Enantioselective total synthesis of angucyclinone-type antibiotics rubiginones A2 and C2

Article abstract of DOI:10.1002/1521-3773(20020802)41:15<2755::AID-ANIE2755>3.0.CO;2-A

The tetracyclic skeleton of C4-oxygenated angucyclinone-type antibiotics rubiginones A₂ ((+)-3) and C₂ ((-)-4) is constructed by Diels-Alder reaction of a racemic sulfinyl-substituted methyl juglone and the enantiopure vinyl cyclohex

Full text of DOI:10.1002/1521-3773(20020802)41:15<2755::AID-ANIE2755>3.0.CO;2-A

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[3] Acyclic dienones: H. Hagiwara, A. Okano, H. Uda, J. Chem. Soc.
Chem. Commun. 1985, 1047 1047.
Me
HO
O
O
Me
OR
O
4
4
¬
[4] M. C. Carrenƒo, M. C. GarcÌa Luzon, M. Ribagorda, Chem. Eur J. 2002,
OR
8, 208 216.
[5] ™MTP International Review of Sciences∫: Alkaloids, Ser. 1, Vol. 9
(Ed.: K. Wiesner), Butterworths, London, 1973.
[6] M. C. Carrenƒo, M. Ribagorda, J. Org. Chem. 2000, 65, 1231 1234.
MeO
MeO
O
O
rubiginone A1: R = H
rubiginone C1: R = COiPr
rubiginone A2: R = H
rubiginone C2: R = COiPr
¬
¬
ƒ
[7] a) M. C. Carreno, M. Perez Gonzalez, M. Ribagorda, J. Fischer, J.
¬
¬
ƒ
Org. Chem. 1996, 61, 6758 6759; b) M. C. Carreno, M. Perez Gonza-
lez, M. Ribagorda, K. N. Houk, J. Org. Chem. 1998, 63, 3687 3693.
[8] M. T. Reetz in Titanium in Organic Synthesis (Ed.: M. Schlosser),
Wiley, New York, 1994, chap. 3, pp. 198 282.
O
TBDMSO
Me
S(O)pTol
[9] The structure of 10a was established by X-ray diffraction. CCDC-
179112contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax:
(‡44)1223-336-033; or deposit@ccdc.cam.ac.uk).
+
OCOiPr
MeO
O
(±)-1
2
Scheme 1. Retrosynthetic analysis of rubiginones A and C.
[10] a) R. O Duthaler, A. Hafner, Chem. Rev. 1992, 92, 807 832, and
references therein.
The most general strategy employed is based on the Diels
Alder reaction between a substituted naphthoquinone and a
vinyl cyclohexene. Although several efficient total syntheses
of angucyclinones have focused on racemic forms,[8] only a few
asymmetric syntheses have been described so far.[9] Recently,
we reported an asymmetric approach to angucyclinones based
on the reaction of an enantiopure sulfinyl-substituted 1,4-
naphthoquinone and a chiral racemic vinyl cyclohexene.[10]
The sulfoxide group on the quinone framework promoted a
double induction in the Diels Alder reactions which led to
the efficient kinetic resolution of the diene partner. This
method has been applied to the enantioselective preparation
of differently substituted natural angucyclinone derivatives.[11]
Despite the numerous synthetic efforts towards this family of
compounds, to the best of our knowledge no total synthesis of
C4-oxygenated derivatives have been reported to date.
We describe herein the first enantioselective total synthesis
of rubiginones A2 and C2 based on the Diels Alder reaction
of 5-methoxy-2-(p-tolylsulfinyl)-1,4-naphthoquinone (1) and
enantiopure vinyl cyclohexene 2, which bears all the stereo-
genic centers present in the natural products (Scheme 1). The
quinone is used in the racemic form because the role of the
sulfoxide in this approach is limited to controlling the
regioselectivity of the Diels Alder reaction and facilitating
the recovery of the quinone structure after the cycloaddition
by pyrolytic elimination. The enantiopure diene 2 was
synthesized from [(S)S]-[(p-tolylsulfinyl)methyl]-p-quinol
(3) by means of a stereocontrolled conjugate addition of
AlMe3 as the key step (Scheme 2).
Thus, highly chemo- and diastereoselective conjugate
addition of AlMe3 to [(S)S]-3[12] afforded derivative 4, which
has the R configuration at the new C5 stereogenic center.[13]
Compound 4 was further transformed into the sulfone 5 with
MCPBA. Reduction of the carbonyl group of 5 with DIBAL-H
provided 6. The stereoselective reduction of 5 must be a
consequence of its rigid structure and the small size of
DIBAL-H, whose axial attack at the cyclohexenone ring was
expected. The S absolute configuration at C4 of 6 was
confirmed through the formation of the corresponding
Mosher×s esters.[14] After protection of 6 as the TBDMS
derivative 7, and elimination of methyl p-tolylsulfone by a
Cs2CO3-promoted retrocondensation, ketone 8 was obtained
in 87% yield. The treatment of 8 with Br2 and Et3N yielded
[11] a) A. Barco, S. Benetti, G. Spalluto, A. Casolari, G. P. Pollini, V.
Zanirato, J. Org. Chem. 1992, 57, 6279 6286; b) R. A. Bunce, E. J.
Wamsley, J. D. Pierce, A. J. Shellhamer, Jr., R. E. Drumright, J. Org.
Chem. 1987, 52, 464 466.
[12] D. P. Curran, H. Qi, N. C. DeMello, C.-H. Lin, J. Am. Chem. Soc. 1994,
116, 8430 8341.
Enantioselective Total Synthesis of
Angucyclinone-Type Antibiotics
Rubiginones A2 and C2**
ƒ
M. Carmen Carreno,* MarÌa Ribagorda,
¬
Alvaro Somoza, and Antonio Urbano*
The wide range of biological properties associated with the
angucycline antibiotics has stimulated great interest in these
compounds.[1] Among the angucyclinone subclass, rubigin-
ones A and C are unique owing to the hydroxy function at C4
(Scheme 1). Moreover, rubiginones C1 and C2 represent the
only natural angucyclinones that have an ester substituent at
the same carbon center. Rubiginones A and C were isolated
from the fermentation broth of Streptomyces griseorubigino-
sus and exhibited potentiation of vincristine-induced cytotox-
icity against multidrug-resistant tumor cells.[2] Rubiginone A2,
also named fujianmycin B[3] or SNA-8073-B,[4] is claimed to be
useful in the treatment of AIDS and Alzheimer×s disease.[5]
The absolute stereochemistry of all rubiginones has been
determined by the O-methylmandelate method.[6]
The angularly fused tetracyclic skeleton of angucyclinones
has been synthesized regioselectively by several methods,
which are summarized in an excellent recent review article.[7]
¬
ƒ
[*] Prof. M. C. Carreno, Dr. A. Urbano, Dr. M. Ribagorda, A. Somoza
¬
¬
Departamento de QuÌmica Organica (C-I), Universidad Autonoma
Cantoblanco, 28049 Madrid (Spain)
Fax : (‡34)91-397-3966
E-mail: carmen.carrenno@uam.es, antonio.urbano@uam.es
[**] We thank the DGICYT (Grant PB98-0062) for financial support and
the MEC and CAM for fellowships to M.R. and A.S.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 15
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4115-2755 $ 20.00+.50/0
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(1,8-diazabicyclo[5.4.0]undec-7-ene), or K2CO3 were unsuc-
cessful and gave rise to complex reaction mixtures. Serendip-
itously, we found that the exposure of (‡)-12 to daylight under
O
OR
S
OH
4
c)
a)
O
pTol(O)nS
5
Me
solvent-free conditions,[17] afforded 13 in 35% yield ([a]2D0
ˆ
Me
R
O
H
HO
SS
H
DIBAL-H
À57 (c ˆ 0.5 in CHCl3)) which gave physical and spectro-
scopic data identical to those of natural (À)-rubiginone C2
{[a]D20 ˆ À61 (c ˆ 0.5 in CHCl3)}.[2] This unprecedented one-
pot transformation involves three consecutive reactions of
(‡)-12 in a very efficient way: aromatization of the B ring,
deprotection of the silyl group, and oxidation of the resulting
carbinol to give the corresponding benzylic ketone group.
Finally, hydrolysis of the isobutyric ester at C4 of (À)-13 with
K2CO3/MeOH/THF afforded 14 in 91% yield ([a]2D0 ˆ ‡78
(c ˆ 0.2in CHCl 3)), which was identical to natural (‡)-
rubiginone A2.[18]
S(O)2pTol
pTol
O
4: n = 1
5: n = 2
6: R = H
b)
d)
[(S)S]-3
7: R = TBDMS
e)
MeS(O)2pTol
OTBDMS
OTBDMS
OTBDMS
S
i)
g)
1
R
Br
S
Me
S
Me
O
X
Me
OCOiPr
OR
10: R = H
8: X = H
9: X = Br
2
h)
f)
11: R = COiPr
In summary, we have reported the first total enantioselec-
tive synthesis of the C4-oxygenated angucyclinones rubigin-
ones A2 and C2 based on the asymmetric Diels Alder
reaction of the enantiopure vinyl cyclohexene (‡)-2 and the
racemic methoxy-substituted sulfinylnaphthoquinone 1. The
successful route involved the chemo- and stereoselective
addition of AlMe3 to [(S)S]-[(p-tolylsulfinyl)methyl]-p-quinol
(3) and the elimination of the chiral sulfoxide as methyl p-
tolylsulfone as the key steps for the synthesis of enantiopure
(1S,4S,6R)-2, which was obtained over 9 steps in 26% overall
yield. The total synthesis of natural angucyclinones (À)-13
and (‡)-14 was completed after a cycloaddition/sulfoxide
elimination process, through a practical light-induced se-
quence that involved partial aromatization, OTBDMS de-
protection, and oxidation of derivative (‡)-12 over 11 steps
from p-quinol 3 with >95% ee in 4.8 and 4.4% overall yield
for rubiginones C2 and A2, respectively.
j)
Me
O
O
TBDMSO
O
Me
4
OR
H
12b
k)
OCOiPr
B
MeO
O
MeO
O
(–)-13: rubiginone C2 (R = COiPr)
(+)-14: rubiginone A2 (R = H)
l)
(+)-12
Scheme 2. Enantioselective total synthesis of rubiginones A2 and C2:
a) AlMe3, CH2Cl2, À788C, 4 h, 65%; b) MCPBA, CH2Cl2, 08C, 30 min,
96%; c) DIBAL-H, THF, À788C, 30 min, 99%; d) TBDMSOTf, 2,6-
lutidine, CH2Cl2, 08C, 2h; e) Cs 2CO3, CH3CN, room temperature, 17 h,
87% over two steps; f) Br2, CCl4, 08C, then Et3N, room temperature, 32h,
80%; g) LiAlH4, THF, À1008C, 30 min; h) iPrCOCl, DMAP, CH2Cl2, 1 h,
ˆ
79% over two steps; i) [Pd(PPh3)4], [CH2 CHSnBu3], toluene, 908C, 24 h,
78%; j) (Æ)-1 (2equiv), CH 2Cl2, reflux, 24 h, 52%; k) hn, air, room
temperature, 16 h, 35%; l) K2CO3, THF/MeOH, room temperature,
90 min, 91%. MCPBA ˆ meta-chloroperbenzoic acid; DIBAL-H ˆ diiso-
butylaluminum hydride; TBDMSOTf ˆ tert-butyldimethylsilyl trifluoro-
methanesulfonate; DMAP ˆ 4-dimethylaminopyridine.
Received: March 21, 2002 [Z18944]
[1] a) R. H. Thomson, Naturally Occurring Quinones IV, 4th ed., Blackie
Academic & Professional, London, 1996, pp. 519 544; b) J. Rohr, R.
Thiericke, Nat. Prod. Rep. 1992, 9, 103 137.
[2] M. Oka, H. Kamei, Y. Hamagishi, K. Tomita, T. Miyaki, M. Konishi, T.
Oki, J. Antibiot. 1990, 43, 967 976.
[3] R. W. Rickards, J. P. Wu, J. Antibiot. 1985, 38, 513 515.
[4] K. Kimura, F. Kanou, H. Koshino, M. Uramoto, M. Yoshihama, J.
Antibiot. 1997, 43, 967 976.
[5] K. Kimura, F. Kano, K. Kurosawa, M. Yoshihama, JP 06234693 1994
[Chem. Abstr. 1995, 122, 8155].
[6] M. Oka, M. Konishi, T. Oki, Tetrahedron Lett. 1990, 31, 7473 7474.
[7] K. Krohn, J. Rohr, Top. Curr. Chem. 1997, 188, 127 195.
[8] a) D. MaI, H. N. Roy, J. Chem. Soc. Perkin Trans. 1 1999, 3167 3171;
b) M. L. Patil, H. B. Borate, D. E. Ponde, B. M. Bhawal, V. H.
Deshpande, Tetrahedron Lett. 1999, 40, 4437 4438; c) K. Krohn, J.
Micheel, M. Zukowski, Tetrahedron 2000, 56, 4753 4758; d) K. A.
Parker, Q.-J. Ding, Tetrahedron 2000, 56, 10249 10254; e) T. Rozek,
J. H. Bowie, S. M. Pyke, B. W. Skelton, A. H. White, J. Chem. Soc.
Perkin Trans. 1 2001, 1826 1830; f) G. A. Kraus, N. Zhang, A.
Melekhov, J. H. Jensen, Synlett 2001, 521 522; g) K. Krohn, P. Frese,
Tetrahedron Lett. 2001, 42, 681 682; h) K. Krohn, Eur. J. Org. Chem.
2002, 1351 1362, and references therein.
[9] a) M. Yamaguchi, T. Okuma, A. Horiguchi, C. Ikeura, T. Minami, J.
Org. Chem. 1992, 57, 1647 1649; b) D. S. Larsen, M. D. O×Shea, S.
Brooker, Chem. Commun. 1996, 203 204; c) K. Kim, V. A. Boyd, A.
Sobti, G. A. Sulikowski, Isr. J. Chem. 1997, 37, 3 22; d) G. Matsuo, Y.
Miki, M. Nakata, S. Matsumura, K. Toshima, J. Org. Chem. 1999, 64,
7101 7106; e) F. L. Andrews, D. S. Larsen, L. Larsen, Aust. J. Chem.
the a-bromoenone 9, whose stereoselective reduction with
LiAlH4 at À1008C afforded (1S)-10 and its 1R epimer (93:7).
The S absolute configuration at C1 of the major epimer was
again confirmed after transformation of 10 into the Mosher×s
esters.[14] Finally, protection of 10 as the isobutyrate derivative
11 and Stille coupling with tributylvinylstannane gave rise to
vinyl cyclohexene 2 with the appropriate absolute configu-
ration present at the three stereogenic centers in the natural
products.
With enantiopure diene 2 in hand, we undertook the
regioselective construction of the tetracyclic skeleton of the
rubiginones (Scheme 2) through the Diels Alder reaction
with racemic 5-methoxy-2-(p-tolylsulfinyl)-1,4-naphthoqui-
none (1).[15] After heating the mixture of 1 and 2 in CH2Cl2
at reflux for 24 h, we obtained the unstable tetracyclic
quinone (‡)-12 as the sole diastereoisomer. Compound 12
results from the spontaneous elimination of the sulfoxide in
the initially formed cycloadduct. The stereoselective forma-
tion of C12b was expected according to the preferred
approach of the dienophile from the face of the diene anti
to the bulky allylic OTBDMS substituent.[16]
Several attempts to aromatize the B ring of (‡)-12 with
DDQ (2,3-dichloro-5,6-dicyano1,4-benzoquinone), DBU
2756
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4115-2756 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 15

COMMUNICATIONS
2000, 53, 15 24; f) T. Matsumoto, H. Yamaguchi, M. Tanabe, Y.
Yasui, K. Suzuki, Tetrahedron Lett. 2000, 41, 8393 8396; g) G. B.
Caygill, D. S. Larsen, S. Brooker, J. Org. Chem. 2001, 66, 7427 7431.
of stilbenes have been reported, in which aldehyde tosylhy-
drazones were treated with benzotriazole-stabilized carban-
ions,[5] trimethyl borate/lithium tert-butoxide, trialkylboranes,
and alkylboron chlorides.[6]
ƒ
[10] M. C. Carreno, A. Urbano, J. Fischer, Angew. Chem. 1997, 109, 1695
1697; Angew. Chem. Int. Ed. Engl. 1997, 36, 1621 1623.
ƒ
[11] a) M. C. Carreno, A. Urbano, C. Di Vitta, Chem. Commun. 1999,
Organozinc complexes are powerful reagents for the
formation of carbon carbon bonds.[7] Recently, transition-
metal-catalyzed coupling reactions of halides with organozinc
complexes have been reported.[8] In addition, we have
reported that the nitro group of 1-aryl-2-nitroethenes can be
substituted by organozinc halides, using [Ni(acac)2] (acac ˆ
acetylacetonato) as a catalyst in the presence of a tertiary
amine, to give 1-aryl-1-alkenes in excellent yields.[9]
817 818; b) M. C. Carrenƒo, A. Urbano, C. Di Vitta, Chem. Eur. J.
2000, 6, 906 913.
[12] Compound [(S)S]-3 was synthesized according to the procedure
reported for the (S)R enantiomer, by reaction of 4,4-dimethoxy-2,5-
cyclohexadienone with the lithium anion derived from [(S)S]-methyl-
p-tolylsulfoxide followed by acetal hydrolysis with aqueous oxalic
acid: M. C. Carreno, M. Perez Gonzalez, K. N. Houk, J. Org. Chem.
1997, 62, 9128 9137.
[13] M. C. Carrenƒo, M. Perez Gonzalez, M. Ribagorda, K. N. Houk, J. Org.
¬
¬
ƒ
¬
¬
The reaction of alkylzinc reagents and carbonyl compounds
represents one of the most reliable methods to prepare
optically active secondary alcohols.[10, 11]. Herein we show that
E-stilbenes can be formed by the reaction of organozinc
halides with aryl aldehydes in the presence of a silylating
agent and using [NiCl2(PPh3)2] as the catalyst. To our knowl-
Chem. 1998, 63, 3687 3693.
[14] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512 519.
ƒ
[15] M. C. Carreno, J. L. GarcÌa Ruano, A. Urbano, Synthesis 1992, 651
653.
ƒ
[16] M. C. Carreno, A. Urbano, C. Di Vitta, J. Org. Chem. 1998, 63, 8320
8330.
[17] K. Krohn, F. Ballwanz, W. Baltus, Liebigs Ann. Chem. 1993, 911 913.
[18] Different values of the optical rotation of the natural product are
reported in the literature: (‡)-rubiginone A2: [a]2D0 ˆ ‡92( c ˆ 0.5 in
CHCl3),[2] (‡)-fujianmycin B: [a]D20 ˆ ‡50 (c ˆ 0.176 in CHCl3),[3] and
(‡)-SNA-8073-B: [a]D20 ˆ ‡47 (c ˆ 0.141 in CHCl3).[4] The enantio-
meric excess of our synthetic (‡)-14 was shown to be >95% after
transformation into the corresponding Mosher esters.[14]
ˆ
edge, the formation of C C bonds by the reaction of
aldehydes and organozinc reagents, using this catalyst in the
presence of chlorotrimethylsilane, is yet to be reported.
Herein, we report that a number of E-alkenes can be obtained
by this route. To investigate the scope and limitations of this
new reaction for the synthesis of E-alkenes, various aldehydes
and organozinc reagents, including some functionalized
species, have been utilized as substrates (Scheme 1). The
results are summarized in Table 1.
Carbon Carbon Double-Bond Formation
from the Reaction of Organozinc Reagents with
Aldehydes Catalyzed by a Nickel(ii) Complex**
Jin-Xian Wang,* Ying Fu, and Yulai Hu
Reactions that form carbon carbon bonds are of the
utmost importance in modern organic synthesis, and the
development of new methods to form such bonds is still a
formidable challenge for organic chemists. It is well known
ˆ
that reactions forming C C bonds have been extensively used
in the synthesis of various polyfunctional unsaturated com-
pounds and natural products, while some applications in
combinatorial chemistry have also been described. Many
ˆ
methods have been developed for C C bond formation such
Scheme 1.
as Wittig reactions,[1] reductive coupling of carbonyl com-
pounds,[2] self-coupling of a-lithiated benzylic sulfones,[3] and
condensation of aldehyde tosylhydrazones with stabilized
carbanions.[4] More recently, new procedures for the synthesis
We observed that certain organozinc reagents worked best
at particular reaction conditions. For the benzylic zinc halides,
reactions at room temperature gave the corresponding E-
stilbenes in good-to-excellent yields after 8 h (78 92%,
entries 1 8). However, when alkylzinc iodides were used,
yields of E-alkenes were optimized by carrying out reactions
at À188C, and then warming to room temperature (54 89%,
entries 10 15, 18 21). Both electron-withdrawing and elec-
tron-donating substituents on the phenyl ring, such as methyl,
chloro, bromo, benzyloxy, hydroxy, and methoxy, are toler-
ated in these reactions and generally have little effect on
product yield, except for 2,4-dinitrobenzaldehyde which gave
no olefination product (entries 2 11 and 17). Where organo-
[*] Prof. J.-X. Wang, Y. Fu, Dr. Y. Hu
Institute of Chemistry, Department of Chemistry
Northwest Normal University
Lanzhou 730070 (P. R. China)
Fax : (‡86)931-776-8159
E-mail: wangjx@nwnu.edu.cn
[**] This work was supported by the National Natural Science Foundation
of China and the Northwest Normal University Science and Technol-
ogy Development Foundation of China.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 15
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4115-2757 $ 20.00+.50/0
2757