26
B. Schmidt
opening of epoxide 96 with ethyl magnesium bromide was used to introduce the C-9propyl side chain and Steglich esterification of the secondary alcohol gave the RCM
precursor 97. Ring-closing metathesis of 97 proceeded with moderate diastereoselectivity ((E):(Z) = 4:1). Chromatographic removal of the undesired (Z)-isomer was
only possible after cleavage of the acetal. The resulting product, herbarumin I (41),
was selectively oxidized at C-7, the allylic position, to furnish stagonolide A (85).
In summary, two out of three configurationally stable stereocenters in the ex-chiral
pool starting material d-ribose were retained in the product stagonolide A (Table 1,
entry 1 and Scheme 19).
The other total syntheses of stagonolide A rely on very similar synthetic strategies.
Two of these also use carbohydrates (d-ribose: Table 1, entry 2 [93] or d-glucose:
Table 1, entry 3 [94]) as ex-chiral pool starting materials, while a third synthesis
makes use of the well-established aldol methodology based on thiaoxazolidinone
auxiliaries to control the absolute and relative configurations at C-8 and C-9 (Table 1,
entry 4) [95]. As in the first synthesis, ring closure is accomplished in the other three
syntheses by RCM. By using one or two benzyl ethers as hydroxy protecting groups at
C-7 and C-8 and second-generation catalysts, the RCM step can be notably improved
with regard to diastereoselectivity, yield and catalyst loading [94, 95].
The structures of stagonolides B–K (83, 86–94) were elucidated via HRMS, IR
spectroscopy, and 1D- and 2D-NMR spectroscopic methods. While (in contrast to
stagonolide A (85)) specific rotations were reported for all these natural products,
the absolute configurations were not assigned based on chiroptical methods, suitable
NMR methods or X-ray-crystallography, but mostly by analogy to structurally related
decanolides, such as the herbarumins [78, 89, 90]. As outlined in the case of one of the
most recently discovered stagonolides, stagonolide J (93), application of Mosher’s
method gives ambiguous results for vicinal diols, which is a serious limitation if
absolute configurations need to be determined [90]. So far, no total syntheses of
stagonolides H–J (91–93) have been reported (Table 1, entries 36–38). The originally
assigned absolute and relative configurations of stagonolides B (86) (Table 1, entries
5–8), C (83) (Table 1, entries 9–15) and E (88) (Table 1, entries 20–26) could be
confirmed via enantioselective total syntheses. In the case of stagonolide D (original
structure: 87) total synthesis led to a revision of the absolute and relative configuration
(revised structure: 98) (Table 1, entries 16–19) [98], and stagonolide G (original
structure: 90) turned out to be a γ-butyrolactone 99 rather than the ten-membered
lactone 90 (Table 1, entries 31–35) [99]. In the case of stagonolide F (89) the results
from a synthetic study suggest that the constitution was erroneously assigned, but
no revised structure has so far been proposed. It has, however, been suggested to
use the name (–)-5-epi-aspinolide A rather than stagonolide F for structure 89 in the
future (Table 1, entries 27–30) [23]. The total syntheses of stagonolides isolated from
Stagonospora cirsii and their implications for structure elucidation are summarized
in Table 1.
The most notable erroneous structural assignment in the stagonolide family is
probably that of stagonolide G as a ten-membered lactone. This misassignment was
discovered as a result of an enantioselective total synthesis published by AnguloPachón et al. [99] (Table 1, entry 32 and Scheme 20): the two key fragments, alcohol
B. Schmidt
opening of epoxide 96 with ethyl magnesium bromide was used to introduce the C-9propyl side chain and Steglich esterification of the secondary alcohol gave the RCM
precursor 97. Ring-closing metathesis of 97 proceeded with moderate diastereoselectivity ((E):(Z) = 4:1). Chromatographic removal of the undesired (Z)-isomer was
only possible after cleavage of the acetal. The resulting product, herbarumin I (41),
was selectively oxidized at C-7, the allylic position, to furnish stagonolide A (85).
In summary, two out of three configurationally stable stereocenters in the ex-chiral
pool starting material d-ribose were retained in the product stagonolide A (Table 1,
entry 1 and Scheme 19).
The other total syntheses of stagonolide A rely on very similar synthetic strategies.
Two of these also use carbohydrates (d-ribose: Table 1, entry 2 [93] or d-glucose:
Table 1, entry 3 [94]) as ex-chiral pool starting materials, while a third synthesis
makes use of the well-established aldol methodology based on thiaoxazolidinone
auxiliaries to control the absolute and relative configurations at C-8 and C-9 (Table 1,
entry 4) [95]. As in the first synthesis, ring closure is accomplished in the other three
syntheses by RCM. By using one or two benzyl ethers as hydroxy protecting groups at
C-7 and C-8 and second-generation catalysts, the RCM step can be notably improved
with regard to diastereoselectivity, yield and catalyst loading [94, 95].
The structures of stagonolides B–K (83, 86–94) were elucidated via HRMS, IR
spectroscopy, and 1D- and 2D-NMR spectroscopic methods. While (in contrast to
stagonolide A (85)) specific rotations were reported for all these natural products,
the absolute configurations were not assigned based on chiroptical methods, suitable
NMR methods or X-ray-crystallography, but mostly by analogy to structurally related
decanolides, such as the herbarumins [78, 89, 90]. As outlined in the case of one of the
most recently discovered stagonolides, stagonolide J (93), application of Mosher’s
method gives ambiguous results for vicinal diols, which is a serious limitation if
absolute configurations need to be determined [90]. So far, no total syntheses of
stagonolides H–J (91–93) have been reported (Table 1, entries 36–38). The originally
assigned absolute and relative configurations of stagonolides B (86) (Table 1, entries
5–8), C (83) (Table 1, entries 9–15) and E (88) (Table 1, entries 20–26) could be
confirmed via enantioselective total syntheses. In the case of stagonolide D (original
structure: 87) total synthesis led to a revision of the absolute and relative configuration
(revised structure: 98) (Table 1, entries 16–19) [98], and stagonolide G (original
structure: 90) turned out to be a γ-butyrolactone 99 rather than the ten-membered
lactone 90 (Table 1, entries 31–35) [99]. In the case of stagonolide F (89) the results
from a synthetic study suggest that the constitution was erroneously assigned, but
no revised structure has so far been proposed. It has, however, been suggested to
use the name (–)-5-epi-aspinolide A rather than stagonolide F for structure 89 in the
future (Table 1, entries 27–30) [23]. The total syntheses of stagonolides isolated from
Stagonospora cirsii and their implications for structure elucidation are summarized
in Table 1.
The most notable erroneous structural assignment in the stagonolide family is
probably that of stagonolide G as a ten-membered lactone. This misassignment was
discovered as a result of an enantioselective total synthesis published by AnguloPachón et al. [99] (Table 1, entry 32 and Scheme 20): the two key fragments, alcohol