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Propene as an Atom Economical Linchpin for Concise Total Synthesis of Polyenes; Piericidin A Barry M. Trost, and Hadi Gholami J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08974 • Publication Date (Web): 01 Sep 2018 Downloaded from http://pubs.acs.org on September 1, 2018
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Journal of the American Chemical Society
Propene as an Atom Economical Linchpin for Concise Total Synthesis of Polyenes; Piericidin A Barry M. Trost* and Hadi Gholami Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States Supporting Information Placeholder ABSTRACT: A concise and convergent total synthesis
of piericidin A is disclosed. The synthesis hinges on the utilization of propene as a synthetic linchpin to merge the properly elaborated alkyne fragments, leading to the 1,3,6–triene motif of piericidin A. Utilization of propene as a unique alkene, capable of sequential coupling with two alkynes, is further illustrated in the context of various 1,3,6–triene products. The latter process proceeds with high atom economy and efficiently gives rise to complex frameworks from readily accessible alkyne substrates. This strategic C–C bond formation offers an orthogonal paradigm in the design of synthetic routes, leading to higher step economy and more efficient syntheses of polyunsaturated natural products.
Scheme 1. A linchpin strategy to construct 1,3,6trienes featuring the alkene–alkyne coupling a. natural products bearing 1,3,6-triene motif OH
O
MeO
MeO
OR N
MeO
H 10 O Coenzyme Q10 (3)
MeO Piericidin A1 (1) R = H Piericidin B1 (2) R = Me OH
O Kalipyrone (5)
O O
OMe
Actinopyrone A (4)
MeO
O OH
HO H
O
O
Granuloside (6)
Piericidin A (1) and B (2) are notable members of a family of natural products isolated from Streptomyces mobaraensis and S. pactam.1 This class of molecules contains a highly substituted pyridine fragment with a lipophilic side chain. The structural resemblance of piericidin natural products to coenzyme Q10 (3, dashed box, Scheme 1) results in fascinating biological activity of this family.2 Piericidin A, for instance, is a potent inhibitor (with nM activity) of protein I complex, which is the first step in the mitochondrial respiration.3 The impressive biological activity of these natural products along with their intriguing structural features has stimulated the development of efficient and convergent synthetic strategies so that structure function relationships can be more profitably explored. Two particularly elegant contributions to the synthesis of piericidin A are reported by the Boger4 and the Lipshutz group.5,6 Central to the structure of piericidins and many other natural products and drug molecules is a 1,3,6-triene motif (highlighted by the large numbers of structures in Scheme 1).1a, 7 Traditionally, access to such a motif relies on utilization of olefination methodologies in conjunction with various cross coupling reactions. We aim to devise an alternative convergent strategy in which the 1,3,6-triene can be obtained via coupling of two alkyne
b. access to 1,3,6-triene motif current state of the art cross coupling: Stille, Negishi, etc.
R2
our approach
olefination: Julia, HWE, etc.
R4
R1
R3
2nd alkene-alkyne coupling
1st alkene-alkyne coupling R4 synthetic linchpin
R2
R3
R1 1st alkene-alkyne coupling R2 R1
2nd
alkene-alkyne coupling
R4 R3
✰ > 2500 natural prodcut hits (Dictionary of Natural Products) ✰ 40 drug hits (Drugbank)
fragments with propene as a synthetic linchpin. Sequential alkene–alkyne coupling reactions were envisioned as the key transformation to deliver the featured moiety with high atom, step, and redox economy (Scheme 1, b).8 This strategic C–C bond formation is modular in design and by simple switching the order of the two alkene-alkyne couplings, isomeric trienes with complementary substitution pattern about the central double bond can be obtained (Scheme 1, b). This flexibility allows rapid access to analogues of a compound for library synthesis and screening. The synthetic utility of this approach is demonstrated in the concise total syn-
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thesis of piericidin A and, more generally, in the synthesis of various examples bearing the highlighted triene moiety, thus leading to a practical strategy to such motifs. Retrosynthetically, piericidin A can be obtained from alkynes 7 and 8 via their sequential coupling with propene (eq 1). Coupling of propene with alkyne 8 should proceed first, then the resulting product must be coupled with alkyne 7 to obtain the triene motif embedded in the natural product. Alkyne 8 could be synthesized from chiral propargylic alcohol 9 via the Marshall−Tamaru reaction.9 Furthermore, we aimed to evolve a catalytic asymmetric alkynylation, which sets the absolute configuration of the natural product. OH MeO
OH
(eq 1)
N
MeO
1 OH
OH
MeO
+ N
MeO
+ OR
9
8
7
Our synthesis commenced with the direct preparation of chiral alcohol 9 using our reported asymmetric alkynylation of acetaldehyde employing dinuclear zinc ProPhenol as catalyst (Scheme 2).10 Since propyne must be used as the alkynyl nucleophile, the reported methodology needs to be adjusted to accommodate the gaseous alkyne. Conveniently, diethyl zinc under an atmospheric pressure of propyne (i.e. via a balloon) generated the desired propynyl zinc reagent for the asymmetric addition to acetaldehyde. Further optimization of the reaction revealed an enabling effect of THF as co-solvent to deliver the propargylic alcohol 9 in good yield and high enantioselectivity (see Table S1 for additional details).11In contrast, a common alternative procedure using the asymmetric reduction of an ynone requires three steps to deliver alcohol 9.12 To complete the synthesis of alkyne 14, the Marshall−Tamaru propargylation was implemented using the mesylate 12 and aldehyde 13 to Scheme 2. Preparation of the alkyne fragments + 10 OMs
O
(R,R)-ProPhenol Ph3PO, Et2Zn
11
PhMe/THF, 0 ºC (70%, 96:4 er)
13, [Pd(dppf)Cl2], InI THF/HMPA (3:1) (76%, ~10:1 anti:syn)
12 OH
9
O 14
13
OH
N PMB 15 OH
NBS AIBN CCl4 (>98%)
OH
MeO
propyne n-BuLi
MeO
O
N CuI, THF PMB Br (80%) 16
O
N PMB 17 OH
MeO
MeO MeOTf
MeO
MsCl, Et3N CH2Cl2, –78 ºC (95%)
OH
MeO O
OH
N 7
DCE, 75 ºC (78%)
TFA (81%)
O
N H 18
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deliver the alkyne 14 in good yield and diastereoselectivcity.13, 9 To synthesize the second alkyne fragment (7), the known 2-pyridone 15,5 which can be readily prepared from ethyl 2-methyl acetoacetate, was utilized (Scheme 2). Halogenation of the methyl group on the C6 position of 15 was envisioned to provide a path for installation of the propynyl moiety. A radical mediated bromination successfully gave rise to the bromopyridone 16 in nearly quantitative yield. The product 16 was utilized without any chromatographic purification. Propynyllithium addition to 16 in the presence of catalytic copper (I) iodide delivered the alkyne 17 in good yield. The pyridone core in 17 was elaborated to the fully substituted pyridine 7 via a novel concurrent methylative debenzylation reaction that was carried out using methyl triflate. In parallel, the PMB group in 17 can also be readily removed using TFA to give 2-pyridone 18 in good yield.5 These three analogues (17, 18, and 7) were proposed as the possible alkynes for coupling with alkyne 14 through propene as the linchpin. Scheme 3. Coupling of the alkyne fragments with propene
TBSOTf 2,6-Lutidine (80%)
OR R = H (14) R = TBS (19)
OH MeO N PMB
O
17
propene [Ru] (10 mol%) acetone (0.1 M) –78 ºC to rt (R = H 98%)
R = H (20) OR R = TBS (21) [Ru] : [CpRu(CH3CN)3]PF6 OH
1-hexene [Ru] (10 mol%)
MeO
acetone (0.5 M) rt 95% (>98:2 l:b)
O
N PMB
22
OH 21 + 17
MeO
[Ru] (10 mol%) CH2Cl2/DMF (0.12 M), rt 45% (4:1 l:b) (60% brsm)
O
OTBS N PMB
1
23 linear (l) OH
MeO O
N PMB
OTBS 24 branched (b)
With the alkynes from both sides in hand, the key sequential alkene–alkyne couplings with propene were pursued (Scheme 3). First, coupling of alkyne 14 with propene was investigated. Due to the gaseous nature of propene, the challenge of introducing this alkene for coupling with 14 in the presence of catalytic ruthenium complex needed to be addressed. To that end, performing the coupling reaction under atmospheric pressure of propene (i.e. via balloon) proved to be incompetent to deliver the desired product. To improve the efficiency of coupling, the reaction vessel containing the ruthenium catalyst was connected to a balloon of propene (bp = – 47.6 ºC) and the vessel was cooled to –78 ºC (dryice/acetone bath) to condense an appropriate amount of propene (~1 ml/mmol of alkyne). A solution of alkyne 14 in acetone was then added to the reaction mixture at –
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Journal of the American Chemical Society
78 ºC, the balloon was removed and the reaction vessel was sealed and allowed to warm to room temperature. This procedure effectively led to complete consumption of 14, and the double coupling of propene with two molecules of alkyne 14 was not observed due to the presence of excess propene. Despite the improved conversion of 14, the isolated yield of the coupled product 20, did not exceed ~45% (see table S2). Multiple unidentified side products accounted for the remaining mass balance. Gratifyingly, employing TBS protected alcohol 19, under the same conditions delivered the 1,4-diene 21 in nearly quantitative yield.14 The coupled product 21 was utilized in the following reactions without further purification. To test the feasibility of alkynes 17, 18, and 7 for the second alkene–alkyne coupling, their reactions with 1hexene as a model alkene was evaluated (Scheme 3). Alkynes 18 and 7 proved to be unreactive towards coupling with 1-hexene, presumably due to deactivation of ruthenium catalyst via the coordination of the pyridine in 7 or unprotected 2-pyridone in 18. Alkyne 17, on the other hand, underwent coupling with 1-hexene and gave rise to the coupled product 22 in high yield and selectivity. With this notion, the coupling of alkyne 17 with 1,4diene 21 was carried out and the desired product 23 was obtained in 35% yield (60% brsm) along with the minor branched coupled product 24. Formation of the coupled product 23 proved the success of the proposed linchpin strategy. Unfortunately, the subsequent removal of the PMB group on 23 could not be accomplished. Scheme 4. Completion of the total synthesis of piericidin A OH
NaH TeocCl
MeO
tBuOH
MeO
N
(98%)
7
N OTeoc
OTBS 26 branched (b) +
MeO MeO
27 linear (l)
entry
Ru
1st couplinga
2nd couplingb
1st alkyne
R2
R4
R1
R3 36a-k
2nd alkyne
1,3,6-triene product TBSO
1
2
R3
R4
Ru
32 OH
36a (83%)
HO
TBSO TBSO 28
36b (80%)
OH
33
HO
OTBS 3 34
TMS
36c (54%, >3:1 b:l)
TMS HO
4
OH
33
36d (52%)
29
13 OH 36e (56%, 76% brsm) OH HO
O
N
6
21 OTBS [Cp*Ru(CH3CN)3]PF6 (10 mol%) Acetone (0.25 M)
32
OH 36f (63%) OH OH
7 OH 9
(60%) (71% brsm, 4:1 l:b)
32
OH
36g (72%)
OH
8
OTBS N
R2
R1
TMS
25
MeO MeO
Teoc: O
MeO
OTeoc
Table 1. Exploring the synthetic utility of the sequential alkene-alkyne coupling via linchpin strategy
5
OTeoc
MeO
this optimized condition with the 1,4-diene 21 gave low conversion and unsatisfactory yield of the coupled product (
