Stereocontrol with lithium trimethylzincate toward gibberellin synthesis

Article abstract of DOI:10.1002/ejoc.201200156

Substrate control in target-oriented synthesis is generally important in establishing the required stereogenic center rather than reagent control. During the course of the total synthesis toward Gibberellin A₃ (1), a model compound (21) as the A-ring of 1 was accomplished in five overall steps with an overall yield of 15 %, starting from furfural through conjugate addition of lithium trimethylzincate to oxabicyclo[2.2.1]heptadienedicarboxylic ester (2) as the key step. Relative to more common lithium dimethylcuprate or aluminum reagents, this zincate complex showed a complete selectivity with higher reactivity than with other simple enone compounds. The incoming methyl group was 100 % selective from the ring oxygen side of 2, and the enolate intermediate can be protonated stereoselectivly without the bridge-oxygen-ring opening.

Full text of DOI:10.1002/ejoc.201200156

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200156
Stereocontrol with Lithium Trimethylzincate toward Gibberellin Synthesis
Minoru Isobe,*[a] Ching-Te Chiang,[a] Kuo-Wei Tsao,[a] Chia-Yi Cheng,[a] and
Reimar Bruening[b][‡]
Keywords: Synthetic methods / Conjugate addition / Zinc / Gibberellin / Natural products
Substrate control in target-oriented synthesis is generally im-
portant in establishing the required stereogenic center rather
than reagent control. During the course of the total synthesis
toward Gibberellin A3 (1), a model compound (21) as the A-
enedicarboxylic ester (2) as the key step. Relative to more
common lithium dimethylcuprate or aluminum reagents, this
zincate complex showed a complete selectivity with higher
reactivity than with other simple enone compounds. The in-
ring of 1 was accomplished in five overall steps with an over- coming methyl group was 100% selective from the ring oxy-
all yield of 15%, starting from furfural through conjugate ad-
dition of lithium trimethylzincate to oxabicyclo[2.2.1]heptadi-
gen side of 2, and the enolate intermediate can be protonated
stereoselectivly without the bridge-oxygen-ring opening.
Organic synthesis utilizes a variety of organometallic rea- A-ring in the structure of several Gibberellins, a class of
gents, which activate the substrate molecules and express important plant hormones, as represented by GA3 1 (Fig-
unique chemoselectivity and stereoselectivity. Various kinds ure 1). Six GAn analogs (n = 3, 7, 30, 32, 68, and 80) feature
of organozinc reagents are known in organic synthetic the same substructure as A (Scheme 1).[6]
methodology such as the Clemmensen reduction, the Re-
formatsky reaction, the Simmons–Smith reaction, the
Staudinger ketene cycloaddition, the Negishi reaction,
among others. Isobe et al. first reported in 1977 that lithium
trialkylzincate, R3ZnLi·2LiX, reagents (R = Me, nBu; sBu,
tBu, Ph, etc.) undergo conjugate addition to α,β-unsatu-
Figure 1. Structure of Gibberellin A3 (1).
rated ketones such as cyclohexenone and cyclopen-
tenones.[1] Lithium trimethylzincate(II) was directly pre-
pared from zinc chloride or its non-hygroscopic tetra-
methylethylenediamine crystals (TMEDA-ZnCl2) and
3 equiv. MeLi·LiBr in THF solvent.[1] Seebach et al. re-
ported enantioselective 1,4-addition with the zincate com-
plex with chiral amine ligands in 1979. Watson et al. con-
firmed the conjugate addition in 1986.[2] Yamamoto et al.
Scheme 1. Retrosynthesis of the A-ring of Gibberellin A3 aiming at
also reported an asymmetric conjugate addition of the zinc-
the use of lithium trimethylzincate.
ate complex,[3] which they later applied to several total syn-
theses of natural products.[4] There have been extensive
To assure the correct complex stereochemistry of A
studies recently on the structure and reactivity of the zinc
(Scheme 1), the key features of such a synthesis must be the
reagents including multinuclear catalysis for copper-zinc
strict steric control of the transformation at the stereogenic
carbon atoms in a cyclohexene precursor such as C
(Scheme 1). To ensure the trans-stereochemical correlation
at the two allylic positions, we planned a lactone ring for-
reagents.[5]
We became interested in the further development of zinc-
ate reagents in an application towards the synthesis of the
mation with stepwise opening from the bridge oxygen (B).
However, the selective introduction of a methyl group in
[a] Chemistry Department, National Tsing Hua University,
101, Sec. 2, Kuang Fu Road, Hsinchu, Taiwan
step b from the bridge-oxygen side of precursor C poses a
challenge. Different acetal moieties are available for C
through a Diels–Alder reaction between a protected fur-
fural D and dimethyl but-2-ynedioate E. In fact, this oxa-
bicyclo[2.2.1]heptadiene (X = O or S) compound was read-
ily prepared in good yields by heating. Now selective conju-
gate addition for the methyl group to C was examined.
Fax: +886-35736494
E-mail: minoru@mx.nthu.edu.tw
[b] Nagoya University, School of Bioagriculture,
Chikusa, Nagoya 464, Japan
[‡] Current address: 647 Pickering Avenue, Fremont, CA 94536,
USA
E-mail: rcbruening@mac.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200156.
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M. Isobe, C.-T. Chiang, K.-W. Tsao, C.-Y. Cheng, R. Bruening
SHORT COMMUNICATION
First lithium trimethylzincate reagent was tried with di- trimethylzincate reagent in THF solvent (as described
thioacetal 2 (C, X = S) to see whether its use would address above) was placed in a flask, which was then cooled to
the stereochemical problem. Lithium trimethylzincate –78 °C.
(Me3ZnLi) was prepared by mixing 3.3 equiv. MeLi·LiBr
A solution containing equivalent amounts of 2 and 7 was
and 1.1 equiv. ZnCl2 solution in THF at 0 °C,[1] and this added at the same time to this solution, and the reaction
zincate was allowed to react with 2 at this temperature for temperature was then gradually allowed to reach 0 °C. Af-
30 min. The following aqueous workup afforded a crystal- ter workup, the crude reaction products were analyzed by
line product 6, and the structure was determined by X-ray NMR spectroscopy to show that the maleic diester sub-
analysis. The methyl group was stereo- and regioselectively structure of 2 disappeared at a faster rate than 7 (details of
introduced by an assumed chelative interaction as shown in the data can be seen in the Supporting Information). The
3 and 4. The product 6 was obtained in 89% yield. Addition simple enone 7 was demonstrated to react at 0 °C or higher
of the proton source at 0 °C afforded 6 (Scheme 2). We con- to give 8. Such a difference in reactivity may be attributed
firmed that the zinc enolate 4 did not open the ether ring to chelation-driven preferred activation of the diester carb-
at –78 °C but did so at higher temperatures below 0 °C. In onyl groups by the zinc reagent.
order to avoid the ether ring opening to 6, the lithium tri-
Addition of Me3ZnLi to 9 (C, X = O as ethylene acetal),
methylzincate complex (prepared at 0 °C) was cooled down on the other hand, afforded different stereoisomeric prod-
to –78 °C, to which 2 was added, and the temperature was ucts such as 10 and 11 (Scheme 4). The selectivity changed
maintained for 30 min. Quenching of the reaction with in the case of ethylene acetal 9 as a result of some additional
2 equiv. phenol in THF solution at –78 °C before aqueous coordination, and the products were analyzed as a mixture
workup afforded 5 as a mixture of diastereomers 5a and 5b of isomers such as 10 and 11 (for detail see ref.[11] and the
(in a ratio of 1.6:1) in 87% yield. These results imply that Supporting Information). The 1,3-dithiane moiety seems
the bridge-oxygen side is more chelative to deliver the therefore to be indispensable for the regioselectivity, in ad-
methyl group in a complete stereoselective manner.
dition to the directing of the methyl addition from the β-
face by the bridge oxygen atom.
Scheme 4. Addition of the lithium trimethylzincate complex to eth-
ylene acetal precursor 9 gives 10 and 11 with Me from the bridge-
oxygen side but without regioselectivity.
Addition of Me2CuLi (lithium dimethylcuprate) to 2 at
–78 °C instead of Me3ZnLi largely yielded 5 together with
the bridge-opening product 6, even when the reaction was
quenched with a proton source at –78 °C (Scheme 5). In
this case, the intermediate copper enolate might change to
lithium enolate in equilibrium at a much faster rate, which
causes the ring opening at –78 °C.[7] In all of these cases,
conjugate addition of the zincate complexes was ac-
companied by ether-ring opening.
Scheme 2. Addition of lithium trimethylzincate to oxabicyclo-
[2.2.1]heptadiene gives enolate 4 which can lead to 5 or 6 by
quenching at different reaction temperatures.
A difference in the nucleophilic reactivity of lithium tri-
methylzincate could be observed by directly comparing the
two typical electrophiles such as the unsaturated diester 2
and the simple enone 7 (Scheme 3). Only 1.0 equiv. lithium
Scheme 5. (a) Me2CuLi: 5 (57% yield) plus 6 (14%) (quenched at
–78 °C). (b) Me4Al·Li (Me3Al·MeLi +LiCl, LiBr, NaBr): 6 (55%
yield). (c) Me2AlCl (from tBuCl+Me3Al): 6 (55% yield). (d) Et2-
AlCl/CH2Cl2: 12a and 12b (ca. 1:1, in 81% yield).
Alexakis et al. reported the dinuclear catalysis with a Zn-
or Al-ate complex and CuTC [CuTC = copper(I)thiophene-
2-carboxylate] in a similar addition to dimethyl 7-oxabicy-
Scheme 3. Competitive addition of lithium trimethylzincate to 2
and 7.
2110
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Stereocontrol with Lithium Trimethylzincate toward Gibberellin Synthesis
clo[2.2.1]heptadienedicarboxylate without a substituent at Table 1. Proton-source effects to selective formation of 5a or 5b.
–40 °C to obtain the dienol in quantitative yields, with com-
plete stereospecificity of the incoming nucleophile cis to the
hydroxy group.[8] Yang et al. reported an aluminum reagent
involved in a similar conjugate addition to 15, which pro-
vides largely 16 with ring opening.[9] Thus, diene alcohol
products of type 6 are formed stereoselectively. For alumi-
num reagents, a cationic mechanism[10] might be at work
(Scheme 6).[11]
Scheme 6. Oxygen-atom-directed conjugate addition to the unsatu-
rated diester.
In our own experiments on 2, treatment with tetrameth-
[a] Prepared by ZnCl2 and MeLi·LiBr, with stirring for 30 min at
ylaluminumate reagent Me4AlLi (prepared from AlMe3 and
0 °C. [b] Combined yield of 5a and 5b. [c] Separated ratio.
MeLi) or Me2AlCl (prepared from tBuCl and Me3Al) did
not afford any addition product below 0 °C only starting
material. But at higher temperatures such as 32 °C, it af-
drolysis of the diesters 5a or 5b (KOH in THF/H2O) was
only successful for the latter, which gave the monoacid 20
in 95% yield (Scheme 7). This selectivity might be attrib-
uted to the difference in the steric interaction of the possible
forded 6 in 55% yield in the presence of additional salts
LiCl (LiBr or NaBr)[12] (Scheme 5). Treatment of 2 with
dimethylchloroaluminum, which was prepared from tert-
tetrahedral intermediates 18 and 19; thus, 19 must have a
butyl chloride and trimethylaluminum, also provided 6 at
greater steric interaction with the surrounding substructures
room temperatures. Diethylchloroaluminum in dichloro-
than 18. This assumption is supported by the fact that no
methane, on the other hand, yielded a mixture of 12a and
selectivity was found with 5a, which afforded a 1:1 mixture
12b in 81% total yield. The incoming ethyl group of the
of the corresponding monoacids under the same conditions.
In both cases, the second hydrolysis of the remaining ester
minor product 12b was opposite to the bridge oxygen
atom.[11]
group became very slow under these conditions because of
Obviously the fate of the zinc enolate is important in
the anion-repulsive interaction required for OH– to attack
the carboxylate anion molecule to isolate the monoacids in
high yields.
obtaining the protonated products of type 5 without ring
opening. Thus, we embarked on a systematic investigation
of the protonation conditions. Use of various proton
sources toward the intermediate 4 yielded either 5a or 5b as
shown in Table 1. Each proton-source reagent was added in
THF solution directly to the reaction mixture at –78 °C af-
ter 30 min of mixing 2 with Me3ZnLi. The products were
isolated, crystallized, and analyzed by X-ray crystallogra-
phy to be 5a (m.p. 81.8 °C, δ(Me) = 1.65 ppm) and 5b (m.p.
114.8 °C, δ(Me) = 1.40 ppm), respectively. The results are
summarized in Table 1. Among the four phenols (Entries
1–4), the bulkier ones provide less amounts of 5b, and the
smaller cerium chloride (Entry 5) afforded 5a as the major
product in 88% yield. In contrast, phenolphthalein gives
only 5b as the dominant product (Entry 6), while di-
Scheme 7. Selective hydrolysis of the diester 5b to 20 and γ-lactone
formation.
thiothreitol did not give a preferential product (Entry 7).
The zinc enolate remains stable at –78 °C without ring
opening, and it can be protonated in a stereoselective man-
ner.
The anticipated lactonization was examined with various
kinds of Lewis acids. Among those, trimethylsilyl triflate
For subsequent formation of the γ-lactone (step a in afforded the γ-lactone 21 (ν 1783 cm–1) and its isomeric lac-
Scheme 1), the protonated product dimethyl ester 5 was hy- tone 22 (ν 1790 cm–1) in a 5:2 ratio in 52% combined yield
drolyzed under alkaline conditions. Attempted selective hy- (Scheme 7).
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M. Isobe, C.-T. Chiang, K.-W. Tsao, C.-Y. Cheng, R. Bruening
SHORT COMMUNICATION
2.14 mmol, 2.0 equiv.) at –78 °C with stirring for 30 min, and the
mixture was then poured into saturated NH4Cl (pH = 4, 10 mL)
solution at 0 °C. The mixture solution was extracted with diethyl
ether (3ϫ10 mL) and brine (30 mL), dried with MgSO4, and con-
centrated. The residue was purified by column chromatography
(SiO2, EtOAc/hexane, 2:8) to afford both 5a (199 mg, 0.578 mmol,
54%) and 5b (121 mg, 0.353 mmol, 33%) as yellow solids.
In summary, the synthesis of a model for the A-ring of
Gibberellin 21 was accomplished in five overall steps with
a 15% overall yield, starting from commercially available
furfural 23 and the use of a lithium trimethylzincate reagent
as the critical step (Scheme 8). Relative to more common
cuprate or aluminate reagents, the zincate complex showed
a differentiated high specific activity. Further research on
the conjugate addition chemistry of the zincates is ongoing.
Dimethyl
(2R*,3S*)-1-(1,3-Dithian-2-yl)-3-methyl-7-oxabicyclo-
[2,2,1]hept-5-ene-2,3-dicarboxylate (5a): Rf = 0.74 (EtOAc/hexane,
1
2:3). M.p. 79.3–81.8 °C. H NMR (400 MHz, CDCl3): δ = 1.65 (s,
3 H), 1.89–1.99 (m, 1 H), 2.02–2.11 (m, 1 H), 2.74–2.82 (m, 2 H),
2.98–3.03 (m, 2 H), 3.21 (s, 1 H), 3.59 (s, 3 H), 3.65 (s, 3 H), 4.47
(s, 1 H), 4.67 (d, J = 1.6 Hz, 1 H), 6.45 (dd, J = 1.6, 6.0 Hz, 1 H),
6.60 (d, J = 6.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
25.3, 25.6, 29.0, 29.2, 45.6, 51.6, 51.7, 56.9, 58.6, 85.2, 94.6, 134.7,
136.5, 171.0, 172.6 ppm. HRMS (EI): calcd. for C15H20O5S2
344.0752; found 344.0743.
Dimethyl
(2S*,3S*)-1-(1,3-Dithian-2-yl)-3-methyl-7-oxabicyclo-
[2,2,1]hept-5-ene-2,3-dicarboxylate (5b): Rf = 0.68 (EtOAc/hexane,
1
2:3). M.p. 114.3–114.8 °C. H NMR (400 MHz, CDCl3): δ = 1.40
(s, 3 H), 1.80–1.91 (m, 1 H), 2.08–2.15 (m, 1 H), 2.79–2.85 (m, 2
H), 2.89–2.98 (m, 2 H), 3.24 (s, 1 H), 3.66 (s, 3 H), 3.72 (s, 3 H),
4.71 (d, J = 1.6 Hz, 1 H), 5.13 (s, 1 H), 6.39 (d, J = 6.0 Hz, 1 H),
6.54 (d, J = 6.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
20.9, 25.5, 29.7, 30.4, 47.3, 51.2, 51.6, 52.2, 55.0, 84.6, 92.0, 136.5,
136.7, 170.8, 173.8 ppm. HRMS (EI): calcd. for C15H20O5S2
344.0752; found 344.0758.
Scheme 8. Synthesis of Gibberellin A-ring via lithium trimethyl-
zincate addition.
Experimental Section
Effects of Different Proton Sources After Methylation of 2. General
Procedure: Under Ar (or nitrogen) atmosphere, MeLi·LiBr (2.2 m
in Et2O solution, 0.46 mL, 1.01 mmol, 3.3 equiv.) was added to a
mixture of dry THF (1.6 mL), ZnCl2 (45.7 mg, 0.336 mmol,
1.1 equiv.), and Ph3CH (as an indicator, 1.0 mg) at 0 °C. The mix-
ture was stirred for 30 min at the same temperature and then cooled
to –78 °C. 7-Oxanorbornadiene 2 (100 mg, 0.305 mmol, 1.0 equiv.)
in THF (1.5 mL) was added dropwise at –78 °C, and the mixture
was stirred for 30 min. The reaction was quenched by addition of
different proton sources (in 2 mL THF, excluding phenol, and
CeCl3·7H2O was just added to the mixture solution, 0.610 mmol,
2.0 equiv.) at –78 °C with stirring for 30 min, and the mixture was
then poured into saturated NH4Cl (pH = 4, 5 mL) solution at 0 °C.
The mixture solution was extracted with diethyl ether (3ϫ5 mL)
and brine (15 mL), dried with MgSO4, and concentrated. The resi-
due was purified by column chromatography (SiO2, EtOAc/hexane,
2:8) to afford compounds 5a and 5b. The details of results are
shown in Figure 2.
Dimethyl
3-(1,3-Dithian-2-yl)-6-hydroxy-1-methylcyclohexa-2,4-
diene-1,2-dicarboxylate (6): Under Ar (or nitrogen) atmosphere,
MeLi·LiBr (2.2 m in Et2O solution, 1.54 mL, 3.38 mmol, 3.3 equiv.)
was added to a mixture of dry THF (5.3 mL), ZnCl2 (154 mg,
1.13 mmol, 1.1 equiv.), and Ph3CH (as an indicator, 1.0 mg) at
0 °C. The mixture was stirred for 30 min at the same temperature
and then cooled to –78 °C. 7-Oxanorbornadiene 2 (337 mg,
1.03 mmol, 1.0 equiv.) in THF (5 mL) was added dropwise at
–78 °C; the cooling bath was then removed, and the mixture was
stirred for 30 min at 0 °C. The reaction was quenched by addition
of phenol (C6H5OH, 0.18 mL, 2.05 mmol, 2.0 equiv.) at 0 °C with
stirring for 30 min, and the mixture was then poured into saturated
NH4Cl (pH = 4, 10 mL) solution at 0 °C. The mixture solution was
extracted with diethyl ether (3ϫ10 mL) and brine (30 mL), dried
with MgSO4, and concentrated. The residue was purified by col-
umn chromatography (SiO2, EtOAc/hexane, 2:8) to afford alcohol
6 (313 mg, 0.91 mmol, 89%) as a yellow solid. Rf = 0.71 (EtOAc/
hexane, 2:3). M.p. 136.8–137.6 °C. 1H NMR (400 MHz, CDCl3): δ
= 1.41 (s, 3 H), 1.75–1.85 (m, 1 H), 1.92 (d, J = 5.6 Hz, 1 H), 2.06–
2.11 (m, 1 H), 2.79–2.85 (m, 2 H), 2.94–3.04 (m, 2 H), 3.69 (s, 3
H), 3.72 (s, 3 H), 4.87–4.89 (m, 1 H), 5.94 (dd, J = 2.0, 9.6 Hz, 1
H), 5.97 (s, 1 H), 6.38 (dd, J = 2.8, 9.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.7, 24.5, 30.3, 30.7, 47.1, 51.5, 52.4, 54.0,
72.8, 123.6, 129.0, 136.1, 139.9, 166.7, 175.9 ppm. HRMS (EI):
calcd. for C15H20O5S2 344.0752; found 344.0753.
Methyl Addition to 2 with Organozinc Reagents: Under Ar (or ni-
trogen) atmosphere, MeLi·LiBr (2.2 m in Et2O solution, 1.61 mL,
3.54 mmol, 3.3 equiv.) was added to a mixture of dry THF
(5.7 mL), ZnCl2 (160 mg, 1.18 mmol, 1.1 equiv.), and Ph3CH (as
an indicator, 1.0 mg) at 0 °C. The mixture was stirred for 30 min at
the same temperature and then cooled to –78 °C. 7-Oxanorborna-
diene 2 (352 mg, 1.07 mmol, 1.0 equiv.) in THF (5 mL) was added
dropwise at –78 °C, and the mixture stirred for 30 min. The reac-
tion was quenched by addition of phenol (C6H5OH, 0.19 mL,
Figure 2. Ortep drawings of the crystal structures of 6, 5a, and 5b.
Lactone 21: Yellow solid. Rf = 0.38 (EtOAc/hexane, 2:3). M.p.
128.8–130.3 °C. IR: ν = 3399 (br.), 1783, 1712 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.53 (3H, s), 1.94–2.03 (m, 1 H), 2.10–2.15
2112
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Stereocontrol with Lithium Trimethylzincate toward Gibberellin Synthesis
[3] K. Yamamoto, M. Kanoh, N. Yamamoto, J. Tsuji, Tetrahedron
(m, 1 H), 2.50–2.56 (m, 2 H), 3.13–3.28 (m, 2 H), 3.71 (s, 3 H),
3.94 (d, J = 11.6 Hz, 1 H), 3.96 (s, 1 H), 4.04 (s, 1 H), 4.05–4.09
(m, 1 H), 6.09 (dd, J = 3.2, 9.6 Hz, 1 H), 6.48 (d, J = 9.6 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 16.5, 24.5, 26.4, 26.5, 42.9,
48.7, 52.9, 54.3, 67.6, 88.3, 129.5, 135.0, 170.2, 176.3 ppm. HRMS
(EI): calcd. for C14H18O5S2 330.0596; found 330.0594.
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Lactone 22: Yellow solid. Rf = 0.36 (EtOAc/hexane, 2:3). M.p.
128.7–129.6 °C. IR: ν = 3384 (br.), 1790, 1714 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.84–1.93 (m, 1 H), 2.03–
2.09 (m, 1 H), 2.76–2.82 (m, 3 H), 2.85–2.91 (m, 1 H), 3.63 (s, 3
H), 3.84 (s, 1 H), 4.15 (dd, J = 4.8, 9.6 Hz, 1 H), 4.26 (s, 1 H), 4.79
(dd, J = 4.8, 5.6 Hz, 1 H), 5.07 (d, J = 9.6 Hz, 1 H), 6.67 (d, J =
6.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6, 24.9,
30.2, 30.2, 45.1, 47.5, 49.9, 53.7, 72.7, 73.2, 128.1, 139.6, 173.3,
176.4 ppm. HRMS (EI): calcd. for C14H18O5S2 330.0596; found
330.0600.
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Supporting Information (see footnote on the first page of this arti-
cle): Gibberellin congeners, complete experimental details, competi-
tive experimental details, crystal structures.
[10] O. Equey, E. Vrancken, A. Alexakis, Eur. J. Org. Chem. 2004,
2151–2159.
[11] Different chelation mechanisms for the formation 11 and 12.
Acknowledgments
The authors are indebted to the National Science Foundation and
NTHU for financial support of the current research.
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Published Online: March 2, 2012
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