A Double Allylation Strategy for Gram-Scale Guaianolide Production: Total Synthesis of (+)-Mikanokryptin

Abstract

With over 5000 members isolated to date, sesquiterpene lactones represent a prolific source of medicinal agents with several derivatives in human clinical trials. The guaianolides, a major subset of this group, have been intensely investigated from both medicinal and chemical synthesis perspectives for decades. To date, the myriad stereochemical permutations presented by this enormous family have precluded the synthesis of many unique members. Herein we report the first total synthesis of the trans-fused 8,12-guaianolide (+)-mikanokryptin in 10 steps from (+)-carvone. Notably this represents the first gram-scale total synthesis of any guaianolide natural product.

Graphical Abstract

Sesquiterpene lactones from the Asteraceae family of plants represent one of the largest and most biologically significant classes of plant secondary metabolites.^[1] Their presence in both traditional herbal medicine regimes as well as modern human medicine have been extensively documented.^[1–2] In particular, α-methylene-γ-lactone-containing members have strong documented anticancer,^[3] anti-inflammatory,^[4] anthelmintic,^[5] and anti-migraine activity.^[6] Multiple members have also been shown to inhibit aspects of the NF-κB signaling pathway,^[7] a central mediator of the human immune response whose deregulation is noted in inflammatory and autoimmune diseases as well as various human cancers.^[8]

The 5,7-fused bicyclic family of guaianolides is perhaps the flagship subset of sesquiterpene lactone natural products and two major, isomeric sub-types, the 6,12-guaianolides and 8,12-guaianolides, have been isolated (Figure 1A). Despite extensive studies on the chemical synthesis of 6,12-guaianolides,^[9] 8,12-guaianolides have received relatively limited attention from the synthetic community.^[10] Mikanokryptin (1), isolated in 1975 by Herz and co-workers, belongs to the continually growing family of trans-fused 8,12-guaianolides which are largely unexplored and present stereochemistry patterns not easily addressed by current strategies (Figure 1A).^[11] In developing a synthetic route to this family, we viewed a double allylation disconnection as potentially being capable of constructing the guaianolide ring system (see 2) from two simple, hypothetical fragments (see 3 and 4, Figure 1B). Of significant concern to us was the paucity of examples of 7-membered ring formation via metal-mediated intramolecular Barbier-type allylation relevant to this synthetic problem.^[12,13] Herein we disclose the realization of this plan resulting in a simple total synthesis of 1 capable of forming multi-gram quantities of advanced intermediates and a gram of natural product in a single synthetic pass.

Figure 1.

(A) Guaianolide ring systems and various 8,12-guaianolide members. (B) A double allylation disconnection to access 8,12-guaianolides from simple precursors.

Our studies began with constructing a precursor to intermediate 3, and to accomplish this task we turned to the chiral pool of terpenes. For the past several decades, limonene,^[14] isopulegol,^[15] and carvone^[16] have found broad application in the synthesis of guaianane sesquiterpenes, among which carvone is of particular utility for the synthesis of guaianolides bearing oxidation at C-3. Favorskii-type ring contractions have featured prominently in this regard, typically resulting in cyclopentane containing building blocks in 5–8 synthetic steps.^{[13a,c–g][16a–d]} Considering the desire for Δ_4,5 unsaturation, a robust 3-step protocol was developed from carvone (Scheme 1). The isopropenyl group of carvone was first chlorinated at the allylic position (SO₂Cl_2, Na₂CO₃), and then directly subjected to the Luche reduction conditions. This one-pot procedure afforded chloro-cis-carveol (5) reliably on 30-gram scales in approximately 80% yield. Silylation of 5 with tert-butyldiphenylsilyl chloride cleanly provided silyl ether 6 in excellent yield (>90%). Inspired by previous work with limonene,^[17] ozonolysis of 6 in the presence of catalytic quantities of pyridine (0.3 equiv) resulted in chemoselective cleavage of the tri-substituted olefin under carefully monitored cryogenic conditions.^[18] The sensitive di-carbonyl intermediate thus formed following reductive quench with dimethylsulfide underwent intramolecular aldol condensation in the presence of piperidine and acetic acid, affording enal 7 in a one-pot procedure. Large quantities of 7 (~100 grams) have been easily prepared in our laboratory through this three-step procedure, which is envisioned to serve as the foundation for syntheses of numerous guaianolides bearing Δ_4,5 unsaturation.

Scheme 1.

Gram-scale total synthesis of (+)-mikanokryptin (1). Reagents and conditions: a) carvone (1 equiv), Na₂CO₃ (3 equiv), SO₂Cl₂ (1.2 equiv) added slowly over 2 h, DCM, 0 °C, then add CeCl₃·7H₂O (1.1 equiv), NaBH₄ (3 equiv), MeOH, 0 °C, 1 h, 78%; b) TBDPSCl (1.2 equiv), imidazole (3 equiv), DMAP (0.05 equiv), DMF, rt, 8 h, 90%; c) O₃, pyridine (0.3 equiv), DCM, −78 °C, 20–40 min, then add DMS (2 equiv), rt, 8 h, then add piperidine (0.15 equiv), AcOH (0.2 equiv), 40 °C, 16 h, 42%; d) In (1.5 equiv), 7 (1.2 equiv), 8 (1 equiv), H₂O (1 equiv), DMF, rt, 8 h, 67%, 2:1 dr; e) TESOTf (4 equiv), 2,4,6-collidine (6 equiv), DCM, 0 °C, 24 h, 78%; f) SnCl₂ (4.5 equiv), NaI (9 equiv), DMF, 60 °C, 12 h, 90%; g) NaOMe (0.1 equiv), MeOH, 16 h, then add AcOH (0.1 equiv), PtO₂ (0.1 equiv), H₂ (1 atm), 6 h, 96%; h) Rh(PPh₃)₃Cl (0.1 equiv), H₂ (1 atm), PhH, 1 h, 54%; i) TBAF (3 equiv), THF, rt, 24 h; DBU (1.1 equiv), toluene, DCM, Δ, 69%; j) MnO₂, DCM, rt, 16 h, 97%; DMS = dimethylsulfide, TBDPSCl = tert-butyldiphenylsilyl chloride, TESOTf = triethylsilyl trifluoromethanesulfonate, TBAF = tetra-n-butylammonium fluoride, DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene. All X-ray structures shown were obtained during preliminary studies conducted with (−)-carvone.

With the western fragment completed, we turned toward the first of two allylation reactions. For mikanokryptin (1), and related 8,12-guianolides (Figure 1), a cis-arrangement between the C-6 hydroxyl and neighboring acrylate group is required on the future cycloheptane ring. Although guaianolides with a trans arrangement of these groups have been studied (see geigerin for example, Figure 1A),^[10b–d] fewer tactics exist to access this pattern and sometimes rely on the inversion or epimerization of trans-configured precursor.^[19] We were pleased to find that allylic bromide 8, which can be prepared in two steps from commercially available materials on decagram scale, functioned well in this setting.^[20,21] Under indium-mediated conditions, 8 could be chemoselectively activated in the presence of allylic chloride 7, and was found to cleanly add to the aldehyde moiety resulting in a 67% isolated yield of 9 (2:1 dr at C-6) on a 14-gram scale. Allylation protocols based on activation with Cr, Zn, Pd, Cd, Sn, Pb, and Bi were found to be inferior both with respect to yield and diastereoselectivity.^[22] Notably, the incorporation of 1 equivalent of H₂O proved important; without it, slightly lower diastereoselectivity was observed as well as extensive in-situ formation of the 6,12-lactone framework. With larger quantities, increased decomposition of 8 was observed. Sensitive homoallylic alcohol 9 and the minor diastereomer were then subjected to Fujioka and Kita’s mild deacetalization protocol (TESOTf, 2,4,6-collidine),^[23] which also silylated the C-6 alcohol leading to 10.^[24] At this stage, the minor diastereomer could also be separated.

With substrate 10 accessible on large scales, we were well positioned to evaluate the second, 7-membered ring forming allylation reaction (Table 1). We commenced our investigation exploring the venerable Nozaki–Hiyama–Kishi (NHK) reaction (entry 1), which has proven efficient in many medium-sized ring syntheses.^[22a] The desired transformation was achieved but with low yield (10%) and with moderate diastereoselectivity (2:1 dr). Surprisingly, the major products formed in this reaction were a mixture of two diastereomeric cyclooctanes (see 14). This competition (8- vs 7-membered ring) was also observed in samarium iodide-mediated cyclization conditions utilizing an allylic iodide substrate, although in this case the 7-membered ring (see 11) prevailed slightly (entry 3).^[25] In contrast, indium- and zinc-mediated conditions were more selective for a single product (entries 2 and 4). In the former case, 11 was afforded as a single diastereomer (13%) while the latter produced 14 (51%) and recovered 10 (34%). Magnesium-based conditions were ineffective for this transformation (entries 5 and 6). Gratifyingly, Tin(II)chloride proved to be a superior reductant.^[26] Finkelstein conversion of 10 to an allylic iodide followed by SnCl₂-mediated cyclization afforded synthetically useful quantities of 11 (53%), along with recovered 10, and cycloheptanol 15 (entry 7). Notably, only one diastereomer was obtained for each cyclized product. When all reagents (SnCl₂, NaI, and 10) were simply mixed together and heated in a single step (entry 8), a remarkably clean reaction ensued at 60 °C affording 11 in 90% isolated yield as a single diastereomer. Notably, this result was performed on a 7-gram scale without a depression in yield.

Table 1.

Investigation of metal-mediated allylation conditions for the synthesis of the 5,7,5-fused guaianolide lactone system.

Entry	Conditions[a,b]	11	14	15	rsm
1	CrCl2, cat. NiCl2, DMF, 60 °C	10%[e]	17%	↕	↕
2	In0, NaI, DMF, 60 °C	13%[f]	↕	↕	↕
3[c]	NaI; SmI2, HMPA-THF, −78 °C	27%[e]	17%	↕	↕
4[c]	NaI; Zn0, aq. NH4Cl, THF, rt	0%	51%	↕	34%
5[c]	NaI; Mg0, cat. (CH2Br)2, THF, rt	0%	↕	↕	↕
6[c]	NaI; iPrMgCl, THF, 0 °C	0%	↕	↕	↕
7[c]	NaI; SnCl2, DMF, rt	53%[f]	↕	20%	9%
8[d]	SnCl2, NaI, DMF, 60 °C	90%[f]	↕	↕	↕

^[a]Reaction performed on a 30-mg scale unless otherwise stated;

^[b]Isolated yields are reported;

^[c]Starting material first reacted with NaI in acetone for 8 h;

^[d]Reaction performed on a 7-gram scale;

^[e]Diastereomeric ratio 2:1 11:8-epi-11;

^[f]Single diastereomer obtained.

With a 6-step, multi-gram scale synthesis of the full guaianolide skeleton complete, only redox manipulations were required to complete the target. The Δ_10,14 alkene in 11 proved challenging to chemoselectively reduce in the presence of the more reactive α-methylene-lactone. In the presence of Wilkinson’s catalyst, only the latter is reduced (see 13, Scheme 1). With PtO₂/H₂ both olefins can be easily hydrogenated. Taking advantage of the high reactivity of the α-methylene-lactone toward conjugate addition, we first treated 11 with catalytic quantities of sodium methoxide (10 mol%) in MeOH, forming a methanol addition product, which could be reduced with Adam’s catalyst (PtO₂, AcOH, H₂) in near quantitative yield (96%) in the same flask. When attempting global desilylation of 12 (TBAF, THF), we notice that a base-mediated retro-conjugate addition of MeOH would occur, resulting in a 5:2 mixture of the deprotected conjugated ester:methanol adduct in 83% yield. When quantities of DBU were added to the crude mixture, the reaction could be pushed to completion, favoring the conjugated ester product and resulting in 69% isolated yield of material on a gram scale. Finally, the addition of freshly activated MnO₂, forged mikanokryptin (1) in near quantitative yield via highly chemoselective, allylic oxidation. Notably, one gram of 1 was synthesized in a single pass from (+)-carvone with 6% overall yield. The absolute configuration of 1 was confirmed as reported in literature (synthetic [α]_D = +235.0°, natural [α]_D = +264° (c 0.098, MeOH). Moreover, intermediate 11, readily accessable in multi-gram quantities is envisioned to serve as a versatile intermediate for guaianolides bearing both Δ_4,5 and Δ_10,14 functionalization.^[27]

In summary, we have accomplished a short, enantiospecific gram-scale total synthesis of mikanokryptin, a complex 8,12-guaianolide. While guaianolides have been the subject of numerous synthetic campaigns, most total synthetic routes to date produce low milligram quantities of material.^[28] To the best of our knowledge, this work represents the first gram-scale, fully synthetic entry into this coveted sesquiterpene family. Two highly robust and scalable allylation processes were critical in processing large quantities of material. Through variations on this strategy, the synthesis of other mikanokryptin-type 8,12-guaianolides should be possible. Such endeavors, in addition to the exploration of alternative reagent-controlled allylation methods to enable the synthesis of all guaianolide stereochemical patterns, are currently underway and will be reported in due course.