Recent Progress in the Chemistry of Daphniphyllum Alkaloids

Feb 16, 2017 - Department of Chemistry, Université de Montréal, Post Office Box 6128, Station Centre Ville, Montreal, Quebec H3C 3J7, Canada. ABSTRA...
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Recent Progress in the Chemistry of Daphniphyllum Alkaloids† Amit Kumar Chattopadhyay and Stephen Hanessian* Department of Chemistry, Université de Montréal, Post Office Box 6128, Station Centre Ville, Montreal, Quebec H3C 3J7, Canada ABSTRACT: Daphniphyllum is an evergreen species known since 1826. After initial systematic investigations, more than 320 members of this family have been isolated, which comprise complex and fascinating structures. Unique azapolycyclic architectures containing one or more quaternary stereocenters render these alkaloids synthetically challenging. This review covers efforts toward the synthesis of Daphniphyllum alkaloids spanning the period from 2005 to the beginning of 2016, including reported biological activities as well as the isolation of new members of this genus.

CONTENTS 1. Introduction 2. Isolation of New Daphniphyllum Alkaloids (End of 2012 to 2015) Himalenines A−E and Hydroxylated Calyciphylline A-type Alkaloids Logeracemin A Daphnicyclidins M and N Calyciphyllines Q, R, and S Longphyllinesides A and B Hybridaphniphyllines A and B Macrodumines A, B, and C Daphmacromines K, L, M, N, and O Daphmacrodins A and B Longeracemine Demethyl Calyciphylline A 2-Hydroxyyunnandaphnine D and Methyl-7hydroxyhomodaphniphyllate 3. Biological Activities 4. General Synthetic Strategies Based on a Biomimetic Approach 5. Initial Efforts toward the Synthesis of Daphniphyllum Alkaloids 5.1. Synthesis of the ACDE Ring System of Secodaphniphylline 5.2. Total Syntheses of Daphniphyllum Alkaloids 5.2.1. Total Synthesis of (±)-Methyl Homodaphniphyllate 5.2.2. Total Synthesis of (+)-Codaphniphylline 6. Recent Progress in the Synthesis of Daphniphyllum Alkaloids (2005 to Beginning of 2016) 6.1. Syntheses of Yuzurimine-type Alkaloids 6.1.1. Asymmetric Synthesis of the ABDG Ring System of Daphcalycine 6.1.2. Synthesis of Yuzurimine Core Structure © XXXX American Chemical Society

6.1.3. Synthesis of the BCDE Ring System of Yunnandaphnine C and Yuzurimine 6.2. Syntheses of Daphnilactone B-type Alkaloids 6.2.1. Synthesis of the ABC Ring System of Daphnilactone B 6.2.2. Asymmetric Synthesis of the ABC Ring System of Daphnilactone B 6.2.3. Synthesis of the ABC Ring System of Daphnilactone B 6.3. Synthesis of Daphnicyclidin A-type Alkaloids 6.3.1. Asymmetric Synthesis of the BCD Ring System of Daphnicyclidin A 6.3.2. Asymmetric Synthesis of the ABC Ring System of Daphnicyclidin A 6.4. Synthesis of Daphmanidin A-type Alkaloids 6.4.1. Asymmetric Total Synthesis of (+)-Daphmanidin E 6.4.2. Asymmetric Total Synthesis of (−)-Calyciphylline N 6.5. Synthesis of Calyciphylline A-type Alkaloids 6.5.1. Synthesis of the ABC Ring System of Calyciphylline A 6.5.2. Synthesis of the ACD Ring System of Daphniyunnine B 6.5.3. Synthesis of the DEF Ring System of Daphniyunnine D 6.5.4. Asymmetric Synthesis of the ABCD Ring System of Daphnilongeranin B 6.5.5. Asymmetric Synthesis of the ADE Ring System of Longeracinphyllin B

C C C C C D D D D E E E F F F G G G H H I J K K L

L M M N O O O Q R R S U V W W W X

Received: July 28, 2016

A

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Figure 1. Daphniphyllum alkaloid skeletal structures.

6.5.6. Asymmetric Synthesis of the ABC Ring System of ent-Daphniyunnine C 6.5.7. Asymmetric Synthesis of the ABCD Ring System of Daphnilongeranin B 6.5.8. Asymmetric Synthesis of the ABC Ring System of ent-Calyciphylline A 6.5.9. Synthesis of the ACD Ring System of Calyciphylline A-type Alkaloids

6.5.10. Synthesis of the ACD Ring System of Calyciphylline A-type Alkaloids 6.6. Synthesis of Calyciphylline B-type Alkaloids 6.6.1. Asymmetric Synthesis of the ABCE Ring System of Calyciphylline B-type Alkaloids 6.6.2. Asymmetric Synthesis of Isodaphlongamine H (6-epi-Deoxycalyciphylline B)

Y Y Z AA

B

AA AA

AC AC

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Chemical Reviews 6.7. Synthesis of Daphniglaucin A- and C-type Alkaloids 6.7.1. Synthesis of the BCG Ring System of Daphniglaucin A 6.7.2. Synthesis of the AD Ring System of Daphniglaucin C 6.7.3. Asymmetric Synthesis of the ABCD Ring System of Daphniglaucin C 6.8. Synthesis of Daphnipaxinin-type Alkaloids 6.8.1. Asymmetric Synthesis of the ABCD Ring System of Daphnipaxinin 6.9. Synthesis of Daphenylline-type Alkaloids 6.9.1. Synthesis of the ABCE Ring System of Daphenylline 6.9.2. Second Synthesis of the ABCE Ring System of Daphenylline 6.9.3. Asymmetric Total Synthesis of Daphenylline 6.9.4. Asymmetric Synthesis of the ACDE Ring System of Daphenylline 7. Conclusion Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Dedication Abbreviations References

Review

By 2013 a number of seminal review articles had been published focusing on the isolation of Daphniphyllum alkaloids and providing some insights into possible biosynthetic pathways, principally by Yamamura,40,41 Kobayashi,42,43 Guo,44 Kiyota,45 and Xu.46 Only two reviews are available regarding progress in the total and partial (core) syntheses of Daphniphyllum alkaloids. In 1992, Heathcock reviewed the field in reference to his seminal contributions.47 A review from Dixon in 2014 focused mostly on strategies toward the synthesis of calyciphylline A-type alkaloids.48 In this review, we discuss total and partial syntheses of Daphniphyllum alkaloids spanning the period 2005 to beginning of 2016, including the most recent isolation of new members and their biological activities.

AE AE AF AF AG AG AH AI AJ

2. ISOLATION OF NEW DAPHNIPHYLLUM ALKALOIDS (END OF 2012 TO 2015)

AJ

Himalenines A−E and Hydroxylated Calyciphylline A-type Alkaloids

AJ AK AK AK AK AK AL AL AL AL AL

In 2015, Yue and co-workers49 isolated 13 new hydroxylated calyciphylline A-type alkaloids, including himalenines A−E (1− 5), 3β-hydroxydaphniyunnine A (6), 12α-hydroxydaphniyunnine A (7), 12β-hydroxydaphniyunnine A (8), 11α-hydroxydaphniyunnine A (9), 11β-hydroxydaphniyunnine A (10), 17β-hydroxydaphniyunnine A (11), 4β-hydroxylongistylumphylline A (12), and 17-epi-daphlongamine F (13), from the twigs and leaves of the Nepalese Daphniphyllum himalense (Figure 2). All of these products were isolated as white amorphous powders, and their structures were established on the basis of NMR and mass spectroscopic data analysis. Most interestingly, according to the initial report, the C-2 position possesses an α-H atom, which is uncommon in the calyciphylline A family.49 A recent additional correction reported that the C-2 position actually possesses a β-H atom.50 Oxidation at the C-3, C-9, C-11, and C-12 positions was reported for the first time for this family of alkaloids. These alkaloids exhibit inhibitory activity at a concentration of 20 μg/mL against three kinase enzymes, PTP 1B, aurora A, and IKK-β.

1. INTRODUCTION The genus Daphniphyllum, which is the sole member of the family Daphniphyllaceae, is of wide occurrence in the plant kingdom and is among the oldest known, first established by Blume in 1826.1 The genus is geographically distributed principally in the eastern and southeastern parts of Asia and the Indian subcontinent. Currently, this genus contains over 34 species of dioecious evergreen shrubs and trees.2 The isolation of an alkaloid named daphnimacrin from Daphniphyllum macropodum Miquel in 1909 by Yagi3 is a landmark event that launched the rich history of D. macropodum alkaloids. The structure of daphnimacrin remains unknown to this day. A systematic investigation by Hirata and co-workers in 19664,5 led to the isolation of daphniphylline and yuzurimine among other related alkaloids. Their structures were determined by X-ray diffraction studies, thereby providing valuable insights into their azapolycyclic cagelike architectures. Since then, over 320 other members of the Daphniphyllum family of alkaloids have been isolated, and their structures have been assigned by NMR spectroscopic and (or) X-ray crystallography methods. Nature’s ingenuity in creating carbon skeletal diversity in this class of alkaloids is manifested in their unique azapolycyclic architectures, often containing one or more stereogenic quaternary carbon atoms at ring junctions and a single tertiary nitrogen atom at another ring junction. In order to appreciate this skeletal diversity, we list the carbon frameworks of all known alkaloids in this class devoid of their substituents, in chronological order of isolation (Figure 1).4−39 It is remarkable that such structural variety is generated essentially from the same biogenetic pathway.

Logeracemin A

In 2014, Yue and co-workers51 isolated logeracemin A (14), having a unique dimeric skeleton with a conjugated trispiro[4,5]decane backbone, from Daphniphyllum longeracemosum (Figure 3). Its structure, stereochemistry, and absolute configuration were established by X-ray crystallography and spectroscopic analysis. Logeracemin A exhibits significant antiHIV activity with an EC50 value of 4.5 ± 0.1 μM. From a structural viewpoint, it belongs to the calyciphylline A-type alkaloids. According to Yue and co-workers, logeracemin A could be derived biosynthetically from daphniyunnines B and D (Scheme 1). Daphnicyclidins M and N

Tang and co-workers52 isolated daphnicyclidins M and N (15 and 16) from the stem bark of D. macropodum (Figure 3). Their structures and relative configurations were established on the basis of spectroscopic methods. Daphnicyclidins M and N exhibit cytotoxicity against P-388 cells with IC50 values of 5.7 and 6.5 μM. These two alkaloids also exhibit IC50 values of 22.4 and 25.5 μM against SGC-7901 cell lines. Structurally, they belong to the daphnicyclidin-type alkaloids. C

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Figure 3. Newly isolated Daphniphyllum alkaloids.

Figure 2. Newly isolated Daphniphyllum alkaloids.

Hybridaphniphyllines A and B

Tang and co-workers52 isolated calyciphyllines Q, R, and S (17−19) along with daphnicyclidins M and N from the stem bark of D. macropodum (Figure 3). Their structures and relative configurations were established on the basis of spectroscopic methods. So far, no biological activities have been reported for these alkaloids. Structurally, they belong to the calyciphylline Atype alkaloids (Figure 1).

In 2013, Liu and co-workers54 isolated hybridaphniphyllines A and B (22 and 23) from the stems and leaves of D. longeracemosum (Figure 3). Both alkaloids possess a unique decacyclic fused skeleton. Their structures and stereochemistry were determined on the basis of spectroscopic analysis. From a structural viewpoint, they belong to the calyciphylline A-type alkaloids (Figure 1). Biosynthetically, hybridaphniphyllines A and B could be derived from daphnilongeranin C. A plausible biosynthetic path of these alkaloids was proposed by Liu and co-workers (Scheme 2).

Longphyllinesides A and B

Macrodumines A, B, and C

Longphyllinesides A and B (20 and 21) were isolated by Hao and co-workers53 from leaves of D. longeracemosum (Figure 3). Their structures and tentative stereochemistry were assigned by spectroscopic analysis. It was proposed that longphyllinesides A and B could be biosynthetically derived via a Diels−Alder cycloaddition pathway.

In 2013, Yue and co-workers55 isolated three yuzurine-type alkaloids, macrodumines A−C (24−26), from the leaves and twigs of D. macropodum (Figure 3). Their structures and tentative stereochemistry were established on the basis of spectroscopic analysis. So far, no biological activities have been reported for these alkaloids.

Calyciphyllines Q, R, and S

D

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Daphmacromines K, L, M, N, and O

Scheme 1. Plausible Biosynthetic Pathway for Logeracemin Aa

a

In the same year, Hao and co-workers56 reported the isolation of five yuzurimine-type Daphniphyllum alkaloids, daphmacromines K, L, M, N, and O (33−37), from the leaves and stems of D. macropodum (Figure 4). Their structures and stereo-

According to Yue and co-workers.51.

Scheme 2. Plausible Biosynthetic Pathway for Hybridaphniphyllines A and Ba

Figure 4. Newly isolated Daphniphyllum alkaloids.

chemistry were determined on the basis of NMR and mass spectrometric analysis. Daphmacromine O exerts moderate cytotoxicity against the brine shrimp Artemia salina. Daphmacrodins A and B

Daphmacrodins A and B (38 and 39) were isolated from the leaves and stems of D. macropodum (Figure 4).57 Their structures were established on the basis on spectroscopic analysis and the relative configuration of daphmacrodins A was further confirmed by X-ray crystallography. Daphmacrodins A and B possess a daphnicyclidin-type skeleton (Figure 1). Longeracemine a

In 2013, Di, Hao, and co-workers39 isolated longeracemine (40), having a unique skeleton, from the fruits of D. longeracemosum (Figure 4). The alkaloid possesses a novel C7/C-9 bonding. The structure and relative configuration were established on the basis of spectral analysis relying on a quantum chemical approach. The alkaloid possesses plant

According to Liu and co-workers.54

E

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growth-regulating activity. A plausible biogenetic pathway was proposed. (Scheme 3).

relative configuration were determined by spectroscopic analysis.

Scheme 3. Plausible Biogenetic Pathway for Longeraceminea

2-Hydroxyyunnandaphnine D and Methyl-7-hydroxyhomodaphniphyllate

In 2010, Luo and co-workers58 isolated 2-hydroxyyunnandaphnine D (42) and methyl 7-hydroxyhomodaphniphyllate (43) from the leaves and stems of Daphniphyllum calycinum (Figure 4). Their structures and relative configurations were deduced by spectroscopic methods and confirmed by single-crystal X-ray analysis. 2-Hydroxyyunnandaphnine possesses a calyciphylline A-type skeleton, whereas methyl 7-hydroxyhomodaphniphyllate possesses a daphniphylline-type skeletal structure (Figure 1).

a

3. BIOLOGICAL ACTIVITIES Since ancient times, Daphniphyllum plants have been used in Chinese herbal medicine. The extracts of the bark and leaves of Yuzuriha have been used as a folk remedy for asthma.46 The Chinese patented drug Fengliao Changweikang, which is used to cure bowel disease, is derived from the plant material of D. calycinum.59 To date, more than 320 new alkaloids have been isolated from the evergreen plants of the Daphniphyllum genus. These alkaloids display a significant range of anticancer, antioxidant, and vasorelaxant activities among others (Tables 1 and 2).

According to Di, Hao, and co-workers.39.

Demethyl Calyciphylline A

Demethyl calyciphylline A (41) was isolated by Di, Hao, and co-workers39 in 2013, together with longeracemine, from the fruits of D. longeracemosum (Figure 4). The structure and Table 1. Cytotoxic Activities of Daphniphyllum Alkaloids

cytotoxic activity IC50

against

ref

daphnicyclidin A daphnicyclidins A−H daphnicyclidins A−H daphnicyclidins J and K daphnicyclidins J and K daphnicyclidins M and N daphnicyclidins M and N

alkaloid

13.8 μM 0.8, 0.1, 3.0, 1.7, 0.4, 4.3, 4.2, and 0.5 μg/mL 6.0, 2.6, 7.2, 4.6, 5.2, 7.6, >10, and 0.9 μg/mL 1.9 and 4.7 μg/mL 2.5 and 6.5 μg/mL 5.7 and 6.5 μM 22.4 and 25.5 μM

P-388 cells murine lymphoma L1210 human epidermoid carcinoma KB cells murine lymphoma L1210 human epidermoid carcinoma KB cells P-388 cells SGC-7901 cells

52 17 17 19 19 52 52

daphmanidins A and B

8.0 and 7.6 μg/mL

murine lymphoma L1210

20

daphnezomine B daphnezomine B daphnezomines F and G daphnezomines F and G daphnezomines L and N daphnezomines P, Q, R, and S

0.46 μg/mL 8.5 μg/mL 8.4 and 5.3 μg/mL >10 and 7.3 μg/mL 4.0 and 8.7 μg/mL 8.5, 9.2, 4.8, and 2.7 μg/mL

murine lymphoma L1210 human epidermoid carcinoma KB cells murine lymphoma L1210 human epidermoid carcinoma KB cells murine lymphoma L1210 murine lymphoma L1210

15 15 16 16 18 60

daphniglaucins A and B daphniglaucins A and B daphniglaucin C

2.7 and 3.9 μg/mL 2.0 and 10 μg/mL 0.1 μg/mL

murine lymphoma L1210 human epidermoid carcinoma KB cells murine lymphoma L1210

21 21 24

daphnilongeridine daphnilongeridine

2.4−7.9 μM 2.7 μM

HL-60, p-388, A-549, Bel-7420 cells HMEC

61 61

daphangustifoline B daphangustifoline B daphangustifoline B

28.64% ± 13.56% at 10−5 M 11.80% ± 17.17% at 10−5 M 53.25% ± 1.68% at 10−5 M

HL-60 cells MCF-7 cells A549 cells

62 62 62

calyciphyllines A and B calyciphylline G

2.1 and 4.2 μg/mL 9 μg/mL

murine lymphoma L1210 murine lymphoma L1210

22 32

macropodumine C

10.3 μM

P-388 cells

52

F

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Table 2. Alkaloids with Other Bioactivities alkaloid calyciphylline K daphtenidine C daphmanidin C daphnioldhanine J daphniglaucin C

activity

enhances mRNA expression of NGF insecticidal against Plutella xylostella elevated activity of NGF biosynthesis inhibits platelet aggregation induced by PAF inhibits polymerization of tubulin; IC50 = 25 μM daphmacromines A−J pesticide activity against brine shrimp daphmacromine O pesticide activity against brine shrimp daphmanidins A, E, relaxation activity;a 38% and 46% at and F 10−5 M for A and E, 35% at 10−5 M for F deoxycalyciphylline B hepatotoxic himalenines A−E inhibitory activity against kinase enzymes, PTP 1B, aurora A, and IKK-β logeracemin A anti-HIV activity; EC50 = 4.5 ± 0.1 μM longeracemine stimulates shoot elongation of wheat pordamacrines relaxation activity;a 50.0% and 47.1% at A and B 10−4 M

Scheme 4. Biosynthesis of Daphniphylline and Daphnilactone Ba

ref 36 63 26 64 24 65 55 66 59 48 49 39 67

a

Relaxation activity against norepinephrine-induced contractions of thoracic rat aortic rings with endothelium.

4. GENERAL SYNTHETIC STRATEGIES BASED ON A BIOMIMETIC APPROACH In 1973, Suzuki, Yamamura, and co-workers studied the biosynthesis of daphniphylline (45)68 and daphnilactone B69 (46) using 14C- and 3H-labeled DL-mevalonic acid (44) in typical feeding experiments on growing leaves of D. macropodum Miq and fruits of Daphniphyllum teijsmanni (Scheme 4). Chemical degradation studies showed that daphniphylline and daphnilactone B are produced from six molecules of mevalonic acid. In the event, six molecules of mevalonic acid (44) combine to form a squalene-type intermediate (I), which undergoes an ene-type reaction to form the first ring system (II). Two successive enzyme-mediated cyclization reactions construct the tricyclic intermediate IV. In an undefined path, intermediate IV is converted to daphniphylline (45), which undergoes a ring-opening reaction to form V. Finally, an oxidative process gives rise to daphnilactone B (46). Inspired by Yamamura’s biosynthetic proposal, Heathcock and co-workers70,71 reported a plausible biosynthetic route for all Daphniphyllum alkaloids (Scheme 5). The first step involved oxidation of squalene (I) to squalene dialdehyde (II), followed by condensation with a primary amine or amino acid and then a prototopic rearrangement of 1-azadiene (III) to 2-azadiene (IV). A nucleophilic amine addition would give V, which would cyclize to VII. Further steps would lead to a dihydropyridine derivative (X), which would undergo an enzyme-catalyzed azaDiels−Alder-type reaction followed by an ene-cyclization to afford the pentacyclic intermediate (XIII). To justify the above biosynthetic proposal, Heathcock and co-workers70,71 simulated a similar sequence in the laboratory, which involved formation of six σ-bonds in a single step (Scheme 6). The squalene dialdehyde (48) was prepared from homogeranyl iodide (47) in eight steps. An initial attempt toward a one-pot cyclization reaction involved treatment of 48 with ammonia and triethylamine hydrochloride in dichloromethane, followed by evaporation of the solvent to dryness and treatment of the crude residue with acetic acid at 80 °C. The one-pot sequence gave the pentacyclic intermediate 49 in 17% yield. A better overall yield of 65% was achieved by treating squalene dialdehyde (48) sequentially with methylamine and then acetic acid, which led to the pentacyclic intermediate 50.

a

According to Suzuki, Yamamura, and co-workers.68,69 Carbon labeling is indicated with an asterisk (*).

5. INITIAL EFFORTS TOWARD THE SYNTHESIS OF DAPHNIPHYLLUM ALKALOIDS 5.1. Synthesis of the ACDE Ring System of Secodaphniphylline

In 1983, Orban and Turner72 reported a convergent synthesis of the tetracyclic core structure of secodaphniphylline, using a Diels−Alder reaction as a key step (Scheme 7). The synthesis began with the protection of m-cresol (51) as the MOM ether, followed by Birch reduction to 52. Lithiation with n-BuLi, carbonylation, and subsequent methyl ester formation gave intermediate 53. Treatment of 53 with 1 M HCl in THF led to the conjugated enone 54. A highly stereocontrolled solvent-free Diels−Alder reaction between enone 54 and silyloxy diene 55, derived from 1-acetyl cyclopentene, afforded 56 in moderate yield. Fluoride-mediated alkylation with allyl bromide from the convex face of 56 afforded 57 with a quaternary carbon center in a highly stereocontrolled manner. The structure and stereochemistry of 57 were confirmed by single X-ray crystallography. Successive steps involved ozonolysis of 57, followed by an aldol reaction to afford the tetracyclic core unit (58) of secodaphniphylline, in which four rings and five contiguous stereocenters of secodaphniphylline were assembled in four linear steps. G

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Scheme 5. Proposed Biosynthetic Pathway for Daphniphyllum Alkaloidsa

a

Scheme 6. Biomimetic Synthesis of Pentacyclic Core Intermediates of Daphniphyllum Alkaloidsa

According to Heathcock and co-workers.70,71

5.2. Total Syntheses of Daphniphyllum Alkaloids

During the period 1986−1995, Heathcock and co-workers achieved biomimetic total syntheses of (±)-methyl homodaphniphyllate (60),73−76 methyl homosecodaphniphylline (61),77,78 daphnilactone A (62),76−79 secodaphniphylline (59),80,81 bukittinggine (63),82 and codaphniphylline (64)83 (Figure 5). Heathcock’s seminal contributions toward the total synthesis of Daphniphyllum alkaloids have been reviewed.42,43 Here we shall discuss only his first and last total syntheses, as a tribute to the body of his work.73−86 5.2.1. Total Synthesis of (±)-Methyl Homodaphniphyllate. In 1969, Hirata and co-workers87 reported methyl homodaphniphyllate as one of the key intermediates between daphniphylline and yuzurimine. The synthetic intermediate was derived from daphniphylline via chemical transformations. Seventeen years later, Heathcock et al.73 reported the first total synthesis of (±)-methyl homodaphniphyllate. The synthesis began with amide bond formation between keto acid 65 and amine 66 to give 67 (Scheme 8). The successive steps involved acid-mediated cyclization to lactam 68, followed by stereoselective alkylation with the benzyl ether of 3-bromopropanol to afford 69. Tricyclic lactam 69 was converted to thiolactam 70 in two steps. An LDA-promoted Michael-type addition reaction with pent-3-en-2-one afforded intermediate 71 as a 4.8:1 diastereomeric mixture in 84% yield. Upon treatment with triethyloxonium fluoroborate, intermediate 71 underwent ring closure via a thio-iminium intermediate to give tetracyclic enaminone 72. Sequential treatment of 72

a

Heathcock and co-workers.70,71

with trimethyloxonium fluoroborate, NaBH4, and acid treatment afforded β-amino ketone 73 in 87% yield. The cis stereochemistry of the newborn stereocenter was assigned by NMR spectroscopic analysis. Selenylation with PhSeCl and LTMP (lithum 2,2,6,6-tetramethylpiperidide), followed by mCPBA-mediated selenoxide formation and elimination, afforded enone 74 in two steps. Successive steps involved LDAmediated aldol reaction with acetaldehyde, followed by acidcatalyzed dehydration and concomitant deprotection of the ketal to provide a transient intermediate 76, which underwent a spontaneous stereocontrolled Michael-type addition reaction to afford pentacyclic intermediate 77. 1,4-Conjugate addition of lithium dimethylcuprate to 77, followed by trapping of the enolate with diethyl phosphochloridate, afforded 78 (Scheme 9). A second enolization, followed by trapping of the enolate with diethyl phosphochloridate, afforded the bis(enolphosphate) 79, which upon treatment with Li in tBuOH gave alkene 80. High-pressure hydrogenation of 80 provided an equal mixture of diasterH

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Scheme 7. Synthesis of the ACDE Ring System of Secodaphniphyllinea

a

Scheme 8. Total Synthesis of (±)-Methyl Homodaphniphyllate, Part 1a

Orban and Turner.72

a

Heathcock and co-workers.73

daphniphylline via chemical degradation and functional group interconversions. In 1995, Heathcock and co-workers83 reported the biomimetic total synthesis of (+)-codaphniphylline. The synthesis began with a highly enantioselective Noyori asymmetric reduction of methyl 2-oxocyclopentanecarboxylate 84, followed by a Fráter−Seebach alkylation88,89 with homogeranyl iodode 47, to afford β-hydroxy ester 86 with 88% de and 65% yield over two steps (Scheme 10). Swern oxidation of intermediate 86 followed by ketal formation afforded 87, which was reduced to the primary alcohol and then esterified with 2-bromo-4-chlorobutanoyl chloride (88), and the ketal moiety was hydrolyzed to give the corresponding ketone. Upon treatment with Zn dust in presence of ZnCl2 in refluxing THF, keto ester 89 afforded the tricyclic lactone ether 92 via formation of organozinc transient intermediates 90 and 91. Reduction of 92 with LiAlH4 afforded diol 93, which was converted to dialdehyde 94 under Swern oxidation conditions

Figure 5. Total syntheses of Daphniphyllum alkaloids by Heathcock and co-workers.

eomers 81 and 82 in quantitative yield. In two successive steps, the diastereomeric mixture was converted to the corresponding methyl esters 83 and 60, which were easily separable. The synthesis of (±)-methyl homodaphniphyllate (60) was accomplished in 16 linear steps from known starting material 65. 5.2.2. Total Synthesis of (+)-Codaphniphylline. Codaphniphylline was isolated in 1966 by Hirata and co-workers4 from the leaves and bark of D. macropodum. The structure and relative configuration were established by spectral analysis and correlation with a synthetic intermediate obtained from I

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Scheme 9. Total Synthesis of (±)-Methyl Homodaphniphyllate, Part 2a

a

Scheme 10. Total Synthesis of (+)-Codaphniphylline, Part 1a

Heathcock and co-workers.73

and then treated with methylamine and acetic acid to give the pentacyclic amine 95. In this remarkable cascade reaction sequence, four new rings and five new σ-bonds were formed. A plausible mechanistic interpretation was suggested by Heathcock and co-workers.83 Upon treatment with excess DIBAL-H in refluxing toluene, 95 underwent a reductive fragmentation reaction to give imine 96, which was further reduced to the corresponding amino alcohol 97 (Scheme 11). Conversion to the N,O-protected derivative 98 and heating in formic acid led to ring closure to give 99. Tosylation of alcohol 100 followed by displacement with NaSPh gave phenylthio intermediate 101, which was converted to the hydrochloride salt and then oxidized with hydrogen peroxide in the presence of a catalytic amount of sodium tungstate to afford phenylsulfone 102 in excellent yield. Lithiation and then coupling with enantiomerically pure aldehyde 106a provided a mixture of alcohols, which was further oxidized and reductively desulfonylated to obtain (+)-codaphniphylline. The enantiomerically pure aldehyde was prepared in four linear steps from previously reported ynone 103 (Scheme 11). The synthesis of (+)-codaphniphylline (64) was accomplished in 19 steps in 8.9% overall yield from commercially available methyl 2-oxocyclopentanecarboxylate 84. The intramolecular Reformatsky reaction (90 → 92), the biomimetic cascade sequences, and the DIBAL-Hpromoted reductive fragmentation reactions are noteworthy features in this synthesis.

a

Heathcock and co-workers.83

6. RECENT PROGRESS IN THE SYNTHESIS OF DAPHNIPHYLLUM ALKALOIDS (2005 TO BEGINNING OF 2016) Since the seminal work of Heathcock and co-workers, several groups have reported syntheses of diverse polycyclic core structures corresponding to different structural types encompassed by Daphniphyllum alkaloids. In this section, we have summarized contributions covering the period from 2005 to the beginning of 2016. J

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Scheme 11. Total Synthesis of (+)-Codaphniphylline, Part 2a

Figure 6. Representative yuzurimine-type alkaloids.

Scheme 12. Proposed Biosynthetic Pathway for Yuzuriminetype Alkaloidsa

a

a

According to Kobayashi and Kubota.43

form V. Finally, SN2′ ring closing followed by oxidation could provide yuzurimine (107). 6.1.1. Asymmetric Synthesis of the ABDG Ring System of Daphcalycine. In 2011, Coldham et al.95 reported the synthesis of the daphcalycine core structure (Scheme 13), based on their previously reported cascade of ring-closure reactions strategy. 96,97 The synthesis commenced with alkylation of optically pure nitrile 113 with 1-(3-iodopropyl)cyclopent-1-ene (114) to give intermediate 115 as a 2:1 inseparable mixture of diastereomers. In two successive steps, cyano intermediate 115 was desilylated and sulfenylated to provide 116 as a 1:1 inseparable mixture of diastereoisomers. Under Appel reaction conditions, the cyano alcohol 116 was converted to the corresponding chloro compound, which was followed by selective reduction of the cyano group with DIBAL-H. Subsequent hydrolysis of the resulting imine intermediate afforded aldehyde 117 as a 7:3 inseparable mixture in 54% yield over two steps. Treatment of this mixture with hydroxylamine hydrochloride led to the corresponding oximes, which underwent intramolecular displacement of the primary chloride to give intermediates 118a and 118b. Subsequent heating in refluxing toluene promoted a [3 + 2]

Heathcock and co-workers.83

6.1. Syntheses of Yuzurimine-type Alkaloids

In 1966, Hirata and co-workers4 reported the isolation of yuzurimine (107) from the bark and leaves of D. macropodum Miquel, whose structure was confirmed by X-ray crystallography. Subsequently, several yuzurimine-type alkaloids were isolated and their structures were established either by spectral data analysis or by X-ray crystallography (Figure 6).90−,94 A proposed biosynthetic pathway for these alkaloids by Kobayashi and Kubota43 is shown in Scheme 12. In consideration of Heathcock’s proposal, yuzurimine might be generated from secodaphylline-type intermediate III, obtained from common imine precursor II. C−C bond cleavage of intermediate III, followed by two successive [1,2]-hydride shifts, would lead to IV, which could undergo a C−N bond-formation reaction to K

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Scheme 13. Asymmetric Synthesis of the ABDG Ring System of Daphcalycinea

a

Scheme 14. Synthesis of the ABEF Ring System of Yuzuriminea

Coldham and co-workers.95

cycloaddition to give 119a and 119b. The structure of the minor isomer 119b was confirmed by single-crystal X-ray analysis and found to correspond to the desired stereochemistry. Reductive cleavage of the N−O bond, followed by treatment with paraformaldehyde under acidic conditions, afforded 1,3-oxazine 120 in 58% yield over two steps. Intermediate 120 represents the ABDG rings of daphcalycine. 6.1.2. Synthesis of Yuzurimine Core Structure. In 2011, Bélanger et al.98 reported a synthesis of the tricyclic core of yuzurimine (Scheme 14), which began with double deprotonation and monoallylation of succinic acid monoethyl ester 121. Reduction of the carboxylate ester gave a transient γhydroxy acid, which underwent a spontaneous lactonization to give lactone 122. trans-Selective alkylation of 122 followed by reduction of the lactone functionality led to 123, whose stereochemistry was established by X-ray studies of the pbromobenzoate derivative after catalytic hydrogenation. Onecarbon Wittig olefination followed by Appel reaction afforded the bromo compound 124, which was converted to the vinyl allyl ether 125 through an addition−elimination sequence. Conversion to an amine, followed by protection as the Ncyanomethyl-N-formyl derivative, gave 126 in three steps. Claisen rearrangement99,100 of 126, followed by ring-closing metathesis with Grubbs’ second-generation catalyst,101 afforded 127. Conversion to the corresponding TBS enol ether, followed by debenzylation, gave the corresponding alcohol 128 in moderate yield, which was converted to the homologated unsaturated methyl ester 129. Activation of the

a

Bélanger and co-workers.98

N-formyl unit of 129 in the presence of triflic anhydride, followed by an intramolecular trapping, generated the iminium intermediate 130, which upon treatment with Hünig’s base provided the racemic [3 + 2] cycloaddition product 132 via an azomethine ylide intermediate 131. In this two-step one-pot process, three rings and three σ-bonds were formed. The tetracyclic core of yuzurimine was accomplished in 16 steps from a known 3-allylbutyrolactone. Vilsmeier−Haack cyclization and intramolecular azomethine ylide cycloaddition are key steps in this synthesis. 6.1.3. Synthesis of the BCDE Ring System of Yunnandaphnine C and Yuzurimine. In 2015, Hayakawa, Niida, and Kigoshi102 reported the synthesis of a tetracarbocyclic core structure of yunnandaphnine C and yuzurimine alkaloids. The synthesis commenced with ozonolysis of the known racemic alcohol 133 to give the tricyclic lactol aldehyde L

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134, which was further oxidized under Iwabuchi oxidation conditions103 using 1-methyl-2-azaadamantane N-oxyl to provide tricyclic lactone acid 135 (Scheme 15). Subsequent

SmI2 in t-BuOH, led to a radical-mediated ring-closing reaction to give a separable mixture of γ-hydroxy ester 146a and lactone 146b (Scheme 16). The stereochemistry of 146b was assigned

Scheme 15. Synthesis of the BCDE Ring System of Yunnandaphnine C and Yuzurimine, Part 1a

Scheme 16. Synthesis of the BCDE Ring System of Yunnandaphnine C and Yuzurimine, Part 2a

a

a

Hayakawa, Niida, and Kigoshi.102

by NMR analysis. Thus, the tetracyclic core of yunnandaphnine C and yuzurimine was synthesized in 21 steps starting from known racemic alcohol 133. The intramolecular Wittig reaction is a key step in this synthesis.

Hayakawa, Niida, and Kigoshi.102

steps involved reduction of the carboxylic acid group of 135, followed by protection of the primary alcohol as the TBDPS silyl ether, to give 136. Stereoselective enolate addition from the convex face of lactone 136 with aldehyde 137 generated a new quaternary stereogenic center as a mixture of chromatographically separable diastereomeric alcohols. TBS protection of the newly formed secondary alcohol 138, followed by reduction of the lactone to the diol, selective protection of the primary alcohol, and oxidation of the secondary alcohol, provided intermediate 139 in four steps. Trapping of the potassium enolate of 139 with the McMurry reagent,104,105 followed by Stille coupling106 with vinyl tributyl tin, afforded the diene 140. The subsequent steps involved hydroboration of 140 to the primary alcohol, tosylation with TsCl, and displacement of the tosylate with sodium iodide to provide the iodo compound 141 in moderate yield. Deprotection of the pivaloyl ester of 141 with DIBAL-H followed by Iwabuchi oxidation gave aldehyde 142. Treatment of 142 with (methoxycarbonylmethylene)tributylphosphorane in refluxing toluene generated a transient phosphonium ylide intermediate 143, which spontaneously underwent an intramolecular Wittig reaction to give 144. Conversion to the aldehyde 145, followed by treatment with

6.2. Syntheses of Daphnilactone B-type Alkaloids

In 1972, Sasaki and Hirata11 reported the isolation of daphnilactone B (46) from the fruits of D. macropodum Miquel. Its structure and relative stereochemistry were assigned on the basis of spectral data analysis and confirmed by X-ray crystallography. Daphnilactone B possesses a fused hexacyclic framework with seven stereogenic centers. In 1973, Yamamura and co-workers68 proposed a plausible biosynthetic pathway using a typical feeding experiment with 14C-labeled mevalonic acid and subsequent chemical degradation of the 14C-labeled natural product (Scheme 4). Over a span of 40 years, several daphnilactone B-type alkaloids were isolated from the Daphniphyllum genus33,107 (Figure 7). 6.2.1. Synthesis of the ABC Ring System of Daphnilactone B. In 2006, Denmark and Baiazitov108 carried out a model study toward the total synthesis of daphnilactone B while testing a tandem double-intramolecular [4 + 2]/[3 + 2] nitroalkene cycloaddition reaction for the stereocontrolled construction of tetracyclic alkaloid core structures (Scheme 17). The synthesis commenced with aldehyde 150, which was converted to the dimethyl acetal 151, and the latter was M

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cycloaddition reaction of 154 provided a diastereomeric mixture of products, which after fractional crystallization afforded the major isomer 155. The predominant formation of the exo product 155 was explained on the basis of DFT calculations (Figure 8). Figure 7. Representative daphnilactone B-type alkaloids.

Scheme 17. Synthesis of the ABC Ring System of Daphnilactone Ba

Figure 8. Transition-state models (exo vs endo).

a

Ozonolysis of 155 gave aldehyde 156, which after Raney Ni hydrogenation and treatment with base afforded lactam 160. The cascade reaction involved first cleavage of the N−O bond and then intramolecular condensation between the primary amine and the aldehyde, reduction of imine 158 to secondary cyclic amine 159, and finally an intramolecular attack to form the lactam ring. Swern oxidation of 160 afforded diketone 161, which underwent a chemoselective Grignard (TMSCH2MgCl) addition to provide 162. Sequential reduction led to diol 163, which was converted to the corresponding exomethylene compound in the presence of KHMDS. Hydrogenation provided racemic 164 as a 7:1 separable mixture of diastereomers. The stereochemistry of the major isomer 164 was assigned by NMR spectroscopic analysis. The highly stereocontrolled Me3Al-mediated tandem double-intramolecular cycloaddition and the Raney Ni-mediated cascade cyclizations are noteworthy features in this synthesis. 6.2.2. Asymmetric Synthesis of the ABC Ring System of Daphnilactone B. Denmark et al.109,110 reported the asymmetric synthesis of a more functionalized variation of the ABC rings of daphnilactone B. The synthesis commenced with the hydrolytic kinetic resolution of Jacobsen and co-workers111 of racemic epoxide 165 (Scheme 18). Subsequent steps involved regioselective opening of the enantioenriched epoxide with TMS-acetylide, followed by protection as a MOM ether and cleavage of the C−Si bond to give 166. Conversion to 168 was followed with addition of the dianion generated from methyl 3-nitropropionate to the primary iodide to give a 1:1 inseparable mixture of diastereomers, which was treated with HF in acetonitrile/water mixture to afford alcohol 169. Parikh− Doering oxidation followed by Wittig olefination gave the unsaturated ester 170 as a 20:1 regioisomeric mixture. Successive steps involved cleavage of the MOM ether with methanolic HBr, followed by lactone formation and dehydrogenation to give unsaturated β-nitro lactone 171. Treatment of 171 with SnCl4 in 9:1 dichloromethane−toluene at −60 °C afforded a 2.5:1 mixture of inseparable diastereomers 172 and 173, whose structure and stereochemistry were determined by X-ray analysis. It should be noted that four new σ-bonds, four new rings, and seven stereogenic centers were formed in a highly stereocontrolled manner in a single step, reminiscent of the biomimetic synthesis of Daphniphyllum alkaloids by Heathcock and co-workers.70,71 Ozonolysis of the epimeric mixture of 172 and 173 under the modified conditions of Marshall and Sedrani112 afforded a 2.5:1 mixture of methyl

Denmark and Baiazitov.108

subjected to carbocupration followed by Pd(0)-catalyzed crosscoupling with 1-iodo-2-methylpropene to afford Z-diene 152. A two-carbon homologation to unsaturated methyl ester 153 and subsequent deprotection of the dimethyl acetal, followed by nitro-aldol condensation and dehydration of the aldol product, gave the vinyl nitro compound 154. A Lewis acid-assisted tandem double-intramolecular [4 + 2]/[3 + 2] nitroalkene N

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Scheme 18. Asymmetric Synthesis of the ABC Ring System of Daphnilactone B, Part 1a

Scheme 19. Asymmetric Synthesis of the ABC Ring System of Daphnilactone B, Part 2a

a

Denmark and co-workers.109,110

of daphnilactone B. The synthesis began with 1,4-conjugate addition of silyl ketene acetal 180 to unsaturated aldehyde 179 to give 181 in 93% yield (Scheme 21). Subsequent steps involved reduction of aldehyde to alcohol, followed by mesylation and displacement with LiBr, to provide bromide 182. Transformation to 183, followed by a cross-metathesis reaction with methyl acrylate in presence of Grubbs’ secondgeneration catalyst,101 led to the one-carbon homologated unsaturated ester 184. Upon treatment with hydroxylamine hydrochloride in refluxing toluene, 184 underwent in situ Nalkylation, followed by nitroso iminium formation and [3 + 2] cycloaddition, to give the bridged tricyclic amine 186 in excellent yield. Raney Ni-mediated N−O bond cleavage followed by concomitant cyclization afforded lactam 187, which was converted to the model tricyclic racemic intermediate 188. The structure and stereochemistry of 187 and 188 were confirmed by X-ray analysis. Synthesis of the tricyclic ABC ring system of daphnilactone B was achieved in 12 steps and 12% overall yield from aldehyde 179. a

Denmark and co-workers.109,110

6.3. Synthesis of Daphnicyclidin A-type Alkaloids

In 2001, Kobayashi et al.17 reported the isolation of daphnicyclidins A−H from the stems of Daphniphyllum humile and D. teijsmanni. Their structures and stereochemistry were determined on the basis of spectroscopic data and by chemical means and were further confirmed by X-ray crystallography. Daphnicyclidin A-type alkaloids possess fused hexa- or pentacyclic structures harboring five stereogenic centers (Figure 9).17,116 According to the biosynthetic proposal by Kobayashi et al.,17 the daphnicyclidins could originate from yuzurimine Atype alkaloids (Scheme 22). The loss of an acetate leaving group, followed by N−C bond formation, leads to intermediate I from yuzurimine A (107). Enlargement of ring A via bond cleavage, followed by aromatization, would generate biogenetic intermediate III. Finally, oxidative cleavage, followed by cyclization of IV, would provide daphnicyclidin A (189). 6.3.1. Asymmetric Synthesis of the BCD Ring System of Daphnicyclidin A. In 2009, Iwabuchi and co-workers117 reported a highly convergent synthesis of the BCD ring system, possessing five stereogenic centers, of daphnicyclidin A (189). Synthesis of the first fragment commenced with the carbomethoxylation of cycloheptanone (192), followed by transesterification with (−)-8-phenylmenthol to give 193

esters 174 and 175. Compounds 172 and 174 possess the required stereochemistry to enable further elaboration. In accordance with the previous synthesis (Scheme 17), 174 was converted to 176 in two steps (Scheme 19). Reduction of the lactam functionality in 176 with BH3·THF gave the amine− borane complex, which upon treatment with 5% Pd/C in methanol furnished the free amine. In situ treatment of the intermediate amine with triethylamine provided the pentacyclic lactam 177. Treatment of 177 with Martin’s sulfurane reagent,113 followed by hydrogenation with Wilkinson’s catalyst,114 gave 178, which possesses six stereocenters encompassed in the ABC ring system of daphnilactone B. A tandem double-intramolecular cycloaddition sequence to establish the six contiguous stereogenic centers is a noteworthy feature in this 24-step synthesis. A mechanism for the intramolecular cycloaddition reaction to form 172 and 173 according to Denmark et al.109,110 is shown in Scheme 20. 6.2.3. Synthesis of the ABC Ring System of Daphnilactone B. Inspired by the tandem cycloaddition approach of Denmark et al.,109,110 Coldham et al.115 reported the synthesis of a tricyclic amine representing a partial structure O

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Scheme 20. Proposed Mechanistic Path for Formation of 172 and 173a

Scheme 21. Synthesis of the ABC Ring System of Daphnilactone Ba

a

a

Coldham and co-workers.115

Denmark and co-workers.109,110 Figure 9. Representative daphnicyclidin A-type alkaloids.

(Scheme 23). Regioselective dehydrogenation using the Mukaiyama−Matsuo reagent118 afforded 194, which was subjected to face-selective 1,4-conjugate addition with nitromethane, followed by in situ trapping of the enolate as a TIPS ether, to give 195. Reductive removal of the chiral auxiliary, followed by reduction of the nitro group, gave 196 in 96% ee. Synthesis of the second fragment began with commercially available D-mannitol, which was converted to 198 in four linear steps (Scheme 24). A protection−deprotection protocol led to 199, which was subjected to a typical Ireland−Claisen119 rearrangement to give 201 as a 9:1 inseparable mixture of diastereomers. Conversion to 202 and treatment with methyl chloroformate generated the corresponding methyl carbonate, which was subjected to Tsuji conditions120 to give 203. Ozonolysis of 203, followed by in situ dimethyl acetal formation, afforded 204. Debenzylation of 204, followed by coupling with 196 (Scheme 23), led to amide 205 in good yield (Scheme 25).

Tosylation, followed by treatment with TBAF, gave the exocyclic enone via an SN2′ displacement mode, which upon hydrogenation with Pd-on-carbon gave 206 as an equal mixture of diastereomers. Upon treatment with AcCl in iPrOH, ketone 206 underwent acetal cleavage, followed by iminium ion formation and subsequent Mannich-type addition, to give a separable mixture of 207 and 208. At this stage, the minor isomer generated earlier during the Ireland−Claisen rearrangement could be separated (Scheme 24). The stereochemistry of 207 was confirmed by NMR analysis and found to be the correct isomer, and that of 208 was determined by X-ray diffraction data analysis. Finally, an enolate alkylation of 207 with allyl bromide afforded 209 as a single isomer. Thus, the BCD core structure of daphnicyclidine A was achieved in 20 linear steps from D-mannitol. The highly diastereoselective addition of nitromethane to a chiral enoate and tandem acyl P

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Scheme 22. Proposed Biosynthetic Pathway for Daphnicyclidin A-type Alkaloidsa

Scheme 24. Synthesis of the BCD Ring System of Daphnicyclidin A, Part 2a

a

Iwabuchi and co-workers.117

Scheme 25. Synthesis of the BCD Ring System of Daphnicyclidin A, Part 3a

a

According to Kobayashi and co-workers.17

Scheme 23. Synthesis of the BCD Ring System of Daphnicyclidin A, Part 1a

a

Iwabuchi and co-workers.117

iminium/Mannich-type reactions are notable transformations in this synthesis. 6.3.2. Asymmetric Synthesis of the ABC Ring System of Daphnicyclidin A. In 2014, Williams et al.121 reported a stereocontrolled synthesis of the ABC core of daphnicyclidin A. The synthesis began with trans-lithiation of 210, followed by

a

Q

Iwabuchi and co-workers.117

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bridging seven-membered ring was achieved by SmI2-mediated radical cyclization to afford a mixture of diastereomeric alcohols, which were oxidized under Dess−Martin conditions to give diketone 222. Finally, hydrogenolytic cleavage of the NCbz group gave the corresponding secondary amine, which upon treatment with NaBH(OAc)3 gave 223 via an iminium intermediate. Synthesis of the 4-azabicyclo[5.3.2]dodecane core of daphnicyclidin A, containing five stereogenic centers, was achieved in 20 linear steps starting from 210. Introduction of a quaternary chiral center via the Ireland−Claisen rearrangement in a highly stereocontrolled manner and SmI2-mediated radical conjugate addition to form the bridged bicycle are key steps in this synthesis.

1,2-addition to 211, to afford enone 212 (Scheme 26). (S)CBS-catalyzed122 face-selective hydride addition to 212, Scheme 26. Synthesis of the ABC Ring System of Daphnicyclidin Aa

6.4. Synthesis of Daphmanidin A-type Alkaloids

In 2002, Kobayashi et al.20 reported the isolation of daphmanidin A (224), a novel fused hexacyclic alkaloid, from the leaves of D. teijsmanii. The structure and relative stereochemistry of daphmanidin A were determined by spectroscopic analysis, and the absolute stereochemistry was determined by a combination of NOESY correlations and a modified Mosher ester method. Daphmanidin A-type alkaloids contain three quaternary stereogenic centers embedded in the central bicyclo[2.2.2]octane core. Several new daphmanidin Atype alkaloids have also been isolated by Kobayashi and coworkers, such as daphmanidin E (225) from the leaves of D. teijsmannii123 and calyciphylline N (226) from the leaves and stems of D. calycinum124 (see Figure 10). A biosynthetic

Figure 10. Representative daphmanidin A-type alkaloids.

a

pathway was proposed by Kobayashi and co-workers20,123,124 and is summarized in Scheme 27. Daphmanidin A (224) might be obtained from Heathcock’s proposed secodaphniphyllinetype intermediate III. Cleavage of the C−C bond in III, followed by hydride migration and SN2′-type ring closing, would lead to a yuzurimine-type skeleton VI, which would undergo oxidations to daphmanidin A (224). Daphmanidin E and calyciphylline N bear the same skeletal structures and belong to the daphmanidin A-type alkaloids. The structure and relative stereochemistry of daphmanidin E and calyciphylline N were elucidated on the basis of spectroscopic data studies. 6.4.1. Asymmetric Total Synthesis of (+)-Daphmanidin E. In 2011, Weiss and Carreira125 reported the first total synthesis of (+)-daphmanidin E (226). Daphmanidin E possesses three quaternary stereogenic centers in the central bicyclo[2.2.2]octane core. The synthesis began with the C2symmetric building block 227, already possessing a bicyclo[2.2.2]octane core with two quaternary stereogenic centers. Bis-ketalization of 227 followed by chemoselective hydrolysis generated monoketal 228 (Scheme 28). Subsequent steps involved enolate trapping with the Comins reagent, followed by Suzuki cross-coupling with the in situ-generated boronate of H2CCHCH2OTBDPS, to give 229 in 75% yield over two steps. Upon treatment with BH3·DMS, 229

Williams and co-workers.121

followed by esterification with TBDPS-protected 5-hydroxypentanoic acid, led to 213 in 62% yield and 99% ee over two steps. Upon treatment with LDA and TMSCl, 213 underwent an Ireland−Claisen rearrangement to give 214 in 88% de, which was converted to 215. Oxidation to the aldehyde, followed by reductive amination in the presence of 216 and subsequent N-Cbz protection, provided 217. Subsequent steps involved deprotection of the PMB ether, oxidation to the aldehyde, addition of vinyl-MgBr, and oxidation of the secondary alcohol to give enone 218. Ring-closing metathesis using Grubbs’ second-generation catalyst generated the hexahydro azocinone 219, which was converted to aldehyde 221 in two steps. The construction of a R

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Scheme 28. Total Synthesis of Daphmanidin E, Part 1a

Scheme 27. Biosynthetic Pathway for Daphmanidin A-type Alkaloidsa

a

According to Kobayashi and co-workers.20,123,124

underwent hydroboration as well as reduction of the carboxylate ester to provide a triol, which was sequentially protected as the six-membered acetonide and benzoylated to give 230. Chemoselective O-alkylation of 230 with 231 gave vinyl allyl ether 232, which underwent a thermal [3,3] sigmatropic rearrangement at 155 °C to provide 233 as a 10:1 mixture of separable diastereomers. A second O-alkylation with allyl bromide, followed by Claisen rearrangement under thermal conditions, introduced the third quaternary center in 234. Over four consecutive steps involving hydroboration, acetylation, silyl ether cleavage, and Grieco elimination, 234 was transformed to 235. Hydrolysis of the acetonide in 235, followed by selective protection of the primary alcohol, etherification of the secondary alcohol, silyl ether deprotection, and finally oxidation of the primary alcohol, afforded 236 in 67% yield over five steps. A Henry reaction with nitromethane, followed by in situ dehydration, yielded 237, which was subjected to an asymmetric Cu-catalyzed dimethylzinc addition mediated by catalyst 238 to afford a 5:1 inseparable mixture of epimers (Scheme 29). Treatment with Zn/(aq)NH4Cl in ethanol, followed by in situ Boc protection of the primary amine, provided 239 as the major isomer. Ozonolysis of 239 under reductive conditions followed by chemoselective reduction of the aldehyde afforded 240 over two steps. Conversion of 240 to

a

Weiss and Carreira.125

241, followed by a photochemical alkyl-Heck cyclization reaction126,127 in the presence of cobaloxime 242, yielded the enone 243. A mechanism for the alkyl-Heck reaction is shown in Scheme 30. Cleavage of the acetate ester in 243, followed by oxidation of the primary alcohol and intramolecular aldol condensation− dehydration, afforded doubly conjugated ester 244, which was converted to 245 through a functional group interconversion and deprotection−protection sequence. Subsequent steps led to (+)-daphmanidin E (225). The synthesis was accomplished in 38 linear steps starting from 227. The original choice of diketone 227 possessing the bicyclo[2.2.2]octane core, Claisen rearrangement to install a sterically hindered quaternary center, asymmetric conjugate addition of Me2Zn, and cobalt-catalyzed Heck coupling are notable highlights of the synthesis. 6.4.2. Asymmetric Total Synthesis of (−)-Calyciphylline N. In 2014, Shvartsbart and Smith128 reported the first total synthesis of (−)-calyciphylline N, which contains three stereogenic quaternary carbon centers as part of an azahexacyclic ring system. The synthesis of calyciphylline N S

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Scheme 29. Total Synthesis of Daphmanidin E, Part 2a

commenced with optically pure alcohol 246, which was subjected to Birch reduction to 247, followed by partial isomerization under strong basic conditions to give a 3.5:1 inseparable mixture of 247 and 248 (Scheme 31). EtherScheme 31. Total Synthesis of (−)-Calyciphylline N, Part 1a

a

Weiss and Carreira.125

Scheme 30. Mechanism of the Cobalt-Catalyzed Alkyl-Heck Reaction

a

Shvartsbart and Smith.128

ification of 248 with the silyl acrylate 249 afforded silyl ether 250, which underwent Et2AlCl-promoted thermal intramolecular Diels−Alder reaction to give a 9:1 mixture of separable diastereomers. Exclusive formation of the cycloaddition adduct 251 was explained by assuming an endo approach in a transition-state model that lacks A1,3 strain (Scheme 32). In five successive transformations, cycloadduct 251 was converted to 252 in 77% yield. Epoxidation of 252, followed by acid-catalyzed face-selective epoxide ring opening and oxidation of the secondary alcohol with Dess−Martin periodinane, yielded 254. SmI2-mediated C−O bond cleavage followed by silyl ether protection provided ketone 255, which was subjected to an LDA-mediated aldol reaction with acetaldehyde, followed T

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Scheme 33. Total Synthesis of (−)-Calyciphylline N, Part 2a

Scheme 32. Diels−Alder Transition-State Model

by Dess−Martin oxidation of the resulting alcohol, to give 256. Introduction of the third quaternary center via Tsuji−Trost allylation129 afforded 257 in excellent yield. Deprotection of the silyl ether in 257, followed by conversion of the primary alcohol to the iodo intermediate and intramolecular enolate alkylation, provided 258. Hydroboration of 258 with 9-BBN, followed by oxidative workup and TBS ether protection, afforded 259. Cleavage of the silyloxy bond by use of p-methoxyphenyl lithium as nucleophile, followed by a Mitsunobu amination reaction with phthalimide, furnished 260. Upon treatment with KHMDS in the presence of Comins’ reagent, 260 gave the vinyl triflate, which underwent a Stille carbonylation130 reaction to give 261 (Scheme 33). Nazarov cyclization with HBF4 effected deprotection of the TBS ether and formation of the fluorosilane 262. Fleming−Tamao oxidation with KF and m-CPBA afforded alcohol 263, which was sequentially protected to give 264 in 73% yield over two steps. Upon treatment with IBX in DMSO, 264 underwent in situ silyl deprotection and oxidation to give an aldehyde, which was then subjected to an intramolecular aldol reaction and dehydration in the presence of Bn2NH·TFA salt in toluene at 50 °C to furnish conjugated aldehyde 265. Oxidation to the corresponding methyl ester 266 via Corey’s procedure131 and high-pressure hydrogenation with a modified Crabtree catalyst afforded a 4:1 mixture of 267 and its diastereomer, which was finally converted to (−)-calyciphylline N in three successive steps. Total synthesis of (−)-calyciphylline N (226) was achieved in 37 linear steps starting from known enantiopure alcohol 246. The highly stereoselective substrate-controlled intramolecular Diels−Alder reaction, a transannular enolate alkylation, and the Stille carbonylation−Nazarov cyclization sequence are key steps in this synthesis.

a

Shvartsbart and Smith.128

6.5. Synthesis of Calyciphylline A-type Alkaloids

In 2003, Morita and Kobayashi22 isolated calyciphylline A (268) from the leaves of D. calycinum. Calyciphylline A possesses a fused hexacyclic ring with eight stereogenic centers. The structure and relative stereochemistry of this alkaloid were determined by spectroscopic analysis. Subsequently, several calyciphylline A-type alkaloids were isolated from the plants of D. longeracemosum,132,135,136 Daphniphyllum longistylum,133 and Daphniphyllum yunnanense134 (Figure 11). Some representative members of this class are longistylumphylline A, daphnilonger-

Figure 11. Representative calyciphylline A-type alkaloids.

U

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anins A−C, daphniyunnines A−E, longeracinphyllins A and B, and daphlongamine E. A plausible biosynthetic path wherein calyciphylline A could be derived from yuzurumine A-type alkaloids was proposed22 (Scheme 34).

Scheme 35. Synthesis of the ABC Ring System of Calyciphylline Aa

Scheme 34. Proposed Biosynthesis of Calyciphylline A-type Alkaloidsa

a a

According to Morita and Kobayashi.22

Bonjoch and co-workers.137

vinyl bromide and ketone enolate of 277 provided the azatricyclic core 278; a plausible mechanism for this transformation is shown in Scheme 36.138 A 2012 paper reported a detailed mechanistic study of the Pd-catalyzed enolate arylation reaction.139 A face-selective Luche reduction of the ketone functionality of 278 afforded borane complex 279. It was postulated that formation of the borane complex was necessary to create more steric crowding on the top face, thus favoring reduction of the exomethylene from the bottom face. More interestingly, a hydroxyl-directed hydrogenation using [Rh(NBD)(DIPHOS-

Since 2005, more than 15 syntheses of core structures of calyciphylline A-type alkaloids have been reported. The unique fused penta- or hexacyclic structure with at least six stereogenic carbon atoms makes it a challenging target among the other members of the Daphniphyllum alkaloids. Below we discuss salient features of syntheses of different core structures belonging to individual alkaloids in this series. 6.5.1. Synthesis of the ABC Ring System of Calyciphylline A. The first synthetic effort toward a calyciphylline A-type alkaloid core structure was reported by Bonjoch and co-workers in 2005.137 The synthesis involved the construction of 4azatricyclo[5.2.2.04,8]undecan-10-one skeleton of calyciphylline A by use of a palladium-catalyzed intramolecular coupling of an amino-tethered vinyl bromide with a ketone moiety. The synthesis commenced with the three-step selective monoallylation of 273, via formation of an activated β-keto ester followed by chemoselective allylation and thermal decarboxylation of the allylated β-keto ester to give 274 (Scheme 35). A two-step α-methylation via formation of a tetrasubstituted TMS enol ether afforded 275 in 85% yield and complete regioselectivity. Ozonolysis of 275, followed by reductive amination in the presence of benzylamine hydrochloride, furnished azabicycle 276. Successive steps involved debenzylation of 276, followed by N-alkylation with 2,3-dibromopropene and hydrolysis of the ketal moiety, to give 277 in three steps. Finally, a palladium-catalyzed intramolecular coupling of the

Scheme 36. Mechanism of Pd(0)-Catalyzed Ketone Alkylation

V

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4)]BF4 afforded the intended 280 in 56% de. Initially, hydrogenation of 278 with Pd/C and H2 afforded the unrequired epi-280 diastereomer. Finally, Swern oxidation and cleavage of the N-BH3 complex afforded azatricyclic ketone 281. Further efforts toward the synthesis of core structures of calyciphylline A-type alkaloids produced the azacyclic compounds 282−284, shown in Figure 12.140−143

Scheme 37. Synthesis of the ACD Ring System of Daphniyunnine Ba

Figure 12. Synthesis of calyciphylline A-type alkaloid core structures by Bonjoch and co-workers.140−143

6.5.2. Synthesis of the ACD Ring System of Daphniyunnine B. In 2011, Dixon and co-workers144 reported the synthesis of the ACD core structure of daphniyunnine B (28) in racemic form. The salient steps involved an intramolecular Michael addition/allylation sequence, a ring-closing metathesis, and a highly stereocontrolled face-selective formation of a quaternary stereogenic center. The synthesis commenced with the preparation of amine 286 from ketone 285 via enolate formation, followed by γ-iodination and displacement with benzylamine to give 286 (Scheme 37). Nacylation with acid chloride 287 afforded 288, which upon treatment with KHMDS underwent an intramolecular Michael addition reaction, with the enolate being trapped by in situ addition of allyl tosylate, to give azabicyclic intermediate 289 with complete stereoselectivity. Thus, two quaternary stereogenic centers were introduced with the desired stereochemistry in a single step. Claisen rearrangement in refluxing mesitylene gave 290, which was subjected to ring-closing metathesis with Grubbs’ first-generation catalyst145 to give 291. Decarboxylation, followed by treatment with KHMDS and in situ trapping with allyl tosylate, afforded vinyl allyl ether 293, which underwent a highly stereocontrolled [3,3] sigmatropic rearrangement in refluxing mesitylene to give 294. The stereochemistry of 294 was confirmed by X-ray crystallographic analysis. The construction of two quaternary carbon centers in a single transformation via an intramolecular Michael addition sequence is noteworthy. 6.5.3. Synthesis of the DEF Ring System of Daphniyunnine D. In 2012, Dixon and co-workers146 reported a streamlined synthesis of the all-carbon tricyclic DEF core of daphniyunnine D (27) that relied on an intramolecular Pauson−Khand reaction and double-bond migration. The synthesis began with cycloheptanone 192 and proceeded through formation of a β-keto ester and a Michael addition to acrolein to give 295, which was converted to alkyne 296 by a modified Seyferth−Gilbert homologation prototocol (Scheme 38).147−149 Reduction of 296 under Luche conditions, followed by mesylation and in situ elimination, provided eneyne 297, which was the desired substrate for the intramolecular Pauson−Khand reaction. Upon treatment with dicobalt octacarbonyl, 297 was converted to cobalt−alkyne complex 298, which in the presence of an amine N-oxide promoter underwent [2 + 2 + 1] cycloaddition reaction to give 299 and 300 in 58% yield and 3.7:1 diastereomeric ratio. An initial

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Dixon and co-workers.144

Pauson−Khand reaction150 with Mo(CO)6 did not lead to any product formation. After several trials of olefin isomerization, upon treatment with K2CO3 in ethanol, the mixture of 299 and 300 gave the more substituted enone 301. Treatment under radical oxygenation conditions afforded 302 as a single regioand stereoisomer in moderate yield due to degradation of the starting material. A plausible reaction mechanism151 is shown in Scheme 39. This synthetic strategy offered a scalable route for the late-stage construction of the all-carbon tricyclic core of Daphniphyllum alkaloids. 6.5.4. Asymmetric Synthesis of the ABCD Ring System of Daphnilongeranin B. In 2012, Hao, Wang, and coworkers152 reported the synthesis of the ABCD core of daphnilongeranin B. Starting with the known enantiopure diol 303, available from (S)-carvone in four steps, tosylation followed by nucleophilic displacement with 4-methoxyphenoxide afforded 304 (Scheme 40). In two successive steps, allylic alcohol 304 was converted to 305 via an Overman rearrangement153 of the corresponding trichloroacetimidate. Methanolysis of 305 followed by N-hydroxylmethylation afforded 306, which was reacted with 307 in the presence of Sn(NTf2)4 to afford 309 via an in situ-generated iminium ion 308. Acetylation and photoinduced intramolecular [2 + 2] cycloaddition reaction afforded 310 as a major product. Reduction of the ketone, followed by mesylation and base-promoted Grob fragmentation, afforded azatricyclic compound 311. With the W

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Scheme 38. Synthesis of the DEF Ring System of Daphniyunnine Da

a

Scheme 40. Synthesis of the ABCD Ring System of Daphnilongeranin Ba

Dixon and co-workers.146

Scheme 39. Mechanism of Radical Oxygenation

a

BCD ring in hand, the subsequent steps involved deprotection of the 4-methoxyphenyl group, followed by mesylation to provide 312 in excellent yield. Cleavage of the carbamate, followed by intramolecular displacement of the mesylate, generated the tetracyclic core structure 313. The bowl-shaped architecture and highly strained ring junction associated with the double bond resulted in a highly stereoselective hydrogenation to give 314. The appropriate choice of chiron 303 allowed elaboration of the A−D ring core structure of daphnilongeranin B in enantiopure form. Two other syntheses154,155 from the same group also employing (S)carvone as a starting material led to the azacyclic model compounds shown in Figure 13.

By Hao, Wang, and co-workers.152

Figure 13. Synthesis of azacyclic core structures of daphnilongeranin B by Hao, Wang, and co-workers.152

6.5.5. Asymmetric Synthesis of the ADE Ring System of Longeracinphyllin B. In 2012, Tu, Zhang, and coworkers156 reported a synthesis of the ADE ring core structure of longeracinphyllin B. The synthesis started with a one-pot tandem semipinacol-type 1,2-carbon migration of 317 in the presence of MeAlCl2, followed by an in situ aldol reaction with X

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ology to construct 6-substituted spiro[4.5]decane-1,7-diones was an extension of a previously developed methodology157 in which a chiral amine and a Brønsted acid were used. 6.5.6. Asymmetric Synthesis of the ABC Ring System of ent-Daphniyunnine C. Yao and Liang158 reported a concise and scalable route for the construction of the ABC core structure of ent-daphniyunnine C (271). Like the synthesis by Hao and Wang and co-workers152 of the azatricyclic core of daphnilongeranin B, this synthesis also commenced with enantiopure 328, derived in four linear steps from (R)-carvone 327 (Scheme 43). The successive steps involved selective

aldehyde 318 to give a mixture of 6-substituted spiro[4,5]decane-1,7-diones (Scheme 41). The reaction provided a Scheme 41. Synthesis of the ADE Ring System of Longeracinphyllin Ba

Scheme 43. Synthesis of the ABC Ring System of entDaphniyunnine Ca

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Tu, Zhang, and co-workers.156

separable mixture of 319/320 and 321/322 in a 4.7:1 ratio, whose structures were determined by NMR analysis and later confirmed by X-ray crystallography. The methodology was successfully applied to a range of aldehyde substrates to access several 6-substituted spirodiketones. A plausible mechanism is shown in Scheme 42. Chemoselective reduction of 319 and 320 with NaBH(OAc)3, followed by protection of the diol as the acetonide, afforded 323 in 58% yield and 41% de. In the following step, 323 was treated with KHMDS to form the potassium enolate, and in situ reaction with PhNTf2 led to 324. Pd(0)-catalyzed intramolecular cyclization afforded diene 325, which was further converted to 326. This expedient method-

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Yao and Liang.158

tosylation of the primary alcohol, followed by azidation and oxidation of the secondary allylic alcohol, to give 329. Staudinger reduction afforded a mixture of amine 330 and inseparable aza-Michael product 331. The mixture of 330 and 331 was subjected to alkylation with allylic bromide 332 to provide 333. Pd(0)-catalyzed alkylation of ketone 333 gave azatricycle 334, which upon hydrogenation afforded 335 with complete diastereoselectivity. A similar Pd(0)-catalyzed alkylation of a ketone was used in the synthesis by Bonjoch and coworkers137 of calyciphylline A-type alkaloid core. The synthesis of the ABC core of ent-daphniyunnine C was achieved in seven steps in 48% yield from 328. 6.5.7. Asymmetric Synthesis of the ABCD Ring System of Daphnilongeranin B. In 2014, Shao, Li, and co-workers159 reported a synthesis of the ABCD core of daphnilongeranin B, relying on Au(I)-catalyzed Conia-ene reaction160 to construct a bridged 6,6-bicyclic intermediate. The synthesis commenced with the racemic cyclohexenone 336, which was subjected to Mitsunonu amination with propargylamine 337 to afford 338 (Scheme 44). Treatment of the enol silane derivative 339 with gold(I) catalyst resulted in a Conia-ene reaction to give the bridged 6,6-bicyclic enone 340 (Scheme 45). The following

Scheme 42. Mechanism of Lewis Acid-Promoted Tandem Semipinacol-type 1,2-Carbon Migration/Aldol Reaction

Y

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Scheme 44. Synthesis of the ABCD Ring System of Daphnilongeranin Ba

Scheme 45. Mechanism of Au(I)-Catalyzed Conia-ene Reaction

selective reduction of the aldehyde functionality of 346, followed by TBS protection furnished 347. Hydrogenation with Crabtree’s catalyst furnished the desired 348 as a single isomer. Interestingly, hydrogenation in the presence of Pd/C gave exclusively the opposite epimer. Finally, in three successive steps, 348 was converted to 349 through a deprotection− protection and decarboxylation sequence. Construction of the tetracyclic core of daphnilongeranin B was accomplished in 17 steps. The Au(I)-catalyzed Conia-ene reaction and two diastereoselective intramolecular Michael addition reactions are worthy of note. 6.5.8. Asymmetric Synthesis of the ABC Ring System of ent-Calyciphylline A. In 2014, Stockdill and co-workers161 reported an expedient synthesis of the ABC core of entcalyciphylline A that used a radical-mediated tandem cyclization of a neutral aminyl radical. The synthesis began with the previously reported 350, derived from (R)-carvone 327 in three steps (Scheme 46). Reduction of lactone to the corresponding lactol, followed by reductive amination in the presence of propargylamine, afforded 351. N-chlorination followed by Dess−Martin oxidation furnished 352, which was subjected Scheme 46. Synthesis of the ABC Ring System of entCalyciphylline Aa

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Shao, Li, and co-workers.159

steps involved deprotection of the nosyl group and carbodiimide-mediated coupling of the secondary amine with 341 to give amide 342. Michael reaction in the presence of K2CO3 afforded 343 in 82% yield and 78% de. Two adjacent quaternary stereocenters were introduced in a highly stereocontrolled manner in this intramolecular Michael addition reaction. Introduction of an exocyclic methylene by use of Eschenmoser’s salt gave 344, which was converted to the alcohol and then oxidized to aldehyde 345. Upon treatment with Et3N in dichloromethane at 60 °C, a second intramolecular Michael addition reaction took place to provide an epimeric mixture of products, which was eventually converted to 346 via epimerization under strong basic conditions. The structure of 346 was confirmed via X-ray crystallographic analysis of the corresponding diacetate derivative. Chemo-

a

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to a free radical-initiated tandem cyclization to afford 353 as a single isomer. The structure and relative stereochemistry were determined by NMR spectroscopic analysis. This transformation involved a homolytic cleavage of the N−Cl bond to give N-centered radical (I), which underwent a 6-exo Michael-type addition to the enone intermediate and a concomitant attack on the alkyne unit to give the exocyclic vinyl radical intermediate (III), which finally led to 353 (Scheme 47). Synthesis of the ABC core of ent-calyciphylline A

Scheme 48. Synthesis of the ACD Ring System of Calyciphylline A-type Alkaloidsa

Scheme 47. Radical-Mediated Tandem Cyclization Mechanism

was accomplished in five linear steps starting from the known 350 in 61% yield. The 6-exo cyclization of secondary aminyl radical under neutral conditions in excellent yield is noteworthy. In the following year, the same group reported an extension162 of the above synthesis. Instead of propargylamine, they used 5-methylhex-5-en-2-yn-1-amine and continued the synthesis by a similar approach. 6.5.9. Synthesis of the ACD Ring System of Calyciphylline A-type Alkaloids. Zhai and co-workers163 reported a model synthesis of the ACD core of calyciphylline A-type alkaloids such as daphlongamine E. The synthesis began with condensation of amine 268 with the acid chloride corresponding to 354 to give 355 (Scheme 48A). Upon heating in toluene in the presence of BHT at 140 °C, 355 underwent an intramolecular Diels−Alder reaction to give 356. The one-pot operation generating four new stereogenic centers with complete stereocontrol can be explained by considering a transition-state model shown in Scheme 48B. The endo transition state is destabilized due to the H−H interaction, which is absent in the exo transition state. Unfortunately, the αcarbon of lactam 356 possessed the incorrect stereochemistry. Prolonged heating of the reaction mixture led to epimerization to afford 357. Alternatively, 356 could be easily epimerized to 357 upon treatment with LDA in THF−HMPA mixture. However, dibromocyclopropane formation from 357 was not possible. Instead, 356 was converted to the corresponding dibromo derivative 358, which upon treatment with hot formic acid underwent a ring-expansion reaction to give 359. Several attempts to epimerize the α-center of lactam 359 were unsuccessful. Ultimately, a palladium(II)-mediated dehydrobromination of 359 afforded 360. Thus, a tricyclic model core structure of a calyciphylline A-type alkaloid was accomplished in six linear steps in 18% overall yield from 354. 6.5.10. Synthesis of the ACD Ring System of Calyciphylline A-type Alkaloids. In 2015, Xu and coworkers164 reported a synthesis of the [6,5,7] azatricyclic core

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Zhai and co-workers.163

of calyciphylline A-type alkaloids based on an intramolecular [3 + 2] cycloaddition involving a nonstabilized azomethine ylide intermediate. The first step involved the carbomethoxylation of 192, followed by reduction of the carbonyl group, mesylation, and DBU-mediated elimination to afford unsaturated ester 361 (Scheme 49). LDA-promoted deconjugative alkylation of 361 with 362 led to 363. An allylic oxidation with PDC and tertbutyl hydroperoxide provided 364. In two successive steps, 364 was converted to aldehyde 365, which upon treatment with Nbenzyl-N-(trimethylsilyl)methylamine afforded 368 via iminium ion formation, subsequent desilylation, and [3 + 2] cycloaddition through the nonstabilized azomethane ylide intermediate 367. The stereochemistry of 368 was determined by NMR spectroscopic analysis. The [3 + 2] cycloaddition reaction involving a nonstabilized azomethine ylide generated by desilylation of an N-(trimethylsilyl)methyliminium salt with an enolizable hydrogen is unprecedented. 6.6. Synthesis of Calyciphylline B-type Alkaloids

In 2003, Morita and Kobayashi22 isolated calyciphylline B (369) from the leaves of D. calycinum and a tentative structure was assigned by NMR spectroscopic analysis. Six new calyciphylline B-type alkaloids have been reported since 2003 (Figure 14). Deoxycalyciphylline B (370) and deoxyisocalyciphylline B (371) were isolated from stems of Daphniphyllum subverticillatum and the structure was confirmed by X-ray analysis.23 Oldhamiphylline A (372)165 and daphnioldhanine J AA

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daphlongamine H (376), which is the first example of a calyciphylline B-type alkaloid with a C-6/C-7 cis junction. As such, daphlongamine H is the C-5 epimer of deoxyisocalyciphylline B. The eight known calyciphylline B-type alkaloids to date possess complex hexa- or pentacyclic frameworks encompassing 8−9 stereogenic centers (Figure 14). Morita and Kobayashi22 and Yang and Yue23 independently proposed biosynthetic pathways for calyciphylline B-type alkaloids (Scheme 50). According to Morita and Kobayashi,22

Scheme 49. Synthesis of the ACD Ring System of Calyciphylline Aa

Scheme 50. Two Biosynthetic Proposals for Calyciphylline B-type Alkaloidsa

a

Xu and co-workers.164

a

According to (A) Morita and Kobayashi22 and (B) Yang and Yue.23

calyciphylline B might be generated via a series of bond migrations and eventual lactone formation as represented by intermediates II−IV (Scheme 50 A). The origin of the trans stereochemistry at C-6/C-7, arising from an enamine intermediate during backbone rearrangement steps, was not explained. Yang and Yue23 proposed the generation of carbonium ion intermediates V and VI from IV, leading to a tetrasubstituted alkene intermediate VII, which picks up a

Figure 14. Representative calyciphylline B-type alkaloids.

(373)64 were isolated from stems and leaves of Daphniphyllum oldhami. The pentacyclic methyl ester longistylumphylline C (374)133 was isolated from stems and leaves of D. longistylum, and its epimer, caldaphnidine R (375), was isolated from twigs of D. calycinum.166 In 2009, Hao and co-workers136 reported AB

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eight linear steps from 4-(R)-hydroxy-L-proline. Grieco elimination168 to alkene 378 and a three-step sequence led to 379 in good overall yield. Treatment of 379 under Dieckmann conditions with KHMDS in THF provided the β-keto ester, which was decarboxylated to the azabicyclic ketone 380, whose structure was confirmed by X-ray analysis. Under Wittig reaction conditions, ketone 380 underwent a two-carbon homologation to 381, which was converted to the allylic alcohol 382 in excellent overall yield. Various methods of sigmatropic rearrangement were unsuccessful to introduce the quaternary stereocenter. Via the Johnson−Claisen169 protocol, 382 was converted to 383 as a 7:3 mixture of chromatographically separable diastereomers. The structure and stereochemistry of 383 were unambiguously confirmed by X-ray analysis. In three linear steps, 383 was homologated to 384 by the Arndt−Eistert protocol. After several unsuccessful attempts to functionalize the olefin to the corresponding ketone under Wacker conditions, 384 was treated with Br2 in chloroform to afford the corresponding bromolactone, which was debrominated by use of Raney Ni to give 385. In three successive steps, carbamate 385 was converted to ketone 386. Upon treatment with TFA, followed by addition of cyclohexanone in toluene, 386 underwent an iminium ion−enamine cascade reaction to give the corresponding conjugated iminium intermediate, which was further treated with NaBH4 to afford 387.170 A proposed mechanism for this cascade is shown in Scheme 52. The Dieckmann cyclization,

proton to give the tertiary carbocation intermediate VIII that is captured by the carboxylic acid (Scheme 50B). It is curious that VI should lose the C-6 proton to give a neutral intermediate VII, only to be reprotonated to VIII, now containing a C-6/C-7 trans junction. It should be noted that ring C exists as a boat conformation based on the X-ray crystal structure of deoxycalyciphylline B.23 Although the absolute stereochemistry of calyciphylline B is established from the X-ray structure, the definitive biosynthetic steps that lead to the C-6/C-7 trans junction in the two proposals remain to be confirmed. 6.6.1. Asymmetric Synthesis of the ABCE Ring System of Calyciphylline B-type Alkaloids. In 2016, Hanessian and co-workers167 reported a model tetracyclic core structure of calyciphylline B-type alkaloids (Scheme 51). The synthesis commenced from the previously reported all-syn 3,4-disubstituted L-proline ester derivative 377, which was synthesized in Scheme 51. Synthesis of the ABCE Core System of Calyciphylline Ba

Scheme 52. Iminium Ion−Enamine Cascade Cyclization Mechanism

a

Johnson−Claisen rearrangement, and an iminium ion−enamine cascade sequence are worthy of note in this synthesis, although the stereochemistry of the newly introduced hydrogen did not correspond to that in calyciphylline B according to NMR analysis. 6.6.2. Asymmetric Synthesis of Isodaphlongamine H (6-epi-Deoxycalyciphylline B). In 2009, Hao and coworkers136 reported the isolation of a calyciphylline B-type alkaloid from D. longeracemosum Rosenth., which was named daphlongamine H. Remarkably, daphlongamine H contains a C-6/C-7 cis junction, which is reminiscent of biosynthetic intermediate VI in the proposal of Yang and Yue23 (Scheme 50

Hanessian and co-workers.167 AC

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Scheme 54. Total Synthesis of Isodaphlongamine H, Part 1a

B). In principle, simple lactonization can lead to daphlongamine H or its hitherto unknown C5 epimer (Scheme 53). The structure and stereochemistry of daphlongamine H were deduced from its similarity to 6-epi-deoxycalyciphylline B. Scheme 53. Biosynthetic Proposal for Deoxycalyciphylline B-type Alkaloid Quartet

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conjugate addition to enaminone 395, afforded the intended azatricyclic intermediate 400 in 92% yield and 90% de. The stereochemistry of the newly created stereogenic carbon was confirmed by X-ray crystallography at a late stage. Silyl deprotection of 400 followed by PCC oxidation provided the aldol precursor 401. An aldol reaction mediated by TBD (1,5,7triazabicyclo[4.4.0]dec-5-ene)174 led to the corresponding βhydroxy ketone, which was treated with p-TSA in 1,1,2trichloroethane at 65 °C to afford enone 402 in good yield. LSelectride was found to be the best reagent for 1,4-conjugate hydride addition to provide pentacyclic ketone 403. Addition of MeLi led to the tertiary alcohol 404, whose structure and stereochemistry were ascertained from an X-ray crystal structure of the corresponding methiodide. Hydroboration of 404 with 9-BBN, followed by PCC oxidation of the resulting alcohol, gave 5-isodaphlongamine H 388 (which is same as 6-epi-deoxycallyciphylline B). The structure and stereochemistry were confirmed by X-ray analysis. The total synthesis of 5-epi-daphlongamine H (6-epi-deoxycalyciphylline B) was accomplished in 24 linear steps from commercially available 2-(ethoxycarbonyl)cyclopentanone 84. According to the biosynthetic proposal for calyciphylline B by Yang and Yue,23 epimerization at C-6 took place via formation of a tetrasubstituted alkene, followed by lactonization (Scheme 53). To correlate with their proposed biosynthetic path (Scheme 50 B), intermediate 404 was subjected to E1 or E2 elimination conditions, only to provide the exocyclic 405 (Scheme 56). All attempted isomerizations of 405 to the endocyclic analogue 406 failed, most likely due to severe A1,3 strain in the product. DFT calculations concur with these results, showing that endocyclic 406 is 2.5 kcal/mol higher in energy compared to exocyclic 405. It is of interest that ring C in

Total synthesis of isodaphlongamine H, the C5 epimer of the natural product, was reported by Hanessian and co-workers.171 Synthesis of the aza-octahydropentalene unit began with the known enantiopure compound 389, which was synthesized in two consecutive steps from 2-(ethoxycarbonyl)cyclopentanone 84 by adopting a chemoenzymatic method (Scheme 54). Allylation of 84, followed by kinetic resolution of the racemic product with baker’s yeast, afforded enantioenriched 389 in 40% overall yield and 99% ee. Swern oxidation led to the corresponding β-keto ester, which was subjected to a diastereoselective enolate alkylation with the triflate derived from (S)-methyl lactate to give a 1:1 inseparable mixture of ketone 390 in moderate yield. A Luche reduction allowed the separation of the desired enantiopure alcohol, which was then subjected to DIBAL-H reduction to give diol 391. Bismesylation, followed by selective monoazidation with Bu4NN3 in toluene, afforded 392. Under Staudinger reduction conditions, 392 was converted to the primary amine, which underwent an intramolecular cyclization to provide the bicyclic ester 393 after in situ protection with (Boc)2O. In four successive steps, 393 was transformed to ynone 394 in 58% overall yield. Via the Georg protocol,172,173 ynone 394 was converted to the cyclic enaminone 395. Elaboration of the perhydroindene segment started with conversion of cyclopentenone 396 to the known iodocyclopenten-1-ol 397 (Scheme 55). Upon treatment with 1,1,1trimethoxyethane in the presence of catalytic propionic acid at 145 °C, 397 underwent a typical Johnson−Claisen rearrangement to give a mixture of esters, which were subjected to DIBAL-H reduction to afford 398. Protection as the TBS ether, following conversion to a cuprate and diastereoselective 1,4AD

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Scheme 55. Total Synthesis of Isodaphlongamine H, Part 2a

isodaphlongamine H (6-epi-calyciphylline B) adopts a chair conformation as seen in the X-ray studies, while the same ring in deoxycalyciphylline B has a boat conformation. DFT calculations estimate that 6-epi-deoxycalyciphylline B is 3.3 kcal/mol more stable than deoxycalyciphylline B.171 6.7. Synthesis of Daphniglaucin A- and C-type Alkaloids

In 2003, Kobayashi and co-workers21 isolated two cytotoxic Daphniphyllum alkaloids named daphniglaucins A and B (407 and 408) from the leaves of Daphniphyllum glaucescens (Figure 15). These alkaloids possess an unprecedented fused-polycyclic

Figure 15. Representative daphniglaucin A- and C-type alkaloids.

a

skeleton with 1-azoniatetracyclo[5.2.2.0.1,60.4,9]undecane ring system. Their structures and relative stereochemistry were determined by spectroscopic data. In the following year, daphniglaucin C (409), having a new Daphniphyllum skeleton and possessing a different skeletal structure in comparison with A and B, was isolated from the leaves of D. glaucescens (Figure 15).24 The structure and relative stereochemistry were resolved by spectroscopic analysis. According to Kobayashi and coworkers,21,24 daphniglaucins A and B might be biogenetically derived from yuzurimine A (Scheme 57). Biosynthetically, daphniglaucin C could originate from Heathcock’s proposed imine intermediate II (Scheme 5) via a successive fragmentation of the secodaphnane skeleton III, ring opening, then closing, oxidation of VII, and subsequent Polonovski-type cleavage of the epoxide. 6.7.1. Synthesis of the BCG Ring System of Daphniglaucin A. In 2008, Wipf and co-workers175 reported synthesis of the tricyclic quaternary ammonium core of daphniglaucins. The synthesis commenced with the protection of 1,5-pentanediol 412 as the trityl ether, followed by Swern oxidation and formation of p-tolylsulfinyl imine precursor 413 (Scheme 58). Successive addition of MeLi and tBuLi to 1,1dibromo-2-chloromethylcyclopropane (414) generated the bicyclic[1.1.0]butan-1-yllithium reagent, which was added to 413 to afford amide 415 via elimination of sulfinylate and addition to the resulting imine intermediate. N-alkylation with allyl bromide 416 gave 417, which was deprotected to the alcohol and then oxidized to give 418. Refluxing in benzene led to a formal Alder-ene reaction to give 419 in 39% yield and 71% de in four steps. NaBH4 reduction of 419, followed by three successive protection−deprotection steps, provided 420. Mesylation followed by carbamate deprotection afforded the corresponding aminomesylate intermediate, which underwent an intramolecular cyclization under basic conditions to provide

Hanessian and co-workers.171

Scheme 56. Attempted Simulation of a Biosynthetic Pathway toward Isodaphlongamine Ha

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Hanessian and co-workers.171

AE

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Scheme 57. Biosynthesis of Daphniglaucin A- and C-type Alkaloidsa

a

Scheme 58. Synthesis of the BCG Ring System of Daphniglaucin Aa

According to Kobayashi and co-workers.21,24

421. Oxidative cleavage of cyclobutene 421 by the Lemieux− Johnson method, followed by reduction of the resulting dialdehyde with sodium borohydride, afforded diol 422. Upon treatment with MsCl and NaHCO3, 422 gave the quaternary salt 423, which corresponds to the tricyclic core of daphniglaucin A. The synthesis was accomplished in 17 steps starting with 1,5-pentanediol 412. The use of a strained bicyclobutane ring system in alkaloid synthesis to construct a spirocyclic compound via an Alder-ene-type reaction is worthy of note. 6.7.2. Synthesis of the AD Ring System of Daphniglaucin C. The octahydroindole skeleton is common in several Daphniphyllum alkaloids such as daphniglaucin C, daphnilactone B, and caldaphnine. In 2014, Hanessian and co-workers176 reported the synthesis of a functionalized octahydroindole unit of daphniglaucin C, relying on a radical-mediated intramolecular enyne cyclization. The synthesis began with epoxidation of commercially available (±)-cyclohex-2-en-1-ol (424), followed by benzylation to give 425 (Scheme 59). Regioselective epoxide opening gave the corresponding trimethylsilyl ether intermediate, which upon methanolysis afforded 426 over two steps. A Mitsunobu amination with Ntosylpropargylamine furnished 427. An intramolecular radical enyne cyclization with AIBN and tributyltin hydride afforded octahydroindole 428 after protonolysis of the vinyl stannane

a

Wipf and co-workers.175

intermediate. The structure and relative stereochemistry of 428 were established by X-ray crystallography. Successive functional-group manipulations converted 428 into 429. It is of interest that hydrogenation of the exomethylene to the α-Me group was achieved after deprotection of the N-tosyl group. An acetyl-protected amine led exclusively to the β-Me group upon hydrogenation. After several unsuccessful trials for C-6 functionalization of ketone 429, α-bromination was achieved by use of NBS in hot acetic acid to give 430, which upon treatment with tetrabutylammonium acetate led to the corresponding acetoxy analogue 431. Further functionalization was achieved when 430 was treated with KCN in THF−MeOH to give 432, whose structure and stereochemistry were confirmed by X-ray analysis. The epoxynitrile intermediate 432 was synthesized in 13 steps in 20% overall yield from commercially available racemic cyclohex-2en-1-ol (424). 6.7.3. Asymmetric Synthesis of the ABCD Ring System of Daphniglaucin C. In 2013, Hanessian et al.177 reported a highly convergent synthesis of the tetracyclic core of AF

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Scheme 59. Synthesis of the AD Ring System of Daphniglaucin Ca

a

Scheme 60. Synthesis of the ABCD Ring System of Daphniglaucin Ca

Hanessian and co-workers.176

daphniglaucin C. The key steps involved a Grignard addition to an enaminone, a novel reductive allylic rearrangement under hydrogenation conditions, a Stille coupling with a cyclopentenyl stannane and a Dieckmann cyclization. The synthesis commenced with commercially available 433, which was converted to an enaminone by refluxing with 1,1-dimethoxyN,N-dimethylmethanamine (DMA) in toluene (Scheme 60). Treatment with 3-benzyloxypropyl magnesium bromide gave enone 434. Addition of MeMgBr to 434 in the presence of LaCl3·LiCl afforded 435 as the major isomer (88% for the mixture of diastereomers, 68% de). Hydrogenation with Pearlman’s catalyst led to a reductive allylic rearrangement and debenzylation to give a tetrasubstituted intermediate. Further hydrogenation with Pd/C gave the all-syn pyrrolidine 377 in 70% yield and 90% de. In 2014, the same group reported a mechanistic interpretation of this reductive allylic transposition of tertiary allylic alcohol that involved a Tsuji−Trosttype reaction pathway178 In two successive steps, alcohol 377 was converted to the corresponding methyl ester 436. Enolization with KHMDS followed by Dieckmann cyclization gave the corresponding enolate, which was converted to 437 with Comins’ reagent. The structure and stereochemistry of the Dieckmann cyclization product were confirmed by X-ray analysis. The known iodocyclopentene 438, obtained in four steps from cyclopentenone 396, was lithiated and then converted to the cyclopentenylstannane 439. A Pd2(dba)3·CHCl3-mediated Stille coupling of 437 with 439 in the presence of triphenylarsine and LiCl in DMF led to 440. In three successive steps, 440 was converted to 441, which was cyclized under Dieckmann reaction conditions, and the resulting β-keto ester was decarboxylated to give the tetracyclic core structure 442. The structure and stereochemistry of 442 were confirmed by crystal X-ray crystallography of the corresponding

a

Hanessian and co-workers.177

bromocarbamate derivative. Synthesis of the tetracyclic core of daphniglaucin C was achieved in 15 steps and 15% overall yield from the commercially available 4-keto-N-Boc methyl Lprolinate (433). A novel allylic ether transposition under hydrogenation conditions and a Stille coupling reaction are worthy of note. 6.8. Synthesis of Daphnipaxinin-type Alkaloids

In 2004, Yang and Yue25 isolated daphnipaxinin, the first Daphniphyllum alkaloid containing two nitrogen atoms in a unique hexacyclic fused skeleton from the stems of Daphniphyllum paxianum Rosenth. The structure and absolute stereochemistry of daphnipaxinin were determined by spectroscopic studies and CD analysis. The structure of daphnipaxinin has a close similarity with daphnicyclidin A-type alkaloids. Yang and Yue 25 proposed a plausible biogenetic path for daphnipaxinin, which might be derived from macrodaphniphyllamine-type and calyciphylline A-type alkaloids (Scheme 61). 6.8.1. Asymmetric Synthesis of the ABCD Ring System of Daphnipaxinin. In 2009, Overman and co-workers179 reported a synthesis of the ABCD ring structure of AG

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Scheme 61. Biosynthesis of Daphnipaxinin-type Alkaloidsa

a

Scheme 62. Synthesis of the ABCD Ring System of Daphnipaxinin, Part 1a

According to Yang and Yue.25

daphnipaxinin, relying on an aza-Cope−Mannich reaction and ring-closing metathesis. The synthesis commenced with an organocatalytic Diels−Alder reaction180 between dienophile 444 and diene 445 in the presence of MacMillan catalyst 446 to afford 447 in 77% yield and 91% ee (Scheme 62). Stereoselective Ni-catalyzed methylation of 447 with phosphoramidite catalyst 448 afforded 449 in 94% yield and 72% de. Palladium-catalyzed allylic rearrangement of the OTBDPS ether and silyl enol ether formation led to 450. The amino group was then introduced in a hetero-Diels−Alder reaction of diene 450 with nitrosocarbonylbenzene to furnish 451. Upon treatment with Mo(CO)6, the cycloadduct 451 afforded enone 452 as a 5:1 separable mixture of diastereomers. In two successive steps, 452 was converted to 453 via 1,4-conjugate addition and base-catalyzed epimerization. The dimethylphenylsilyl substituent in 453 was assumed to be a latent carbonyl group of daphnipaxinin. Reduction of 453, followed by selective N-cyanomethylation and subsequent oxidation of the secondary alcohol, led to ketone 454. Addition of the vinyllithium reagent 455 afforded 456. Upon treatment with AgNO3 in ethanol, 456 underwent iminium ion (457) formation, followed by a [3,3] sigmatropic rearrangement and Mannich-type addition to give 459 (Scheme 63). The stereochemistry of 459 was confirmed by X-ray analysis of its corresponding quaternary salt of the corresponding deprotected alcohol. The stereocontrolled, one-pot aza-

a

Overman and co-workers.179

Cope−Mannich tandem reaction led to a highly functionalized 5,7-fused azabicycle harboring a quaternary stereogenic center. A CeCl3·LiCl-activated Grignard addition to 459 gave 460, which was subjected to ring-closing metathesis in the presence of Grubbs’ second-generation catalyst to give 461. Upon treatment with thionyl chloride, 461 afforded the allylic chloride, which was hydrolyzed by use of alumina and water to give the corresponding allylic acohol. Oxidation under Swern conditions led to 462. Finally, deprotection to the alcohol, followed by mesylation and in situ intramolecular SN2 displacement, afforded 463. The synthesis of tetracyclic 463 was accomplished in 20 steps. The tandem aza-Cope−Mannich reaction sequence is a highlight of this synthesis. 6.9. Synthesis of Daphenylline-type Alkaloids

In 2009, Hao and co-workers38 reported a novel Daphniphyllum alkaloid from the fruits of D. longeracemosum called daphenylline, which possesses a 22-nor-calyciphylline A skeleton. The structure of daphenylline was determined by mass spectrometric and NMR spectroscopic analysis. The absolute stereochemistry was deduced on the basis of DFT methods. Hao and co-workers38 proposed a plausible biogenetic path for daphenylline where it could be derived from calyciphylline Atype alkaloids such as daphnilongeranin C (Scheme 64). AH

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would provide III and IV, which would undergo one or two steps of syn-[1,3] sigmatropic rearrangement to give daphenylline (464). After its isolation, several partial syntheses and one total synthesis of daphenylline were reported in literature. 6.9.1. Synthesis of the ABCE Ring System of Daphenylline. In 2012, She and co-workers181 reported a synthesis of the tetracyclic core of daphenylline. The synthesis commenced with LDA-mediated monoalkylation of (3methoxyphenyl)acetonitrile 465 with 2-iodoethanol THP ether, followed by reductive conversion of the cyano group to an aldehyde by use of DIBAL-H to give 466 (Scheme 65).

Scheme 63. Synthesis of the ABCD Ring System of Daphnipaxinin, Part 2a

Scheme 65. Synthesis of the ABCE Ring System of Daphenyllinea

a

Overman and co-workers.179

Scheme 64. Plausible Biogenetic Path for Daphenyllinea

a

a

She and co-workers.181

Addition of allylzinc bromide to 466 afforded 467 in 88% yield and 71% de. In two successive steps, 467 was converted to 468 via mesylation and subsequent azidation. The following steps involved reduction of the azide to the primary amine, nosylation, and amide formation with acryloyl chloride to give 469. Ring-closing metathesis with Grubbs’ secondgeneration catalyst led to α,β-unsaturated δ-lactam 470.181 A Brønsted acid-promoted intramolecular Friedel−Crafts-type Michael addition afforded 471, which was transformed to 472 and then subjected to intramolecular displacement of the OMs ester to furnish the ABCE ring structure (473) of daphenylline as the racemate. The synthesis was accomplished in 13 linear steps in 6.3% overall yield from 465.

According to Hao and co-workers.38

Biosynthetically, daphnilongeranin C (29) might be reduced to I and a Wagner−Meerwein-type rearrangement could provide intermediate II. Decarboxylation via a decarboxylase enzyme AI

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6.9.2. Second Synthesis of the ABCE Ring System of Daphenylline. Later in 2012, Xie, She, and co-workers182 reported a second synthesis of the tetracyclic skeleton of daphenylline. This synthesis was initiated with Cu-mediated 1,4-conjugate addition of lithiated 474 to α,β-unsaturated δlactone 475 to give lactone 476 in 69% yield with complete diastereoselectivity (Scheme 66). In three successive steps, 476

Scheme 67. Synthesis of the DEF Ring System of Daphenyllinea

Scheme 66. Second Synthesis of the ABCE Ring System of Daphenyllinea

a

a

She and co-workers.183

give 338 (Scheme 68). Formation of a silyl enol ether 338, followed by a gold-catalyzed 6-exo-dig Conia-ene160 reaction, gave the bridged 6,6-azabicyclic enone 340. In two successive steps, 340 was converted to 342, which, upon treatment with K2CO3 in hot acetonitrile, underwent a Michael addition reaction to give 343 containing two contiguous quaternary carbon atoms. The structure of 343 was confirmed by X-ray analysis. In the following steps, 343 was converted to the enol triflate and then subjected to a Suzuki cross-coupling reaction with 484 to afford 485 in 73% yield. Irradiation of 485 with a 125-W Hg lamp led to a cis-triene intermediate via a photoinduced isomerization process, which was reluctant to undergo the desired 6π-electrocyclization. However, irradiation with a 500-W Hg lamp as a photoinducer led to the pentacyclic intermediate 486. Upon treatment with DBU and air at elevated temperature, intermediate 486 underwent aromatization to afford 487, which was converted to enone 488 via Saegusa−Ito oxidation.185 Deprotection of 488, followed by conversion of the alcohol to an iodo intermediate and subsequent 7-exo-trig radical cyclization with AIBN and tris(trimethylsilyl)silane, furnished 489 in excellent yield. Hydrogenation of the exocyclic olefin with Crabtree’s catalyst afforded the desired diastereomer (94% de), which upon demethoxycarbonylation according to the Krapcho procedure furnished 490. The structure and stereochemistry of 490 were determined by X-ray analysis. Finally in two successive steps, 490 was converted to daphenylline via benzylic deoxygenation promoted by Pd/C and H2, followed by reduction of the lactam. Total synthesis of daphenylline was accomplished in 19 steps in 5.4% overall yield starting from known intermediate 336. This highly stereocontrolled synthesis featured a gold-catalyzed 6-exo-dig cyclization and Michael addition to construct the bridged 6,6,5-azatricyclic skeleton of daphenylline, as well as a photoinduced olefin isomerization/ 6π-electrocyclization cascade followed by oxidative aromatization. 6.9.4. Asymmetric Synthesis of the ACDE Ring System of Daphenylline. In 2015, Cao and co-workers186 reported a synthesis of the ACDE ring structure of daphenylline. The synthesis began with a Jeffrey−Heck coupling187 between 1bromo-2-iodobenzene (491) and allyl alcohol to give 492 (Scheme 69). Upon treatment with ferric chloride in dichloromethane at 45 °C, 492 and N-tosylamino alcohol 493 underwent an aza-Cope−Mannich reaction via iminium ion intermediate 494 to afford 496. Reduction of the aldehyde group, followed by conversion to the corresponding phenylthio ether via a modified protocol of Isoe et al.188 and 6-exo-trig radical alkene cyclization via SN2′ sulfide displacement, led to 497 over three steps. Hydroboration of 497 followed by oxidative workup provided 498 in moderate yield. In three successive steps, alcohol 498 was converted to the two-carbon homologated ester 499, which was converted to the acid

Xie, She, and co-workers.182

was transformed to 477 through conversion to the corresponding Weinreb amide, followed by protection of the primary alcohol as the TBS ether and DIBAL-H reduction to the aldehyde. Upon treatment with tributyltin methylamine, 477 was converted to imine 478, which was further transformed to the azomethine ylide 479 by in situ addition of n-BuLi. The latter then underwent a [3 + 2] cycloaddition reaction to give 480. It was assumed that the high stereoselectivity of this transformation was associated with the twist-boat conformation of 479, in which the bulky group adopted a pseudo-equatorial orientation. Finally, acid-promoted silyl ether deprotection of 480, followed by conversion of the primary alcohol to the bromide and subsequent intramolecular displacement, afforded the racemic ABCE tetracyclic core structure (481) of daphenylline. The synthesis of 481 was achieved in eight linear steps in 14% overall yield from 474. The azomethine ylide [1,3] dipolar cycloaddition step is worthy of note. An asymmetric synthesis of a model compound related to rings DEF of daphenylline, relying on alkylation with an Evans auxiliary, was also reported by She and co-workers183 (Scheme 67). 6.9.3. Asymmetric Total Synthesis of Daphenylline. Inspired by the work of Dixon and co-workers,144 Li and coworkers184 disclosed the first total synthesis of daphenylline in 2013. The synthesis began with Mitsunobu amination of enantioenriched 336 with N-nosylpropargylamine (337) to AJ

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Scheme 68. Asymmetric Total Synthesis of Daphenyllinea

Scheme 69. Synthesis of the ACDE Ring System of Daphenyllinea

a

a

Cao and co-workers.186

longphyllinesides A and B, and hybridaphniphyllines A and B (Figure 3) have added further complexity and architectural beauty to this family of alkaloids. Skeletal diversity, coupled with one or more quaternary stereogenic carbon centers at the ring junctions, makes these alkaloids veritable challenges for total or partial syntheses. The potent anticancer, antioxidant, vasorelaxant, and anti-HIV properties of these alkaloids warrant further efforts toward their synthesis. To date only a small number of members of this family have been subjected to synthetic studies. A major challenge and highly rewarding endeavor associated with alkaloid synthesis is the development of new synthetic methodologies to construct the azapolycyclic core structures in a shorter number of steps with good global yields. We hope that this review will incite further studies toward the isolation and structural elucidation of new members of the Daphniphyllum family of alkaloids. Further insights into the biological activities and modes of action of these complex natural alkaloids, as well as their chemically modified congeners, may find useful therapeutic applications. As a result, further innovations in their total syntheses will undoubtedly emerge.

Li and co-workers.184

chloride and subjected to an intramolecular Friedel−Crafts acylation to afford tetracyclic 500 as the racemate. The one-pot iron(III)-catalyzed aza-Cope−Mannich reaction sequence and the 6-exo-trig aryl radical alkene cylization are key steps.

AUTHOR INFORMATION Corresponding Author

7. CONCLUSION Since 1966, the isolation, structure elucidation, and synthesis of Daphniphyllum alkaloids have attracted considerable attention. In the last 50 years, more than 320 Daphniphyllum alkaloids belonging to over 15 species were isolated. The recent isolation of highly complex and hybrid structures like logeracemin A,

*E-mail [email protected]. ORCID

Stephen Hanessian: 0000-0003-3582-6972 Notes

The authors declare no competing financial interest. AK

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Biographies

IBX IC50 IKK-β KAPA LDA LTMP MOM Ms NBD NBS NCS NGF NMO Ns PAF PCC PDC Piv PMB PPTS PTP 1B Py salen

2-iodoxybenzoic acid half-maximal inhibitor concentration IκB kinase β-subunit 7-keto-8-aminopelargonic acid lithium diisopropylamide 2,2,6,6-tetramethylpiperidine lithium salt methoxymethyl methanesulfonyl 7-nitrobenzo-2-oxa-1,3-diazole N-bromosuccinimide N-chlorosuccinimide nerve growth factor N-methylmorpholine N-oxide nosyl or 4-nitrobenzenesulfonyl platelet activating factor pyridinium chlorochromate pyridinium dichromate pivaloyl p-methoxybenzyl pyridinium p-toluenesulfonate protein tyrosine phosphatase 1B pyridine 2,2′-ethylenebis(nitrilomethylidene)diphenol or N,N′-ethylenebis(salicylimine) L-selectride tri-sec-butylborohydride, lithium salt TBAF tetrabutylammonium fluoride TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene TBDPS tert-butyldiphenylsilane TBS tert-butyldimethylsilane TCCA trichloroisocyanuric acid TEBA triethylbenzylammonium chloride TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran THP tetrahydropyranyl TIPS triisopropylsilyl TPAP tetrapropylammonium perruthenate TPP triphenylphosphine TMS trimethylsilyl Ts tosyl or p-toluenesulfonyl p-TSA p-toluenesulfonic acid

Amit Kumar Chattopadhyay was born in Purulia, West Bengal, India. He obtained his M.Sc. (2004) from The University of Burdwan, India. He then moved to the Indian Institute of Chemical Technology (Hyderabad, India) to pursue his doctoral research and received his Ph.D. (2010) from Osmania University (India) under the supervision of Professor Tushar Kanti Chakraborty. He is currently working as a postdoctoral research associate with Professor Stephen Hanessian at Université de Montréal. His research focuses on complex alkaloid syntheses and medicinal chemistry. Stephen Hanessian holds the Ionis Pharmaceuticals Research Chair at the Université de Montréal. He is also on the faculty in the Department of Pharmaceutical Sciences, with joint appointments in the Departments of Chemistry and Pharmacology at the University of California, Irvine, as the Director of the Medicinal Chemistry and Pharmacology Graduate Program. His research interests are in organic, bioorganic, and medicinal chemistry.

ACKNOWLEDGMENTS We are thankful to NSERCC for financial support. DEDICATION † Dedicated to Professor Clayton H. Heathcock for his seminal contributions to the field of Daphniphyllum alkaloids. ABBREVIATIONS Ac acetyl acac acetylacetonate AIBN azobis(isobutyronitrile) 9-BBN 9-borabicyclo[3.3.1]nonane BHT butylated hydroxytoluene Bt benzotriazole Bz benzoate CAN ceric ammonium nitrate CBS Corey−Bakshi−Shibata m-CPBA m-chloroperoxybenzoic acid CD circular dichroism CSA 10-camphorsulfonic acid dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene de diastereomeric excess DFT density functional theory DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminium hydride DIPEA diisopropylethylamine DIPHOS 1,2-bis(diphenylphosphino)ethane DMA 1,1-dimethoxy-N,N-dimethylmethanamine DMAC N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMS dimethyl sulfide DMSO dimethyl sulfoxide dppe 1,2-bis(diphenylphosphino)ethane dr diastereomeric ratio DTBMP 2,6-di-tert-butyl-4-methylpyridine EC50 half-maximal effective concentration ee enantiomeric excess HIV human immunodeficiency virus HMDS hexamethyldisilazane HMEC human microvascular endothelial cell line HMPA hexamethylphosphoramide

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AQ

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