Unusual reactions of methylsulfonyl esters: Syntheses of 3α-methyl and 3β-methyl gibberellin A20

Article abstract of DOI:10.1039/a605570b

Gibberellin A₃ has been converted to 3α-methylGA₂₀ 8 in 33% yield via catalytic hydrogenation of the 3-exo-methylene derivative 14. In an attempt to prepare 3β-methylGA₂₀ 9, the 3α-methanesulfonate 25 has been treated with lithium dimethylcuprate; only the β-keto sultones 26 and 27 have been isolated (84% yield). In contrast, under similar conditions the 3α-methanesulfonate 35 gave the 2-oxopropylsulfonyloxy derivatives 36 and 37. Synthesis of 3β-methylGA₂₀ has been achieved via reaction of the 3α-trifluoromethane-sulfonate 38 with lithium dimethylcuprate. 3α-MethylGA₂₀ and 3β-methylGA₂₀ show similar activity to GA₂₀ (and significantly less activity than GA₃) in the stimulation of stem elongation of dwarf rice seedlings.

Full text of DOI:10.1039/a605570b

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Unusual reactions of methylsulfonyl esters: syntheses of 3á-methyl
and 3â-methyl gibberellin A20
Michael H. Beale,b Huw Loaring,a Torren Peakman,a Martin Pennya and
Christine L. Willis*,a
a
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
b IACR-Long Ashton Research Station, Department of Agricultural Sciences,
University of Bristol, Bristol BS18 9AF, UK
G ibberellin A3 has been converted to 3á-methylG A20 8 in 33% yield via catalytic hydrogenation of the 3-
exo-methylene derivative 14. In an attempt to prepare 3â-methylG A20 9, the 3á-methanesulfonate 25 has
been treated with lithium dimethylcuprate; only the â-keto sultones 26 and 27 have been isolated (84%
yield). In contrast, under similar conditions the 3á-methanesulfonate 35 gave the 2-oxopropylsulfonyloxy
derivatives 36 and 37. Synthesis of 3â-methylG A20 has been achieved via reaction of the 3á-trifluoromethane-
sulfonate 38 with lithium dimethylcuprate. 3á-M ethylG A20 and 3â-methylG A20 show similar activity to G A20
(and significantly less activity than G A3) in the stimulation of stem elongation of dwarf rice seedlings.
Gibberellin 3β-hydroxylase is one of the key enzymes in gibberel-
O
O
R
lin (GA) biosynthesis and is responsible for the production of
bioactive gibberellins.1 Indeed GA1, which is formed via 3β-
hydroxylation of GA20 has been proposed to be the only GA
required for the control of stem elongation in pea and maize
(Scheme 1).2 More recently GA3, which displays similar bioac-
CO
CO
R
HO
CO2H
CO2H
1 R = Cl
2 R = F
3 R = OMe
4 R = H
5 R = OH
6 R = H
12
11
O
10
O
13
OH
16
OH
1
–3β-H
2
3
9
7
19
8
6
CO
CO
14
17
O
O
OH
OH
5
HO
15
4
CO2H
CO2H
GA1
18
CO
CO
GA20
CO2H
CO2H
–2β, 3β-H2
7
8
O
O
OH
OH
O
OH
–1β-H
CO
CO
CO
HO
CO2H
GA5
CO2H
GA3
CO2H
9
Scheme 1
little inhibition of the 3β-hydroxylases isolated from Cucurbita
maxima (giant cucumber) and Phaseolus vulgaris (French
bean) and displayed moderate activity in stem elongation assays
with Oryza sativa (rice) and Cucumis sativus (cucumber). Since
both 5 and 6 have a 3β-hydroxy group (believed to be necessary
for bioactivity) and there is no evidence that the 3-methyl group
in the GA5 derivative 7 would interfere with its metabolism to a
bioactive GA3 analogue, these results are not too surprising.
The biological assessment of 3β-methyl gibberellin analogues
would be expected to be more informative. We now describe
the synthesis of 3α-methyl- and 3β-methyl-GA20 8 and 9 which
led to the discovery of some unexpected reactions of gibberellin
3-methanesulfonates.
tivity to GA1, has been detected in the stem tissue of maize
where it is formed indirectly from GA5.3 3β-Hydroxylation of
GA20 proceeds with retention of configuration and GA3 is
formed with the loss of 1β-H, 2β-H and 3β-H.4 Therefore GAs
substituted at the 3β-position would be expected to be blocked
for 3-hydroxylation and show little or no bioactivity.
In an early investigation of the inhibition of the 3β-hydroxyl-
ation process, Beale and MacMillan prepared a series of deriv-
atives with 3β-chloro 1, -fluoro 2 and -methoxy 3 substituents.5
Each compound showed similar activity to the parent com-
pound GA9 4 but significantly less activity than GA3. It was
suggested that polar substituents at C-3 may mimic 3β-
hydroxylated GAs in the active site. More recently Saito et al.6
reported the first accounts of the syntheses and biological
assessments of some 3-methylgibberellin derivatives, most not-
ably 3α-methylGA1 5, 3α-methylGA4 6 and 3-methylGA5 7. The
bioactivities of these derivatives were assessed. Each showed
Results and discussion
3á-Methylgibberellin A20
8
It has been shown previously that catalytic deuteriogenation of
J. Chem. Soc., Perkin Trans. 1, 1997
433

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O
OAc
O
OAc
O
OAc
O
O
OAc
O
i
ii
+
CO
CO
CO
CO
O
O
O
O
CO2Me
10
CO2Me
11
CO2Me
12
CO2Me
13
iii
O
OAc
O
O
OAc
O
O
OAc
O
iv
+
CO
CO
CO
CO2Me
16
CO2Me
15
CO2Me
iv
14
v
O
OAc
O
OH
vi
CO
CO
CO2Me
17
CO2H
8
Scheme 2 Reagents: i, Bu3SnH, Pd(Ph3P)4; ii, MCPBA, CHCl3; iii, Ph3PCH3Br, NaH; iv, H2, 10% Pd on CaCO3; v, NaOAc, NaI, Zn, AcOH;
vi, NaOH (2 )
Table 1 1H NMR Assignments of the ring A protons in GA20 and 3α-
conformation with an equatorial methyl group at C-3. The
methylGA20
8
chair conformation of ring A was substantiated by the signal
assigned to 1β-H which resonated at δ 1.52 as a doublet of
doublets of doublets (Jgem 13 Hz, Jax,ax 12 Hz and Jax,eq 6 Hz).
δH
Assignment
3α-MethylGA20
8
GA20
3â-Methylgibberellin A20 9
1β-H
1α-H
2β-H
2α-H
3β-H
3α-H
3α-CH3
1.52
2.05
1.80
1.27
1.73
—
1.39
2.05
1.73
1.57
1.51
1.68
—
Three approaches were examined for the synthesis of 3β-
methylGA20 each based upon the use of an organometallic
reagent to displace a leaving group at the 3α-position. First the
2α,3α-epoxide 21 was prepared in a three-stage procedure from
0.93
O
OAc
O
O
OAc
O
AcO
Br
i
CO
CO
a 2,3-olefin in C19-gibberellins occurs exclusively from the β-face
with isomerisation of the double bond leading to the introduc-
tion of deuterium at the 1β, 2β and 3β positions.7 Therefore, by
analogy, the proposed route for the synthesis of 3α-methylGA20
was via catalytic hydrogenation of the exo-methylene 14 or of
the 3-methyl-2-olefin 15. Olefin 14 was prepared as shown in
Scheme 2. Selective reduction of the 1,2-double bond in the
known enone 108 was achieved in excellent yield using Bu3SnH
in the presence of a catalytic amount of tetrakis(triphenyl-
phosphine)palladium(0).9 Protection of the exocyclic olefin as
the epoxide followed by a Wittig methylenation at C-3 gave 14
in 48% yield over the two steps. Catalytic hydrogenation of 14
gave an inseparable mixture of the unsaturated ester 15 and a
fully reduced product. Exhaustive hydrogenation of the mixture
gave solely the 3α-methyl derivative 16. The 16,17-olefin was
regenerated using the method of Cornforth 10 and the 13-
acetate and 7-methyl ester hydrolysed with sodium hydroxide
giving 3α-methylGA20 8 in 33% overall yield from GA3. The
stereochemical assignment of the 3-methyl substituent was
CO2Me
18
CO2Me
19
ii
O
OAc
O
OAc
O
iii
O
CO
O
CO
CO2H
21
CO2Me
20
iv
O
OAc
HO
CO
confirmed by the H NMR and H–1H phase sensitive COSY
spectra. The assignments of the ring A protons in 8 are shown
in Table 1 and, as expected, they bear a close similarity to
the reported assignments of the parent compound GA20.7
Although the 3-proton was partially masked, 2α-H was clearly
visible as a doublet of triplets of doublets (Jgem 14 Hz, 2 × Jax,ax
each 12 Hz and Jax,eq 6 Hz) confirming that ring A was in a chair
1
1
CO2Me
Scheme 3 Reagents: i, CH3CONHBr, NaOAc, AcOH; ii, K2CO3,
MeOH; iii, NaOAc, NaI, Zn, AcOH; iv, organometallic reagents
the known olefin 18 (Scheme 3).7 Reaction of 18 with N-
bromoacetamide and lithium acetate in acetic acid gave the
434
J. Chem. Soc., Perkin Trans. 1, 1997

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OAc
OAc
i
HO
O
CO2Me
CO2Me
CO2Me
CO2Me
22
23
ii
OAc
OAc
OAc
iii
v
TsO
HO
MsO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
28
24
25
iv
vi
iv
OAc
OAc
OH
OAc
+
+
28
TfO
O
O
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O2S
O2S
CO2Me
O
O
29
30
26
27
iv
29 + 30
Scheme 4 Reagents: i, CrO3, H2SO4, H2O, Me2CO; ii, NaBH4, MeOH; iii, MsCl, pyridine; iv, Me2CuLi; v, TsCl, pyridine; vi, Tf2O, pyridine
bromo acetate 19 as the sole product in 91% yield. Treatment of
19 with anhydrous potassium carbonate in methanol gave the
diepoxide 20 which under Cornforth conditions10 led to select-
ive regeneration of the exocyclic olefin. Treatment of 21 with
lithium dimethylcuprate in the presence or absence of boron
trifluoride–diethyl ether 11 returned starting material. Higher
order dimethylcyanocuprates have been reported to be more
effective towards the opening of di- and tri-substituted epox-
ides12 but treatment of 21 with lithium dimethylcyanocuprate
in the presence or absence of boron trifluoride again returned
starting material. Similar results were obtained with a copper
catalysed Grignard reagent 13 and with trimethylaluminium.14
The inert nature of the 2α,3α-epoxide was surprising and it was
apparent that a different leaving group at C-3 was required.
It has been reported that sulfonate esters may be displaced
with organocuprate reagents15 and indeed we have shown in the
gibberellin field that reaction of a bridgehead methanesulfon-
ate with a range of lithium dialkylcuprate reagents gives 13-
alkylated derivatives.16 3α-Methanesulfonate 25, toluene-p-
sulfonate 28 and trifluoromethanesulfonate 30 were prepared
from hydroxy ester 22 (Scheme 4). The 3β-alcohol was inverted
via a two-stage oxidation-reduction procedure giving the 3α-
alcohol 24 in 68% yield which was then converted to the sulfon-
ate esters 25, 28 and 30 under standard conditions. The
methanesulfonate 25 was treated with lithium dimethylcuprate
at Ϫ10 ЊC for 4 h giving a mixture of two products which were
abstraction of the acidic proton on the sulfonyl ester followed
by nucleophilic attack of the resultant anion on C-19. The for-
mation of the sultone was unexpected and although the reac-
tion is unusual, the formation of sultones has been reported in
carbohydrate chemistry17 and more recently in a study of the
citreamicin antibiotics.18
Reaction of the 3α-toluene-p-sulfonate 28 with lithium
dimethylcuprate returned starting material and the eliminated
product 29. Similar results were obtained with the trifluoro-
methanesulfonate. Hence none of these reactions had led to
the formation of the required 3β-methyl gibberellin. The final
approach to the target compound also involved the displace-
ment of a good leaving group at C-3 but this time on a substrate
with the 19,10γ-lactone intact. It was anticipated that in this
case, if deprotonation of the methanesulfonate 35 occurred,
then there would be insufficient orbital overlap of the resultant
anion with the lactone carbonyl to form a sultone-type product.
In addition it was hoped the competing elimination reaction to
form the 2,3-olefin may be less of a problem.
The 3α-methanesulfonate 35 was prepared from 31 as shown
in Scheme 5. Hydrogenolysis of the allylic lactone moiety fol-
lowed by iodolactonisation gave the iodide 32 as previously
described.19 Barton and co-workers have recently reported that
dialkyl phosphites can be used in place of the more com-
monly used tributylstannane in the radical reduction of hal-
ides.20 Treatment of iodide 32 with dimethyl phosphite in
the presence of benzoyl peroxide gave GA1 methyl ester 33
in 87% yield. The high yield of 33 and the low toxicity and
cost of the reagent combine to make dehalogenation with
dimethyl phosphite an attractive alternative in GA chem-
istry. Inversion of the 3β-alcohol proceeded smoothly and
the resultant 3α-alcohol 34 converted to 3α-methanesulfonate
35 in excellent yield.
1
purified by flash chromatography. The H NMR spectrum of
the major product displayed a singlet at δ 3.71 assigned to a
methyl ester and a pair of doublets (each J 16.5 Hz) at δ 4.12
and 4.32. In addition there was a signal present at δ 4.84 (t, J 5
Hz) of similar chemical shift (δ 4.83) to 3β-H in the starting
material 25. Hence the compound was tentatively assigned as
keto sultone 27 and this was confirmed by the 13C NMR [δ 198
(C-19), 175 (C-7) and 61 (19-COCH2)] and mass spectrum (M+,
422.1391). The less polar compound was the corresponding 13-
acetate 26. The reaction can be envisaged as proceeding via
Treatment of 35 with 5 equiv. of lithium dimethylcuprate at
Ϫ10 ЊC for 4 h gave a mixture of products which was separated
into two components by flash chromatography (Scheme 5). The
J. Chem. Soc., Perkin Trans. 1, 1997
435

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I
O
OAc
O
OAc
O
OAc
i
ii
CO
CO
CO
HO
HO
HO
CO2Me
31
CO2Me
32
CO2Me
33
iii
O
OAc
O
OAc
iv
CO
CO
MsO
v
HO
CO2Me
35
CO2Me
34
vi
O
OAc
O
OH
O
OAc
+
CO
CO
CO
O
O
S
TfO
O
O
S
O
O
CO2Me
CO2Me
CO2Me
O
O
38
H3C
H3C
36
37
v
O
OH
O
OAc
O
OAc
vii
+
CO
CO
CO
CO2H
CO2Me
39
CO2Me
40
9
Scheme 5 Reagents: i, H2, 10% Pd on CaCO3, MeOH, pyridine then I2, CH2Cl2, NaHCO3; ii, DMP, (PhCO2)2, toluene, heat; iii, CrO3, H2SO4, H2O,
Me2CO then NaBH4, MeOH; iv, MsCl, pyridine; v, Me2CuLi; vi, Tf2O, pyridine; vii, NaOH (2 )
Table 2 Rice seedling bioassay
Length (mm)
Second leaf sheath Total
less polar fraction was a 1:1 mixture of starting material and a
new product; the more polar fraction gave a very similar H
1
NMR spectrum showing two compounds in which it was evi-
dent that the 13-hydroxy rather than 13-acetoxy group was
present. In an attempt to obtain pure products, the reaction was
1
repeated with 10 equiv. of lithium dimethylcuprate. The H
Control
GA3
GA20
3α-MeGA20
3β-MeGA20
16
57
26
24
28
22
73
42
35
38
NMR spectrum of the less polar product displayed a doublet of
doublets (J 11 and 6 Hz) at δ 4.79 which was very similar to the
signal assigned to 3-H in the starting methanesulfonate δ 4.73
(dd, J 11 and 6 Hz); however no singlet was apparent at ca. δ 3.0
which could be assigned to the CH3 of the methanesulfonate.
There were new signals apparent in the spectrum of the product
which were not present in that of the starting material: at δ 2.41
(3 H, s), 4.15 (1 H, d, J 14.5 Hz) and 4.19 (1 H, d, J 14.5 Hz).
Interestingly the 13C NMR spectrum had a signal at δ 194 char-
acteristic of a ketonic carbonyl as well as signals at δ 172 and
175 assigned to C-19 and C-17 respectively. A structure in
accord with these data is the 2-oxopropylsulfonyloxy gibberellin
36 and the more polar product was the corresponding 13-
alcohol 37. The reaction may be envisaged as proceeding via
deprotonation of the methanesulfonate methyl to generate the
anion which then undergoes intermolecular attack on the
bridgehead acetate of a further GA molecule. To confirm this
proposal, both the corresponding 13-deoxy- and 13-hydroxy-
gibberellin 3α-methanesulfonates 41 and 42 were treated with
lithium dimethylcuprate but both simply returned starting
material. In contrast reaction of GA1 3β-methanesulfonate 13-
acetate 43 with lithium dimethylcuprate gave the 3β-(2-oxo-
propylsulfonyloxy) derivatives 44 and 45. Interestingly in all of
these cases no elimination or displacement of the 3-methane-
sulfonate had occurred.
8
9
(Scheme 5). In the 1H NMR spectrum of 38, the protons
assigned to the 3-methyl group resonated at δ 1.07 (d, J 7 Hz)
whereas in the corresponding 3α-methyl derivative 17 the 3-
methyl group resonated at δ 0.93 (d, J 7 Hz). Treatment of
39 with aqueous sodium hydroxide gave the required 3β-
methylGA20 9.
Bioassay of 8 and 9 with Tanginbozu dwarf rice
The biological activities of 3α-methylGA20 8 and 3β-methyl
GA20 9 were assessed in a bioassay with Tanginbozu dwarf rice
against GA20, GA3 and a control. After 7 days the total lengths
of the plants were measured and the results are given in Table 2.
It is apparent that both 8 and 9 exhibit significantly less ac-
tivity than GA3 but interestingly show approximately the same
activity as each other, albeit very low. The alkylated gibberellins
will be tested in further bioassays.
Experimental
General experimental details have been described previously.21
Enone 10 was prepared as described by Beale and MacMillan.8
1
Reaction of the trifluoromethanesulfonate 38 with lithium
dimethylcuprate gave the protected 3β-methylGA20 derivative
39 and substantial amounts of elimination product 40 (49%)
Only selected H NMR data are reported. For the number-
ing system used throughout this paper see structure GA20,
Scheme 1.
436
J. Chem. Soc., Perkin Trans. 1, 1997

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O
R
CO
MsO
CO2Me
41 R = H
42 R = OH
O
OAc
O
OAc
O
OH
Me2CuLi
O
O
S
O
O
S
+
CO
CO
CO
MsO
CH3
O
CH3
O
O
O
CO2Me
CO2Me
CO2Me
43
44
45
O
OH
CO
MsO
CO2Me
46
ent-13-Acetoxy-10â-hydroxy-3-oxo-20-norgibberell-16-ene-7,19-
dioic acid 7-methyl ester 19,10-lactone 11
319 (38), 287 (60), 273 (42), 243 (30), 111 (26), 91 (56), 77
(26) and 55 (60). Finally elution with 45 and 50% ethyl
acetate in light petroleum gave ent-13-acetoxy-10β,16β,17-
trihydroxy-3-oxo-20-norgibberellane-7,19-dioic acid 7-methyl
ester 19,10-lactone which crystallised from ethyl acetate–light
petroleum (106 mg), mp 179–180 ЊC (Found: C, 60.2; H, 6.6.
C22H28O9 requires C, 60.55; H, 6.42%); δH 1.16 (s, 18-H3),
2.08 (s, OCOCH3), 2.82 (d, J 10, 6-H), 3.08 (d, J 10, 5-H),
3.71 (d, J 12, CHOH), 3.75 (s, OCH3) and 3.84 (d, J 12,
CHOH); m/z 436 (M+, 11%), 401 (89), 394 (34), 376 (71), 362
(24), 359 (39), 358 (33), 316 (35), 298 (29), 287 (54), 274 (31),
141 (20), 91 (65) and 55 (100).
Enone 10 (1.75 g, 4.38 mmol) in THF (75 ml) was added to
tetrakis(triphenylphosphine)palladium(0) (150 mg, 3 mol%) in
THF (20 ml) at room temperature under a nitrogen atmosphere.
Tributylstannane (2.30 ml, 8.75 mmol) was added slowly over a
period of 1.5 h. The reaction mixture was stirred for 0.5 h at
room temperature and then worked-up as usual to give an
orange oil which was purified by flash column chromatography.
Elution with 5% ethyl acetate in light petroleum removed the
tin residues. Further elution with 40% ethyl acetate in light pet-
roleum returned the title compound 11 as a white powder,
which was recrystallised from acetone–light petroleum (1.76
g), mp 158–160 ЊC (lit.,8 reports this as a gum); δH 1.17 (s, 18-
H3), 2.03 (s, OCOCH3), 2.87 (d, J 10, 6-H), 3.10 (d, J 10,
5-H), 3.73 (s, OCH3), 5.00 and 5.16 (2 br s, 17-H2); m/z 402
(M+, 30%), 371 (9), 360 (97), 342 (24), 83 (27), 55 (27) and 43
(100).
ent-13-Acetoxy-16â,17-epoxy-10â-hydroxy-3-methylene-20-
norgibberellane-7,19-dioic acid 7-methyl ester 19,10-lactone 14
Methyltriphenylphosphonium bromide (2 g) in THF (25 ml)
was gently warmed with sodium hydride (480 mg of a 60%
dispersion in mineral oil, pre-washed with hexane), under
nitrogen, with stirring, until a pale green colour appeared. The
mixture was stirred at room temperature for 16 h and then
allowed to settle. An aliquot (12 ml) of the yellow supernatant
(10 ml) was added to the 3-oxo-16α,17-epoxide 12 (450 mg, 1.08
mmol) and stirred for 4 h at room temperature under a nitrogen
atmosphere. Acetone (5 ml) was added and the solvents were
removed under a stream of nitrogen gas. The crude mixture was
purified by flash column chromatography. Elution with 40%
ethyl acetate in light petroleum gave the required 3-methylene
derivative 14, which crystallised from ethyl acetate–light pet-
roleum as needles (385 mg), mp 141–143 ЊC (Found: M+,
416.1842. C23H28O7 requires M, 416.1835); δH 1.23 (s, 18-H3),
2.01 (s, OCOCH3), 2.72 (d, J 10.5, 5-H), partially masking 2.73
(d, J 5, 17-H), 2.82 (d, J 10.5, 6-H), 3.11 (d, J 5, 17-H), 3.73 (s,
OCH3), 4.93 and 4.97 (2 br s, 3-CH2); m/z 416 (M+, 5%), 385 (3),
372 (6), 357 (2), 343 (3), 330 (5), 312 (41), 294 (31), 271 (24), 253
(26), 225 (22) and 43 (100).
Treatment of 3-oxoGA1 methyl ester 13-acetate 11 with 3-
chloroperoxybenzoic acid
Ketone 11 (700 mg, 1.74 mmol) and 3-chloroperoxybenzoic
acid (720 mg of a 50–60% commercial supply) were stirred in
chloroform (150 ml) for 18 h. The reaction mixture was
diluted with chloroform (50 ml) and washed sequentially with
aq. sodium sulfite (2 × 10 ml), saturated aq. sodium hydrogen
carbonate (3 × 40 ml) and water (2 × 20 ml). The chloroform
was dried (Na2SO4) and was removed under reduced pressure
to give a gum, which was purified by flash column chroma-
tography. Elution with 30% ethyl acetate in light petroleum
returned unchanged starting material (157 mg). Further elu-
tion with 45% ethyl acetate in light petroleum returned the
16β,17-epoxide 13, which crystallised from acetone–light pet-
roleum as needles (155 mg), mp 152–155 ЊC (Found: C, 63.4;
H, 5.9. C22H26O8 requires C, 63.16; H, 6.22%); δH 1.16 (s, 18-
H3), 2.00 (s, OCOCH3), 2.81 (d, J 5.5, 17-H) partially mask-
ing 2.82 (d, J 10, 6-H), 3.05 (d, J 5.5, 17-H), 3.11 (d, J 10, 5-
H) and 3.74 (s, OCH3); m/z 418 (M+, 13%), 390 (11), 387
(12), 376 (52), 358 (45), 319 (64), 287 (100), 273 (56), 213
(33), 91 (69), 71 (41) and 55 (88). Further elution with 45%
ethyl acetate in light petroleum gave the 16α,17-epoxide 12,
which crystallised from acetone–light petroleum (316 mg), mp
161–165 ЊC (Found: C, 63.2; H, 6.1. C22H26O8 requires C,
63.16; H, 6.22%); δH 1.18 (s, 18-H3), 2.02 (s, OCOCH3), 2.76
(d, J 5.5, 17-H), 2.86 (d, J 10, 6-H), 3.10 (d, J 5.5, 17-H)
partially masking 3.11 (d, J 10, 5-H) and 3.73 (s, OCH3); m/z
418 (M+, 8%), 390 (9), 387 (13), 376 (100), 375 (32), 358 (39),
ent-13-Acetoxy-16â,17-epoxy-10â-hydroxy-3â-methyl-20-
norgibberellane-7,19-dioic acid 7-methyl ester 19,10-lactone 16
Alkene 14 (100 mg, 0.24 mmol) in THF (8 ml) was stirred under
a hydrogen atmosphere in the presence of 10% palladium on
calcium carbonate (15 mg) for 1 h at room temperature. The
catalyst was filtered off and washed with ethyl acetate (50 ml)
and the solvents removed under reduced pressure, to give solely
the 3α-methyl derivative 16, which crystallised from ethyl
acetate–light petroleum (102 mg), mp 149–152 ЊC (Found: M+,
418.1990. C23H30O7 requires M, 418.1992); δH 0.89 (d, J 6.5, 3α-
CH3), 1.01 (s, 18-H3), 1.97 (s, OCOCH3), 2.55 (d, J 10.5, 5-H),
J. Chem. Soc., Perkin Trans. 1, 1997
437

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2.69 (d, J 5.5, 17-H), 2.73 (d, J 10.5, 6-H), 3.06 (d, J 5.5, 17-H)
and 3.68 (s, OCH3); m/z 418 (M+, 3%), 387 (4), 376 (32), 358
(10), 319 (11), 314 (14), 287 (13), 273 (26), 241 (17), 213 (13),
105 (10), 91 (20), 55 (34) and 43 (100).
OCH3), 4.11 (br s, 3-H) and 5.34 (br s, 2-H); m/z 542 (M+, 4%)
and 540 (M+, 4%), 500 (14), 498 (14), 359 (6), 351 (7), 349 (7),
341 (8), 296 (21), 197 (17), 155 (11), 55 (11) and 43 (100).
ent-13-Acetoxy-2â,3â:16â,17-diepoxy-10â-hydroxy-20-
norgibberellane-7,19-dioic acid 7-methyl ester 19,10-lactone 20
Bromo acetate 19 (1.30 g, 2.41 mmol) in methanol (40 ml) was
stirred with potassium carbonate (665 mg, 4.82 mmol) for 10
min at room temperature. The usual work-up gave a yellow
solid, which was crystallised from acetone–light petroleum to
give the diepoxide 20 (994 mg), mp 146–149 ЊC (Found: M+,
418.1619. C22H26O8 requires M, 418.1627); δH 1.34 (s, 18-H3),
1.99 (s, OCOCH3), 2.42 (dd, J 1.8 and 12, 14α-H), 2.58 (d, J 16,
15α-H), 2.64 (d, J 10, 6-H), 2.73 (d, J 5.5, 17-H), 2.98 (d, J 10,
5-H), 3.09 (d, J 5.5, 17-H), 3.20 (d, J 4, 3-H), 3.32 (t, J 4, 2-H)
and 3.74 (s, OCH3); m/z 418 (M+, 3%), 396 (6), 387 (9), 376 (59),
314 (19), 287 (25), 273 (13), 241 (13), 197 (18), 155 (16), 91 (19),
55 (27) and 43 (100).
ent-13-Acetoxy-10â-hydroxy-3â-methyl-20-norgibberell-16-ene-
7,19-dioic acid 7-methyl ester 19,10-lactone 17
16α,17-Epoxide 16 (350 mg, 0.84 mmol) in acetone (4 ml) was
added to a stirred mixture of sodium acetate (824 mg, 10.0
mmol), sodium iodide (1.26 g, 8.37 mmol) and freshly activated
zinc powder (655 mg, 10.0 mmol) in acetic acid (7.5 ml) and
water (1.5 ml). The green–grey mixture was stirred at room
temperature for 2 h and then worked-up. The zinc was filtered
off and washed with water (50 ml) and ethyl acetate (50 ml).
The aqueous layer was extracted with ethyl acetate (3 × 50 ml)
and the combined organic fractions were washed with aq.
sodium thiosulfate (2 × 10 ml) and water (2 × 25 ml). The
organic layer was dried (Na2SO4) and the solvent was removed
under vacuum. The crude mixture was purified by flash column
chromatography. Elution with 12.5 and 15% ethyl acetate in
light petroleum returned the required olefin 17, which crystal-
lised from ethyl acetate–light petroleum (315 mg), mp 161–
165 ЊC (Found: M+, 402.2053. C23H30O6 requires M, 402.2042);
δH 0.93 (d, J 7, 3α-CH3), 1.04 (s, 18-H3), 2.02 (s, OCOCH3),
2.59 (d, J 10.5, 5-H), 2.73 (d, J 10.5, 6-H), 3.72 (s, OCH3), 4.98
and 5.12 (2 br s, 17-H2); m/z 402 (M+, 10%), 371 (6), 370 (4), 360
(58), 342 (24), 328 (15), 314 (30), 300 (26), 272 (24), 258 (25),
155 (10), 105 (12), 55 (18) and 43 (100).
ent-13-Acetoxy-2â,3â-epoxy-10â-hydroxy-20-norgibberell-16-
ene-7,19-dioic acid 7-methyl ester 19,10-lactone 21
Diepoxide 20 (950 mg, 2.27 mmol) in acetone (10 ml), was
added dropwise to a stirred mixture of sodium iodide (1.02 g,
6.82 mmol), sodium acetate (2.37 g, 27.2 mmol) and freshly
activated zinc powder (1.50 g, 22.7 mmol) in acetic acid (10
ml) and water (1 ml). The reaction mixture was stirred at
room temperature for 2 h and then worked-up. The zinc was
filtered off and washed with water (50 ml) and ethyl acetate
(75 ml). The aqueous layer was extracted with ethyl acetate
(3 × 50 ml) and the combined organic fractions were washed
with aq. sodium thiosulfate (2 × 20 ml) and water (2 × 30
ml). The organic layer was dried (Na2SO4) and the solvent
was removed under vacuum. The crude mixture was purified
by flash column chromatography. Elution with 35% ethyl
acetate in light petroleum gave the 2α,3α-epoxide 21, which
was crystallised from ethyl acetate–light petroleum (596 mg),
mp 164–165 ЊC (Found: C, 65.7; H, 7.0. C22H26O7 requires C,
65.67; H, 6.47%); δH 1.34 (s, 18-H3), 2.01 (s, OCOCH3), 2.60
(d, J 10, 6-H), 2.97 (d, J 10, 5-H), 3.19 (d, J 3.5, 3-H), 3.30
(t, J 4, 2-H), 3.74 (s, OCH3), 4.98 and 5.11 (2 br s, 17-H2); m/z
402 (M+, 23%), 376 (14), 360 (19), 328 (36), 298 (43), 282 (17),
239 (17), 195 (17), 155 (19), 91 (33), 55 (26) and 43 (100).
ent-10â,13-Dihydroxy-3â-methyl-20-norgibberell-16-ene-7,19-
dioic acid 19,10-lactone (3á-methylGA20) 8
3α-MethylGA20 methyl ester 13-acetate 17 (180 mg, 0.45 mmol)
in methanol (5 ml) and 6  sodium hydroxide (10 ml) was
heated to reflux for 48 h. The usual work-up gave a gum, which
was purified by flash column chromatography. Elution with
50% ethyl acetate in light petroleum (containing 2% acetic acid)
gave the required 3α-methylGA20 8 which crystallised from ethyl
acetate–light petroleum as needles (128 mg), mp 187–188 ЊC
(Found: C, 68.9; H, 7.6. C20H26O5 requires C, 69.36; H, 7.51%);
δH 0.94 (d, J 6.5, 3α-CH3), 1.08 (s, 18-H3), 1.27 (dtd, J 6, 12 and
14, 2α-H), 1.52 (ddd, J 6, 12 and 13, 1β-H), 2.54 (d, J 10, 5-H),
2.74 (d, J 10, 6-H), 4.96 and 5.27 (2 br s, 17-H2); δC 14.5 (3-
CH3), 15.8 (C-18), 17.1 (C-11), 28.8 and 31.1 (C-1 and C-2), 38.1
(C-12), 38.3 (C-3), 42.8 and 44.4 (C-14 and C-15), 49.6 (C-8),
51.4 (C-9), 52.2 (C-4), 53.0 (C-6), 58.8 (C-5), 78.3 (C-13), 93.1
(C-10), 107.7 (C-17), 155.8 (C-16), 175.3 (C-7) and 178.4 (C-
19); m/z 346 (M+, 68%), 328 (91), 302 (50), 300 (58), 289 (82),
272 (24), 259 (97), 213 (43), 173 (53), 105 (63), 91 (94), 79 (60),
69 (45) and 55 (100). The methyl ester trimethylsilyl ether
derivative gave KRI 1057; m/z 432 (M+, 100%), 417 (14), 403
(5), 375 (53), 359 (5), 315 (13), 235 (9), 207 (44), 180 (13), 167
(9), 73 (67) and 55 (6).
ent-13-Acetoxy-3-oxo-20-norgibberella-1(10),16-diene-7,19-
dioic acid 7,19-dimethyl ester 23
3β-Hydroxy-1,10-olefin 227 (1.00 g, 2.48 mmol) in acetone (60
ml) was treated with Jones reagent at 0 ЊC, until the orange
colour persisted. The reaction was stirred for a further 0.5 h
at 0 ЊC and then quenched by dropwise addition of methanol
(10 ml). Half of the solvent was removed in vacuo, and the
reaction mixture was worked-up as usual and purified by
flash column chromatography. Elution with 25 and 30%
ethyl acetate in light petroleum gave the required β-keto ester
23 as a gum (715 mg) (Found: M+, 416.1850. C23H28O7
requires M, 416.1835); δH 1.33 (s, 18-H3), 2.01 (s, OCOCH3),
3.18 (br s, 5-H and 6-H), 3.69 and 3.72 (2 s, 7 and 19 OCH3),
5.04 (br s, 17-H2) and 5.54 (m, 1-H); m/z 416 (M+, 17%), 401
(19), 385 (8), 369 (9), 357 (66), 356 (63), 324 (39), 297 (100),
237 (55) and 43 (42).
ent-2â,13-Diacetoxy-3á-bromo-16â,17-epoxy-10â-hydroxy-20-
norgibberellane-7,19-dioic acid 7-methyl ester 19,10-lactone 19
Gibberellin A5 methyl ester 13-acetate 16α,17-epoxide 187 (1.10
g, 2.74 mmol), N-bromoacetamide (945 mg, 6.84 mmol) and
lithium acetate dihydrate (630 mg, 6.16 mmol), were stirred in
acetic acid (10 ml) for 18 h at room temperature. The reaction
mixture was diluted with ethyl acetate (50 ml) and washed with
water (2 × 30 ml). The organic layer was dried (Na2SO4) and the
solvent was removed in vacuo (residual acetic acid was removed
by azeotropic distillation with toluene). The crude reaction
mixture was purified by flash column chromatography. Elution
with 55% ethyl acetate in light petroleum returned the bromo
acetate 19 as a foam (1.35 g) (Found: M+, 540.1032, C24-
H29O979Br requires M, 540.0994); δH 1.21 (s, 18-H3), 2.01 and
2.05 (2 s, 2 and 13 OCOCH3), 2.76 (d, J 5.5, 17-H), 2.80 (d, J
10.5, 6-H), 3.09 (d, J 5.5, 17-H), 3.35 (d, J 10.5, 5-H), 3.74 (s,
ent-13-Acetoxy-3â-hydroxy-20-norgibberella-1(10),16-diene-
7,19-dioic acid 7,19-dimethyl ester 24
Sodium borohydride (680 mg, 18.0 mmol) was slowly added to
ketone 23 (1.50 g, 3.61 mmol) in methanol (70 ml) at room
temperature. The reaction was stirred for 1.5 h and then
worked-up as normal. Purification of the product by flash
chromatography, eluting with 40% ethyl acetate in light pet-
roleum returned the 3β-alcohol 22 (63 mg); spectroscopic data
as previously described.7 Further elution with 45% ethyl acetate
in light petroleum gave the required 3α-alcohol 24 as a gum
438
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(1.43 g) [Found: (M Ϫ 18)+, 400.1884. C23H28O6 requires
M, 400.1886]; δH 1.33 (s, 18-H3), 1.98 (s, OCOCH3), 2.77
(d, J 5, 6-H), 2.92 (m, 5-H), 3.65 (s, OCH3), 3.71 (br s, OCH3
and 3-H), 4.98 (br s, 17-H2) and 5.37 (br s, 1-H); m/z 418 (M+,
1%), 400 (9), 385 (27), 368 (27), 340 (77), 325 (58), 281 (94), 221
(89), 91 (40) and 43 (100).
mg, 0.89 mmol) and methyllithium (1.25 ml, 1.75 mmol) in
diethyl ether (5 ml)] was added to the 3α-toluene-p-sulfonate 28
(100 mg, 0.17 mmol) in diethyl ether (2.5 ml) and THF (1 ml), at
Ϫ10 ЊC under nitrogen. The yellow solution was stirred at
Ϫ10 ЊC for 6 h with monitoring by TLC and then allowed to
warm to room temperature over 3 h. The usual work-up gave a
gum which was purified by flash column chromatography. Elu-
tion with 20% ethyl acetate in light petroleum returned
unchanged starting material 28 (76 mg); spectroscopic data as
previously described.
The above reaction was repeated with 10 equiv. of lithium
dimethylcuprate [from copper() iodide (340 mg, 1.78 mmol)
and methyllithium (2.65 ml, 3.50 mmol) in diethyl ether (7.5
ml)]. The reaction was stirred at Ϫ10 ЊC for 1 h and then
warmed to room temperature over 28 h, with monitoring by
TLC. The usual work-up gave a gum which was purified by
flash column chromatography. Elution with 10% ethyl acetate in
light petroleum gave the triene 29 as a gum (11 mg) (Found:
M+, 400.1885. C23H28O6 requires M, 400.1886); δH 1.33 (s,
18-H3), 1.99 (s, OCOCH3), 2.94 (d, J 4.5, 6-H), 3.31 (m, 5-H),
3.65 and 3.71 (2 s, 7 and 19 OCH3), 5.00 (br s, 17-H2), 5.38
(d, J 9.5, 3-H), 5.63 (ddd, J 2.5, 2.5 and 6, 1-H) and 6.08 (dd,
J 6 and 9.5, 2-H); m/z 400 (M+, 5%), 340 (22), 325 (22), 308
(15), 296 (12), 281 (39), 221 (43) and 43 (100). Further elu-
tion with 20% ethyl acetate in light petroleum returned
unchanged starting material 28 (59 mg); spectroscopic data as
previously described.
ent-13-Acetoxy-3â-methylsulfonyloxy-20-norgibberella-1(10),16-
diene-7,19-dioic acid 7,19-dimethyl ester 25
3α-Alcohol 24 (325 mg, 0.78 mmol) in pyridine (5 ml) and
methanesulfonyl chloride (180 µl, 2.33 mmol) were stirred for 2 h
at room temperature. The crude product was recovered by the
usual work-up and purified by flash chromatography. Elution
with 25% ethyl acetate in light petroleum returned the title 3α-
methanesulfonate 25 as a foam (352 mg) [Found: (M Ϫ 31)+,
465.1569. C23H29O8S requires M, 465.1583]; δH 1.34 (s,
18-H3), 1.99 (s, OCOCH3), 2.65 (d, J 5, 6-H), 2.70 (m, 5-H),
3.05 (s, OSO2CH3), 3.69 and 3.72 (2 s, 7 and 19 OCH3), 4.83 (dd,
J 7 and 9, 3-H), 4.98 (br s, 17-H2) and 5.38 (m, 1-H); m/z 465
[(M Ϫ 31)+, 4%], 436 (2), 414 (1), 368 (53), 340 (81), 325 (57)
and 281 (100).
Reaction of the 1,10-olefin 3á-methanesulfonate 25 with lithium
dimethylcuprate
Lithium dimethylcuprate [prepared from copper() iodide (230
mg, 1.07 mmol) and methyllithium (1.40 ml, 2.02 mmol) in
diethyl ether (5 ml)] was added to the 3α-methanesulfonate 25
(100 mg, 0.20 mmol) in diethyl ether (3 ml) at Ϫ10 ЊC under
a nitrogen atmosphere. The reaction mixture was stirred at
Ϫ10 ЊC for 3 h and then allowed to warm to room temperature
over 1 h. The usual work-up gave a blue–grey gum which was
purified by flash column chromatography. Elution with 25%
ethyl acetate in light petroleum gave the β-keto sultone 13-
acetate 26 as a gum (11 mg) (Found: M+, 464.1508. C23H28O8S
requires M, 464.1504); δH 1.37 (s, 18-H3), 2.01 (s, OCOCH3),
3.70 (s, OCH3), 4.09 and 4.30 (2 d, each J 16, OSO2CH2CO),
4.82 (t, J 5, 3-H), 4.99 (br s, 17-H2) and 5.37 (m, 1-H); m/z 464
(M+, 8%), 433 (4), 422 (35), 404 (31), 362 (31), 344 (32), 281
(46), 239 (70), 221 (48) and 43 (100). Further elution with 30%
ethyl acetate in light petroleum gave the β-keto sultone 27 as a
gum (61 mg) (Found: M+, 422.1391. C21H26O7S requires M,
422.1399); δH 1.37 (s, 18-H3), 3.71 (s, OCH3), 4.12 and 4.32 (2 d,
each J 16.5, OSO2CH2CO), 4.84 (t, J 5, 3-H), 4.98 and 5.15 (2
br s, 17-H2) and 5.37 (m, 1-H); δC 19.0 (C-11), 22.8 (C-18), 26.7,
37.8 and 39.5 (C-12, C-14 and C-15), 45.9 and 48.0 (C-5 and
C-6), 49.2 (C-2), 49.5 and 49.8 (C-4 and C-8), 51.2 and 52.2
(C-9 and OCH3), 61.4 (OSO2–CH2–CO), 79.0 (C-3), 81.6
(C-13), 107.0 (C-1), 109.5 (C-17), 141.7 (C-10), 154.2 (C-16),
174.8 (C-7) and 197.7 (C-19); m/z 422 (M+, 5%), 391 (2), 390 (3),
388 (5), 362 (32), 299 (7), 239 (100), 211 (31) and 84 (13).
ent-13-Acetoxy-3â-trifluoromethylsulfonyloxy-20-norgibberella-
1(10),16-diene-7,19-dioic acid 7,19-dimethyl ester 30
Trifluoromethanesulfonic anhydride (120 µl, 0.72 mmol) was
added dropwise to a stirred solution of the 3α-alcohol 24 (100
mg, 0.24 mmol) in dichloromethane (4 ml) and pyridine (60 µl,
0.72 mmol) at Ϫ10 ЊC under a nitrogen atmosphere. A yellow–
white precipitate formed immediately and the pale orange solu-
tion was stirred at Ϫ10 ЊC for 20 min and then allowed to warm
to room temperature over 1 h, with monitoring by TLC. The
reaction mixture was poured into dichloromethane (20 ml),
washed with 10% copper sulfate solution (2 × 5 ml), saturated
aqueous sodium hydrogen carbonate (2 × 10 ml) and brine (10
ml). The dichloromethane layer was dried over anhydrous
sodium sulfate and then concentrated in vacuo. The resulting
trifluoromethanesulfonate, a clear gum, was used immediately
in the following cuprate reaction.
Lithium dimethylcuprate [prepared from copper() iodide
(227 mg, 1.19 mmol) and methyllithium (2.10 ml, 2.39 mmol) in
diethyl ether (5 ml)], was added to the 3α-trifluoromethane-
sulfonate 30 (as prepared above) in diethyl ether (2 ml) at
Ϫ78 ЊC under nitrogen. The yellow solution was stirred at
Ϫ78 ЊC for 3 h with monitoring by TLC and then warmed up to
Ϫ10 ЊC over 2 h and then worked-up as usual. The crude mix-
ture was purified by flash column chromatography. Elution with
5% ethyl acetate in light petroleum returned the 3α-trifluoro-
methanesulfonate 30 as a gum (64 mg) [Found: (M Ϫ 60)+,
490.1258. C22H25O7SF3 requires M, 490.1273]; δH 1.37 (s,
18-H3), 1.99 (s, OCOCH3), 2.75 (br s, 5-H and 6-H), 3.71 and
3.73 (2 s, 7-OCH3 and 19-OCH3), 5.02 (br s, 17-H2 and 3-H) and
5.37 (m, 1-H); δF (84 MHz, external CFCl3) Ϫ75.5; δC 18.5
(C-11), 22.4 (C-18), 22.9 (OCOCH3), 30.9, 35.3 and 38.6 (C-12,
C-14 and C-15), 43.8 (C-2), 46.0 (C-5 or C-6), 48.2 (C-8), 49.9
(C-5 or C-6), 51.2 (C-4), 51.3 (C-9), 52.3 and 52.5 (7-OCH3 and
19-OCH3), 86.0 (C-13), 92.0 (C-3), 106.8 (C-17), 112.8 (C-1),
119.0 (q, J 320, CF3), 140.0 (C-10), 149.9 (C-16), 169.9 and 171.1
(C-7 and C-19) and 175.4 (OCOCH3); m/z 519 [(M Ϫ 31)+, 1%],
490 [(M Ϫ 60)+, 3%], 490 (3), 458 (4), 430 (3), 429 (3), 415 (2),
400 (19), 340 (47), 326 (27), 298 (51), 239 (66), 221 (53), 155
(37), 69 (30) and 43 (100). Further elution with 15% ethyl acet-
ate in light petroleum returned the triene 29 (7 mg); spectro-
scopic data as described previously. Finally elution with 50%
ethyl acetate in light petroleum returned the 3α-alcohol 24 (36
ent-13-Acetoxy-3â-(4-methylphenylsulfonyloxy)-20-nor-
gibberella-1(10),16-diene-7,19-dioic acid 7,19-dimethyl ester 28
3α-Alcohol 24 (500 mg, 1.20 mmol), DMAP (75 mg, 0.60
mmol) and 4-methylbenzenesulfonyl chloride (2.29 g, 12.0
mmol) were stirred in pyridine (20 ml) at room temperature for
96 h, with monitoring by TLC. The usual work-up gave a brown
oil, which was purified by flash column chromatography. Elu-
tion with 20% ethyl acetate in light petroleum gave the required
3α-toluene-p-sulfonate 28 as a foam (464 mg) [Found: (M Ϫ
31)+, 541.1889. C29H33O8S requires M, 541.1896]; δH 1.09 (s, 18-
H3), 1.98 (s, OCOCH3), 2.45 (s, OSO2C6H4CH3), 2.63 (d, J 4.5,
6-H), 2.70 (m, 5-H), 3.65 and 3.69 (2 s, 7 and 19 OCH3), 4.60
(dd, J 7 and 9.5, 3-H), 4.96 (br s, 17-H2), 5.28 (m, 1-H), 7.33 and
7.79 (2 d, each J 8.5, OSO2C6H4CH3); m/z 541 [(M Ϫ 31)+, 2%],
512 (1), 480 (4), 414 (2), 385 (35), 340 (86), 281 (100), 221 (70),
173 (26), 155 (72) and 91 (97).
Treatment of the 3á-toluene-p-sulfonate 28 with lithium
dimethylcuprate
Lithium dimethylcuprate [prepared from copper() iodide (170
J. Chem. Soc., Perkin Trans. 1, 1997
439

View Article Online
mg); spectroscopic data consistent with previously obtained
values.
COCH3), 2.67 (d, J 10, 5-H), 2.77 (d, J 10, 6-H), 3.74 (s, OCH3),
4.16 and 4.20 (2 d, each J 14.5, OSO2CH2COCH3), 4.79 (dd, J
6.5 and 11, 3-H), 4.96 and 5.26 (2 br s, 17-H2); m/z 482 (M+, 37,
16%) and 440 (M+, 42, 8%).
The reaction was repeated using lithium dimethylcuprate
[prepared from copper() iodide (227 mg, 1.19 mmol) and
methyllithium (2.10 ml, 2.39 mmol) in diethyl ether (5 ml)],
which was added to the 3α-trifluoromethanesulfonate 30 in
diethyl ether (2 ml) at Ϫ25 ЊC under nitrogen. The reaction was
stirred at Ϫ25 ЊC for 4 h and then warmed to Ϫ5 ЊC over 6 h.
The usual work-up returned the crude product which was puri-
fied by flash column chromatography. Elution with 15% ethyl
acetate in light petroleum returned the triene 29 (78 mg);
spectroscopic data as previously described. Further elution
with 45% ethyl acetate in light petroleum returned the 3α-
alcohol 24 (9 mg); spectroscopic data consistent with previously
obtained values.
The reaction was repeated using 10 equiv. of lithium di-
methylcuprate [prepared from copper() iodide (402 mg, 2.12
mmol) and methyllithium (2.95 ml, 4.14 mmol) in diethyl ether
(5 ml)]. The mixture was stirred at Ϫ10 ЊC for 2.5 h and then
allowed to warm to room temperature for 6 h. The crude prod-
uct was recovered by the usual work-up and purified by flash
column chromatography. Elution with 30% ethyl acetate in light
petroleum gave a complex mixture of at least two components
1
(17 mg) unidentifiable by H NMR spectroscopy. Further elu-
tion with 40 and 45% ethyl acetate in light petroleum returned
a 1:6 mixture of 35 and 36 (37 mg); spectroscopic values con-
sistent with those obtained previously. Finally elution with 60%
ethyl acetate in light petroleum gave a 1:4 mixture of 42 and 37
(36 mg). Repeated flash chromatography of this mixture gave
on elution with 57.5% ethyl acetate in light petroleum a clean
sample of the 3α-(2-oxopropylsulfonyloxy) derivative 37 as a
gum (22 mg) (Found: M+, 482.1604. C23H30O9S requires M,
482.1611); δH as described previously; δC 13.2 (C-18), 17.3
(C-11), 27.0 and 29.5 (C-1 and C-2), 30.7 (OSO2CH2COCH3),
38.0 (C-12), 42.9 and 45.4 (C-14 and C-15), 50.5 (C-8), 50.9,
52.2, 52.3 and 56.9 (C-5, C-6, C-9 and 7-OCH3), 52.6 (C-4),
62.4 (OSO2CH2COCH3), 78.1 (C-13), 81.1 (C-3), 91.6
(C-10), 107.6 (C-17), 156.3 (C-16), 172.3 (C-19), 174.9 (C-7) and
194.4 (OSO2CH2COCH3); m/z 482 (M+, 68%), 464 (6), 450 (82),
438 (7), 423 (37), 362 (7), 344 (38), 312 (58), 303 (100), 300 (95),
284 (56), 241 (90), 157 (52), 135 (69), 106 (67), 91 (68) and 55
(62).
Dehalogenation using dimethylphosphite
1β-Iodide 327 (500 mg, 0.94 mmol) in toluene (25 ml) was heated
to reflux. Benzoyl peroxide (15 mg) and dimethyl phosphite
(605 µl, 6.60 mmol) were added slowly and the mixture was
heated under reflux for 24 h with monitoring by TLC. The
solvent was removed in vacuo and the residue purified by flash
column chromatography. Elution with 40% ethyl acetate in light
petroleum returned unchanged starting material 32 (46 mg).
Further elution with 50% ethyl acetate in light petroleum gave
GA1 methyl ester 13-acetate 33 (330 mg), mp 131–132 ЊC (lit.,7
mp 137–140 ЊC); spectroscopic data as described previously.
ent-13-Acetoxy-10â-hydroxy-3â-methylsulfonyloxy-20-nor-
gibberell-16-ene-7,19-dioic acid 7-methyl ester 19,10-lactone 35
3-epi-Gibberellin A1 methyl ester 13-acetate 347 (300 mg, 0.74
mmol) in pyridine (5 ml) and methanesulfonyl chloride (170 µl,
2.23 mmol) were stirred for 2 h at room temperature. The usual
work-up gave a gum which was purified by flash column chro-
matography. Elution with 45 and 50% ethyl acetate in light
petroleum gave the required 3α-methanesulfonate 35 as a gum
(310 mg) (Found: M+, 482.1607. C23H30O9S requires M,
482.1611); δH 1.19 (s, 18-H3), 2.09 (s, OCOCH3), 2.69 (d, J 10,
5-H), 2.77 (d, J 10, 6-H), 3.07 (s, OSO2CH3), 3.74 (s, OCH3),
4.73 (dd, J 6 and 11, 3-H), 5.00 and 5.15 (2 br s, 17-H2); m/z 482
(M+, 7%), 451 (4), 440 (75), 422 (13), 344 (30), 298 (47), 282
(100), 223 (60), 155 (65), 105 (69), 91 (79) and 79 (85).
ent-13-Acetoxy-10â-hydroxy-3á-methylsulfonyloxy-20-nor-
gibberell-16-ene-7,19-dioic acid 7-methyl ester 19,10-lactone 43
Gibberellin A1 methyl ester 13-acetate 33 (120 mg, 0.30 mmol)
in pyridine (3 ml) and methanesulfonyl chloride (69 µl, 0.89
mmol) were stirred for 2 h at room temperature. The usual
work-up gave the crude product which was purified by flash
chromatography. Elution with 50% ethyl acetate in light pet-
roleum returned the required 3β-methanesulfonate 43 as a gum
(143 mg) (Found: M+, 482.1601. C23H30O9S requires M,
482.1611); δH 1.18 (s, 18-H3), 2.02 (s, OCOCH3), 2.69 (d, J 10.5,
6-H), 3.10 (s, OSO2CH3), 3.12 (d, J 10.5, 5-H), 3.73 (s, OCH3),
4.74 (br s, 3-H), 5.00 and 5.17 (2 br s, 17-H2); m/z 482 (M+, 1%),
451 (2), 440 (6), 422 (1), 386 (8), 355 (4), 344 (25), 242 (25), 282
(100), 223 (27), 105 (25), 91 (25) and 79 (26).
Treatment of 3á-methanesulfonate 35 with lithium
dimethylcuprate
Lithium dimethylcuprate in diethyl ether (5 ml) [prepared from
copper() iodide (200 mg, 1.06 mmol) and methyllithium (1.48
ml, 2.07 mmol)] was added dropwise to the 3α-methane-
sulfonate 35 (100 mg, 0.21 mmol) in diethyl ether (3 ml) and
THF (1 ml) at Ϫ10 ЊC, under a nitrogen atmosphere. The mix-
ture was stirred at Ϫ10 ЊC for 4 h and then allowed to warm to
room temperature over 4 h. The crude product was recovered by
the usual work-up and purified by flash column chromato-
graphy. Elution with 30% ethyl acetate in light petroleum
gave a complex mixture of unidentifiable compounds. Further
elution with 40% ethyl acetate in light petroleum gave a 1:1
mixture of starting material 35 and the 3α-(2-oxopropyl-
sulfonyloxy) 13-acetoxy derivative 36 (27 mg); δH 1.18 (s, 18-H3),
2.02 (s, OCOCH3), 2.41 (s, OSO2CH2COCH3), 2.67 (d, J 10, 5-
H), 2.77 (d, J 10, 6-H), 3.74 (s, OCH3), 4.15 and 4.19 (2 d, each
J 14.5, OSO2CH2COCH3), 4.79 (dd, J 6.5 and 11, 3-H), 4.99
and 5.14 (2 br s, 17-H2); δH 35; as previously described; m/z 524
(M+, 36, 12%) and 482 (M+, 35, 6%). (Repeated flash chroma-
tography failed to separate the two compounds.) Finally, fur-
ther elution with 50 and 55% ethyl acetate in light petroleum
returned a 1.2:1 mixture of the 2-oxopropylsulfonyloxy deriva-
tive 37 and the 13-hydroxy-3α-methanesulfonate 42 (31 mg); δH
1.19 (s, 18-H3), 2.67 (d, J 10, 5-H), 2.77 (d, J 10, 6-H), 3.06 (s,
OSO2CH3), 3.73 (s, OCH3), 4.72 (dd, J 6.5 and 11, 3-H), 4.96
and 5.26 (2 br s, 17-H2); δH 1.20 (s, 18-H3), 2.41 (s, OSO2CH2-
Treatment of the 3â-methanesulfonate 43 with lithium dimethyl-
cuprate
Lithium dimethylcuprate [prepared from copper() iodide (101
mg, 0.53 mmol) and methyllithium (740 µl, 1.04 mmol) in diethyl
ether (5 ml)] was added dropwise to the 3β-methanesulfonate 43
(50 mg, 0.10 mmol) in diethyl ether (2.5 ml) at Ϫ10 ЊC under a
nitrogen atmosphere. The mixture was stirred at Ϫ10 ЊC for 6 h
with monitoring by TLC and then allowed to warm to room
temperature over 18 h. The crude product was recovered by the
usual work-up and purified by flash column chromatography.
Elution with 55% ethyl acetate in light petroleum gave a 2:7
mixture of the starting material 43 and the 3β-(2-oxopropyl-
sulfonyloxy) 13-acetate 44 (12 mg); δH (major component) 1.18
(s, 18-H3), 2.02 (s, OCOCH3), 2.46 (s, OSO2CH2COCH3), 2.68
(d, J 10.5, 6-H), 3.08 (d, J 10.5, 5-H), 3.73 (s, OCH3), 4.16 and
4.23 (2 d, each J 14, OSO2CH2COCH3), 4.83 (br s, 3-H), 5.00
and 5.16 (2 br s, 17-H2); δH (minor component); as previously
described; m/z 524 (M+, 44, 14%) and 482 (M+, 43, 1%) both
apparent. (Repeated flash chromatography failed to separate
the two compounds.) Further elution with 60 and 62.5% ethyl
acetate in light petroleum returned a 1:4 mixture of the 13-
hydroxy-3β-methanesulfonate 46 and the 13-hydroxy-3β-(2-
oxopropylsulfonyloxy) compound 45 (30 mg); δH (major com-
440
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
ponent) 1.18 (s, 18-H3), 2.46 (s, OSO2CH2COCH3), 2.68 (d, J
10.5, 6-H), 3.07 (d, J 10.5, 5-H), 3.74 (s, OCH3), 4.18 and 4.24 (2
d, each J 14, OSO2CH2COCH3), 4.83 (br s, 3-H), 4.97 and 5.27
(2 br s, 17-H2); δH (minor component) 1.18 (s, 18-H3), 2.69 (d, J
10, 6-H), 3.11 (d, J 10, 5-H), 3.12 (s, OSO2CH3), 3.73 (s, OCH3),
4.74 (br s, 3-H), 4.97 and 5.27 (2 br s, 17-H2); m/z 482 (M+, 45,
11%) and 440 (M+, 46, 7%). (Repeated flash column chrom-
atography failed to separate the two compounds.)
ative 39 and GA5 methyl ester 13-acetate 40 (14 mg). Further
elution with 30% ethyl acetate in light petroleum returned GA5
methyl ester 13-acetate 40 (34 mg); spectroscopic data as pre-
viously described.7 Finally elution with 50 and 60% ethyl
acetate in light petroleum returned epi-GA1 methyl ester 13-
acetate 34 (57 mg); spectroscopic data consistent with pre-
viously obtained values.
ent-10â,13-Dihydroxy-3á-methyl-20-norgibberell-16-ene-7,19-
dioic acid 7-methyl ester 19,10-lactone 9
ent-13-Acetoxy-10â-hydroxy-3â-trifluoromethylsulfonyloxy-20-
norgibberell-16-ene-7,19-dioic acid 7-methyl ester 19,10-lactone
38
3β-MethylGA20 13-acetate 7-methyl ester 39 in methanol (5 ml)
and sodium hydroxide (6 , 10 ml) was heated to reflux for 16 h.
After cooling, the usual work-up gave required acid 9 as a gum
(18 mg, 100%) (Found: M+, 346.1783. C20H26O5 requires M,
346.1780); δH 1.07 (d, J 7, 3-CH3), 1.09 (s, 18-H3), 2.71 (d,
J 10.5, 5-H), 2.75 (d, J 10.5, 6-H), 4.96 and 5.28 (each br s,
17-H2); m/z 346 (M+, 40%), 328 (100), 300 (26), 289 (75), 282
(22), 258 (16) and 83 (72).
Trifluoromethanesulfonic anhydride (250 µl, 1.49 mmol) was
added dropwise to a stirred solution of the 3α-alcohol 34 (200
mg, 0.50 mmol) in dichloromethane (6 ml) and pyridine (200 µl,
2.48 mmol) at Ϫ10 ЊC under nitrogen. An off-white precipitate
was formed immediately and the orange–yellow solution was
stirred for 1 h at Ϫ10 ЊC and then warmed to room temperature
for 1 h. The reaction mixture was poured into dichloromethane
(20 ml) and washed sequentially with 10% aq. copper sulfate
(2 × 5 ml), saturated aq. sodium hydrogen carbonate (2 × 10
ml) and brine (10 ml). The dichloromethane was dried over
anhydrous sodium sulfate and the solvent removed under vac-
uum. The resulting trifluoromethanesulfonate 38, a pale
yellow gum, was used immediately in the cuprate reaction. A
sample of the trifluoromethanesulfonate was purified by flash
chromatography eluting with 20% ethyl acetate in light pet-
roleum to give 38 as a white foam (Found: M+, 536.1313.
C23H27O9F3S requires M, 536.1328); δH 1.22 (s, 18-H3), 2.02 (s,
OCOCH3), 2.71 (d, J 10, 6-H), 2.78 (d, J 10, 5-H), 3.75 (s,
CO2CH3), 4.88 (dd, J 11 and 6.3, 3-H), 4.99 and 5.16 (each br s,
17-H2); m/z 536 (M+, 19%), 505 (9), 494 (81), 476 (17), 462 (10),
435 (14), 344 (50) and 282 (100).
Tanginbozu dwarf rice immersion assay
Tanginbozu dwarf rice seedlings22 were soaked in water for 2
days at 28 ЊC under constant light (the water was changed at 12
h intervals) by which time the coleoptiles had emerged. The ger-
minated seeds were selected for uniformity and were placed in
groups of six in cylindrical vials (18 mm diameter and 50 mm
depth), which contained sterile water (1 ml) and a methanolic
solution of the substrate (10 µg in 10 µl). Two vials containing
sterile water (1 ml) and methanol (10 µl) were used as controls.
After 7 days the total length of the plants was measured (see
Table 2).
Acknowledgements
The EPSRC is thanked for the award of studentships (H. L. and
M. P.) and financial support from IACR, Long Ashton is grate-
fully acknowledged.
Treatment of the 3á-trifluoromethanesulfonate 38 with lithium
dimethylcuprate
Lithium dimethylcuprate [prepared from copper() iodide (480
mg, 2.52 mmol) and methyllithium (3.54 ml, 4.95 mmol) in
diethyl ether (10 ml)] was added dropwise to the 3α-
trifluoromethanesulfonate 38 (as prepared above) in diethyl
ether (4 ml) at Ϫ10 ЊC under a nitrogen atmosphere. The mix-
ture was stirred at Ϫ10 ЊC for 2 h and then worked-up as nor-
mal. The crude product was purified by flash column chrom-
atography. Elution with 20% ethyl acetate in light petroleum,
returned the required ent-13-acetoxy-10β-hydroxy-3α-methyl-
20-norgibberell-16-ene-7,19-dioic acid 7-methyl ester 19,10-
lactone 39 as a gum (7 mg) (Found: M+, 402.2043. C23H30O6
requires M, 402.2042); δH 1.04 (s, 18-H3), 1.07 (d, J 7, 3β-CH3),
2.02 (s, OCOCH3), 2.70 (d, J 10.5, 6-H), 2.80 (d, J 10.5, 5-H),
3.72 (s, OCH3), 4.98 and 5.14 (2 br s, 17-H2); m/z 402 (M+, 39%),
371 (16), 360 (100), 342 (58), 328 (31), 314 (72), 298 (85), 283
(62), 282 (62), 258 (54), 157 (38), 129 (44), 105 (53), 91 (71) and
55 (69). Further elution with 30 and 40% ethyl acetate in light
petroleum returned GA5 methyl ester 13-acetate 40 (94 mg);
spectroscopic data consistent with previously obtained values.7
Finally, elution with 50% ethyl acetate in light petroleum
returned the original 3α-alcohol 34 (38 mg); spectroscopic data
as previously described.
The reaction was repeated using lithium dimethylcuprate (5
equiv., prepared as previously described), which was added drop-
wise to the 3α-trifluoromethanesulfonate 38 in diethyl ether (4
ml) at Ϫ78 ЊC under a nitrogen atmosphere. The reaction was
stirred at Ϫ78 ЊC for 1.5 h. No reaction was apparent by TLC
and so the reaction was warmed to Ϫ42 ЊC and was stirred at
this temperature for 1.5 h. The usual work-up gave a pink gum
which was purified by flash column chromatography. Elution
with 20% ethyl acetate in light petroleum, returned the required
3β-methyl compound 39 (27 mg); spectroscopic data as pre-
viously described. Further elution with 25% ethyl acetate in
light petroleum returned a 2:1 mixture of the 3β-methyl deriv-
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Paper 6/05570B
Received 9th August 1996
Accepted 26th September 1996
442
J. Chem. Soc., Perkin Trans. 1, 1997