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Total Synthesis of Taiwaniadducts B, C, and D Jun Deng, Shupeng Zhou, Wenhao Zhang, Jian Li, Ruofan Li, and Ang Li J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja503972p • Publication Date (Web): 27 May 2014 Downloaded from http://pubs.acs.org on May 30, 2014
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Total Synthesis of Taiwaniadducts B, C, and D Jun Deng,† Shupeng Zhou,† Wenhao Zhang, Jian Li, Ruofan Li, and Ang Li* State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China Supporting Information Placeholder 5,6
ABSTRACT: The first total synthesis of taiwaniadducts B, C, and D have been accomplished. Two diterpenoid segments were prepared with high enantiopurity, both through Ircatalyzed asymmetric polyene cyclization. A sterically demanding intermolecular Diels–Alder reaction promoted by Er(fod)3 assembled the scaffold of taiwaniadducts B and C. A carbonyl-ene cyclization forged the cage motif of taiwaniadduct D at a late stage, providing over 200 mg of this compound.
of 3 from the Diels–Alder reaction. Herein, we report the total synthesis of taiwaniadducts B, C, and D based on the above biosynthetic hypothesis.
Scheme 1. Retrosynthetic Analysis OH Me O
OH Me O
Me
carbonyl-ene
Me Me O
H Me CO2H
6
Me O Me
H 14' Me MeH HO 1: taiwaniadduct D
Taiwaniaquinoids are a class of terpenoids with impressive biological activities isolated from the endangered species 1 Taiwania cryptomerioides, which have attracted remarkable 1,2 attentions from a synthetic perspective. A few members of 3 this family, namely taiwaniadducts A–J, possess a characteristic Diels–Alder cycloadduct scaffold. From a biosynthetic perspective, taiwaniadduct D (1, Figure 1), the most complex molecule among them, could be derived from taiwaniadduct B (2) through a carbonyl-ene cyclization, and 2 may arise from a intermolecular Diels–Alder reaction between natural3 ly occurring taiwaniaquinone A or F (3 or 4) and trans-ozic 4 acid (5). Taiwaniadduct C (6) is presumably the regioisomer
Me
Me
H Me Me CHO 2: taiwaniadduct B
H Me CO2H
Diels Alder
Me
OMe
O Me
Me
Me Me
+ O H Me Me CHO
Me CO2Me 7
4: taiwaniaquinone F
12
Me
OMe Me MeO Me
O Me
4
Me OMe
H H
10
8
Ir-catalyzed asymmetric polyene cyclization
Me
OMe Me
OH Me
MeO Me
OH
Me OMe
OH 11
9
I OMe Me OTBS Me
Me
+
+
OMe
R2B OTBS 14
Figure 1. Taiwaniadducts B, C, and D, taiwaniaquinones A and F, and trans-ozic acid.
MeO
Me
12
R2B 13
We first undertook a retrosynthetic analysis of taiwaniadduct D (1), as illustrated in Scheme 1. The initial disconnection takes place at the C6−C14′ bond to provide
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Scheme 2. Synthesis of the Dienophile and Diene through Ir-Catalyzed Asymmetric Polyene Cyclization OMe Me
a) 9-BBN b) aq. NaOH, 12, Me Pd(dppf)Cl2 (10%)
OMe Me MeO
MeO Me
Me
OMe Me
d) [Ir(cod)] 2 (4%) (R)-16 (16%), Zn(OTf)2 (20%)
MeO Me
Me
OMe c) TBAF
OMe
73% (3 steps)
15
12 Me
or
72%
O
Me Me OMe
or i) CAN
H Me Me CHO 20
OMe Me
OMe
MeO Me
h) K2CO3 i) CAN
Me
7
O H CHO Me Me 4: taiwaniaquinone F
H Me Me CHO 19
MeO Me
5 steps
Me OMe
ref. 2h H Me Me
18
82%
76% (2 steps)
OH
H Me CHO 17
g) N2H4, 160 oC; KOH, 180 oC
OMe
O Me
Me
7
8
4
16
OMe
Me
H
O P N O
Me
O Me
Me OMe
89% (2 steps)
9
OTBS
I
MeO Me
OMe 69%, >99% ee
HO
OMe Me
e) K2OsO2(OH)4 NaIO 4, 2,6-lutidine f) t-BuOK, MeI
j) TBSCl, Im k) Sia2BH
Me
n) [Ir(cod)] 2 (4%), (R)-16 (16%), Zn(OTf)2 (20%)
OH Me
Me
9
O
Me
p) O3
o) BF3 OEt2
l) aq. NaOH, 12, Pd(dppf)Cl2 (10%) HO m) TBAF
Me 21
96%
H
79% (2 steps) >99% ee, 10:1 dr
11
H O
10
56% (4 steps) Me
Me
N
OMe O OH
t) MeNHOMe HCl i-PrMgCl, 78 to 0 oC
O Me
Me
O
H
Me
r) N2H4, 160 C; KOH, 180 oC
Me
Me
H Me
26
o
Ph3P
H
70%
O Me
4
67% Me BnO
22
q) t-BuOK, BOMCl; aq. HCl
H
OHC BnO 23
25
CHO
28
u) SOCl2, py, 78 oC v) DIBAL-H, 78 oC CHO
O
81% Me BzO
27
58% (2 steps)
Me
Me 79%
Me HO
12
s) RuCl3 3H2O, NaIO4, pH 7 buffer
O Me
Me
Me o
w) 28, 120 C x) Ph3P=CH2, 0 oC
Me
y) AZADO (5%), NaClO2, pH 4.6 buffer z) TMSCHN2, MeOH
Me Me Me
O Me
H H Me HO 30
54% (2 steps) Me HO
67% (2 steps)
H 29
taiwaniadduct B (2) as a carbonyl-ene substrate, which could be further disassembled through a retro Diels–Alder fashion to give taiwaniaquinone F (4) and trans-ozic acid methyl ester (7). It should be noted that the both fragments need to be prepared in the enantioenriched forms, to avoid the diastereomerically mismatched Diels–Alder reactions. Having noticed the inherent similarity between 3 and 7, we consider 7 the Ir-catalyzed asymmetric polyene cyclization elegantly developed by Carreira and co-workers as a general tool to construct the carbon skeleton of the both compounds. Based 2h on the ring-contraction strategy reported by us previously, 2 could be directly simplified to an optically active 6,6,6tricycle 8, which is further traced back to the substrate for the polyene cyclization, allylic alcohol 9. In parallel, the synthesis of 7 may exploit an enantioenriched 6,6,5-tricycle 10; modifications at C4 and C12 would install the carboxylate and diene functionalities, respectively. This intermediate is anticipated to arise from dienyl alcohol 11, through a mechanistically similar Ir-mediated cyclization, despite few prece7,8 dents of heteroatom trapping. The linear precursors 9 and 7a 11 could be prepared by cross-coupling of known iodide 12 with alkylboranes 13 and 14, respectively.
H Me CO2Me 7
BOMO 24
ORTEP of 26
The synthesis commenced with the enantioselective constructions of the two segments 4 and 7 (Scheme 2). Hydroboration of styrene 15 with 9-BBN gave a 13-type alkylborane, which underwent Suzuki–Miyaura coupling [cat. Pd(dppf)Cl2, 2h,7a aq. NaOH] with 12 and subsequent desilylation to afford alcohol 9 in 73% overall yield, setting the stage for the Ircatalyzed asymmetric polyene cyclization. Thus, 9 was subjected to Carreira′s catalyst system {[Ir(cod)Cl]2, (R)-16, 7,8 Zn(OTf)2} to yield the desired tricycle 8 (69%) with an excellent level of stereoselectivity (> 99% ee, a single detectable diastereomer). Notably, this reaction was successfully carried out on 15 gram scale with the consistent efficiency and selectivity. Olefin cleavage (OsO4, NaIO4) followed by Cmethylation (KOt-Bu, MeI) of the resulting aldehyde furnished compound 17 in 89% yield as a single diastereomer at C4, which was converted to tricycle 18 (72% yield) under 9 Wolff–Kishner–Huang conditions (N2H4•H2O, KOH, 180 °C). This compound entered a 5-step sequence involving Wolff ring contraction developed by us previously to reach 6,5,6trycylic aldehyde 19; treatment with K2CO3/EtOH provided 2h its epimer at C7. The both aldehydes were oxidized by CAN to generate essentially enantiopure taiwaniaquinone F (4)
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and its C7-epimer 20, respectively, which served as the dienophiles for the devised Diels–Alder reaction. The synthesis of the diene fragment 7 also took advantage of the Ir chemistry (Scheme 2). Silylation of known dienyl 10 alcohol 21 followed by selective hydroboration of the monosubstituted C═C bond with Sia2BH afforded a 14-type alkyl7b borane, which was subjected to a similar Suzuki–Miyaura coupling/desilylation sequence to furnish diol 11. This compound turned out to be a suitable substrate for the expected heteroatom-terminating Ir-catalyzed cyclization; 6,6,5tricycle 10 was obtained in 59% yield and > 99% ee under the standard conditions. Notably, a high level of diastereoselectivity at C9 (ca. 10:1) was also achieved, making this chemistry applicable to the synthesis of the framework of a wide range of terpenoids. Mono-cyclization products (an olefin 7a mixture) were isolated in 25% yield, which were readily converted to 10 (80% yield) by exposure to BF3•OEt2. Thus, the overall yield of 10 from 11 reached 79%. These transformations were easily amplified to 5 gram scale. With 10 in hand, we introduced the carboxylate and diene functionalities to its scaffold. Similar to the sequence used for the dienophile synthesis, double bond cleavage by ozonolysis gave aldehyde 22 (96% yield), and subsequent alkylation with BOMCl generated compound 23 in 70% yield as a single diastereomer at C4. The by-product 24 resulted from Oalkylation was hydrolyzed during acid work up, leading to 26% of recovered 22. Aldehyde 23 underwent Wolff–Kishner– Huang reduction to afford compound 25 (67% yield). Treatment of 25 with RuCl3/NaIO4 resulted in the C12−H oxida11 tion, providing lactone 26 in 81% yield, the structure of which was confirmed by X-ray crystallographic analysis (Scheme 2). Under these conditions, the benzyl was also oxidized to a benzoyl for convenient removal. Lactone opening 12 (MeNHOMe•HCl, i-PrMgCl) formed amide 27 (79% yield) with the primary hydroxyl released. Dehydration (SOCl2, 12,13 and DIBAL-H reduction, followed by two Wittig olepy) finations (with reagent 28 and methylenetriphenylphosphorane, respectively) gave 1,3-diene 29 with the intermediacy of 14 aldehyde 30. Finally, oxidation (AZADO, NaClO2) followed by esterification (TMSCHN2, MeOH) rendered trans-ozic acid methyl ester (7) in an essentially enantiopure form.
ly, a variety of conventional conditions, such as thermal, 15 acidic, neat, and high-pressure conditions, failed to effect the cycloaddition. The instability of both taiwaniaquinone F (4) and its alternative 7-epi-taiwaniaquinone F (20) under forcing conditions was found to be a severe problem. The undesired reaction of 20 was depicted in Scheme 3; exposure to Sc(OTf)3 gave a naturally occurring taiwaniaquinoid, 1,2i,3 namely taiwaniaquinol D (31), presumably through a double tautomerization process with the intermediacy of 32. 7epi-Taiwaniaquinone A (33) underwent a similar sequence followed by spontaneous aerobic oxidation to arrive at an1,2i,3 other natural product taiwaniaquinone D (34). Distinct from its 7-epimer, taiwaniaquinone F (4) underwent a much slower but more complicated decomposition. These observations suggest a plausible biosynthetic model of 31 and 32, and imply the fate of 7-epi-taiwaniaquinones A and F which have not been isolated as natural products.
Scheme 4. Intermolecular Diels–Alder Reaction and Completion of the Total Synthesis of Taiwaniadducts B, C, and D
Scheme 3. Unexpected Reactions of 7-epiTaiwaniaquinones A and F under Acidic Conditions
With the both diene and dienophile in hand, we investigated the intermolecular Diels–Alder reaction. Unfortunate-
At this point, we directed our attention to the dienophiles more stable against acidic and thermal conditions (Scheme 4). Alcohol 35, which is readily available from aldehyde 19 and secured from the tautomerization observed before, was
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considered as such an alternative. This compound was prepared on 4 gram scale and used for extensive examinations of Diels−Alder conditions. To our delight, Er(fod)3 turned out 16 to be a effective promoter, despite few precedents of utilizing it in Diels−Alder reactions to our knowledge. Neat conditions and elevated temperature were also required. 35 (1.0 eq.) and 7 (1.2 eq) reacted under these optimized conditions to afford cycloadduct 36 (52% yield) and its regioisomer 37 (21% yield), and no other positional or diastereomeric isomers were detected. The site selectivity toward the C8-olefin over the C12-olefin may be attributable to the bulky isopropyl and the electron-donating methoxyl that make the latter olefin a worse dienophile. The facial selectivity may arise from the steric effect of the axial C20 methyl group (see the single crystal structure in ref. 2h for information). The homodimeric cycloaddition of 7 was not observed either, presuma17 bly due to its poor dienophilicity. The both cycloadducts were subjected to a three-step sequence of oxidation (DMP) 18,19 and demethylations (LiI and then t-BuOK/DMSO), to furnish taiwaniadducts B and C (2 and 6) via the intermediacy of 38 and 39, respectively. Treatment of 2 with Et2AlCl realized the final carbonyl-ene cyclization to render taiwaniadduct D (1) in 91% yield; over 200 mg of 1 were prepared. The structure of the bis-methylated derivative of 1 (compound 40) was verified by X-ray crystallographic analysis (Scheme 4). The synthetic samples display identical spectral and physical properties with those of authentic samples (supporting information). In summary, we have accomplished the first total synthesis of taiwaniadducts B, C, and D (2, 6, and 1). Ir-catalyzed asymmetric polyene cyclization was exploited to construct the scaffolds of the both diene and dienenophile. Er(fod)3 promoted intermolecular Diels−Alder and Et2AlCl mediated carbonyl-ene reactions forged the core of 1. The chemistry may find further applications in terpenoid synthesis.
ASSOCIATED CONTENT Supporting Information Experimental procedures and compound characterization (cif, pdf). This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected] Author Contributions †
These authors contributed equally.
ACKNOWLEDGMENT This paper is dedicated to Prof. Li-Xin Dai on the occasion of th his 90 birthday. We thank Profs. Yunheng Shen and Lihong Hu for helpful discussions. Financial support was provided by Ministry of Science & Technology (2013CB836900) and National Natural Science Foundation of China (21290180, 21172235, and 21222202).
REFERENCES
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