Enantioselective Total Synthesis of (?)-Doliculide Using Catalytic Asymmetric Hydrogenations

Article abstract of DOI:10.1002/hlca.201900023

A concise and efficient strategy has been developed to construct a polyketide chain by employing relay asymmetric hydrogenations catalyzed by two chiral spiro iridium catalysts. By using this strategy, an enantioselective total synthesis of (?)-doliculide

Full text of DOI:10.1002/hlca.201900023

DOI: 10.1002/hlca.201900023
FULL PAPER
Enantioselective Total Synthesis of (À )-Doliculide Using Catalytic
Asymmetric Hydrogenations
Wen Che,a Danyang C. Wen,a Shou-Fei Zhu,a and Qi-Lin Zhou*a, b
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, P. R. China, e-mail: qlzhou@nankai.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China
b
Dedicated to Prof. Dr. François Diederich for his enormous contributions to science
A concise and efficient strategy has been developed to construct a polyketide chain by employing relay
asymmetric hydrogenations catalyzed by two chiral spiro iridium catalysts. By using this strategy, an
enantioselective total synthesis of (À )-doliculide has been achieved in 19 steps with 6.9% overall yield. The route
features high enantioselectivity and diastereoselectivity. The catalyst loading can be as low as 0.005 mol-%. It is
convenient to obtain natural polyketides and their analogues by this strategy.
Keywords: doliculide, natural products, polyketides, total synthesis, asymmetric catalysis, hydrogenation.
Introduction
doliculide is special. Doliculide and borrelidin are the
Polyketides are a class of widespread natural products, only known examples of macrocyclic natural products
which originate from the condensation of acetyl-CoA which contain three and four deoxypropionate units
or propionyl-CoA biogenetic precursors catalyzed by within their carbon frameworks, respectively.[11] To
polyketide synthases.[1][2] Polyketides commonly con- date, only a few total syntheses of doliculide have
tain a series of methyl or hydroxy groups in the been reported in literature. Yamada et al.[6–8] reported
sequence with divergent stereochemistry. Over the the isolation, structure determination, and total syn-
past decades, tremendous efforts have been made to thesis of doliculide in 1994. They used chiral substrates
the syntheses of polyketides because of their various derived from menthone and chiral auxiliary-induced
pharmacological activities.[3–5] Doliculide is a novel 16- aldol reactions to construct the key polyketide chain
membered polyketide isolated from Japanese sea hare of doliculide, and achieved the total synthesis of
Dolabella auricularia. It exhibited potent in vitro anti- doliculide in 31 linear steps. Ghosh et al.[12] synthesized
proliferative activity against the human leukemia cell doliculide in 36 linear steps, using Charette cyclo-
line HeLa-S3 with an IC50 value of 1 ng/mL.[6–8] propanation and ring opening in the presence of chiral
Recently, doliculide was also shown to induce actin dioxaborolane reagent to introduce methyl-substi-
assembly into clump-like aggregates and apoptosis in tuted stereogenic centers, and the asymmetric epox-
cancer cells, which makes it a potential anticancer idation to construct 1,3-diol structure. Hanessian
agent.[9][10] However, the content of doliculide in et al.[11] achieved the total synthesis of doliculide in
nature is very low (8.2 mg of doliculide was isolated linear 25 steps, starting from chiral-pool materials.
from 33 kg of wet sea hare D. auricularia), which limits Altmann et al.[13] developed two approaches to dolicu-
its pharmacological study. Also, the structure of lide in linear 15 and 14 steps, respectively, using chiral
auxiliary- or chiral reagent-induced aldol reactions as
key steps. The only total synthesis of doliculide using
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/hlca.201900023
asymmetric catalysis as a key step was reported by
Minnaard et al.[14] in linear 26 steps. They constructed
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Helv. Chim. Acta 2019, 102, e1900023
Scheme 1. Retrosynthetic analysis of doliculide and our synthetic plan.
the 1,3-diol unit by CoreyÀ Itsuno reduction and
asymmetric catalytic hydrogenation, and the syn-
Results and Discussion
trimethyl unit by asymmetric catalytic conjugate Scheme 1 showed our retrosynthetic analysis for the
addition. construction of 1,3-diol and syn-trimethyl of deoxypro-
Although important progress has been made in the pionate. We envisioned that if stereogenic centers can
synthesis of doliculide, most of the synthetic strategies be incorporated into the carbon chain one by one in a
reported in the literature relied on chiral building catalytic way, it could provide an effective solution for
blocks or auxiliaries, except Minnaard’s work. On the the synthesis of natural products with repeating
other hand, despite immense endeavor to gain stereogenic centers. Also, it becomes convenient to
synthetic access to polyketide natural products and prepare derivatives in this manner regardless of inter-
derivatives, the controlled formation of elaborate play of each stereogenic center. The key for reaching
polyketide structures, the construction of multiple this target is to find suitable asymmetric catalytic
stereogenic centers and carbon chain elongation, reactions that produce chiral hydroxy or methyl
remains a challenge. For instance, the reported groups, in which the configuration of the stereogenic
methods to construct the polyketide chain having five center is determined by the chiral catalyst, but not by
stereogenic centers were very intricate. Transformation the substrate. Our group has developed a number of
of functional groups, and the controls of absolute and highly effective catalytic asymmetric hydrogenation
relative configuration of the hydroxy or methyl groups reactions.[15][16] We wish to use Ir-catalyzed asymmetric
must be taken into account together in the synthesis hydrogenation of a β-keto ester[17] to construct a 1,3-
of doliculide.
diol unit and Ir-catalyzed asymmetric hydrogenation
of α-acrylic acid,[18][19] to build the 1,3-methyl unit of
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Scheme 2. Synthesis of β-carbonyl methyl esters 7 and 8.
Table 1. Construction of 1,3-diol.
deoxypropionates. By varying the configuration of
catalysts, the absolute and relative configuration of
newly formed stereogenic centers can be controlled.
The asymmetric hydrogenation of substrate 1 was
carried out to evaluate chiral catalysts and the (R)-cat-
1 was found to be the choice of catalyst, which
produces compound 2 in 93% yield with 98% ee
under 60 atm of H2 at room temperature in methanol
Entry Catalyst R[a]
S/C
P(H2) Time Yield dr
[atm] [h][b] [%]
t
1[c]
2[c]
3[c]
4[f]
(S)-cat-1 Bn
500 10
6.5
2
2
77
62
58
85
6.2:1[d]
40:1[e]
70:1[e]
39:1[e]
using BuOK as a base (Scheme 2). The catalyst (R)-cat-
1 is very active, only 0.005 mol-% is needed. The
reaction could be scaled up to 30 grams. The hydroxy
group was protected by methoxymethyl (MOM) and
benzyl (Bn), respectively. To extend the carbon chain
and construct another β-carbonyl ester unit in com-
pounds 3 and 4, a Claisen condensation with tert-butyl
acetate was firstly performed. However, the reaction
gave the condensation product in low yield (data not
show). We then hydrolyzed esters 3 and 4 to the acids
(S)-cat-1 MOM 500 10
(R)-cat-1 MOM 500 10
(S)-cat-1 MOM 1000 100
5
[a]
[b]
Bn=benzyl, MOM=methoxymethyl.
Time needed to
[c]
[d]
complete the reaction. Base/catalyst=27. Determined by
[e]
HPLC using a Chiralpak AD-H column. Determined by GC
using a Supelco Chiral β-dex-325 column. Base/catalyst=100.
[f]
5 or 6, which yielded β-carbonyl ester 7 and 8 in 85% β-carbonyl ester 7 having a benzyl protecting group
and 95% yield, respectively, by treating with mono- was hydrogenated in MeOH under 10 atm of H2 at
t
methyl malonate, carbonyldiimidazole, and magnesi- room temperature in the presence of BuOK as a base.
um ethoxide.[20]
The catalyst (S)-cat-1 (0.2 mol-%) afforded the desired
After extending the carbon chain, the hydrogena- product 11 in 77% yield and 6.2:1 dr within 6.5 h
tion conditions were investigated for introducing the (Table 1, Entry 1). By subjecting the MOM-protected
1,3-diol structure in the second iteration (Table 1). The substrate 8 to the same reaction conditions, the
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Scheme 3. Synthesis of acid 17.
reaction time was reduced to 2 h, and the diastereo-
The asymmetric hydrogenation of compound 17
selectivity was improved to 40:1 dr (Entry 2). When the was performed to generate the second methyl-sub-
catalyst (R)-cat-1 was used, the configuration of the stituted stereogenic center. The catalyst (R)-cat-2a
second hydroxy group was inverted, indicating that (0.1 mol-%) containing two 3,5-dimethylphenyl groups
the configuration of the newly formed hydroxy group at the P-atom of the ligand afforded the desired
was controlled by the catalyst, not by the existing product 18 in 72% yield with 86.2:13.8 dr (Table 2,
stereogenic center in the substrate (Entry 3). These Entry 1). The catalyst (R)-cat-2b which has bulker aryl
results showed that the MOM is a better protecting groups at the P-atom of the ligand remarkably
group in the hydrogenation of carbonyl in the second improved the yield and diastereoselectivity of the
iteration. In order to improve the yield of the desired reaction. The catalyst (R)-cat-2c having two methyl
product, it is essential to suppress the side reaction, groups at the benzyl position of the ligand further
the retro oxa-Michael reaction, and accelerate the increased the diastereoselectivity of the reaction
hydrogenation reaction. When the hydrogenation was (Entries 4 and 5). It is noteworthy that if Cs2CO3 was
performed with 0.1 mol-% of catalyst (S)-cat-1 under used as additive, its amount must be controlled to half
100 atm of H2 using less base, the yield of product 12 of equivalent to the substrate. Slight excess resulted in
was increased to 85% (Entry 4).
incomplete conversion of the substrate.
With the 1,3-diol fragment 12 in hand, we then
After establishing the hydrogenation condition, the
attempted to introduce the methyl-substituted stereo- acid 18 was subjected to the next iterative synthesis of
genic centers (Scheme 3). The first methyl-substituted deoxypropionate (Scheme 4). The acid 21 with a new
stereogenic center was introduced in 84% yield and methyl-substituted stereogenic center was obtained in
7.3:1 dr by using Fráter’s protocol through intra- high yield with 97.3:2.7 dr by carboxymethylation
molecular chiral induction.[21] The protection of the with Meldrum’s acid, alkenylation with Eschenmoser’s
hydroxy group in compound 13, followed by hy- salt, and asymmetric hydrogenation catalyzed by (R)-
drolysis, afforded acid 15 in 85% yield for two steps. cat-2c.[18] The acid 21 was treated with glycine tert-
Subsequently, acid 15 was converted to α-substituted butyl ester hydrochloride in the presence of diethyl
acrylic acid 17 in 65% yield by means of the protocol phosphorocyanidate (DEPC) to provide amide 22. The
we developed previously, that are carboxymethylation selective deprotection of MOM of amide 22 produced
with Meldrum’s acid, alkenylation with Eschenmoser’s compound 23 by using 2.5 equivalent of B-bromo-
salt.[18] The TBS protecting group is intact under the catecholborane in dichloromethane at À 78 C, while
°
acidic reaction conditions.
the TBS was intact in this condition.[22] The reaction
°
temperature should be kept at À 78 C or lower,
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Conclusions
Table 2. Optimization of the asymmetric hydrogenation to
introduce the second methyl-substituted stereogenic center.[a]
In summary, a stereocontrolled synthesis of potent
anti-cancer agent doliculide has been accomplished in
linear 19 steps with 6.9% overall yield. The stereogenic
centers in the polyketide chain were established by
iridium-catalyzed asymmetric hydrogenation in high
enantioselectivity and diastereoselectivity. It is conven-
ient to change the absolute and relative configuration
of stereogenic centers by choosing the right catalyst,
thus providing an effective method to prepare
analogues of doliculide for biological evaluation. This
synthetic strategy has a high potential for wide
application in the synthesis of other polyketide natural
products containing multiple chiral hydroxy and
methyl groups.
Entry Catalyst
Additive (equiv.) Yield [%][b] dr[c]
1
2
3
4
5
(R)-cat-2a Et3N (5.0)
72
>99
>99
>99
>99
86.2:13.8
93:7
94:6
95.4:4.6
(R)-cat-2b Et3N (5.0)
(R)-cat-2b Cs2CO3 (0.5)
(R)-cat-2c Et3N (5.0)
(R)-cat-2c Cs2CO3 (0.5)
Experimental Section
General Experimental Information
95.2:4.8
[a]
[b]
1
substrate=50 mg. Determined by H-NMR. [c] Determined
All chemicals were purchased from J&K, Acros, Alfa,
and Aldrich, and were used as received. Melting points
were measured on a RY-I apparatus and uncorrected.
1H- and 13C-NMR spectra were recorded on a Bruker AV
400 spectrometer or a Varian Mercury Plus 400
by HPLC of the corresponding amide using a Chiralpak AD-3
column.
otherwise the TBS group was also deprotected (for spectrometer at 400 MHz (1H-NMR), 100 MHz (13C-
details, see Supporting Information).
NMR) in CDCl3. Chemical shifts were reported in ppm
Naturally, after establishment of the polyketide down field from internal Me4Si and external 85%
chain 23, our synthetic plan called for combining 23 H3PO4, respectively. Optical rotations were determined
with a tyrosine derivative (Scheme 5). Commercially using a Perkin Elmer 341 MC polarimeter. HR-MS were
available 3-iodo-L-tyrosine was converted to N-Boc-3- recorded on IonSpec FT-ICR mass spectrometer with
iodo-N-methyl-O-TBS-D-tyrosine (24) by four steps ESI resource. Enantiomeric excesses and diastereoiso-
according to previous procedures.[13] Esterification of meric ratios of the asymmetric hydrogenation prod-
23 with 24 gave fully protected 25 in 85% yield. ucts were determined by chiral HPLC and GC analyses.
Treatment of 25 with trifluoroacetic acid deprotected HPLC analyses were performed using a Hewlett
O-TBS, N-Boc, and tert-butyl ester. The resulting amino Packard Model HP 1100 instrument with a Chiralcel AD-
acid underwent selective cycloamidation in the pres- 3 column. GC Analyses were performed using a
ence of BOPCl to form the macrocyclic lactam 27 in Hewlett Packard Model HP 7890 Series. Absolute MeOH
70% yield along with a minor trifluoroacetate deriva- was distilled from magnesium under nitrogen atmo-
tive 26 (20% yield). Compound 26 can be converted sphere. Hydrogen gas (99.999%) was purchased from
to 27 by reacting with aqueous ammonia in MeOH. Boc Gas Inc., Tianjin.
Removal of the protecting group TBS in 27 by
exposure to tetrabutylammonium fluoride in THF
General Procedure for Asymmetric Hydrogenations of
afforded the target molecule, (À )-doliculide in 83%
β-Keto Esters and -Substituted Acrylic Acids
yield. The NMR spectroscopic data and the optical
rotation of the synthetic doliculide are identical to To a 20 mL hydrogenation vessel was added the
t
those reported in literature.[7][13]
catalyst (S)-cat-1 or (R)-cat-1, BuOK, β-ketoester, and
anhydrous MeOH under nitrogen atmosphere. The
vessel was then placed in an autoclave and purged
with hydrogen by pressurizing to 1 atm and releasing
the pressure. This procedure was repeated three times,
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Scheme 4. Synthesis of polyketide chain 23.
1
and the autoclave was then pressurized to 10 atm or afford the product. The yield was determined by H-
100 atm of H2. The mixture was stirred at room NMR analysis. The diastereoisomeric ratio of product
°
temperature (25–30 C), until no obvious hydrogen was determined after converting to amide with ani-
pressure drop was observed. After releasing the hydro- line.
gen pressure, the mixture was evaporated and
1
analyzed by H-NMR to determin2e the conversion.
Methyl (3S)-3-(Methoxymethoxy)-4-methylpenta-
The residue was purified by column chromatography noate (4). Rf =0.55 (petroleum ether/ethyl acetate
over silica gel with petroleum ether/ethyl acetate to 5:1). [α]D20 =28.3 (c=1.72, CHCl3). IR (KBr): 3851, 3741,
determine the yield. The diastereoisomeric ratio of the 3445, 2953, 2355, 1735, 1642, 1525, 1459, 1384, 1264,
1
product was determined by chiral GC or HPLC.
1153, 1093, 1038, 915, 748, 682. H-NMR (400 MHz,
CDCl3): 4.63 (q, J=6.9, 2 H); 3.85–3.81 (m, 1 H); 3.66 (s,
A hydrogenation tube with a stir bar was charged 3 H); 3.32 (s, 3 H); 2.45 (qd, J=15.2, 6.3, 2 H); 2.01–1.76
with α-substituted acrylic acid and cat-2 (S/C=1000), (m, 1 H); 0.89 (t, J=6.9, 6 H). 13C-NMR (101 MHz,
in an argon-filled glovebox. Then, the additives and CDCl3): 172.60; 96.61; 79.66; 55.74; 51.69; 36.76; 31.67;
MeOH were injected into the hydrogenation tube by a 17.99; 17.55. HR-ESI-MS: 213.1099 (C9H18NaO4+, [M+
syringe. The hydrogenation tube was put into an Na]+; calc. 213.1097).
autoclave. Hydrogen was charged into the autoclave
and released for three times. The autoclave was then
Methyl (5S)-5-(Methoxymethoxy)-6-methyl-3-oxo-
charged with hydrogen to 6 atm, and the mixture was heptanoate (8). Rf =0.52 (petroleum ether/ethyl acetate
stirred at 45 C for specified time before releasing the 3:1). [α]D25 =À 2.44 (c=1.8, CHCl3). IR (KBr): 3855, 3741,
°
hydrogen. The mixture was concentrated under 3612, 2958, 2895, 2358, 1743, 1646, 1520, 1452, 1383,
reduced pressure, acidified with 2 N HCl and extracted 1321, 1255, 1151, 1095, 1037, 917, 840, 747, 656, 581.
with diethyl ether. After evaporation of the solvent, 1H-NMR (400 MHz, CDCl3): 4.62 (q, J=6.9, 2 H); 3.90 (dt,
the residue was passed through a pad of silica gel to J=8.1, 3.9, 1 H); 3.73 (s, 3 H); 3.51 (s, 2 H); 3.32 (s, 3 H);
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Scheme 5. Synthesis of doliculide.
2.75 (dd, J=16.2, 8.5, 1 H); 2.56 (dd, J=16.2, 3.4, 1 H); CHCl3). IR (KBr): 3852, 3742, 3451, 2956, 2357, 1731,
1.99–1.80 (m, 1 H); 0.89 (dd, J=10.9, 6.9, 6 H). 13C-NMR 1642, 1526, 1457, 1378, 1263, 1156, 1095, 1037, 912,
1
(101 MHz, CDCl3): 201.81; 167.69; 96.70; 78.84; 55.83; 750, 528. H-NMR (400 MHz, CDCl3): 4.66 (s, 2 H); 4.31–
52.45; 50.12; 44.57; 31.60; 18.16; 17.38. HR-ESI-MS: 4.18 (m, 1 H); 3.68 (s, 3 H); 3.63–3.54 (m, 1 H); 3.46 (d,
250.1647 (C11H24NO5+, [M+NH4]+; calc. 250.1649).
J=4.0, 1 H); 3.40 (s, 3 H); 2.57–2.34 (m, 2 H); 1.93–1.76
(m, 1 H); 1.64–1.57 (m, 1 H); 1.52–1.35 (m, 1 H); 0.87
Methyl (3S,5S)-3-Hydroxy-5-(methoxymethoxy)-6- (dd, J=6.8, 2.2, 6 H). 13C-NMR (101 MHz, CDCl3):
methylheptanoate (12). Rf =0.17 (petroleum ether/ 172.95; 97.36; 80.51; 64.74; 56.08; 51.75; 41.81; 37.49;
ethyl acetate 5:1). [α]D25 =À 53.2 (c=1.39, CHCl3). IR 31.86; 18.48; 17.60. HR-ESI-MS: 271.1517 (C12H24O5Na+,
(KBr): 3744, 3485, 3055, 2957, 2359, 1734, 1542, 1441, [M+Na]+; calc. 271.1516).
1373, 1264, 1155, 1092, 1037, 910, 742. 1H-NMR
(400 MHz, CDCl3): 4.66 (s, 2 H); 4.31–4.18 (m, 1 H); 3.68
Methyl
(2S,3S,5S)-3-{[tert-Butyl(dimethyl)silyl]-
(s, 3 H); 3.63–3.54 (m, 1 H); 3.46 (d, J=4.0, 1 H); 3.40 (s, oxy}-5-(methoxymethoxy)-2,6-dimethylheptanoate
3 H); 2.57–2.34 (m, 2 H); 1.93–1.76 (m, 1 H); 1.61–1.43 (14). Rf =0.74 (petroleum ether/ethyl acetate 3:1).
(m, 2 H); 0.87 (dd, J=6.8, 2.2, 6 H). 13C-NMR (101 MHz, [α]D25 =À 21.85 (c=0.65, CHCl3). IR (KBr): 3852, 3743,
CDCl3): 172.95; 97.36; 80.51; 64.74; 56.08; 51.75; 41.81; 3445, 3056, 2951, 2887, 2357, 1737, 1644, 1526, 1460,
1
37.49; 31.86; 18.48; 17.60. HR-ESI-MS: 257.1358 1380, 1264, 1154, 1087, 1043, 905, 833, 744. H-NMR
(C11H22O5Na+, [M+Na]+; calc. 257.1359).
(400 MHz, CDCl3): 4.62 (q, J=6.9, 2 H); 4.24–4.10 (m,
1 H); 3.65 (s, 3 H); 3.47–3.41 (m, 1 H); 3.37 (s, 3 H); 2.69
Methyl
(2S,3S,5S)-3-Hydroxy-5-(methoxymeth- (qd, J=7.0, 4.5, 1 H); 1.86 (ddquint., J=10.9, 6.9, 4.1,
oxy)-2,6-dimethylheptanoate (13). Rf =0.36 (petrole- 1 H); 1.53–1.29 (m, 2 H); 1.11 (d, J=7.1, 3 H); 0.93–0.78
um ether/ethyl acetate 4:1). [α]D25 =À 54.2 (c=1.1, (m, 15 H); 0.13–0.04 (m, 6 H). 13C-NMR (101 MHz,
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CDCl3): 174.55; 96.43; 80.72; 70.55; 55.58; 51.67; 46.21;
5-[(2S,4R,5S,7S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-
34.60; 31.92; 25.94; 18.20; 18.13; 17.17; 10.07; À 4.36; 7-(methoxymethoxy)-2,4,8-trimethylnonyl]-2,2-di-
À 4.42. HR-ESI-MS: 363.2561 (C18H39O5Si+, [M+H]+; methyl-1,3-dioxane-4,6-dione (19). Rf =0.36 (petrole-
calc. 363.2561).
um ether/ethyl acetate 2.5:1). [α]D25 =À 60.0 (c=2.19,
CHCl3). IR (KBr): 3745, 3446, 3056, 2959, 2359, 2320,
1728, 1647, 1543, 1459, 1380, 1265, 1208, 1154, 1093,
5-[(2R,3S,5S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-5-
(methoxymethoxy)-2,6-dimethylheptyl]-2,2-dimeth-
1
1039, 902, 834, 742. H-NMR (400 MHz, CDCl3): 4.75–
yl-1,3-dioxane-4,6-dione (16). Rf =0.39 (petroleum 4.47 (dd, J=27.6, 6.8 2 H); 3.72 (dd, J=5.5, 2.8, 1 H);
ether/ethyl acetate 3:1). [α]D25 =À 44.1 (c=0.79, 3.44 (q, J=5.6, 2 H); 3.34 (s, 3 H); 2.05–2.00 (m, 1 H);
CHCl3). IR (KBr): 3744, 3056, 2955, 2356, 2315, 1719, 1.96–1.83 (m, 3 H); 1.79 (s, 4 H); 1.73 (s, 3 H); 1.34–1.17
1
1544, 1426, 1265, 1154, 1038, 898, 834, 744. H-NMR (m, 3 H); 1.06–1.01 (m, 1 H); 0.95 (d, J=6.1, 3 H); 0.87–
(400 MHz, CDCl3): 4.68–4.49 (m, 2 H); 3.82–3.78 (m, 0.82 (m, 18 H); 0.04 (d, J=1.6, 6 H). 13C-NMR (101 MHz,
1 H); 3.58–3.55 (m, 1 H); 3.49–3.40 (m, 1 H); 3.36–3.24 CDCl3): 166.04; 166.02; 104.85; 96.44; 80.97; 72.36;
(m, 3 H); 2.12–2.07 (m, 1 H); 2.03–1.82 (m, 3 H); 1.78 (s, 55.62; 44.40; 40.67; 36.33; 33.33; 32.32; 31.42; 28.72;
3 H); 1.72 (s, 3 H); 1.43–1.28 (m, 2 H); 0.97–0.73 (m, 28.68; 26.71; 26.00; 20.40; 18.39; 18.16; 16.67; 14.12;
18 H); 0.03 (t, J=2.7, 6 H). 13C-NMR (101 MHz, CDCl3): À 3.90; À 4.45. HR-ESI-MS: 525.3222 (C26H50NaO7Si+, [M
165.88; 104.85; 96.60; 81.24; 72.46; 55.45; 44.08; 36.23; +Na]+; calc. 525.3218).
32.81; 31.48; 29.69; 28.64; 26.58; 25.95; 18.10; 16.90;
13.74;
À 4.18;
À 4.65.
HR-ESI-MS:
483.2750
(4S,6R,7S,9S)-7-{[tert-Butyl(dimethyl)silyl]oxy}-9-
(methoxymethoxy)-4,6,10-trimethyl-2-methyli-
(C23H44NaO7Si+, [M+Na]+; calc. 483.2749).
deneundecanoic Acid (20). Rf =0.34 (petroleum ether/
ethyl acetate 3:1). [α]D20 =À 40.6 (c=0.33, CHCl3). IR
(KBr): 3850, 3743, 3443, 2947, 2361, 1697, 1641, 1525,
(4R,5S,7S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7-
(methoxymethoxy)-4,8-dimethyl-2-methylidenenona-
noic Acid (17). Rf =0.36 (petroleum ether/ethyl acetate 1462, 1385, 1262, 1154, 1046, 928, 831, 756, 671, 560.
3:1). [α]D20 =À 21.6 (c=0.25, CHCl3). IR (KBr): 3855, 1H-NMR (400 MHz, CDCl3): 6.31 (d, J=1.4, 1 H); 5.62 (s,
3743, 3444, 2949, 2359, 1697, 1640, 1520, 1461, 1384, 1 H); 4.73–4.49 (m, 2 H); 3.80–3.64 (m, 1 H); 3.53–3.42
1256, 1150, 1080, 1041, 924, 834, 769, 669, 548. 1H-NMR (m, 1 H); 3.37 (s, 3 H); 2.40 (dd, J=13.6, 4.9, 1 H); 1.99–
(400 MHz, CDCl3): 6.31 (d, J=1.5, 1 H); 5.65 (s, 1 H); 1.85 (m, 2 H); 1.86–1.68 (m, 2 H); 1.38–1.26 (m, 2 H);
4.75–4.54 (m, 2 H); 3.86–3.70 (m, 1 H); 3.58–3.44 (m, 1.26–1.14 (m, 1 H); 1.07–0.95 (m, 1 H); 0.94–0.77 (m,
1 H); 3.38 (s, 3 H); 2.37 (dd, J=13.5, 4.7, 1 H); 2.02 (dd, 21 H); 0.06 (d, J=0.8, 6 H). 13C-NMR (101 MHz, CDCl3):
J=13.2, 8.9, 1 H); 1.96–1.86 (m, 2 H); 1.47–1.32 (m, 2 H); 172.74; 139.20; 128.29; 96.55; 81.17; 72.68; 55.62; 40.95;
0.97–0.76 (m, 18 H); 0.05 (d, J=10.0, 6 H). 13C-NMR 39.08; 36.49; 32.25; 31.71; 29.36; 26.08; 20.35; 18.35;
(101 MHz, CDCl3): 172.59; 138.83; 128.60; 96.59; 81.05; 18.24; 16.85; 14.03; À 3.85; À 4.44. HR-ESI-MS: 453.3003
72.78; 55.68; 37.93; 35.41; 33.06; 31.59; 26.05; 18.22; (C23H46NaO5Si+, [M+Na]+; calc. 453.3007).
18.19; 17.04; 13.53; À 4.10; À 4.42. HR-ESI-MS: 411.2535
(C20H40NaO5Si+, [M+Na]+; calc. 411.2537).
(2S,4S,6R,7S,9S)-7-{[tert-Butyl(dimethyl)silyl]oxy}-
9-(methoxymethoxy)-2,4,6,10-tetramethyl-
(2S,4R,5S,7S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7-
(methoxymethoxy)-2,4,8-trimethylnonanoic
undecanoic Acid (21). Rf =0.38 (petroleum ether/ethyl
Acid acetate 3:1). [α]D25 =À 30.0 (c=0.28, CHCl3). IR (KBr):
(18). Rf =0.36 (petroleum ether/ethyl acetate 3:1). 3443, 3056, 2961, 2307, 1736, 1707, 1651, 1541, 1427,
[α]D25 =À 37.0 (c=0.47, CHCl3). IR (KBr): 3852, 3743, 1379, 1265, 1155, 1042, 897, 832, 741. 1H-NMR
3446, 2952, 2885, 2357, 1707, 1647, 1525, 1463, 1383, (400 MHz, CDCl3): 4.72–4.54 (m, 2 H); 3.80–3.66 (m,
1
1255, 1150, 1043, 928, 833, 764, 665, 556. H-NMR 1 H); 3.52–3.42 (m, 1 H); 3.38 (s, 3 H); 2.66–2.47 (m,
(400 MHz, CDCl3): 4.69–4.61 (m, 2 H); 3.78–3.65 (m, 1 H); 2.02–1.86 (m, 1 H); 1.81–1.65 (m, 2 H); 1.61–1.49
1 H); 3.48–3.44 (m, 1 H); 3.38 (s, 3 H); 2.60–2.51 (m, (m, 1 H); 1.33 (dd, J=13.5, 7.8, 2 H); 1.22–1.04 (m, 5 H);
1 H); 1.95–1.84 (m, 1 H); 1.71–1.64 (m, 2 H); 1.44–1.29 1.02–0.78 (m, 22 H); 0.06 (s, 6 H). 13C-NMR (101 MHz,
(m, 2 H); 1.21–1.11 (m, 4 H); 0.98–0.79 (m, 18 H); 0.03 CDCl3): 182.71; 96.56; 81.21; 72.60; 55.67; 41.37; 41.17;
(d, J=12.4, 6 H). 13C-NMR (101 MHz, CDCl3): 183.21; 37.54; 36.38; 32.18; 31.61; 28.46; 26.08; 20.72; 18.33;
96.61; 81.15; 73.17; 55.66; 37.73; 37.20; 32.95; 31.67; 18.24; 18.04; 16.84; 14.14; À 3.85; À 4.43. HR-ESI-MS:
26.05; 18.30; 18.20; 18.17; 17.08; 13.70; À 4.10; À 4.46. 455.3159 (C23H48NaO5Si+, [M+Na]+; calc. 455.3163).
HR-ESI-MS: 413.2687 (C20H42NaO5Si+, [M+Na]+; calc.
413.2694).
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Helv. Chim. Acta 2019, 102, e1900023
tert-Butyl
N-[(2S,4S,6R,7S,9S)-7-{[tert-Butyl(di- 21 H); 0.23 (s, 6 H); 0.01 (s, 6 H). 13C-NMR (101 MHz,
methyl)silyl]oxy}-9-(methoxymethoxy)-2,4,6,10-
CDCl3, rotamer mixture): 176.76; 176.42; 170.76;
tetramethylundecanoyl]glycinate (22). Rf =0.72 (pe- 170.72; 169.33; 169.27; 155.65; 155.13; 154.01; 153.87;
troleum ether/ethyl acetate 1:1). [α]D25 =À 21.8 (c= 139.88; 139.59; 132.08; 131.99; 129.87; 118.26; 118.20;
0.76, CHCl3). IR (KBr): 3850, 3744, 3310, 3065, 2953, 90.61; 90.36; 82.12; 81.91; 80.35; 80.04; 77.75; 77.58;
2359, 1743, 1657, 1538, 1462, 1374, 1256, 1157, 1043, 77.36; 72.56; 72.22; 59.58; 41.96; 41.07; 40.90; 40.63;
1
925, 835, 747, 568. H-NMR (400 MHz, CDCl3): 6.03 (t, 40.33; 38.99; 38.78; 36.34; 36.19; 33.90; 33.54; 32.24;
J=4.4, 1 H); 4.75–4.49 (m, 2 H); 4.01–3.79 (m, 2 H); 32.05; 32.00; 31.66; 31.40; 29.79; 28.73; 28.42; 28.38;
3.75–3.62 (m, 1 H); 3.46 (dt, J=8.9, 4.5, 1 H); 3.35 (s, 28.14; 26.03; 25.95; 25.93; 21.17; 19.11; 19.08; 18.42;
3 H); 2.46–2.21 (m, 1 H); 1.94–1.86 (m, 1 H); 1.78–1.59 18.15; 17.70; 17.58; 14.07; 13.86; À 3.87; À 3.95; À 4.64.
(m, 2 H); 1.54–1.45 (m, 10 H); 1.35–1.25 (m, 2 H); 1.23– HR-ESI-MS: 1019.5071 (C48H88IN2O9Si2+, [M+H]+; calc.
1.01 (m, 5 H); 0.97–0.71 (m, 21 H); 0.04 (s, 6 H). 13C- 1019.5068).
NMR (101 MHz, CDCl3): 176.67; 169.40; 96.56; 82.18;
81.12; 72.58; 55.63; 41.98; 41.47; 40.47; 39.04; 36.25;
(3R,9S,11S,13R,14S,16S)-3-[(4-{[tert-Butyl(dimeth-
32.38; 31.54; 28.34; 28.15; 26.05; 21.03; 18.73; 18.22; yl)silyl]oxy}-3-iodophenyl)methyl]-14-hydroxy-
18.20; 16.90; 14.29; À 3.85; À 4.43. HR-ESI-MS: 568.3999 4,9,11,13-tetramethyl-16-(propan-2-yl)-1-oxa-4,7-dia-
(C29H59NNaO6Si+, [M+Na]+; calc. 568.4004).
zacyclohexadecane-2,5,8-trione (27). Rf =0.20 (petro-
leum ether/ethyl acetate 2:1). [α]D25 =À 32.8 (c=0.5,
tert-Butyl
N-[(2S,4S,6R,7S,9S)-7-{[tert-Butyl(di- CHCl3). IR (KBr): 3852, 3742, 3448, 2934, 2357, 1728,
methyl)silyl]oxy}-9-hydroxy-2,4,6,10-tetrameth-
1645, 1526, 1464, 1385, 1265, 1152, 1090, 1038, 916,
ylundecanoyl]glycinate (23). Rf =0.19 (petroleum 834, 746, 689, 566, 520. 1H-NMR (400 MHz, CDCl3): 7.57
ether/ethyl acetate 5:1). [α]D25 =À 7.1 (c=0.53, CHCl3). (d, J=1.7, 1 H); 7.02 (dd, J=8.3, 1.9, 1 H); 6.72 (d, J=
IR (KBr): 3740, 3304, 2958, 2927, 2861, 2359, 1742, 8.3, 1 H); 6.17 (d, J=8.4, 1 H); 5.43 (dd, J=12.4, 4.3,
1657, 1543, 1462, 1374, 1256, 1159, 1067, 945, 834, 1 H); 5.11–4.96 (m, 1 H); 4.78 (dd, J=16.9, 8.9, 1 H);
1
758, 670, 565, 453. H-NMR (400 MHz, CDCl3): 5.97 (s, 3.61–3.52 (m, 1 H); 3.41 (dd, J=15.5, 4.2, 1 H); 3.28 (d,
1 H); 4.03–3.84 (m, 2 H); 3.84–3.75 (m, 1 H); 3.59–3.48 J=16.7, 1 H); 2.92 (s, 3 H); 2.89–2.81 (m, 1 H); 2.67 (s,
(m, 1 H); 2.57 (s, 1 H); 2.42–2.33 (m, 1 H); 1.89–1.68 (m, 1 H); 2.45–2.34 (m, 1 H); 2.05–1.97 (m, 1 H); 1.89–1.81
2 H); 1.66–1.58 (m, 1 H); 1.46 (s, 10 H); 1.40–1.22 (m, (m, 1 H); 1.53–1.39 (m, 2 H); 1.34–1.22 (m, 1 H); 1.11 (d,
3 H); 1.15 (d, J=6.9, 3 H); 1.06–0.84 (m, 20 H); 0.80 (d, J=6.6, 3 H); 1.04 (s, 12 H); 0.95 (t, J=6.9, 9 H); 0.83 (d,
J=6.8, 3 H); 0.07 (d, J=8.8, 6 H). 13C-NMR (101 MHz, J=6.8, 3 H); 0.25 (s, 6 H). 13C-NMR (101 MHz, CDCl3):
CDCl3): 176.64; 169.48; 82.34; 73.56; 73.38; 42.07; 41.63; 177.76; 172.03; 171.77; 154.31; 139.24; 130.87; 128.89;
39.33; 35.64; 34.99; 34.40; 29.84; 28.24; 28.19; 26.06; 118.50; 90.78; 77.43; 65.70; 58.19; 45.13; 43.14; 39.90;
20.77; 19.31; 18.65; 18.18; 17.94; 14.73; À 4.17; À 4.35. 39.29; 34.36; 32.93; 32.50; 30.77; 30.42; 27.08; 25.93;
HR-ESI-MS: 502.3923 (C27H56NO5Si+, [M+H]+; calc. 19.06; 18.45; 18.44; 18.14; 17.80; 14.53; À 3.90; À 3.92.
502.3922).
HR-ESI-MS: 753.2770 (C33H55IN2NaO6Si+, [M+Na]+;
calc. 753.2766).
(3S,5S,6R,8S,10S)-11-[(2-tert-Butoxy-2-oxoethyl)-
amino]-5-{[tert-butyl(dimethyl)silyl]oxy}-2,6,8,10-tet-
(3R,9S,11S,13R,14S,16S)-14-Hydroxy-3-[(4-
ramethyl-11-oxoundecan-3-yl N-(tert-Butoxycarbon- hydroxy-3-iodophenyl)methyl]-4,9,11,13-tetrameth-
yl)-O-[tert-butyl(dimethyl)silyl]-3-iodo-N-methyl-D– yl-16-(propan-2-yl)-1-oxa-4,7-diazacyclohexadecane-
tyrosinate (25). Rf =0.48 (petroleum ether/ethyl 2,5,8-trione, (À )-Doliculide. Rf =0.17 (hexane/acetone
acetate 5:1). [α]D25 = +11.3 (c=1.17, CHCl3). IR (KBr): 5:2). [α]D25 =À 26.4 (c=0.5, MeOH). IR (KBr): 3740,
3849, 3741, 3614, 3340, 2956, 2860, 2355, 1740, 1683, 3565, 3432, 2963, 2927, 1725, 1642, 1507, 1462, 1416,
1532, 1385, 1261, 1158, 1076, 988, 922, 839, 783, 740, 1262, 1034, 825, 580. 1H-NMR (600 MHz, CDCl3): 7.50 (s,
1
672. H-NMR (400 MHz, CDCl3): 7.59 (s, 0.5 H); 7.04 (d, 1 H); 7.06 (d, J=8.3, 1 H); 6.81 (d, J=8.2, 1 H); 6.38 (d,
J=8.2, 0.5 H); 6.98 (d, J=8.2, 0.5 H); 6.71 (s, 0.5 H); 6.69 J=8.2, 1 H); 5.51 (dd, J=12.4, 4.3, 1 H); 5.06 (dd, J=
(s, 0.5 H); 6.31 (s, 0.5 H); 6.10 (s, 0.5 H); 5.00–4.61 (m, 10.9, 4.5, 1 H); 4.80 (dd, J=16.8, 8.9, 1 H); 3.64–3.55 (m,
2 H); 3.88 (dd, J=9.8, 4.9, 2 H); 3.48 (s, 1 H); 3.15 (td, J= 1 H); 3.44 (dd, J=15.4, 3.5, 1 H); 3.21 (d, J=16.8, 1 H);
14.1, 5.0, 1 H); 2.96–2.77 (m, 1 H); 2.76 (s, 1.5 H); 2.68 2.97 (s, 3 H); 2.92–2.83 (m, 1 H); 2.64–2.55 (m, 1 H);
(s, 1.5 H); 2.36 (q, J=7.0, 6.6, 1 H); 2.04–1.81 (m, 1 H); 2.46 (ddt, J=13.0, 10.0, 4.9, 1 H); 2.08–1.98 (m, 1 H);
1.78–1.61 (m, 2 H); 1.43 (s, 11 H); 1.37 (s, 45 H); 1.24 (s, 1.87 (dq, J=13.1, 6.6, 1 H); 1.53 (t, J=12.5, 1 H); 1.45 (t,
4.5 H); 1.13 (t, J=6.0, 4 H); 1.02 (s, 10 H); 0.95–0.72 (m, J=12.2, 1 H); 1.34 (t, J=12.1, 1 H); 1.22–1.15 (m, 1 H);
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depsipeptide of marine origin and structure-cytotoxicity
relationships of synthetic doliculide congeners’, Tetrahe-
dron 1994, 50, 12853–12882.
1.13 (d, J=6.6, 3 H); 1.11–1.01 (m, 3 H); 0.99–0.91 (m,
9 H); 0.85 (d, J=6.8, 3 H). 13C-NMR (101 MHz, CDCl3):
177.89; 172.06; 171.40; 154.44; 138.27; 129.96; 129.29;
115.14; 85.03; 77.20; 65.84; 58.13; 44.84; 43.11; 39.59;
39.13; 34.27; 32.77; 32.29; 30.97; 29.95; 26.97; 18.76;
18.36; 18.10; 17.64; 14.39.
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[11] S. Hanessian, V. Mascitti, S. Giroux, ‘Total synthesis of the
cytotoxic cyclodepsipeptide (-)-doliculide: the “ester” effect
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Acknowledgements
We thank the National Natural Science Foundation of
China (21790332, 21625204, 21532003), the “111”
project (B06005) of the Ministry of Education of China,
and the National Program for Support of Top-notch
Young Professionals for financial support.
[12] A. K. Ghosh, C. Liu, ‘Total Synthesis of Antitumor Depsipep-
tide (À )-Doliculide’, Org. Lett. 2001, 3, 635–638.
[13] T. Chen, K.-H. Altmann, ‘Directed Hydrogenations and an
IrelandÀ Claisen
Rearrangement
Linked
to
EvansÀ Tishchenko Chemistry: The Highly Efficient Total
Synthesis of the Marine Cyclodepsipeptide Doliculide’,
Chem. Eur. J. 2015, 21, 8403–8407.
[14] K. Matcha, A. V. R. Madduri, S. Roy, S. Ziegler, H. Waldmann,
A. K. H. Hirsch, A. J. Minnaard, ‘Total Synthesis of (À )-
Doliculide, StructureÀ Activity Relationship Studies and Its
Binding to F-Actin’, ChemBioChem 2012, 13, 2537–2548.
[15] S.-F. Zhu, Q.-L. Zhou, ‘Iridium-Catalyzed Asymmetric Hydro-
genation of Unsaturated Carboxylic Acids’, Acc. Chem. Res.
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[16] J.-H. Xie, D.-H. Bao, Q.-L. Zhou, ‘Recent Advances in the
Development of Chiral Metal Catalysts for the Asymmetric
Hydrogenation of Ketones’, Synthesis 2015, 47, 460–471.
[17] D.-H. Bao, H.-L. Wu, C.-L. Liu, J.-H. Xie, Q.-L. Zhou, ‘Develop-
ment of Chiral Spiro PÀ N-S Ligands for Iridium-Catalyzed
Asymmetric Hydrogenation of β-Alkyl-β-Ketoesters’, An-
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[18] W. Che, D. C. Wen, S.-F. Zhu, Q.-L. Zhou, ‘Iterative Synthesis
of Polydeoxypropionates Based on Iridium-Catalyzed
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8875.
Author Contribution Statement
Q.-L. Z. conceived the idea and designed the experi-
ments. W. C. and D. C. W. performed the experiments.
W. C. wrote the manuscript with contributions and
review from all authors. S.-F. Z. and Q.-L. Z. supervised
the work.
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