Scholarly article on topic 'Catalytic asymmetric reactions in alkaloid and terpenoid syntheses'

Catalytic asymmetric reactions in alkaloid and terpenoid syntheses Academic research paper on "Chemical sciences"

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Tetrahedron Letters
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{"Asymmetric synthesis" / "Chiral catalyst" / Alkaloids / Terpenoids / Efficiency}

Abstract of research paper on Chemical sciences, author of scientific article — Tomoyuki Yoshimura

Abstract Catalytic asymmetric induction is one of the most important methods in current synthetic organic chemistry for designing efficient and attractive synthetic routes. The efficient total synthesis of a natural product can be achieved through the identification of appropriate method and strategy. This Letter introduces the catalytic asymmetric syntheses of alkaloids and terpenoids based on an overview of four recently reported types of asymmetric reaction: (1) asymmetric decarboxylative allylation, (2) organocatalytic cascade reaction, (3) polyene cyclization, and (4) asymmetric [2+2]-photocycloaddition catalyzed by a chiral Lewis acid.

Academic research paper on topic "Catalytic asymmetric reactions in alkaloid and terpenoid syntheses"

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Tetrahedron Letters

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Catalytic asymmetric reactions in alkaloid and terpenoid syntheses


Tomoyuki Yoshimura

Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan


Article history: Received 30 April 2014 Revised 17 July 2014 Accepted 17 July 2014 Available online 25 July 2014


Asymmetric synthesis Chiral catalyst Alkaloids Terpenoids Efficiency


Catalytic asymmetric induction is one of the most important methods in current synthetic organic chemistry for designing efficient and attractive synthetic routes. The efficient total synthesis of a natural product can be achieved through the identification of appropriate method and strategy. This Letter introduces the catalytic asymmetric syntheses of alkaloids and terpenoids based on an overview of four recently reported types of asymmetric reaction: (1) asymmetric decarboxylative allylation, (2) organocatalytic cascade reaction, (3) polyene cyclization, and (4) asymmetric [2+2]-photocycloaddition catalyzed by a chiral Lewis acid.

© 2014 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecom-


Introduction.......................................................................................................... 5109

Total synthesis of aspidosperma alkaloids using asymmetric decarboxylative allylation........................................5110

Total synthesis of alkaloids using organocatalytic cascade reactions........................................................5111

Synthesis of terpenoids using enantioselective polyene cyclization.........................................................5114

Asymmetric synthesis of natural products through the catalytic [2+2]-photocycloaddition......................................5116

Conclusions.......................................................................................................... 5117

References and notes.................................................................................................. 5118


Novel natural products that display attractive bioactivities have been isolated from a variety of natural resources. The structural determination of these natural products has been accelerated recently through the development of a range of instrumental and analytical techniques. Natural resources play an important role in the search for biologically active compounds in the field of pharmaceuticals and agrochemicals;1 however, the isolation of an attractive bioactive compound as a minor component in nature typically does not allow for the elucidation of its biological mode of action or for the development of a pharmaceutical or agrochem-ical product without the establishment of a supply method. One solution to this problem is presented by natural product synthesis methods using synthetic organic chemistry. Such methods are an indispensable research field.

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In the past, the efficiency of a target molecule synthesis tended to receive little attention as researchers worked toward the fastest route to total synthesis; however, the realization of a sustainable society2 requires the development of effective synthetic routes to natural products that utilize limited resources efficiently in addition to achieving total synthesis. Several measures of a synthetic route's efficiency have been proposed, including the atom economy,3 redox economy,4 and step economy,5 and several total syntheses focusing on efficiency have been reported.6 In general, synthetic strategies are planned using a retrosynthetic analysis upon initiating the total synthesis of a target molecule. When considering a synthetic route for a complex natural product, many possible retrosynthetic analyses are available. The key to achieving an efficient total synthesis lies in selecting the most appropriate synthetic route based on a variety of retrosynthetic considerations. Asymmetric reactions are indispensable when the selective preparation of one enantiomer of a target molecule must be performed. Because each enantiomer of a certain biologically active compound 0040-4039/® 2014 Elsevier Ltd.

This is an open access article under the CC BY-NC-ND license (

can display distinct effects, new methods for asymmetric synthesis have remained under active development. Asymmetric synthesis may be divided roughly into four categories:7 the chiral pool method;8 optical resolution;9 the use of chiral auxiliaries;10 and the use of a chiral catalyst.11 Recently, asymmetric reactions that rely on the memory of chirality (MOC), in which asymmetric induction occurs via a chiral enolate intermediate with a lifetime in its chirality, have been applied in natural product synthesis.12 These reactions play significantly important roles in the total synthesis of natural products. Among these reactions, the catalytic asymmetric reactions have several advantages for natural product synthesis: compared to the chiral pool method, any starting materials may be selected because an achiral compound can be used. Catalytic asymmetric reactions can shorten a synthetic route relative to a route based on the use of chiral auxiliaries because asymmetric induction proceeds from the chirality of the catalysis reaction. Theoretically, a chiral compound may be obtained in quantitative chemical yield compared to the optical resolution. However, in some cases, catalytic asymmetric reactions put synthetic chemists into trouble if the asymmetric induction cannot occur efficiently due to the narrow and limited scope of the catalyst's substrates, due to reconsideration of the substrates or the synthetic route, or due to the inability to improve the enantioselec-tivity. In these cases, strict optimization of reaction conditions is then required to improve the enantiomeric excess. Synthetic chemists must choose an appropriate catalytic asymmetric reaction to achieve the effective total synthesis of a natural product by assessing these merits and drawbacks.

This review provides an overview of recent attractive and interesting reports of catalytic asymmetric total syntheses of alkaloids and terpenoids. Asymmetric dihydroxylation,13 asymmetric epoxi-dation,14 and asymmetric hydrogenation15 are frequently applied to enantioselective total synthesis of natural products not only because their experimental procedures are simple and versatile, but also because the chemical yield and optical purity resulting from these reactions are relatively highly reproducible. This discussion will focus on enantioselective total syntheses using several recently developed asymmetric catalytic reactions that are distinct from these famous reactions.

Total synthesis of aspidosperma alkaloids using asymmetric decarboxylative allylation

Terpenoid indole alkaloids make up a major fraction of the alkaloids present in plants, and more than 3000 such alkaloids have been recognized.16 Several synthetic studies of these alkaloids have been reported because most of them have complex and interesting chemical structures and show attractive biological activities.16 One such class of alkaloids, the aspidosperma alkaloids, includes a quaternary carbon in their ring-fused structure. A key to the successful achievement of an effective total synthesis of the aspidosperma alkaloids is to select an appropriate strategy for constructing the quaternary stereogenic center. Catalytic asymmetric decarboxyla-tive allylation is often applied in the total synthesis of natural products bearing a quaternary carbon17 because these reactions present a powerful tool for the effective and highly enantioselec-tive construction of quaternary stereogenic centers. Recently, Shao and co-workers reported the total syntheses of aspidosperma alkaloids using a key intermediate prepared by the asymmetric decarb-oxylative allylation of carbazolone derivatives.18a-c The decarboxylative allylation of carbazolone derivatives presents a significant challenge, unlike the corresponding reaction of the p-ketoester derivatives, because the nucleophilicity at the indole C(3) can affect the decarboxylative allylation. Shao and co-workers investigated a catalytic asymmetric decarboxylative allylation using carbazolone derivative 1 (Scheme 1, Eq. 1).18a While investi-

gating the optimized conditions through the use of a variety of chiral ligands, they found that treatment of 1 in the presence of Pd2(dba)3 and phosphinooxazoline ligand L1 in toluene gave desired compound 2a in 93% yield and in 92% ee with the concomitant formation of small amounts of 2a' as a side product of the deallyloxycarbonyl reaction. The optimal conditions provided car-bazole derivatives containing a variety of substituents at the quaternary stereogenic center a to the ketone in up to 97% ee. The total syntheses of (—)-aspidospermidine (3), (+)-kopsihainanine A (4), and (—)-limaspermidine (5), and the formal total synthesis of (—)-1-acetylaspidoalbidine (6) were accomplished from 2a (Scheme 1, Eqs. 2-4).18a,b The conversion of 2a into amide 7 under acidic conditions, followed by the chemoselective reduction at the keto carbonyl group and the intramolecular cyclization under acidic conditions, between the benzylic secondary alcohol and amide, gave 8 (Scheme 1, Eq. 2). Oxidative degradation at the vinyl group led to aldehyde 9 and its thioacetal formation followed by desulfurization in the presence of a Raney-Ni catalyst under hydrogen provided 10. The reduction of 10 with LiAlH4 and debenzyla-tion under Birch conditions gave the key intermediate 11, which was converted to (—)-aspidospermidine (3) in three steps, as reported by Heathcock and co-workers:19 (1) N-chloroacetylation, (2) formation of the y-lactam, and (3) reduction of amide. Synthesis of (+)-kopsihainanine A (4) was commenced from 8 (Scheme 1, Eq. 3). Hydroboration of 8 and oxidative treatment gave alcohol 12. O-mesylation of 12 followed by intramolecular N-alkylation under basic conditions led to 13. Amide 13 was converted into (+)-kopsihainanine A (4) through known methods, a stereoselective a-hydroxylation followed by N-debenzylation, as reported by Xie, She, and co-workers;20 however, it was not clear whether the synthetic 4 was identical to the natural compound because the synthetic 4 was not soluble in chloroform (although it was soluble in DMSO), whereas the natural 4 was soluble in chloroform. After several analyses and investigations, they speculated that the product of the debenzylation of 14 with aluminum chloride was the chelate compound A in complex with aluminum. The pure synthetic 4 was obtained through the addition of Rochelle salt in a workup of the debenzylation with aluminum chloride. The synthesis of (—)-limaspermidine (5) was begun from 9 (Scheme 1, Eq. 4).18c The reduction of aldehyde and amide moieties in 9, followed by the debenzylation and protection of the primary alcohol with a tert-butyldiphenylsilyl group, gave 15, which led to 5 using a sequence similar to those applied to obtain 3 from 11 in the (—)-aspidospermidine synthesis. The conversion of 5 into 6 was reported in two steps,21 so the formal synthesis of 6 was also achieved. Using catalytic asymmetric decarboxylative allylation, Shao and co-workers recently reported the total syntheses of (+)-10-oxocylindrocarpidine, (+)-cylindrocarpidine, (—)-N-acetylcylin-drocarpinol, and (+)-aspidospermine.18c

Zhu and co-workers reported the total syntheses of five terpenoid indole alkaloids:22 (—)-mersicarpine (18), (—)-scholarisine G (19), (+)-melodinine E (20), (—)-leuconoxine (21), and (—)-leucon-olam (22), from the key intermediate 17 (90% yield, 92% ee), which was prepared from p-ketoester 16 using a catalytic asymmetric decarboxylative allylation developed by Stoltz (Scheme 2).23 The key to these total syntheses was that the nucleophilic addition of the nitrogen (N(4)) residue occurred selectively via discrimination between the two carbonyl carbons (C(7) and C(21) positions) in 23, thereby controlling their electrophilicities. Ozonolysis of cyclo-hexenone 24, which was converted from 17 in four steps, including functionalization at the residual chain and a-arylation, gave a-diketone 23. Hydrogenolysis in the presence of Pd/C under a H2 atmosphere, followed by the sequential treatment with KOH in ethanol, with molecular oxygen, and with dimethyl sulfide in the same flask, gave (—)-mersicarpine (18) in 75% yield (Scheme 2, Eq. 1). In this one-pot reaction, it was assumed that the sequential

2a (92% ee)

a) HCO2H

rt, 93%

Conh2 b)LiAlH4

THF, -20 "C then HCl (2 M)

h)ClCH2COCl Et3N, CH2Cl2 0 "C, 69%

i) Nal, acetone, reflux

then AgOTf, THF, 72% j) LiAlH4, THF 0 "C~reflux 62%

d) HSCH2CH2SH BF3^OEt2, CH2Cl2, 94%

e) Raney-Ni, H2 EtOH, 60 "C 91%

c) K2OsO4^2H2O NMO

THF/H2O (1:1)

then NaIO4 95%

(Eq. 2)

liq. NH3/THF -78 "C, 95%

(-)-aspidospermidine (3)

k) BH3^THF, THF, -20 "C then NaBO3, rt

n) AlCl3 toluene 100 "C

l) MsCl, Et3N, CH2Cl2, 0 "C

then NaH, DMF, 0 "C~rt 50%

THF, 0 "C 58%

o) aq. Rochelle salt rt

(Eq. 3)

(+)-kopsihainanine A (4)

p) LiAlH4 Et2O, reflux 86%

q) Na/liq. NH3

THF, 93% r) TBDPSCl imidazole 98%

N ,, -


(-)-limaspermidine (5)

- ,.C(Eq. 4)

(-)-l-acetylaspidoalbidine (6)

Scheme 1. Catalytic asymmetric decarboxylative allylation of carbazolone (Eq. 1) and total syntheses of aspidosperma alkaloids (Eqs. 2-4).

reactions proceeded through the reduction of azide and nitro groups of 23, bond formation between N(1) and C(21) and between N(4) and C(7) to give 26, lactamization of 26 under basic conditions, oxidation of 27 with molecular oxygen, and reduction of peroxide 28 by dimethyl sulfide. Next, the syntheses of (—)-scholarisine G (19), (+)-melodinine E (20), (—)-leuconoxine (21), and (—)-leuconolam (22) commenced from 23 (Scheme 2, Eq. 2). Hydrogenolysis of 23 in the presence of acetic anhydride gave N-acetylated 29. Under these conditions, intramolecular cyclization between N(4) and C(7) was prevented because the nucleophilicity of nitrogen was decreased by N-acetylation. Direct oxidation of 29 without isolation gave unstable indol-3-one 30, which was treated with KOH in ethanol to afford a 2/1 diastereomeric mixture of 31. Cyclization of 31 with trifluoroacetic acid (TFA) in dichlorometh-

ane proceeded via the N-acyliminium intermediate 32 to give 33. Finally, an intramolecular aldol reaction with tert-BuOK gave (—)-scholarisine G (19). From 19, the syntheses of (+)-melodinine E (20), (—)-leuconoxine (21), and (—)-leuconolam (22) were achieved through a two-step dehydration reaction from 19, reduction of the olefin in the cyclopentenone moiety of 20, and a ring-opening reaction of aminal 21 under acidic conditions, respectively.

Total synthesis of alkaloids using organocatalytic cascade reactions

Asymmetric organocatalytic reactions113-® are frequently employed in the total synthesis of natural products along with metal catalysts consisting of chiral ligands and a transition metal.

II || Pd2(dba)3 (2.5 mol%) ,, tt

L1 (6.25 mol%) > ^H'-'N 1b THF, 25 "C, 12 hr L J II

THF, 25 "C, 12 hr 90%, 92% ee

4 steps 39%

O3, NaHCO3, -78 "C CH2Cl2/MeOH (5 : 1)

then Ac2O, Et3N 0 "C~rt, 92%

Pd/C, H2

EtOH, rt, 3 hr

1 nh2 o

225 f^N


2 hr -*


(-)-mersicarpine (18)

Pd/C, H2

Ac2O, EtOH

rt, 3 hr


rt, 18 hr

50% overall yield

dr = 2 : 1

^ ,N MsCl, Et3N > DBU, 75 "C ClCH2CH2Cl 16 hr, 75% 75 "C

(Eq. 2)

(+)-melodinine E (20)

(-)-leuconoxine (21)

(-)-leuconolam (22)

Scheme 2. Asymmetric syntheses of (-)-mersicarpine (18) (Eq. 1), (-)-scholarisine G (19), (+)-melodinine E (20), (-)-leuconoxine (21), and (-)-leuconolam (22) (Eq. 2) using asymmetric decarboxylative allylation.

Few organocatalytic asymmetric reactions have been developed over the past 30 years, when the first asymmetric Robinson annulation reaction catalyzed by proline was reported;24 however, the development of asymmetric organocatalytic reactions has attracted significant attention, including the asymmetric aldol reaction reported by List and co-workers in 200025 and the various asymmetric reactions that employ unique and effective organocat-alysts. MacMillan and co-workers achieved the total syntheses of (+)-aspidospermidine ((+)-3), (+)-vincadifformine (35), (—)-kopsi-nine (36), (—)-kopsanone (37), (—)-strychnine (38), and (—)-akuammicine (39)26 using the imidazolidinone catalyst 34, originally developed by MacMillan's group. These terpenoid indole alkaloids are divided into aspidosperma types, including 3 and 35-37, and corynanthe types, including 38 and 39.16 The alkaloids are categorized according to the rearrangement pattern in the secologanin moiety derived from terpene. While planning a synthesis of a natural product and its various congeners, a divergent synthesis from a key intermediate bearing the main scaffold of the natural product would be general and effective. Shao and Zhu have synthesized several congeners from key intermediates. This methodology is frequently applied to the synthesis of related congeners but is rarely used for the synthesis of different families, for example, the synthesis of aspidosperma-type and corynanthe-type compounds from the same key intermediate. Focusing on these points, MacMillan and co-workers synthesized aspidosperma-type

and corynanthe-type alkaloids from similar key intermediates 40a and 40b, appropriately functionalized (Scheme 3, Eq. 1). Carbazole derivative 40a was prepared in 82% yield and in 97% ee from 42a (R = PMB), which was derived from 41 in three steps, by treatment with propynal (43) in the presence of catalytic amounts of the trib-romoacetic acid salt of 34 (34TBA). The main process of this reaction was thought to proceed through a cascade reaction consisting of asymmetric intermolecular Diels-Alder reactions and a sequential intramolecular conjugate addition reaction catalyzed by 34 (Scheme 3, Eq. 2). Namely, iminium 44, which was generated from the condensation of 34 and 43, underwent an endo-selective intermolecular Diels-Alder reaction with 42a to give 45, p-elimination of methyl selenide from 45 then gave 46. An intramolecular conjugate addition reaction of 46 via several processes afforded the pyr-rolidine-ring-forming 47. Finally, recycle of 34 proceeded through the hydrolysis of 47 with the concomitant release of 40a.

The total synthesis of (-)-strychnine (38) from 40a is shown in Scheme 3, Eq. 3 as a representative synthesis of congeners. After decarbonylation of 40a in the presence of the Wilkinson catalyst, the methoxycarbonyl group was installed at the a position of dien-amine by treating with phosgene and methanol. The stereoselective reduction of enamine, obtained through methoxycarbonylation, with diisobutylaluminum hydride (DIBAL-H) gave an olefinic regio-isomeric mixture of 48 in 61% yield in three steps. N-allylation of 48 with 49 using DBU followed by the simultaneous reduction of ester

a) NaH, PMBCI or BnBr DMF, 0 "C

N b) Se02

Boc dioxane, H20 100 'C


(20 mol%)

SeMe -40 *C~rt

tnli iona

CHO PMB 43 40a, 82%, 97% ee

(Eq. 1)

c) (Et0)2P(0)CH2SeMe 42a (63%): R = PMB IB-crown-6. KHMDS. 42b (61%): R = Bn f^34-TBA THF,-78'C~rt r 7=\ | (20 mol%)

40b, 83%, 97% ee

(1-Nap = 1-naphthyl) 44 „

34 + 43 -


/ \ .1-Nap ^N^ PMB [4+2]

MeSe^!^. A

1,4-addition f

PMB 46


40a + 34 (Eq. 2)

d) (Ph3P)3RhCI toluene, PhCN,

120 'C_^

e) COCI2, Et3N toluene, -45 'C~rt then MeOH

f) DIBAL-H, CH2CI2, -78 "C~rt

then TFA, -78 'C~rt 61%

g) DBU, K2CO3, DMF, 49, rt

h) DIBAL-H, CH2CI2,1

T'T ~78°c

¿MB 00^76%. 48

i) Pd(OAc)2 OH (25 mol%)


HO o Wieland-Gumlich aldehyde (57)

12 steps, 6.4% overall yield

(+)-aspidospermine (3) 9 steps, 24% overall yield

(+)-vincadifformine (35) 11 steps, 8.9% overall yield

(-)-kopsinine (36) 9 steps, 14% overall yield

(-)-kopsanone (37) 11 steps, 10% overall yield

(-)-akuammicine (39) 10 steps, 10% overall yield

Scheme 3. Organocatalytic cascade reactions (Eqs. 1 and 2) and the shortest synthesis of (—)-strychnine (38) using the key intermediate 40a (Eq. 3).

and deprotection of the acetyl group with DIBAL-H gave allylic alco- Heck cyclization/lactol formation reaction of 50 gave 56, which hol 50 as a sole product. Isomerization of the olefin occurred at the was converted into Wieland-Gumlich aldehyde (57) by deprotec-allylation step due to the basic conditions. The contiguous Jeffery- tion of the PMB group. Conversion of 50 into 56 occurred in the

following reaction sequence: (1) insertion of Pd(0) into vinyl iodide 50 gave 51, which underwent carbopalladation to give alkylpalladi-um intermediate 52, which formed a six-membered ring; (2) after conversion into enol 53 through p-elimination from 52, the hydro-xyl group proximal to enol moiety formed a lactol. The total synthesis of (—)-strychnine (38) was accomplished by the treatment of 57 with malonic acid, acetic anhydride, acetic acid, and sodium acetate. The authors mentioned that this total synthesis had been achieved in 6.4% yield in 12 steps, and this approach offered the shortest synthetic route among those reported previously. The other 5 alkaloids were also synthesized in 8.9-24% yields in 9-11 steps using the key intermediates 40a or 40b.

Synthesis of terpenoids using enantioselective polyene cyclization

Terpenoids are derived from monoterpene, which is a dimer of isoprene (C5) units bonded in a head-to-tail fashion. Divergent structural motifs may be present in this class of compounds.16 The chiral polycyclic terpenoids consisting of 6-membered rings are thought to be biosynthetically produced from farnesyl diphos-phate (C15), geranyl geranyl diphosphate (C20), geranyl farnesyl diphosphate (C25), or squalene (C30) via a cationic intermediate generated enzymatically through asymmetric protonation via a contiguous polyene cyclization.16,27 Although many synthetic methods for preparing polycyclic compounds based on the proposed biosynthesis have been developed,28 relatively few reports have applied this method to natural product synthesis.29 The Carreira29c and Corey29d groups recently reported a natural product synthesis that employed an enantioselective polyene cyclization.

Carreira and co-workers developed a variety of enantioselective transformations in the presence of catalytic amounts of a chiral iridium complex.30 These reactions include the enantioselective polyene cyclization of the inactivated allylic alcohol in the presence of an iridium complex (Scheme 4, Eq. 1).30c The catalytic enantioselective polyene cyclization of 58 with a chiral iridium complex formed from the chiral ligand L2 proceeds by addition of Zn(OTf)2, which acts as an activator of the allylic alcohol to give the cyclized compound 59 in 90% yield and in more than 99.5% ee. This reaction is expected to proceed through the formation of ally-liridium intermediate 60 derived from allylic alcohol 58 activated by Zn(OTf)2 and the iridium catalyst. Highly electrophilic arenes may be introduced at the ends of a polyene to effectively terminate this cationic cascade reaction. An investigation of the arenyl sub-stituents revealed that 3,4-dimethoxyphenyl, 3-methoxyphenyl, N-protected pyrrole and indole, and benzofuran groups were tolerated in this cyclization. Carreira and co-workers applied this method to the total synthesis of asperolide C (61) (Scheme 4, Eq. 2).29c The triene 62a (R1 = H) was proposed as a precursor for an asymmetric polyene cyclization because 61 does not include an arenyl substituent in its structure; however, because triene 62a is expected to provide a lower electrophilicity compared with the substrate bearing an arenyl substituent, the polyene cyclization may not proceed effectively. These considerations led the selection of the allylsilane 62b (R1 = TMS) as a precursor, because the poly-ene cyclization was expected to proceed effectively due to the p-effects of the silane31 and because functionalization after cyclization was expected to proceed easily. Vinyl ketone 65 derived from y-butyrolactone in three steps was treated with lithium hexameth-yldisilazide (LiHMDS) and TBSCl to give silyl enol ether 66, which was converted into enol triflate 67 through the use of CsF and PhNTf2 (Scheme 4, Eq. 3). The direct conversion of 65 into 67 was problematic; therefore, the two-step conversion described above was employed. The coupling reaction between 68 and 67, catalyzed by [Pd(dppf)Cl2] CH2Cl2 and Ph3As, gave the allylsilane 69, which led to the precursor 71 for the asymmetric polyene

cyclization via regioselective hydroboration of 69, followed by Suzuki coupling with 70 and the sequential desilylation. The key enantioselective polyene cyclization reaction was performed through the use of 71. That is, the treatment of 71 in the presence of 3.2 mol % [{Ir(cod)Cl2}], 12.8 mol% chiral ligand (R)-L2, and 16 mol% Zn(OTf)2 gave a 9/1 diastereomeric mixture of 72 in 73% yield and a 98/2 enantiomeric mixture of the major product of 72. After conversion into epoxy ester 73 from 72 in four steps, y-lactone 74 was obtained through the treatment of 73 with trifluo-roacetic acid. The protection of the hydroxyl group of 74, followed by Lemieux-Johnson oxidation, gave the aldehyde 75, which was subjected to an alkylation reaction via an aldehyde enolate intermediate to construct a quaternary carbon center. This a-alkylation reaction of aldehyde was problematic due to the presence of the acidic proton (pKa ~ 20) at the y-lactone moiety. To achieve the direct a-alkylation of the aldehyde (the pKa value of a-proton of the aldehyde is ~17), the chemoselective deprotonation was investigated using t-BuOK (the pKa value of t-BuOH, which is the conjugate acid of t-BuOK is ~18).32 The generation of the aldehyde enolate in the presence of t-BuOK at low temperatures, followed by treatment with methyl iodide and the gradual elevation of the temperature, gave 76 in a 36% yield. Finally, the synthesis of asperolide C (61) was achieved by the Pinnick oxidation of 76 and the sequential desilylation.

Yamamoto and co-workers reported that a complex 77 SnCl4 prepared from BINOL mono-ether 77 and Lewis acidic SnCl4 catalyzed the enantioselective polyene cyclization to give 79 in 88% ee (Scheme 5).29b This complex was thought to work as a Brensted acid. The acidic phenolic proton (the circled proton in the structure), the acidity of which increased due to chelation to SnCl4, initiated the polyene cyclization reaction through the regio- and enantioselective protonation at the terminal olefin of 78. This reaction proceeded even in the presence of catalytic amounts (0.2 equiv) of 77 SnCl4, although a decrease in the enantioselectiv-ity was observed.

The enantioselectivity of the asymmetric polyene cyclization reaction was improved by Corey and co-workers through the development of a complex 80SbCl5 prepared from the o,o'-dichlo-roBIONL 80 and SbCl5, which provided a stronger Lewis acid compared to the SnCl4 complex described by Yamamoto (Scheme 6).33 The results of an investigation of the optimal conditions revealed that the cyclizations of 81a-81c proceeded through the addition of 50 mol% 80SbCl5 to give the bicyclic compounds 82a-82c in up to 91% ee, respectively (Scheme 6, Eq. 1). Bicyclic compound 82c was afforded as a mixture of the regioisomers because the cyclization proceeded at the ortho- or para-positions in bromoben-zene. Next, tricyclization reactions were tried. The cyclization of 83a and 83b with 1 equiv of 80SbCl5 gave the tricyclic compounds 84a and 84b, respectively, in high enantioselectivities (Scheme 6, Eq. 2). The use of 80SbCl5 in the asymmetric polyene cyclization reaction improved the enantioselectivity and shortened the reaction time relative to the reaction time of 77 SnCl4. Corey's group applied these conditions to the total synthesis of a polycyclic terpe-noid (Scheme 6, Eq. 3).29d The treatment of polyene 85 bearing five olefins with an equivalent amount of 80SbCl5 gave bicyclic compound 86 as a mixture of three olefinic regioisomers in 75% yield and in 82% ee. This reaction proceeded through the regioselective protonation at the disubstituted olefin due to steric repulsion. Aldehyde 87 was prepared from 86 in four steps: regioselective hydrogenation at the disubstituted olefin via the P-2 nickel boride catalyst under a hydrogen atmosphere, desilylation, Swern oxidation, and isomerization of the olefin. Homologation of 87 via the Wittig reaction gave 88, which yielded (+)-dysideapalaunic acid (90) via hydroboration, followed by a Suzuki coupling reaction with 89 and the hydrolysis of the methyl ester. Although the poly-ene cyclization reactions catalyzed by 80 SbCl5 are attractive,

MeO. Me

OMe MeOv

4 mol% [{Ir(cod)Cl}2], Me|' I

16 mol% (R)-L2 /-xMe^

20 mol% Zn(OTf)2 (CH2Cl)2, 24 hr, 25 "C

MeO ¿0

Wyie MeO

(Eq. 1)

90%, >99.5% ee

Ir-catalyzed R1 polyene cyclization

62a: R1 = H 62b: R1 = TMS


(Eq. 2)

asperolide C (61)

^ormb TiHsMCDS


(HO)2^'6a tms

-78 "C

dr > 95 : 5, 95%

PhNTf2, CsF (CH3OCH2)2 rt, dr > 95 : 5,

^^ v -:2- 60 ----

r OpMB [Pd(dppf)Cl2]^CH2Cl2 f OPMB

Ph3As, Cs2CO3

THF/DMF/H2O dr = 10 : 1, 62%

a) 9-BBN, THF then 70,

[Pd(dppf)Cl2]^CH2Cl2 NaOH, THF/H2O

b) PPTS, MeOH, 81%" (2 iterations)

i— 66: L.-67:

66: R = TBS : R = Tf

OPMB 3.2 mol% [{Ir(cod)Cl}2] 12.8 mol% (R)-L2 TMS 16 mol% Zn(OTf)2

dichloroethane, rt dr = 9 : 1, er = 98 : 2 73%

f^OPMB Mel

: H 72

c) DDQ

pH7 buffer/CH2Cl2, 98%

d) DMP, CH2Cl2, 80%

e) NaClO2, NaH2PO4 2-methyl-2-butene t-BuOH/H2O; then TMSCHN2 MeOH, 79%

f) DMDO, acetone, 45% (66% brsm)

CF3CO2H CH2Cl2, 70%

= H 74

i) NaClO2, NaH2PO4 2-methyl-2-butene t-BuOH/H2O, 76%

i) TBAF, THF, 74%

. g)TBSCl, imidazole J DMAP, CH2Cl2, 81% | h) OsO4, NaIO4 OH 2,6-lutidine

1,4-dioxane/H2O, 81% CHO

61 (Eq. 3)


-20"C~ 0 "C OTBS 36%

Scheme 4. Enantioselective polyene cyclization (Eq. 1), strategy for the synthesis of asperolide C (61) (Eq. 2), and the total synthesis of asperolide C (61) using the enantioselective polyene cyclization induced by the allyliridium complex (Eq. 3).

SnCI4 (1 eq.) toluene, -78 'C, 2 day; CF3C02H, SnCI* /-PrN02 1 day

69%, 88% ee

77-Sncii 0Me

Scheme 5. Enantioselective cyclization of 78 using complex (S)-77 SnCl4 (Yamamoto's work).

Scheme 6. Enantioselective bicyclization (Eq. 1) and tricyclization (Eq. 2) using the complex 80 SbCl5, and the total synthesis of (+)-dysideapalaunic acid (90) by the cationic double annulation reaction (Eq. 3).

decrease of loading amount of 80 SbCl5 is left as an important challenge.

Asymmetric synthesis of natural products through the catalytic [2+2]-photocycloaddition

Photoreactions have been employed recently in natural product synthesis.34 In these reactions, the [2+2]-photocycloaddition (PCA) reaction between enones and olefins gives cyclobutanones, which are useful as synthetic intermediates due to their versatility with respect to chemical transformations.35 After the [2+2]-PCA was initiated by the direct or photosensitizer-mediated excitation of enone from the ground state to the lowest excited triplet state, the excited enone underwent cycloaddition with olefin to give cyclobutanone via a 1,4-diradical intermediate. Bach and co-workers developed a catalytic asymmetric [2+2]-PAC of 5,6-dihydro-4-pyridones employing a chiral Lewis acid (Scheme 7, Eq. 1). The application of this reaction to alkaloid syntheses has been reported.36 The UV spectrum of the 5,6-dihydro-4-pyridone 91a in dichloromethane at a concentration of 0.5 mM showed a strong absorption at kmax = 291 nm (molar absorption coefficient e = 17,400) and a weak absorption at kmax = 360nm (e =70). On the other hand, whereas the UV spectrum of 91a in the presence of a Lewis acid, such as ethylaluminum dichloride or boron trichlo-

ride, displayed a red shift in the strong absorption at kmax = 343 nm (e = 21,400) or at kmax = 348 nm (e = 24,200), respectively, a weak absorption was undetectable. These results indicate the possibility of asymmetric synthesis in the presence of a chiral Lewis acid via the selective excitation of complexes between 91a and a Lewis acid. In other words, the irradiation of the [2+2]-PCAs at 419 nm or 366 nm in the presence of the catalyst 92 was investigated. Although irradiation of the [2+2]-PCA at 419 nm did not induce the reaction, the reaction proceeded cleanly at -70 °C upon irradiation at 366 nm under the optimal conditions to give 93a in 84% yield and in 88% ee as the sole product. The concentration of the substrate and the purity of the solvent considerably affected the progress of the [2+2]-PCA reaction. The optimal concentration was determined to be 20 mM, and the solvent should be dehydrated and degassed. A decrease in the amount of the Lewis acid reduced the enantioselectivity. The scope and limitations of this reaction were investigated using a variety of substrates. Some results are shown in Scheme 7, Eq. 2. The 6-6 fused cyclic compound 93b and the 6-7 fused cyclic compound 93c containing a quaternary stereogenic center were obtained in 81% yield and 88% ee and in 83% yield and 81% ee, respectively, under the optimal conditions. This reaction was attractive because the chiral compound with a quaternary carbon center, such as 93b and 93c could provide a high yield and a high enantioselectivity. The chlorinated

91b-d R3

hv (X = 366 nm) 92

-75 "C, CH2CI2 n = 1, 2

(Eq. 2)

O-^ —/ O'

93b: R1= R2=H, R3=Me, n=1 93c: R1 = R2=H, R3=Me, n=2 93d: R1=CI, R2=R3=H, n=1 81%, 88% ee 83%, 81 % ee 83%, 82% ee

a) PMBOH i-PrjNEt, rt

b) separation of enantiomers by chiral HPLC O 59% 96

(>95% ee)


MeOH, 99%

H T"H d) NaH,

then CS2 then Mel DMF, 87%


benzene 75 "C 69%

,„H f) LiAIH4

"N' S^OPMB THF, 76% g) H2, Pd/C

MeOH/AcOH 83% (+)-lupinine (94)

(+)-thermopsine (95)

Scheme 7. Chiral Lewis acid-catalyzed [2+2]-photocycloaddition (PCA) reaction (Eq. 1), its applications (Eq. 2), total synthesis of (+)-lupinine (94) (Eq. 3), and formal synthesis of (+)-thermopsine (95) (Eq. 4).

compound 91d (R1 = Cl) was also converted cleanly into 93d in 83% yield and in 82% ee under the optimal conditions. Next, the synthesis of (+)-lupinine (94) and the formal synthesis of (+)-thermopsine from 93d were investigated (Scheme 7, Eqs. 3 and 4). The conversion of 93d into 96 through treatment with p-methoxybenzyl alcohol and diisopropylethylamine gave 96, with an ee of up to 95% upon separation using chiral HPLC. Diastereoselective reduction of the ketone moiety in 96 gave secondary alcohol, which led to xanthate 97 through the sequential treatment of NaH, CS2, and MeI. A ring-opening reaction of 97 was performed by treating with tributyltin hydride in the presence of AIBN to afford 98 in 69% yield. The release of the cyclic strain in cyclobutane drove this ring-opening reaction. The synthesis of (+)-lupinine (94) was accomplished from 98 through the reduction of the amide car-bonyl, followed by deprotection of the PMB group and reduction

of olefin under hydrogenolysis. Synthesis of (+)-thermopsine (95) was also commenced from 93d. Treatment of 93d with 2-pyridone under basic conditions in DMF gave 99, which was delivered into quinolizidine 100 through the use of a sequence similar to those applied to obtain 98 from 96. Finally, the formal synthesis of (+)-thermopsine (95) was achieved through the hydrogenolysis of 100 with Raney-Ni under a H2 atmosphere to give 101, which is an intermediate in the total synthesis of (±)-thermopsin, as reported by Gallagher.37


The recently reported catalytic asymmetric total syntheses of alkaloids and terpenoids were overviewed here. These attractive syntheses were achieved by employing the strategies developed

originally by each respective author based on catalytic asymmetric reactions. In addition to the total syntheses introduced in this review, enormous studies of catalytic asymmetric reactions have been reported. This area of research has become popular in the field of total synthesis. Certain reactions require some or a significant level of improvement; for example, the catalyst loading, enantioselectivity, and other features of the reaction should be significantly improved. With the development of new catalytic asymmetric reactions, we look forward to the future development of numerous new attractive and interesting asymmetric total syntheses based on novel strategies using chiral catalysts.

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