Synthetic studies toward GKK1032s, novel antibiotic antitumor agents: Enantioselective synthesis of the fully elaborated tricyclic core via an intramolecular Diels-Alder cycloaddition

Article abstract of DOI:10.1021/jo0610208

An enantioselective synthesis of the fully elaborated tricyclic decahydrofluorene core (ABC-ring system) of GKK1032s, novel antimicrobial and antitumor agents, has been accomplished for the first time by employing a highly diastereoselective intramolecula

Full text of DOI:10.1021/jo0610208

Synthetic Studies toward GKK1032s, Novel Antibiotic Antitumor
Agents: Enantioselective Synthesis of the Fully Elaborated Tricyclic
Core via an Intramolecular Diels-Alder Cycloaddition
Moriteru Asano,† Munenori Inoue,*,†,‡ Kazuhiro Watanabe,§ Hideki Abe,§ and
Tadashi Katoh*,§
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502,
Japan, Sagami Chemical Research Center, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan, and
Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical UniVersity,
4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
katoh@tohoku-pharm.ac.jp
ReceiVed May 18, 2006
An enantioselective synthesis of the fully elaborated tricyclic decahydrofluorene core (ABC-ring system)
of GKK1032s, novel antimicrobial and antitumor agents, has been accomplished for the first time by
employing a highly diastereoselective intramolecular Diels-Alder (IMDA) reaction. The key substrate
for the IMDA reaction was efficiently prepared through (i) an intermolecular Diels-Alder reaction between
a siloxydiene and an optically active enone derived from D-mannitol to construct the appropriately
functionalized C-ring and (ii) CuCl-promoted Stille coupling of an (E)-vinyl iodide and a vinylstannane
to install the requisite triene side chain as the crucial steps.
Introduction
pyrrocidines A (4) and B (5) from the fermentation broth of a
fungus, LL-Cyan426, as antimicrobial agents against Gram-
positive bacteria including drug-resistant strains and their
structures were assigned as 3,6-bis-epi-3-demethyl analogues.3
More recently, Isaka and co-workers reported the isolation of
structurally related antituberculous agents, hirsutellones A-E
from the insect pathogenic fungus Hirustella niVea BCC 2594
and hirsutellone F from the seed fungus Trichoderma sp. BCC
7579.4
GKK1032A1 (1), A2 (2), and B (3) were isolated in 2001 by
the Kyowa Hakko research group from the culture broth of
Penicillium sp. GKK1032 (Figure 1).1 The GKK1032s exhibit
antitumor activity against the human cervical cancer-derived
HeLaS3 cells, as well as antimicrobial activity against Bacillus
subtilis no. 10707.1 In 2002, Ohmura and co-workers also
reported the isolation of a novel antimicrobial agent FO-
7711CD6 from the culture broth of Penicillium sp.,2 whose
planar structure was incidentally identical to that of GKK1032A2
(2). Subsequently, He and co-workers reported the isolation of
The gross structure and relative stereochemistry of these
natural products were determined by extensive spectroscopic
studies including 2D NMR experiments (COSY, HMBC,
† Tokyo Institute of Technology.
(2) Ohmura, S.; Komiyama, K.; Hayashi, M.; Masuma, R.; Fukami, A.
Jpn. Kokai Tokkyo Koho JP 2002255969, 2002; Chem. Abstr. 2002, 137,
231476.
(3) He, H.; Yang, H. Y.; Bigelis, R.; Solum, E. H.; Greenstein, M.; Carter,
G. T. Tetrahedron Lett. 2002, 43, 1633.
(4) (a) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai,
S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (b) Isaka, M.; Prathum-
pai, W.; Wongsa, P.; Tanticharoen, M. Org. Lett. 2006, 8, 2815.
‡ Sagami Chemical Research Center.
§ Tohoku Pharmaceutical University.
(1) (a) Koizumi, F.; Hasegawa, A.; Ando, K.; Ogawa, T.; Hara, M.;
Yoshida, M. Jpn. Kokai Tokkyo Koho JP 2001247574, 2001; Chem. Abstr.
2001, 135, 209979. (b) Hasegawa, A.; Koizumi, F.; Takahashi, Y.; Ando,
K.; Ogawa, T.; Hara, M.; Yoshida, M. 43rd Symposium on the Chemistry
of Natural Products, Symposium Paper; Osaka, Japan, 2001, 467.
10.1021/jo0610208 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/05/2006
6942
J. Org. Chem. 2006, 71, 6942-6951

Synthetic Studies toward GKK1032s
SCHEME 1. General Synthetic Strategy for GKK1032A2 (2)
by Employing Intramolecular Diels-Alder (IMDA) Reaction
FIGURE 1. Structures of GKK1032A1 (1), A2 (2), and B (3);
pyrrocidines A (4) and B (5); and decahydrofluorenes 6 and 7.
model compound 6 as well as the real decahydrofluorene core
7 that stands for a fully elaborated ABC-ring system of the
GKK1032s (1-3).
NOESY, and ROESY spectra) and X-ray crystallographic
analysis,1-4 whereas their absolute configurations have not been
revealed to date. Structural features of note include (i) an
unprecedented tricyclic decahydrofluorene core (ABC-ring) and
(ii) 12- or 13-membered macrocycles containing a δ-lactam or
succinimide ring and para-substituted phenyl ether moiety. In
2003, Oikawa reported that the unique backbone of GKK1032A2
(2) is biosynthetically constructed from L-tyrosine and a
nonaketide chain flanked with five methyl groups probably by
a polyketide synthase and a nonribosomal peptide synthetase
hybrid.5
The quite unique structural features and attractive biological
properties have made the GKK1032s and their related natural
products exceptionally intriguing and timely targets for total
synthesis. Synthetic studies toward these architecturally complex
natural products have been presented by several research
groups;6 however, to the best of our knowledge, no total
synthesis has been reported so far. In 2003, we embarked on a
project directed toward the total synthesis of optically active
GKK1032s and their analogues with the aim of exploring the
structure-activity relationships. We have already reported our
preliminary results concerning the enantioselective synthesis of
the tricyclic decahydrofluorene model core 6, which lacks two
methyl groups at C9 and C11 (GKK1032s numbering) in the
C-ring, by employing an intramolecular Diels-Alder (IMDA)
cycloaddition strategy.7 This work represents the first entry to
the tricyclic core (ABC-ring) of the GKK1032s. Additionally,
we have also disclosed an efficient and facile method for the
construction of the characteristic alkyl aryl ether portion of the
GKK1032s via Mitsunobu inversion.8 In this paper, we wish to
disclose the full details of our enantioselective synthesis of the
Results and Discussion
Our general strategy for the synthesis of the GKK1032s is
outlined in Scheme 1. The key element in this scheme consists
of the intramolecular Diels-Alder (IMDA) reaction9,10 of
(9) For recent reviews on IMDA reactions, see: (a) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, p 513. (b) Thomas, E. J. Acc. Chem. Res.
1991, 24, 229. (c) Fallis, A. G. Pure Appl. Chem. 1997, 69, 495. (d) Fallis,
A. G. Acc. Chem. Res. 1999, 32, 464. (e) Bear, B. R.; Sparks, S. M.; Shea,
K. J. Angew. Chem., Int. Ed. 2001, 40, 820. (f) Marsault, E.; Toro´, A.;
Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243. (g) Nicolaou,
K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668. (h) Takao, K.; Munakata, R.; Tadano, K. Chem.
ReV. 2005, 105, 4779.
(10) For selected recent reports on natural products syntheses based on
the IMDA reactions, see the following. Lepicidin A: (a) Evans, D. A.;
Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497. Endiandlic acid A: (b)
May, S. A.; Grieco, P. A.; Lee, H.-H. Synlett 1997, 493. Ircinianin: (c)
Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem. 1997, 62, 1691.
Isopulo’upone: (d) Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62,
786. Lycopodine: (e) Grieco, P. A.; Dai, Y. J. Am. Chem. Soc. 1998, 120,
5128. Bakkenolide: (f) Back, T. G.; Nava-Salgado, V. O.; Payne, J. E. J.
Org. Chem. 2001, 66, 4361. Equisetin: (g) Yuki, K.; Shindo, M.; Shishido,
K. Tetrahedron Lett. 2001, 42, 2517. Macquarimicins: (h) Munakata, R.;
Ueki, T.; Katakai, H.; Takao, K.; Tadano, K. Org. Lett. 2001, 3, 3029. (i)
Dineen, T. A.; Roush, W. R. Org. Lett. 2003, 5, 4725. (j) Munakata, R.;
Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.; Tadano, K. J. Am. Chem.
Soc. 2003, 125, 14722. (k) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka,
J.; Takao, K.; Tadano, K. J. Am. Chem. Soc. 2004, 126, 11254. FR182877:
(l) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc.
2002, 124, 4552. (m) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed.
2002, 41, 1787. (n) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen,
E. J. J. Am. Chem. Soc. 2003, 125, 5393. (o) Evans, D. A.; Starr, J. T. J.
Am. Chem. Soc. 2003, 125, 13531. (p) Suzuki, T.; Tanaka, N.; Matsumura,
T.; Hosoya, Y.; Nakada, M. Tetrahedron Lett. 2006, 47, 1593. Cochleamycin
A: (q) Tatsuta, K.; Narazaki, F.; Kashiki, N.; Yamamoto, J.; Nakano, S. J.
Antibiot. 2003, 56, 584. (r) Paquette, L. A.; Chang, J.; Liu, Z. J. Org. Chem.
2004, 69, 6441. Spinosyn A: (s) Mergott, D. J.; Frank, S. A.; Roush, W.
R. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11955. Tubelactomicin A: (t)
Motozaki, T.; Sawamura, A.; Suzuki, A.; Yoshida, K.; Ueki, T.; Ohara,
A.; Munakata, R.; Takao, K.; Tadano, K. Org. Lett. 2005, 7, 2261. (u)
Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.; Ohara,
A.; Munakata, R.; Takao, K.; Tadano, K. Org. Lett. 2005, 7, 2265. (v)
Hosokawa, S.; Seki, M.; Fukuda, H.; Tatsuta, K. Tetrahedron Lett. 2006,
47, 2439.
(5) Oikawa, H. J. Org. Chem. 2003, 68, 3552.
(6) (a) Arai, N.; Ui, H.; Omura, S.; Kuwajima, I. Synlett 2005, 1691. (b)
Hasegawa, D.; Sakuma, Y.; Takagi, Y.; Uchiro, T. The 125th Annual
Meeting of the Pharmaceutical Society of Japan; Tokyo, Japan, 2005,
Abstract 4, 71. (c) Nagase, K.; Shiwaku, M.; Noyama, T.; Arakawa, Y.;
Miyazaki, Y.; Kurosaka, J.; Munakata, R.; Takao, K.; Tadano, K. 89th
Symposium on Organic Synthesis, Japan, Symposium Paper; Tokyo, Japan,
2006, 45.
(7) Asano, M.; Inoue, M.; Katoh, T. Synlett 2005, 1539.
(8) Asano, M.; Inoue, M.; Katoh, T. Synlett 2005, 2599.
J. Org. Chem, Vol. 71, No. 18, 2006 6943

Asano et al.
SCHEME 3. Synthesis of Intermediate 12a and Its
SCHEME 2. Retrosynthetic Analysis for Tricyclic Model
Core 6 (ABC-Ring System) of GKK1032s
Derivative 16
14,14 where we believed that the requisite stereochemistry at
C7 and C12 in 12a should be created.
1.2. Synthesis of the Key Intermediate 12a. For the
preparation of the key intermediate 12a, we investigated the
intermolecular Diels-Alder reaction between siloxydiene 13a13
and the known optically active enone 14,14 readily prepared from
D-mannitol, as shown in Scheme 3. After several experiments,
we found that the Diels-Alder reaction proceeded effectively
by heating a mixture of 13a and 14 in toluene in a sealed tube
at 150 °C for 3 days; the desired cycloaddition product 12a
was obtained in 66% yield as the single diastereomer after
hydrochloric acid treatment. The stereostructure of 12a was
proven by NOE studies of the transformed bicyclic enone 16,
which was prepared via a two-step sequence of reactions
involving acid-catalyzed transacetalization of 12a and acetyla-
tion of the resulting alcohol 15 (86% overall yield). The
remarkable diastereoselectivity observed in this Diels-Alder
reaction can be explained, as shown in Figure 2, by the
preferential approach of diene 13a to dienophile 14A (14) from
the opposite side of the bulky acetonide group, as previously
reported by Ortun˜o and co-workers,15 providing 12a as the sole
stereoisomer.
tetraene II to construct the tricyclic core I in one step; the
structure I contains the requisite substituents, functional groups,
and asymmetric carbon centers at C3, C6, C14, and C15. We
envisaged that compound I would be elaborated to the targeted
molecule 2 via a Mitsunobu-type alkyl aryl ether formation8
and macrocyclization. To explore the feasibility of the designed
IMDA reaction (II f I), we initially undertook model studies
concerning construction of the tricyclic core 6 (cf. Figure 1)
that lacks two methyl groups at C9 and C11 in the C-ring.
1. Synthesis of the Tricyclic Model Compound 6.
1.1. Synthetic Plan. We first pursued the synthesis of the
tricyclic compound 6 as model studies. Our synthetic plan for
the initial target 6 is outlined in Scheme 2. The crucial IMDA
reaction of tetraene 8 would proceed via an endo-transition state
such as 8A, where both the A- and B-rings would be built up
while controlling the stereochemistries at C3, C6, C14, and C15
(8 f [8A] f 6). The IMDA precursor 8 would be accessed in
a straightforward manner by employing Stille coupling11 of vinyl
iodide 9 and vinylstannane 10. Intermediate 9 would be derived
from methyl ketone 12a via methyl acetylene 11 by sequential
functional group manipulation, protection, and deprotection or
vice versa. Intermediate 12a could, in turn, be accessed through
an intermolecular Diels-Alder reaction12 between the Dan-
ishefsky-Kitahara diene 13a13 and the known enulose derivative
FIGURE 2. Consideration for the stereoselectivity on the Diels-Alder
reaction between 14 (14A) and 13a.
As shown in Scheme 4, compound 12a was further converted
to dimethylacetal 18 in 67% overall yield by hydrogenation of
the olefinic double bond and subsequent regioselective acetal
formation of the resulting cyclohexanone 17. Vinyl triflate
formation16 [KN(SiMe3)2 (1.1 equiv), PhNTf2 (1.6 equiv), THF,
-78 °C] of 18 delivered the corresponding vinyl triflate 19,
which was immediately subjected to base-induced elimination/
methylation17 [LDA (3.0 equiv), MeI (5.0 equiv), THF, 0 °C]
(11) For recent reviews on Stille coupling reaction, see: (a) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1. (b) Kosugi, M.;
Fugami, K. In Handbook of Organopalladium Chemistry of Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol. 1,
p 263. (c) Espinet, P.; Echavarren, A. E. Angew. Chem., Int. Ed. 2004, 43,
4704.
(12) For reviews on the Diels-Alder reactions using siloxydienes, see:
(a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. (b) Petrzilka, M.;
Grayson, J. I. Synthesis 1981, 753. (c) Brownbridge, P. Synthesis 1983, 85.
(13) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
(14) (a) Izquierdo Cubero, I.; Portal Olea, M. D.; Garcia Poza, D.
Carbohydr. Res. 1985, 138, 135. (b) Schmid, C. R.; Bryant, J. D.;
Dowlatzedah, M.; Phillips, J. L.; Prather, D. E.; Schantz, R. D.; Sear, N.
L.; Vianco, C. S. J. Org. Chem. 1991, 56, 4056.
(15) Ortun˜o, R. M.; Ibarzo, J.; d’Angelo, J.; Dumas, F.; Alvarez-Larena,
A.; Piniella, J. F. Tetrahedron: Asymmetry 1996, 7, 127.
(16) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14, 4607.
6944 J. Org. Chem., Vol. 71, No. 18, 2006

Synthetic Studies toward GKK1032s
SCHEME 4. Synthesis of Intermediate 9
SCHEME 5. Synthesis of Tricyclic Model Core 27 through
an IMDA Reaction of Tetraene 26
most reliable. Thus, treatment of 11 in hexane with a mixture
of (n-Bu)3SnH (10.0 equiv), Pd(OAc)2 (0.3 equiv), and PCy3
(0.6 equiv) at room temperature for 12 h provided the desired
(E)-vinyl stannane 20 in 56% yield (69% yield based on
recovery of 11) with complete regioselectivity, which was then
allowed to react with I2 (1.5 equiv) to furnish the requisite vinyl
iodide 21 in 84% yield.
In the next stage, we carried out installation of an R,â-
unsaturated ester moiety that would serve as a dienophile in
the devised key IMDA reaction. Acid-catalyzed hydrolysis of
the acetonide moiety of 21 led to the formation of five-
membered acetal 22 in 87% yield. Swern oxidation23 of 22 (82%
yield) followed by Wittig reaction of the resultant aldehyde 23
provided the desired (E)-R,â-unsaturated ester 24 (74% yield)
along with its (Z)-isomer (14% yield), which were separated
by silica gel column chromatography. Finally, exposure of 24
to 1,3-propanedithiol (5.0 equiv) in the presence of BF3‚Et2O
(2.4 equiv)24 afforded the requisite key intermediate 9 in 99%
yield.
1.3. Preliminary Investigations into the Construction of
the Tricyclic Model Core 27 through an IMDA Reaction of
Tetraene 26. Having obtained the key intermediate 9, as shown
in Scheme 5, we next pursued the model experiments for the
construction of the tricyclic core 27 that lacks a methyl
substituent at C3 in the A-ring; the sequence involved Stille
coupling11 of vinyl iodide 9 with the known vinylstannane 2525
and subsequent key IMDA reaction of the formed tetraene 26.
Corey and co-workers recently reported that Stille coupling was
dramatically accelerated by the addition of CuCl;26 therefore,
we looked at the Corey protocol. Thus, treatment of 9 with 25
under Corey’s improved conditions26 [Pd(PPh3)4 (0.1 equiv),
CuCl (1.0 equiv)/LiCl (1.0 equiv), DMF/THF, rt, 12 h] afforded
the expected tetraene 26 in 38% yield. In this reaction, to our
to give methyl acetylene 11 in 81% overall yield from 18.
Transformation of 11 to vinyl iodide 21 was next examined
under standard conditions such as radical-mediated hydrostan-
nylation/iodination18,19 [(n-Bu)3SnH, AIBN; I2], Pd(0)-catalyzed
hydrostannylation/iodination20 [(n-Bu)3SnH, Pd(PPh3)4; I2], or
hydrozirconation/iodination21 (Cp2ZrHCl; I2); however, unfor-
tunately, poor yield of the expected product 21 was obtained in
all cases. After several experiments, we were pleased to find
that the use of Semmelhack’s conditions22 turned out to be the
(17) For examples of the conversion of methyl ketones to methyl
acetylenes, see: (a) Schwede, W.; Cleve, A.; Ottow, E.; Wiechert, R.
Tetrahedron Lett. 1993, 34, 5257. (b) Negishi, E.; King, A. O.; Klima, W.
L. J. Org. Chem. 1980, 45, 2526 and references therein.
(18) For recent reviews on the metal-catalyzed hydrostannations, see:
(a) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100, 3257.
(b) Makabe, H.; Negishi, E. In Handbook of Organopalladium Chemistry
of Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002;
Vol. 2, p 2789.
(19) (a) Corey, E. J.; Wollenberg, R. H. J. Am. Chem. Soc. 1974, 96,
5581. (b) Chen, S.-M. L.; Schaub, R. E.; Grudzinskas, C. V. J. Org. Chem.
1978, 43, 3450.
(20) (a) Ichinose, Y.; Oda, H.; Oshima, K.; Utimoto, K. Bull. Chem.
Soc. Jpn. 1987, 60, 3468. (b) Smith, N. D.; Mancuso, J.; Lautens, M. Chem.
ReV. 2000, 100, 3257.
(21) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679.
(23) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (b) Tidwell, T.
T. Synthesis 1990, 857. (c) Tidwell, T. T. Org. React. 1991, 39, 297.
(24) Zhou, W.-S. Pure Appl. Chem. 1986, 58, 817.
(22) Semmelhack, M. F.; Hooley, R. J. Tetrahedron Lett. 2003, 44, 5737.
(25) Go´mez, A. M.; Lo´pez, J. C.; Fraser-Reid, B. Synthesis 1993, 943.
J. Org. Chem, Vol. 71, No. 18, 2006 6945

Asano et al.
SCHEME 6. Synthesis of Tetraene 8, a Key IMDA
Precursor
FIGURE 3. s-cis- and s-trans-Conformations 8A and 8B.
SCHEME 7. Synthesis of Tricyclic Core 6 through an
IMDA Reaction of Tetraene 8
great surprise, the desired IMDA cycloaddition product 27 was
also produced in 30% yield as the single stereoisomer. The
stereostructure of 27 was proven by NOE measurements in the
500 MHz 1H NMR spectrum; the newly formed stereochemistry
at C3, C6, C14, and C15 was fully consistent with that of the
GKK1032s. We also observed that leaving a solution of 26 in
CDCl3 at ambient temperature for 3 days resulted in the
formation of 27 in 76% yield. In addition, expeditious conver-
sion of 26 to 27 was efficiently achieved by refluxing a solution
of 26 in toluene for 3 h.
1.4. Synthesis of the Tricyclic Core 6 Through an IMDA
Reaction of Tetraene 8. Encouraged by the successful results
described above, we next directed our attention to the synthesis
of the tricyclic core 6, which possesses a methyl substituent at
C3 in the A-ring, by Stille coupling11 of vinyl iodide 9 and
vinylstannane 10 followed by IMDA reaction of the resulting
tetaene 8 (Schemes 6 and 7). The requisite vinylstannane 10
was prepared in two steps from the known allyl alcohol 29,27
readily accessible from the commercially available diethyl
methylmalonate 28. Thus, oxidation of 29 with MnO2 followed
by Wittig olefination of the resulting aldehyde 30 with Ph3Pd
CH2 provided vinylstannane 10 in 60% yield for the two steps.
Stille coupling of 9 with 10 under the same conditions used for
the preliminary experiments (cf. 9 + 25 f 26 + 27, Scheme
5) furnished the desired tetraene 8 in 69% yield. Contrary to
the preliminary studies, no cycloaddition products were pro-
duced in this Stille coupling reaction. The difference in reactivity
between tetraenes 8 and 26 must be attributed to the structural
nature inherent in these molecules. Thus, as shown in Figure 3,
in the case of 8, s-trans-conformation 8B might be preferentially
formed rather than s-cis-conformation 8A due to a steric
interaction between C3-Me and C6-H (cf. 8A vs 8B); this
phenomenon is obviously unfavorable for the IMDA reaction.
On the other hand, in the case of 26, there is no such steric
interaction, facilitating the formation of the s-cis-conformation
to produce the cycloadduct 27 even at ambient temperature.
As shown in Scheme 7, conversion of 8 to the targeted
tricyclic core 6 through the key IMDA reaction was successfully
achieved by heating a solution of 8 in toluene in a sealed tube
with a small amount of 2,6-di-tert-butyl-4-methylphenol (BHT)
(0.5 equiv) at 120 °C for 24 h, giving rise to 61% yield of 6 as
the isolated diastereomer. The stereostructure of 6 was confirmed
by NOE experiments, proving that the stereochemistry at C3,
C6, C14, and C15 was fully identical with that of the
GKK1032s. Interestingly, in this IMDA reaction a small amount
(13% yield) of the indene derivative 31 was also generated as
an inseparable mixture of the C14 epimers (ca. 2:1 by 500 MHz
1H NMR); this byproduct 31 would be formed by an ene
reaction28,29 via transition states 8C and 8D as shown in Scheme
8.
2. Synthesis of the Fully Elaborated Tricyclic Core 7.
2.1. Synthetic Plan. Having established the synthetic pathway
to the tricyclic model core 6, we next conducted the synthesis
of the fully elaborated tricyclic core 7 that represents the ABC-
ring system of the GKK1032s (1-3).
Our synthetic plan for the final targeted compound 7 is
outlined in Scheme 9, which is based on the model studies
mentioned above. The targeted molecule 7 would be stereo-
selectively constructed by an IMDA reaction of the tetraene 32
via an endo-transition state 32A (32 f [32A] f 7). The IMDA
precursor 32 should be prepared from methyl acetylene 34 via
Stille coupling of vinyl iodide 33 and vinylstannane 10 in a
manner similar to that described in the model studies. Interme-
(26) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600.
(27) (a) Scarlato, G. R.; DeMattei, J. A.; Chong, L. S.; Ogawa, A. K.;
Lin, M. R.; Armstrong, R. W. J. Org. Chem. 1996, 61, 6139. (b) Baker,
R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
(28) For a review on intermolecular ene reaction, see: Snider, B. B. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, p 1.
(29) An example of the ene reaction during Diels-Alder reaction, see:
Campi, E. M.; Jackson, W. R. Aust. J. Chem. 1998, 42, 471.
6946 J. Org. Chem., Vol. 71, No. 18, 2006

Synthetic Studies toward GKK1032s
TABLE 1. Examinations of Intermolecular Diels-Alder Reaction
between Siloxydienes 13a-d and Enone 14
SCHEME 8. Plausible Pathway to Indene Derivative 31
from Tetraene 8 through an Ene Reaction
entry diene R1 R2
conditionsb
product yield (%)c
1a
2
3
13a
H
H
toluene, 150 °C, 72 h
12a
12b
12c
12d
66
13b Me Me xylene, 190 °C, 72 h
13c
13d
NRd
NRd
NRd
Me
H
H
xylene, 190 °C, 72 h
4
Me xylene, 190 °C, 72 h
a This reaction was already carried out in section 1.2 (cf. Scheme 3).
b All reactions were performed in a sealed tube. c Isolated yield. d NR: no
reaction.
SCHEME 9. Retrosynthetic Analysis for Fully Elaborated
Tricyclic Core 7 (ABC-Ring System of GKK1032S)
13a with 14 proceeded smoothly to form 12a (entry 1); however,
to our chagrin, all attempts to realize the Diels-Alder reactions
between 13b-d with 14 turned out to be fruitless; none of the
desired cycloaddition products 12b-d was obtained, and the
starting materials 13b-d and 14 were recovered unchanged even
under harsh conditions (entries 2-4). We assumed that these
failures were due to the very low reactivity of dienes 13b-d,
which may be attributed to the steric hindrance of the methyl
group(s) present in siloxydienes 13b-d. Consequently, we
decided to elaborate the key intermediate 35 in a step-by-step
manner starting from cyclohexenone 12a; the sequence involved
the regio- and stereoselective methylation at the C9 and C11
positions followed by elimination of the C10 carbonyl function.
As shown in Scheme 10, compound 15 was converted to the
MOM ether 36 in 94% yield by MOM protection of the
secondary hydroxy group. The first methyl group was efficiently
introduced to the C11 position by exposure of 36 to LDA (1.3
equiv) at -78 °C followed by addition of MeI (2.0 equiv),
giving rise to enone 37 in 82% yield with complete stereo-
selectivity. Subsequent Birch reduction of 37 generated the
corresponding lithium enolate, which was then methylated in
situ with MeI (3.0 equiv) to deliver dimethylcyclohexanone 38
in 83% yield as the sole stereoisomer. The stereostructure of
38 was proven by X-ray crystallographic analysis31 of the
transformed cyclohexanol 39a, which was prepared by hydro-
genation of 38 in the presence of a catalytic amount of PtO2
(40-60% yield). The secondary hydoroxy group in 39a was
then eliminated by using the Barton-McCombie protocol.32
Thus, treatment of 39a with NaN(SiMe3)2 (2.0 equiv) in THF
at -78 °C followed by addition of CS2 (3.0 equiv) and MeI
(5.0 equiv) at the same temperature, furnished the corresponding
methyl xanthate. This was allowed to react with (n-Bu)3SnH
(2.3 equiv) in toluene in the presence of a catalytic amount of
AIBN (0.1 equiv) at 110 °C, providing the desired deoxygenated
product 35 in 67% overall yield from 39a. Although we were
able to develop a pathway to 35 from 38, we encountered
diate 34 could be derived from acetal 35 by appropriate
elaboration. We envisioned that the access to 35 could be
achieved by the stereocontrolled introduction of two methyl
groups to the C9 and C11 positions in cyclohexenone 12a, which
was already prepared in section 1.2 (cf. Scheme 3). Alterna-
tively, the intermediate 35 would be accessible more directly
through an intermolecular Diels-Alder reaction12 between
dimethyl substituted siloxydiene 13b and enone 14.
(30) For a synthesis of 13b, see: (a) Myles, D. C.; Bigham, M. H. Org.
Synth. 1992, 70, 231. For a synthesis of 13c, see: (b) Clive, D. L. J.;
Bergstra, R. J. J. Org. Chem. 1991, 56, 4976. For a synthesis of 13d, see:
(c) Burger, M. T.; Still, W. C. J. Org. Chem. 1996, 61, 775.
2.2. Synthesis of the Key Intermediate 35. For a straight-
forward access to the key intermediate 35 possessing the two
methyl groups at C9 and C11 in the C-ring, we initially
investigated the intermolecular Diels-Alder reaction between
(di)methylsiloxydienes 13b-d30 and enone 1414 as shown in
Table 1. As mentioned in section 1.2 above, the reaction of
(31) X-ray ORTEP drawing of 39a and detailed crystallographic data
are provided in Supporting Information.
(32) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574. (b) Izuhara, T.; Katoh, T. Org. Lett. 2001, 3, 1653. (c) Inoue,
M.; Yokota, W.; Murugesh, M. G.; Izuhara, T.; Katoh, T. Angew. Chem.,
Int. Ed. 2004, 43, 4207. (d) Katoh, T.; Izuhara, T.; Yokota, W.; Inoue, M.;
Watanabe, K.; Nobeyama, A.; Suzuki, T. Tetrahedron 2006, 62, 1590.
J. Org. Chem, Vol. 71, No. 18, 2006 6947

Asano et al.
SCHEME 11. Synthesis of Key IMDA Precursor 32
SCHEME 10. Synthesis of Intermediate 35
problems with a large-scale operation in the hydrogenation step
(38 f 39a); the yields of 39a were reduced to ∼40%. Several
attempts to realize reduction of 38 using other reducing agents
such as NaBH4, LiAlH4, and DIBALH resulted in failure;
considerable epimerization at C9 and/or C11 was observed in
the reduction product 39a. Eventually, to our delight, we found
that Birch reduction was quite effective for this purpose; the
reduction product 39b was obtained in 80% yield without any
epimerization at C9 and/or C11. Compound 39b was efficiently
converted to the desired cyclohexane derivative 35 in 90%
overall yield via methyl xanthate 40 similarly employing the
Barton-McCombie protocol.32
2.3. Synthesis of the Key IMDA Precursor 32. With the
requisite dimethylcyclohexane 35 in hand, we next focused our
attention on elaboration of the key IMDA precursor 32 as shown
in Scheme 11. Acidic hydrolysis of methylacetal 35 followed
by silylation of an equilibrium mixture of the resulting δ-lactol
41 and methyl ketone 42 (2:1 in CDCl3 by 500 MHz 1H NMR)
afforded TBDMS ether 43 in 82% yield for the two steps.
Compound 43 was further converted to methyl acetylene 45 in
73% overall yield through a two-step sequence involving vinyl
triflate formation16 [KN(SiMe3)2 (2.1 equiv), PhNTf2 (2.6 equiv),
THF, -78 °C] and base-induced elimination/methylation17
[LDA (3.6 equiv), THF, -78 °C; MeI (3.3 equiv), -78 f 0
°C] of the formed vinyl triflate 44. Hydrostannylation of 45
was next examined by employing Semmelhack’s conditions22
identical to those used on 11 (cf. 11 f 21, Scheme 4); however,
in this case the expected vinyl stannane was not obtained, and
the starting material 45 was recovered unchanged. We reasoned
that this failure arose from the presence of a bulky TBDMS
protecting group within 45 that would interrupt the reaction.
After several trials, the desired hydrostannylation was success-
fully realized by exchanging the TBDMS group with a less
bulky acetyl group. Thus, deprotection of the TBDMS group
in 45 with tetra-n-butylammonium fluoride (TBAF) and sub-
sequent acetylation of the liberated alcohol 46 provided the
corresponding acetate 34 in 88% overall yield. Hydrostannyl-
ation of 34 under Semmelhack’s conditions,22 as we expected,
proceeded satisfactorily to afford the requisite vinyl stannane
47 in 57% yield (71% yield based on recovery of 34).
Subsequent treatment of 47 with I2 (2.0 equiv) furnished the
desired vinyl iodide 48 in 84% yield.
In the next stage, we further investigated the installation of
the dienophile and diene moieties required for the key IMDA
reaction. Toward this end, alkali hydrolysis of the acetyl group
in 48 followed by Swern oxidation23 delivered aldehyde 50 in
89% overall yield. Initial attempts to realize Wittig reaction of
50 with Ph3PdCH2CO2Me met with failure; however, Horner-
Emmons reaction33 using (MeO)2P(O)CH2CO2Me provided the
desired R,â-unsaturated ester 33 in 63% yield. Finally, Stille
coupling of 33 with vinyl stannane 10 was carried out under
(33) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
6948 J. Org. Chem., Vol. 71, No. 18, 2006

Synthetic Studies toward GKK1032s
TABLE 2. Screening of Lewis Acids for IMDA Reaction of
Tetraene 32
SCHEME 12. Synthesis of Fully Elaborated Tricyclic Core 7
via IMDA Reaction of Tetraene 32
yield (%)a
51 52
76
traceb
entry
1
conditions
Et2AlCl (0.87 M in hexane), toluene,
-40 °C, 2 h
LiClO4 (1.8 M in Et2O), Et2O, 0 °C f rt
ZnCl2 (1.0 M in Et2O), CH2Cl2, 0 °C f rt
2
3
decomp
decomp
a Isolated yield. b A trace amount (<2%) of 52 could be detected in the
1
500 MHz H NMR spectrum of the crude reaction mixture.
suppressed at rather low temperatures. After several experiments,
we were pleased to find that the desired IMDA reaction
proceeded efficiently by the use of Et2AlCl (entry 1). Thus,
treatment of 32 with Et2AlCl (2.0 equiv) in toluene at -40 °C
for 2 h provided 76% yield of the desired IMDA product 51
along with a trace amount (<2% yield) of the ene reaction
product 52. When LiClO4 or ZnCl2 was used as a Lewis acid,
the requisite 51 was not formed and only unidentified decom-
position products were generated in the reaction mixture (entries
2 and 3).
The remarkable stereochemical outcome observed in the
IMDA reactions (cf. 8 f 6, Scheme 7; 32 f 51, Scheme 12
and Table 2) can be rationalized as follows. With respect to the
endo/exo- and π-facial selectivity, as depicted in Scheme 13,
four possible transition states such as 32A (endo-TS1), 32C
(endo-TS2), 32D (exo-TS1), and 32E (exo-TS2), are considered.
Among them, the two endo-TSs (32A and 32C) are more
favorable than the two exo-TSs (32D and 32E) as a result of
the so-called secondary orbital interaction between the diene
and dienophile moieties. Comparing the two endo-TSs (32A
and 32C), the former is favored because the latter suffers a
severe steric repulsion (A1,3 strain) between the C5 methyl group
and C7-C8 carbon bond in the cyclohexane ring. As a result,
the IMDA reaction must have proceeded exclusively through
an endo-TS1 such as 32A, leading to the predominant formation
of the desired decahydrofluorene 51 with complete stereo-
selectivity.
Corey’s improved conditions,26 which furnished the requisite
tetraene 32, a key IMDA precursor, in 75% yield.
2.4. Synthesis of the Decahydrofluorene 7, a Fully Elabo-
rated Tricyclic Core of the GKK1032s, through an IMDA
Reaction of Tetraene 32. Having obtained the key IMDA
precursor 32 in an efficient way, the stage was now set for the
crucial IMDA reaction of 32 to access the final targeted
molecule 7, a fully elaborated tricyclic core (ABC-ring) of the
GKK1032s. As shown in Scheme 12, the key IMDA reaction
of 32 was carried out under the same conditions (toluene, BHT,
120 °C, 24 h) employed in section 1.4. The desired decahy-
drofluorene 51 was obtained in 46% yield as the sole IMDA
product along with a 20% yield of the undesired indene
derivative 52 that was presumably generated through an ene
reaction via a transition state such as 32B. The stereostructures
of both 51 and 52 were confirmed by NOESY experiments,
respectively, as depicted in Figure 4; the stereochemistry within
51 was again fully identical with that of GKK1032s (1-3).
Deprotection of the MOM group in 51 under conventional
conditions furnished the final target 7 in 83% yield.
We further investigated Lewis acid mediated IMDA reaction
of tetraene 32, as shown in Table 2, in the hope that the
formation of the undesired ene reaction product 52 would be
Conclusion
We have accomplished the enantioselective synthesis of the
fully elaborated tricyclic decahydrofluorene core 7 (ABC-ring
system) of GKK1032s, novel antibiotic antitumor agents, for
the first time. A strategic IMDA reaction of tetraene 32 was
employed to effectively build up the desired ABC-ring system
while controlling the stereogenic centers at C3, C6, C14, and
C15 (32 f 51, Scheme 12 and Table 2). Access to the substrate
FIGURE 4. Selected NOESY Correlation of Compounds 51 and 52.
J. Org. Chem, Vol. 71, No. 18, 2006 6949

Asano et al.
SCHEME 13. Four Possible endo- and exo-Transition States (TSs) in the IMDA Reaction of Tetraene 32
afforded a residue, which was purified by column chromatography
(hexane-ethyl acetate, 30:1 f 4:1) to give 26 (13.2 mg, 38%)
and 27 (10.4 mg, 30%).
for the IMDA reaction involved the following crucial steps: (i)
the intermolecular Diels-Alder reaction of siloxydiene 13a and
enantiomerically pure enone 14 to form the appropriately
functionalized C-ring portion 12a (cf. 13a + 14 f 12a, Scheme
3), (ii) the efficient conversion of methyl ketone 43 to vinyl
iodide 48 via sequential vinyl triflate formation, base-induced
elimination/methylation, and Pd-catalyzed hydrostannylation/
iodination (cf. Scheme 11), and (iii) CuCl-promoted Stille
coupling of vinyl iodide 33 and vinylstannane 10 to install the
requisite triene side chain (33 + 10 f 32, Scheme 11). On the
basis of the present research, total synthesis of GKK1032s and
related natural products is currently under investigation in our
laboratories.
Compound 26: pale yellow oil; [R]20 +29.7 (c 0.44, CHCl3);
D
IR (neat) 650, 731, 779, 874, 906, 984, 1001, 1097, 1165, 1194,
1240, 1275, 1435, 1624, 1655, 1705, 1720, 2910, 2933, 3465 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.23-1.44 (m, 2H), 1.30 (s, 3H),
1.45-1.50 (m, 1H), 1.96 (s, 3H), 1.70-2.27 (m, 6H), 2.31 (dt, J
) 12.4, 2.7 Hz, 1H), 2.64-2.74 (m, 2H), 2.82-2.90 (m, 2H), 3.73
(br s, 3H), 4.46-4.55 (m, 1H), 5.03-5.09 (m, 1H), 5.21 (dd, J )
1.5, 16.8 Hz, 1H), 5.46 (br s, 1H), 6.00 (dd, J ) 1.9, 15.6 Hz, 1H),
6.15-6.21 (m, 2H), 6.30-6.43 (m, 1H), 6.90 (dd, J ) 4.3, 15.6
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.3, 14.0, 21.3, 25.9,
26.0, 26.3, 32.4, 33.6, 34.5, 39.7, 44.8, 50.1, 51.6, 71.4, 116.4,
119.7, 127.1, 134.5, 140.0, 143.4, 151.1, 166.7; HREIMS (m/z)
calcd for C22H32O3S2 (M+), 408.1793, found 408.1793.
Experimental Section
Procedure for Stille Coupling of Vinyl Iodide 9 with Vinyl-
stannane 25 and Subsequent IMDA Reaction: (1′R,2′R)-2′-
[(1R,2E)-1-Hydroxy-3-methoxycarbonyl-2-propenyl]-1′-[(1E,3E)-
2-methylhexa-1,3,5-trienyl]-1′-methyl-spiro[1,3-dithiane-2,4′-
cyclohexane] (26) and (1′S,2′S,4a′S,4b′S,8a′R,9′R,9a′S)-4′,4b′-
Dimethyl-9′-hydroxy-1′-methoxycarbonyl-2′-vinyl-spiro[1,3-
dithinane-2,7′-2,4a,4b,5,6,7,8,8a,9,9a-decahydro-1H-fluorene] (27).
Tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 17 µmol),
copper(I) chloride (17.0 mg, 0.17 mmol), and lithium chloride (7.4
mg, 0.17 mmol) were added successively to a stirred solution of
vinyl iodide 9 (41.0 mg, 85 µmol) and vinylstannane 25 (58.5 mg,
0.17 mmol) in a mixture of dry DMF (3.0 mL) and dry THF (3.0
mL) at room temperature. After 13 h, the reaction mixture was
diluted with ethyl acetate (60 mL). The organic layer was washed
with saturated aqueous NaHCO3 (2 × 20 mL) and brine (2 × 20
mL), then dried over MgSO4. Concentration of the solvent in vacuo
Compound 27: colorless prisms (recrystallization from hexane-
Et2O); mp 56-58 °C; [R]20D +90.8 (c 0.15, CHCl3); IR (neat) 731,
783, 802, 903, 1043, 1159, 1211, 1238, 1333, 1373, 1435, 1734,
1
2933, 3483 cm-1; H NMR (500 MHz, CDCl3) δ 0.78 (s, 3H),
1.75 (s, 3H), 1.70-1.80 (m, 2H), 1.80-1.85 (m, 2H), 1.90-2.10
(m, 3H), 2.01-2.10 (m, 2H), 2.10-2.18 (m, 1H), 2.23 (dt, J )
8.1, 11.8 Hz, 1H), 2.56 (dt, J ) 13.3, 2.3 Hz, 1H), 2.69 (ddd, J )
3.1, 6.9, 14.3 Hz, 1H), 2.78-2.89 (m, 2H), 2.94 (dd, J ) 6.6, 11.8
Hz, 1H), 3.02 (ddd, J ) 3.1, 9.8, 14.3 Hz, 1H), 3.20-3.29 (m,
1H), 3.67 (s, 3H), 4.08 (dt, J ) 7.9, 3.6 Hz, 1H), 5.00-5.07 (m,
2H), 5.12 (t, J ) 1.5 Hz, 1H), 5.67 (ddd, J ) 8.3, 10.5, 16.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 13.3, 21.3, 25.9, 26.1, 26.4,
34.6, 35.1, 35.4, 40.8, 41.2, 43.9, 45.7, 50.4, 51.5, 54.7, 54.8, 72.5,
117.0, 125.0, 137.4, 137.8, 175.5; HREIMS (m/z) calcd for
C22H32O3S2 (M+), 408.1793, found 408.1787.
6950 J. Org. Chem., Vol. 71, No. 18, 2006

Synthetic Studies toward GKK1032s
A solution of 26 (8.0 mg, 20 µmol) in CDCl3 (0.5 mL) was
allowed to stand at room temperature for 3 days to give 27 (6.1
mg, 76%) after purification by column chromatography (hexane-
18 µmol) in dry toluene (2.0 mL) in the presence of 2,6-di-tert-
butyl-4-methylphenol (BHT) (2.0 mg, 9.0 µmol) was heated at 120
°C in a sealed tube for 12 h. After cooling, the mixture was
concentrated in Vacuo to afford a residue, which was purified by
column chromatography (hexane-ethyl acetate, 40:1 f 8:1) to give
51 (3.2 mg, 46%) and 52 (1.4 mg, 20%).
1
ethyl acetate, 10:1 f 4:1). The H NMR spectrum of this sample
was identical with that recorded for compound 27.
A solution of 26 (10.2 mg, 25 µmol) in toluene (1.0 mL) was
heated at reflux for 3 h to provide 27 (8.2 mg, 80%) after
purification by column chromatography (hexane-ethyl acetate, 10:1
Compound 51: colorless oil; [R]20 +114.2 (c 0.32, CHCl3);
D
IR (neat) 667, 756, 862, 920, 999, 1036, 1045, 1068, 1099, 1157,
1
1211, 1230, 1255, 1325, 1375, 1435, 1454, 1732, 2925, 2949 cm-1
;
f 4:1). The H NMR spectrum of this sample was identical with
1H NMR (500 MHz, CDCl3) δ 0.62 (q, J ) 12.1 Hz, 1H), 0.75 (s,
3H), 0.88 (d, J ) 6.4 Hz, 3H), 0.93 (t, J ) 12.1 Hz, 1H), 0.97 (d,
J ) 6.6 Hz, 3H), 1.14 (t, J ) 6.0 Hz, 1H), 1.26 (s, 3H), 1.55-1.68
(m, 1H), 1.68-1.80 (m, 1H), 1.75-1.88 (m, 1H), 1.76 (s, 3H),
1.92 (dd, J ) 4.1, 12.1 Hz, 1H), 1.98 (d, J ) 12.0 Hz, 1H), 2.36
(dt, J ) 7.2, 12.0 Hz, 1H), 2.62 (d, J ) 12.0 Hz, 1H), 3.29 (s, 3H),
3.65 (s, 3H), 3.82 (dd, J ) 6.0, 7.2 Hz, 1H), 4.44 (d, J ) 5.9 Hz,
1H), 4.54 (d, J ) 5.9 Hz, 1H), 4.88 (s, 1H), 4.95 (dd, J ) 1.6, 17.2
Hz, 1H), 5.02 (dd, J ) 1.6, 10.4 Hz, 1H), 5.67 (dd, J ) 10.4, 17.2
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 15.7, 20.6, 21.9, 22.8,
26.7, 28.1, 29.5, 42.9, 43.3, 43.4, 46.3, 48.5, 50.9, 51.9, 53.5, 56.0,
66.4, 80.0, 97.8, 114.0, 131.6, 135.3, 143.3, 174.0; HREIMS (m/z)
calcd for C24H38O4 (M+), 390.2770, found 390.2770.
that recorded for 27.
Procedure for IMDA Reaction of Tetraene 26: (1′S,2′S,4a′S,
4b′S,8a′R,9′R,9a′S)-9′-Hydroxy-1′-methoxycarbonyl-2′,4′,4b′-tri-
methyl-2′-vinyl-spiro[1,3-dithiane-2,7′-2′,4a′,4b′,5′,6′,7′,8′,8a′,9′,
9a′-decahydro-1H-fluorene] (6) and (1′R,2′RS,3′S,3a′S,7a′R)-1′-
Hydroxy-2′-(2-methoxycarbonyl)methyl-3a′-methyl-3′-[(E)-4-
methylhexa-1,3,5-trien-2-yl]-spiro[1,3-dithiane-2,6′-octahydro-
1H-indene (31). A solution of tetraene 8 (14 mg, 23 µmol) in dry
toluene (3.0 mL) in the presence of 2,6-di-tert-butyl-4-methylphenol
(BHT) (2.5 mg, 12 µmol) was heated at 120 °C in a sealed tube
for 24 h. After cooling, the mixture was concentrated in vacuo to
give a residue, which was purified by column chromatography
(hexane-ethyl acetate, 20:1 f 5:1) to furnish 6 (8.5 mg, 61%)
and 31 (1.8 mg, 13%).
Compound 52: colorless oil; [R]20 +43.2 (c 0.14, CHCl3); IR
D
Compound 6: colorless needles (recrystallization from hexane-
(neat) 733, 877, 899, 1036, 1105, 1138, 1157, 1167, 1192, 1246,
Et2O); mp 163-166 °C; [R]20 +65.7 (c 0.85, CHCl3); IR (neat)
1
1259, 1383, 1435, 1454, 1736, 2908, 2922, 2949 cm-1; H NMR
D
607, 621, 688, 783, 804, 852, 908, 995, 1047, 1159, 1223, 1259,
(500 MHz, CDCl3) δ 0.50-0.64 (m, 1H), 0.68-0.78 (m, 1H), 0.85
(d, J ) 6.1 Hz, 3H), 0.89 (s, 3H), 0.94 (d, J ) 6.2 Hz, 3H), 1.03
(t, J ) 10.0 Hz, 1H), 1.60-1.78 (m, 4H), 1.87 (s, 3H), 2.55 (d, J
) 9.6 Hz, 1H), 2.55-2.67 (m, 2H), 2.71-2.80 (m, 1H), 3.35 (s,
3H), 3.53 (dd, J ) 4.4, 10.0 Hz, 1H), 3.56 (s, 3H), 4.61 (d, J ) 6.9
Hz, 1H), 4.71 (d, J ) 6.9 Hz, 1H), 5.04 (d, J ) 10.9 Hz, 1H), 5.04
(s, 1H), 5.17 (d, J ) 17.3 Hz, 1H), 5.26 (s, 1H), 5.83 (s, 1H), 6.38
(dd, J ) 10.9, 17.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.3,
16.7, 20.5, 22.6, 27.6, 30.1, 37.8, 43.4, 44.4, 45.8, 47.7, 51.4, 56.1,
57.8, 60.9, 88.8, 96.6, 112.6, 117.9, 134.8, 135.2, 142.1, 142.8,
173.6; HREIMS (m/z) calcd for C24H38O4 (M+), 390.2770, found
390.2761.
1
1331, 1375, 1435, 1716, 2875, 2931, 3500 cm-1; H NMR (500
MHz, CDCl3) δ 0.79 (s, 3H), 1.28 (s, 3H), 1.42-1.53 (m, 1H),
1.69-1.83 (m, 3H), 1.75 (s, 3H), 1.89-2.00 (m, 3H), 2.00-2.10
(m, 2H), 2.11-2.18 (m, 1H), 2.33 (dt, J ) 8.3, 12.0 Hz, 1H), 2.52
(dt, J ) 13.4, 2.2 Hz, 1H), 2.61 (d, J ) 12.0 Hz, 1H), 2.65-2.75
(m, 1H), 2.77-2.87 (m, 2H), 2.95-3.03 (m, 1H), 3.68 (s, 3H),
3.93-3.99 (m, 1H), 4.85 (s, 1H), 4.98 (dd, J ) 1.5, 17.2 Hz, 1H),
5.05 (dd, J ) 1.5, 10.4 Hz, 1H), 5.69 (dd, J ) 10.4, 17.2 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 13.3, 21.2, 25.9, 26.1, 26.4, 26.7,
34.5, 35.0, 35.3, 41.3, 42.4, 44.0, 50.3, 51.3, 52.3, 54.4, 55.5, 72.7,
114.5, 131.3, 135.4, 142.8, 174.8; HREIMS (m/z) calcd for
C23H34O3S2 (M+), 422.1949, found 422.1950.
(b) Under Lewis Acid Conditions. Diethylaluminum chloride
in hexane (0.87 M solution, 52 mL, 46 µmol) was added slowly to
a stirred solution of 32 (8.9 mg, 23 µmol) in dry toluene (2.5 mL)
at -40 °C under argon. After 2 h, the reaction was quenched with
15% aqueous Rochelle salt (8 mL) at -40 °C, and the resulting
mixture was extracted with ethyl acetate (3 × 10 mL). The
combined extracts were washed with 3% aqueous HCl (2 × 6 mL),
saturated aqueous NaHCO3 (2 × 6 mL), and brine (2 × 6 mL),
andthen dried over MgSO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(hexane-ethyl acetate, 30:1 f 10:1) to give 51 (7.0 mg, 76%) as
Compound 31: pale yellow oil; [R]20 +25.6 (c 0.18, CHCl3);
D
IR (neat) 667, 752, 901, 989, 1174, 1205, 1236, 1255, 1277, 1331,
1340, 1379, 1415, 1437, 1601, 1622, 1720, 2925, 2949, 3948 cm-1
;
1H NMR (500 MHz, CDCl3) δ 0.93 (s, 1/3H), 0.93 (s, 2/3 × 3H),
1.55-1.70 (m, 1H), 1.70-1.90 (m, 3H), 1.87 (s, 1/3H), 1.91 (s,
2/3H), 1.88-1.99 (m, 2H), 1.97-2.10 (m, 3H), 2.35-2.48 (m, 2H),
2.56-2.73 (m, 3H), 2.74-2.83 (m, 1H), 2.85-2.95 (m, 1H), 3.01-
3.10 (m, 1H), 3.55 (d, J ) 2.1 Hz, 1/3H), 3.58 (d, J ) 2.0 Hz,
2/3H), 3.57-3.67 (m, 1H), 3.68 (s, 3H), 5.02 (s, 1/3H), 5.05 (s,
2/3H), 5.08 (d, J ) 10.7 Hz, 2/3H), 5.12 (d, J ) 10.9 Hz, 1/3H),
5.18 (s, 1/3H), 5.21 (s, 2/3H), 5.21 (d, J ) 17.4 Hz, 2/3H), 5.28
(d, J ) 17.4 Hz, 1/3H), 5.76 (br s, 1/3H), 5.80 (br s, 2/3H), 6.37
(dd, J ) 10.7, 17.4 Hz, 2/3 × 1H), 6.92 (dd, J ) 10.9, 17.4 Hz,
1/3H); 13C NMR (125 MHz, CDCl3) δ 13.4 (2/3C), 13.6 (1/3C),
16.1 (2/3C), 16.2 (1/3C), 17.5 (1/3C), 20.3 (2/3C), 25.9 (2/3C),
26.0 (2/3C), 26.4 (2/3C), 26.9 (1/3C), 27.9 (1/3C), 29.7 (1/3C),
34.3, 34.7, 37.3 (2/3C), 37.4 (1/3C), 42.8, 45.4 (2/3C), 45.5 (1/
3C), 50.1, 50.5 (1/3C), 50.6 (2/3C), 51.9, 57.3 (1/3C), 57.5 (2/
3C), 80.0, 113.2 (2/3C), 114.8 (1/3C), 118.1 (2/3C), 119.1 (1/3C),
133.2 (1/3C), 134.7 (2/3C), 135.1 (1/3C), 135.4 (2/3C), 141.7,
142.4, 175.6; HREIMS (m/z) calcd for C23H34O3S2 (M+), 422.1949,
found 422.1951.
a colorless oil; [R]20 +114.8 (c 0.70, CHCl3). The 1H NMR
D
spectrum of this sample were identical with those described in (a).
Acknowledgment. We are grateful to Dr. T. Mori (Tokyo
Institute of Technology) for his assistance in MS spectra
measurements. This work was supported in part by Grants-in-
Aid for Scientific Research on Priority Areas (no. 17035073)
and for High Technology Research Program from the Ministry
of Education, Culture, Sports, Science and Technology of Japan.
Supporting Information Available: Experimental procedures
and spectroscopic and analytical data for all other new compounds.
Copies of 1H and 13C NMR spectra for all new compounds. X-ray
crystallographic information for 39a in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
Procedure for IMDA Reaction of Tetraene 32: (1R,2S,4aS,
4bS,6R,8S,8aR,9R,9aS)-9- Methoxymethoxy-2,4,4b,6,8-penta-
methyl-2-vinyl-2,4a,4b,5,6,7,8,8a,9,9a-decahydro-1H-fluorene-1-
carboxylic acid methyl ester (51) and [(1R,2S,3S,3aS,5R,7S,
7aR)-1-Methoxymethoxy-3a,5,7- trimethyl-3-[(E)-4-methylhexa-
1,3,5-trien-2-yl]octahydro-1H-inden-2-yl]acetic acid methyl ester
(52). (a) Under Thermal Conditions. A solution of 32 (7.0 mg,
JO0610208
J. Org. Chem, Vol. 71, No. 18, 2006 6951