to cyclic amino ether 26. Interestingly, compound 26 was
converted to 25 with EtSH in the presence of Hf(OTf)4 in 88%
yield. These results indicated that 1,3-oxazepine 26 was in
equilibrium with the N-acyliminium under these conditions. Due
to the low thiophilicity of Hf(OTf)4, amino thioether 25 was
apparently stable under the reaction conditions providing thus
the deriving force for its formation. Interestingly, if other Lewis
acids (BF3 • Et2O, Bu3SnF) or Brønsted acids (pTSA, HF) were
used instead of Hf(OTf)4, the 1,3-oxazepine 26 was produced
even in the presence of EtSH. Presumably, the amino thioether
25 underwent rapid equilibrium with the incipient N-acylimin-
ium species under these conditions. The high tendency to form
the 1,3-oxazepine 26 could be accounted for by the conforma-
tional preference of the iminium A. Due to the inherent allylic
A1,3 interaction,24 the alkyl side chain might adopt preferentially
a pseudoaxial position, favoring thus the formation of 1,3-
oxazepine 26 for the entropic reason.25
Construction of the 3,8-diazabicycle [3.2.1]-octane ring
system was depicted in Scheme 5. A chemoselective Swern
oxidation of 25 followed by silyl enol ether formation afforded
compound 27 (E/Z ) 8/1) in 92% overall yield. The amino
thioether function was perfectly stable in the presence of
TIPSOTf, a Lewis acid that is frequently used for the generation
of N-acyliminium from the aminal or aminonitrile.26 The
intramolecular Mannich reaction of 27 was realized in the
presence of silver tetrafluoroborate to furnish the tetracyclic
compound 28 with an exo-oriented aldehyde function in 88%
yield.27,28 In this cyclization, silver tetrafluoroborate served as
an activator of both electrophile and nucleophile leading to an
efficient, although disfavored 5-endo-Trig cyclization.29
a TIPS ) triisopropylsilyl.
Parallel to this approach, we have developed an alternative
synthesis of functionalized tricycle 33 using a preformed enol
ether 31 as a coupling partner of 8 (Scheme 6). Selective
reduction of L-methyl-N,N-dibenzoxycarbamoyl-glutamate (29,
see Supporting Information) afforded the corresponding alde-
hyde,22 which after treatment with TIPSOTf and Et3N afforded
the silyl enol ether 30. Mono N-deprotection of 31 followed by
selective hydrolysis of the methyl ester provided the amino acid
31. The protection of amine as imide in 29 was found to be
important for both the regioselective reduction of δ-ester and
for avoiding the formation of 5-hydroxy proline derivative.30
Coupling of 31 with tetrahydroisoquinoline 8 went smoothly
to afford the amide 32 in 73% yield, which after a sequence of
reduction and oxidation provided the cyclization precursor 33
in 83% overall yield. However, cyclization of 33 under a variety
of acidic conditions failed to produce the desired tetracyclic
skeleton. Under the conditions developed for the cyclization of
27 [EtSH/Hf(OTf)4 or EtSH/AgBF4], the enol silyl ether 33 was
converted to the thioacetal 34 in almost quantitative yield. The
rapid and irreversible conversion of enol ether to thioacetal
hampered thus the desired cyclization.
With the tetracyclic compound 28 in hand, the total synthesis
of (-)-quinocarcin was realized as shown in Scheme 7. Jones
oxidation of 28 afforded the carboxylic acid 35 in 93% yield.
The N-Cbz and the O-Bn protective groups were selected based
on the consideration that they could potentially be removed
under the same conditions as that for the reduction of aryl
bromide. Indeed, global deprotection was realized in a one-pot
fashion under hydrogenolysis conditions. Selective N-methy-
lation of the resultant amino acid was realized under reductive
alkylation conditions to provide quinocarcinamide (4) in 95%
overall yield. The labile oxazolidine ring of quinocarcin has
previously been installed in a three-step sequence via aminal
and aminonitrile intermediates. By modifying the workup
procedure, we found that this can be realized in a one-pot
fashion. Thus, partial lactame reduction of 4 with an excess of
(24) (a) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296. (b) Husson,
H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383–394.
(25) Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949–1964.
(26) For reviews on N-acyliminium chemistry, see: (a) Hiemstra, H.;
Speckamp, W. N. ComprehensiVe Organic Synthesis; Trost, B.,
Fleming, I., Heathcock, C. H., Eds.; Pergmon: Oxford, 1991; Vol. 2,
pp 1047-1082. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–1628. (c)
Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311–2352.
(27) (a) Hiemstra, H.; Jan Vijn, R.; Speckamp, W. N. J. Org. Chem. 1988,
53, 3884–3886. (b) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc.
2005, 127, 12476–12477. (c) Rikimaru, K.; Mori, K.; Fukuyama, T.
Chem. Commun. 2005, 394–396.
(28) Hiemstra and Speckamp have reported a stereospecific 5-exo-Trig
cyclization; see ref 27a. In our case, only one diasteromer 28 with an
exo-oriented aldehyde substituent was isolated from the cyclization
of a mixture of E/Z isomers (8/1) of enol ether 27.
(29) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736. (b)
Johnson, C. D. Acc. Chem. Res. 1993, 26, 476–482.
(30) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826–7834.
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NMR, 13C NMR, [R]D, and HRMS) of the synthetic material
are identical to those of natural (-)-quinocarcin.10
Scheme 7. Total Synthesis of (-)-Quinocarcin (1)
Conclusion
In conclusion, (-)-quinocarcin has been synthesized in a
longest linear sequence of 22 steps from 3-hydroxybenzaldehyde
with an overall yield of 16% (11 steps and 33% overall yield
from the point of assembly). Our approach is highly convergent,
modular, and easily amenable to multigram synthesis. It
represented one of the most efficient syntheses to this natural
product (Myers’ synthesis: 16 steps, with 3.6% overall yield).
We believe that the Hf(OTf)4 catalyzed transformation of
hemiaminal to amino thioether developed in the course of this
study should find application to the synthesis of other related
molecules.
Acknowledgment. Financial supports from CNRS and this
institute (ICSN) are gratefully acknowledged. Y.C.W. thanks ICSN
for a postdoctoral fellowship.
Note Added after ASAP Publication. Due to a production
error, the images were incorrect for Figures 1 and 2 in the version
published ASAP on May 3, 2008. The figures were corrected on
May 7, 2008.
lithium in liquid ammonia31 followed by slow sequential
addition of methanol and ammonium chloride, evaporation of
ammonia, acidification, and neutralization afforded directly (-)-
quinocarcin (1) in 87% yield after purification on C18 column.
Supporting Information Available: Experimental procedures;
1
characterization data; and copies of H and 13C NMR spectra.
1
The physical, spectroscopic, and spectrometric data (UV, H
This material is available free of charge via the Internet at http://
pubs.acs.org.
(31) Evans, D. A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986,
108, 2478–2479.
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