Dedicated to E.J. Corey on the Occasion of his 90th BirthdayPublished as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Key words
kweichowenol A - Kiyooka aldol - asymmetric synthesis - natural product synthesis - acyclic stereocontrol
The flowering plants of the Uvaria genus are widely distributed in southern and southwestern China as well as southeastern Asian counties.[1] Prominent members of this genus are commonly used in traditional Chinese medicine as herbs to treat inflammation and tumors.[2] For example, the roots and leaves of Uvaria micropara are used to prepare the herb Zi Yu Pan, whereas Uvaria grandiflora is used for the preparation of the herb Shan Jiao Zi.[3] This has attracted much attention to their secondary metabolites and it was found that they contain a wealth of polyoxygenated cyclohexenes.[4]
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[8] Kweichowenol A (1), C (2), and D (3, Scheme [1]), for instance, were extracted from Uvaria kweichowesis. They incorporate distinct benzoyl esters at their C3- and C6-positions but differ in their C1- and C7-substitution.[7]
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[9] Kweichowenol A (1) and C (2) contain unusual acetone- and acetaldehyde-derived spiro 1,3-dioxolane moieties[10]
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[14] whereas kweichowenol D contains a 1,2-diol. These cyclohexenes share the oxygenation pattern with the kweichowenol-type natural products ferrudiol (4) and ellipeiopsol B (5) which were isolated from Uvaria ferruginea and the closely related Ellipeiopsis cherrevensis, respectively.[6]
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[15] Ferrudiol (4) and ellipeiopsol B (5) have shown to inhibit efflux-related antibiotic resistance in Staphylococcus aureus whereas kweichowenol A, C, and D showed antitumor activities against the bronchogenic carcinoma cells A549, SK-MES-1, and NCI-H446.[7]
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Scheme 1 Retrosynthesis of kweichowenol A (1); structures of kweichowenol C (2), D (3), ferrudiol (4), and ellipeiopsol B (5)
We were intrigued by the oxygenation pattern of the kweichowenols, since it is also present in more complex targets such as the members of the tetrodotoxin family of natural products.[17]
[18] This prompted us to develop a synthetic approach to the kweichowenols, which is outlined in Scheme [1]. Our retrosynthesis focused on kweichowenol A (1), which could serve as a precursor to kweichowenol C (2), D (3), ferrudiol (4), and ellipeiopsol B (5). To enable a rapid, stereoselective construction of the fully functionalized cyclohexene core, we planned to exploit acyclic stereocontrol and cyclize the resulting linear precursor 6 using a ring-closing metathesis (RCM). On this linear precursor 6, the C3 and C6 stereocenters could be diastereoselectively installed using Grignard additions into the corresponding aldehydes via Cram chelate transition states.[19] These disconnections led to the aldehyde 7 which could be accessed through a Kiyooka aldol reaction.[20]
Our synthesis of kweichowenol A (1) starts with the preparation of the TBS ketene acetal 9 from acetonide ester 8 (Scheme [2]). The acetonide ester 8 could be commercially obtained or synthesized on decagram scale using a 3-step sequence that started from serine and required only one purification step (see Supporting Information).
Scheme 2 Asymmetric synthesis of kweichowenol A. Reagents and conditions: 1) TBSCl, LiHMDS, THF/HMPA, –78 °C → 0 °C, then 8, –78 °C; 2) N-Ts-d-valine, BH3·THF, CH2Cl2, 0 °C → rt, then 11, 9, –78 °C; 3) NaHMDS, THF, –78 °C → 0 °C; 4) ethynylmagnesium chloride, THF, –78 °C → 0 °C, then BzCl, DMAP, 0 °C → rt; 5) OsO4, NMO, citric acid, t-BuOH/acetone/H2O, 60 °C; 6) Lindlar cat., H2, EtOAc/pyridine; 7) NaIO4, THF/H2O; 8) vinylmagnesium chloride, THF, –78 °C → 0 °C; 9) HG-II, PhMe, 50 °C; 10) TASF, DMF; 11) BzCl, pyridine, –27 °C → –20 °C. DMAP = 4-(dimethylamino)pyridine, HG-II = second-generation Hoveyda–Grubbs catalyst, HMDS = bis(trimethylsilyl)amide, HMPA = hexamethylphosphoramide, NMO = N-methylmorpholine N-oxide, TASF = tris(dimethylamino)sulfonium difluorotrimethylsilicate, TBS = tert-butyldimethylsilyl.
The Kiyooka aldol reaction is known to proceed with excellent enantioselectivity and diastereoselectivity if disubstituted tert-butyldimethylsilyl (TBS) ketene acetals are used as nucleophiles.[21] The use of 9 as a nucleophile in Kiyooka aldol reactions was pioneered by Kalesse who prepared ent-7 on a small scale.[20] For the synthesis of kweichowenol A, we devised a modified procedure for the multigram scale synthesis of aldehyde 7. Our procedure relied on a d-valine-derived oxazaborolidinone reagent 10 which initiated the asymmetric addition of TBS ketene acetal 9 to cinnamaldehyde (11). In contrast to the TMS ketene acetal nucleophiles in Mukaiyama aldol reactions, the use of a TBS-ketene acetal enables the in situ reduction of the latent ester group of 9 to the corresponding mixed tert-butyldimethylsilanol methanol acetal via a hydride transfer from the oxazaborolidinone 10 to the reaction intermediate. This powerful opening step installed the contiguous C1 and C2 stereocenters (12) in a single transformation.[22] To liberate the aldehyde functionality 7, the TBS group could be transferred from the acetal moiety (12) to the C2 alcohol with NaHMDS. By subjecting aldehyde 7 to NMR analysis, we found that the C1 tertiary alcohol and the C2 secondary alcohol stereocenters were formed with 5.4:1.0 dr. Thereafter, we determined that the major diastereomer of 7 was formed with 85% ee by using Mosher ester analysis (see Supporting Information). The secondary alcohol at C6 was installed through a diastereoselective addition of ethynylmagnesium chloride to aldehyde 7, which presumably proceeded via a 5-membered Cram chelate transition state.[19] By directly intercepting the magnesium alkoxylate intermediate with benzoyl chloride, alkyne 13 was obtained in a one-pot sequence with 60% yield. A successful Upjohn dihydroxylation required the use of citric acid as an additive and was followed by a Lindlar hydrogenation to generate a vinyl group (14). Sodium periodate mediated Criegee oxidation afforded aldehyde 15. The C3 stereocenter was introduced by a second Cram chelate-controlled addition, in this case of vinylmagnesium chloride, which provided vinyl alcohol 6 in good yield. We subjected the resultant diene 6 to a RCM, using the second-generation Hoveyda–Grubbs catalyst (HG-II), and obtained the fully oxygenated cyclohexene 16. It is worth noting, that the free allylic C3 alcohol was essential for a successful RCM reaction and a successful TBS deprotection with tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF). The resulting diol 17 was regioselectively benzoylated at the sterically more accessible C3 alcohol by using benzoyl chloride in pyridine at low temperatures. These optimized conditions provided kweichowenol A (1) in good yield.[23] To confirm the structure of the natural product and gain insight into its preferred conformation, we subjected a sample of 1 to X-ray analysis (Scheme [3]). Remarkably, kweichowenol A (1) crystallized as a racemate from the enantioenriched mixture that was obtained through the synthesis.
Scheme 3 X-Ray structure of kweichowenol A (1)
In summary, we have devised a short asymmetric synthesis of the polyoxygenated cyclohexene natural product kweichowenol A (1), which proceeds in 11 steps starting from commercially available starting materials. The installation of the oxygenation pattern on a linear precursor allowed a rapid access to the cyclohexene core by exploiting acyclic stereocontrol. Carbon–carbon bonds were formed using a Kiyooka aldol reaction, Cram chelate-controlled Grignard reactions, and a RCM. Due to the common cyclohexene oxygenation pattern, kweichowenol A (1) could serve as a precursor to other members of the kweichowenol-type natural product family, such as kweichowenol C (2), kweichowenol D (3), ferrudiol (4), and ellipeiopsol B (5). It is also worth noting that the C1, C2, and C6 stereocenters of the kweichowenol-type natural products correspond to the C5, C6, and C7 stereocenters on the cyclohexane core of tetrodotoxin. As such, we have laid the foundation towards an asymmetric synthesis of this celebrated target.[17]
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