Synthetic study of azaspiracid-1: synthesis of the EFGHI-ring fragment

Here, we report a synthesis of the lower half C21-C40 fragment of the shellfish toxin, azaspiracid-1. The C28-C40 fragment was synthesized by a coupling between the C28-C35 epoxide and the C36-C40 dithioacetal anion, followed by the HI-ring spiroaminal formation. An aldehyde corresponding to the C28-C40 fragment was then coupled with the C21-C27 allylic stannane by using InCl3. Finally, the FG-ring was constructed by HF.pyridine to accomplish the synthesis of the suitably protected C21-C40 fragment.     

Total synthesis and structural elucidation of azaspiracid-1. Synthesis-based analysis of originally proposed structures and indication of their non-identity to the natural product

The key building blocks (6, 7, and 8) for the intended construction of the originally proposed structures of azaspiracid-1, a potent marine-derived neurotoxin, were coupled and the products elaborated to the targeted compounds (1a,b) and their C-20 epimers (2 and 3). The assembly of the three intermediates was accomplished by a dithiane-based coupling reaction that united the C(1)-C(20) (7) and C(21)-C(27) (8) fragments, followed by a Stille-type coupling which allowed the incorporation of the C(28)-C(40) fragment (6) into the growing substrate. Neither of the final products (1a,b) matched the natural substance by TLC or (1)H NMR spectroscopic analysis, suggesting one or more errors in the originally proposed structure for this notorious biotoxin.     

Total synthesis and structural elucidation of azaspiracid-1. Construction of key building blocks for originally proposed structure

Syntheses of the three key building blocks (65, 98, and 100) required for the total synthesis of the proposed structure of azaspiracid-1 (1a) are described. Key steps include a TMSOTf-induced ring-closing cascade to form the ABC rings of tetracycle 65, a neodymium-catalyzed internal aminal formation for the construction of intermediate 98, and a Nozaki-Hiyama-Kishi coupling to assemble the required carbon chain of fragment 100. The synthesized fragments, obtained stereoselectively in both their enantiomeric forms, were expected to allow for the construction of all four stereoisomers proposed as possible structures of azaspiracid-1 (1a-d), thus allowing the determination of both the relative and absolute stereochemistry of the natural product.     

Synthesis of the ABCD and ABCDE ring systems of azaspiracid-1

The efficient syntheses of the ABCD ring system of the originally proposed structure of azaspiracid-1 and the ABCDE ring system of the revised structure of azaspiracid-1 containing the correct stereochemistry at C(6), C(10), C(13), C(14), C(16), C(17), C(19), C(21), C(22), C(24) and C(25) have been achieved.     

Asymmetric total synthesis of spongistatins 1 and 2

The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.     

Studies on the synthesis of apoptolidin: synthesis of a C1-C27 fragment of apoptolidin D

Synthesis of a C(1)-C(27) fragment, a key intermediate in the synthesis of apoptolidin D, is reported. The synthesis involves a combination of Heck coupling and Horner-Wadsworth-Emmons reaction for the C(1)-C(7) trienoate portion and an efficient Suzuki cross-coupling protocol for the C(10)-C(13) diene portion.     

Enantioselective total synthesis of (+)-amphidinolide t1

An enantioselective first total syntheis of amphidinolide T1 (1) is described. Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C21 segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi macrolactonization sequence. The synthesis of fragment 2 involves an efficient cross metathesis and hydrogenation sequence between the terminal olefins of 5 and 6 to form the C4-C5 carbon-carbon bond. Enol ether 4 is designed to be the surrogate of fragment 3 where the sensitive C16-exo-methylene and the C13-hydroxyl group were protected as the bromoether derivative during the Lewis acid-catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C2 and C3 stereocenters in fragment 4 are accessed by a highly diastereoselective ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether derivative 24 was unraveled at the final stage of the synthesis, providing (+)-amphidinolide T1.     

Approach to the synthesis of dolabelides A and B: fragment synthesis by tandem silylformylation-crotylsilylation

[structure: see text] A synthesis of the C(15)-C(30) fragment of Dolabelides A and B has been achieved. The recently developed asymmetric silane alcoholysis and tandem silylformylation-crotylsilylation reactions were used as the key steps to establish the C(23)-C(27) 1,5-syn-diol. In addition, the flexibility of this methodology has been demonstrated with an efficient synthesis of the C(24)-C(25) trisubstituted olefin.     

Expedient access to the okadaic acid architecture: a novel synthesis of the C1-C27 domain.

A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constitutent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.     

Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions

Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.     

Asymmetric total synthesis of (-)-laulimalide: exploiting the asymmetric glycolate alkylation reaction

A concise total synthesis of the potent antitumor macrolide (-)-laulimalide is described. The observation that homoallylic (or latent homoallylic) C-O bonds are present at C5, C9, C15, C19, and C23 led to the strategic decision to rely heavily on the asymmetric glycolate alkylation to construct both the C1-C14 fragment 3 and the C15-C27 subunit 4. A diastereoselective addition of a C1-C14 allylstannane to a C15-C27 alpha,beta-epoxyaldehyde served to join the two advanced fragments. A Mitsunobu macrolactonization of hydroxy acid 2 avoided isomerization of the sensitive 2,3-Z-enoate, which has been observed in base-catalyzed macrolactonizations. Removal of two TBS protecting groups to reveal the C15 and C20 hydroxyls occurred without rearrangement to isolaulimalide.     

Synthesis of the azaspiracid-1 trioxadispiroketal

The de novo analysis, design, and synthesis of the azaspiracid-1 trioxadispiroketal system is described. A revised structural model was developed on the basis of an independent analysis of the NMR spectral data of the natural product that fit all of the data and the thermodynamically favored spiroketal paradigm. This model was then tested via synthesis using a novel trioxadispiroketalization process and supported by spectroscopic correlation.     

Total synthesis of cruentaren B

A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C11 benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C7-C8 bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C12-C20 polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C21-C28 tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an SN2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.     

Total synthesis of (+)-superstolide A

A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired cycloadduct with lower stereoselectivity (6:1:1).     

Stereocontrolled and convergent total synthesis of amphidinolide T3

Stereocontrolled and convergent total synthesis of amphidinolide T3 has been described. A retrosynthetic scheme was constructed that led to the recognition of readily available and enantiomerically related compounds as starting materials for the total synthesis of amphidinolide T3. Thus, the two key building blocks 6 and 7 were defined as subtargets and synthesized in optically active forms. The C1-C12 fragment 6 was derived from commercially available D-glutamic acid or its synthetically equivalent (R)-5-hydroxymethyltetrahydrofuran-2-one 16 as starting material involving highly diastereoselective asymmetric allylation as a key step. The C13-C21 fragment 7 was efficiently synthesized in high yield through the dithiane coupling of the segment 10 and iodide 11, followed by subsequent deprotection and Petasis olefination. Eventually, assembly of the fragment aldehyde 6 and dithiane 7 along with C-C bond formation, a two-step oxidation-reduction sequence, selective macrolactonization, and functional transformation furnished the convergent total and formal synthesis of amphidinolide T3 and T4, and this approach also provides a flexible and practical synthesis of amphidinolide T macrolides.     

Toward the synthesis of norzoanthamine: complete fragment assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.     

Synthesis of the C(1)-C(25) fragment of amphidinol 3: application of the double-allylboration reaction for synthesis of 1,5-diols

[structure: see text] A synthesis of the C(1)-C(25) fragment of amphidinol 3 is described. The synthesis features two applications of double allylboration reaction methodology for the highly stereoselective synthesis of 1,5-diol units in the C(1)-C(15) segment.     

Design, total synthesis, and evaluation of novel open-chain epothilone analogues

[structure: see text] The design, total synthesis, and biological evaluation of two open-chain analogues of epothilone incorporating the critical C1-C8 fragment and the aromatic side chain held together by a small molecular scaffold have been achieved. Biological evaluation revealed that further restraint between the flexible C1-C8 region and the molecular scaffold may be necessary for potent inhibition of cell proliferation.     

Studies directed toward the synthesis of rhizopodin: stereoselective synthesis of the C1-C15 fragment

A stereoselective synthesis of the C1-C15 fragment of a G-actin binding natural macrodiolide, rhizopodin was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1-C7 fragment, one pot oxazole synthesis and an asymmetric Keck allylation reaction to build the C8-C15 fragment and finally, a Stille reaction to couple both the fragments.     

Total synthesis of everninomicin 13,384-1--Part 1: retrosynthetic analysis and synthesis of the A1B(A)C fragment

In this first of a series of four articles we introduce everninomicin 13,384-1 (1), a powerful antibiotic effective against drug resistant bacteria, as a target for total synthesis and discuss its retrosynthetic analysis. From the three defined fragments required for the synthesis (2: A1B(A)C fragment; 4: DE fragment; 5: FGHA2 fragment), we describe herein two approaches to the A1B(A)C block. The first strategy relied on an olefin metathesis reaction to construct a common intermediate for rings B and C, but was faced with final protecting group problems. The second, and successful approach, involved a 1,2-phenylsulfeno migration and a sulfur directed glycosidation procedure to link rings B and C, as well as an acyl fluoride intermediate to install the sterically hindered aryl ester moiety (ring A1). The final stages of the synthesis of the required 2-phenylseleno glycosyl fluoride 2 required introduction of a phenylseleno group at C-1 of ring C followed by a novel, DAST-promoted 1,2-migration to produce the desired 2-beta-phenylseleno glycosyl fluoride moiety.