Angucyclinone antibiotics: Total syntheses of YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755

Article abstract of DOI:10.1021/jo070709p

(Chemical Equation Presented) A concise and highly enantioselective route has been developed for the synthesis of angucyclinone-type natural products. Utilizing this strategy, total syntheses of five natural products YM-181741, (+)-ochromycinone, (+)-rubi

Full text of DOI:10.1021/jo070709p

Angucyclinone Antibiotics: Total Syntheses of YM-181741,
(+)-Ochromycinone, (+)-Rubiginone B2, (-)-Tetrangomycin, and
MM-47755
Krishna P. Kaliappan* and Velayutham Ravikumar
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400076, India
kpk@chem.iitb.ac.in
ReceiVed April 9, 2007
A concise and highly enantioselective route has been developed for the synthesis of angucyclinone-type
natural products. Utilizing this strategy, total syntheses of five natural products YM-181741, (+)-
ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755 have been accomplished in 22%,
23%, 19%, 18%, and 12% overall yields, respectively. Our approach for the synthesis of these natural
products having the benz[a]anthraquinone skeleton is based on a sequential intramolecular enyne
metathesis, intermolecular Diels-Alder reaction (DAR), and aromatization. The intramolecular enyne
metathesis reaction was employed for the synthesis of enantiopure 1,3-dienes in excellent yields.
Furthermore, the synthesis of YM-181741 as well as structurally similar angucyclinones such as (+)-
ochromycinone and (+)-rubiginone B2 was achieved via asymmetric enolate alkylation of an oxazolidinone
in excellent de. The related angucyclinones (-)-tetrangomycin and MM-47755, bearing a labile tertiary
alcohol, were synthesized via Sharpless asymmetric epoxidation of a known allylic alcohol followed by
opening the epoxide with Red-Al. The introduction of oxygen functionality at C-1 in all these natural
products was accomplished by photooxygenation under a positive pressure of oxygen.
Introduction
bears oxygen functionalities at both C-1 and C-8 along with a
single alkyl group or a combination of alkyl group and oxygen
functionality at C-3. Angucyclines can be further classified into
two subgroups depending on the presence or absence of
C-glycoside moiety. The latter group of angucyclines,
which do not possess a hydrolyzable sugar moiety, are called
angucyclinones.
(+)-Ochromycinone (1) and (+)-rubiginone B2 (2) are a set
of structurally similar and simple angucyclinones which differ
only at the C-8 functionality. The (+)-rubiginone B2, which
bears a phenolic methyl ether functionality at C-8 in contrast
The angucycline family1 represents a large number of novel
antibiotic natural products, isolated from the culture broths of
different microorganisms. They exhibit a broad spectrum of
biological activities including antitumor, enzyme inhibitory,
antiviral, and antifungal effects.2 Furthermore, a few members
of this group of antibiotics are known to be selective against
certain microorganisms.1a This group of antibiotics includes
naturally occurring quinones3 having an angular tetracyclic
framework which are believed to be biosynthesized from a
decaketide derivative.4 In general, the angucyclines possess a
benz[a]anthraquinone as a common structural framework that
(3) Thomson, R. H. Naturally Occurring Quinones IV, 4th ed.; Blackie:
London, UK, 1996.
(1) (a) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 103-137. (b) Krohn,
K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127-195. (c) Carren˜o, M. C.;
Urbano, A. Synlett 2005, 1-25.
(4) (a) Simpson, T. J. Nat. Prod. Rep. 1987, 4, 339-376. (b) O’Hagan,
D. The Polyketide Metabolites; Ellis Horwood: Chichester, UK, 1991. (c)
Gould, S. J.; Cheng, X. C.; Melville, C. J. Am. Chem. Soc. 1994,
116, 1800-1804. (d) O’Hagan, D. Nat. Prod. Rep. 1995, 12, 1-32.
(2) Schindler, P. W. Biotech. Forum 1989, 2, 142.
10.1021/jo070709p CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/11/2007
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J. Org. Chem. 2007, 72, 6116-6126

Synthesis of Angucyclinone-Type Natural Products
possess a labile tertiary alcohol at C-3 along with the methyl
group present in (+)-ochromycinone. Tetrangomycin, one of
the first members of angucyclinones, was isolated from the
culture broth of Streptomyces rimosus and found to display a
broad spectrum of biological activities.11 MM-47755 [or (-)-
8-O-methyltetrangomycin (5)] was isolated from certain
strains of Streptomyces bacteria and shows activity against
Gram-positive organisms such as Bacillus subtilis (MIC ) 32
µg/mL).12 As a consequence of their remarkable biological
activity profile and their low availability from micro-
organisms, many synthetic groups are actively involved in the
synthesis of these natural products. Various strategies such as
Diels-Alder,13,18-22 Friedel-Crafts reactions,14 anionic15 and
free radical benzannulations,16a-d,f,g rearrangements of cyclobute-
nones,16e and cobalt-mediated [2+2+2] cycloadditions17 have
(8) (a) Unge, P. Gastroenterology 1997, 113, 131-148. (b) Tanimura,
H.; Kawano, S.; Kubo, M.; Abe, T.; Goto, M.; Tanabe, J.; Asai, A.; Ito, T.
J. Gastroenterol. 1998, 33, 23-26. (c) Smith, S. I.; Oyedeji, K. S.; Arigbabu,
A. O.; Atimomo, C.; Coker, A. O. J. Gastroenterol. 2001, 36, 67-68. (d)
Eun, C. S.; Han, D. S.; Park, J. Y.; Jeon, Y. C.; Hahm, J. S.; Kim, K. S.;
Kang, J. O. J. Gastroenterol. 2003, 38, 436-441.
(9) Lim, A. G.; Walker, C.; Chambers, S.; Gould, S. R. Aliment.
Pharmacol. Ther. 1997, 11, 537-540.
(10) (a) Domizio, P.; Farthing, M. J. G. Aliment Pharmacol. Ther. 1995,
9, 205-208. (b) Megraud, F. Br. Med. Bull. 1998, 54, 207-216.
(11) (a) Dann, M.; Lefemine, D. V.; Barbatschi, F.; Shu, P.; Kunstmann,
M. P.; Mitscher, L. A.; Bohonos, N. Antimicrob. Agents Chemother. 1965,
832-835. (b) Kunstmann, M. P.; Mitscher, L. A. J. Org. Chem. 1966, 31,
2920-2925.
(12) (a) Shigahara, Y.; Koizumi, Y.; Tamamura, T.; Homma, Y.; Isshiki,
K.; Dobashi, K.; Naganawa, H.; Takeuchi, T. J. Antibiot. 1988, 41, 1260-
1264. (b) Gilpin, M. L.; Balchin, J.; Box, S. J.; Tyler, J. W. J. Antibiot.
1989, 42, 627-628. (c) Grabley, S.; Hammann, P.; Hu¨tter, K.; Kluge, H.;
Thiericke, R.; Wink, J. J. Antibiot. 1991, 44, 670-673.
FIGURE 1. Examples of angucyclinone natural products.
to the phenolic OH of (+)-ochromycinone, was isolated by Oka
and co-workers5 from the culture broth of Streptomyces grise-
orubiginosus and found to enhance the cytotoxicity of vincristine
against vincristine-resistant P388 leukemia and Moser cells. On
the other hand, (+)-ochromycinone was isolated from several
strains of streptomyces by Bowie6 in 1967. Recently, Taniguchi
et al. found that (+)-ochromycinone could be effective in the
treatment of peptic ulcer.7 In the same paper, they also reported
the isolation of a novel angucylinone YM-181741 (3) from the
culture broth of Streptomyces sp. Q57219, which bears a
hydroxy methyl functionality at C-3 in place of the methyl group
in (+)-ochromycinone, and further revealed that both (+)-
ochromycinone and YM-181741 (3) are selective against H.
pylori, the major cause of peptic ulcer with MIC values of 0.1
and 0.2 µg/mL, respectively. The existing treatment for the
peptic ulcer involves the use of broad-spectrum antibiotics like
amoxicillin and clarithromycin to kill this bacterium with
reasonable success.8 Nevertheless, the unselective nature of these
broad-spectrum antibiotics causes several side effects9 like
diarrhea, build up of drug resistance, etc., which necessitated
the need for the development of new drugs for the selective
peptic ulcer treatment.10 In this context, the selectivity of (+)-
ochromycinone and YM-181741 against H. Pylori significantly
kindles the interest toward the synthesis of these angucyclinones
and their simpler analogues.
(13) (a) Guingant, A.; Barreto, M. M. Tetrahedron Lett. 1987, 28, 1307-
3110. (b) Larsen, D. S.; O’Shea, M. D. Tetrahedron Lett. 1993, 34, 1373-
1376. (c) Krohn, K.; Ballwanz, F.; Baltus, W. Liebigs Ann. Chem. 1993,
911-913. (d) Larsen, D. S.; O’Shea, M. D. J. Chem. Soc., Perkin Trans.
1 1995, 1, 1019-1028. (e) Matsumoto, T.; Sohma, T.; Yamaguchi, H.;
Murata, S.; Suzuki, K. Tetrahedron 1995, 51, 7347-7360. (f) Krohn, K.;
Micheel, J. Tetrahedron 1998, 54, 4827-4838. (g) Matsuo, G.; Miki, Y.;
Nakata, M.; Matsumura, S.; Toshima, K. J. Org. Chem. 1999, 64, 7101-
7106. (h) Krohn, K.; Michael, J.; Zukowski, M. Tetrahedron 2000, 56,
4753-4758. (i) Caygill, G. B.; Larsen, D. S.; Broker, S. J. Org. Chem.
2001, 66, 7427-7431. (j) Rozek, T.; Bowie, J. H.; Pyke, S. M.; Skelton,
B. W.; White, A. J. Chem. Soc., Perkin Trans. 1 2001, 1, 1826-1830. (k)
Kraus, G. A.; Zhang, N.; Melekhov, A.; Jensen, J. H. Synlett 2001, 521-
522. (l) Krohn, K.; Agocs, A.; Ba¨uerlein, C. J. Carbohydr. Chem. 2003,
22, 579-592.
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S.; Stone, D. J. M.; Bowie, J. H. Aust. J. Chem. 1998, 51, 515-523. (b)
Patil, M. L.; Borate, H. B.; Ponde, D. E.; Deshpande, V. H. Tetrahedron
2002, 58, 6615-6620.
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3171.
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37, 7615-7618. (b) Kraus, G. A.; Zhiwen, W. Tetrahedron Lett. 1997, 38,
6509-6512. (c) Chuang, C.-P.; Wang, S.-F. Tetrahedron 1998, 54, 10043-
10052. (d) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki,
K. Tetrahedron Lett. 2000, 41, 8393-8396. (e) Hergueta, A. R.; Moore,
H. W. J. Org. Chem. 2002, 67, 1388-1391. (f) Hauser, F. M.; Dorsch, W.
A.; Mal, D. Org. Lett. 2002, 4, 2237-2239. (g) Sato, K.; Asao, N.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 8977-8981.
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Kalogerakis, A.; Groth, U. Synlett 2003, 1886-1888. (c) Kasenheimer, C.;
Groth, U. Org. Lett. 2006, 8, 2507-2510.
(18) (a) Boyd, V. A.; Drake, B. E.; Sulikowski, G. A. J. Org. Chem.
1993, 58, 3191-3193. (b) Boyd, V. A.; Sulikowski, G. A. J. Am. Chem.
Soc. 1995, 117, 8472-8473. (c) Kim, K.; Sulikowski, G. A. Angew. Chem.,
Int. Ed. 1995, 34, 2396-2398. (d) Kim, K.; Boyd, V. A.; Sobti, A.;
Sulikowski, G. A. Isr. J. Chem. 1997, 37, 3-22.
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15, 713-718.
(20) Motoyoshiya, J.; Masue, Y.; Iwayama, G.; Yoshioka, S.; Nishii,
Y.; Aoyama, H. Synthesis 2004, 2099-2102.
Another set of structurally very similar angucyclinones, which
again differ only at C-8 functionality, includes (-)-tetrango-
mycin (4) and MM-47755 (5). These two angucyclinones
(5) Oka, M.; Kamei, H.; Hamagishi, Y.; Tomita, K.; Miyaki, T.; Konishi,
M.; Oki, T. J. Antibiot. 1990, 43, 967-976.
(6) Bowie, J. H.; Johnson, A. W. Tetrahedron Lett. 1967, 34, 1449-
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(7) Taniguchi, M.; Nagai, K.; Watanabe, M.; Nimura, N.; Suzuki, K.-I.;
Tanaka, A. J. Antibiot. 2002, 55, 30-35.
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Kaliappan and Ravikumar
SCHEME 1
1,3-dienes directly from an acyclic precursor in a highly
regioselective manner and thus an efficient general strategy
could be developed for the synthesis of anguyclinones. With
this plan, we set out to design a new versatile strategy for the
synthesis of angucyclinones based on sequential enyne metath-
esis and Diels-Alder reaction/aromatization.
Results and Discussion
In recent times, olefin metathesis23 has become a more
attractive and frequently used synthetic tool in organic synthesis
due to the ready availability of many air-stable metathetic
catalysts [Grubbs’ I-generation catalyst,24 Grubbs’ II-generation
catalyst,25 and phosphine-free Hoveyda’s catalyst26] that can
tolerate numerous functional groups. Among the metathetic
reactions, the intramolecular enyne metathesis27 reaction has
received significant attention because of its atom economical
nature and its ability to form a conjugated diene. Furthermore,
the intramolecular enyne metathesis reaction efficiently trans-
forms an enyne into a 1,3-diene, which not only could act as a
diene in the Diels-Alder reaction but also could be easily
functionalized further to yield complex natural and unnatural
products.28 However, to the best of our knowledge, until our
recent preliminary communication,29d no metathetic approach
had been utilized for the synthesis of angucyclinones. As a part
of our ongoing efforts in exploiting the synthetic utility of
sequential enyne metathesis and DAR,29 we initiated an attempt
been employed for the construction of the tetracyclic skeleton
of angucyclines. A comprehensive account of all these efforts
is available in three excellent reviews.1 In spite of the notable
accomplishments made so far, there is always room for the
development of simple and efficient strategies for the synthesis
of these natural products and also for some of the simpler
analogues of these molecules, which could be designed to
modulate their biological activity.
Among the above-mentioned strategies, the Diels-Alder
reaction between a quinone and a 1,3-diene has been widely
used for the construction of the angular benz[a]anthraquinone
skeleton. One of the important advantages of the DAR is the
ease of predicting the regioselective outcome of the product by
changing substituents at the quinone part. Apart from its
operational simplicity, the other benefit of Diels-Alder reaction
is its convergent approach that allows for introduction of
diversity into the molecules while we plan for the synthesis of
simpler analogues of angucyclinones. As far as the synthesis
of enantiopure angucyclinones is concerned, the chirality in
angucyclinones has been derived by one of the following
means: (i) chiral 1,3-dienes,18-20 (ii) chiral dienophiles,21 and
(iii) chiral Lewis acid.22
Among the three sources of chirality, the chiral 1,3-dienes
have been used for the synthesis of enantiopure angucyclinones
with limited success because of the difficulties associated with
the synthesis of optically pure 1,3-dienes. However, a few
elegant methods demonstrated the utility of chiral 1,3-dienes
for the synthesis of angucyclinones (Scheme 1). Sulikowski has
synthesized enantiopure 1,3-diene 16 starting from quinic acid
15 in 13 steps that was subsequently utilized for the synthesis
of various angucyclines such as (+)-urdamycinone B, shunt
metabolite 104-2, and (+)-SF-2315A (7).18 Krohn19 and Mo-
toyoshiya20 independently synthesized chiral 1,3-diene 18 as a
mixture of regioisomers along with 19 in 3 steps starting from
commercially available (R)-3-methylcyclohexanone (99% ee)
17 and further elaborated the mixture to (+)-ochromycinone
and (+)-rubiginone B2. It is clear from the above syntheses that
most of the existing strategies start from cyclic precursors and
hence either require more steps or result in a mixture of
regioisomeric 1,3-dienes. With the advent of enyne metathesis,
we envisioned the possibility of obtaining these optically pure
(23) For reviews on metathetic reactions see: (a) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413-4450. (b) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371-388. (c) Randall, M. L.; Snapper, M. L. Strem
Chem. 1998, 17, 1-9. (d) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39,
2073-2077. (e) Yet, L. Chem. ReV. 2000, 100, 2963-3007. (f) Karle, K.;
Koert, U. Organic Synthesis Highlights IV; Wiley-VCH: Weinheim,
Germany, 2000; pp 91-96. (g) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012-3043. (h) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18-29. (i) Kotha, S; Sreenivasachary, N. Indian J. Chem. 2001, 40B,
763-780. (j) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826-2830. (k)
Walters, M. A. Prog. Heterocycl. Chem. 2003, 15, 1-36. (l) Grubbs, R. H.
Tetrahedron 2004, 60, 7117-7140. (m) Schmidt, B. Eur. J. Org. Chem.
2004, 1865-1880. (n) Schmidt, B.; Hermanns, J. Top. Organomet. Chem.
2004, 7, 223-267. (o) Connon, S. J.; Blechert, S. Top. Organomet. Chem.
2004, 7, 93-124. (p) Hoveyda, A. H.; Schrock, R. R. ComprehensiVe
Asymmetric Catalysis; Springer-Verlag: Berlin, Germany, 2004; Supplement
1, pp 207-233. (q) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490-4527. (r) Gradillas, A.; Pe´rez-Castells, J. Angew.
Chem., Int. Ed. 2006, 45, 6086-6101.
(24) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
(25) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(26) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka,
O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem.
2004, 2, 8-23.
(27) For recent reviews on enyne metathesis, see: (a) Mori, M. Top.
Organomet. Chem. 1998, 1, 133-154. (b) Poulsen, C. S.; Madsen, R.
Synthesis 2003, 1-18. (c) Mori, M. Handbook of Metathesis; Grubbs, R.
H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, p 176. (d) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
(28) For selected examples for sequential enyne metathesis and Diels-
Alder reaction, see: (a) Bentz, D.; Laschat, S. Synthesis 2000, 1766-1773.
(b) Kotha, S.; Sreenivasachary, N.; Brahmachary, E. Eur. J. Org. Chem.
2001, 787-792. (c) Moreno-Manas, M.; Pleixats, R.; Santamaria, A. Synlett
2001, 1784-1786. (d) Guo, H.; Madhushaw, R.; Shen, F.-M.; Liu, R.-S.
Tetrahedron 2002, 58, 5627-5637. (e) Dolhem, F.; Lievre, C.; Demailly,
G. Eur. J. Org. Chem. 2003, 2336-2342. (f) Yang, Y.-K.; Tae, J. Synlett
2003, 2017-2020.
(29) (a) Kaliappan, K. P.; Ravikumar, V. Org. Biomol. Chem. 2005, 848-
851. (b) Kaliappan, K. P.; Ravikumar, V.; Pujari, S. A. Tetrahedron Lett.
2006, 47, 981-984. (c) Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett.
2007, 9, 1121-1124. (d) Kaliappan, K. P.; Ravikumar, V. Synlett 2007,
977-979.
(21) (a) Carren˜o, M. C.; Urbano, A.; Fischer, J. Angew. Chem., Int. Ed.
1997, 36, 1621-1623. (b) Carren˜o, M. C.; Urbano, A.; Di Vitta, C. J. Org.
Chem. 1998, 63, 8320-8330. (c) Carren˜o, M. C.; Urbano, A.; Di Vitta, C.
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C. Chem. Eur. J. 2000, 6, 906-913. (e) Carren˜o, M. C.; Somoza, A.;
Ribagorda, M.; Urbano, A. Chem. Eur. J. 2007, 23, 879-890.
(22) (a) Larsen, D. S.; O’Shea, M. D.; Broker, S. Chem. Commun. 1996,
203-204. (b) Larsen, D. S.; O’Shea, M. D. J. Org. Chem. 1996, 61, 5681-
5683. (c) Landells, J. S.; Larsen, D. S.; Simpson, J. Tetrahedron Lett. 2003,
44, 5193-5196.
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Synthesis of Angucyclinone-Type Natural Products
SCHEME 2
SCHEME 3
SCHEME 4
to develop a general strategy for the synthesis of angucyclinone
natural products. As an outcome of our endeavor, we recently
published the first total synthesis of YM-181741 (3).29d Herein,
we discuss in detail all our efforts which culminated in the
syntheses of (+)-ochromycinone (1), (+)-rubiginone B2 (2),
(-)-tetrangomycin (4), and MM-47755 (5) in addition to
YM-181741 (3).
Total Synthesis of YM-181741. Our retrosynthetic analysis
of YM-181741 (3) is depicted in Scheme 2 and not surprisingly,
our thought was to utilize a Diels-Alder reaction between the
diene 21 and bromoquinone 20. We envisaged that the requisite
diene 21 could be formed by an intramolecular enyne metathesis
of 22. Enyne 22 could then be traced back to N-acyloxazoli-
dinone 23 and propargyl bromide 24, which could be coupled
via an asymmetric enolate alkylation.
presence of HMPA32 followed by quenching with propargyl
bromide to afford the enyne 28 in greater than 95% de, which
was confirmed by HPLC.33 After chromatographic purification,
it was possible to obtain 28 as a single diastereomer. The chiral
auxiliary was then reductively removed by LiBH4 to afford the
primary alcohol 29, which was subsequently protected as its
TBS ether 30. When this enyne 30 was subjected to the
metathesis reaction conditions under an argon atmosphere with
Grubbs’ catalyst 31, the reaction was found to be sluggish.
However, when the reaction was carried out under an ethylene34
atmosphere, the required diene 33 was obtained in 73% yield.
Subsequently, the yield of the reaction was improved to 88%
by performing the reaction with Grubbs’ second-generation
catalyst 32 under an ethylene atmosphere.
With diene 33 in hand, its Diels-Alder reaction with the
appropriate quinone was then investigated (Scheme 4). Treat-
ment of diene 33 with 5-acetoxy-2-bromo-1,4-naphthoquinone
2035 at 80 °C in toluene afforded the cycloadduct 34, which
The synthesis of diene 21 (Scheme 3) began with the
preparation of known 2730 from hexenoic acid 25, using a
modified protocol.31 The key asymmetric enolate alkylation was
successfully accomplished by treatment with LDA in the
(32) Pettigrew, J. D.; Wilson, P. D. Org. Lett. 2006, 8, 1427-1429.
(33) HPLC conditions: YMC Pack Pro-C18, 4.6 × 250 mm, eluents
10% H2O/90% MeCN, flow 1.0 mL/min, UV detector at 254 nm; retention
times 2.928 min.
(34) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082-6083.
(30) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085-1093.
(31) (a) Ho, G. J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271-2273.
(b) Hu, X.; Nguyen, K. T.; Verlinde, C. L. M. J.; Hol, W. G. J.; Pei, D. J.
Med. Chem. 2003, 46, 3771-3774.
J. Org. Chem, Vol. 72, No. 16, 2007 6119

Kaliappan and Ravikumar
SCHEME 5
was immediately subjected to the aromatization reaction with
K2CO3 in MeOH to provide an inseparable mixture of 35 and
its regioisomer in 9:1 ratio as confirmed by 1H NMR spectros-
copy. Subsequent photooxygenation36 (Hg Lamp, 125 W, Philips
India) of 35 provided the ketone 36 in 70% yield and the other
regioisomer, which was separated by column chromatography,
was found to be unreactive under this condition. Finally, removal
of the TBS group with TBAF afforded the natural product YM-
181741 (3) in 68% yield. The spectral data of the synthesized
product in all aspects matched that reported, thus confirming
the first total synthesis of YM-181741.7,29d
SCHEME 6
Total Syntheses of (+)-Ochromycinone and (+)-Rubigi-
none B2. After the successful synthesis of YM-181741, we
shifted our focus to the synthesis of other important angucy-
clinones and devised a general strategy for these natural products
as depicted in Scheme 5.
Synthesis of (+)-ochromycinone (1) and (+)-rubiginone
B2 (2) was based on the Diels-Alder reaction between 1,3-
diene 18 and 5-acetoxy-2-bromo-1,4-naphthoquinone 20.
From the retro-synthetic perspective, we envisaged that the
requisite diene 18 could be generated by an enyne metathesis
reaction of the corresponding enyne 37, which in turn could be
obtained from the known oxazolidinone 38 by functional group
transformations.30
As planned, we embarked upon the synthetic journey (Scheme
6) toward (+)-ochromycinone and (+)-rubiginone B2, with
methylation of known oxazolidinone 43, by following the
previously established protocol.30 The reductive removal of
chiral auxiliary followed by treatment of alcohol 44 with p-TsCl
in pyridine yielded the tosylate 45 in 71% yield over two steps.
Subsequently, our attempts to convert the tosylate 45 to the
enyne 37 in three steps via conventional route did not provide
the product in respectable yield. The poor yield was presumably
due to the volatility of the enyne 37, which also hampered the
handling of this compound in small scale as well as the
preparation of an analytically pure sample.
metathesis reaction and prior to Diels-Alder reaction. Toward
this end, we set off for the synthesis of diene 18 from the tosylate
46 by an intramolecular enyne metathesis reaction followed by
reductive removal of the tosyl group. We envisaged that the
enyne tosylate 46 could be traced back to the corresponding
alcohol 29, which was used in the synthesis of YM-181741.
As planned, our modified approach commenced with the
tosylation of alcohol 29 by treatment with tosyl chloride in
pyridine to afford the enyne 46 in 89% yield (Scheme 7). The
synthesis of enyne 46 set the stage for the key intramolecular
enyne metathesis reaction. The enyne 46 on treatment with
Grubbs’ first-generation catalyst 31 in refluxing CH2Cl2 under
ethylene atmosphere afforded the diene 47 in quantitative yield.
The diene tosylate 47 upon treatment with LiAlH4 in THF
yielded the diene 18, and due to its volatile nature it was treated
as such with the jugulone derivative 20 in toluene at 80 °C for
16 h. The resultant adduct after the dehydrobromination/
aromatization reaction with K2CO3 in MeOH yielded the
tetracycle 48 in respectable yield (45% over three steps starting
from 47). Having the tetracycle 48 in hand, our next task was
to introduce the oxygen functionality at C-1 by the well-
established photooxygenation procedure.36 Although this reac-
tion has been exploited in many angucyclinone syntheses, we
were skeptical about this reaction on the tetracycle 48. Mo-
toyoshiya et al. have reported22 that the photooxygenation on
the tetracycle 48 was sluggish and resulted in a low yield along
with byproducts. When we irradiated 48 (Hg lamp, 125 W,
Philips India) under a positive pressure of oxygen for 20 h, we
were delighted to see that the reaction went smoothly and
yielded (+)-ochromycinone (1) in excellent yield (82%). The
(+)-ochromycinone (1) upon methylation under a mild condi-
tion37 yielded the (+)-rubiginone B2 (2) and thus completed
To circumvent this difficulty, we decided to introduce a bulky
functionality in the enyne 37 that would be removed after enyne
(35) (a) Heinzman, S. W.; Grunwell, J. R. Tetrahedron Lett. 1980, 21,
4305-4308. (b) Jung, M. E.; Hagenah, J. A. J. Org. Chem. 1983, 48, 5359-
5361.
(36) (a) Huffman, K. R.; Loy, M.; Ullman, E. F. J. Am. Chem. Soc.
1965, 87, 5417-5423. (b) Blankespoor, R. B.; De Jong, R. L.; Dystra, R.;
Hamstra, D. A.; Rozema, D. B.; VanMeurs, D. P.; Vink, P. J. Am. Chem.
Soc. 1991, 113, 3507-3513. (c) Garcia-Garibay, M. A.; Gamarnik, A.;
Pang, L.; Jenks, W. S. J. Am. Chem. Soc. 1994, 116, 12095-12096. (d)
Krohn, K.; Khanbabaee, K.; Micheel, J. Liebigs Ann. Chem. 1995, 1529-
1537.
6120 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of Angucyclinone-Type Natural Products
SCHEME 7
SCHEME 8
the total syntheses of (+)-ochromycinone and (+)-rubiginone
B2. The chemical and physical data of these two natural products
were in agreement in all aspects with the reported values.4c,5,6,17b,22
Total Syntheses of (-)-Tetrangomycin and MM-47755.
After the successful syntheses of YM-181741, (+)-ochromy-
cinone (1), and (+)-rubiginone B2 (2), we targeted (-)-
tetrangomycin (4) and MM-47755 (5) for total synthesis. Our
synthetic approach for (-)-tetrangomycin (4) made use of 1,3-
diene 39 as the starting material for the pivotal DAR (Scheme
5). The requisite 1,3-diene 39 in turn could be derived from
the corresponding enyne 40 by an intramolecular enyne me-
tathesis reaction. We envisaged that the enyne 40 could be
derived from the alcohol 41 through routine functional group
transformations and the alcohol 41 could be traced back to the
known allylic alcohol 42.38
Our synthesis as delineated in Scheme 8 began with the
Sharpless asymmetric epoxidation of alcohol 42 to afford the
epoxide 49 in excellent yield, which was subsequently opened
with Red Al to furnish the 1,3-diol 50 in 96% yield.17c The
diol 50 was protected as its PMB-acetal 51 by using anisalde-
hydedimethyl acetal in quantitative yield and the resulting acetal
51 was regioselectively opened with DIBAL-H to afford the
primary alcohol 41 in 76% yield. The alcohol 41 upon oxidation
under Swern condition yielded the aldehyde 52. Unfortunately,
our attempts to convert the aldehyde 52 to enyne 40 in a single
step employing the Ohira-Bestmann protocol were not suc-
cessful.39 However, as anticipated, the conventional Corey-
Fuchs’ protocol worked very well for this purpose.40 Accord-
ingly, we converted the aldehyde 52 to the corresponding
n
dibromo compound 53, followed by treatment with BuLi to
afford the enyne 40 in excellent yield. Having made the
precursor 40, our next task was to carry out the key intramo-
lecular enyne metathesis reaction, which was achieved with
Grubbs’ first-generation catalyst 31 in toluene at 80 °C under
an ethylene atmosphere.
The enantiopure 1,3-diene 39 was then treated with the
bromojugulone 20 in toluene to yield a tetracycle, which on
further treatment with K2CO3 in MeOH yielded the aromatized
product 54 in 62% yield over two steps (Scheme 9). Oxidative
removal of PMB group in 93% yield followed by photooxy-
genation furnished the natural product (-)-tetrangomycin (4)
in 64% yield.
(39) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Muller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
(40) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(41) For a general section on the experimental procedure, please see the
Supporting Information of ref 29c.
(37) Krohn, K.; Khanbabaee, K. Liebigs Ann. Chem. 1994, 1109-1112.
(38) Foote, K. M.; Hayes, C. J.; John, M. P.; Pattenden, G. Org. Biomol.
Chem. 2003, 1, 3917-3948.
J. Org. Chem, Vol. 72, No. 16, 2007 6121

Kaliappan and Ravikumar
SCHEME 9
impurities. Evaporation of the solvent and purification by silica
gel column chromatography (5-10% ethyl acetate in hexanes)
provided the 1,3-dienes.
General Procedure for DAR Followed by Aromatization. A
solution of 5-acetoxy-2-bromo-1,4-naphthaquinone (20) (1.1 mmol)
in toluene (15 mL) was treated with a solution of 1,3-diene (1.0
mmol) in toluene (3 mL) at room temperature and then the mixture
was heated at 80 °C for 12 h followed by 100 °C for 2 h. After
removing the solvent in vacuo, the crude Diels-Alder adduct was
dissolved in MeOH (10 mL), treated with solid K2CO3 (3 mmol),
and stirred in the dark for 12 h. The solvent was removed in vacuo,
treated with water, and extracted with CHCl3. The organic layer
was washed with brine, dried (Na2SO4), concentrated, and purified
by silica gel column chromatography to afford the tetracycle.
General Procedure for Photooxygenation. A solution of
tetracyclic quinone (1 mmol) in benzene (315 mL) was irradiated
with a mercury lamp (125 W, Philips India) under a positive
pressure of oxygen for 20 to 24 h. Solvent was removed in Vacuo
and then purified by silica gel column chromatography.
SCHEME 10
General Procedure for the Removal of PMB Protection. A
solution of PMB-ether (1 mmol) in a mixture of CH2Cl2 (16 mL)
and pH 7 buffer (1.6 mL) at 0 °C was treated with DDQ (1.5 mmol)
portion-wise and stirred at the same temperature for 30 min. The
reaction mixture was treated with a saturated solution of NaHCO3
and extracted with CH2Cl2. The organic layer was washed with
brine, dried (Na2SO4), concentrated, and purified by silica gel
column chromatography.
(S)-4-Benzyl-3-((R)-2-(prop-2-ynyl)hex-5-enoyl)oxazolidin-2-
one (28).29d To a solution of hexenoic acid (1.2 g, 10.52 mmol)
and NEt3 (3.81 mL, 27.35 mmol) in THF (55 mL) was added
pivolyl chloride (1.32 mL, 10.52 mmol) at -10 °C and the stirring
was continued at the same temperature for 1 h. LiCl (0.49 g, 11.57
mmol) and (S)-4-benzyloxazolidin-2-one (26) (1.77 g, 10.0 mmol)
were added to the reaction mixture and then warmed to room
temperature. After being stirred for 12 h at room temperature, the
suspension was treated with NaHCO3 and the organic layer was
separated. The aqueous layer was extracted with ethyl acetate. The
combined organic layer was washed with brine, dried (Na2SO4),
concentrated, and purified by silica gel column chromatography
(10% ethyl acetate in hexanes) to afford the oxazolidinone 27
(2.6 g) as a colorless syrup in 96% yield. Rf 0.33 (1:9 ethyl acetate/
hexanes).30
After the synthesis of (-)-tetrangomycin, our initial attempt
to selectively methylate the phenolic OH using diazomethane
was not fruitful. This forced us to go one step backward to
methylate the tetracyclic alcohol 54 with MeI in the presence
of Ag2O to yield the methyl ether 56 in 96% yield (Scheme
10). Removal of the PMB group followed by photooxygenation
of the resultant tertiary alcohol 57 yielded the natural product
MM-47755 (5). The chemical and physical data of these two
natural products were in agreement in all aspects with the
reported values.15,16,17c,37
A solution of N,N-diisopropylamine (1.41 mL, 9.99 mmol) in
THF (8 mL) at 0 °C was treated with BuLi (5.65 mL, 1.6 M
n
Conclusion
solution in hexanes, 9.04 mmol) and stirred for 30 min at the same
temperature. Then, the reaction mixture was cooled to -78 °C,
HMPA (1.14 mL) and a solution of (4S)-4-benzyl-3-hexeinoylox-
azolidin-2-one (27) (1.72 g, 6.32 mmol) in THF (2.5 mL) were
added. The resulting mixture was stirred for 30 min at the same
temperature and then propargyl bromide (2.25 mL, 25.3 mmol) was
added dropwise. After being stirred for 24 h at - 78 °C, a saturated
aqueous solution of ammonium chloride was added. The mixture
was extracted with ether. The organic layer was washed with brine,
dried (Na2SO4), concentrated, and purified by silica gel column
chromatography (10% ethyl acetate in hexanes) to afford the enyne
28 (1.74 g) as a brown syrup in 89% yield. Rf 0.3 (1:9 ethyl acetate/
In conclusion, we have disclosed a straightforward and
effective enantioselective strategy involving sequential intramo-
lecular enyne metathesis and Diels-Alder reaction as key
steps for the synthesis of angucyclinone natural products such
as YM-181741 (3), (+)-ochromycinone (1), (+)-rubiginone
B2 (2), (-)-tetrangomycin (4), and MM-47755 (5). YM-181741,
(+)-ochromycinone, and (+)-rubiginone B2 were synthesized
in 9, 8, and 9 steps with 22%, 23%, and 19% overall yields,
respectively. The related angucyclinones (-)-tetrangomycin
and MM-47755 were obtained in 12 and 13 steps in 18% and
12% overall yields, respectively. This strategy could be easily
extended for the synthesis of other angucyclinones as well as
analogues of these natural products.
hexanes); [R]20 +113.7 (c 1.56, CHCl3); IR (neat) cm-1 3462,
D
2927, 2376, 2108, 1948, 1779, 1694, 1390; 1H NMR (CDCl3, 300
MHz) δ 7.36-7.20 (m, 5H), 5.83-5.74 (m, 1 H), 5.06-4.96 (m,
2 H), 4.74-4.68 (m, 1 H), 4.22-4.14 (m, 2 H), 4.04-3.97 (m, 1
H), 3.31 (dd, 1 H, J ) 13.2, 3.2 Hz), 2.78 (dd, 1 H, J ) 13.2, 9.2
Hz), 2.64-2.52 (m, 2 H), 2.14-2.06 (m, 2 H), 2.03 (t, 1 H, J )
5.2 Hz), 2.01-1.89 (m, 1 H), 1.8-1.59 (m, 1 H); 13C NMR (CDCl3,
100 MHz) δ 174.5, 153, 137.7, 135.3, 129.6, 129.0, 127.4, 115.4,
81.1, 70.5, 66.1, 55.4, 41.5, 38.0, 31.2, 30.2, 21.2. HRMS (EI) calcd
for C19H21NO3Na m/z 334.1419, found m/z 334.1406.
Experimental Section41
General Procedure for Intramolecular Enyne Metathesis
Reaction. A solution of enyne (1.0 mmol) in toluene or CH2Cl2
(310 mL) was purged with ethylene gas for 10 min before being
treated with a solution of 31 or 32 (10 mol %) in toluene or CH2-
Cl2 (10 mL) and then refluxed for 12 h. The reaction mixture was
cooled to room temperature and stirred with DMSO (50 equiv with
respect to the catalyst, 5.0 mmol) for 6 h to remove the Ru
(R)-2-(Prop-2-ynyl)hex-5-en-1-ol (29).29d To a solution of 28
(1.7 g, 5.48 mmol) in ether (16 mL) at 0 °C was added MeOH (0.4
mL, 7.18 mmol). After the solution was stirred at 0 °C for 5 min,
6122 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of Angucyclinone-Type Natural Products
LiBH4 (4.64 mL, 9.28 mmol, 2 M solution in THF) was added and
the stirring was continued for 2 h at 0 °C. The reaction mixture
was treated with a saturated aqueous solution of sodium potassium
L-(+)-tartrate at 0 °C. After being warmed to room temperature,
the reaction mixture was stirred for 5 h and then the mixture was
extracted with ether (3 × 20 mL). The organic layer was washed
with brine, dried (Na2SO4), concentrated, and purified by silica gel
column chromatography (25% ether in pentane) to afford the enyne
29 (0.618 g) as a colorless oil in 82% yield. Rf 0.4 (1:4
ether/pentane); [R]20D -20.39 (c 1.03, CHCl3); IR (neat) cm-1 3425,
(dd, 1 H, J ) 8.4, 1.2 Hz), 3.68-3.29 (m, 2 H), 3.28-3.20 (m, 1
H), 3.0 (dd,1 H, J ) 17.2, 2.8 Hz), 2.67 (dd, 1 H, J ) 17.2, 10.8
Hz), 2.09-2.0 (m, 2 H), 1.47-1.25 (m, 1H), 3.05-2.81 (m, 2 H),
0.92 (s, 9 H), 0.07 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 188.8,
161.9, 146.2, 141.7, 136.6, 136.5, 135.1, 135.0, 132.8, 131.2, 124.8,
123.1, 119.4, 115.7, 67.5, 35.7, 34.5, 28.9, 26.1, 18.5, -5.1, -5.2;
HRMS (EI) calcd for C25H31O4Si m/z 423.1992, found m/z
423.1981.
(S)-3-((tert-Butyldimethylsilyloxy)methyl)-8-hydroxy-3,4-di-
hydrotetraphene-1,7,12(2H)-trione(36).29d Following the general
procedure for photooxygenation, a solution of quinone 35 (0.17 g,
0.4 mmol) in benzene (45 mL) on irradiation for 20 h afforded
compound 36 (0.122 g) in 70% yield as an orange solid along with
0.036 g of unreacted regioisomer. Rf 0.33 (1:9 ethyl acetate/
1
2926, 2378, 1653, 1091; H NMR (CDCl3, 400 MHz) δ 5.86-
5.76 (m, 1 H), 5.07-4.96 (m, 2 H), 3.72-3.61 (m, 2 H), 2.39-
2.21 (m, 2 H), 2.16-2.0 (m, 2 H), 1.99 (t, 1 H, J ) 2.4 Hz), 1.82-
1.55 (m, 1 H), 1.54-1.47 (m, 2 H); 13C NMR (CDCl3, 100 MHz)
δ 138.3, 114.8, 82.4, 69.7, 64.6, 38.8, 30.9, 29.1, 19.9. HRMS (EI)
calcd for C9H14OK m/z 177.0682, found m/z 177.0674.
hexanes); mp 91-93 °C; [R]20 +56.5 (c 0.52, CHCl3); IR (KBr)
D
1
cm-1 3425, 2927, 1706, 1672, 1592, 1457, 1363, 1284, 1099; H
NMR (CDCl3, 300 MHz) δ 12.30 (s, 1H), 8.30 (d, 1 H, J ) 7.8
Hz), 7.69 (dd, 1 H, J ) 5.4, 1.8 Hz), 7.65 (d, 1 H, J ) 7.8 Hz),
7.58 (d, 1 H, J ) 8.1 Hz), 7.28 (dd, 1 H, J ) 8.1, 2.1 Hz), 3.71
(dd, 1 H, J ) 9.9, 5.1 Hz), 3.62 (dd, 1 H, J ) 10.2, 6.3 Hz), 3.05-
2.81 (m, 2 H), 2.73 (dd, 2 H, J ) 16.2, 10.8 Hz), 2.56-2.49 (m,
1 H), 0.91 (s, 9 H) , 0.07 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ
199.3, 187.6, 183.0, 162.2, 150.4, 137.2, 136.9, 135.8, 135.1, 133.5,
133.4, 129.1, 123.8, 119.8, 115.5, 66.2, 42.3, 38.0, 33.0, 26.0, 18.4,
-5.3; HRMS (EI) calcd for C25H29O5Si m/z 437.1784, found m/z
437.1779. Anal. Calcd for C25H28O5Si: C, 68.78; H, 6.46. Found:
C, 69.1675; H, 6.8989.
YM-181741 (3).29d A solution of TBS-ether 36 (0.1 g, 0.23
mmol) in THF (4 mL) at 0 °C was treated with a solution of TBAF
(0.045 g, 0.34 mmol) in THF (2 mL) at 0 °C and then allowed to
warm to room temperature and stirred for 2 h. The reaction mixture
was treated with water and then extracted with CHCl3. The organic
layer was washed with brine, dried (Na2SO4), concentrated, and
purified by silica gel column chromatography to afford YM 181741
(3) (0.05 g) in 68% yield. Rf 0.3 (3:2 ethyl acetate/hexanes); mp
192 °C; [R]25D +27.2 (c 0.367, CHCl3); IR (KBr) cm-1 3433, 2927,
1702, 1671, 1588, 1453, 1362, 1276, 1588, 1453, 1362, 1276, 1215;
UV(MeOH) λmax nm (ꢀ) 276, 402; 1H NMR (CDCl3, 400 MHz) δ
12.30 (s, 1H), 8.30 (d, 1 H, J ) 7.6 Hz), 7.68 (dd, 1 H, J ) 7.6,
2.4 Hz), 7.65 (d, 1 H, J ) 7.2 Hz), 7.58 (d, 1 H, J ) 8.0 Hz), 7.28
(dd, 1 H, J ) 8.0, 2.4 Hz), 3.77 (dd, 1 H, J ) 10.4, 4.8 Hz), 3.70
(dd, 1 H, J ) 10.4, 7.2 Hz), 3.10 (dd, 1 H, J ) 16.8, 4.8 Hz), 3.03
(dd, 1 H, J ) 16.0, 6.4 Hz), 2.85 (dd, 1 H, J ) 16.4, 10.4 Hz),
2.69 (dd, 1 H, J ) 16.0, 10.4 Hz), 2.61-2.54 (m, 1 H), 1.86 (br s,
1 H); 13C NMR (CDCl3, 100 MHz) δ 198.8, 187.4, 182.9, 162.0,
149.8, 137.0, 136.7, 135.6, 134.9, 133.5, 133.2, 129.1, 123.8, 119.6,
115.4, 65.8, 42.0, 37.6, 32.7; HRMS (EI) calcd for C19H15O5 m/z
323.0919, found m/z 323.0910. Anal. Calcd for C19H16O6: C, 67.05;
H, 4.74. Found: C, 66.7777; H, 4.9084.
(R)-2-Methylhex-5-enyl 4-Methylbenzenesulfonate (45). A
suspension of LAH (2.3 g, 60.62 mmol) in ether at 0 °C was treated
with a solution of oxazolidinone 38 (5.8 g, 20.20 mmol)30 in ether
and stirred at the same temperature for 45 min. The reaction mixture
was slowly treated with a saturated solution of Na2SO4 at 0 °C.
The resulting granules were filtered and washed well with ether.
The filtrate was concentrated in vacuo and proceeded further without
any purification.
To a stirred solution of the resulting alcohol in pyridine (30 mL)
at 0 °C was added p-TsCl (9.6 g, 50.5 mmol) followed by a catalytic
amount of DMAP. The reaction mixture was warmed to room
temperature and after being stirred for 5 h it was treated with cold
water. The mixture was extracted with CHCl3 (3 × 100 mL). The
organic layer was washed with brine, dried (Na2SO4), concentrated,
and purified by silica gel column chromatography (10% ethyl
acetate in hexanes) to afford the compound 45 (3.85 g) as a colorless
oil in 71% yield over two steps. Rf 0.59 (1:4 ethyl acetate/hexanes);
[R]20D -5.098 (c 1.04, CHCl3); IR (neat) cm-1 2974, 2925, 2638,
1597, 1458, 1368, 1176; 1H NMR (CDCl3, 300 MHz) δ 7.79 (d, 2
H, J ) 10.8 Hz), 7.35 (d, 2 H, J ) 10.8 Hz), 5.78-5.65 (m, 1 H),
(R)-tert-Butyldimethyl(2-(prop-2-ynyl)hex-5-enyloxy)silane
(30).29d A solution of alcohol 29 (0.25 g, 1.81 mmol), imidazole
(0.246 g, 3.62 mmol), and a catalytic amount of DMAP in CH2Cl2
(15 mL) was treated with TBSCl (0.41 g, 2.71 mmol) at 0 °C. After
being stirred at the same temperature for 1 h, the reaction mixture
was treated with water and extracted with CH2Cl2. The organic
layer was washed with brine, dried (Na2SO4), concentrated, and
purified by silica gel column chromatography (2% ethyl acetate in
hexanes) to afford the silyl ether 30 (0.419 g) as a colorless oil in
82%. Rf 0.9 (3:7 ethyl acetate/hexanes); [R]20 +267.9 (c 1.09,
D
CHCl3); IR (neat) cm-1 3307, 2936, 2859, 1641, 1465, 1257, 1216;
1H NMR (CDCl3, 400 MHz) δ 5.87-5.74 (m, 1 H), 5.06-4.94
(m, 2 H), 3.63-3.51 (m, 2 H), 2.27 (dd, 2 H, J ) 8.0, 2.7 Hz),
2.24-2.05 (m, 2 H), 1.92 (t, 1 H, J ) 2.7 Hz), 1.73-1.64 (m, 1
H), 1.52-1.43 (m, 2 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13C NMR
(CDCl3, 100 MHz) δ 138.6, 114.5, 82.8, 69.1, 64.2, 39.1, 31.1,
29.1, 25.9, 19.8, 18.3, -5.4, -5.5. HRMS (EI) calcd for C15H29-
OSi m/z 253.1988, found m/z 253.1987.
(R)-tert-Butyldimethyl((3-vinylcyclohex-3-enyl)methoxy)si-
lane (33).29d Following the general procedure for intramolecular
enyne metathesis reaction, a solution of enyne 30 (0.25 g, 0.99
mmol) and 32 (0.14 g, 10 mol %) in toluene was heated at 80 °C
for 12 h. After the solution was treated with DMSO, solvent was
removed in vacuo and purification by silica gel column
chromatography (1% ethyl acetate in hexanes) provided the
diene 33 (0.22 g) as a colorless oil in 88% yield. Rf 0.9 (3:7 ethyl
acetate/hexanes); [R]20 +99.1 (c 1.35, CHCl3); IR (neat) cm-1
D
3454, 2930, 1655, 1465, 1257, 1104; 1H NMR (CDCl3, 300 MHz)
δ 6.37 (dd, 2 H, J ) 17.6, 10.8 Hz), 5.75 (br s, 1 H), 5.07 (d, 1 H,
J ) 17.7 Hz), 4.9 (d, 1 H, J ) 10.8 Hz), 3.59-3.49 (m, 2 H),
2.3-2.18 (m, 2 H), 2.3-2.18 (m, 1 H), 1.8-1.76 (m, 2 H), 1.29-
1.20 (m, 1H), 0.89 (s, 9 H), 0.06 (s, 6 H); 13C NMR (CDCl3, 75
MHz) δ 140.0, 135.3, 129.6, 109.8, 67.9, 36.3, 26.9, 26.0, 25.3,
18.4, -5.4, -5.3. HRMS (EI) calcd for C15H29OSi m/z 253.1988,
found m/z 253.1984.
(R)-3-((tert-Butyldimethylsilyloxy)methyl)-8-hydroxy-1,2,3,4-
tetrahydrotetraphene-7,12-dione (35).29d Following the general
procedure for Diels-Alder reaction followed by aromatization, a
solution of 5-acetoxy-2-bromo-1,4-naphthaquinone 20 (0.27 g, 0.92
mmol) and diene 33 (0.21 g, 0.83 mmol) in toluene was heated at
80 °C for 12 h and then at 100 °C for 2 h. After the solvent was
removed in vacuo, the crude Diels-Alder adduct was dissolved in
MeOH (10 mL), treated with solid K2CO3 (0.35 g, 2.49 mmol),
and stirred in the dark for 12 h. The solvent was removed in vacuo,
treated with water, and extracted with CHCl3. The organic layer
was washed with brine, dried (Na2SO4), concentrated, and purified
by a silica gel column chromatography (2% ethyl acetate in hexanes)
to afford the tetracycle 35 (0.25 g) as a yellow solid in 71% yield
for three steps. Rf 0.4 (1:19 ethyl acetate/hexanes); mp 86-88 °C;
[R]20 +130.0 (c 0.9, CHCl3); IR (KBr) cm-1 3444, 2896, 2930,
D
1667, 1634, 1454, 1284, 1256, 1107; 1H NMR (CDCl3, 300 MHz)
δ 12.55 (s, 1H), 8.14 (d, 1 H, J ) 8.4 Hz), 7.72 (dd, 1 H, J ) 7.6,
1.2 Hz), 7.64 (t, 1 H, J ) 7.8 Hz), 7.50 (d, 1 H, J ) 7.6 Hz), 7.24
J. Org. Chem, Vol. 72, No. 16, 2007 6123

Kaliappan and Ravikumar
4.99-4.90 (m, 2 H), 3.89 (dd, 1 H, J ) 12.0, 8.0 Hz), 3.82 (dd, 1
H, J ) 12.4, 8.0 Hz), 2.45 (s, 3 H), 2.02-1.91 (m, 2 H), 1.84-
1.75 (m, 1 H), 1.50-1.39 (m, 1 H), 1.26-1.16 (m, 1 H), 0.9 (d, 3
H, J ) 8.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 144.9, 138.3, 133.2,
130.0, 128.1, 115.0, 75.1, 32.4, 31.9, 30.9, 21.8, 16.4; HRMS (EI)
calcd for C14H20O3NaS m/z 291.1031, found m/z 291.1031.
(R)-2-(Prop-2-ynyl)hex-5-enyl 4-Methylbenzenesulfonate (46).
To a stirred solution of alcohol 29 (0.4 g, 2.9 mmol) in pyridine (5
mL) at 0 °C was added p-TsCl (1.4 g, 7.33 mmol) followed by a
catalytic amount of DMAP. The reaction mixture was warmed to
room temperature and after being stirred for 5 h it was treated with
cold water. The mixture was extracted with CHCl3 (3 × 20 mL).
The organic layer was washed with brine, dried (Na2SO4),
concentrated, and purified by silica gel column chromatography
(15% ethyl acetate in hexanes) to afford the enyne 46 (0.752 g) as
a colorless oil in 89% yield. Rf 0.44 (3:7 ethyl acetate/hexanes);
[R]20D +11.617 (c 0.835, CHCl3); IR (neat) cm-1 3294, 2923, 1640,
Hz), 7.22 (dd, 1 H, J ) 8.4, 1.2 Hz), 3.55 (dq, 1 H, J ) 19.2, 3.2
Hz), 3.25-3.18 (m, 1 H), 2.94 (dq, 1 H, J ) 17.2, 1.6 Hz), 2.53
(dd, 1 H, J ) 17.2, 10.4 Hz), 2.05-2.0 (m, 2 H), 1.99-1.83 (m,
1H), 1.41-1.31 (m, 1H), 1.09 (d, 3 H, J ) 6.8 Hz); 13C NMR
(CDCl3, 100 MHz) δ 188.9, 184.9, 161.8, 146.5, 141.6, 136.6,
135.2, 134.8, 132.8, 131.3, 124.8, 123.0, 119.3, 115.6, 39.9, 31.4,
29.2, 27.8, 21.7; HRMS (EI) calcd for C19H17O3 m/z 293.1178,
found m/z 293.1175. Anal. Calcd for C19H16O3: C, 78.06; H, 5.52.
Found: C, 78.4790; H, 5.7794.
(+)-Ochromycinone (1). Following the general procedure for
photooxygenation, a solution of quinone 48 (0.07 g, 0.24 mmol)
in benzene (90 mL) on irradiation for 20 h afforded (+)-
ochromycinone (1) (0.06 g, 82%) as a yellow solid. Rf 0.24 (2:3
ethyl acetate/hexanes); mp 159-160 °C; [R]20D +103.246 (c 0.345,
CHCl3); IR (KBr) cm-1 2956, 2923, 1703, 1667, 1635, 1589, 1453;
1H NMR (CDCl3, 400 MHz) δ 12.21 (s, 1 H), 8.29 (d, 1 H, J )
8.0 Hz), 7.70-7.58 (m, 2 H), 7.55 (d, 1 H, J ) 8.0 Hz), 7.29-
7.24 (m, 1 H), 3.06-2.98 (m, 2 H), 2.69 (dd, 1 H, J ) 16.0, 10.4
Hz), 2.58 (dd, 1 H, J ) 16.0, 10.4 Hz), 2.5-2.42 (m, 1 H), 1.21
(d, 3 H, J ) 6.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 199.1, 187.5,
182.9, 161.9, 150.3, 136.9, 136.5, 135.8, 135.0, 133.4, 132.9, 128.9,
123.6, 119.5, 115.3, 47.4, 38.3, 30.7, 21.4; HRMS (EI) calcd for
C19H15O4 m/z 307.0970, found m/z 307.0976. Anal. Calcd for
C20H16O4: C, 74.50; H, 4.61. Found: C, 75.5750; H, 4.3945.
(+)-Rubiginone B2 (2). A solution of alcohol 1 (0.04 g, 0.13
mmol) and MeI (0.32 mL, 5.17 mmol) in CH2Cl2 (4 mL) was
treated with freshly prepared Ag2O (0.5 g, 2.1 mmol) at room
temperature and the solution was stirred for 5 h. The mixture was
filtered, the filtrate was concentrated, and the resultant residue was
purified by silica gel column chromatography (40% ethyl acetate
in hexanes) to afford (+)-rubiginone B2 (2) (0.034 g, 82%) as a
yellow solid. Rf 0.16 (2:3 ethyl acetate/hexanes); mp 237-239 °C;
[R]20D +77.545 (c 0.44, CHCl3); IR (KBr) cm-1 1706, 1697, 1674,
1
1363, 1177; H NMR (CDCl3, 400 MHz) δ 7.8 (d, 2 H, J ) 8.0
Hz), 7.35 (d, 2 H, J ) 8.0 Hz), 5.76-5.67 (m, 1 H), 5.66-4.94
(m, 2 H), 4.05 (dd, 1 H, J ) 9.6, 4.8 Hz), 4.0 (dd, 1 H, J ) 9.6,
6.4 Hz), 2.45 (s, 3 H), 2.31-2.27 (m, 2 H), 2.21-2.02 (m, 2 H),
1.99-1.88 (m, 1 H), 1.86 (t, 1 H, J ) 2.4 Hz), 1.51-1.42 (m, 2
H); 13C NMR (CDCl3, 75 MHz) δ 144.8, 137.6, 132.8, 129.9, 128.0,
115.3, 80.7, 71.3, 70.3, 36.2, 30.6, 28.7, 21.7, 19.8. HRMS (EI)
calcd for C16H20O3NaS m/z 315.1031, found m/z 315.1129.
(R)-(3-Vinylcyclohex-3-enyl)methyl 4-Methylbenzenesulfonate
(47). Following the general procedure for intramolecular enyne
metathesis reaction, a solution of enyne 46 (0.5 g, 1.71 mmol) and
31 (0.14 g, 10 mol %) in CH2Cl2 was refluxed for 12 h. After the
solution was treated with DMSO, solvent was removed in vacuo
and purification by silica gel column chromatography (15% ethyl
acetate in hexanes) furnished the diene 47 (0.5 g) as a colorless oil
in quantitative yield. Rf 0.44 (3:7 ethyl acetate/hexanes); [R]20
D
+50.963 (c 0.675, CHCl3); IR (neat) cm-1 2924, 1600, 1361, 1190,
1
1592, 1585; H NMR (CDCl3, 400 MHz) δ 8.26 (d, 1 H, J ) 8.4
1
1177, 1098; H NMR (CDCl3, 400 MHz) δ 7.81 (d, 2 H, J ) 8.0
Hz), 7.77 (dd, 1 H, J ) 7.6, 0.8 Hz), 7.70 (t, 1 H, J ) 8.0 Hz),
7.51 (d, 1 H, J ) 8.0 Hz), 7.30 (d, 1 H, J ) 8.4 Hz), 4.04 (s, 3 H),
3.02-2.97 (m, 2 H), 2.68 (dd, 1 H, J ) 16.4, 10.4 Hz), 2.56 (dd,
1 H, J ) 15.6, 10.8 Hz), 2.5-2.42 (m, 1 H), 1.19 (d, 3 H, J ) 6.4
Hz); 13C NMR (CDCl3, 75 MHz) δ 198.9, 184.5, 181.6, 159.8,
149.2, 137.6, 135.4, 135.1, 135.0, 133.1, 129.6, 120.6, 119.6, 117.2,
56.5, 47.6, 38.3, 30.9, 21.5; HRMS (EI) calcd for C20H17O4 m/z
321.1127, found m/z 321.1128. Anal. Calcd for C20H16O4: C, 74.99;
H, 5.03. Found: C, 74.8822; H, 4.8840.
Hz), 7.36 (d, 2 H, J ) 8.0 Hz), 6.31 (dd, 1 H, J ) 17.2, 10.8 Hz),
5.72 (br s, 1 H), 4.99 (d, 1 H, J ) 17.2 Hz), 4.89 (d, 1 H, J ) 10.8
Hz), 3.96 (d, 2 H, J ) 6.8 Hz), 2.46 (s, 3 H), 2.27-2.18 (m, 1 H),
2.05-1.96 (m, 1 H), 1.77-1.70 (m, 2 H), 1.29-1.22 (m, 1 H);
13C NMR (CDCl3, 75 MHz) δ 144.8, 139.4, 134.2, 133.0, 129.9,
129.1, 127.9, 110.3, 74.4, 33.2, 26.4, 24.7, 24.6, 21.7. HRMS (EI)
calcd for C16H20O3NaS m/z 315.1031, found m/z 315.1034.
(R)-8-Hydroxy-3-methyl-1,2,3,4-tetrahydrotetraphene-7,12-
dione (48). A suspension of LAH (0.122 g, 3.22 mmol) in THF (5
mL) at 0 °C was treated with a solution of diene 47 (0.47 g, 1.61
mmol) in THF (1 mL), and after being warmed to room temperature,
the reaction mixture was stirred for 12 h. Then, the reaction
mixture was treated with a saturated solution of Na2SO4 at
0 °C. The resultant granules were filtered and washed well
with ether. The filtrate was concentrated under atmospheric
pressure at 40 °C to afford diene 18, which was used for the next
step without making any attempt to remove the THF from the crude
mixture.
Following the general procedure for Diels-Alder reaction
followed by aromatization, a solution of 5-acetoxy-2-bromo-1,4-
naphthaquinone 20 (0.52 g, 1.77 mmol) and diene 18 in toluene
was heated at 80 °C for 12 h. After the solvent was removed in
vacuo, the crude Diels-Alder adduct was dissolved in MeOH
(16 mL), treated with solid K2CO3 (0.67 g, 4.83 mmol), and stirred
in the dark for 12 h. The solvent was removed in Vacuo, treated
with water, and extracted with CHCl3. The organic layer was
washed with brine, dried (Na2SO4), concentrated, and purified by
silica gel column chromatography (20% ethyl acetate in hexanes)
to afford the tetracycle 48 (0.21 g) as a yellow solid in 45% yield
for three steps. Rf 0.8 (1:4 ethyl acetate/hexanes); mp 160-161
°C; [R]20D +106.634 (c 0.615, CHCl3); IR (KBr) cm-1 3431, 2952,
2922, 1664, 1631, 1580, 1451, 1371, 1272; 1H NMR (CDCl3, 400
MHz) δ 12.54 (s, 1H), 8.11 (d, 1 H, J ) 7.6 Hz), 7.70 (dd, 1 H, J
) 7.2, 0.8 Hz), 7.62 (t, 1 H, J ) 8.0 Hz), 7.44 (d, 1 H, J ) 8.0
((2S, 3S)-3-(But-3-enyl)-3-methyloxiran-2-yl)methanol (49). A
suspension of 4 Å MS (0.69 g) in CH2Cl2 at room temperature
was treated with L-(+)-diisopropyl tartrate (0.82 mL, 3.85 mmol)-
and Ti(OiPr)4 (0.76 mL, 2.5 mmol) and the mixture was cooled to
-20 °C. Dry tert-butyl hydroperoxide (4 mL, 3.3 M solution in
toluene, 37.5 mmol) was added to this mixture, which was stirred
at the same temperature for 40 min. A solution of alcohol 42 (3.2
g, 25 mmol) in CH2Cl2 (25 mL) was added dropwise and the stirring
was continued for an additional 2 h. The reaction mixture was
warmed to 0 °C and treated with water (15 mL). Finally, the mixture
was warmed to room temperature and treated with a 30% solution
of NaOH in saturated NaCl solution (3.5 mL). The mixture was
stirred at room temperature for about 1 h until the two layers
separated and then extracted with CH2Cl2. The organic layer was
washed with brine, dried (Na2SO4), concentrated, and purified by
silica gel column chromatography (35% ethyl acetate in hexanes)
to afford the epoxy alcohol 49 (3.1 g) as a colorless oil in 90%
yield. Rf 0.5 (1:1 ethyl acetate/hexanes); [R]20 -4.277 (c 1.59,
D
CHCl3); IR (neat) cm-1 3424, 3077, 2933, 1643, 1450, 1389, 1251,
1
1034; H NMR (CDCl3, 400 MHz) δ 5.86-5.76 (m, 1 H), 5.07-
4.97 (m, 2 H), 3.83 (d, 1 H, J ) 12.4 Hz), 3.68 (dd, 1 H, J ) 12.0,
6.8 Hz), 2.99 (dd, 1 H, J ) 6.8, 4.0 Hz), 2.23-2.10 (m, 2 H), 1.87
(br s, 1 H), 1.79-1.72 (m, 1 H), 1.60-1.52 (m, 1 H), 1.31 (s, 3
H); 13C NMR (CDCl3, 75 MHz) 137.7, 115.1, 63.3, 61.3, 61.1,
37.7, 29.3, 16.8; HRMS (EI) calcd for C8H14O2Na m/z 165.0891,
found m/z 165.0891.
6124 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of Angucyclinone-Type Natural Products
(S)-3-Methylhept-6-ene-1,3-diol (50). A solution of epoxy
alcohol 49 (3.2 g, 22.5 mmol) in THF (108 mL) at 0 °C was treated
with a solution of Red Al (14 mL, 3.5 M solution in toluene, 49.5
mmol) in THF (32 mL). After being stirred at the same temperature
for 10 min, the reaction mixture was warmed to room temperature
and stirred for 12 h. A saturated solution of potassium sodium
L-tartrate tetra hydrate was added at 0 °C to the reaction mixture,
which was then warmed to room temperature. The stirring was
continued for 1 h until the two layers separated and then extracted
with ethyl acetate. The organic layer was washed with brine, dried
(Na2SO4), concentrated, and purified by silica gel column chro-
matography (40% ethyl acetate in hexanes) to afford the 1,3-diol
50 (3.25 g) as a colorless oil in quantitative yield. Rf 0.2 (1:1 ethyl
acetate/hexanes); [R]20D +23.186 (c 1.13, CHCl3); IR (neat) cm-1
3364, 2972, 2935, 1643, 1452, 1378, 1126, 1060; 1H NMR (CDCl3,
300 MHz) δ 5.91-5.78 (m, 1 H), 5.07-4.93 (m, 2 H), 3.92-3.80
(m, 2 H), 3.64 (s, OH), 2.18-2.03 (m, 2 H), 1.83-1.44 (m, 4 H),
1.23 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 138.8, 114.5, 73.6,
61.5, 59.5, 41.4, 28.4, 26.5; HRMS (EI) calcd for C8H16O2Na m/z
167.1048, found m/z 167.1048.
concentrated, and the crude product 52 was used for further reaction
without any purification. Rf 0.5 (3:7 ethyl acetate/hexanes); IR (neat)
cm-1 2929, 1720, 1639, 1515, 1248.
(S)-1-((1,1-Dibromo-4-methylocta-1,7-dien-4-yloxy)methyl)-
4-methoxybenzene (53). To a stirred solution of triphenylphosphine
(7.15 g, 27.2 mmol) in CH2Cl2 (42 mL) was added carbon
tetrabromide (4.52 g, 13.63 mmol) at room temperature. After the
solution was stirred for 30 min at room temperature, NEt3 (7.6 mL,
54.5 mmol) was added and the mixture was cooled to -78 °C. To
this cold mixture was added a solution of aldehyde 52 (1.8 g, 6.8
mmol) in CH2Cl2 (5 mL) and then mixture was stirred at -78 °C
for 1 h and then at room temperature for 12 h. The reaction mixture
was concentrated and purified by silica gel column chromatography
(3% ethyl acetate in hexanes) to afford the product 53 (2.47 g) as
a colorless oil in 87% yield for two steps from alcohol. Rf 0.8 (1:4
ethyl acetate/hexanes); [R]20 +6.452 (c 1.55, CHCl3); IR (neat)
D
cm-1 2934, 1614, 1514, 1460, 1379, 1248; 1H NMR (CDCl3, 300
MHz) δ 7.25 (dt, 2 H, J ) 9.6, 2.7 Hz), 6.88 (dt, 2 H, J ) 9.6, 2.7
Hz), 6.54 (t, 1 H, J ) 7.5 Hz), 5.91-5.78 (m, 1 H), 5.08-4.94 (m,
2 H), 4.32 (s, 2 H), 3.80 (s, 3 H), 2.46-2.31 (m, 2 H), 2.16-2.10
(m, 2 H), 1.76-1.57 (m, 2 H), 1.25 (s, 3 H); 13C NMR (CDCl3, 75
MHz) 159.1, 138.6, 135.0, 131.1, 128.9, 114.6, 113.9, 89.8, 76.4,
63.4, 55.4, 42.1, 37.5, 28.0, 23.4; HRMS (EI) calcd for C17H22O2-
NaBr2 m/z 438.9884, found m/z 438.9897.
(4S)-4-(But-3-enyl)-2-(4-methoxyphenyl)-4-methyl-1,3-diox-
ane (51). To a solution of 1,3-diol 50 (2 g, 13.88 mmol) and
anisaldehydedimethyl acetal (3.54 mL, 20.82 mmol) in CH2Cl2 (150
mL) at room temperature was added a catalytic amount of TsOH
and the solution was stirred for 1 h at room temperature. The
reaction mixture was treated with 10 drops of NEt3, and after
concentrating the reaction mixture, the residue was purified by silica
gel column chromatography (7% ethyl acetate in hexanes) to afford
the acetal 51 (3.9 g) as a colorless oil in quantitative yield. Rf 0.6
(S)-1-Methoxy-4-((4-methyloct-7-en-1-yn-4-yloxy)methyl)ben-
zene (40). A solution of dibromo compound 53 (2.45 g, 5.86 mmol)
n
in THF (60 mL) at -78 °C was treated with BuLi (8.42 mL, 1.6
M solution in hexane) and the solution was stirred at the same
temperature for 10 min. The reaction mixture was slowly warmed
to room temperature over a period of 2 h, quenched with saturated
aqueous NH4Cl solution, and extracted with ethyl acetate. The
organic layer was washed with brine, dried (Na2SO4), concentrated,
and purified by silica gel column chromatography (4% ethyl acetate
in hexanes) to afford the enyne 40 (1.35 g) as a colorless oil in
(1:9 ethyl acetate/hexanes); [R]20 +17.293 (c 1.33, CHCl3); IR
D
1
(neat) cm-1 2939, 1611, 1516, 1458, 1382, 1251, 1095; H NMR
(CDCl3, 300 MHz) δ 7.41 (d, 2 H, J ) 8.7 Hz), 6.88 (d, 2 H, J )
8.7 Hz), 5.94-5.79 (m, 1 H), 5.69 (s, 1 H), 5.10-4.93 (m, 2 H),
4.17-4.05 (m, 2 H), 3.79 (s, 3 H), 2.30-1.61 (m, 4 H), 1.59-
1.30 (m, 2 H), 1.41 (s, 3 H); HRMS (EI) calcd for C16H23O3 m/z
263.16547, found m/z 263.1655.
90% yield. Rf 0.4 (1:19 ethyl acetate/hexanes); [R]20 -2.025 (c
D
1.20, CHCl3); IR (neat) cm-1 3302, 2975, 2111, 1734, 1611, 1513,
1460, 1249; 1H NMR (CDCl3, 300 MHz) δ 7.27 (dt, 2 H, J ) 9.6,
3 Hz), 6.86 (dt, 2 H, J ) 9.6, 3.0 Hz), 5.92-5.79 (m, 1 H), 5.09-
4.94 (m, 2 H), 4.37 (s, 2 H), 3.79 (s, 3 H), 2.47(d, 2 H, J ) 2.7
Hz), 2.20-2.12 (m, 2 H), 2.03 (t, 1 H, J ) 2.4 Hz), 1.88-1.68 (m,
2 H), 1.35 (s, 3 H); 13C NMR (CDCl3, 75 MHz) 159.1, 138.6, 135.0,
131.1, 114.6, 113.9, 89.8, 76.4, 63.4, 55.4, 42.1, 37.5, 28.0, 23.4;
HRMS (EI) calcd for C17H22O2Na m/z 281.1517, found m/z
281.1510.
(S)-3-(4-Methoxybenzyloxy)-3-methylhept-6-en-1-ol (41). A
solution of acetal 51 (3 g, 11.5 mmol) in CH2Cl2 (150 mL)
was treated with DIBAL-H (46 mL, 1 M solution in toluene) at
-20 °C over a period of 15 min and the solution was stirred at the
same temperature for 2 h. The reaction mixture was treated with
ethylacetate and warmed to room temperature. A saturated solution
of potassium sodium L-tartrate tetrahydrate was added to the reaction
mixture, and after being stirred for 30 min, the reaction mixture
was extracted with ethyl acetate. The organic layer was washed
with brine, dried (Na2SO4), concentrated, and purified by silica gel
column chromatography (50% ethyl acetate in hexanes) to afford
the primary alcohol 41 (2.3 g) as a colorless oil in 76% yield. Rf
0.3 (2:3 ethyl acetate/hexanes); [R]20D +36.22 (c 1.27, CHCl3); IR
(neat) cm-1 3423, 2934, 1611, 1515, 1463, 1249; 1H NMR (CDCl3,
300 MHz) δ 7.23 (dt, 2 H, J ) 9.6, 2.7 Hz), 6.86 (dt, 2 H, J ) 9.6,
3.0 Hz), 5.91-5.77 (m,1 H), 5.08-4.95 (m, 2 H), 4.34 (s, 2 H),
3.90-3.55 (m, 2 H), 3.79 (s, 3 H), 2.42 (br s, 1 H), 2.17-2.08 (m,
2 H), 2.04-1.93 (m, 1 H), 1.82-1.76 (m, 1 H), 1.75-1.64 (m, 2
H), 1.33 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 159.0, 138.5, 130.9,
129.0, 114.5, 113.8, 78.2, 63.2, 59.3, 55.2, 39.8, 37.3, 28.0, 23.0;
HRMS (EI) calcd for C16H24O3Na m/z 287.1623, found m/z
287.1628.
(S)-3-(4-Methoxybenzyloxy)-3-methylhept-6-enal (52). To a
solution of oxalyl chloride (0.72 mL, 8.18 mmol) in CH2Cl2 (24
mL) was added DMSO (1.11 mL, 15.68 mmol) at -78 °C, and
after the solution was stirred at the same temperature for 10 min a
solution of alcohol 41 (1.8 g, 6.8 mmol) in CH2Cl2 (12 mL) was
added. The stirring was continued for an additional 1 h and
triethylamine (5.03 mL, 36.1 mmol) was added to the reaction
mixture at -78 °C. After being stirred at the same temperature for
20 min, the mixture was gradually warmed to room temperature
and treated with water. The mixture was extracted with CH2Cl2,
the organic layer was washed with brine, dried (Na2SO4), and
(S)-1-Methoxy-4-((1-methyl-3-vinylcyclohex-3-enyloxy)meth-
yl)benzene (39). Following the general procedure for intramolecular
enyne metathesis reaction, a solution of enyne 40 (0.27 g, 1.05
mmol) and 31 (0.086 g, 10 mol %) in toluene (335 mL) was heated
at 80 °C for 12 h. After the mixture was treated with DMSO (0.37
mL, 5.3 mmol), the solvent was removed in vacuo and purification
by silica gel column chromatography (6% ethyl acetate in hexanes)
furnished the 1,3-diene 39 (0.26 g) as a colorless oil in 92% yield.
Rf 0.4 (1:19 ethyl acetate/hexanes); [R]20D +65.0 (c 1.56, CHCl3);
IR (neat) cm-1 3442, 2926, 2385, 1964, 1611, 1511, 1251; 1H NMR
(CDCl3, 400 MHz) δ 7.25 (d, 2 H, J ) 8.0 Hz), 6.85 (dt, 2 H, J )
9.6, 2.8 Hz), 6.39 (dd, 1 H, J ) 17.6, 10.8 Hz), 5.75 (br s, 1 H),
5.07 (d, 1 H, J ) 17.2 Hz), 4.9 (d, 1 H, J ) 10.4 Hz), 4.42 (dd, 2
H, J ) 16.0, 11.2 Hz), 3.78 (s, 3 H), 2.46-2.22 (m, 2 H), 2.18-
2.15 (m, 2 H), 1.85 (dt, 1 H, J ) 13.2, 6.8 Hz), 1.69 (dt, 1 H, J )
13.2, 6.8 Hz), 1.31 (s, 3 H); 13C NMR (CDCl3, 100 MHz) 158.9,
139.7, 134.0, 131.9, 128.8, 128.5, 113.8, 109.9, 73.4, 63.2, 55.3,
35.6, 32.6, 23.9, 23.8; HRMS (EI) calcd for C17H22O2Na m/z
281.1517, found m/z 281.1513.
(S)-3-(4-Methoxybenzyloxy)-11-hydroxy-3-methyl-1,2,3,4-tet-
rahydrotetraphene-7,12-dione (54). Following the general pro-
cedure for Diels-Alder reaction followed by aromatization, a
solution of 5-acetoxy-2-bromo-1,4-naphthaquinone 20 (0.3 g, 1.02
mmol) and diene 39 (0.24 g, 0.93 mmol) in toluene (15 mL) was
heated at 80 °C for 12 h followed by 100 °C for 2 h. After the
J. Org. Chem, Vol. 72, No. 16, 2007 6125

Kaliappan and Ravikumar
solvent was removed in vacuo, the crude Diels-Alder adduct was
dissolved in MeOH (10 mL), treated with solid K2CO3 (0.39 g,
2.79 mmol), and stirred in the dark for 12 h. The solvent was
removed in vacuo, treated with water, extracted with CHCl3. The
organic layer was washed with brine, dried (Na2SO4), concentrated,
and purified by a silica gel column chromatography (20% ethyl
acetate in hexanes) to afford the tetracycle 54 (0.245 g) as a yellow
solid in 62% yield for two steps. Rf 0.33 (1:9 ethyl acetate/hexanes);
mp 129-131 °C; [R]20D -119.464 (c 1.12, CHCl3); IR (KBr) cm-1
3443, 2925, 1664, 1632, 1613, 1581, 1514, 1451, 1369, 1271, 1251;
1H NMR (CDCl3, 400 MHz) δ 12.56 (s, 1 H), 8.16 (d, 1 H, J )
8.0 Hz), 7.75 (dd, 1 H, J ) 8.4, 0.8 Hz), 7.65 (t, 1 H, J ) 8.0 Hz),
7.45 (d, 1 H, J ) 8.0 Hz), 7.25 (dd, 1 H, J ) 8.4, 1.2 Hz), 7.14 (d,
2 H, J ) 8.8 Hz), 6.78 (dt, 2 H, J ) 9.6, 2.8 Hz), 4.46 (dd, 2 H,
J ) 16.8, 10.4 Hz), 3.74 (s, 3 H), 3.51 (t, 2 H, J ) 6.4 Hz), 3.17
(d, 1 H, J ) 17.6 Hz), 2.97 (d, 1 H, J ) 17.6 Hz), 2.27-2.20 (m,
1 H), 1.89-1.82 (m, 1 H), 1.42 (s, 3 H); 13C NMR (CDCl3, 100
MHz) 188.6, 184.6, 161.6, 158.8, 144.5, 140.7, 136.4, 134.9, 132.7,
131.1, 130.6, 128.7, 124.8, 122.9, 119.2, 115.4, 113.6, 71.8, 63.3,
55.2, 55.1, 42.7, 32.4, 26.4, 23.8; HRMS (EI) calcd for C27H24O5-
Na m/z 451.1521, found m/z 451.1509. Anal. Calcd for C27H26O6:
C, 72.63; H, 5.87. Found: C, 72.47; H, 5.87.
silica gel column chromatography (40% ethyl acetate in hexanes)
to afford the methyl ether 56 (0.14 g, 96%) as a yellow solid. Rf
0.3 (2:3 ethyl acetate/hexanes); mp 130-131 °C; [R]20 -60.754
D
(c 1.22, CHCl3); IR (KBr) cm-1 3435, 2924, 1666, 1612, 1586,
1513, 1463, 1274, 1249, 1098; 1H NMR (CDCl3, 400 MHz) δ 8.20
(d, 1 H, J ) 7.6 Hz), 7.87 (dd, 1 H, J ) 7.6, 1.2 Hz), 7.69 (t, 1 H,
J ) 8.0 Hz), 7.42 (d, 1 H, J ) 8.0 Hz), 7.27 (dd, 1 H, J ) 8.0, 0.4
Hz), 7.15 (dt, 2 H, J ) 9.6, 2.4 Hz), 6.78 (dt, 2 H, J ) 11.6, 2.4
Hz), 4.49 (d, 1 H, J ) 10.4 Hz), 4.42 (d, 1 H, J ) 11.2 Hz), 4.04
(s, 3 H), 3.74 (s, 3 H), 3.49 (t, 2 H, J ) 6.4 Hz), 3.14 (d, 1 H, J
) 16.8 Hz), 2.92 (d, 1 H, J ) 17.2 Hz), 2.23-2.17 (m, 1 H), 1.90-
1.83 (m, 1 H), 1.41 (s, 3 H); 13C NMR (CDCl3, 75 MHz) 185.7,
183.1, 159.6, 158.8, 142.5, 139.3, 137.5, 135.0, 134.7, 131.3, 129.9,
128.7, 125.2, 120.9, 119.6, 116.7, 113.6, 72.0, 63.3, 56.4, 55.2,
55.1, 42.6, 32.7, 26.3, 23.7; HRMS (EI) calcd for C28H27O5 m/z
443.1858, found m/z 443.1878. Anal. Calcd for C28H26O5: C, 76.00;
H, 5.92. Found: C, 76.2522; H, 5.9684.
(S)-3-Hydroxy-8-methoxy-3-methyl-1,2,3,4-tetrahydrotet-
raphene-7,12-dione (57). Following the general procedure for the
removal of the PMB group, a solution of PMB-ether 56 (0.12 g,
0.27 mmol) in a mixture of CH2Cl2 (5 mL) and pH 7 buffer (0.5
mL) upon treatment with DDQ (0.11 g, 0.46 mmol) afforded the
diol 57 (0.077 g) as a yellow solid in 89% yield. Rf 0.2 (2:3 ethyl
acetate/hexanes); mp 191-193 °C; [R]20D -0.661 (c 0.515, CHCl3);
IR (KBr) cm-1 3520, 2921, 1664, 1647, 1586, 1567, 1464, 1269;
1H NMR (CDCl3, 400 MHz) δ 8.11 (d, 1 H, J ) 8.0 Hz), 7.86 (dd,
1 H, J ) 7.6, 0.8 Hz), 7.69 (t, 1 H, J ) 8.0 Hz), 7.44 (d, 1 H, J )
8.0 Hz), 7.28 (dd, 1 H, J ) 9.6, 8.4 Hz), 4.04 (s, 3 H), 3.50 (t, 2
H, J ) 8.0 Hz), 2.97 (s, 2 H), 2.01-1.95 (m, 1 H), 1.89-1.81 (m,
1 H), 1.59 (br s, 1 H), 1.39 (s, 3 H); 13C NMR (CDCl3, 75 MHz)
185.6, 182.9, 142.2, 138.5, 137.4, 135.2, 135.1, 134.8, 130.1, 125.3,
120.7, 119.6, 116.8, 67.9, 56.4, 44.1, 35.7, 28.6, 26.3; HRMS (EI)
calcd for C20H19O4 m/z 323.1283, found m/z 323.1273. Anal. Calcd
for C20H18O4: C, 74.52; H, 5.63. Found: C, 75.0741; H, 5.5600.
MM-47755 (5). Following the general procedure for photooxy-
genation, a solution of quinone 57 (0.06 g, 0.186 mmol) in benzene
(90 mL) on irradiation for 24 h provided MM-47755 (5) (0.029 g,
46%) as a yellow solid. Rf 0.2 (7:3 ethyl acetate/hexanes); mp 160-
170 °C dec; [R]20D -89.079 (c 0.315, MeOH); IR (KBr) cm-1 3415,
(S)-3,11-Dihydroxy-3-methyl-1,2,3,4-tetrahydrotetraphene-7,-
12-dione (55). Following the general procedure for removal of the
PMB group, a solution of PMB-ether 54 (0.16 g, 0.37 mmol) in
a mixture of CH2Cl2 (6 mL) and pH 7 buffer (0.6 mL) upon
treatment with DDQ (0.13 g, 0.56 mmol) afforded the diol 55 (0.107
g) as a yellow solid in 93% yield. Rf 0.2 (3:7 ethyl acetate/hexanes);
mp 165-170 °C dec; [R]20 -58.566 (c 1.06, CHCl3); IR (KBr)
D
cm-1 3423, 2961, 2930, 1664, 1632, 1582, 1478, 1454, 1274, 1249;
1H NMR (CDCl3, 400 MHz) δ 8.18 (d, 1 H, J ) 8.0 Hz), 7.74 (dd,
1 H, J ) 7.6, 1.2 Hz), 7.64 (t, 1 H, J ) 8.4 Hz), 7.48 (d, 1 H, J )
8.4 Hz), 7.25 (dd, 1 H, J ) 8.4, 1.2 Hz), 3.53 (t, 2 H, J ) 6.8 Hz),
2.99 (s, 2 H), 2.01-1.97 (m, 1 H), 1.89-1.82 (m, 1 H), 1.54 (br s,
1 H), 1.41 (s, 3 H); 13C NMR (CDCl3, 100 MHz) 188.9, 185.0,
162.0, 144.7, 140.3, 136.8, 135.2, 135.0, 133.3, 131.3, 125.3, 123.3,
119.6, 115.7, 68.1, 45.1, 35.9, 28.9, 26.7; HRMS (EI) calcd for
C19H17O4 m/z 309.1127, found m/z 309.1113. Anal. Calcd for
C19H16O4: C, 74.01; H, 5.23. Found: C, 74.3297; H, 5.0838.
(-)-Tetrangomycin (4). Following the general procedure for
the photooxygenation, a solution of quinone 55 (0.06 g, 0.19 mmol)
in benzene (60 mL) on irradiation for 24 h provided (-)-
tetrangomycin (4) (0.04 g, 64%) as a yellow solid. Rf 0.29 (3:2
1
2925, 2856, 1695, 1668, 1591, 1466, 1301, 1268, 1232; H NMR
(CDCl3, 400 MHz) δ 8.29 (d, 1 H, J ) 8.0 Hz), 7.76 (dd, 1 H, J
) 7.6, 1.2 Hz), 7.70 (t, 1 H, J ) 8.0 Hz), 7.52 (d, 1 H, J ) 8.0
Hz), 7.30 (dd, 1 H, J ) 9.6, 1.2 Hz), 4.04 (s, 3 H), 3.17 (s, 2 H),
3.10 (d, 1 H, J ) 14.4 Hz), 3.0 (d, 1 H, J ) 14.8 Hz), 1.88 (br s,
1 H), 1.51 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 197.1, 184.7,
181.5, 159.9, 146.5, 137.7, 135.5, 135.2, 135.1, 134.2, 133.8, 130.1,
120.6, 119.7, 117.3, 72.6, 56.6, 53.8, 44.0, 30.0; HRMS (EI) calcd
for C20H17O5 m/z 337.1076, found m/z 337.1093. Anal. Calcd for
C40H34O11: C, 69.56; H, 4.96. Found: C, 69.2920; H, 5.0658.
ethyl acetate/hexanes); mp 173-175 °C; [R]20 -85.612 (c 0.49,
D
CHCl3); IR (KBr) cm-1 3426, 2965, 2924, 1700, 1667, 1633, 1589,
1
1455, 1366, 1282; H NMR (CDCl3, 400 MHz) δ 12.26 (s, 1 H),
8.32 (d, 1 H, J ) 8.0 Hz), 7.68-7.64 (m, 2 H), 7.56 (d, 1 H, J )
8.0 Hz), 7.28 (dd, 1 H, J ) 7.6, 2.4 Hz), 3.18 (s, 2 H), 3.13 (d, 1
H, J ) 14.8 Hz), 3.02 (d, 1 H, J ) 14.8 Hz), 1.87 (br s, 1 H), 1.52
(s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 197.3, 187.4, 183.2, 162.0,
147.8, 137.1, 136.1, 135.7, 135.5, 135.2, 133.9, 129.4, 123.7, 119.6,
115.4, 72.6, 53.8, 44.1, 30.2; HRMS (EI) calcd for C19H14O5Na
m/z 345.0739, found m/z 345.0739. Anal. Calcd for C38H30O11: C,
68.88; H, 4.56. Found: C, 69.3096; H, 4.2692
Acknowledgment. Authors acknowledge DST, New Delhi
for the financial support and SAIF, IIT Bombay for provid-
ing spectral facilities. VRK thanks CSIR, New Delhi for a
fellowship.
(S)-8-Methoxy-3-(4-methoxybenzyloxy)-3-methyl-1,2,3,4-tet-
rahydrotetraphene-7,12-dione (56). A solution of alcohol 54 (0.14
g, 0.33 mmol) and MeI (0.82 mL, 13.12 mmol) in CH2Cl2 (10 mL)
was treated with freshly prepared Ag2O (1.23 g, 5.23 mmol) at
room temperature and stirred for 5 h. The mixture was filtered, the
filtrate was concentrated, and the resultant residue was purified by
Supporting Information Available: Characterization data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO070709P
6126 J. Org. Chem., Vol. 72, No. 16, 2007