Total syntheses of cladoacetals A and B: confirmation of absolute configurations

The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S.     

Microwave-assisted concise total syntheses of quinazolinobenzodiazepine alkaloids

[reactions: see text] One-pot total syntheses of the quinazolinobenzodiazepine alkaloids sclerotigenin (1), (+/-)-circumdatin F (2), and (+/-)-asperlicin C (3) via novel microwave-assisted domino reactions were achieved in 55%, 32%, and 20% yields, respectively, from commercially available starting materials. A two-step total synthesis of (+/-)-benzomalvin A (4) was accomplished with an overall yield of 16%. Additionally, analogues of circumdatin E were synthesized via the three-component one-pot sequential reactions promoted by microwave irradiation. Finally, a two-step formal total synthesis of (+/-)-asperlicin E (5) was also realized by using this microwave-assisted protocol.     

Formal [3 + 3] cycloaddition approach to chromenes and chromanes. Concise total syntheses of (+/-)-rhododaurichromanic acids A and B and methyl (+/-)-daurichromenic ester

[reaction: see text] Total syntheses of (+/-)-rhododaurichromanic acids A and B and methyl (+/-)-daurichromenic ester are described here. Despite the complex appearances of these compounds, their syntheses are completed in six steps with a 15% overall yield as a mixture by featuring our formal oxa-[3 + 3] cycloaddition methodology.     

Enantioselective total syntheses of (+)-arborescidine A, (-)-arborescidine B, and (-)-arborescidine C

Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield, respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic asymmetric hydrogen-transfer reaction to introduce chirality in dihydro-beta-carbolines 6 and 8. On the basis of an ample precedent from Noyori's work, the reduction produces dihydro-beta-carbolines, and ultimately the natural products, possessing the R absolute configuration. The synthetic arborescidines displayed optical rotations that were opposite in sign those of the natural products, thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S) configuration for natural arborescidine C (3). Our results are in agreement with the initial stereochemical assignment by Pa?s and co-workers, and are counter to their recently revised assignment.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

Total synthesis of (-)-leuconicine A and B

Concise asymmetric total syntheses of Strychnos alkaloids (-)-leuconicine A (14 steps, 9% overall yield) and B (13 steps, 10% overall yield) have been accomplished. Key steps include (1) our sequential one-pot spiro-cyclization/intramolecular aza-Baylis-Hillman method to prepare the ABCE framework; (2) a novel domino acylation/Knoevenagel cyclization to prepare the F-ring; and (3) a Heck cyclization to access the D-ring.     

Highly stereoselective total synthesis of fully hydroxy-protected mycolactones A and B and their stereoisomerization upon deprotection

Unprecedentedly efficient and highly (≥98 %) stereoselective syntheses of mycolactones A and B side chains relied heavily on Pd‐catalyzed alkenylation (Negishi version) and were completed in 11 longest linear steps from ethyl (S)‐3‐hydroxybutyrate in 12 % and 11 % overall yield, respectively, roughly corresponding to an average of 82 % yield per step. The synthesis of mycolactone core was realized by using Pd‐catalyzed alkenyl? allyl coupling and an epoxide‐opening reaction with a trialkylalkenylaluminate as key steps. Fully hydroxy‐protected mycolactones A and B of ≥98 % isomeric purity were synthesized successfully for the first time. However, unexpected 4:3–5:4 inseparable mixtures of mycolactones A and B were obtained upon deprotection.     

First total syntheses of (+/-)-penicillones A and B

The first total syntheses of (+/-)-penicillones A (1) and B (2) have been accomplished from 2-methoxy-4,6-dimethylphenol (7) in 9 and 8 synthetic steps, respectively. Intramolecular Diels-Alder reaction of masked o-benzoquinone 8 and aqueous acid-catalyzed intramolecular aldol reaction are the key steps.     

Asymmetric synthesis of trans-2,3-piperidinedicarboxylic acid and trans-3,4-piperidinedicarboxylic acid derivatives

Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid beta-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-beta-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.     

Total synthesis of (-)-indolactam V

The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from L-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.     

A short and economical synthesis of orthogonally protected C-linked 2-deoxy-2-acetamido-alpha-D-galactopyranose derivatives

A short and high-yielding synthesis has been devised to prepare C-linked 2-deoxy-2-acetamido-alpha-D-galactopyranose derivative 3. One of the main advantages of this approach is that it employs commercially available and inexpensive d-glucosamine as the starting material. The key steps include a highly stereoselective C-allylation followed by epimerization of the C-4 hydroxyl group. Building block 3 and orthogonally protected C-linked 2-deoxy-2-acetamido-alpha-D-galactopyranose derivative 2 were obtained in 44% overall yield (six steps) and 29% overall yield (eight steps), respectively. This represents a significant improvement over previously reported syntheses.     

Asymmetric synthesis of the cis- and trans-stereoisomers of 4-aminopyrrolidine-3-carboxylic acid and 4-aminotetrahydrofuran-3-carboxylic acid

The diastereoselective conjugate addition of lithium (S)-N-benzyl-N-[small alpha]-methylbenzylamide has been successfully applied to the first asymmetric syntheses of cis-(3S,4R)- and trans-(3R,4R)-4-aminotetrahydrofuran-3-carboxylic acids (26% and 25% overall yield respectively, >98% d.e. and >97% e.e. in each case). Furthermore, the most efficient asymmetric synthesis to date of cis-(3R,4R)- and trans-(3R,4S)-4-aminopyrrolidine carboxylic acids is delineated: for cis-(3R,4R), four steps, >98% d.e., 52% overall yield; for trans-(3R,4S), five steps, >98% d.e., 50% overall yield.     

A carbohydrate-based total syntheses of (+)-pyrenolide D and (-)-4-epi-pyrenolide D

Efficient total syntheses of (+)-pyrenolide D (5) and (-)-4-epi-pyrenolide D (6) have been achieved from a known 5-deoxy-d-xylose derivative 9 in ten steps with 19% overall yield either exclusively as 5 or as pure 5 and 6 in a 3:2 ratio. Key steps involved are one-pot epoxidation-cyclization by Corey-Chaykvosky reagent, reductive Barton-McCombie deoxygenation, and per-acid mediated oxidative spiroketalization.     

Synthesis of (-)-7-epiaustraline and (-)-1-epicastanospermine

Highly efficient and selective syntheses of the title compounds are described. The cornerstone of the synthetic plan is the tandem inter [4 + 2]/inter [3 + 2] cycloaddition process. These syntheses differ from previous applications of this strategy in that they incorporate an alkylation in the hydrogenolysis step to close the second ring of the azabicyclic systems. Notable features of the sequence are (1) the highly regio- and stereoselective [3 + 2] cycloaddition of nitronate 15 with siloxymethyl (Z)-beta-silylvinyl ketone (Z)-22b and (2) the highly selective reduction of the resulting ketone 24a with L-Selectride. A single-crystal X-ray structure analysis of synthetic (-)-7-epiaustraline confirmed that the targeted structure was successfully synthesized. This stimulated a reexamination of the structural assignment of the natural product. (-)-1-Epicastanospermine was synthesized in four steps from the common intermediate 27a. The absolute configuration of (-)-1-epicastanospermine was assured by single-crystal X-ray structure analysis of intermediate (-)-27a. Thus, the sign of the optical rotation had to be revised. The overall efficiency of these syntheses were 9 steps and 23% yield for (-)-7-epiaustraline and 10 steps and 20% yield for (-)-1-epicastanospermine     

A novel approach for the synthesis of lophocladines A, B and C1 analogues

A novel approach for the syntheses of lophocladines A and B has been developed. These compounds were prepared in 4-6 steps with moderate to excellent overall yields. The key step involved the nucleophilic substitution of 4-chloronicotinic acid with the carbanion generated from phenylacetonitrile. Subsequent reduction of the cyano group, lactamization and oxidation furnished lophocladine A in 50% yield over 4 steps. Further amination with various amines led to lophocladine B and its C1 analogues in good yields. In addition, the synthesized compounds were evaluated for their cytotoxicity against leukaemia cells.     

Total synthesis of dispyrin, purpurealidin E, and aplysamine-1

Bromotyrosine alkaloids dispyrin (1), purpurealidin E (2), and aplysamine-1 (3) isolated from marine sponge, were synthesized from commercially available tyramine (4) as a common starting material. The overall yield was 18%, 39%, and 22% for 1 from 4 in 5 steps, 2 in 5 steps, and 3 in 6 steps, respectively.     

Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine c, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).     

Efficient total syntheses of phytoalexin and (+/-)-paniculidine B and C based on the novel methodology for the preparation of 1-methoxyindoles

A general route to 2-unsubstituted-1-methoxyindoles, based on our methodology for the synthesis of 1-methoxyindoles, is reported. This synthesis renders accessibility to a variety of natural products possessing the said skeleton. A direct synthesis of phytoalexin (1), (+/-)-paniculidine B (2), and (+/-)-paniculidine C (3) is disclosed based on the methodology. The synthesis of paniculidine B (2) has been achieved from aldehyde 10 in only two steps in 88% yield and in five steps from a methoxyindole compound 8 obtained using our earlier methodology.     

Total synthesis of (+/-)-aspidospermidine

(+/-)-Aspidospermidine (1) has been synthesized from readily available methyl 3-ethyl-2-oxocylo-pentanecarboxylate (17) in 5.9% yield over 13 steps. The key step of the synthesis is an intramolecular cascade reaction that simultaneously forms the B, C, and D rings of 1. A high-yielding method of closing the remaining E ring is also described.     

Stereocontrolled synthesis of kelsoene by the homo-favorskii rearrangement

[reaction: see text] (+/-)-Kelsoene (4) has been synthesized from 2,5-dihydroanisole in 16 steps in 12.5% overall yield. The key step involves a base-catalyzed reaction of gamma-keto tosylate (5), which effects a homo-Favorskii rearrangement to 16 as well as the corresponding intramolecular S(N)2 product 15 from the enolate of 5. Ketone 15 can efficiently be isomerized to cyclobutanone 17 having the kelsoene carbon skeleton upon acid treatment.