The continuing saga of the marine polyether biotoxins

Abstract

The unprecedented structure of the marine natural product brevetoxin B was elucidated by the research group of Nakanishi and Clardy in 1981. The ladderlike molecular architecture of this fused polyether molecule, its potent toxicity, and fascinating voltage-sensitive sodium channel based mechanism of action immediately captured the imagination of synthetic chemists. Synthetic endeavors resulted in numerous new methods and strategies for the construction of cyclic ethers, and culminated in several impressive total syntheses of this molecule and some of its equally challenging siblings. Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, but is also the largest nonpolymeric natural product known to date. This Review begins with a brief history of the isolation of these biotoxins and highlights their biological properties and mechanism of action. Chemical syntheses are then described, with particular emphasis on new methods developed and applied to the total syntheses. The Review ends with a discussion of the, as yet unfinished, story of maitotoxin, and projects into the future of this area of research.

Figure 1

Molecular structures of selected marine biotoxins.

Figure 2

Molecular structures of ladder-like polyether marine biotoxins (6–12) constructed in the laboratory by total synthesis.

Figure 3

Molecular structure of maitotoxin (13), the largest of the polyether marine biotoxins and of any non-polymeric natural product isolated to date.

Figure 4

Model of the anchoring of maitotoxin into the cell membrane (see Murata et al.).[11,24]

Figure 5

Structures of amphidinol 3 (AM3, 14) and yessotoxin (15).

Figure 6

Structures of prymnesin-1 (16) and prymnesin-2 (17) and gambieric acid A (18).

Figure 7

Hypothetical model for the binding of ladder-like polyethers to their receptor a-helix motifs of membrane protein ion channels as exemplified by brevetoxin B (precise oxygens involved in the binding not defined (see Murata et al.).[11]

Figure 8

Differences (Δδ, in ppm) in calculated and experimental ¹³C chemical shifts for compounds 412, 413 and 414 (Nicolaou et al., 2007).[126]

Figure 9

Comparison of the ¹³C chemical shifts of the GHIJK domain 444 with those reported for the same domain of maitotoxin (Nicolaou et al., 2007).[127a]

Figure 10

Comparison of the ¹³C chemical shifts of the maitotoxin GHIJKLMNO domain (459) with those reported for the same domain of maitotoxin (Nicolaou et al., 2007).[127b]

Scheme 1

Nakanishi’s proposed biosynthetic hypothesis for brevetoxin B (6).[33]

Scheme 2

The 6-endo hydroxy epoxide opening method for cyclic ether formation (Nicolaou et al., 1985).[37]

Scheme 3

The hydroxy dithioketal cyclization method involving mixed O,S-acetals for cyclic ether formation (Nicolaou et al., 1986).[39]

Scheme 4

The dithionolactone bridging method for cyclic ether formation (Nicolaou et al., 1986).[42]

Scheme 5

The dithionoester photolytic cyclization method for cyclic ether formation (Nicolaou et al., 1989).[44]

Scheme 6

The thionolactone nucleophilic addition/reduction method for cyclic ether formation (Nicolaou et al., 1987).[45]

Scheme 7

The intramolecular hydroxy Michael addition reaction for cyclic ether formation (Nicolaou et al., 1989).[46]

Scheme 8

The hydroxy ketone reductive cyclization method for cyclic ether formation (a: Nicolaou et al., 1989,[44] b: Evans et al., 2003;[49] c: Sasaki et al., 2007).[48]

Scheme 9

The allyl tin cyclization method for the formation of cyclic ethers (Yamamoto et al., 1991,[50] 2001).[51]

Scheme 10

First examples of cyclic ether formation by ring closing metathesis (Grubbs et al., a: 1992; b: 1993).[55a,b]

Scheme 11

Early example of cyclic enol ether formation by ring closing metathesis (Grubbs et al., 1994).[55c]

Scheme 12

General, one-pot, ester methylenation/metathesis method for the formation of cyclic polyethers (Nicolaou et al., 1996).[56]

Scheme 13

The ester methylenation/metathesis method in the construction of complex polycyclic ethers (Nicolaou et al., 1996).[56]

Scheme 14

The ester methylenation/metathesis method in the synthesis of JKL (88, a) and UVW (92, b) maitotoxin model systems (Nicolaou et al., 1996).[58]

Scheme 15

The two-step version of the methylenation/metathesis method for cyclic ether formation (Clark et al., 1997).[60]

Scheme 16

Intramolecular, carbene-ester addition method for the formation of cyclic ethers (Takeda et al., 1997).[63]

Scheme 17

A ring expansion-based method for oxepane formation (Nakata et al., 1996).[64]

Scheme 18

The oxiranyl anion addition/cyclization method for the formation of cyclic ethers (Mori et al., 1996).[65]

Scheme 19

The vinyl phosphate/cross-coupling method for the formation of cyclic ethers (a: Nicolaou et al., 1997;[67] b: Sasaki et al., 1999).[69]

Scheme 20

The mixed O,S-acetal radical cyclization/ring closing metathesis sequence for the formation of cyclic polyethers (Sasaki and Tachibana et al., 1999).[70]

Scheme 21

The SmI₂-induced reductive cyclization method for the formation of cyclic ethers (Nakata et al., 1999).[71]

Scheme 22

Alkyne functionalization/cyclization methods (Fujiwara/Murai et al.,[73] Nakata et al.,[74] and Mori et al., 2000).[75]

Scheme 23

Hydroxy methoxyenone cyclization in the formation of cyclic ethers (Nakata et al., 2002).[76]

Scheme 24

Methoxymethyl-directed cascade hydroxy epoxide opening to fused pyran systems (Murai et al., 1999).[77]

Scheme 25

Lewis acid-promoted, carbonate polyepoxide opening cascade to fused polyoxepane systems (McDonald et al., 2000).[78]

Scheme 26

TMS-directed hydroxy polyepoxide opening cascade to form fused polypyran systems (Jamison et al., 2003).[80]

Scheme 27

Thermally-induced hydroxy polyepoxide opening cascade in water (Vilotijevic and Jamison, 2007).[81]

Scheme 28

The first total synthesis of hemibrevetoxin (8) (Nicolaou et al., 1992).[84]

Scheme 29

Second total synthesis of hemibrevetoxin (8) (Y. Yamamoto et al., 1995).[85]

Scheme 30

Third total synthesis of hemibrevetoxin (8) (Nakata et al., 1996).[86]

Scheme 31

Fourth (formal) total synthesis of hemibrevetoxin (8) (Mori et al., 1997).[87]

Scheme 32

Fifth (formal) total synthesis of hemibrevetoxin (8) (Rainier et al., 2001).[88]

Scheme 33

Sixth (formal) total synthesis of hemibrevetoxin (8) (Nelson et al., 2001).[90]

Scheme 34

Seventh total synthesis of hemibrevetoxin (8) (Holton et al., 2003).[92]

Scheme 35

Eighth (formal) total synthesis of hemibrevetoxin (8) (Fujiwara et al., 2004).[95]

Scheme 36

Ninth (formal) total synthesis of hemibrevetoxin (8) (Y. Yamamoto et al., 2007).[96]

Scheme 37

The first total synthesis of brevetoxin B (6). Construction of the ABCDEFG domain (238) (Nicolaou et al., 1995).[97]

Scheme 38

The first total synthesis of brevetoxin B (6). Construction of the IJK domain (244) (Nicolaou et al., 1995).[97]

Scheme 39

The first total synthesis of brevetoxin B (6). Completion of the total synthesis (Nicolaou et al., 1995).[97]

Scheme 40

Second total synthesis of brevetoxin B (6). Construction of the IJK fragment (244) (Nakata et al., 2004).[98]

Scheme 41

Second total synthesis of brevetoxin B (6). Construction of the ABCDEFG fragment (2627) and completion of the synthesis (Nakata et al., 2004).[98]

Scheme 42

The total synthesis of brevetoxin A (7). Construction of the BCDE fragment (271) (Nicolaou et al., 1998).[101]

Scheme 43

The total synthesis of brevetoxin A (6). Construction of the GHIJ fragment (280) (Nicolaou et al., 1998).[101]

Scheme 44

The total synthesis of brevetoxin A (6). Completion of the synthesis (Nicolaou et al., 1998).[101]

Scheme 45

Total synthesis of ciguatoxin 3C (9). Construction of the ABCDE fragment (291) (Hirama et al., 2001).[102]

Scheme 46

Total synthesis of ciguatoxin 3C (9). Construction of the HIJKLM fragment (303) (Hirama et al., 2001).[102]

Scheme 47

Total synthesis of ciguatoxin 3C (9). Final stages of the synthesis (Hirama et al., 2001).[102]

Scheme 48

The first total synthesis of gambierol. Synthesis of the ABC domain (312) (Sasaki et al., 2002).[105]

Scheme 49

The first total synthesis of gambierol (10). Synthesis of the EFGH domain (320) (Sasaki et al., 2002).[105]

Scheme 50

The first total synthesis of gambierol (10). Final stages of the synthesis (Sasaki et al., 2002).[105]

Scheme 51

Second total synthesis of gambierol (10). Construction of ABC domain (326) (Y. Yamamoto et al., 2003).[106]

Scheme 52

Second total synthesis of gambierol (10). Construction of FGH domain (333) (Y. Yamamoto et al., 2003).[106]

Scheme 53

Second total synthesis of gambierol (10). Completion of the synthesis (Y. Yamamoto et al., 2003).[106]

Scheme 54

Third total synthesis of gambierol (10). Construction of the ABC fragment (342) (Rainier et al., 2005).[108]

Scheme 55

Third total synthesis of gambierol (10). Construction of the FGH domain (346) (Rainier et al., 2005).[108]

Scheme 56

Third total synthesis of gambierol (10). Completion of the synthesis (Rainier et al., 2005).[108]

Scheme 57

Total synthesis of gymnocin A (12). Construction of ABCD domain (363) (Sasaki et al., 2003).[110]

Scheme 58

Total synthesis of gymnocin A (12). Synthesis of common precursor (358) (Sasaki et al., 2003).[110]

Scheme 59

Total synthesis of gymnocin A (12). Construction of FGHIJKLMN domain (363) (Sasaki et al., 2003).[110]

Scheme 60

Total synthesis of gymnocin A (12). Final stages of the synthesis (Sasaki et al., 2003).[110]

Scheme 61

Total synthesis of brevenal (11). Construction of the AB ring system (370) (Sasaki et al., 2006).[114]

Scheme 62

Total synthesis of brevenal (11). Construction of the DE ring system (375) (Sasaki et al., 2006).[114]

Scheme 63

Total synthesis of brevenal (11). Final stages of the synthesis (Sasaki et al., 2006).[114]

Scheme 64

Degradation of maitotoxin (13) (Yasumoto et al., 1992).[118]

Scheme 65

Determination of the relative stereochemistry of the C₁–C₁₅ domain of maitotoxin (a: Kishi et al., 1996;[120] b: Tachibana et al., 1996[121]).

Scheme 66

Determination of the relative stereochemistry of the C₃₅–C₃₉ domain of maitotoxin (13) (a: Kishi et al., 1996;[120] b: Tachibana et al., 1995[122]).

Scheme 67

Determination of the relative stereochemistry of the C₆₃–C₆₈ domain of maitotoxin (13) (a: Kishi et al., 1996;[120] b: Tachibana et al., 1995[123]).

Scheme 68

Confirmation of the relative stereochemistry of the C₉₉–C₁₀₀ junction of maitotoxin (13) (Kishi et al., 1996).[124]

Scheme 69

Determination of the relative stereochemistry of the C₁₃₄–C₁₄₂ domain (a: Kishi et al., 1996)[120] and of the absolute stereochemistry of maitotoxin (13) (b: Tachibana et al., 1996).[125]

Scheme 70

The Nakanishi/Gallimore–Spencer postulated hypothesis for the biosynthesis of maitotoxin (13) that brings into question the JK ring junction (C₅₁ and C₅₂).

Scheme 71

Furan-based asymmetric synthesis of substituted pyrans through the Noyori reduction/Achmatowicz rearrangement sequence method (Nicolaou et al., 2007).[127]

Scheme 72

Silver-promoted, hydroxy ynone cyclization for the formation of fused cyclic ethers (Nicolaou et al., 2007).[127]

Scheme 73

Construction of the maitotoxin J ring fragment 431 through the Noyori reduction/Achmatowicz rearrangement sequence method (Nicolaou et al., 2007).[127a]

Scheme 74

Construction of the maitotoxin G ring fragment 437 through the Noyori reduction/Achmatowicz rearrangement sequence method (Nicolaou et al., 2007).[127a]

Scheme 75

Construction of the maitotoxin IJK fragment 441 through the silver-promoted, hydroxy ynone cyclization method (Nicolaou et al., 2007).[127a]

Scheme 76

Synthesis of the maitotoxin GHIJK fragment 444 (Nicolaou et al., 2007).[127a]

Scheme 77

Synthesis of the maitotoxin LM and NO fragments 450 and 451 through the Noyori reduction/Achmatowicz rearrangement sequence method (Nicolaou et al., 2007).[127b]

Scheme 78

Synthesis of the GHIJKLMNO domain (459) of maitotoxin (Nicolaou et al., 2007).[127b]