& Natural Products

Heathcock-Inspired Strategies for the Synthesis of Fawcettimine-Type Lycopodium Alkaloids

Rebecca A. Murphy and Richmond Sarpong*[a]

Chem. Eur. J. 2014, 20, 42 – 56 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim42

ConceptDOI: 10.1002/chem.201303975

Abstract: The fawcettimine-type Lycopodium alkaloidshave garnered significant attention from synthetic organicchemists since the isolation of fawcettimine in 1959. De-spite being targets of interest for over 50 years, most ofthe strategies employed in the syntheses of fawcettiminecongeners have built upon Inubushi and Heathcock’s orig-inal work, realized in 1979 and 1986, respectively. This ele-gant strategy has been explored and expanded upon inthe intervening years since the original publications, inwhat we now call the Heathcock-inspired strategy. Whileother disconnections have been disclosed, this strategy re-mains one of the most efficient. In this Concept article, wefocus on exploring a number of recent Heathcock-inspiredsyntheses of fawcettimine-type Lycopodium alkaloids. Wealso briefly discuss alternative, novel disconnections.

Introduction

Since their discovery, the Lycopodium alkaloids have been ofgreat interest to the scientific community as compounds thatare both structurally interesting and biologically active. Thislarge class of compounds includes nearly 300 natural productsisolated from over 50 of the 500 extant species in the Lycopo-dium genus of club mosses.[1] These club mosses are found allover the world, with various species in Northern Ontario,Canada;[2] the Guizhou province of China;[3] the Blue Mountainrange of Jamaica;[4] the Eastern Transvaal region of SouthAfrica;[5] and many other locations.

The Lycopodium alkaloids were first known in the context oftraditional Chinese folk medicine. “Qian Ceng Ta”, the Chineseherbal medicine made from the club moss Huperzia serrata,was used to treat a variety of maladies including contusions,schizophrenia, fever, inflammation, and more. The name “QianCeng Ta” means “thousand-laid pagodas” in reference to thetall leafy appearance of the plant. It is also called “Jin BuHuan”, which means “more valuable than gold”—this time re-ferring to its medicinal properties.[6] In the late 19th centurythe Lycopodium alkaloids became of interest to isolation chem-ists. Lycopodine (1, Figure 1) was the first member of this largeclass of natural products to be isolated and was described in1881 by Bçdeker.[7] In the modern era, the organic chemistrycommunity has become enamored with these compounds asstructurally complex targets for total synthesis.

From their beginnings in Chinese folk medicine to now, theLycopodium alkaloids have retained their allure as medicinallyuseful molecules. Over the past few decades, many of these al-kaloids have been and continue to be investigated as treat-ments for the symptoms of cognitive deterioration that is char-

acteristic of a number of diseases, such as Alzheimer’s and Par-kinson’s disease. Of particular interest is huperzine A (2,Figure 1), which was isolated from Huperzia Serrata.[8] It hasbeen found to be a potent, reversible inhibitor of acetylcholi-nesterase (AChE).[9] This inhibition results in increased levels ofthe neurotransmitter acetylcholine and a corresponding im-provement in cognitive ability. Huperzine A has an IC50 anda half-life in the body that compare favorably to other acetyl-cholinesterase inhibitors that are on the market as treatmentsfor Alzheimer’s disease (Table 1). Aricept (3), which is marketed

by Pfizer, was the top-selling drug to combat Alzheimer’s as of2011 with an IC50 of 0.01 mm and a t1/2 of 70 h. Another com-mercially available drug for the treatment of Alzheimer’s dis-ease is galantamine (4), which has an IC50 of 1.995 mm and at1/2 of 7 h. Comparatively, huperzine A has an IC50 of 0.082 mm

and a t1/2 of 4.8 h.[6] Along with excellent biological activity, hu-perzine A has been shown to be devoid of unexpected toxicityand has a low rate of side effects.[10]

Despite these advantageous properties, the FDA has not ap-proved huperzine A in the United States, although it is sold asa nonprescription dietary supplement. Likely, this is becausethe process for extracting huperzine A was published withoutpatent, making it non-profitable for pharmaceutical companiesto pursue clinical trials and obtain FDA approval. Huperzine Ahas been the subject of clinical trials and is used as a treatmentfor Alzheimer’s disease in China, even though it has not beenpursued with as much vigor elsewhere. In addition to patent-ing challenges, the lack of interest in commercializing huperzi-ne A is also attributable to the fact that AChE inhibition likelyonly treats symptoms of cognitive decline, as opposed to erad-

Figure 1. Lycopodium alkaloids and other acetylcholine esterase inhibitors.

Table 1. Acetylcholine esterase inhibition.

Compound IC50 AChE [mM] t1/2 [h] Dosage[times per day]

huperzine A (2) 0.082 4.8 2–3aricept (3) 0.010 70 1galantamine (4) 1.995 7 2

[a] R. A. Murphy, Prof. R. SarpongCollege of ChemistryUniversity of California, BerkeleyLatimer Hall, Berkeley, CA 94720 (USA)Fax: (+ 1) 510-642-9675E-mail : rsarpong@berkeley.edu

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icating the root cause of Alzheimer’s disease. Much effort isnow being devoted to developing treatments related to theother pathologies of Alzheimer’s disease. Nonetheless, biologi-cal activity among various members of the Lycopodium alka-loids continues to attract attention to these molecules. For ex-ample, lycojapodine A (5, Figure 2) has anti-HIV-1 activity with

an EC50 value of 85 mg mL�1 (MTT method; MTT = 3-(4,5-dime-thylthiazol-2-yl)-2,5-diphenyltetrazolium bromide).[3, 11] Lycoja-ponicumins A–C (6–8) inhibit lipopolysaccharide (LSP)-inducedpro-inflammatory factors in BV2 macrophages with IC50 rangingfrom 43.61 to 64.97 mm

[12] and siebolidine A (9) is cytotoxicagainst murine lymphoma L1210 cells with an IC50 of5.1 mg mL�1 in vitro.[13] Finally, complanadine A (10) has beenshown to induce neurite extension through the secretion ofneurotrophic growth factor from 1321N1 cells and promotionof neuronal differentiation of PC-12 cells.[14]

This fascinating array of biological activity as well as thecomplex and elegant structural features inherent in these mol-ecules has continued to inspire many synthetic efforts for thepreparation of Lycopodium alkaloid natural products.

As with many natural products, total synthesis is an impor-tant tool for the biological study of the Lycopodium alkaloids.This is especially important because the Lycopodium genus hasa particularly low content of these alkaloids (0.1–0.3 %).[15] Forexample, to isolate 30–40 mg of lycojaponicumins A–C (6–8),100 kg of the whole plant was required.[12] These club mossesare known to be very slow growing and difficult to cultivate.As a consequence, biosynthetic studies have been fairly limit-ed. Initial feeding studies were conducted with radiolabledlysine, within their natural environment in Ontario (Canada) be-cause of the aforementioned difficulty in cultivation.[16] Thesestudies were able to provide support for the hypothesis thatthese alkaloids are derived from the amino acid lysine (11,Figure 3).

While all Lycopodium alkaloids are thought to be biosynthet-ically derived from lysine, they have been divided into fourclasses in order to further characterize them based on structur-al features. These classes include the lycodine, lycopodine, faw-cettimine, and miscellaneous classes. They are generally de-scribed by the molecules they are named after: lycodine (16),lycopodine (1), and fawcettimine (17, Figure 4). The miscellane-ous class is commonly associated with phlegmarine (18), al-though it contains a wide range of structurally diverse alka-loids.

In this article we focus on the fawcettimine class, which con-tains over 80 members. As exhibited by fawcettimine (17), thisclass contains a cis-fused 6-5 bicycle and an azonine ring withone quaternary center.

Early Synthetic Work

Fawcettimine (17, Figure 5), also referred to as Burnell’s Base A,was first isolated as the perchlorate salt in 1959.[17] Its structure

Figure 2. Representative biological activity of the Lycopodium alkaloids.

Figure 3. Proposed biosynthesis of Lycopodium alkaloids from lysine (11).

Figure 4. The four classes of Lycopodium alkaloids.

Figure 5. Hemiaminal isomers of fawcettimine.

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was originally assigned as tricycle 19 with isomerism to hemi-aminal 17 and 20. In 1967, a collaboration between three re-search groups suggested that the correct structure of fawcetti-mine was the hemiaminal form (17), with minimal isomerismto 19 or 20.[18]

Twenty years after its initial discovery, Inubushi completedthe first synthesis of fawcettimine in 1979 via 6-5-9 tricycle 21(Scheme 1).[19] Hydrogenation of 21 under standard conditions

gave 22 as a mixture of diastereomers at C4, which followinghydrolysis of the trifluoroacetamide gives fawcettimine. This26-step synthesis yielded fawcettimine in 0.1 % yield.

Even after the publication of the Inubushi synthesis, therewas still continued doubt about the stereochemistry at the C4center. Since Inubushi had a mixture of diastereomers at theC4 center (resulting from the hydrogenation), it was still un-known which corresponded to the natural product.

Heathcock pioneered conformational studies on this systemwhen he applied a similar 6-5-9 tricycle to the synthesis of faw-cettimine in 1986.[20] In this landmark synthesis, he was able toaccess 6-5-9-tricycle 19 a from bicycle 23 through intramolecu-lar displacement of the tosylate to form the nine-memberedring, oxidation, and ozonolysis (Scheme 2).

This tricycle (19 a) was available as a single diastereomer atthe C4 center. NMR studies of 19 a showed minimal isomerismto 20, and none at all to 17 a. Diastereomer 19 b was more rel-evant, as it was shown to correspond to the natural product.In this case, hemiaminal 17 b was favored over the diketo-

amine form (19 b). In fact, exposure of 19 a to basic conditionsleads to formation of fawcettimine (17 b ; henceforth referredto as 17), which is formed in 95 % yield via isomerization tothe thermodynamically favored b-diastereomer at the C4 posi-tion. Heathcock’s 13-step synthesis arrives at fawcettimine inan impressive 16.6 % overall yield. This efficient synthesis setthe stage for the first X-ray analysis and complete structural as-signment of fawcettimine.

Heathcock and Inubushi’s early work has had a lasting influ-ence on other strategies employed in the synthesis of thesemolecules ever since the time their work was completed. Evenwith the great advances in chemistry made since then, this6-5-9 tricycle, and derivatives thereof, have long been consid-ered the best way to access fawcettimine and related mole-cules. Because of the elegance of this type of route, Heath-cock’s observations have been exploited to access many relat-ed fawcettimine-type Lycopodium alkaloids. Significant efforthas been dedicated to creative ways to access the Heathcocktricycle (24, Figure 6), but there is limited diversity in methodsto advance this intermediate. Much of the novelty in the syn-theses of fawcettimine related molecules comes from the inno-vative construction of the initial cis-fused 6-5 bicycle (25).

One particularly challenging aspect of the synthesis of tricy-cles related to 24 is installation of the quaternary center at thering fusion. The following subsections will discuss a selectionof the methodologies that have been employed toward theseends in the past decade. These strategies include Diels–Alder,radical, metal-catalyzed, and miscellaneous approaches. Arecent review focuses on the application of the Pauson–Khandreaction to the synthesis of the Lycopodium alkaloids. As such,we will not discuss the application of the Pauson–Khand reac-tion in this context.[1e]

Diels–Alder Approaches

Diels–Alder reactions have long been attractive transforma-tions in total synthesis. The stereospecific nature of this reac-tion represents an elegantly simple way to set relative stereo-chemistry and rapidly generate molecular complexity. Not sur-prisingly, the Diels–Alder reaction was envisioned as a usefulstrategy for the synthesis of the 6-5 bicycle in the context ofthe fawcettimine-type Lycopodium alkaloids. While advanta-geous in some senses, it is still a challenge to perform a Diels–Alder reaction enantioselectively.

In 2013, the Williams group was able to access fawcettimine(17), lycoflexine (26), fawcettidine (27), and lycoposerramine B(28) from the elaboration of a common 6-5-9 tricycle (29,

Scheme 1. Inubushi’s synthesis of fawcettimine.

Scheme 2. Heathcock’s synthesis of fawcettimine.

Figure 6. General Heathcock-inspired approach to fawcettimine.

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Scheme 3).[21] This key Heathcock-type tricycle was availablefrom diene (30) and dienophile (31) as precursors usinga Diels–Alder reaction in the forward sense.

Williams’ Diels–Alder reaction was very challenging due tothe fact that enones such as 31 are known to be poor dieno-philes. This is because of the lack of a second activating groupand the electronically and sterically deactivating b-substituent.Additionally, dienophile 31 is sensitive to Brønsted and Lewisacidic conditions because of the labile ketal group. The Wil-liams group was able to surmount these challenges by react-ing diene 30 and dienophile 31 at 180 8C (neat) for 9 h to givetricycle 32 in 74 % yield (Scheme 4), which constitutes the first

Diels–Alder reaction of this type. While this reaction is notenantioselective, the precursor to dienophile 31 was subjectedto kinetic resolution to provide an enantioselective synthesis.

The product of the Diels–Alder reaction, tricycle 32, was fur-ther elaborated in five steps to give g-lactone 33. Opening ofthis lactone and further manipulation to give diol 34 consti-tutes a creative way to access the precursor to the key Heath-cock-type 6-5-9 tricycle. This diol (34) was converted to theazonine ring by means of a challenging double Fukuyama-Mit-sunobu reaction.

Tricycle 29 served as a common intermediate that was dif-ferentially functionalized to provide Lycopodium alkaloids faw-cettimine (17), lycoflexine (26), fawcettidine (27), and lycopo-serramine B (28). Oxidation of 29 affords the N-nosyl-protectedversion of the Heathcock tricycle (35, Scheme 5).

Consistent with Heathcock’s observations, unveiling theamine group in 35 proceeds with equilibration of the C4 ste-reocenter to furnish the b-diastereomer, which adds into thecyclohexanone carbonyl group to give fawcettimine (17). Faw-cettimine (17) can then be dehydrated to give fawcettidine(27).

Alternatively, tricycle 35 can be converted to lycoflexine (26)by deprotection of the secondary amine and subsequent Man-nich reaction. This transformation is based on the biosyntheticproposal made by Ayer in 1973 when lycoflexine was first iso-lated.[5] In 2010 Ramharter and Mulzer also exploited this bio-synthetic transformation to access lycoflexine.[22] Tricycle 29was applied to the synthesis of lycoposerramine B (28) by ex-change of the nosyl-protecting group for a methyl group andselective oxime formation.

The Williams work (outlined in Schemes 3, 4, and 5) consti-tutes a very effective approach to the Heathcock-type tricyclesthat can be applied to the synthesis of a range of Lycopodiumalkaloids. This use of the Diels–Alder reaction provides an effi-cient way to access the initial 6-5 bicycle that is easily resolvedusing a kinetic resolution of the dienophile precursor.

The Taniguchi group subsequently published a second ex-ample of the Diels–Alder reaction being applied to great effectin the synthesis of a number of Lycopodium alkaloids in2013.[23] They were able to access lycopoclavamine B (37), lyco-poserramine T (38), and serratine (39) from a common Heath-cock-like tricycle (40, Scheme 6). This tricycle was elaboratedfrom the Diels–Alder adduct forged from diene 30, identical tothat used in the Williams work, and dienophile 41.

Scheme 3. Williams’ retrosynthetic analysis.

Scheme 4. Williams’ Diels–Alder reaction and elaboration to access Heath-cock-type tricycle 29.

Scheme 5. Williams’ endgame to lycoflexine (26), fawcettidine (27), fawcetti-mine (17), and lycoposerramine B (28).

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In line with the Williams’ group observations, this Diels–Alder reaction was also very difficult to effect. Ultimately, heat-ing diene 30 and dienophile 41 neat at 80 8C yielded 70 % ofthe endo product (42, Scheme 7) in addition to 7 % of the exoproduct (not shown). This hydrindinone derivative could befurther elaborated into the key 6-5-9 tricycle (40) in 13 steps.The nine-membered ring was formed using two sequentialMitsunobu reactions.

Tricycle 40 was applied to the synthesis of lycopoclavami-ne B (37), lycoposerramine T (38), and serratine (39) via the in-termediate epoxides 43 a and 43 b, respectively (Scheme 8).

The two epoxide diastereomers (43 a and 43 b) can be sepa-rated and used in a divergent synthesis of the aforementionednatural products. The major diastereomer of the epoxide (43 b)cyclizes to form the core structure of serratine (44) upon de-protection of the amine. Oxidation and protecting group cleav-age then furnishes the natural product (39).

The minor diastereomer of the epoxide (43 a) can beopened by elimination to give 45, which is further manipulat-ed through oxidation and Boc (tert-butoxycarbonyl) cleavageto give lycoposerramine T (38). Alternatively, 45 can be ex-posed to KOH in methanol to unveil the hydroxyl groups. Sub-sequent oxidation furnishes enone 46. Interestingly, uponcleavage of the Boc-protecting group, the amine adds into theadjacent carbonyl on the six-membered ring to give lycopocla-vamine B (37).

This is a fascinating reaction because it mimics the reactivitythat Heathcock observed in his 1989 synthesis of fawcettimine.His work showed that only the b-diastereomer at C4 wouldadd into the carbonyl on the six-membered ring (Scheme 2).Taniguchi’s work sheds further light on the equilibrium of theketoamines and shows that the corresponding unsaturated

system is capable of forming a similar hemiaminal, albeit withdifferent stereochemistry.

While this synthesis was achieved in a racemic fashion, it isa valuable demonstration of the use of a Diels–Alder reactionto create the initial 6-5 cis-fused bicycle. The use of a Diels–Alder reaction in this context is appropriate, because the dien-ophile (41) already has the required three-carbon chain instal-led, which increases convergency.

Radical Approaches

A number of radical cyclization approaches have been success-fully applied to the synthesis of the 6-5 bicyclic precursor ofthe Heathcock-type tricycle in the context of Lycopodium alka-loid synthesis. In 2007, Liu, Chau, and co-workers discloseda formal enantiospecific synthesis of fawcettimine (17) basedon Heathcock’s work from bicycle 47 (Scheme 9).[24] The syn-

Scheme 6. Taniguchi’s retrosynthesis of lycopoclavamine B (37), lycoposerra-mine T (38) and serratine (39).

Scheme 7. Taniguchi’s Diels–Alder reaction and elaboration to tricycle 35.

Scheme 8. Taniguchi’s endgame to lycopoclavamine B (37), lycoposerramineT (38), and serratine (39).

Scheme 9. Liu and Chau’s retrosynthesis to fawcettimine (17).

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thesis of 47 was enabled by the radical cyclization of iodide48, which was accessed using an early stage intermolecularradical addition of a radical generated from enone 49 intoacrylonitrile. Enone 49 was derived from chiral pool compound(+)-pulegone (50).

In the forward sense, (+)-pulegone (50) can be readily trans-formed into the requisite a-iodoenone (49, Scheme 10).[25]

Upon exposure to AIBN (azobisisobutyronitrile) and tributyltin

hydride, the a-carbonyl vinyl radical generated from49 adds to acrylonitrile to yield enone 51 in 70 %yield. This represents a useful method to prepare a-substituted cyclic enones that are typically difficult toprepare using other methods. Important for the suc-cess of this sequence is the portion-wise addition ofreagents and the use of an electron-poor olefin. Thisis due to the fact that a-carbonyl vinyl radical speciesare electron-rich radical donors that do not reactwith electron-rich olefins, such as vinyl acetate.

From 51, copper-mediated conjugate addition,trapping with TMSCl (trimethylsilyl chloride), and ex-posure to m-CPBA (meta-chloroperoxybenzoic acid)and sodium iodide yields iodoketone 48. This unsta-ble intermediate (48) is taken on without purificationusing another key radical addition step. Thus, 48 wasexposed to AIBN and tributyltin hydride to generatethe a-keto radical, which undergoes 5-exo-dig cycliza-tion to give 52 in a 64 % yield. This 6-5 bicycle canbe readily advanced to Heathcock-type intermediates(47, Scheme 9) and ultimately to fawcettimine (17).

The radical addition/cyclization approach that Liu and Chauemploy is particularly useful here, because it allows them todraw from the chiral pool and achieve an enantiospecific syn-thesis. Using this strategy, they were able to rapidly intersectHeathcock-type intermediates and complete an enantiospecificformal synthesis of fawcettimine (17).

A unique approach to access 6-5-9 tricycles en route to faw-cettimine-type alkaloids lycojapodine A (5), alopecuridine (53),and siebolidine (9) was reported by Tu and Wang in two sepa-rate publications in 2011 and 2012.[26] Their strategy builds thetricycle (54, Scheme 11) through the late-stage installation of

the five-membered ring through an intramolecular SmI2-medi-ated pinacol coupling reaction from 55. The spirocycle in 55can be accessed from a semipinacol rearrangement of epoxide56, which was synthesized from 57 and 58.

Similar to Liu and Chau’s synthesis, Tu and Wang utilize ana-haloketone (59, Scheme 12) derived from (+)-pulegone (50).This ketone was converted to vinyl bromide 57 over five steps.Vinyl bromide 57 underwent lithium halogen exchange witht-BuLi followed by addition into ketone 58. To avoid elimina-

tion, this adduct was subjected to epoxidation conditionsusing m-CPBA to afford 56 as a 3.5:1 mixture of diastereomers(major diastereomer shown). Upon exposure to BF3 etherate,the epoxide (56) undergoes a semipinacol rearrangement toform the quaternary spirocenter. The resulting alcohol is thenprotected as the methoxy methyl ether, and the alkene is con-verted to aldehyde 55 using ozonolysis conditions.

Aldehyde 55 is the substrate for the key SmI2-mediated pi-nacol coupling. Upon exposure to SmI2, the cis-diol (60) isformed as a result of chelation of samarium between the ketylradical and the carbonyl. Diol 60 can be further elaborated to

Scheme 10. Liu and Chau’s forward synthesis highlighting 5-exo-dig radicalcyclization.

Scheme 11. Tu and Wang’s retrosynthesis to lycojapodine A (5), alopecuri-dine (53) and siebolidine A (9).

Scheme 12. Tu and Wang’s forward synthesis to access alopecuridine (53).

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diketone 54 in 44 % yield over three steps. Analogous to whatHeathcock showed with the fawcettimine system, upon cleav-age of the protecting group on nitrogen, the secondary aminegroup adds into the adjacent carbonyl on the six-memberedring to provide alopecuridine (53). It is notable that this hy-droxylated version of fawcettimine has the same stereochemis-try at C4. Tu and Wang were also able to advance alopecuri-dine (53) to two other natural products, siebolidine A (9) andlycojapodine A (5, Scheme 11).

Tu and Wang’s use of a SmI2-mediated radical cyclizationconveniently allowed them to incorporate the additional hy-droxyl group at C4. This enabled the use of the Heathcock-type endgame strategy to access a range of alkaloids relatedto fawcettimine.

In 2012, the Lei group was able to access fawcettimine (17),fawcettidine (27), and 8-deoxyserratinine (61) also usinga SmI2-mediated pinacol coupling (Scheme 13).[27] Fawcetti-mine and fawcettidine were accessed from 8-deoxyserratinine(61), which was derived from 6-5-9 tricycle 62. Like the Tu/Wangintermediate (54, Scheme 11 and12), this tricycle is an oxygenat-ed version of the Heathcock tri-cycle (19 a/19 b, Scheme 2). Tri-cycle 62 was accessed from 63by means of a SmI2-mediated pi-nacol coupling.

This coupling gives the oppo-site diastereomer to Tu andWang’s, by virtue of the hydroxydirecting group on the six-mem-bered ring. The Tu/Wang andthe Lei work together providecomplementary descriptions ofmethods by which these Heath-cock-type tricycles can be ac-cessed and futher manipulated.In this retrosynthetic analysis, Leitakes 63 back to functionalizedketone 64, which can be accessed through the tandem conju-gate addition/aldol reaction of enone 65, which is once againderived from (+)-pulegone.[25]

In the forward sense, enone 65 was treated with allyl cup-rate, and the resulting enolate was trapped with the appropri-ate aldehyde to provide 64 (Scheme 14). A four-step procedureconverts the protected alcohol to the alkyl iodide and oxidizesthe secondary alcohol to yield dione 66. This intermediate isused in a rare example of intramolecular alkylation of a 1,3-dione to form a spirocycle (67).

Reduction, dihydroxylation, and sodium periodate cleavageof 67 yields aldehyde 63 (major diastereomer shown). Whilethis aldehyde is similar to the one that Tu and Wang employed(55, Scheme 12), in this case the hydroxyl group is not protect-ed. Therefore, samarium-mediated pinacol coupling proceedsthrough an intermediate in which the samarium is coordinatedto the alcohol group. This coordination yields trans-diol 68, asopposed to the cis-diol that Tu and Wang observed (60,

Scheme 12). Oxidation of diol 68 furnishes diketone 62. Start-ing with a substrate that possesses the opposite stereochemis-try at the C4 position relative to the Tu/Wang intermediate(54, Scheme 12), Lei was able to access the carbon skeleton of8-deoxyserratinine (69) through cleavage of the Boc group anddisplacement of the tertiary alcohol. It is important to notethat deprotection of the amine group does not yield a fawcetti-mine/alopecuridine-type hemiaminal because of the stereo-chemistry at C4, which is the opposite epimer that undergoesthe favorable cyclization.

Diketone 69 can be converted to 8-deoxyserratinine (61)through selective reduction (Scheme 15). Alternatively, reduc-tive cleavage of the C4�N bond in 69 yields the Heathcock6-5-9 tricycle, which cyclizes to give fawcettimine (17). Harsherreductive conditions cleave the C4�N bond and eliminatewater in one pot to yield fawcettidine (27).

Lei’s divergent approach to three related fawcettimine-typealkaloids builds upon the work pioneered by Heathcock. It is

Scheme 13. Lei’s retrosynthesis to fawcettidine (27), fawcettimine (17) and8-deoxyserratinine (61).

Scheme 14. Lei’s forward synthesis to tetracycle 69.

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enabled by a versatile radical cyclization to build thekey 6-5-9 tricycle that has also been employed by Tuand Wang.

Metal-Catalyzed Approaches

In 2007, the Toste group applied their gold(I)-cata-lyzed Conia-ene methodology to the enantioselectivesynthesis of fawcettimine (17).[28] Retrosynthetically(Scheme 16), they envisioned accessing fawcettimine(17) from the N-Boc-protected version of the Heath-cock 6-5-9 tricycle (70). The nine-membered ringcould be formed from an intramolecular iodide dis-placement of 71. Functionalized bicycle 71 couldarise from the elaboration of 6-5 bicycle 72. In theirkey step, this bicycle (72) was synthesized by usingthe gold(I)-catalyzed cyclization of silyl enol ether 73.Silyl enol ether 73 can be accessed from simpleb-keto ester 74 and trans-crotonaldehyde (75).

In the forward sense, asymmetric Robinson annulation be-tween b-keto ester 74 and trans-crotonaldehyde (75) givesenone 76 in 72 % yield and 88 % ee (Scheme 17). Enone 76 wasexposed to conditions based on a method developed in theHaruta group, in which trimethylsilyl trifluoromethanesulfonate(TBSOTf) activates an enone for 1,4-addition of an allenyltribu-

tylstannane.[29] Iodination of the resulting terminal alkyne fur-nishes silyl enol ether 73. Upon exposure to a gold(I) catalyst,this substrate undergoes a 5-endo-dig cyclization to cleanlyprovide 6-5 bicycle 72. Protection of the carbonyl group,Suzuki cross coupling, and hydroboration furnishes 77, whichpossesses all of the carbons required for the natural product.An Appel reaction followed by intramolecular displacement ofthe iodide under basic conditions permits the closure of theazonine ring. Cleavage of the ketal, hydroboration, and oxida-tion gives diketone 70, which is the N-Boc version of theHeathcock tricycle. As previously shown, upon cleavage of theBoc protecting group, the C4 position is isomerized to thethermodynamically favored b-diastereomer, and the amineadds into the carbonyl to give fawcettimine (17).

The Toste synthesis furnishes fawcettimine in a concise13 steps from crotonaldehyde. It is an elegant demonstrationof how their gold(I)-catalyzed cyclization can be applied to nat-ural product synthesis.

In addition to the gold-catalyzed approach by the Tostegroup, other metal-catalyzed approaches have also been ap-plied to the synthesis of the Heathcock-type tricycle. Grubbsmetathesis reactions are powerful transformations in the con-text of natural product synthesis. In 2010, Ramharter andMulzer applied this methodology to the racemic total synthesisof lycoflexine (26, Scheme 18).[22] Lycoflexine (26) was accessedfrom 6-5-9 tricycle 78, which was formed using a Grubbsenyne-ring-closing metathesis (RCM) of substituted cyclohexa-none 79, which in turn can be obtained from (+)-pulegone de-rivative 65,[25] a compound that has been used many times asa starting point for a number of synthetic efforts toward otherLycopodium alkaloids.

From cyclohexenone 65 (Scheme 19), tandem Sakurai reac-tion/aldol reaction followed by oxidation with IBX (2-iodoxy-benzoic acid) affords 80, which was further alkylated to give

Scheme 15. Lei’s divergent approach to fawcettimine (17), fawcettidine (27),and 8-deoxyserratinine (61).

Scheme 16. Toste’s retrosynthesis to fawcettimine (17).

Scheme 17. Toste’s forward synthesis to access fawcettimine (17).

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81. Vinyl triflate formation of the less hindered carbonyl andelimination yields terminal alkyne 79. In their key step, alkyne79 undergoes enyne RCM upon exposure to Grubbs second-generation catalyst (Grubbs II). In this case, Grubbs II also actsas a selective hydrogenation catalyst after introduction of hy-drogen to reduce the carbon–carbon double bond formed inthe nine-membered ring (see 82). This impressive tandemRCM/reduction procedure provides 78 in 52 % yield, formingthe five- and nine-membered rings in a single step.

Tricycle 78 was hydroborated and oxidized in a one-pot pro-cedure to give the N-Boc version of the Heathcock tricycle thatthe Toste group also accessed (70, Scheme 20). Upon cleavage

of the Boc group, the C4 stereocenter isomerizes to give thethermodynamically favored b-isomer, as described by Heath-cock (17 and 19 b). This species is mainly in the hemiaminalform as fawcettimine (17), but the open form (19 b) is alsopresent in solution. The open form can be treated with formal-dehyde to generate an iminium species that undergoes an in-tramolecular Mannich reaction to furnish lycoflexine (26). Thistransformation is based on the lycoflexine biosynthesis thatwas first proposed by Ayer in 1979.[5]

This highly efficient synthesis permits access to lycoflexine(26) in eight steps and a 13 % overall yield. It is enabled bya number of tandem and one-pot reaction sequences. Mostimportant to the strategy employed by Ramharter and Mulzerto access the Heathcock-like 6-5-9 tricycle is the simultaneousinstallation of the five- and nine-membered rings usinga Grubbs enyne ring-closing metathesis and hydrogenation se-quence.

Miscellaneous Approaches

In 2010, the Jung group completed a formal synthesis of faw-cettimine (17) via the intermediacy of Heathcock’s functional-ized bicycle (83, Scheme 21).[30] They were able to access thisbicycle using an intramolecular attack of a silyl enol ether ontoan activated cyclopropane (84), which was synthesizedthrough a triflimide-mediated Mukaiyama–Michael addition ofsilyl enol ether 85 to enone 86.

In the forward sense, silyl enol ether 85 was synthesizedfrom S-phenylglycinol-derived chiral bicyclic lactam 87(Scheme 22). Lactam 87 was converted to a-b-unsaturated ke-

Scheme 18. Ramharter and Mulzer’s retrosynthesis toward lycoflexine (26).

Scheme 19. Ramharter and Mulzer’s forward synthesis and metathesis keystep.

Scheme 20. Ramharter and Mulzer’s endgame to access lycoflexine (26).

Scheme 21. Jung’s retrosynthesis of fawcettimine (17).

Scheme 22. Jung’s synthesis of silyl enol ether 85.

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toester 88 over three steps in 77 % yield. The carbon–carbondouble bond underwent cyclopropane formation under stan-dard Corey–Chaykovsky conditions to give 89. Hydrolysis thenfurnished enantioenriched cyclopropane 90. Silyl enol etherformation proceeded smoothly to give 85.

Silyl enol ether 85 was then used in a Mukaiyama–Michaeladdition with enone 86 in the presence of triflimide to furnish91 (Scheme 23). This intermediate was not a good substrate

for the cyclopropane ring opening, so the carbonyl group wasconverted to alkene 84 using standard Wittig methylation con-ditions. This substrate underwent the desired nucleophilic ad-dition upon exposure to scandium triflate to furnish 6-5 bicycle92. This is the first example of this type of reaction (attack ofa silyl enol ether on a cyclopropane-1,1-diester) in an intramo-lecular sense to form a new carbon–carbon bond and give anannulated product. Bicycle 92 is obtained as a single diastereo-mer. Further studies from the Jung group have showed thatthis reaction occurs via a stereospecific “SN2-like” transitionstate. Bicycle 92 can be decarboxylated to give ester 83, whichwas previously reported by Heathcock.

This formal enantiospecific synthesis of fawcettimine exhibitsa creative way to form the initial 6-5 bicycle, using a stereose-lective intramolecular opening of a cyclopropane.

Another unique approach to a functionalized 6-5 bicycle enroute to the Heathcock-type tricycles was demonstrated bythe Yang group in 2011.[31] They were able to access fawcetti-mine (17), lycoflexine (26), and 8-deoxyserratinine (61) fromthe elaboration of 6-5-9 tricycle 78 (Scheme 24; also seeRamharter and Mulzer’s synthesis, Scheme 19). Tricycle 78could be derived from 93 by means of a double iodide dis-placement. Alkyl iodide 93 could arise from the functionaliza-tion of 6-5 bicycle 94, which was accessed using a Helquist an-nulation of enone 76. Similar to many other related syntheticefforts, enone 76 was derived from (+)-pulegone.

From 76, Michael addition followed by trapping of the eno-late with TMSCl affords silyl enol ether 95 (Scheme 25). Hel-quist annulation followed by oxidation with PCC provides bicy-cle 94 as a single diastereomer of the desired product. Protec-tion of the carbonyl group, allyl Grignard addition and elimina-tion yields alkene 96. This intermediate was further elaboratedto 6-5-9 tricycle 97 through a five-step sequence, featuring

a double iodide displacement to forge the nine-memberedring.

Tricycle 97 was epoxidized from the concave face using anasymmetric Shi epoxidation, to give 98 (Scheme 26). This epox-ide was converted to 8-deoxyserratinine (61) using Inubushi’sprocedure.[19] Exposure to potassium hydroxide cleaves the tri-fluoroacetamide and the resulting unprotected amine cleanlyopens the epoxide to form the 6-5-6-5 core of the natural

Scheme 23. Jung’s synthesis of Heathcock’s bicycle (83).

Scheme 24. Yang’s retrosynthesis of fawcettimine (17), lycoflexine (26) and8-deoxyserratinine (61).

Scheme 25. Yang’s synthesis of tricycle 97.

Scheme 26. Yang’s endgame to 8-deoxyserratinine (61).

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product. Oxidation of the resulting secondary alcohol and che-moselective reduction furnishes 8-deoxyserratinine (61).

Alternatively, the N-Boc-protected tricycle (78) can be dihy-droxylated, oxidized, and selectively deoxygenated to give theBoc-protected version of the Heathcock tricycle (70,Scheme 27), which was previously used in the Toste and

Ramharter/Mulzer syntheses.[22, 28] Analogous to what theHeathcock group has shown, the protecting group on nitrogencan be cleaved to give fawcettimine (17) by the epimerizationof the C4 stereocenter to the thermodynamically favored dia-stereomer. As Ayer originally proposed,[5] and as Ramharterand Mulzer exhibited earlier in 2010,[22] fawcettimine was con-verted to lycoflexine (26) through a biomimetic Mannich reac-tion. The conditions developed by Yang are particulary effec-tive, with the desired transformation taking place overa period of 5 min, in a 95 % yield.

This synthesis demonstrates yet another way to accessHeathcock-type tricycles through the functionalization of cis-fused 6-5 bicycles. The Yang group is able to achieve this bythe use of an early stage Helquist annulation.

Recent Novel Discon-nections

Inubushi and Heathcock’s pio-neering work on the synthesisand conformational studies offawcettimine has heavily influ-enced the strategies and tacticsthat chemists have used in thesynthesis of related Lycopodiumalkaloids. While there are manyHeathcock-inspired syntheses ofthe fawcettimine-type Lycopodi-um alkaloids, there have alsobeen a number of elegant syn-theses that do not proceedthrough the common 6-5-9 tricy-clic intermediate. Syntheses thattake advantage of the Heathcocktricycle typically have a final C�Nbond-forming step that is often

based on amine addition into a carbonyl or the displacementof an activated oxygen. A number of the alternative ap-proaches form the C�N bonds earlier in the synthesis and/or ina unique way. These syntheses are notable for their markedlydifferent and creative disconnection strategies.

In 2002, the Zard group published a unique synthesis of 13-deoxyserratinine (99, Scheme 28).[32] They forged the 6-5-6-5tetracyclic core of the natural product by the generation of anamidyl radical intermediate from 100. O-Benzoyl-N-allylhydrox-amine 100 can be elaborated from 6-5 bicycle 101, which inturn can be forged from alkyne 102 by using a Pauson–Khandreaction.

Starting from 5-hexyn-2-one (103), allyl Grignard additionfollowed by TBS (tert-butyldimethylsilyl) protection of the re-sulting tertiary alcohol group yields 104 (Scheme 29). Deproto-nation of the terminal alkyne and alkylation then furnishes102. Alkyne 102 was complexed to dicobalt octacarbonyl andexposed to NMO (N-methylmorpholine-N-oxide) to provide thePauson–Khand product, which was oxidized to yield the de-sired 6-5 bicycle (101) in high diastereoselectivity (93:7). Car-boxylic acid 101 can be converted to the O-benzoyl-N-allylhy-droxamine 100 in 81 % yield over three steps. Compound 100

Scheme 27. Yang’s endgame to fawcettimine (17) and lycoflexine (26).

Scheme 28. Zard’s retrosynthesis of 12-deoxyserratinine (99).

Scheme 29. Zard’s forward synthesis highlighting radical cyclization.

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is an ideal substrate for radical cyclization reactions, becauseexposure to a tributyltin radical induces cleavage of the weakN�O bond to generate amidyl radical 105.

In this case, 1,1’-azobis(cyclohexanecarbonitrile) (ACCN) wasused as an initiator along with two equivalents of tributyltinhy-dride. Two equivalents of ACCN are necessary for the concur-rent cleavage of the C�Cl bond to furnish tetracycle 106through a 5-exo/6-endo cyclization sequence. The installationof the chlorine atom was an im-portant substrate modification,because without it, the unde-sired 5-exo/5-exo cyclization toform 6-5-5-5 tetracycle 107 wasobserved exclusively. Tetracycle106 was transformed to 13-de-oxyserratinine (99) through silylenol ether formation to protectthe ketone carbonyl, reductionof the amide, and finally cleav-age of the sily enol ether tounveil the carbonyl.

While this synthesis divergesfrom the standard way of think-ing about these molecules, itcompares well with the otherwork done within this class ofcompounds. The Zard groupwas able to access 13-deoxyser-ratinine rapidly in ten steps with12 % overall yield. Their creativeuse of a cascade radical reactionsets the C4 and C12 stereocen-ters in a single step. This is particularly impressive given thatcontrol of these stereocenters has been a significant challengeinherent to the synthesis of these molecules.

The Dake group accomplished the synthesis of (+)-fawcetti-dine (27) using a very unique disconnection strategy enabledby a Ramberg–B�cklund reaction (Scheme 30).[33] Retrosyntheti-cally, they brought fawcettidine back to enone 108, whicharises from the oxidation of 6-6-5 tricycle 109. In turn, 109 isforged from bicycle 110 by using a platinum-catalyzed annula-tion. This material, analogous to other tactics discussed, is de-

rived from the chiral pool compound (+)-pulegone (50). Pule-gone has been very effectively utilized as a starting material ina number of the Heathcock-type strategies employed in thesynthesis of fawcettimine-type natural products. In this case, itagain maps onto the D ring of the natural product (seeScheme 2), but is elaborated quite differently.

Pulegone (50) was converted to enone 111 in 53 % yieldover five steps (Scheme 31). From enone 111, alkyl cuprate ad-

dition and desilylation of the terminal alkyne yielded 112 as aninconsequential mixture of diastereomers a to the carbonyl.Ketone 112 was condensed with the appropriate amine togive 110. This terminal alkyne underwent facile platinum-cata-lyzed annulation to give 6-6-5 tricycle 109. It was fortuitousthat this step proceeded with such ease given sulfur’s affinityfor platinum. Tricycle 109 was then converted to tetracycle113 by allylic oxidation of the carbon–carbon double bondand cleavage of the carbamate protecting group. Upon cleav-age of the carbamate, the sulfur underwent 1,4-addition intothe enone to provide 113. Protection of the carbonyl as theketal, oxidation of the sulfide to the sulfone, and Ramberg–B�cklund reaction to form the final seven-membered ring af-forded alkene 114. Reduction of the carbon–carbon doublebond, reduction of the amide carbonyl, and cleavage of theketal protecting group provided fawcettidine (27).

This synthesis of fawcettimine by Dake is again unique incomparison to the commonly employed Heathcock strategy. Itis particularly interesting because it is, to our knowledge, theonly synthesis that builds the seven-membered ring in thefinal stages of the synthesis. These unique disconnections maypotentially grant access to unnatural derivatives that are inac-cessible from traditional approaches to these molecules.

As discussed above, Tu and Wang have published a numberof papers on the synthesis of the fawcettimine-type Lycopodi-Scheme 30. Dake’s retrosynthesis of fawcettimine (27).

Scheme 31. Dake’s forward synthesis highlighting the Ramberg–B�cklund reaction.

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um alkaloids utilizing the Heathcock disconnection strategy.[26]

Recently, they were successful in the synthesis of a number ofLycopodium alkaloids: (�)-8-deoxyserratinine (61), (�)-lycojapo-nicumins C (8), (+)-fawcettimine (not shown), and (+)-fawcetti-dine (not shown).[34] These four natural products were accessedusing a unique, divergent strategy that goes through 6-5-5 tri-cycle 115 (Scheme 32). This tricycle (115) arises from the car-bene cyclization, decarboxylation, and functionalization of 116,which can be brought back to pulegone derivative 117 and118.

From enone 117, triflimide-promoted Michael addition of118 proceeds smoothly to provide silyl enol ether 116(Scheme 33). This product (116) was isolated in 90 % yield, oralternatively it can be exposed to [Cu(TBS)2] and heated to pro-mote carbene addition/cyclization and decarboxylation in anefficient one-pot procedure to provide 120 via 119. Exposureof 120 to base and allyl acetate produces the desired 6-5-5 tri-cycle. Selective protection of the carbonyl moiety with ethyl-ene glycol affords 121. Hydroboration and Mitsunobu reaction

with DPPA (diphenylphosphoryl azide) furnishes azide 122. Anaza-Wittig reaction and exposure to sodium cyanoborohydrideselectively provides 6-5-5-6 tetracycle 123. From tetracycle123, the ketal was cleaved and the secondary amine can beprotected with CbzCl. The enone was then installed in a two-step procedure to yield 124. Removal of the Cbz protectinggroup and methylation of the amine produces lycojaponicu-mins C (8).

Alternatively, the ketal in tricycle 122 was cleaved to provide115 (Scheme 34). An intramolecular Schmidt reaction, promot-ed by tin tetrachloride, provides tetracycle 125 in 48 % yield.Given that there are six possible sites for nitrogen insertion,

this reaction is particularly impressive. Treatment of this tetra-cycle with Lawesson’s reagent and Raney nickel reduces theamide in the presence of the other two carbonyl groups togive 126. Selective reduction with sodium borohydride thenfurnishes 8-deoxyserratinine (61). Tetracycle 126 can also beconverted to fawcettimine and fawcettidine according to prec-edent by Lei.[27]

This synthesis constitutes another example of creative retro-synthetic disconnection that does not make use of the Heath-

cock strategy. The Tu group hasbeen able to access a range ofstructurally diverse Lycopodiumalkaloids from a 6-5-5 tricyclethat is distinct from the 6-5-9 tri-cycle of the Heathcock-inspiredstrategies.

Summary and Outlook

The Heathcock 6-5-9 tricycle rep-resents an elegant and powerfulintermediate that is often em-ployed in the synthesis of thefawcettimine-type Lycopodiumalkaloids. Since Inubushi’s andHeathcock’s original work on thesynthesis and conformation offawcettimine in 1979 and 1986,respectively, there has beena vast array of syntheses that

Scheme 32. Tu’s retrosynthesis of 8-deoxyserratinine (61) and lycojaponicu-mins (8).

Scheme 33. Tu’s synthesis of lycojaponicumins C (8).

Scheme 34. Tu’s synthesis of 8-deoxyserratinine (61).

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employ this strategy. This has resulted in a number of methodsfor the synthesis of densely functionalized cis-fused 6-5 bicy-cles and their elaboration to a variety of similar 6-5-9 tricycles.In the future, there are sure to be more synthetic effortstoward the wide variety of fawcettimine-type Lycopodium alka-loids that use this strategy. While this is a very worthwhileeffort given the beautiful structural complexity and fascinatingbiological activities of these molecules, room remains for thedevelopment of other novel disconnections. This is a loftygoal, given the elegance of the Heathcock strategy. However,there have been a number of recent refreshing publicationsthat continue to explore novel disconnection strategies.

Keywords: fawcettimine · fused-ring systems · Heathcock-inspired strategy · Lycopodium alkaloids · natural products ·total synthesis

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Published online on December 5, 2013

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