Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems

K. C. Nicolaou, C. K. Hwang, M. E. Duggan, D. A. Nugiel, Y. Abe, K. Bal Reddy, S. A. DeFrees, D. R. Reddy, R. A. Awartani, S. R. Conley, F. P J T Rutjes, E. A. Theodorakis

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

The first generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8) [IJK]. The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHIJK] (6 → 5). The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 → 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 → 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 → 99) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.

Original languageEnglish
Pages (from-to)10227-10238
Number of pages12
JournalJournal of the American Chemical Society
Volume117
Issue number41
DOIs
Publication statusPublished - 1995 Oct 18
Externally publishedYes

Fingerprint

Cyclization
Ketones
Skeleton
Oxepins
Epoxy Compounds
Silicon
Molecules
brevetoxin
brevetoxin B

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Nicolaou, K. C., Hwang, C. K., Duggan, M. E., Nugiel, D. A., Abe, Y., Bal Reddy, K., ... Theodorakis, E. A. (1995). Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems. Journal of the American Chemical Society, 117(41), 10227-10238. https://doi.org/10.1021/ja00146a008

Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems. / Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.; Bal Reddy, K.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Conley, S. R.; Rutjes, F. P J T; Theodorakis, E. A.

In: Journal of the American Chemical Society, Vol. 117, No. 41, 18.10.1995, p. 10227-10238.

Research output: Contribution to journalArticle

Nicolaou, KC, Hwang, CK, Duggan, ME, Nugiel, DA, Abe, Y, Bal Reddy, K, DeFrees, SA, Reddy, DR, Awartani, RA, Conley, SR, Rutjes, FPJT & Theodorakis, EA 1995, 'Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems', Journal of the American Chemical Society, vol. 117, no. 41, pp. 10227-10238. https://doi.org/10.1021/ja00146a008
Nicolaou, K. C. ; Hwang, C. K. ; Duggan, M. E. ; Nugiel, D. A. ; Abe, Y. ; Bal Reddy, K. ; DeFrees, S. A. ; Reddy, D. R. ; Awartani, R. A. ; Conley, S. R. ; Rutjes, F. P J T ; Theodorakis, E. A. / Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems. In: Journal of the American Chemical Society. 1995 ; Vol. 117, No. 41. pp. 10227-10238.
@article{8925ceb0c57c4f5d8160e204a55f02bb,
title = "Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems",
abstract = "The first generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8) [IJK]. The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHIJK] (6 → 5). The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 → 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 → 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 → 99) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.",
author = "Nicolaou, {K. C.} and Hwang, {C. K.} and Duggan, {M. E.} and Nugiel, {D. A.} and Y. Abe and {Bal Reddy}, K. and DeFrees, {S. A.} and Reddy, {D. R.} and Awartani, {R. A.} and Conley, {S. R.} and Rutjes, {F. P J T} and Theodorakis, {E. A.}",
year = "1995",
month = "10",
day = "18",
doi = "10.1021/ja00146a008",
language = "English",
volume = "117",
pages = "10227--10238",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "41",

}

TY - JOUR

T1 - Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems

AU - Nicolaou, K. C.

AU - Hwang, C. K.

AU - Duggan, M. E.

AU - Nugiel, D. A.

AU - Abe, Y.

AU - Bal Reddy, K.

AU - DeFrees, S. A.

AU - Reddy, D. R.

AU - Awartani, R. A.

AU - Conley, S. R.

AU - Rutjes, F. P J T

AU - Theodorakis, E. A.

PY - 1995/10/18

Y1 - 1995/10/18

N2 - The first generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8) [IJK]. The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHIJK] (6 → 5). The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 → 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 → 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 → 99) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.

AB - The first generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8) [IJK]. The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHIJK] (6 → 5). The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 → 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 → 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 → 99) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.

UR - http://www.scopus.com/inward/record.url?scp=0028834767&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028834767&partnerID=8YFLogxK

U2 - 10.1021/ja00146a008

DO - 10.1021/ja00146a008

M3 - Article

AN - SCOPUS:0028834767

VL - 117

SP - 10227

EP - 10238

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 41

ER -