Featured Article Cite This: J. Org. Chem. 2018, 83, 3061−3068
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Azomethine Ylide Cycloaddition Approach toward Dendrobine: Synthesis of 5‑Deoxymubironine C Benjamin M. Williams† and Dirk Trauner*,†,‡ †
Department of Chemistry Ludwig-Maximilians-Universität München Butenandtstrasse 5-13, 81377 München, Germany Department of Chemistry, New York University 100 Washington Square East, Room 712 New York, New York 10003, United States
‡
S Supporting Information *
ABSTRACT: A concise route to the azatricyclo[6.2.1.04,11]undecane core of (−)-dendrobine and (−)-mubironine C is described wherein an unstabilized azomethine ylide cycloaddition provides the complete carbon framework of the natural products. The cyclization precursor is made in short order from (R)-carvone through an unconventional high-pressure Ireland− Claisen reaction. Attempts to install a final hydroxyl group through an intramolecular lactonization strategy and the observation of an unexpected and highly complex enal−ene product are also reported.
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INTRODUCTION Dendrobine (1, Figure 1) is a sesquiterpenoid alkaloid isolated from the Dendrobium nobile and the major alkaloidal
manners (Scheme 1a). Though thoughtful in strategy and inspiring in execution, many approaches require late-stage redox manipulation and/or incremental functional group interconversion. We initially sought a direct route to the molecule that would eliminate unnecessary reactions and constitute a path to synthetically underexplored Orchidaceae alkaloids. We report here the enantioselective synthesis of (−)-5-deoxymubironine C, which differs from the natural product mubironine C (3) by a single hydroxyl group, in eight operations from (R)-carvone. Notable transformations include a high-pressure Ireland−Claisen reaction and an intramolecular unstabilized azomethine ylide cycloaddition with an unactivated dipolarophile. An unusual ene reaction to form contiguous quaternary stereocenters is also reported. Our retrosynthetic strategy (Scheme 1.b) centered on the disconnection of dendrobine’s pyrrolidine ring through an intramolecular 1,3-dipolar cycloaddition of an unstabilized azomethine ylide.21 We posited that ylide 4 would be best formed by high temperature condensation/decarboxylation of sarcosine (N-methylglycine) or a related amino acid with αsubstituted aldehyde 5.22 As many dendrobine-like alkaloids vary in substitution at the 2-position, modifying the amino acid could thereby grant access to dendrine and other congeners. Though azomethine ylide cycloadditions between unstabilized
Figure 1. Alkaloids isolated from the Dendrobium nobile (1 and 2) and Dendrobium Snowflake “Red Star” (3).
constituent of the Chinese folk medicine “Chin-Shih-Hu”.1−4 The lactonic tetracycle exhibits analgesic, antipyretic, and convulsant activity5,6 somewhat reminiscent ofthough mechanistically unrelated topicrotoxinin. A number of closely related congeners from similar orchid species have been identified which often differ in oxidation at the 2-position, as in dendrine (2),4 or more rarely in methanolysis of the lactone, as in mubironine C (3).7 The broad bioactivity of 1, its biogenetic kinship with the picrotoxanes, and its stereochemically crowded skeleton have made it the subject of numerous total8−15 and formal16−20 syntheses which have dissected the molecule in a variety of © 2018 American Chemical Society
Received: January 22, 2018 Published: February 28, 2018 3061
DOI: 10.1021/acs.joc.8b00192 J. Org. Chem. 2018, 83, 3061−3068
The Journal of Organic Chemistry
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Scheme 1. (a) Key Intermediates in Previous Totals Syntheses of 1. (b) Azomethine Ylide Strategy To Achieve the Azatricyclic Core
7.25 Although the asymmetric reduction of commercially available 2-methyl-2-cyclopentenone directly to 8 is known,26 difficulties were encountered with the high catalyst loadings required for good enantioselectivity (up to one full equivalent) and the volatility of the product. A more scalable route ensued from the Itsuno−Corey reduction of iodoenone 10 to grant 11 with excellent enantiomeric purity (>95% ee by Mosher ester analysis),27 followed by iron-catalyzed cross-coupling with methylmagnesium bromide28 to afford alcohol 8 in good yield. The best results for formation of 6 were attained using 1,3,5-trichlorobenzoyl chloride (TCBC), triethylamine, and a 1:1 molar ratio of reactants. The Ireland−Claisen reaction of ester 6 proved to be challenging (Table 1). It quickly became apparent that conventional Ireland−Claisen conditions only afforded very low yields of product 12 (relative configuration confirmed by single-crystal X-ray diffraction) and its undesired diastereomer 13 (entry 1). Higher temperatures and hexamethyldisilamide bases resulted in increased conversion (entries 2 and 3), but yields were still disobligingly low due to extrusion of the cyclopentenol and ketene formation. When alternative silylating agents and additives failed to enhance the yield, we reasoned that ketene formation might be subdued through high-pressure conditions. Although high-pressure Claisen reactions are welldocumented, we could only locate one instance of an Ireland− Claisen reaction conducted under high-pressure conditions in tandem with a Diels−Alder reaction, and the authors specify that these high-pressure conditions were chosen mainly to effect the Diels−Alder reaction.29 Submitting the silyl ketene acetal to high pressure alone (11 kbar) resulted in trace conversion (entry 4). However, a combination of both elevated pressure and temperature proved highly effective and led to enhanced yield and good diastereoselectivity (entry 5). Upon scale-up, LiHMDS was determined to be the base of choice for the reaction (entries 6 and 7).
ylides and unactivated dipolarophiles are rare, we hoped the intramolecular nature of the reaction would overcome this reluctant reactivity.23 We intended to use the wealth of new organocatalytic methodologies reported in the past 15 years to diastereoselectively functionalize the α-position of the aldehyde. The contiguous stereocenters of 5 could be formed through an Ireland−Claisen rearrangement of ester 6, which constitutes the union of two known and easily accessible fragments.
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RESULTS AND DISCUSSION Our synthesis began with the construction of enantioenriched units 7 and 8 (Scheme 2). Acid 7 could be formed in two steps from (R)-carvotanacetone 924 using a modified protocol by Deslongchamps et al. in which the monoterpene was treated with ozone and the resulting aldehyde acetalized to dioxolane Scheme 2. Synthesis of Ester 6a
a
TCBC = 1,3,5-trichlorobenzoyl chloride. 3062
DOI: 10.1021/acs.joc.8b00192 J. Org. Chem. 2018, 83, 3061−3068
The Journal of Organic Chemistry
Featured Article
Table 1. Ireland−Claisen Reaction of Ester 6 at Atmospheric and Elevated Pressure
entry a
1 2a 3a 4a 5a 6b 7b
base
solvent
T (°C)
pressure (kbar)
time (h)
yield (%, 12 [13])c
LDA LiHMDS KHMDS LiHMDS LiHMDS LiHMDS KHMDS
THF PhMe/THF PhMe PhMe/THF PhMe/THF PhMe/THF PhMe
66 110 110 25 70 70 70
atm atm atm 11 14 14 14
5 3 3 5 20 21 21
11 [3] 33 [nd]d 45 [10]
