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Org. Synth. 2012, 89, 267-273
DOI: 10.15227/orgsyn.089.0267
Discussion Addendum for: [3 + 4] Annulation Using a [ß-(Trimethylsilyl) acryloyl]silane and the Lithium Enolate of an a,ß-Unsaturated Methyl Ketone: (1R,6S,7S)-4-(tert-Butyldimethylsiloxy)-6-(trimethylsilyl)bicyclo [5.4.0]undec-4-en-2-one
Submitted by Kei Takeda* and Michiko Sasaki1.
Original Article: Org. Synth. 1999, 76, 199
Discussion
Brook rearrangement-mediated [3 + 4] annulation has evolved as a unique methodology for the construction of not only seven-membered carbocycles but also eight-membered carbo- and oxygen-heterocycles and has been applied to the synthesis of natural products after clarification2 of the precise reaction mechanism accounting for the stereospecificity.
Synthesis of the Tricyclic Skeleton of Allocyathin B2
The synthetic utility of annulation was first demonstrated by the synthesis of the unusual 5-6-7 tricyclic ring skeleton of allocyathin B2, a compound that has been shown to have potent nerve growth factor synthesis-stimulating activity and to be a κ opioid receptor agonist (Scheme 1). The key [3 + 4] annulation proceeded smoothly even with a relatively complex four-carbon unit 1 to afford 2 as a single diastereomer in 50% yield, which was transformed to 3.3
Scheme 1 Synthesis of the tricyclic skeleton of allocyathin B2.
Scheme 1 Synthesis of the tricyclic skeleton of allocyathin B2.
Construction of a Tricyclo[5.3.0.01,4]decenone Ring System
The use of acryloylsilanes 4 with a leaving group such as a halogen atom at the β-position as a three-carbon unit in the [3 + 4] annulation afforded tricyclic ketone derivatives 7a,b in yields dependent upon the β-substituent of 4, in addition to the [3 + 4] annulation-debromosilylation products 9a,b (Scheme 2).4 Small structural changes in the four-carbon unit significantly affect the product distribution. Thus, whereas cyclopentyl methyl ketone enolate gave 7a in almost all cases, 9b was formed as a byproduct in the case of the corresponding cyclohexyl derivative. Mechanistic studies including low-temperature quenching experiments suggested that 7a,b can be formed via an SN'-like intramolecular attack of the enolate at the C-4 position in the intermediate 6a,b, and 9a,b can be formed via tricyclic intermediate 8a,b.
Scheme 2 Construction of a tricyclo[5.3.0.01,4]decenone ring system.
Scheme 2 Construction of a tricyclo[5.3.0.0,]decenone ring system.
BF3·Et2O-Mediated Intramolecular Allylstannane-Ketone Cyclizations
[3 + 4] annulation using a combination of (Z)-(β-(tributylstannnyl)acryloyl)silanes 10 and alkenyl methyl ketone enolate 11 proceeded in the same manner to give cycloheptenone derivative 12, which upon treatment with BF3·Et2O, afforded bicyclo[4.1.0]heptenols 13, an intramolecular addition product of the allylstannane system to the carbonyl group (Scheme 3).5
Scheme 3 BF3·Et2O-Mediated intramolecular allylstannane-ketone cyclizations.
Scheme 3 BF3·Et2O-Mediated intramolecular allylstannane-ketone cyclizations.
Stereoselective Construction of Eight-Membered Carbocycles and Oxygen-Heterocycles
The use of the enolate 15 (X = CH2) derived from 2-cycloheptenone as the four-carbon unit in [3 + 4] annulation instead of the enolates of alkenyl methyl ketones produced bicyclo[3.3.2]decenone derivatives 16.The two-atom internal tether in these products could be oxidatively cleaved after conversion to α-hydroxy ketone 17 to give the cis-3,4,8-trisubstituted cyclooctenone enol silyl ethers 18 stereoselectively (Scheme 4).6 This methodology has also been successfully applied to the construction of oxygen eight-membered heterocycles using enolates of 6-oxacyclohept-2-en-1-one 15 (X = O), affording eight-membered oxygen heterocycles 18 (X = O) possessing functionality that can easily be manipulated to generate other functionalized eight-membered ring products.7
Scheme 4 Stereoselective construction of eight-membered carbocycles and oxygen-heterocycles.
Scheme 4 Stereoselective construction of eight-membered carbocycles and oxygen-heterocycles.
Formal Total Syntheses of (+)-Prelaureatin and (+)-Laurallene
The versatility of the annulation has been highlighted through the formal total synthesis of (+)-prelaureatin, a biogenetic precursor of several members of the laurenan structural subclass (Scheme 5).8 The annulation of 19 and sodium enolate 20 proceeded in a highly diastereoselective manner to afford exclusively 21 in 80% yield. The observed excellent selectivity could be explained in terms of the approach of the acryloylsilane from the same side as the C-7 substituent in 20 that is sterically less hindered because of pseudo equatorial disposition of the substituent on the seven-membered ring. The bicyclic derivative 21 was transformed into Crimmins' intermediate 229 after oxidative cleavage of the two-carbon tether.
Scheme 5 Formal total syntheses of (+)-prelaureatin.
Scheme 5 Formal total syntheses of (+)-prelaureatin.
Stereocontrolled Construction of Seven- and Eight-Membered Carbocycles Using a Combination of Brook Rearrangement-Mediated [3 + 4] Annulation and Epoxysilane Rearrangement
The [3 + 4] annulation has also been expanded to include the construction of densely functionalized seven- and eight-membered carbocycles by combining it with an epoxysilane rearrangement,10 which features a further extension of a stereocontrolled anion relay.11 Reactions of δ-silyl-γ,δ-epoxy-α,β-unsaturated acylsilane 23 with alkenyl methyl ketone enolate 24 afforded highly functionalized cycloheptenone derivative 28 via a tandem process that involves Brook rearrangement followed by the resulting carbanion-induced ring-opening of the epoxide (2526), a second Brook rearrangement, the formation of divinylcyclopropanediolate derivative 27 via internal carbonyl attack by the resulting carbanion, and an anionic oxy-Cope rearrangement (Scheme 6). The reactions using an alternative combination of three and four carbon units (29 + 30), in which an epoxysilane moiety was incorporated in the four-carbon unit, also give satisfactory results, via 1,4-O-to-O silyl migration (3132). Use of enantioenriched acylsilane 33 and 2-cycloheptenone enolate 34 gave a moderate level (62% ee) of asymmetric induction in the bicyclic ketone 35.
Scheme 6 Stereocontrolled construction of seven- and eight-membered carbocycles using a combination of Brook rearrangement-mediated [3 + 4] annulation and epoxysilane rearrangement.
Scheme 6 Stereocontrolled construction of seven- and eight-membered carbocycles using a combination of Brook rearrangement-mediated [3 + 4] annulation and epoxysilane rearrangement.

References and Notes
  1. Department of Synthetic Organic Chemistry, Graduate School of Medical Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
  2. Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.
  3. Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903-1905.
  4. Takeda, K.; Ohtani, Y. Org. Lett. 1999, 1, 677-679.
  5. Takeda, K.; Nakajima, A.; Yoshii, E. Synlett 1996, 753-754.
  6. Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031-1033.
  7. Sawada, Y.; Sasaki, S.; Takeda, K. Org. Lett. 2004, 6, 2277-2279.
  8. (a) Sasaki, M.; Hashimoto, A.; Tanaka, K.; Kawahata, M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803-1806. (b) Sasaki, M.; Oyamada, K.; Takeda, K. J. Org. Chem. 2010, 75, 3941-3943.
  9. Crimmins, M. T.; Elie, A. T. J. Am. Chem. Soc.2000, 122, 5473-5476.
  10. (a) Takeda, K.; Kawanishi, E.; Sasaki, M.; Takahashi, Y.; Yamaguchi, K. Org. Lett. 2002, 4, 1511-1514. (b) Sasaki, M.; Kawanishi, E.; Nakai, Y.; Matsumoto, T.; Yamaguchi, K.; Takeda, K. J. Org. Chem. 2003, 68, 9330-9339. (c) Sasaki, M.; Ikemoto, H.; Takeda, K. Heterocycles 2009, 78, 2919-2941.
  11. Nakai, Y.; Kawahata, M.; Yamaguchi, K.; Takeda, K. J. Org. Chem. 2007, 72, 1379-1387.

Kei Takeda is professor of organic chemistry at Hiroshima University. He was born in 1952 and received both his B.S. degree (1975) and M.S. degree (1977) from Toyama University (with Eiichi Yoshii) and his Ph.D. degree (1980) from the University of Tokyo (with Toshihiko Okamoto). In 1980, he joined the faculty at Toyama Medical and Pharmaceutical University (Prof. Yoshii's group). After working at MIT with Professor Rick L. Danheiser (1988-1989), he was promoted to Lecturer (1989) and then to Associate Professor (1996). He became a professor of Hiroshima University in 2000. His research interests are in the invention of new synthetic reactions and chiral carbanion chemistry. He was the recipient of the Sato Memorial Award (1998) and the 41st Senji Miyata Foundation Award.
Michiko Sasaki is an assistant professor of organic chemistry at Hiroshima University. She obtained her B.S. degree (2002), M.S. degree (2003), and Ph.D. degree (2006) from Hiroshima University under the direction of Professor Kei Takeda and then remained in Takeda's group as an assistant professor. She spent one year (2010-2011) at MIT as a JSPS fellow (Excellent Young Researcher Overseas Visit Program) with Professor Rick L. Danheiser. Her current research interests lie in the area of development of new synthetic reactions. She was the recipient of the Chugoku-Shikoku Branch of Pharmaceutical Society of Japan Award for Young Scientists (2007).