Page 1 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
Asymmetric Total Synthesis of Propindilactone G Lin You,a Xin-Ting Liang,a Ling-Min Xu,a Yue-Fan Wang,a Jia-Jun Zhang,a Qi Su,a Yuanhe Li,a Bo Zhang,a ,a,b,c Shou-Liang Yang,a Jia-Hua Chen*,a and Zhen Yang*
a
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. b Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China c Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao (China) Email: [email protected], [email protected] Supporting Information ABSTRACT: A concise total synthesis of (+)-propindilactone G, a nortriterpenoid isolated from the stems of Schisandra propinqua var. propinqua, has been achieved for the first time. The key steps of the synthesis include an asymmetric Diels–Alder reaction, a Pauson–Khand reaction, a Pd-catalyzed reductive hydrogenolysis reaction, and an oxidative heterocoupling reaction. These reactions enabled the synthesis of (+)-propindilactone G in only 20 steps. As a consequence of our synthetic studies, the structure of (+)-propindilactone G has been revised.
Propindilactone G (1)1 and compounds 2–4 (Chart 1) represent a novel group of nortriterpenoids2 isolated from various species of Schisandracea family by Sun and co-workers. The species are widely distributed throughout Southeast Asia and North America and used as traditional Chinese herb medicines in China for liver protection and immune-regulation.2 Chart 1: Naturally occurring nortriterpenoids O
O A O
H
Me
Me O
H
2
H E
C
O
H
H
3
Me
D
O B Me
Me
HO
30
Me 29
1: propindilactone G Me
O O
HO
Me
Me H
O
H
Me H
H H
Me
9
H
17
23 20
8
6
7
H
15
16
O
22
27
26
Me O
25
Me
24
OH
O
O O
H
O Me H
Me H
H
Me
3: rubriflordilactone A O O
O
O
O
Me
O Me
H
Me
13 14
O
21
18
Me O
H
H Me
H HO
Me
12
O
H O
O
2: schindilactone A O
19
5
Me
O O
10 4
11
HO
1a: C17-epi-propindilactone G (originally proposed structure) H
O
O
1
O
OH
O
O
4: schilancitrilactone B
Me
The intriguing chemical structures and potential biological activity of the nortriterpenoids, in combination with their scarcity in nature, which limits their further biological investigation, have spurred considerable interest among the chemistry community,3 resulting in the total syntheses of schindilactone A (2) in 2011 by the research group of Yang,4 the total syntheses of rubriflordilactone A (3) in 2014 by the research group of Li,5 and the total syntheses of schilancitrilactone B (4) by the research group of Tang in 2015.6 From a structural perspective, propindilactone G (1), distinct from the other nortriterpenoids 2–4, possesses a unique 5/5/7/6/5 pentacyclic core bearing 7 stereocenters, three of which are quaternary centers7 (C9, C10 and C13). The originally proposed structure of propindilactone G (1a in Chart 1) was established by NMRs analysis.1 Preliminary biological assays indicated that these types of nortriterpenoids exhibit promising anti-HIV activity,8 which inspired us to develop synthetic methods and a strategy centered on the construction of the scaffold of propindilactone G, with the hope of providing a general approach for the total synthesis of other family members of propindilactone G. Herein we report our efforts on the development of a concise strategy that allowed the first total synthesis of (+)-propindilactone G (1) in 20 steps. Inspired by recent advances in the oxidative heterocoupling of enolsilanes for the formation of C-C bond,9 we postulated our total synthesis of propindilactone G (1a) to involve the late-stage coupling of the conjugated enolsilane 5 with the in situ generated enolsilane of ketolactone 6 to form the C17-C20 linkage (Scheme 1). This retrosynthetic analysis required the development of an efficient synthetic approach for the stereoselective synthesis of ketolactone 6 bearing a quaternary carbon atom at C13. Encouraged by our recent application of the Pauson–Khand (PK) reaction as a key step in the total synthesis of (+)-fusarisetin A,10 we envisaged that the PK reaction could be used for the synthesis of the cyclopetenone 6 from enyne 7. Enyne 7 in turn could be made from ester 8 by using the chemistry developed in our total synthesis of schindilactone A (2).4 Because we wanted to achieve an asymmetric total synthesis, we explored the use of an asymmetric Diels–Alder reaction of diene 9 and dienophile 10 in the presence of a chiral ligand11 for the synthesis of the chiral
ACS Paragon Plus Environment
Journal of the American Chemical Society
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 2 of 6
The concise enantioselective synthesis of the key vinyl bromide (+) 14 is shown in Scheme 2. We profiled a variety of asymmetric variations of Diels–Alder reaction11 for the synthesis of ester 8 from diene 9 and dienophile 10. The desired Diels–Alder reaction could be effectively achieved in the presence of Hayashi’s ligand,11e leading to the formation of (–)-ester 8 in 88% yield with excellent ee (98%). This reaction worked well on a 100-gram scale, providing a good foundation to pursue the asymmetric total synthesis.
P(OMe)314 in THF followed by the treatment with TESCl to give product 12 in 76% overall yield. Further treatment of 12 with dibromocarbene15 derived from CHBr3/tBuOK resulted in the formation of dibromide 13 as a pair of diastereosiomers in a ratio of 1:1, which then reacted with AgClO4•H2O16 in acetone to give the cycloheptenone-based vinyl bromide 14 in 57% yield over two steps. Scheme 3 depicts the synthesis of the tetracyclic fragment 17. Although stereoselective synthesis of the cyclopentenone subunit containing an all-carbon quaternary stereocenter at C13 of propindilactone G is challenging, the recent applications of the PK reaction to the synthesis of such scaffolds in complex natural product total synthesis17 encouraged us to use this reaction as a key step for the synthesis of intermediate 17. To this end, vinyl bromide 14 was coupled with TMS-acetylene in the presence of a catalytic amount of Pd(PPh2)Cl2/CuI and iPr2NH (DIPA)18 to give enone 15 in 88% yield. Further reaction of 15 with (3-methylbut -3-en-1-yl)-magnesium bromide in the presence of CeCl319 resulted in enyne 7 in 81% yield as a single isomer. To prepare the cyclopentenone subunit bearing an all-carbon quaternary stereocenter, enyne 7 was treated with Co2(CO)8 (0.5 eq) in the presence of celite20 in toluene under reflux. The expected product 16 was indeed obtained in 67% yield, together with a 24% yield of its C13 diastereoisomer. It is worth mentioning that the TMS group substituted at the terminal of the acetylene21 in 7 played a critical role in the PK reaction, since the substrates without TMS did not afford any desired annulated products. Further treatment of 16 with TBAF afforded 17a in 90% yield with retention of the TMS group, and the structure was confirmed by X-ray crystallographic analysis. However, when 16 was reacted with AgF,22 dienone 17 was obtained in 85% yield with removal of its both silyl groups.
Scheme 2. Synthesis of the bromoenone 14a
Scheme 3. Synthesis of the tetracyclic ring fragment 17a
building block 8. In addition, we wanted our strategy to be in an agreement with the notion of concise synthesis by limiting the use of protecting group.12 Scheme 1: Retrosynthetic analysis of propindilactone G O O
H
Oxidative heterocoupling of enolsilanes
HO
Me
OTIPS O
5
O
+
OH
O
H Me
Me
Me H
17
H
O
Me
Me
Me
CF3 N H
O
H
OTIPS
EtO
O
H
5
H Me
8
COOEt
O
10
15
H
Me
8
+
O
F3C
OH 10
TMS
5
H
Me
7
O
N H
OTIPS
H
CF3 CF3
COOEt
10
OTES
O Me
OTIPS d) MeMgCl (84%) e) KHMDS, P(OMe)3, O2 then TESCl (90%)
Me H 12
O O Me
OTES OTIPS Br
g) AgClO4 H2O acetone, rt
Br
(57% in 2 steps)
H Me 13
H
O
OTES O
O Me
TMS Me
H
15
Me OH
b) BrMg
15
17a TMS
OTES
CeCl3 (81%)
O
Me
Me
Me
H
H Me 14
O
As illustrated in Scheme 2, further treatment of aldehyde 8 with MeMgBr in the presence of AlMe313 afforded an alcohol, which was then oxidized with DMP in the presence NaHCO3 in CH2Cl2 to give ketoester 11 in 74% yield over two steps. Grignard reaction of 11 with MeMgBr afforded a lactone, which underwent oxidation by reaction with KHMDS in the presence of O2 and
OH O
TMS
(67%) Me
Me
H
7
Me
OH OH
9
a
Reagents and conditions: (a) 9 (1.2 eq), 10 (1.0 eq), Hayashi ligand (0.1 equiv), TFA (20 mol%), toluene, -10oC, 10 h, 88% (98% ee); (b) AlMe3 (2.3 eq), MeMgBr (1.5 eq), CH2Cl2, -78oC to 0oC, 1 h, 80%; (c) DMP (1.1 eq), NaHCO3 (8.0 eq), CH2Cl2, rt, 93%; (d) MeMgCl, THF, -78oC to -25oC, 84%; (e) KHMDS (2.0 eq), THF, -78 oC to 0oC followed by addition of P(OMe)3 (2.0 eq), O2, 0oC, 1 h. 80%; then TESCl (1.2 eq), THF, rt, 90%; (f) KOtBu (10.0 eq), CHBr3 (7.5 eq), petroleum ether, -20oC; (g) AgClO4·H2O (2.5 eq), acetone, rt, 57% for 2 steps.
15
O
OTES
e) AgF (85%)
Br
O
TMS
16
c) Co2(CO)8
13
O
OTES O
O
Me OH
9
Me
13
d) TBAF (90%) O
O
Me
Me
OTIPS
TMS (88%)
OH
O
O 11
f) t-BuOK, CHBr3, -20 oC
a) Pd(PPh3)2Cl2, CuI DIPA
14
9
Me
EtO Me
H
Me O
b) AlMe3, MeMgBr (80%) c) DMP (93%) O
O Br
(100 grams scale)
OTES CF3
OTES
O Me
O 8
A O
O
OTES
O a) A, toluene, TFA, -10 oC, 10h 9 OTIPS 88% (98% ee) EtO
H
17 16
14
6
O O
H
H
Me 13
Me
OTES CF3
A
9 OTIPS
HO
10
O
CF3
Pauson-Khand Rx
O
H
1a: C17-epi-propindilactone G F3C
O
Dieckmann-type condensation Rx
O Me
13
8 14
Me
7
H
17
H
15
O
CRTEP of 17a
a
Reagents and conditions: (a) ethynyltrimethylsilane (1.25 eq), DIPA (3.0 eq), Pd(PPh3)2Cl2 (0.06 eq), CuI (20 mol%), THF, rt, 88%; (b) (3-methylbut-3-en-1-yl)-magnesium bromide (1.8 eq), CeCl3 (3.0 eq), THF, 0 oC, 81%; (c) Co2(CO)8 (0.5 eq), celite (10 wt.), toluene, reflux, 67%; (d) TBAF (1.5 eq), THF, rt, 90%; (e) AgF (10.0 eq), THF, MeOH, H2O 80 oC, 85%.
We then explored the pathway for stereoselective synthesis of the key intermediate 6 (Scheme 4). Initially, we expected that the C7–C8 double bond in 17 could be saturated by Pd-catalyzed
ACS Paragon Plus Environment
Page 3 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
hydrogenation. However, attempts with various Pd-catalysts could not regioselectively remove this double bond. On the other hand, treatment of 17 with Pd(OH)2/C23 in the presence of Et3N24 under a balloon pressure of hydrogen initiated a reductive isomerization to afford dienone 18 in 98% yield. Further treatment of dienone 18 with m-CPBA in CH2Cl2 afforded epoxide 19 in 73% yield as a single isomer. The observed regio- and stereo-selective epoxidation of dienone 18 could be the result of the free hydroxyl group at C10, which might delivery the m-CPBA to approach the double bond from the bottom face. To install the lactone in 20, epoxide 19 was first reacted with acetic anhydride in the presence of Et3N and the resulting acetate was treated with LiHMDS to initiate a Dieckmann-type condensation4 to afford lactone 20 in 76% overall yield. To achieve the chemo- and stereo-selective synthesis of 6, 20 was first subjected to a dehydration with Martin’s sulfuran,25 and the resulting unsaturated lactone 21 underwent both a Pd-catalyzed hydrogenation to saturate its C1– C2 double bond and hydrogenolysis26 to open the epoxide to give product 6 in 56% yield, together with its C8-epimer 6a, which could be converted to 6 in 41% yield by treatment with DBU in refluxing toluene. The structure of 21 was established by X-ray crystallographic analysis.
-di-tert-butyl pyridine (DTBP) at -50oC to -30oC in acetonitrile, and the ratio for the four diastereoisomers was 2.0:2.0:1.1:1 according to 1H NMR analysis. This mixture without purification then underwent a Horner–Wadsworth–Emmons (HWE) reaction by treatment with ethyl 2-(diphenoxyphosphoryl)propanoate B in the presence of KHMDS as a base in THF at -78oC to give product 23, 24, and inseparable products 25 and 26 in 16%, 15% and 60% yields, respectively (see SI for details). Scheme 5. Synthesis of compounds 23, 24 and 25/26a
OH HO
Me
a) Pd(OH)2/C H2
9
O Me
8 14
Me
7
H
(98%)
O
15
O
Me
1
O
Me
Me
H
7
H
Me
20
f)
2
Me
O
1
O Me
Me
b) KHMDS H O (PhO)2OP CO2Et (60%) B Me Me
O
15
Me
18
OH
O
21
(6a = 56%, 6b = 22%)
O
O
1
Me
HO
Me
6
O
OTIPS
5
Me
Me
H
Me Me 13 17
H Me
20
CO2Et
23
H
Me
22
CHO
20
O
22 Me
Me
Me
Me
H
H
Me
22
O
Me
H
Me
CO2Et
Me
13
Me
17
H
25
Me
Me
+ HO
O
O
22
CO2Et
24 (15%)
H Me
23
O
H
CO2Et
23
Me 20
17
H
O
H H
HO
+O
O
23 (16%) HO
O
H
+ O
Me
O
HO
H
O
26
O g) DBU (41%)
HO
Me
8
Me
Me
Reagents and conditions: (a) 6 (1.0 eq), TBSOTf (1.2 eq), Et3N (2.0 eq), CH2Cl2, 0oC to rt, 1 h; then enolsilane 5 (3.0 eq), CAN (5.0 eq), DTBP (10 eq), CH3CN, -50oC to -30oC, rt, 1.5 h 92%; (b) 22 (1.0 eq), 18-crown-6 (15.0 eq), KHMDS (5.0 eq), HWE reagent B (5.0 eq), THF, -78oC, 1.5 h, 23 (16%), 24 (15%), and a mixture of 25/26 (60%).
Me
+
O
CRTEP of 21
OTIPS
A
(25/26 = 1.5:1, 60%)
H
H
O H
Me
H
17
19
O Me
H
H
a
2
H
Me
O
8
Me
HO
H
H
O
9
H
O
O
Me
10
Me
O
H
O
Pd2dba3 . CHCl3
nBu P 3 HCOOH, DIPEA
O
H
O
e) Martin's sulfuran (83%)
O
Me
d) LiHMDS (84%)
O
Me
6
O 8 14
O
O
O
O
9
10
O
c) Ac2O, Et3N (91%)
Me
H
Me
O
H
then CAN, DTBP (92%) (dr = 2.0:2.0:1.1:1.0)
m-CPBA (73%) O
Me
HO O
H
a) TIPSOTf, Et3N
17
O
Me
OH
O HO
Me
O
Me
17
HO O
H
Scheme 4. Synthesis of ketolactone 6a O
O
O
H
H
O
To complete the total synthesis, we expected that one of the four isomers mentioned above could undergo an OsO4-mediated regio- and stereo-selective dihydroxylation, and the resulting intermediate might undergo an intramolecular lactonization to afford the natural product. Scheme 6. Total synthesis of (+)-propindilactone G (1)a
6a
O
a
Reagents and conditions: (a) Pd(OH)2/C (0.7 wt), CH2Cl2, rt, 98%; (b) m-CPBA (2.5 eq), CH2Cl2, rt, 73% (brsm); (c) Ac2O (3.0 eq), Et3N (10.0 eq), CH2Cl2, 0 oC, 91%; (d) LiHMDS (2.5 eq), THF, -78 oC to -40 oC, 84% (brsm); (e) Martin’s sulfuran (1.8 eq), CH2Cl2, 0o C, 83%; (f) Pd2dba3·∙CHCl3 (0.1 eq), nBu3P (0.2 eq), HCOOH (5.0 eq.), DIPEA (2.0 eq), dioxane, 45 o C, 56%; g) DBU (10.0 eq.), toluene, reflux, 41%.
With ketolactone 6 in hand, we entered the final stage of the total synthesis as shown in Scheme 5. We anticipated that an intermolecular oxidative coupling of the conjugated enolsilane27 5 with enolsilane A could be applied to the synthesis of 22. Realizing that the intermolecular oxidative heterocoupling of enolsilanes was a daunting task,28 we systematically profiled this important coupling reaction by using enolsilane A to react with the conjugated enolsilane 5. After a systematic investigation, we found that when ceric ammonium nitrate29 (CAN) was utilized as an oxidant, this coupling reaction could proceed smoothly to afford 22 as two pairs of diastereoisomers (corresponding to the two newly generated chiral centers C17 and C20) in 92% overall yield. This reaction was carried out in the presence of 2,6
25/26
a) OsO4, NMO
O O
H
Me
HO
17
O
(81%) Me
Me
H
H
H
Me
O
Me
22 20
O
23
OH
propindilactone G (1)
CRTEP of propindilactone G (1) a
Reagents and conditions: (a) 25/26 (1.0 eq), OsO4 (0.07 eq), NMO (2.0 eq), THF/H2O (1:1), 4oC, 72 h, 81% of propindilactone G (1) based on the amount of 25 in the mixture of 25/26.
To this end, 23, 24 and 25/26 were treated with OsO4 in the presence of NMO30 as a co-oxidant, respectively, to our delight, propindilactone G (1) could be made from substrate 25 in 81%
ACS Paragon Plus Environment
Journal of the American Chemical Society
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 6
yield (based on the amount of 25 in the mixture of 25/26, Scheme 6). The 1H NMR and 13C NMR spectra, and specific rotation of the synthesized propindilactone G were in agreement with those reported in literature ([α]25D = + 39.0, c = 0.15 in MeOH; lit. [α]25.6 D = + 41.1, c = 0.15 in MeOH),1 and its structure has been confirmed by X-ray crystallographic analysis. Thus, as a consequence of our synthetic studies, the structure of (+)-propindilactone G has been revised as compound 1 and the originally proposed structure of propindilactone G has been reassigned as 1b (C17-epi-(+)-propindilactone G) (see Chart 1). It is worthwhile to mention that substrate 26 in the mixture of 25/26 was converted to some unidentified products under the reaction conditions. To account for this observation, we carried out a DFT calculation (M11-L//B3LYO),31 and our preliminary calculation showed that the oxidation of 25 to form intermediate 25-Os id 1.5 kcal/mol more exothermic than that of 26. The energy difference can be attributed to the repulsion between the oxygen atom on Os and the labeled carbon in the scaffold of 26-Os (Scheme 7). As a result, the selectivity for the dihydroxylation of 26 would be decreased, leading to the formation of multi-dihydroxylative products.
Experimental procedures and compound characterization (cif, pdf). This material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 7. DFT calculation for the free-energy profiles and geometric information of the Os-dihydroxylation of 25 and 26
REFERENCES
O O
25
OsO4
Os O
H
HO
Me
H
Me
Me
O CO2Et
O
Me
O
ΔG = -23.3 kcal/mol
O
Me
H
H
H
O
25-Os
O
26
OsO4
O
H
HO
Me
Me
H
Me
17
O
ΔG = -21.8 kcal/mol
H
13
Me
H
H
26-Os
O
O
O
CO2Et Me
Os O O
In conclusion, the total synthesis of (+)-propindilactone G (1) was accomplished for the first time in 20 steps (longest liner sequence) starting from (buta-1,3-dien-2-yloxy)triisopropylsilane 9 and (E)-methyl 4-oxobut-2-enoate 10. The key steps in this synthesis were an asymmetric Diels–Alder reaction, a Co-mediated PK reaction, a Pd-catalyzed reductive hydrogenolysis reaction, an oxidative heterocoupling reaction of enolsilanes, and an OsO4-mediated dihydroxylation. This work demonstrates the power of the PK reaction for the stereoselective construction of cyclopentenone bearing an all-carbon quaternary chiral center, and the oxidative heterocoupling reaction of enolsilanes for the concise ligation of cyclopentenone core 6 with its side chain. The true structure of (+)-propindilactone G (1) was revised in accord with our finding, and the originally proposed structure has been reassigned as C17-epi-(+)-propindilactone G (1b). The application of the synthetic propindilactone G and its analogs as probes to study their biology is currently underway in our laboratories, and will be reported in due course.
ASSOCIATED CONTENT Supporting Information
AUTHOR INFORMATION Corresponding Author [email protected], [email protected]
ACKNOWLEDGMENT This paper is dedicated to Prof. Handong Sun on the occasion of his 75th birthday. We thank professor Yu Lan of Chong Qing University for the DFT calculation, and professors Wen-Xiong Zhang and Dr. Neng-dong Wang for the X-ray crystallographic analysis. This work is supported by the National 863 Program (Grant No. 2013AA092903, NSFC-Shandong Joint Fund for Marine Science Research Centers (U1406402), and Natural Science Foundation of China (Grant No. 21272015, 21372016, 21472006).
(1) Lei, C.; Huang, S.-X.; Chen, J.-J.; Yang, L.-B.; Xiao, W.-L.; Chang, Y.; Lu, Y.; Huang, H.; Pu, J.-X.; Sun, H.-D. J. Nat. Prod. 2008, 71, 1228. (2). Shi, Y. -M.; Xiao, W. -L.; Pu, J. -X.; Sun, H. D. Nat. Prod. Rep. 2015, 32, 367. (3) Synthetic studies on Schisandraceae triterpenoids: (a) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 593. (b) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.; Deng, L.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 885. (c) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 1657. (d) Zhang, Y. D.; Tang, Y. F.; Luo, T. P.; Shen, J.; Chen, J. H.; Yang, Z. Org. Lett. 2006, 8, 107. (e) Zhang, Y. D.; Ren, W. W.; Lan, Y.; Xiao, Q.; Wang, K.; Xu, J.; Chen, J. H.; Yang, Z. Org. Lett. 2008, 10, 665. (f) Li, Z.; Cao, Y.; Jiao, Z.; Wu, N.; Wang, D. Z.; Yang, Z. Org. Lett. 2008, 10, 5163. (g) Kan S. B. J.; Anderson, E. A. Org. Lett. 2008, 10, 2323. (h) Cordonnier, M. C. A.; Kan, S. B. J.; Anderson, E. A. Chem. Commun. 2008, 5818. (i) Anderson, E. A. Org. Biomol. Chem. 2011, 9, 3997. (j) Goh, S. S.; Baars, H.; Gockel, B.; Anderson, E. A. Org. Lett. 2012, 14, 6278. (k) Wang, Q.; Chen, C. Org. Lett. 2008, 10, 1223. (l) Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 2111. (m) Lai, K. W.; Paquette, L. A. Org. Lett., 2008, 10, 2115. (n) Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 3781. (o) Chenoweth, D. M.; Chenoweth, K.; Goddard, W. A. J. Org. Chem. 2008, 73, 6853. (p) Mehta, G.; Bhat, B. A. Tetrahedron Lett. 2009, 50, 2474. (q) Mehta, G.; Bhat, B. A.; Kumara, T. H. S. Tetrahedron Lett. 2009, 50, 6597. ® Maity, S.; Matcha, K.; Ghosh, S. J. Org. Chem. 2010, 75, 4192. (s) Bartoli, A.; Chouraqui, G.; Parrain, J. L. Org. Lett. 2012, 14, 122. (4) (a) Xiao, Q.; Ren, W. W.; Chen, Z. X.; Sun, T. W.; Li, Y.; Ye, Q. D.; Gong, J. X.; Meng, F. K.; You, L.; Liu, Y. F.; Zhao, M. Z.; Xu, L. M.; Shan, Z. H.; Tang, Y. F.; Chen, J. H.; Yang, Z. Angew. Chem. Int. Ed. 2011, 50, 7373. (b) Sun, T. W.; Ren, W. W.; Xiao, Q.; Tang, Y. F.; Zhang, Y. D.; Li, Y.; Meng, F. K.; Liu, Y. F.; Zhao, M. Z.; Xu, L. M.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2321. (c) Li, Y.; Chen, Z. X.; Xiao, Q.; Ye, Q. D.; Sun, T. W.; Meng, F. K.; Ren, W. W.; You, L.; Xu, L. M.; Wang, Y. F.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2334. (d) Ren, W. W.; Chen, Z. X.; Xiao, Q.; Li, Y.; Sun, T. W.; Zhang, Z. Y.; Ye, Q. D.; Meng, F. K.; You, L; Zhao, M. Z.; Xu, L. M.; Tang, Y. F.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2341. (5) Li, J.; Yang, P.; Yao, M.; Deng, J.; Li, A. J. Am. Chem. Soc. 2014, 136, 16477. (6) Wang, L.; Wang, H.-T., Li, Y.-H.; Tang, P. P. Angew. Chem. Int. Ed. 2015, 54, 5732. (7) (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (b) Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (8) Li, R. T.; Han, Q. B.; Zheng, Y. T.; Wang, R. R.; Yang, L. M.; Lu, Y.; Sang, S. Q.; Zheng, Q. T.; Zhao, Q. S.; Sun, H. D. Chem. Commun. 2005, 23, 2936. (9) (a) Csákÿ, A. G.; Plumet, J. Chem. Soc. Rev. 2001, 30, 313. (b) Guo, F.; Clift, M. D.; Thomson, R. J. Eur. J. Org. Chem. 2012, 26, 4881. (10) Shi, L.-L.; Shen, H.-J.; Fang, L.-C.; Huang, J.; Li, C.-C.; Yang, Z. Chem. Commun. 2013, 49, 8806.
ACS Paragon Plus Environment
Page 5 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
(11) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (c) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 794. (d) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626. (e) Gotoh, H.; Hayashi, Y. Org. Lett. 2007, 9, 2859. (f) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134. (12) (a) Hoffmann, R. W. Synthesis 2006, 3531. (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193. (13) Webb, T. R. Tetrahedron Lett. 1988, 29, 3769. (14) Gardner, J. N.; Carlon, F. E.; Gnoj, O. J. Org. Chem. 1968, 33, 3294. (15) (a) Amice, P.; Blanco, L.; Conia, J. M. Synthesis 1976, 196. (b) Yun, H.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879. (16) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1995, 117, 9919. (17) (a) Cassayre, J.; Zard. S. Z. J. Am. Chem. Soc. 1999, 121, 6072. (b) Pallerla, M. K.; Fox, J. M. Org. Lett. 2007, 9, 5625. (c) Madu, C. E.; Lovely, C. J. Org. Lett. 2007, 9, 4697. (d) Hayashi, Y.; Miyakoshi, N.; Kitagaki, S.; Mukai, C. Org. Lett. 2008, 10, 2385. (e) Inagaki, F.; Kinebuchi, M.; Miyakoshi, N.; Mukai, C. Org. Lett. 2010, 12, 1800. (f) Huang, J.; Fang, L.-C.; Long, R.; Shi, L.-L.; Shen, H.-J.; Li, C.-C.; Yang, Z. Org. Lett. 2013, 15, 4018. (18) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. (b) Reddy, R. S.; Iguchi, S.; Kobayashi, S.; Hirama, M. Tetrahedron Lett. 1996, 37, 9335. (19) Imamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron Lett. 1985, 26, 4763. (20) Farwick, A.; Engelhart, J. U.; Tverskoy, O.; Welter, C.; Umlauf, Q. A.; Rominger, F.; Kerr, W. J.; Helmchen, G. Adv. Synth. Catal. 2011, 353, 349. (21) (a) Liu, Q.; Yue, G.-Z.; Wu, N.; Lin, G.; Li, Y.-Z. Quan, J.-M.; Li, C.-C.; Wang, G.-X.; Yang, Z. Angew. Chem. Int. Ed. 2012, 51, 12072. Related studies from other groups: (b) Fujioka, K.; Yokoe, H.; Yoshida, M.; Shishido, K. Org. Lett. 2012, 14, 244. (c) Pallerla, M. K.; Fox, J. M. Org. Lett. 2007, 9, 5625. (d) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. Org. Lett. 2006, 8, 83. (22) Kim, S.; Kim, B.; In, J. Synthesis 2009, 1963. (23) Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663. (24) Conquerel, Y.; Rodriguez, J. ARKIVOC, 2008, 227 (25) (a) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5503. (b) Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. (26) (a) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623. (b) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280. (c) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem. 1992, 57, 1326. (d) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (27) Paolobelli, A. B.; Latini, D.; Ruzziconi, R. Tetrahedron Lett. 1993, 34, 721. (28) Selected examples for oxidative heterocoupling: (a) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487. (b) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005, 44, 609. (c) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, 7083. (d) Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.; Castroviejo, P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857. (e)
Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.; Castroviejo, P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857. (f) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546. (29) Baciocchi, E.; Casu, A.; R. Ruzziconi, Tetrahedron Lett. 1989, 30, 3707-3710. (30) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 23, 1973 (31) Peverati, R.; Truhlar, D. G. J. Phys. Chem. Lett. 2011, 2, 2810.
TOC Pauson-Khand Rx
Oxidative heterocoupling of enolsilanes
Me
O O
H
Me Me H
HO
O O
O Me
H Me
H
O
OH
(+)-propindilactone G (1)
ACS Paragon Plus Environment
Journal of the American Chemical Society
Page 6 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment
6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
Asymmetric Total Synthesis of Propindilactone G Lin You,a Xin-Ting Liang,a Ling-Min Xu,a Yue-Fan Wang,a Jia-Jun Zhang,a Qi Su,a Yuanhe Li,a Bo Zhang,a ,a,b,c Shou-Liang Yang,a Jia-Hua Chen*,a and Zhen Yang*
a
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. b Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China c Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao (China) Email: [email protected], [email protected] Supporting Information ABSTRACT: A concise total synthesis of (+)-propindilactone G, a nortriterpenoid isolated from the stems of Schisandra propinqua var. propinqua, has been achieved for the first time. The key steps of the synthesis include an asymmetric Diels–Alder reaction, a Pauson–Khand reaction, a Pd-catalyzed reductive hydrogenolysis reaction, and an oxidative heterocoupling reaction. These reactions enabled the synthesis of (+)-propindilactone G in only 20 steps. As a consequence of our synthetic studies, the structure of (+)-propindilactone G has been revised.
Propindilactone G (1)1 and compounds 2–4 (Chart 1) represent a novel group of nortriterpenoids2 isolated from various species of Schisandracea family by Sun and co-workers. The species are widely distributed throughout Southeast Asia and North America and used as traditional Chinese herb medicines in China for liver protection and immune-regulation.2 Chart 1: Naturally occurring nortriterpenoids O
O A O
H
Me
Me O
H
2
H E
C
O
H
H
3
Me
D
O B Me
Me
HO
30
Me 29
1: propindilactone G Me
O O
HO
Me
Me H
O
H
Me H
H H
Me
9
H
17
23 20
8
6
7
H
15
16
O
22
27
26
Me O
25
Me
24
OH
O
O O
H
O Me H
Me H
H
Me
3: rubriflordilactone A O O
O
O
O
Me
O Me
H
Me
13 14
O
21
18
Me O
H
H Me
H HO
Me
12
O
H O
O
2: schindilactone A O
19
5
Me
O O
10 4
11
HO
1a: C17-epi-propindilactone G (originally proposed structure) H
O
O
1
O
OH
O
O
4: schilancitrilactone B
Me
The intriguing chemical structures and potential biological activity of the nortriterpenoids, in combination with their scarcity in nature, which limits their further biological investigation, have spurred considerable interest among the chemistry community,3 resulting in the total syntheses of schindilactone A (2) in 2011 by the research group of Yang,4 the total syntheses of rubriflordilactone A (3) in 2014 by the research group of Li,5 and the total syntheses of schilancitrilactone B (4) by the research group of Tang in 2015.6 From a structural perspective, propindilactone G (1), distinct from the other nortriterpenoids 2–4, possesses a unique 5/5/7/6/5 pentacyclic core bearing 7 stereocenters, three of which are quaternary centers7 (C9, C10 and C13). The originally proposed structure of propindilactone G (1a in Chart 1) was established by NMRs analysis.1 Preliminary biological assays indicated that these types of nortriterpenoids exhibit promising anti-HIV activity,8 which inspired us to develop synthetic methods and a strategy centered on the construction of the scaffold of propindilactone G, with the hope of providing a general approach for the total synthesis of other family members of propindilactone G. Herein we report our efforts on the development of a concise strategy that allowed the first total synthesis of (+)-propindilactone G (1) in 20 steps. Inspired by recent advances in the oxidative heterocoupling of enolsilanes for the formation of C-C bond,9 we postulated our total synthesis of propindilactone G (1a) to involve the late-stage coupling of the conjugated enolsilane 5 with the in situ generated enolsilane of ketolactone 6 to form the C17-C20 linkage (Scheme 1). This retrosynthetic analysis required the development of an efficient synthetic approach for the stereoselective synthesis of ketolactone 6 bearing a quaternary carbon atom at C13. Encouraged by our recent application of the Pauson–Khand (PK) reaction as a key step in the total synthesis of (+)-fusarisetin A,10 we envisaged that the PK reaction could be used for the synthesis of the cyclopetenone 6 from enyne 7. Enyne 7 in turn could be made from ester 8 by using the chemistry developed in our total synthesis of schindilactone A (2).4 Because we wanted to achieve an asymmetric total synthesis, we explored the use of an asymmetric Diels–Alder reaction of diene 9 and dienophile 10 in the presence of a chiral ligand11 for the synthesis of the chiral
ACS Paragon Plus Environment
Journal of the American Chemical Society
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 2 of 6
The concise enantioselective synthesis of the key vinyl bromide (+) 14 is shown in Scheme 2. We profiled a variety of asymmetric variations of Diels–Alder reaction11 for the synthesis of ester 8 from diene 9 and dienophile 10. The desired Diels–Alder reaction could be effectively achieved in the presence of Hayashi’s ligand,11e leading to the formation of (–)-ester 8 in 88% yield with excellent ee (98%). This reaction worked well on a 100-gram scale, providing a good foundation to pursue the asymmetric total synthesis.
P(OMe)314 in THF followed by the treatment with TESCl to give product 12 in 76% overall yield. Further treatment of 12 with dibromocarbene15 derived from CHBr3/tBuOK resulted in the formation of dibromide 13 as a pair of diastereosiomers in a ratio of 1:1, which then reacted with AgClO4•H2O16 in acetone to give the cycloheptenone-based vinyl bromide 14 in 57% yield over two steps. Scheme 3 depicts the synthesis of the tetracyclic fragment 17. Although stereoselective synthesis of the cyclopentenone subunit containing an all-carbon quaternary stereocenter at C13 of propindilactone G is challenging, the recent applications of the PK reaction to the synthesis of such scaffolds in complex natural product total synthesis17 encouraged us to use this reaction as a key step for the synthesis of intermediate 17. To this end, vinyl bromide 14 was coupled with TMS-acetylene in the presence of a catalytic amount of Pd(PPh2)Cl2/CuI and iPr2NH (DIPA)18 to give enone 15 in 88% yield. Further reaction of 15 with (3-methylbut -3-en-1-yl)-magnesium bromide in the presence of CeCl319 resulted in enyne 7 in 81% yield as a single isomer. To prepare the cyclopentenone subunit bearing an all-carbon quaternary stereocenter, enyne 7 was treated with Co2(CO)8 (0.5 eq) in the presence of celite20 in toluene under reflux. The expected product 16 was indeed obtained in 67% yield, together with a 24% yield of its C13 diastereoisomer. It is worth mentioning that the TMS group substituted at the terminal of the acetylene21 in 7 played a critical role in the PK reaction, since the substrates without TMS did not afford any desired annulated products. Further treatment of 16 with TBAF afforded 17a in 90% yield with retention of the TMS group, and the structure was confirmed by X-ray crystallographic analysis. However, when 16 was reacted with AgF,22 dienone 17 was obtained in 85% yield with removal of its both silyl groups.
Scheme 2. Synthesis of the bromoenone 14a
Scheme 3. Synthesis of the tetracyclic ring fragment 17a
building block 8. In addition, we wanted our strategy to be in an agreement with the notion of concise synthesis by limiting the use of protecting group.12 Scheme 1: Retrosynthetic analysis of propindilactone G O O
H
Oxidative heterocoupling of enolsilanes
HO
Me
OTIPS O
5
O
+
OH
O
H Me
Me
Me H
17
H
O
Me
Me
Me
CF3 N H
O
H
OTIPS
EtO
O
H
5
H Me
8
COOEt
O
10
15
H
Me
8
+
O
F3C
OH 10
TMS
5
H
Me
7
O
N H
OTIPS
H
CF3 CF3
COOEt
10
OTES
O Me
OTIPS d) MeMgCl (84%) e) KHMDS, P(OMe)3, O2 then TESCl (90%)
Me H 12
O O Me
OTES OTIPS Br
g) AgClO4 H2O acetone, rt
Br
(57% in 2 steps)
H Me 13
H
O
OTES O
O Me
TMS Me
H
15
Me OH
b) BrMg
15
17a TMS
OTES
CeCl3 (81%)
O
Me
Me
Me
H
H Me 14
O
As illustrated in Scheme 2, further treatment of aldehyde 8 with MeMgBr in the presence of AlMe313 afforded an alcohol, which was then oxidized with DMP in the presence NaHCO3 in CH2Cl2 to give ketoester 11 in 74% yield over two steps. Grignard reaction of 11 with MeMgBr afforded a lactone, which underwent oxidation by reaction with KHMDS in the presence of O2 and
OH O
TMS
(67%) Me
Me
H
7
Me
OH OH
9
a
Reagents and conditions: (a) 9 (1.2 eq), 10 (1.0 eq), Hayashi ligand (0.1 equiv), TFA (20 mol%), toluene, -10oC, 10 h, 88% (98% ee); (b) AlMe3 (2.3 eq), MeMgBr (1.5 eq), CH2Cl2, -78oC to 0oC, 1 h, 80%; (c) DMP (1.1 eq), NaHCO3 (8.0 eq), CH2Cl2, rt, 93%; (d) MeMgCl, THF, -78oC to -25oC, 84%; (e) KHMDS (2.0 eq), THF, -78 oC to 0oC followed by addition of P(OMe)3 (2.0 eq), O2, 0oC, 1 h. 80%; then TESCl (1.2 eq), THF, rt, 90%; (f) KOtBu (10.0 eq), CHBr3 (7.5 eq), petroleum ether, -20oC; (g) AgClO4·H2O (2.5 eq), acetone, rt, 57% for 2 steps.
15
O
OTES
e) AgF (85%)
Br
O
TMS
16
c) Co2(CO)8
13
O
OTES O
O
Me OH
9
Me
13
d) TBAF (90%) O
O
Me
Me
OTIPS
TMS (88%)
OH
O
O 11
f) t-BuOK, CHBr3, -20 oC
a) Pd(PPh3)2Cl2, CuI DIPA
14
9
Me
EtO Me
H
Me O
b) AlMe3, MeMgBr (80%) c) DMP (93%) O
O Br
(100 grams scale)
OTES CF3
OTES
O Me
O 8
A O
O
OTES
O a) A, toluene, TFA, -10 oC, 10h 9 OTIPS 88% (98% ee) EtO
H
17 16
14
6
O O
H
H
Me 13
Me
OTES CF3
A
9 OTIPS
HO
10
O
CF3
Pauson-Khand Rx
O
H
1a: C17-epi-propindilactone G F3C
O
Dieckmann-type condensation Rx
O Me
13
8 14
Me
7
H
17
H
15
O
CRTEP of 17a
a
Reagents and conditions: (a) ethynyltrimethylsilane (1.25 eq), DIPA (3.0 eq), Pd(PPh3)2Cl2 (0.06 eq), CuI (20 mol%), THF, rt, 88%; (b) (3-methylbut-3-en-1-yl)-magnesium bromide (1.8 eq), CeCl3 (3.0 eq), THF, 0 oC, 81%; (c) Co2(CO)8 (0.5 eq), celite (10 wt.), toluene, reflux, 67%; (d) TBAF (1.5 eq), THF, rt, 90%; (e) AgF (10.0 eq), THF, MeOH, H2O 80 oC, 85%.
We then explored the pathway for stereoselective synthesis of the key intermediate 6 (Scheme 4). Initially, we expected that the C7–C8 double bond in 17 could be saturated by Pd-catalyzed
ACS Paragon Plus Environment
Page 3 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
hydrogenation. However, attempts with various Pd-catalysts could not regioselectively remove this double bond. On the other hand, treatment of 17 with Pd(OH)2/C23 in the presence of Et3N24 under a balloon pressure of hydrogen initiated a reductive isomerization to afford dienone 18 in 98% yield. Further treatment of dienone 18 with m-CPBA in CH2Cl2 afforded epoxide 19 in 73% yield as a single isomer. The observed regio- and stereo-selective epoxidation of dienone 18 could be the result of the free hydroxyl group at C10, which might delivery the m-CPBA to approach the double bond from the bottom face. To install the lactone in 20, epoxide 19 was first reacted with acetic anhydride in the presence of Et3N and the resulting acetate was treated with LiHMDS to initiate a Dieckmann-type condensation4 to afford lactone 20 in 76% overall yield. To achieve the chemo- and stereo-selective synthesis of 6, 20 was first subjected to a dehydration with Martin’s sulfuran,25 and the resulting unsaturated lactone 21 underwent both a Pd-catalyzed hydrogenation to saturate its C1– C2 double bond and hydrogenolysis26 to open the epoxide to give product 6 in 56% yield, together with its C8-epimer 6a, which could be converted to 6 in 41% yield by treatment with DBU in refluxing toluene. The structure of 21 was established by X-ray crystallographic analysis.
-di-tert-butyl pyridine (DTBP) at -50oC to -30oC in acetonitrile, and the ratio for the four diastereoisomers was 2.0:2.0:1.1:1 according to 1H NMR analysis. This mixture without purification then underwent a Horner–Wadsworth–Emmons (HWE) reaction by treatment with ethyl 2-(diphenoxyphosphoryl)propanoate B in the presence of KHMDS as a base in THF at -78oC to give product 23, 24, and inseparable products 25 and 26 in 16%, 15% and 60% yields, respectively (see SI for details). Scheme 5. Synthesis of compounds 23, 24 and 25/26a
OH HO
Me
a) Pd(OH)2/C H2
9
O Me
8 14
Me
7
H
(98%)
O
15
O
Me
1
O
Me
Me
H
7
H
Me
20
f)
2
Me
O
1
O Me
Me
b) KHMDS H O (PhO)2OP CO2Et (60%) B Me Me
O
15
Me
18
OH
O
21
(6a = 56%, 6b = 22%)
O
O
1
Me
HO
Me
6
O
OTIPS
5
Me
Me
H
Me Me 13 17
H Me
20
CO2Et
23
H
Me
22
CHO
20
O
22 Me
Me
Me
Me
H
H
Me
22
O
Me
H
Me
CO2Et
Me
13
Me
17
H
25
Me
Me
+ HO
O
O
22
CO2Et
24 (15%)
H Me
23
O
H
CO2Et
23
Me 20
17
H
O
H H
HO
+O
O
23 (16%) HO
O
H
+ O
Me
O
HO
H
O
26
O g) DBU (41%)
HO
Me
8
Me
Me
Reagents and conditions: (a) 6 (1.0 eq), TBSOTf (1.2 eq), Et3N (2.0 eq), CH2Cl2, 0oC to rt, 1 h; then enolsilane 5 (3.0 eq), CAN (5.0 eq), DTBP (10 eq), CH3CN, -50oC to -30oC, rt, 1.5 h 92%; (b) 22 (1.0 eq), 18-crown-6 (15.0 eq), KHMDS (5.0 eq), HWE reagent B (5.0 eq), THF, -78oC, 1.5 h, 23 (16%), 24 (15%), and a mixture of 25/26 (60%).
Me
+
O
CRTEP of 21
OTIPS
A
(25/26 = 1.5:1, 60%)
H
H
O H
Me
H
17
19
O Me
H
H
a
2
H
Me
O
8
Me
HO
H
H
O
9
H
O
O
Me
10
Me
O
H
O
Pd2dba3 . CHCl3
nBu P 3 HCOOH, DIPEA
O
H
O
e) Martin's sulfuran (83%)
O
Me
d) LiHMDS (84%)
O
Me
6
O 8 14
O
O
O
O
9
10
O
c) Ac2O, Et3N (91%)
Me
H
Me
O
H
then CAN, DTBP (92%) (dr = 2.0:2.0:1.1:1.0)
m-CPBA (73%) O
Me
HO O
H
a) TIPSOTf, Et3N
17
O
Me
OH
O HO
Me
O
Me
17
HO O
H
Scheme 4. Synthesis of ketolactone 6a O
O
O
H
H
O
To complete the total synthesis, we expected that one of the four isomers mentioned above could undergo an OsO4-mediated regio- and stereo-selective dihydroxylation, and the resulting intermediate might undergo an intramolecular lactonization to afford the natural product. Scheme 6. Total synthesis of (+)-propindilactone G (1)a
6a
O
a
Reagents and conditions: (a) Pd(OH)2/C (0.7 wt), CH2Cl2, rt, 98%; (b) m-CPBA (2.5 eq), CH2Cl2, rt, 73% (brsm); (c) Ac2O (3.0 eq), Et3N (10.0 eq), CH2Cl2, 0 oC, 91%; (d) LiHMDS (2.5 eq), THF, -78 oC to -40 oC, 84% (brsm); (e) Martin’s sulfuran (1.8 eq), CH2Cl2, 0o C, 83%; (f) Pd2dba3·∙CHCl3 (0.1 eq), nBu3P (0.2 eq), HCOOH (5.0 eq.), DIPEA (2.0 eq), dioxane, 45 o C, 56%; g) DBU (10.0 eq.), toluene, reflux, 41%.
With ketolactone 6 in hand, we entered the final stage of the total synthesis as shown in Scheme 5. We anticipated that an intermolecular oxidative coupling of the conjugated enolsilane27 5 with enolsilane A could be applied to the synthesis of 22. Realizing that the intermolecular oxidative heterocoupling of enolsilanes was a daunting task,28 we systematically profiled this important coupling reaction by using enolsilane A to react with the conjugated enolsilane 5. After a systematic investigation, we found that when ceric ammonium nitrate29 (CAN) was utilized as an oxidant, this coupling reaction could proceed smoothly to afford 22 as two pairs of diastereoisomers (corresponding to the two newly generated chiral centers C17 and C20) in 92% overall yield. This reaction was carried out in the presence of 2,6
25/26
a) OsO4, NMO
O O
H
Me
HO
17
O
(81%) Me
Me
H
H
H
Me
O
Me
22 20
O
23
OH
propindilactone G (1)
CRTEP of propindilactone G (1) a
Reagents and conditions: (a) 25/26 (1.0 eq), OsO4 (0.07 eq), NMO (2.0 eq), THF/H2O (1:1), 4oC, 72 h, 81% of propindilactone G (1) based on the amount of 25 in the mixture of 25/26.
To this end, 23, 24 and 25/26 were treated with OsO4 in the presence of NMO30 as a co-oxidant, respectively, to our delight, propindilactone G (1) could be made from substrate 25 in 81%
ACS Paragon Plus Environment
Journal of the American Chemical Society
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 6
yield (based on the amount of 25 in the mixture of 25/26, Scheme 6). The 1H NMR and 13C NMR spectra, and specific rotation of the synthesized propindilactone G were in agreement with those reported in literature ([α]25D = + 39.0, c = 0.15 in MeOH; lit. [α]25.6 D = + 41.1, c = 0.15 in MeOH),1 and its structure has been confirmed by X-ray crystallographic analysis. Thus, as a consequence of our synthetic studies, the structure of (+)-propindilactone G has been revised as compound 1 and the originally proposed structure of propindilactone G has been reassigned as 1b (C17-epi-(+)-propindilactone G) (see Chart 1). It is worthwhile to mention that substrate 26 in the mixture of 25/26 was converted to some unidentified products under the reaction conditions. To account for this observation, we carried out a DFT calculation (M11-L//B3LYO),31 and our preliminary calculation showed that the oxidation of 25 to form intermediate 25-Os id 1.5 kcal/mol more exothermic than that of 26. The energy difference can be attributed to the repulsion between the oxygen atom on Os and the labeled carbon in the scaffold of 26-Os (Scheme 7). As a result, the selectivity for the dihydroxylation of 26 would be decreased, leading to the formation of multi-dihydroxylative products.
Experimental procedures and compound characterization (cif, pdf). This material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 7. DFT calculation for the free-energy profiles and geometric information of the Os-dihydroxylation of 25 and 26
REFERENCES
O O
25
OsO4
Os O
H
HO
Me
H
Me
Me
O CO2Et
O
Me
O
ΔG = -23.3 kcal/mol
O
Me
H
H
H
O
25-Os
O
26
OsO4
O
H
HO
Me
Me
H
Me
17
O
ΔG = -21.8 kcal/mol
H
13
Me
H
H
26-Os
O
O
O
CO2Et Me
Os O O
In conclusion, the total synthesis of (+)-propindilactone G (1) was accomplished for the first time in 20 steps (longest liner sequence) starting from (buta-1,3-dien-2-yloxy)triisopropylsilane 9 and (E)-methyl 4-oxobut-2-enoate 10. The key steps in this synthesis were an asymmetric Diels–Alder reaction, a Co-mediated PK reaction, a Pd-catalyzed reductive hydrogenolysis reaction, an oxidative heterocoupling reaction of enolsilanes, and an OsO4-mediated dihydroxylation. This work demonstrates the power of the PK reaction for the stereoselective construction of cyclopentenone bearing an all-carbon quaternary chiral center, and the oxidative heterocoupling reaction of enolsilanes for the concise ligation of cyclopentenone core 6 with its side chain. The true structure of (+)-propindilactone G (1) was revised in accord with our finding, and the originally proposed structure has been reassigned as C17-epi-(+)-propindilactone G (1b). The application of the synthetic propindilactone G and its analogs as probes to study their biology is currently underway in our laboratories, and will be reported in due course.
ASSOCIATED CONTENT Supporting Information
AUTHOR INFORMATION Corresponding Author [email protected], [email protected]
ACKNOWLEDGMENT This paper is dedicated to Prof. Handong Sun on the occasion of his 75th birthday. We thank professor Yu Lan of Chong Qing University for the DFT calculation, and professors Wen-Xiong Zhang and Dr. Neng-dong Wang for the X-ray crystallographic analysis. This work is supported by the National 863 Program (Grant No. 2013AA092903, NSFC-Shandong Joint Fund for Marine Science Research Centers (U1406402), and Natural Science Foundation of China (Grant No. 21272015, 21372016, 21472006).
(1) Lei, C.; Huang, S.-X.; Chen, J.-J.; Yang, L.-B.; Xiao, W.-L.; Chang, Y.; Lu, Y.; Huang, H.; Pu, J.-X.; Sun, H.-D. J. Nat. Prod. 2008, 71, 1228. (2). Shi, Y. -M.; Xiao, W. -L.; Pu, J. -X.; Sun, H. D. Nat. Prod. Rep. 2015, 32, 367. (3) Synthetic studies on Schisandraceae triterpenoids: (a) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 593. (b) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.; Deng, L.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 885. (c) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 1657. (d) Zhang, Y. D.; Tang, Y. F.; Luo, T. P.; Shen, J.; Chen, J. H.; Yang, Z. Org. Lett. 2006, 8, 107. (e) Zhang, Y. D.; Ren, W. W.; Lan, Y.; Xiao, Q.; Wang, K.; Xu, J.; Chen, J. H.; Yang, Z. Org. Lett. 2008, 10, 665. (f) Li, Z.; Cao, Y.; Jiao, Z.; Wu, N.; Wang, D. Z.; Yang, Z. Org. Lett. 2008, 10, 5163. (g) Kan S. B. J.; Anderson, E. A. Org. Lett. 2008, 10, 2323. (h) Cordonnier, M. C. A.; Kan, S. B. J.; Anderson, E. A. Chem. Commun. 2008, 5818. (i) Anderson, E. A. Org. Biomol. Chem. 2011, 9, 3997. (j) Goh, S. S.; Baars, H.; Gockel, B.; Anderson, E. A. Org. Lett. 2012, 14, 6278. (k) Wang, Q.; Chen, C. Org. Lett. 2008, 10, 1223. (l) Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 2111. (m) Lai, K. W.; Paquette, L. A. Org. Lett., 2008, 10, 2115. (n) Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 3781. (o) Chenoweth, D. M.; Chenoweth, K.; Goddard, W. A. J. Org. Chem. 2008, 73, 6853. (p) Mehta, G.; Bhat, B. A. Tetrahedron Lett. 2009, 50, 2474. (q) Mehta, G.; Bhat, B. A.; Kumara, T. H. S. Tetrahedron Lett. 2009, 50, 6597. ® Maity, S.; Matcha, K.; Ghosh, S. J. Org. Chem. 2010, 75, 4192. (s) Bartoli, A.; Chouraqui, G.; Parrain, J. L. Org. Lett. 2012, 14, 122. (4) (a) Xiao, Q.; Ren, W. W.; Chen, Z. X.; Sun, T. W.; Li, Y.; Ye, Q. D.; Gong, J. X.; Meng, F. K.; You, L.; Liu, Y. F.; Zhao, M. Z.; Xu, L. M.; Shan, Z. H.; Tang, Y. F.; Chen, J. H.; Yang, Z. Angew. Chem. Int. Ed. 2011, 50, 7373. (b) Sun, T. W.; Ren, W. W.; Xiao, Q.; Tang, Y. F.; Zhang, Y. D.; Li, Y.; Meng, F. K.; Liu, Y. F.; Zhao, M. Z.; Xu, L. M.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2321. (c) Li, Y.; Chen, Z. X.; Xiao, Q.; Ye, Q. D.; Sun, T. W.; Meng, F. K.; Ren, W. W.; You, L.; Xu, L. M.; Wang, Y. F.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2334. (d) Ren, W. W.; Chen, Z. X.; Xiao, Q.; Li, Y.; Sun, T. W.; Zhang, Z. Y.; Ye, Q. D.; Meng, F. K.; You, L; Zhao, M. Z.; Xu, L. M.; Tang, Y. F.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2341. (5) Li, J.; Yang, P.; Yao, M.; Deng, J.; Li, A. J. Am. Chem. Soc. 2014, 136, 16477. (6) Wang, L.; Wang, H.-T., Li, Y.-H.; Tang, P. P. Angew. Chem. Int. Ed. 2015, 54, 5732. (7) (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (b) Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (8) Li, R. T.; Han, Q. B.; Zheng, Y. T.; Wang, R. R.; Yang, L. M.; Lu, Y.; Sang, S. Q.; Zheng, Q. T.; Zhao, Q. S.; Sun, H. D. Chem. Commun. 2005, 23, 2936. (9) (a) Csákÿ, A. G.; Plumet, J. Chem. Soc. Rev. 2001, 30, 313. (b) Guo, F.; Clift, M. D.; Thomson, R. J. Eur. J. Org. Chem. 2012, 26, 4881. (10) Shi, L.-L.; Shen, H.-J.; Fang, L.-C.; Huang, J.; Li, C.-C.; Yang, Z. Chem. Commun. 2013, 49, 8806.
ACS Paragon Plus Environment
Page 5 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
(11) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (c) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 794. (d) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626. (e) Gotoh, H.; Hayashi, Y. Org. Lett. 2007, 9, 2859. (f) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134. (12) (a) Hoffmann, R. W. Synthesis 2006, 3531. (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193. (13) Webb, T. R. Tetrahedron Lett. 1988, 29, 3769. (14) Gardner, J. N.; Carlon, F. E.; Gnoj, O. J. Org. Chem. 1968, 33, 3294. (15) (a) Amice, P.; Blanco, L.; Conia, J. M. Synthesis 1976, 196. (b) Yun, H.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879. (16) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1995, 117, 9919. (17) (a) Cassayre, J.; Zard. S. Z. J. Am. Chem. Soc. 1999, 121, 6072. (b) Pallerla, M. K.; Fox, J. M. Org. Lett. 2007, 9, 5625. (c) Madu, C. E.; Lovely, C. J. Org. Lett. 2007, 9, 4697. (d) Hayashi, Y.; Miyakoshi, N.; Kitagaki, S.; Mukai, C. Org. Lett. 2008, 10, 2385. (e) Inagaki, F.; Kinebuchi, M.; Miyakoshi, N.; Mukai, C. Org. Lett. 2010, 12, 1800. (f) Huang, J.; Fang, L.-C.; Long, R.; Shi, L.-L.; Shen, H.-J.; Li, C.-C.; Yang, Z. Org. Lett. 2013, 15, 4018. (18) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. (b) Reddy, R. S.; Iguchi, S.; Kobayashi, S.; Hirama, M. Tetrahedron Lett. 1996, 37, 9335. (19) Imamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron Lett. 1985, 26, 4763. (20) Farwick, A.; Engelhart, J. U.; Tverskoy, O.; Welter, C.; Umlauf, Q. A.; Rominger, F.; Kerr, W. J.; Helmchen, G. Adv. Synth. Catal. 2011, 353, 349. (21) (a) Liu, Q.; Yue, G.-Z.; Wu, N.; Lin, G.; Li, Y.-Z. Quan, J.-M.; Li, C.-C.; Wang, G.-X.; Yang, Z. Angew. Chem. Int. Ed. 2012, 51, 12072. Related studies from other groups: (b) Fujioka, K.; Yokoe, H.; Yoshida, M.; Shishido, K. Org. Lett. 2012, 14, 244. (c) Pallerla, M. K.; Fox, J. M. Org. Lett. 2007, 9, 5625. (d) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. Org. Lett. 2006, 8, 83. (22) Kim, S.; Kim, B.; In, J. Synthesis 2009, 1963. (23) Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663. (24) Conquerel, Y.; Rodriguez, J. ARKIVOC, 2008, 227 (25) (a) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5503. (b) Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. (26) (a) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623. (b) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280. (c) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem. 1992, 57, 1326. (d) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (27) Paolobelli, A. B.; Latini, D.; Ruzziconi, R. Tetrahedron Lett. 1993, 34, 721. (28) Selected examples for oxidative heterocoupling: (a) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487. (b) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005, 44, 609. (c) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, 7083. (d) Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.; Castroviejo, P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857. (e)
Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.; Castroviejo, P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857. (f) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546. (29) Baciocchi, E.; Casu, A.; R. Ruzziconi, Tetrahedron Lett. 1989, 30, 3707-3710. (30) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 23, 1973 (31) Peverati, R.; Truhlar, D. G. J. Phys. Chem. Lett. 2011, 2, 2810.
TOC Pauson-Khand Rx
Oxidative heterocoupling of enolsilanes
Me
O O
H
Me Me H
HO
O O
O Me
H Me
H
O
OH
(+)-propindilactone G (1)
ACS Paragon Plus Environment
Journal of the American Chemical Society
Page 6 of 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment
6
