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Enantioselective Divergent Synthesis of C19-Oxo Eburnane Alkaloids via Palladium-Catalyzed Asymmetric Allylic Alkylation of an N-Alkyl-#, #-unsaturated Lactam Barry M. Trost, Yu Bai, Wen-Ju Bai, and Johnathan E. Schultz J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00788 • Publication Date (Web): 08 Mar 2019 Downloaded from http://pubs.acs.org on March 8, 2019
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Journal of the American Chemical Society
Enantioselective Divergent Synthesis of C19-Oxo Eburnane Alkaloids via Palladium-Catalyzed Asymmetric Allylic Alkylation of An N-Alkyl- α , β -unsaturated Lactam Barry M. Trost,* Yu Bai, Wen-Ju Bai, and Johnathan E. Schultz Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States Supporting Information Placeholder
The C19-oxo-functionalized eburnane alkaloids display unique chemical structure and interesting biological activity. Herein, we report a divergent enantioselective strategy to access these alkaloids by use of a challenging palladium-catalyzed asymmetric allylic alkylation of an N-alkyl-α,β-unsaturated lactam. 19-(S)(phutdonginin), (–)-19-OHOH-Δ14-vincamone eburnamine, (+)-19-oxoeburnamine, and (+)-19-OHeburnamonine (1-4) have been concisely synthesized for the first time in 11 to 13 steps. ABSTRACT:
alkaloids, such as these C19-oxo eburnane family natural products, seem to be ideal 9 7
A
NH
12
5
C
B 16
E
N
21 20
O
N
3
D 14
O
15
HO
19
(1)
N
Me
(-)-19-OH-eburnamonine (2)
N
N
H
O
Me
(+)-19-oxoeburnamine (3)
N
N H
O Me
Me
(+)-19-OH-eburnamine (4)
N
H
O HO
Transition metal-catalyzed asymmetric allylic alkylation (AAA) represents a powerful tool to regio- and enantio-selectively building new stereocenters, especially the quaternary carbon centers. During the last two decades, this strategy has been successfully applied for complex natural product synthesis.4 Monoterpene indole
N H
(phutdonginin)
HO
Eburnane indole alkaloids are structurally diverse natural products mainly isolated from the plants of the genus Kopsia, which shown potent bioactivity on the cardiovascular system and brain functions.1 Among these natural products, C19 oxo-functionalized eburnane alkaloids possess favorable antitumor activity (Figure 1).2 For example, 19(S)-OH-Δ14-vincamone (phutdonginin) (1) exhibits activity against A549, HT29, and HCT116 cancer cell lines, with IC50 values of 0.51, 0.36 and 0.40 µg/mL, respectively. (–)-19-OH-eburnamonine (2) also displays similar bioactivity. Interestingly, the isolated eburnane alkaloids show enantiodivergence;3 both of the two absolute configurations at C20- and C21-positions (20α, 21α and 20β, 21β) have been observed. For example, compounds 1-4 possess 20α, 21α configuration, whereas compounds 5 and 6 have the opposite sense of chirality. As a result, developing an asymmetric strategy that can access both enantiomers at C20-position is of significance. To date, no total syntheses of these C19oxo eburnane alkaloids have been reported.
N HO
HO
Me
19-(S)-OH-∆14-vincamone
N H
(+)-larutensine (5)
(+)-eburnamonine (6)
Figure 1. C19-Oxo functionalized eburnane alkaloids.
targets for use of AAA to build the corresponding C20quaternary stereocenter. Biosynthetically, monoterpene indole alkaloids are derived from the condensation between tryptamine and secologanin through an enzymecatalyzed stereoselective Pictet-Spengler reaction.5 The generated strictosidine undergoes deglycosylation and then spontaneously cyclizes to form 4,21dihydrogeissoschizine, a six-membered iminium ion which has been considered as the key intermediate for various skeletal rearrangements. Strategically, a sixmembered lactam could be a potential precursor6 to produce the required iminium ion. From this disconnection, we envisioned that the quaternary stereocenter at C20- position could be accessed by using AAA. Recently, some examples of transition metal-catalyzed AAA of lactams have been reported. However, current methods are limited to the substrates bearing electronwithdrawing N-protecting groups. 7 Substrates suitable for highly enantioselective allylation require electronwithdrawing functionality, as is found in 3-aryl oxindole lactams8 (Figure 2), but it raises a tedious deprotection issue. More problematically, the subsequent N-alkylation is quite challenging due to the steric effect of the quaternary stereocenter at the α-position.9 To avoid these problems, it would be desirable to establish a method for
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the direct AAA of the N-alkyl lactam, which could provide a practical strategy for the synthesis of monoterpene indole alkaloids. Herein we report our findings, showcasing the first enantioselective synthesis of C19-oxo functionalized eburnane alkaloids.
tion of the compound 15 were rather sensitive, we glad to found that upon exposure to FeCl3 on silica, the amides underwent a ketal cleavage/cyclization11 to provide the desired α,β-unsaturated lactams 11a-b to yields of 52% and 88%, respectively.
a. Trost (2004)
Scheme 2. Synthesis of N-alkyl Lactams 11a-b
OAc Ph
[(η3-C 3H 5PdCl)2] (2.5 mol%) L *(5 mol%)
Ph O
O N Me
tBuOH, tol. -78 to 4 oC
N Me
L *=
O
O NH HN
93% yield 81% ee
PPh 2Ph 2P
b. Stoltz (2016)
BnN
[Ir(cod)Cl] 2 (2 mol%) L* (5 mol%)
OMe
BnN
O Ph
OCO2Me
Ph
O
O
TBD(10 mol%) THF, 20 oC
O
Me
66% yield, 12:1 b:l 2:1 dr, 79% (62%) ee
OH
O
O
O P N
L *=
OMe
c. Stoltz (2018)
MeN
CO2Me
O
Ni(COD) 2 (10 mol%), L* (12 mol%)
OEt
MeN
tol./MTBE, 10 oC
N
O OEt
L *=
MeO MeO
PPh 2 PPh 2 N
31% ee
OMe
Figure 2. Current limitations of transition metal-catalyzed AAA of electron-donating N-alkyl lactams.
Retrosynthetically, compound 1 could be realized via a late-state oxidation of hemiaminal 7, followed by diastereoselective reduction of its ketone motif (Scheme 1). The E ring would be constructed by chemoselective oxidative cleavage of the allyl group of compound 8 and subsequent cyclization to form the N1-C16 bond. The methyl ketone moiety might be obtained from the corresponding ester 9 through methylation. Ester 9, in turn, could arise from compound 10 through a BischlerNapieralski reaction. To access compound 10, a challenging Pd-AAA of N-alkyl-α,β-unsaturated lactam 11 would await us to solve. Scheme 1. Retrosynthetic Analysis 9
7 5
12
N
21
N
16 H
20
O
[O]
3 14
[H]
15
HO
19
N
N H H
N
HO Me
7 O
Me
oxid. cleav./ cyclization
N H
8 O
Me
19-(S)-OH-∆14-vincamone (1) methylation
O
O N
O
N OR Boc N-alkyl-α,β-unsaturated lactam (11)
N
Pd-AAA
N Boc
O OR
10
BischlerNapieralski
N H H
9
O
N
With compounds 11a-b in hand, we investigated the key Pd-AAA reaction. We studied both of the two nucleophiles with different electrophiles 16a-c and summarize the results in Table 1. For the pro-nucleophile 11, the use of bulky t-butyl ester was advantageous over a methyl ester. For electrophile 16, the presence of a substituent at C-2 proved universally better (entries 1-3 vs. 4-9). As a simple allyl subunit is ultimately required, we employed a C-2 substitute that could be easily removed. It was found that silyl groups such as -SiMe2Ph or SiMe2Bn proved effective with the latter being the best.12 Indeed, maximizing steric bulk of the ester, allylating agent, and base proved particularly fruitful.13 As to the ligand choice, the standard and less sterically demanding Trost ligand L1 gave better results, whereas the sterically more demanding anthracenyl ligand L3 failed to give any product. Finally, under condition of entry 9, using CpPd(cinnammyl) gave the desired product in 75% yield and 90% ee. Other types of ligands have also been tested, such as Pfaltz and SEGPHOS ligands, and low enatioselectivity (
