Total Synthesis of the Tetracyclic Antimalarial Myrioneuron Alkaloid (±)-Myrioneurinol

The Pennsylvania State University

The Graduate School

Eberly College of Science

TOTAL SYNTHESIS OF THE TETRACYCLIC ANTIMALARIAL MYRIONEURON ALKALOID (±)-MYRIONEURINOL

A Dissertation in

Chemistry

Anthony J. Nocket

Submitted in Partial Fulfillment

of the Requirements

for the Degree of

Doctor of Philosophy

August 2015

The dissertation of Anthony J. Nocket was reviewed and approved* by the following:

Steven M. Weinreb Russell and Mildred Marker Professor of Natural Products Chemistry Dissertation Advisor Chair of Committee

Kenneth E. Feldman Professor of Chemistry

Alexander Radosevich Assistant Professor of Chemistry

Edward G. Dudley Associate Professor of Food Science

Tom Mallouk Evan Pugh Professor of Chemistry, Physics, Biochemistry, and Molecular Biology Head of the Department of Chemistry

*Signatures are on file in the Graduate School

ABSTRACT

The first total synthesis of the tetracyclic antimalarial alkaloid myrioneurinol (19) in racemic form has been completed in twenty-seven steps and in 1.8% overall yield from commercially available materials. The spiranic A/D-ring subunit of the metabolite with the attendant C5,6-stereocenters was constructed via a highly diastereoselective intramolecular

Michael addition (IMA) of N-Cbz lactam/(E)-α,β-unsaturated ester cyclization precursor 61 to afford spirocycle 62. After a series of failed attempts to alkylate various ester enolate and pyrrolidinoenamine derivatives of 62 at C7, an umpolung strategy involving the conjugate addition of a malonate enolate to the nitrosoalkene intermediate 124, derived from α-chloro-O- silylaldoxime 122, provided oxime geometric isomers 123a/b. Both of these isomers possessed the correct C7-stereochemistry for the natural product. Several methods were then explored to accomplish the pivotal C9,10 carbon-carbon bond formation to construct the B-ring within the cis- decahydroquinoline (DHQ) scaffold of the alkaloid. These approaches included the unsuccessful nitrile α-anion/imidate cyclization of precursor 133 and the olefin/lactam Rainier metathesis of N- sulfonyllactam precursors 156 and 160 to provide tricyclic enesulfonamides 157 and 161, respectively. Although the latter ring-closing metathesis method was successful, we were unable to functionalize tricycles 157 and 161 at C9 in order to complete the total synthesis. We were pleased to discover that an intramolecular allyl silane/N-sulfonyliminium ion variant of the Sakurai reaction could be utilized to construct the B-ring of the cis-DHQ system, resulting in a single diastereomer of tricycle 191 with the desired C9,10 relative configuration, which we were able to elaborate to (±)-myrioneurinol.

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TABLE OF CONTENTS

LIST OF FIGURES vii

ACKNOWLEDGEMENTS viii

CHAPTER 1. INTRODUCTION AND BACKGROUND

1.1. Myrioneuron and Nitraria Alkaloids: Typical Structures and a Unified Biosynthetic Pathway 1 1.2. A Novel Tetracyclic Myrioneuron Alkaloid: (+)-Myrioneurinol 5 1.3. Previous Synthetic Studies toward the Myrioneuron Alkaloids 9 1.4. First Generation Retrosynthesis of (±)-Myrioneurinol 12 1.5. Background on Diastereoselective Intramolecular Michael Additions (IMAs) and Related Reactions 13 1.6. Preliminary Studies on the IMA Spirocyclization toward Myrioneurinol 17

CHAPTER 2. IMA STRATEGY TO CONSTRUCT A/D-RING SUBUNIT

2.1. ‘Soft’ Enolization Inspired by Evans, et al. 19 2.2. First Generation Route to N-Cbz Lactam Cyclization Precursor 20 2.3. Attempted ‘Soft’ IMA of Lactam Enoate 61 21 2.4. Determination of the Relative C5,6-Configuration of Spirocycle 62 23 2.5. Second Generation Route to Cyclization Precursor 61 25 2.6. Optimization Studies on the Pivotal IMA Spirocyclization 26 2.7. Exploration of Some Homologous IMA Spirocyclizations 28 2.7.1. Studies with Five-Membered Lactam Analog 74 29 2.7.2. Studies with Seven-Membered Lactam Analog 81 30 2.7.3. Rationalization for Failure of Enoates 74 and 81 to Spirocyclize 31 2.7.4. Modification of the Ester Tether Length 31 2.7.5. Studies with Homologues Pre-Functionalized at C7 33

2.8. Attempted Asymmetric IMA Spirocyclization 35 2.8.1. Studies with (-)-Menthyl Carbamate Cyclization Precursor 103 35 2.8.2. Studies with (+)-TCC Ester Cyclization Precursor 107 36

CHAPTER 3: HOMOLOGATION OF A/D-RING SUBUNIT AT C7

3.1. Attempts to Homologate via Formation of C7 Ester Enolates 39 3.2. Attempts to Homologate at C7 via Enamine Chemistry 41 3.2.1. Studies with N-H Lactam (E)-Pyrrolidinoenamine 112 41 3.2.2. Studies with N-Bn Lactam (E)-Pyrrolidinoenamine 116 43 3.3 C7-Homologation via Nitrosoalkene Umpolung Conjugate Addition 44 3.3.1. Background on Nitrosoalkene Conjugate Additions 44 3.3.2. Nitrosoalkene Michael Addition of α-Chloro-O-Silylaldoxime 122 46 3.3.3. Rationalization of Observed C7-Diastereoselectivity 49

CHAPTER 4: B-RING CLOSURE STRATEGIES

4.1. Imidate/Nitrile α-Anion Cyclization Strategy 50 4.1.1. Preparation of Cyclization Precursor 50 4.1.2. Imidate/Nitrile α-Anion Cyclization Studies 52 4.2. Rainier Metathesis Strategy 54 4.2.1. Background on the Rainier Metathesis Reaction 54 4.2.2. Second Generation Retrosynthesis 55 4.2.3. Preparation of N-Tosyllactam/Terminal Olefin Cyclization Precursor 56 4.2.3.1. Lactam Nitrile System 56 4.2.3.2. Methoxymethyl (MOM) Ether System 57 4.2.3.3. Rainier Metathesis of N-Tosyllactam 156 59 4.2.3.4. Attempted Elaboration of N-Ts Enesulfonamide 157 60 4.2.4. N-SES-Lactam System 62 4.3. Allyl Silane/N-Sulfonyliminium Aza-Sakurai Strategy 63 4.3.1. Background: Weinreb Synthesis of the Sarain A Core Structure 63

4.3.2. Third Generation Myrioneurinol Retrosynthesis 66 4.3.3. Preparation of Cyclization Precursor 67 4.3.3.1. Attempted Allyl Silane Formation via Fleming Cuprate Methodology in Nitrile System 67 4.3.3.2. Attempted Allyl Silane Formation in Methoxymethyl (MOM) Ether-Protected System 68 4.3.3.3. Seyferth-Wittig Homologation of Aldehyde 182 70 4.3.4. Aza-Sakurai Reaction of N-Tosyllactam/Allyl Silane 189 72 4.3.5. Confirmation of the C9,10 Stereochemistry of Tricycle 191 74

CHAPTER 5: COMPLETION OF THE MYRIONEURINOL SYNTHESIS

5.1. Attempted Elaboration of N-Ts Tricyle 191 76 5.2. Alternative Protecting Groups for the Lactam Nitrogen 78 5.2.1. N-SES-Lactam System 78 5.2.2. N-Nosyllactam System 79 5.2.3. Acid-Labile Sulfonamides 80 5.2.4. Attempted Cyclization of N-Cbz Lactam 82 5.3. N-Tosyllactam System Revisted 82 5.4. Endgame: Closure of the 1,3-Oxazine C-Ring 84 5.5. Concluding Remarks 85

CHAPTER 6: EXPERIMENTAL SECTION 89

REFERENCES 163

LIST OF FIGURES

Figure 1. Structures of Some Representative Myrioneuron Alkaloids 2

Figure 2. Structures of Some Representative Spiranic Nitraria Alkaloids 3

Figure 3. Structure and Conformation of (+)-Myrioneurinol (19) 5

Figure 4. Two-Dimensional NMR Analysis of (+)-Myrioneurinol (19) 6

Figure 5. NOESY Correlations for Tricycle 191 75

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ACKNOWLEDGEMENTS

Over the past five and a half years, I have had the great pleasure of pursuing my fascination with organic chemistry under the guidance of my advisor, Professor Steven M. Weinreb. I credit my growth as a scientist both to the challenging nature of natural product synthesis itself, and to the degree of independence and freedom of thought I have gained while working in his laboratory.

Furthermore, I would like to acknowledge the insightful discussions, assistance, and training I have received from other members of the Weinreb laboratory, both past and present. My most heartfelt thanks must also be extended to the many wonderful friends I have made during my time here at Penn State, to whom I owe a great deal of my sanity. Finally, I would be remiss if I did not acknowledge the unwavering support of my beloved family, to whom I dedicate this dissertation.

Without their constant words of encouragement in the face of the uncertainties and unavoidable setbacks of research, none of my accomplishments would have been possible.

viii

CHAPTER 1: INTRODUCTION AND BACKGROUND

1.1. Myrioneuron and Nitraria Alkaloids: Typical Structures and a Unified Biosynthetic

Pathway

The higher plant genus Myrioneuron (family Rubiaceae) includes approximately fifteen species distributed across southeast Asia. In recent years, M. nutans, a diminutive tree endemic to the forests of North Vietnam, has yielded a number of unusual secondary metabolites isolated from its aerial structures.1 These so-called ‘Myrioneuron alkaloids’ typically contain an array of chair six-membered rings including a cis-decahydroquinoline (cis-DHQ) moiety tightly fused to various carbocyclic or heterocyclic structural elements such as 1,3-oxazine and/or 1,3-diazine subunits.

These natural products range in complexity from the simple tricyclic compounds (+)-myrioxazines

A (Figure 1, 1) and B (2)2 to tetracycles such as (-)-schoberine (3) and (+)-myrionamide (4),3 pentacycles such as (+)-myriberine A (5),4 the hexacyclic compound (+)-myrobotinol (6),5 to the most complex metabolite isolated to date, the dimeric decacycle (+)-myrifabine (7).6 Myrioneuron alkaloids exhibit a variety of differing types of biological activity. For example, (+)-myriberine A

(5) was reported to effectively inhibit the hepatitis C virus. Moreover, some alkaloids, including an ester derivative of (+)-myrobotinol (6) as well as (+)-myrifabine (7), have shown promising cytotoxicity against KB cell lines.

H H H H H H H H H H H N O N N R N H N H H H O O N O H

(+)-myrioxazine A (1) (+)-myrioxazine B (2) R = H2, (-)-schoberine (3) R = O, (+)-myrionamide (4)

H H H H H O H N H N H N N H N N N O N H N H H N N H O H H H H HO OH (+)-myriberine A (5) (+)-myrobotinol (6) (+)-myrifabine (7)

Figure 1. Structures of Some Representative Myrioneuron Alkaloids.

Bodo, et al. have suggested that these metabolites all share a common biosynthetic pathway from L-lysine, despite their structural diversity.1 Even more intriguing is the proposed intersection of Myrioneuron alkaloid biosynthesis with that of the alkaloids of the somewhat distantly related higher plant genus Nitraria (family Nitrariaceae) via a common intermediate (vide infra).

The Nitraria species comprise a series of compact shrub-like plants distributed across arid regions of the Old World that have yielded a wealth of alkaloid natural products with varying types of biological activity. Representative examples of these metabolites range in complexity from the simple bicyclic compounds (+)-nitramine (Figure 2, 8)7 and (-)-isonitramine (9),8 to the tricyclic compound (-)-sibirinine (10),9 and the unusual hexacycle nitraramine (11).10 A common structural

2 feature within these and other Nitraria alkaloids is the presence of a distinctive spirocyclic ring system.

H N H N OH OH

(+)-nitramine (8) (-)-isonitramine (9)

O O N O Me N N N N H O H H

(-)-sibirinine (10) nitraramine (11)

Figure 2. Structures of Some Representative Spiranic Nitraria Alkaloids.

The proposed biosynthetic pathway1 for the alkaloids of both the Myrioneuron and Nitraria genera commences with the decarboxylation of L-lysine (12) to provide cadaverine (13), which is then oxidatively deaminated to furnish 5-aminopentanal (14) (Scheme 1). Cyclization of 14 provides imine/enamine pair 15a/b, which undergoes further Mannich-aldol and retro-Michael type transformations via tetrahydroanabasine (16), followed by a second oxidative deamination to furnish vinylogous imino-aldehyde intermediate 17. It is interesting to note that 16 is also implicated as a key intermediate in the biosynthesis of the alkaloids of the genus Lupinus (family

Fabaceae).

Scheme 1. A Unified Biosynthetic Pathway to the Myrioneuron and Nitraria Alkaloids from L-lysine (12)

O oxidative -CO2 NH NH deamination NH3 O 3 3 O NH3 NH3

L-lysine (12) cadaverine (13) 5-aminopentanal (14)

-H2O

H N N Mannich- H N retro-Michael H aldol type H N 2 N N H 15a tetrahydroanabasine (16) 15b oxidative deamination key imine/enamine tautomeric pair O N H N N O [H-] O

H 17 18a 18b

Mannich spirocyclization

quinolinic spiranic Myrioneuron Nitraria alkaloids alkaloids

At this juncture, upon partial reduction of the α,β-unsaturated imine moiety in 17 to form tautomeric pair 18a/b, the biosynthetic pathways within the two genera appear to bifurcate.

Whereas the cis-DHQ system within the Myrioneuron alkaloid scaffold is thought to emerge via

Mannich cyclization of imino-aldehyde tautomer 18a, the simple spiranic Nitraria alkaloids such as 8 and 9 can arise via spirocyclization of the enamine form 18b. The biosynthetic routes to the

4 more complex members of both the spiranic Nitraria and quinolinic Myrioneuron alkaloid classes are postulated to involve the incorporation of additional piperidine subunits derived from L-lysine.

1.2. A Novel Tetracyclic Myrioneuron Alkaloid: (+)-Myrioneurinol.

Evidence in favor of the above putative unified metabolic pathway for Myrioneuron and

Nitraria alkaloid biosynthesis had already come in the form of the isolation of (-)-schoberine (3) from members of both genera.1 However, the isolation of (+)-myrioneurinol (19) from the alkaline leaf extracts of M. nutans by Bodo, et al. in 2007 provided yet another vital piece of the biosynthesis puzzle (vide infra).11 This tightly fused tetracycle contains structural elements emblematic of the Myrioneurion alkaloids including cis-DHQ and 1,3-oxazine ring systems.

However, since 19 also contains an unprecedented C5-spirocyclic quaternary center, this metabolite has been hailed as somewhat of a ‘missing link’ between the biosynthetic pathways of both genera.1 As with some other Myrioneuron alkaloids, (+)-myrioneurinol showed weak inhibitory activity against KB cells, as well as moderate antimalarial activity against Plasmodium falciparum.

H OH H 18 H 7 6 D 5 OH B 10 H C 9 N O N H H A H O 11

Figure 3. Structure and Conformation of (+)-Myrioneurinol (19).

Using flash column chromatographic purification, the free base of (+)-myrioneurinol was isolated by Bodo and coworkers as a colorless microcrystalline solid that provided an ESI-MS

+ protonated molecular ion value of m /z 266.2149, consistent with the formula C16H28NO2. An absorption consistent with a hydroxylic O-H stretching vibration (3400 cm-1) was observed in the infrared spectrum of the compound. The 1D 1H and 13C NMR (APT) spectra revealed the presence of a quaternary center, four methines, and 11 methylene units within the molecule. Detailed 2D

NMR analysis was utilized to establish the connectivity and relative stereochemistry of the metabolite, as outlined below.

16 H 15 16 H 15 H H 17 H 14 14 18 OH H 17 4 3 4 5 H 3 6 H 6 5 7 H N H 2 10 OH H H H 7 18 2 10 13 N 8 H H H 9 9 H O 8 H 11 13 O 11 H H

Figure 4. Two-Dimensional NMR analysis of (+)-Myrioneurinol (19): (left) 1H-1H COSY ( ) and 1H-13C HMBC (H C) Correlations; right ( ) NOESY Correlations (H H).

The 1H-1H COSY and 1H-13C HMBC 2D NMR spectra of 19 were essential in establishing the basic connectivity of the tetracyclic ring system of the metabolite (Figure 4). The relative configuration of the five contiguous stereocenters of the alkaloid were then deduced from NOE experiments. The C9/C10 trans-configuration of the cis-DHQ (A/B) ring system was substantiated

1 1 by the large reciprocal H- H vicinal coupling constant values between both H-10 and H-9, H-11ax and H-9, as well as H-8ax and H-9 obtained from the NOE experiments. Likewise the C6/C7 trans- stereochemical relationship of the A/B-ring subunit was established from similar large reciprocal

J-values between H-6 and both H-7 and H-17ax. Furthermore, strong correlations were observed in the NOESY spectrum between H-10 and H-14ax, H-13ax, H-8ax, and H-6 as well as between H-

6 and H-14ax, H-8ax, and H-16ax which indicated a syn-facial disposition for H-10 and H-6. The results of the 2D NMR experiments led to assignment of an all-chair fused tetracyclic scaffold that shares a common A/B/C-ring core with the tricyclic alkaloid myrioxazine A (1), which had previously been isolated from M. nutans (Cf. Figure 1).

The absolute configuration of (+)-19 was established as 5R,6R,7S,9R,10S utilizing a modified Mosher method involving derivatization of the C7-hydroxymethyl group of the natural product with (R)- and (S)-9-anthrylmethoxyacetic acid (9-AMAA) and subsequent detailed 1H

NMR analysis.

A plausible biosynthetic pathway to (+)-myrioneurinol from L-lysine has been proposed by Bodo and coworkers that shares many similarities with that of other Myrioneuron alkaloids, but also contains some intriguing differences.1,11 In this proposed biogenetic route (Scheme 2), nucleophilic attack of the enamine moiety in Δ2-piperidine 15a on unsaturated imine 17 (Cf.

Scheme 1) results in formation of enamine aldehyde 20. Stereoselective spirocyclization of 20 establishes the C5-quaternary center within the A/D-ring subunit (21) of the alkaloid. Subsequent deoxygenation, imine hydrolysis, and oxidative deamination provide the spirocyclic imino- dialdehyde 22, which can undergo a Mannich-type cyclization in accordance with the biosyntheses of the other Myrioneuron alkaloids (Cf. Scheme 1) to establish the cis-DHQ A/B/D-ring system

23. Global reduction of the aldehyde moieties in 23 followed by incorporation of formaldehyde

7 into the 1,3-oxazine C-ring then provides the tetracyclic scaffold of the alkaloid 19. Particularly noteworthy is the proposed intermediacy of bis-iminoalcohol 21, which has also been implicated in the biosynthetic pathway to the nitraramine (11) metabolite from the genus Nitraria.

Scheme 2. Proposed Biosynthetic Pathway to Myrioneurionol (19)

Complex spiranic Nitraria alkaloids

O Michael- spiro- HO D 1) ring O type cyclization inversion O A 2) cyclization N N N N N H H H N N 17 H N nitraramine (11) 15a 20 21

deoxygenation

1) hydrolysis O 2) oxidative N O N N deamination HO O N

cyclization

D D H H [H] A B O A OH H H B H N H CO H 2 N H2 H C O O 23 myrioneurinol (19)

1.3. Previous Synthetic Studies toward the Myrioneuron Alkaloids.

In spite of their unusual structures and intriguing biological activities, few syntheses of the alkaloids of the genus Myrioneuron have previously been reported. Perhaps due to the relative infancy of the field, especially when compared with the substantial body of work directed toward the Nitraria alkaloids, to date only the simplest members of the class have succumbed to total synthesis.

Bodo and coworkers reported the first asymmetric total syntheses of the simple tricyclic alkaloids (+)-myrioxazine A (1) and B (2) (Scheme 3).2 Employing a pivotal (S)-camphanyl-ester based resolution of easily prepared (±)-8-hydroxymethyl tetrahydroquinoline (24), this group was able to prepare the two natural products via catalytic hydrogenation of the corresponding enantiopure tetrahydroquinolines 25a/b, followed by treatment of the resulting enantiopure DHQs

26a and 26b with formaldehyde to construct the 1,3-oxazine rings of the myrioxazines.

Scheme 3. Bodo Synthesis of (+)-Myrioxazines A and B

Me Me COCl 1)

CH2Cl2, Py (CH2O)n 90 oC 91% H + H

N 37% N 2) NaOH, H2O N N 60 oC (±)-24 OH 24a OH 24b OH 97%

H H /PtO H H 2 2 H2CO AcOH H O H H H H 2 + N N 82% N N 95% H H H H H O 24a OH OH 25a OH (+)-myrioxazine A (1)

H H H H2/PtO2 H2CO H O H AcOH H H 2 H + N N 82% N N 95% H H H H H O 24b OH OH 25b OH (+)-myrioxazine B (2)

Bodo, et al. have also prepared the simple tricyclic alkaloid (-)-myrionine (26) via derivatization of cis-DHQ intermediate 25a obtained from the aforementioned myrioxazine A total synthesis (Scheme 4).12 The same group then elaborated 26 to both the amidinium alkaloid (-)- myrionidine (27) as well as the closely related 1,3-diazine alkaloid (-)-schoberine (3) using straightforward chemistry.13

Scheme 4. Bodo Syntheses of (-)-Myrionine (26), (-)-Myrionidine (27), and (-)-Schoberine (3) from cis-DHQ 25a

1) BnBr, NaHCO3 CH Cl , H O, 93% H 2 2 2 H o 2) MsCl, CH2Cl2, -5 C H H N 3) 2-piperidone, KH N O H H H DMF, -5 oC to rt H OH 75% (2 steps) N 25a 4) H2/Pd/C, HOAc, 90% (-)-myrionine (26)

POCl3, PhMe reflux; LiAlH4 then NaOH, H THF H o H2O, MeOH 0 C to rt H H 97% N 87% N H H N N

(-)-myrionidine (27) (-)-schoberine (3)

More recently, Burrell and coworkers reported a racemic synthesis of the simple tricyclic

Myrioneuron alkaloid myrioxazine A (1) that utilized a pivotal tandem condensation, cyclization, and dipolar cycloaddition sequence via nitrone intermediate 28 to access the tricyclic cis-DHQ system 29 (Scheme 5a).14 Tricycle 29 was then elaborated to the natural product in excellent yield following reductive cleavage of the nitrogen-oxygen bond and cyclization of the resulting 3- aminoalcohol with formaldehyde. Shortly thereafter, the same group employed similar methodology to construct a model compound 30 containing the A/B/C-ring subunit of myrioneurinol (Scheme 5b).15

Scheme 5. Myrioneuron Alkaloid Synthetic Work by Burrell, et al.

a) Synthesis of Racemic Myrioxazine A (1)

H NH2OH Cl DIEA, 110 oC O CHO O [3+2] N N 77% H H Cl 28 29

1) Zn, HOAc H o O H2O, 70 C, 98% 2) (CH O) , p-TsOH N 2 n H H o CHCl3, 70 C, 95%

(±)-myrioxazine A (1)

b) Synthesis of Abbreviated Myrioneurinol Compound 30

H O CHO B C N H Cl A 30

1.4. First Generation Retrosynthesis of (±)-Myrioneurinol

Our interest in performing the first total synthesis of 19 was motivated by the challenging fused tetracyclic structure and reported biological activity of the metabolite (vide supra) as well as the relative dearth of synthetic work that had hitherto been conducted in this area. Our initial retrosynthetic plan was predicated upon the preparation of advanced tricyclic intermediate 31, which contains the A/B/D-ring subunit and five contiguous stereogenic centers of the alkaloid. We anticipated that hydrolysis and/or reduction of the R-groups in tricycle 32 would eventually provide the requisite C7- and C9- hydroxymethyl functionalities, with the latter being incorporated into the 1,3-oxazine C-ring of the metabolite. We further envisioned that stereoselective reduction of either an enecarbamate or cyanoenamine moiety within 32 would establish the requisite C9,10-

12 relative configuration. The B-ring of tricycle 32 would be installed via the cyclization of imidate precursor 33,16 itself prepared via the intermolecular Michael addition of the C7-enolate of bicyclic ester 34 to an appropriate acceptor. We envisaged that spirocycle 34 could arise via a pivotal intramolecular Michael addition (IMA) of a valerolactam-derived α,β-unsaturated ester cyclization precursor such as 36.17 According to literature precedent (vide infra), we postulated that the use of a chelating metal in this spirocyclization would provide diastereocontrol over the C5,6- configuration of 34 via a rigid intermediate such as 35.

Scheme 6. First Generation Retrosynthetic Analysis for Myrioneurinol (19)

H OH H H H H OH H 7 - R X R D B CH O [H ] 2 D B D C B 7 9 R R N O HO 10 9 N H A H H N H N A A

19 31 32 33

OR H 1 CO2R CO R 6 7 O 2 D R O O O 5 M P P N P R = CO R1, CN N N 2 A 34 35 36

1.5. Background on Diastereoselective Intramolecular Michael Additions (IMAs) and

Related Reactions

Over the past several decades, intramolecular Michael additions (IMAs) have been utilized as important carbon-carbon bond forming operations and in a number of total syntheses.17 In our first generation retrosynthesis of 19, we envisaged that the C5,6-connection in spirocyclic ester

13 intermediate 34 could arise via a diastereoselective IMA that utilizes a chelating metal ion (Cf.

Scheme 6). Existing literature precedent for this pivotal transformation included some examples of stereoselective IMAs, as well as related spirocyclizations in approaches to total syntheses of a few of the Nitraria alkaloids.

For example, Fukumoto, Kametani, et al. have reported that the lithium hexamethyldisilazide (LiHMDS)-induced double IMA of bis-α,β-unsaturated dicarbonyl substrate

37 (Scheme 7a) furnished a single diastereomeric tricyclic ketoester 39, presumably via a lithium metal-chelated intermediate such as 38.18 Support for this mechanistic hypothesis came via the addition of the strongly coordinating co-solvent HMPA to the reaction mixture to solvate the Li+ cation, thereby interrupting the chelating effect, which dramatically lowered the yield of 39.

Furthermore, d’Angelo and Ferroud utilized a thermal cyclization of an imine 40 to prepare spirocyclic ketoester 41 as a single diastereomer and enantiomer, a system closely related to the desired intermediate 34 for our myrioneurinol synthesis (Scheme 7b).19 The authors rationalized the syn-C1,2-diastereoselectivity observed for this transformation by invoking a preferred aza-ene- like transition state conformation 42 which places the C1,11 and C2,12 components in a synclinal gauche disposition.

Scheme 7. Relevant Intramolecular Michael Cyclizations.

a) Fukumoto/Kametani Work

Li O LiHMDS O EtO2C EtO2C THF O -78 °C-rt OEt O 30-60% H

37 38 39

b) d'Angelo's Work CO Me H 2 1) DMF CO Me 2 2 120 °C 12 H 2) HOAc 2 Me 1 H2O 1 N O 11 Ph R 85% 12 40 41 H MeO N 11 single diastereomer O and enantiomer H Me Ph

aza-ene-like TS (42)

Koomen and coworkers have utilized two biomimetically-inspired chelation-controlled spirocyclization reactions to construct alkaloids of the genus Nitraria. In their total synthesis of the simple spiranic alkaloid (±)-nitramine (8), a pivotal syn-diastereoselective thiophenolate- induced intramolecular aldol type addition of N-Bn glutarimide/aldehyde 43 was employed that is believed to proceed through an aluminum-chelated enolate intermediate 44 to afford spirocycle 45 in good yield (Scheme 8a).20

The same group reported a similar thiophenolate-induced Michael addition of bis- glutarimide substrate 46 en route to an attempted biomimetic total synthesis of the complex

Nitraria alkaloid nitraramine (11) (Scheme 8b). Although the chelating aluminum metal was

15 effective in establishing the desired syn-C6,7-relative configuration, the C6,11 configuration of 47 was unsuitable for elaboration to the natural product.21

Scheme 8. Chelation Controlled Diastereoselective Spirocyclizations of Koomen, et al.

a) Racemic Total Synthesis of Nitramine (8)

Bn Me Bn O N O O N O PhS-AlMe2 Me Al O THF, rt O 82% SPh

43 44

Bn H O N O N OH OH 6 7 SPh

45 (±)-nitramine (8)

b) Studies Toward Nitraramine (11)

Bn Bn Bn O N O O N O O N O PhS-AlMe2 PhS 6 7 O N THF, rt 11 O 12 81% N H H NBn 46 47 O (±)-nitraramine (11)

dr C11,12 = 3:2

1.6. Preliminary Studies on the IMA Spirocyclization toward Myrioneurinol

Former Weinreb group member Yiqing Feng began our exploratory studies toward effecting the desired diastereoselective IMA for the (±)-myrioneurinol total synthesis.22a He initially decided to attempt the IMA of an N-benzyllactam substrate (Cf. Scheme 6, 36 P = Bn), and thus the appropriate cyclization precursor was prepared from commercially available N- benzyl-2-piperidone (48) (Scheme 9). To this end, lactam 48 was C-monoalkylated with known iodoacetal 4923 to afford lactam acetal 50 in moderate yield. Hydrolysis of the dioxolane in 50 unmasked the aldehyde functionality, giving 51, which was subjected to Wadsworth-Emmons-

Horner olefination to provide the desired (E)-α,β-unsaturated ester 52 in excellent yield.

Scheme 9. Preparation and Cyclization of N-Benzyllactam Enoate 52 by Feng.

HCl, THF LDA, THF, -78 °C rt, 100% N O O N O N O (CH ) CH I Bn 2 3 2 Bn Bn CHO O O O 51 48 49 49% 50

H H H CO Me CO Me CO2Me 6 2 16 H 6 2 (EtO)2POCH2CO2Me LDA, THF H 14 LiCl, DBU, MeCN, rt O -78 °C-rt O 15 O Bn 5 H 5 Bn N N Bn H N 90% ~20% 52 53 H 3 H

Key NOESY Correlations for 53 (H H).

A variety of experimental conditions were then screened in order to effect the desired spirocyclization of enoate 52. Feng ultimately discovered that treatment of the cyclization

17 precursor with lithium diisopropylamide (LDA) at -78 ºC followed by slow warming to room temperature overnight furnished a single spirocyclic product 53. The C5,6 relative configuration of 53 was found to be correct for myrioneuriniol via strong 1H-1H NOESY correlations for H6 with H14ax and H16ax, as well as H3ax with H14eq and H15ax.

Although encouraged that our IMA strategy might indeed be viable, we were disappointed to discover that the maximum attainable yield of 53 in this transformation was ca. 20%, with decomposition products and recovered starting material accounting for the remainder of the mass balance. Attempts to effect the IMA of 52 with a variety of alternative non-nucleophilic bases including KHMDS, NaH, or KOt-Bu were unsuccessful. Thus, given Feng’s inability to perform the lithium amide base-induced spirocyclization of N-benzyllactam enoate 52 in a synthetically useful yield, we began investigating alternative strategies to carry out this pivotal transformation.

CHAPTER 2: IMA STRATEGY TO CONSTRUCT A/D-RING SUBUNIT

2.1. ‘Soft’ Enolization Inspired by Evans, et al.

Although Feng had demonstrated the feasibility of effecting the desired spirocyclization of

N-benzyllactam enoate 52, the low yields obtained from this pivotal IMA forced us to modify our approach. A survey of the chemical literature revealed that Evans and coworkers had reported the

IMA of N-acyloxazolidinone 54 to afford the corresponding diastereomeric cyclopentane derivatives 55a/b using titanium trichloroisopropoxide and triethylamine (Scheme 10).24

Scheme 10. Intramolecular Michael Addition of N-acyloxazolidinones by Evans, et al.

O O O O Ti(Oi-Pr)Cl , Et N O O O 3 3 O O N o CH2Cl2, -78 C N H CO2Me + N H CO2Me CO Me 2 88% Bn Bn Bn

54 55a 55b

dr = 93 : 7

In the presence of the Lewis acidic metal cation Ti4+, the rather weak tertiary amine base is sufficient to effect the enolization of imide 54. This strategy, referred to as “soft” enolization, represents a milder method for the generation of metal enolates when compared to so-called “hard” enolization via the deprotonation of a carbonyl species with a strong amide base.25

Since Feng had hypothesized that competitive γ-deprotonation of the enoate and Michael- type addition of the lithium amide base were possibly complicating the IMA of benzyllactam 52, we hoped that the Evans conditions might improve the chemoselectivity for the enolization of an appropriate cyclization precursor. For this approach, the benzyloxycarbonyl (Cbz) protecting group was selected for the lactam nitrogen in order to approximate the electron withdrawing character of the oxazolidinone auxiliary in 54.

2.2. First Generation Route to N-Cbz Lactam Cyclization Precursor

Because Feng had been unsuccessful in directly alkylating N-Cbz valerolactam 56 with iodoacetal 49 (Scheme 11a), it was decided to reverse the order of the alkylation and protective operations.26 To this end, valerolactam (57) was treated with two equivalents of n-butyllithium to generate the dianion, which was C-monoalkylated with iodide 49 in modest yield (Scheme 11b).27

The N-H lactam acetal 58 was then protected as the N-Cbz derivative 59 via treatment with benzyl chloroformate in acceptable yield, followed by hydrolysis of the dioxolane with aqueous HCl in

THF to cleanly afford aldehyde 60. Wadsworth-Emmons-Horner olefination of 60 then provided the desired (E)-α,β-unsaturated ester cyclization precursor 61 in good yield.

Scheme 11. Preparation of N-Cbz Lactam Cyclization Precursor

a) Attempted Preparation by Feng

LDA, THF, -78 °C

N O N O Cbz O Cbz (CH2)3CH2I O O O 56 49

b) First Generation Route to Cyclization Precursor 61

n-BuLi (2 equiv.) n-BuLi THF, 0 °C THF, -78 °C N O O CbzCl (CH ) CH I N O N O 2 3 2 65% H O H Cbz 49 O O 57 58 O O 24% 59

HCl, THF (EtO)2POCH2CO2Me CO2Me LiCl, DBU, MeCN, rt rt, 100% O N O 82% N Cbz Cbz CHO 60 61

2.3. Attempted ‘Soft’ IMA of Lactam Enoate 61.

At this stage, the spirocyclization of N-Cbz lactam enoate 61 was explored using conditions inspired by the Evans procedure. Thus, substrate 61 was first treated with titanium (IV) chloride and triethylamine at -78 ºC and the mixture was allowed to stir for one hour before an aqueous quench (Scheme 12, entry 1). NMR analysis of the reaction mixture revealed only the presence of unreacted starting material. In a second trial, the addition was performed at -78 ºC and the mixture allowed to warm to room temperature over several hours (entry 2). Proton NMR analysis of the

21 major product upon chromatographic purification suggested that some of the desired spirocyclization of 61 had taken place.28 We were somewhat disappointed, however, to discover that the yield of bicycle 62 from this run was only ca. 15%. A third reaction was allowed to stir for a longer time period (entry 3), but provided only a very polar spot on the TLC, later identified as spirocyclic N-H lactam/ester 63, which could not be separated from the complex mixture. We hypothesized that titanium (IV)-induced deacylation of spirocycle 62 was occurring as a result of the prolonged reaction times, and thought that perhaps carrying the transformation out at a slightly higher temperature might ameliorate this problem. To our delight, treatment of 61 with titanium

(IV) chloride and triethylamine at 0 ºC, followed by gradual warming to room temperature over one hour provided spirocycle 62 in a synthetically useful (but unoptimized) 60% yield (entry 4).

It is worthy of note that exposure of the Feng’s N-benzyllactam substrate 52 to these “soft” IMA conditions led only to the recovery of unreacted starting material (entry 5), thus demonstrating the need to employ the electron withdrawing carbamate protecting group on the lactam nitrogen.

Scheme 12. Development of Pivotal IMA Spirocyclization

H CO Me TiCl4 2 CO2Me Et3N, CH2Cl2 O O P N conditions N P

61 P = Cbz 62 P = Cbz 52 P = Bn 63 P = H

entry substrate temp. (oC) time (h) result (% yield)

1 61 -78 1 NR 2 61 -78 to rt 4 62 (15) + 63*

3 61 -78 to rt 20 62 (trace) + 63* 4 61 0 to rt 1 62 (60) + 63* 5 52 0 to rt 20 NR

NR = no reaction *yield not determined due to purification difficulty

2.4. Determination of the Relative C5,6-Configuration of Spirocycle 62.

Before proceeding with any optimization studies on this novel titanium-induced IMA of

61, we decided to verify that the C5,6-relative stereochemistry of spirocyclic lactam ester 62 was indeed correct for elaboration to myrioneurinol. To this end, the benzyloxycarbonyl group on the lactam nitrogen in 62 was cleaved hydrogenolytically to afford N-H lactam 63 in nearly quantitative yield (Scheme 13). Chemoselective reduction of the ester carbonyl in lactam 63 with lithium aluminum hydride at 0 ºC provided alcohol 64 as a white crystalline solid. Recrystallization of 64 from a mixture of diethyl ether and methanol provided clear prisms that were of suitable quality for single crystal X-ray diffraction analysis which confirmed the structure to be as shown

(ORTEP in Scheme 13). Furthermore, installation of an N-benzyl protecting group on 63 using

23 silver (I) oxide and neat benzyl bromide provided benzyllactam 53 which was found to be identical spectroscopically to the spirocycle prepared by Feng from 52 (Cf. Scheme 9).

Scheme 13. Confirmation of the C5,6 Stereochemistry of Spirocycle 62

HO H H H CO Me CO Me LiAlH 2 2 4 6 H2, EtOAc Et2O O 10% Pd-C O O 0 °C 5 Cbz H H N 98% N 82% N 62 63 64 (X-ray) BnBr 73% Ag2O, TBAI CaSO4, rt

H CO2Me

O 6 Bn N 5 53

We attribute the observed high degree of C5,6 diastereoselectivity in the IMA of 61 to the formation of a rigid titanium chelate such as 65 during the course of the spirocyclization (Scheme

14). The superior yields of spirocycle 62 from this method likely arise from the higher degree of chemoselectivity for soft enolization/cyclization that proceeds without the undesired side reactions observed in Feng’s N-benzyllactam system.

Scheme 14. Rationalization of the Observed C5,6-Diastereoselectivity

OMe H CO2Me CO2Me TiCl4 O 6 O Et3N O Ti Cl O Cbz 5 N N Cbz Cl Cbz CH2Cl2 Cl N 0 °C-rt 61 65 62

2.5. Second Generation Route to Cyclization Precursor 61.

Poor individual reaction yields and scalability issues in the first generation route to (E)-

α,β-unsaturated ester cyclization precursor 61 (Cf. Scheme 11b) prompted us to develop an improved preparation of this compound prior to proceeding further with optimization studies on the pivotal IMA. The issues within the existing sequence appeared to derive from incompatibility between dioxolane 49 and the alkyllithium or lithium amide bases employed to effect the enolization of the lactam 57.

A suitable solution to these problems was envisioned that installed the requisite aldehyde functionality via ozonolytic cleavage of a terminal alkene rather than the unmasking of dioxolane

59. Towards this end, the dianion of valerolactam (57) was treated with commercially available 6- bromo-1-hexene and the resulting N-H lactam olefin 66 was treated with benzyl chloroformate to furnish the N-Cbz derivative 67 in good overall yield (Scheme 15).27 Ozonolytic cleavage of the alkene 67, followed by reductive workup with triphenylphosphine, furnished aldehyde 60 in excellent yield. As had been shown previously (Cf. Scheme 11b), Wadsworth-Emmons-Horner olefination of 60 provided the (E)-α,β-unsaturated ester cyclization precursor 61 in good yield. We

25 were pleased to discover that this synthesis of 61 could be carried out on a multi-decagram scale with no significant attenuation of the individual reaction yields.

Scheme 15. Second Generation Route to N-Cbz Lactam Cyclization Precursor 61

n-BuLi n-BuLi (2 equiv.) THF, -78 °C THF, 0 °C CbzCl N O N O N O H Br H 89% Cbz (2 steps) 57 66 67

O3, CH2Cl2 CO Me -78 °C; PPh3 (EtO)2POCH2CO2Me 2 -78 °C-rt LiCl, DBU, MeCN, rt O Cbz 90% N O 82% N Cbz CHO 60 61

2.6. Optimization Studies on the Pivotal IMA Spirocyclization

With a reliable route to (E)-α,β-unsaturated ester cyclization precursor now established, we next turned our attention toward the optimization of the IMA of 61 by screening different Lewis acids and amine bases (Scheme 16). Titanium (IV) chloride was found to be the best Lewis acid for the soft enolization of lactam 61. Performing the reaction with triethylamine as the base in the presence of titanium (IV) isopropoxide (entry 1), boron trifluoride diethyl etherate (entry 2), or trimethylaluminum (entry 3) resulted only in the recovery of unreacted 61 or deacylated (E)-α,β- unsaturated ester cyclization precursor 68. Titanium (IV) trichloroisopropoxide, the Lewis acid employed by Evans and coworkers in the IMA of imide 54 (Cf. Scheme 10),24 provided some of the desired spirocycle 62 along with a significant amount of an inseparable impurity 69 that

26 appeared to result from transesterification of the nascent spirocycle by the isopropoxide (entry 4).

The use of Hünig’s base (DIEA) in place of triethylamine resulted only in the recovery of deacylated precursor 68 or unreacted starting material (entries 5-6).

With titanium (IV) chloride and triethylamine established as the optimal reagent combination for the spirocyclization of 61, the molar equivalents of each component were next screened. It was determined that, two equivalents of TiCl4 were necessary to ensure complete conversion of precursor 61 to spirocycle 62 (entry 7-8). We were pleased to discover that performing the transformation at 0 ºC with two equivalents of both triethylamine and TiCl4 afforded the desired spirocycle in 86% isolated yield (entry 9). Employing additional equivalents of TiCl4 and Et3N resulted only in greater difficulty in performing the aqueous workup and purification of the reaction mixture without any noticeable improvement in the yield (entry 10).

Thus, with a set of optimized conditions in hand, we next decided to explore the substrate scope of this novel spirocyclization method before proceeding further with the myrioneurinol total synthesis.

Scheme 16. Optimization of Pivotal IMA Spirocyclization of 61

CO Me H 2 Lewis Acid CO2Me base, CH Cl O 2 2 O Cbz N 0 °C to rt N Cbz

61 62

Lewis CO2Me entry acid (equiv.) base (equiv.) time (h) result (% yield) O N H 1 Ti(Oi-Pr)4 (1) Et3N (1) 1.5 68*

2 BF3 OEt2 (1) Et3N (1) 1.5 NR 68

3 Me3Al (1) Et3N (1) 1.5 NR H CO i-Pr 4 Ti(Oi-Pr)3Cl (1) Et3N (1) 1 62 + 69* 2 O 5 TiCl4 (1) DIEA (1) 1 68* N H 6 Ti(Oi-Pr)4 (1) DIEA (1) 1 NR 69

7 TiCl4 (1) Et3N (1) 1.5 62 (20%) + SM H CO Me 8 TiCl4 (2) Et3N (1) 1 62 (60%) + SM 2 O 9 TiCl4 (2) Et3N (2) 1 62 (86%) + 63* N H 10 TiCl4 (3) Et3N (3) 1 62 (51%) + 63* 63

NR = no reaction; SM = starting material *yield not determined due to purification difficulty

2.7 Exploration of Some Homologous IMA Spirocyclizations

Since we had demonstrated that titanium (IV) chloride/triethylamine-induced IMA of (E)-

α,β-unsaturated ester 61 provided a single diastereomer of spirocycle 62 in high yield (vide supra), we sought to explore the scope of this interesting stereoselective transformation. To this end, several cyclization precursors containing varying lactam ring sizes and unsaturated ester tether lengths were prepared via appropriate modifications of the route used to synthesize 61.

2.7.1. Studies with Five-Membered Lactam Analog 74.

To begin these studies, the dianion of 2-pyrrolidinone (70) was treated with 6-bromo-1- hexene and the crude product 71 was protected as the N-Cbz derivative 72 in modest yield (Scheme

17). Ozonolysis of terminal olefin 72 followed by Wadsworth-Emmons-Horner olefination of aldehyde 73 provided cyclization precursor 74 which was subjected to the optimized IMA conditions. However, we were disappointed to recover only the deacylated (E)-α,β-unsaturated ester 76, rather than the desired spirocycle 75 after allowing the reaction mixture to stir overnight at room temperature.

Scheme 17. Studies upon the IMA of 2-Pyrrolidinone Analog 74

n-BuLi n-BuLi (2 equiv.) THF, -78 °C THF, 0 °C CbzCl O O O N N Br N 18% (2 steps) H H Cbz 70 71 72

O3, CH2Cl2 CO2Me -78 °C; PPh (EtO) POCH CO Me 3 CHO 2 2 2 O -78 °C-rt O LiCl, DBU, MeCN, rt N Cbz 79% N Cbz 56% 73 74

TiCl4 Et3N H CH2Cl2 CO2Me CO2Me 0 °C-rt O O H N Cbz N

75 76

2.7.2. Studies with Seven-Membered Lactam Homologue 81.

Similarly, the dianion of caprolactam (77) was alkylated with 6-bromo-1-hexene and the product 78 was protected as the N-Cbz derivative 79. Ozonolysis of 79, followed by Wadsworth-

Emmons-Horner olefination of the resulting aldehyde 80, furnished (E)-α,β-unsaturated ester cyclization precursor 81. Exposure of this compound to the optimized IMA conditions once again led only to the recovery of deacylated (E)-α,β-unsaturated ester 83 rather than the desired spirocycle 82 .

Scheme 18. Studies on the IMA of Caprolactam Analog 81

n-BuLi n-BuLi (2 equiv.) THF, -78 °C THF, 0 °C O O CbzCl O NH Br NH 27% (2 steps) NCbz 77 78 79

O3, CH2Cl2 CO2Me -78 °C; PPh3 (EtO) POCH CO Me 2 2 2 O -78 °C-rt LiCl, DBU, MeCN, rt O Cbz CHO N 58% NCbz 72% 80 81

TiCl4 Et N 3 H CH2Cl2 CO2Me CO2Me 0 °C-rt O O H N Cbz N 82 83

2.7.3. Rationalization for Failure of Enoates 74 and 81 to Spirocyclize

We hypothesize that substrates 74 and 81 may be reluctant to undergo the desired spirocyclization reactions due to their inability to assume the requisite rigid chelated transition state conformations 84 and 85, respectively, for the IMA. In the 2-pyrrolidinone system (74), it is conceivable that the five-membered cyclic enolate is unable to achieve the necessary stereoelectronic alignment with the Michael acceptor due to geometric restrictions imposed by the smaller ring size. For caprolactam homologue 81, the seven-membered ring may, in fact, be too conformationally labile, raising the energy of IMA transition state 85 to a prohibitive level and instead favoring the deacylation pathway to afford N-H lactam 83.

Scheme 19. Hypothetical Chelated Transition States for Homologous Spirocyclizations

OMe OMe O O O Ti Cl O Ti Cl Cbz Cbz N Cl Cl N Cl Cl 84 85

2.7.4. Modification of the Ester Tether Length

In light of our failure to effect the spirocyclization of substrates containing five- and seven- membered lactam rings with six-carbon (E)-α,β-unsaturated ester side chains, we next turned our attention toward modification of the tether of the cyclization precursor. Towards this end, the dianion of valerolactam (57) was C-monoalkylated with commercially available 5-bromo-1- pentene and the resulting N-H lactam 86 was protected as the N-Cbz derivative 87 in good yield

(Scheme 20). Ozonolysis of 87 followed by reductive workup with triphenylphosphine provided the aldehyde 88 which was then elaborated to (E)-α,β-unsaturated ester 89 in moderate yield. We were again disappointed to discover that subjection of 89 to the optimized spirocyclization conditions resulted only in the recovery of the deacylated compound 92 rather than the desired spirocycle 91. Although Evans and coworkers had demonstrated that their IMA of N- acyloxazolidinone 54 (Cf. Scheme 10) resulted in cyclopentane formation,24 it seems reasonable to hypothesize that conformational restrictions imposed by the spiranic nature of chelated transition state 90 disfavor the desired IMA pathway.

Scheme 20. Modification of Ester Tether Length

n-BuLi n-BuLi (2 equiv.) THF, -78 °C THF, 0 °C CbzCl N O Br N O 68% (2 steps) N O H H Cbz 57 86 87

O3, CH2Cl2 -78 °C; PPh3 (EtO)2POCH2CO2Me -78 °C-rt LiCl, DBU, MeCN, rt CO2Me O 64% N O CHO 67% N Cbz Cbz 88 89

TiCl4 OMe Et3N H CH2Cl2 O CO2Me CO Me 0 °C-rt O Cl 2 Ti O O Cbz N Cl Cl N Cbz N H

90 91 92

2.7.5. Studies with Homologues Pre-Functionalized at C7

Since our retrosynthetic strategy toward myrioneurinol was predicated upon the eventual installation of functionality at C7 (Cf. Scheme 6) we decided to prepare a series of cyclization precursors that were pre-functionalized at that position. Thus, aldehyde 60 was subjected to

Wadsworth-Emmons-Horner olefination with both an α-methylphosphonoester and α- allylphosphonoester to afford the corresponding cyclization precursors 93 and 94, respectively, both as inseparable mixtures of E/Z-olefin geometric isomers in acceptable (but unoptimized) yields (Scheme 21). However, upon exposure to the optimized IMA conditions for precursor 61, neither 93 nor 94 underwent any spirocyclization even after being stirred overnight at room temperature. Instead, in each case only the corresponding deacylated α,β-unsaturated esters 95 were isolated from the reaction mixture.

Scheme 21. Preparation and Attempted IMA of C7-Prefunctionalized Cyclization Precursors

O P CO R2 EtO 2 TiCl4 EtO Et N R1 3 CO R2 CH Cl 7 2 2 2 H CO R2 KHMDS, THF, -78 °C 0 °C-rt 7 2 R1 O R1 N O O Cbz N CHO Cbz N 60 Cbz

2 CO2R R1 R2 yield (%) E/Z* R1 O N 93 Me Et 29 ~2.5:1 H 95 94 allyl Me 47 ~4.2:1 R = Me, allyl *E/Z mixture subjected to IMA.

Likewise, (E)-α,β-unsaturated δ-valerolactone cyclization precursor 97 was synthesized via Wadsworth-Emmons-Horner olefination of aldehyde 60 with easily-prepared δ- phosphonolactone 96 (Scheme 22, yield unoptimized). This substrate also failed to undergo the desired spirocyclization reaction, instead providing the N-deacylated compound 98 after being stirred overnight at room temperature.

Scheme 22. Preparation and Attempted IMA of Phosphonolactone 97

O O P O OEt OEt TiCl4 96 O Et3N O O CH2Cl2 H KHMDS, 18-crown-6 7 O 0 °C-rt 7 THF, -78 °C O N O 19% (E)-isomer O Cbz N CHO Cbz N 60 97 Cbz

O O

O N H 98

We hypothesize that C7-prefunctionalized substrates 93, 94, and 97 may have failed to spirocyclize due to excessive steric strain in the chelated transition states leading to the desired

IMA. We next briefly explored the spirocyclization of enedioate 99, which was easily prepared via Knoevenagel reaction of aldehyde 60 with diethyl malonate. Unfortunately, 99 failed to cyclize when subjected to the optimized experimental conditions, providing only the deacylated lactam

100 after stirring overnight at room temperature.

Scheme 23. Synthesis and Attempted Spirocyclization of Enedioate 99

TiCl4 Et3N EtO2C CO2Et CH2Cl2 H piperidine, HOAc CO2Et CO Et 0 °C-rt 2 PhH, 80 °C CO2Et CO Et N O O O 2 Cbz 91% N N CHO Cbz Cbz 60 99

CO2Et

CO Et O 2 N H 100

2.8. Attempted Asymmetric IMA Spirocyclization

2.8.1. Studies with (-)-Menthyl Carbamate Cyclization Precursor 103

We next briefly examined the feasibility of preparing the appropriate azaspiro[5.5]undecane scaffold for myrioneurinol in enantioenriched form via the incorporation of a chiral auxiliary into the cyclization precursor for the IMA. Thus, the nitrogen of lactam olefin 66

(Cf. Scheme 15) was converted to the (-)-menthyl carbamate 101 (Scheme 24). Ozonolysis of 101 with a reductive workup furnished aldehyde 102, which was subjected to Wadsworth-Emmons-

Horner olefination to afford (E)-α,β-unsaturated ester precursor 103 in good yield. Unfortunately, exposure of the cyclization precursor 103 to the optimized IMA conditions led to the formation of a ca. 1:1 diastereomeric mixture of spirocycles 104a/b as determined by HPLC and NMR experiments.

Scheme 24. Preparation and IMA of (-)-Menthyl Carbamate Cyclization Precursor 103.

n-BuLi THF, -78 °C Cl

O O Me

Me O3, CH2Cl2 -78 °C; PPh Me 3 N O N O -78°C-rt CHO N O 67% O O Me 100% O O Me H 66 Me Me

Me 101 Me 102

H CO2Me Me Me O

TiCl4 N O Et3N CO2Me O (EtO)2POCH2CO2Me CH2Cl2 Me Me LiCl, DBU, MeCN, rt O 0 °C-rt 104a Me N O 70% 66% + dr ~ 1:1 O H MeO2C 103 Me Me Me O O N

O Me 104b

2.8.2. Studies with (+)-TCC Ester Cyclization Precursor 107

Given our failure to effect any measurable asymmetric induction in the spirocyclization of

103, an alternative substrate bearing a chiral (+)-trans-2-(α-cumyl)cyclohexyl ((+)-TCC) ester auxiliary was next prepared.29 To this end, commercial (+)-TCC alcohol (105) was first converted to phosphonoester 106 via acylation with diethylphosphonoacetyl chloride.30 Wadsworth-

Emmons-Horner olefination of aldehyde 60 with (+)-TCC phosphonoester 106 furnished the (E)-

α,β-unsaturated ester cyclization precursor 107. However, exposure of 107 to the optimized IMA conditions led to the recovery of deacylated product 109, rather than the desired spirocycle 108.

We hypothesize that precursor 107 may have failed to spirocyclize due to the steric bulk of the

(+)-TCC auxiliary.

Scheme 25. Studies with (+)-TCC Ester 107

O EtO P CO2Cl EtO Et N O O OH Me 3 Ph CH Cl, 0o C P 2 EtO O Me EtO Ph Me 47% Me 105 106

106 Me Me O Ph KHMDS, THF O -78 oC O N O 32% Cbz N CHO Cbz 60 107

TiCl4 Et3N Me Me Me Me CH Cl O O 2 2 H Ph Ph 0 °C-rt O O

O O N N Cbz H 109 108

Although we were disappointed to discover that our novel titanium (IV) induced IMA was

(1) not general outside of the azaspiro[5.5]undecane scaffold, (2) was incompatible with precursors bearing a C7-substituent (myrioneurinol numbering) and (3) was not amenable to auxiliary-based enantioenrichment, the transformation nevertheless permitted us to continue our synthetic studies toward racemic myrioneurinol.

CHAPTER 3: HOMOLOGATION OF A/D-RING SUBUNIT AT C7

3.1. Attempts to Homologate via Formation of C7 Ester Enolates

Since we were unable to incorporate a C7-substituent into the pivotal spirocyclization reaction (vide supra), it was decided instead to investigate various post-Michael methods to homologate spirocycle 62 at C7. We had initially hoped that metalation of spirocyclic N-Cbz lactam/ester 62 would furnish a C7-ester enolate that could react with an appropriate electrophile to accomplish the desired C7,8 bond formation leading eventually to a 1,5-dicarbonyl imidate cyclization precursor like 33 (Cf. Scheme 6).

However, the benzyloxycarbonyl (Cbz) protecting group on the lactam nitrogen of ester 62 proved to be labile to treatment with LDA or LiHMDS, leading either to decomposition or to the recovery of N-H lactam 63 along with significant amounts of benzyl alcohol (Scheme 26, entries

1-4). The reactivities of spirocyclic N-H lactam ester 63 (entry 5) and N-Bn lactam ester 53 upon treatment with the non-nucleophilic bases LDA, LiHMDS, and KH (entries 6-10) followed by the addition of an electrophile were next evaluated. However, neither substrate underwent any detectable C7-functionalization with methyl acrylate, allyl iodide, or even methyl iodide.

Moreover, treatment of 53 with base, followed by a D2O quench, failed to provide any evidence of deuterium incorporation at C7, even with the addition of HMPA or 18-crown-6 to the mixture

(entries 11-12).

Scheme 26. Attempts to Functionalize Spirocyclic Esters at C7

H CO Me H 2 E CO2Me O 1. base, conditions 7 O N P 2. electrophile (E) N P

entry P = base conditions electrophile result

63 1 Cbz LDA THF, -78 °C CO2Me 2 Cbz LDA THF, -78 °C to rt CO2Me D D 3 Cbz LiHMDS THF, -78 °C to rt CO2Me 4 Cbz LDA THF, -78 °C I 63

5 Cbz - HOAc, rt Br2 NR

6 H LDA THF, -78 °C to rt CO2Me D

7 Bn LDA THF, -78 °C to rt CO2Me NR

8 Bn LiHMDS THF, -78 °C to rt CO2Me NR

9 Bn KH THF, 0 °C to rt I NR

10 Bn LDA THF, HMPA, -78 °C to rt MeI NR

11 Bn LDA THF, HMPA, -78 °C to rt D2O NR

12 Bn KHMDS THF, 18-crown-6, -78 °C to rt D2O NR

NR = no reaction; D = decomposition

The methyl imidate 110, easily prepared via treatment of N-H lactam 63 with methyl trifluoromethanesulfonate in quantitative yield, was similarly resistant to attempts at C7- functionalization with a variety of non-nucleophilic bases and electrophiles including methyl acrylate, allyl iodide, TMSCl, methyl iodide and D2O (Scheme 27).

Scheme 27. Preparation and Attempted C7-Functionalization of Imidate 110

H H H CO Me MeOTf CO Me E CO Me 2 CH Cl 2 2 2 2 base, E rt OMe O OMe N H ~100% N N 63 110

3.2. Attempts to Homologate at C7 via Enamine Chemistry

3.2.1. Studies with N-H Lactam (E)-Pyrrolidinoenamine 112.

The failed exchange experiments with D2O, in particular, provided strong evidence that spirocycles 53, 62, 63, and 110 do not undergo the desired ester enolization upon treatment with base. In view of these inexplicable results, we turned to the possibility of accomplishing the desired

C7-functionalization via an enamine alkylation.

Towards this end, N-H lactam ester 63 was chemoselectively reduced with diisobutylaluminum hydride (DIBAL-H) at -78 ºC to afford aldehyde 111 in moderate yield

(Scheme 28). Whereas the conversion of aldehydes to enamines often employs harsh conditions and provides low product yields, the mild procedure developed by Bélanger and coworkers can mitigate these issues.31 Accordingly, treatment of aldehyde 111 with pyrrolidine and molecular sieves in chloroform at 0 ºC provided (E)-pyrrolidinoenamine 112 as a white crystalline solid. We were rather surprised to discover that enamine 112 was remarkably stable, even allowing for recrystallization from diethyl ether, which provided material suitable for single crystal X-ray diffraction analysis (ORTEP in Scheme 28).

Scheme 28. Synthesis and Attempted C7-Functionalization of (E)-Pyrrolidinoenamine 112

H DIBAL-H H CO Me CHO 2 CH2Cl2 O -78 °C O H N H 65% N 63 111

R pyrrolidine R H + H CHCl3, 0 °C N then H3O CHO 4Å MS 7 O O 100% H N R = CO2Me, N H CHO, CN, 112 (X-ray) 113 CH2Br

Since Michael-type addition of enamine 112 to an α,β-unsaturated carbonyl species (Stork enamine chemistry)32 appeared the most direct route to the appropriate 1,5-dicarbonyl cyclization precursor needed to probe the pivotal B-ring closure (Cf. Scheme 6), a number of conditions to perform this transformation were screened. However, we were disappointed to discover that heating enamine 112 in the presence of excess methyl acrylate, acrylonitrile, or acrolein at reflux in a sealed tube overnight, followed by an aqueous acidic quench led only to the recovery of aldehyde 111. Even performing the reaction in neat methyl acrylate at 180 ºC under microwave

42 irradiation, gave no evidence of the desired C7-adduct 113. Likewise, (E)-pyrrolidinoenamine 112 failed to undergo alkylation with allyl bromide even at elevated temperatures.

3.2.2. Studies with N-Bn Lactam (E)-Pyrrolidinoenamine 116.

Reasoning that perhaps better results might be obtained using the enamine derived from the N-benzyllactam series, spirocyclic ester 53 was first converted to N-methoxy-N-methylamide

114 in high yield using a combination of N,O-dimethylhydroxylamine hydrochloride and dimethylaluminum chloride (Scheme 29).33 Chemoselective reduction of amide 114 with lithium aluminum hydride at -40 ºC then furnished aldehyde 115 in excellent yield.34 Conversion of 115 to (E)-pyrrolidinoenamine 116 using the Bélanger protocol was accomplished in quantitative yield.31 However, enamine 116 was again resistant to reaction with various Michael acceptors as well as allyl bromide even under forcing conditions.

Scheme 29. Synthesis and Attempted C7-Functionalization of (E)-Pyrrolidinoenamine 116.

Me(OMe)NH Cl 2 O H H LiAlH , THF H Me2AlCl, CH2Cl2 4 CO2Me Me CHO 0 °C-rt N -40 °C O O O OMe Bn 90% 91% Bn N N Bn N 53 114 115

R R pyrrolidine H H N then H O+ CHO CHCl3, 0 °C 3 7 4Å MS O O Bn 100% N N Bn R = CO2Me, 116 CHO, CN, CH2Br

With our options for C7-homologation dwindling, we next explored the halogenation of N- benzyl (E)-pyrrolidinoenamine 116. Gratifyingly, it was discovered that treatment of 116 with one equivalent of N-chlorosuccinimide,35 followed by hydrolysis with aqueous acetic acid, provided

α-chloroaldehyde 117 as a 2.2:1 mixture of C7-diastereomers (Scheme 30). We hoped, at this stage, that elaboration of this α-chloroaldehyde 117 to the B-ring cyclization precursor might be feasible using nitrosoalkene “umpolung” conjugate addition methodology developed recently in our laboratory (vide infra).

Scheme 30. Chlorination of (E)-Pyrrolidinoenamine 116 at C7

H H N 1) NCS, 65 °C Cl CHO Et O, CHCl O 2 3 O Bn Bn N 2) HOAc, H2O N 82% 116 117 (dr = 2.2:1)

3.3 C7-Homologation via Nitrosoalkene Umpolung Conjugate Addition

3.3.1. Background on Nitrosoalkene Conjugate Additions

Although nitrosoalkenes 120 (Scheme 31) had first been hypothesized as reactive intermediates as early as in the late nineteenth century, spectroscopic evidence for their existence did not come until the 1960’s.36 These transient species, occasionally accompanied by a fleeting blue color in a reaction mixture, readily participate in a number of transformations including thermal [4+2] cycloadditions as well as in conjugate additions, in which they can function as electrophilic “enolonium” ion equivalents.

Often high yielding and reproducible, conjugate additions to nitrosoalkenes provide a reliable route to 1,4-dicarbonyl synthons (as exemplified by 121) that can be difficult to prepare using alternative methods. In recent years, our laboratory has studied both the inter- and intramolecular Michael-type additions of various nucleophiles, primarily 1,3-dicarbonyl species, to nitrosoalkenes generated in situ from α-chloroaldoximes and ketoximes.37

Although a number of procedures for the generation of nitrosoalkenes have been reported, the Weinreb laboratory conjugate addition methodologies have relied upon either the ‘classical’ base promoted 1,4-hydrogen chloride elimination of free α-chlorooximes 118 (Method A) or the fluoride promoted 1,4-elimination of α-halo-O-silyloximes 119 developed by Denmark and coworkers (Method B).38 In the former method, nitrosoalkene formation typically occurs concurrently with the addition of the anionic donor, or in the case of intramolecular reactions, addition of a strong base to generate the nucleophilic species. Thus, the ‘classical’ method can become problematic when expensive nucleophiles are utilized since two or more equivalents of the anionic species are required with one serving sacrificially to generate the nitrosoalkene intermediate. Likewise, intramolecular Michael addition (IMA) reactions can be difficult to achieve using the classical method, since the cyclization precursors typically undergo both deprotonation and nitrosoalkene formation upon addition of the base. In these instances, the

Denmark protocol can offer the synthetic chemist a great deal more flexibility, since nitrosoalkene formation occurs chemoselectively at a specific point in the reaction only after the addition of a fluoride source such as tetra-n-butylammonium fluoride (TBAF) or cesium fluoride. Thus, nitrosoalkene formation and deprotonation (or addition) of the anionic nucleophile precursor can occur independently of one another.

Scheme 31. Conjugate Additions of Nitrosoalkene Intermediates

OH N Cl Method A base OH O EWG N 118 N EWG EWG EWG OSiR N 3 121 Cl Method B 120 F- source 1 1 EWG = R CO, R CO2, 119 CN, RSO2, etc. O

enolonium ion equivalent

3.3.2. Nitrosoalkene Michael Addition of α-Chloro-O-Silylaldoxime 122.

In light of our failure to accomplish the desired C7-homologation en route to myrioneurinol via traditional enolate or enamine chemistry, we hoped that a nitrosoalkene ‘umpolung’ conjugate addition of an appropriate soft nucleophile to an oxime derived from α-chloroaldehyde 117 would provide a solution to this hitherto intractable problem. Towards this end, α-chloroaldehyde C7- diastereomeric mixture 117 was converted to O-TBS-α-chlorooximes 122 in good yield (Scheme

32). Although the C7-configuration of chlorooxime 122 is of no consequence to the proposed nitrosoalkene Michael addition, the O-silyloxime diastereomers were nevertheless separable on a column of silica gel, and could therefore be characterized individually.

Scheme 32. Conversion of Aldehyde 117 to O-Silyloxime 122

OTBS H TBSONH2 H Cl CHO PPTS Cl N CH2Cl2, rt O O Bn 85% N N Bn 117 122 dr ~ 2.2:1

At this stage, we were prepared to investigate the proposed Michael addition to a nitrosoalkene intermediate generated from O-TBS-α-chlorooxime 122 via the Denmark protocol.

The lithium enolate of dimethyl malonate was selected as the nucleophile since this 1,3-dicarbonyl derivative was not particularly sterically demanding and would also permit elaboration of the resulting adduct to the desired B-ring cyclization precursor 33 (Cf. Scheme 6) via decarboxylation and one carbon homologation (vide infra). Since very little is known about the reactive conformation of nitrosoalkene intermediates, we could not easily predict the stereochemical outcome of the addition. We anticipated, however, that a mixture of C7-diastereomers would probably result and hoped that the compound with the correct configuration for elaboration to the natural product would comprise a substantial amount of the product mixture.

In accordance with the experimental protocols which had been developed in our laboratory,

O-TBS-α-chlorooxime 122 was added dropwise to a solution of the pre-generated malonate lithium enolate at -78 ºC, followed by slow addition of a solution of TBAF in THF at that temperature and immediate warming to 0 ºC, which provided a ca. 5:1 mixture of two products

(ratio determined by proton NMR) which were difficult to separate completely using either a column of silica gel or preparative TLC (Scheme 33). Mass spectrometric analysis of the mixture revealed that both compounds possessed the correct molecular weight. The compounds were initially and incorrectly assigned to be a mixture of C7-diastereomers (vide infra).

Despite both compounds having different Rf values on the TLC, complete purification of a sufficient quantity of the minor product for detailed NMR analysis could not be done. A moderate degree of resolution was achieved via iterative flash column chromatographic separation of fractions collected from the extreme ends of product elution from the previous column, resulting in partial crystallizations of both the major and minor components. Recrystallization of the crude solids from diethyl ether provided clear prisms of the pure major and minor products that proved to be of sufficient quality for single crystal X-ray diffraction analysis. We were quite pleased to discover that both compounds possessed the correct C7-configuration needed for elaboration to myrioneurinol and were simply (E)- and (Z)-oxime geometric isomers 123a and 123b, respectively

(ORTEP renderings shown in Scheme 33).

Scheme 33. Diastereoselective Nitrosoalkene Michael Addition

LiHMDS, THF OTBS o -78 C OH H H Cl CO Me N N 2 6 O CO Me 7 CO Me O 2 2 5 H CO2Me N Bn then TBAF N Bn -78 oC to 0 oC 93% 122 123a E-oxime (X-ray) 123b Z-oxime (X-ray) ~5:1 E/Z

6 5 7 5 6 7

(E)-oxime 123a (Z)-oxime 123b

3.3.3. Rationalization of Observed C7-Diastereoselectivity

Because of their transient nature, little is known about the geometry and stereoelectronic disposition of nitrosoalkene intermediates. Our laboratory has conducted detailed studies on the

Michael-type addition of malonate nucleophiles to nitrosoalkenes derived from acyclic γ-chiral α- chloroaldoximes that provided stereochemical outcomes that could be rationalized via a modified

Felkin-Anh model.37d In these studies, the nitrosoalkenes were assumed to adopt the more stable

(E)-configuration and were postulated to be stereoelectronically comparable to (E)-α,β- unsaturated ester species. Although the complexity of spirocyclic scaffold in the oxime 122 precluded our ability to apply these findings to the myrioneurinol system directly, we nevertheless developed a working model to rationalize the stereochemical outcome of the Michael addition that involves attack of the malonate anion onto the least hindered face of hypothetical (E)-nitrosoalkene conformer 124 (Scheme 34). We are unable, however, to provide a rationalization as to why 124 is the reactive conformation.

Scheme 34. Conformational Rationalization for Observed C7 Diastereoselectivity

OH H H H N 6 O NO O C6,7 7 CO Me 7 Bn N 2 N O bond rotation HCO2Me N N Bn Bn O H H CO2Me 124 CO2Me 123a/b

CHAPTER 4: B-RING CLOSURE STRATEGIES

4.1. Imidate/Nitrile α-Anion Cyclization Strategy

4.1.1. Preparation of Cyclization Precursor

With intermediates 123a/b containing the C5, C6, and C7-stereocenters in hand, we turned our attention next toward the construction of the B-ring of the cis-DHQ system of myrioneurinol.

Since our first generation retrosynthesis of the alkaloid was predicated upon the cyclization of an intermediate such as imidate (Cf. Scheme 6) we needed to perform a series of functional group manipulations as well as a one-carbon homologation of 1,4-dicarbonyl surrogate 123a/b.

Thus, E/Z-oxime mixture 123a/b was first dehydrated to afford nitrile malonate 125 in excellent yield (Scheme 35).39 Various reductive and oxidative oxime cleavage methods to afford the corresponding aldehyde from aldoximes 123a/b were also screened at this time. However these experiments ultimately resulted either in the formation of nitrile 125 or decomposition. We reasoned that a late-stage nitrile hydrolysis and reduction of the derived acid moiety could be employed to install the requisite C8-hydroxymethyl functionality, and therefore we decided to proceed with the nitrile substrate.

Krapcho decarboxylation of malonate 125 with lithium chloride in refluxing DMSO/water then furnished nitrile ester 126 in good yield.40 Nitrile ester 126 was then chemoselectively reduced in good yield using lithium borohydride to afford alcohol 127, which was cleanly converted to the corresponding mesylate 128. Heating of mesylate 128 with tetraethylammonium cyanide provided

N-benzyllactam dinitrile 129. Since the N-H lactam 130 was required for methyl imidate formation, the removal of the protecting group on nitrogen was attempted at this stage. However, dissolving metal reduction of N-benzyllactam 129 using sodium in liquid ammonia at -78 ºC

50 resulted in decomposition of the starting material, perhaps due to reduction of one or both of the nitrile moieties under these conditions.

Scheme 35. Attempted Elaboration of Oximes 123a/b to Dinitrile 130

OH H H H N CN CN O7 DCC, CuSO4 O LiCl O Et N, pyr, rt DMSO CO2Me 3 CO2Me CO2Me CH2Cl2 H O HCO2Me HCO2Me 2 H N Bn N Bn N 96% 155 oC Bn 123a/b 125 73% 126

H Et NCN Na/NH O CN 4 H 3 H LiBH O CN Et O CN 4 4Å• MS 2o O THF, rt MeCN -78 C H OR N o H CN H 93% Bn 60 C N N CN 100% Bn H

127 R = H 129 130 MsCl, Et3N CH2Cl2, rt, 64% 128 R = Ms

Gratifyingly, N-benzyllactam alcohol 127 could be deprotected using a dissolving metal reduction to afford the N-H lactam alcohol 131 in excellent yield (Scheme 36). Alcohol 131 was then cleanly converted to the mesylate 132 and homologated to the dinitrile 130 in excellent yield.

Treatment of N-H lactam 130 with methyl trifluoromethanesulfonate furnished the desired methyl imidate 133 in good yield.

Scheme 36. Successful Elaboration of Alcohol Lactam 127 to Imidate 133

H H CN Na/NH3 Et4NCN O O CN Et2O 4Å MS -78 oC MeCN H N OH H OR o Bn N H 60 C 87% 99% 127 131 R = H MsCl, Et3N CH Cl , rt, 99% 2 2 132 R = Ms

H MeOTf H CN CN O CH2Cl2 rt OMe H CN CN N H 75% N 130 133

4.1.2. Imidate/Nitrile α-Anion Cyclization Studies

We were now prepared to explore the proposed C9,10 bond formation via intramolecular cyclization of imidate dinitrile 133. Although no examples of such a nitrile α-anion/imidate cyclization could be found in the literature, we had hoped that treatment of the cyclization precursor with a strong non-nucleophilic base would induce the desired reaction pathway, resulting in tricyclic cyanoenamine 134 (Scheme 37). To this end, dinitrile 133 was treated with freshly- prepared LDA in THF at -78 ºC and the reaction mixture was slowly warmed to room temperature and stirred overnight. After an aqueous workup, NMR analysis of the crude mixture revealed the presence of only starting material (entry 1). Reasoning that perhaps the cyclization would benefit from being performed at a higher temperature, trials in which the LDA was added at 0 ºC and at room temperature were next performed (entries 2-3). However, in both cases, varying degrees of decomposition were observed, along with the recovery of a small amount of unreacted starting material. In neither case was any amount of tricycle 134 detected spectroscopically. The amide

52 base KHMDS was also screened (entry 4) but similarly afforded none of the desired cyclized product 134. Thus, in view of these failures, the nitrile anion/imidate B-ring closure strategy was abandoned in favor of alternative annulation methods.

Scheme 37. Attempted B-ring Closure via Nitrile Anion/Imidate Cyclization

H H CN CN base OMe CN N CN conditions N H 133 134

entry base conditions result

1 LDA THF, -78 oC to rt NR 2 LDA THF, 0 oC to rt SM + D 3 LDA THF, rt SM (trace) + D 4 KHMDS THF, 0 oC to rt NR

NR = no reaction; SM = starting material; D = decomposition

4.2. Rainier Metathesis Strategy

4.2.1. Background on the Rainier Metathesis Reaction

The Rainier laboratory has developed a series of olefin/carbonyl metathesis reactions to construct electron rich heteroatom substituted olefins.41 These useful transformations provide access to synthetically important enol ether and enamide intermediates via the insertion of what are hypothesized to be titanium ethylidenes generated in situ into ester and amide carbonyl groups, respectively. Recently, Rainier and coworkers have reported the ring closing metathesis of substrates containing N-tosyllactam and terminal olefin moieties such as 135 to provide the corresponding bicyclic enesulfonamides 136 (Scheme 38).41d The methodology was tolerant of a variety of lactam ring sizes and olefin tether lengths and provided the enesulfonamide products in moderate to excellent yields, along with minor amounts of the acyclic products 137 resulting from the carbonyl insertion and olefin metathesis of the titanium ethylidene derived from 1,1- dibromoethane.

Scheme 38. Intramolecular Olefinic-Lactam Rainier Metathesis Reaction. n o m TiCl4, Zn , PbCl2 m n Br HCCH + n 2 3 m TMEDA, THF n N N Me m Ts CH2Cl2 Ts Me [Ti] N O N O 136 137 Ts Ts entry m n 135 yield* 136:137 1 1 2 82 >95:5 2 2 2 75 87:13 3 3 2 78 90:10 4 3 1 70 >95:5 5 3 3 82 >95:5 *combined yield of 136 and 137

4.2.2. Second Generation Retrosynthesis

We recognized that such an olefinic-lactam metathesis reaction could potentially be utilized to construct the B-ring of myrioneurinol, accomplishing the pivotal C9,10 bond formation.

Our modified retrosynthetic strategy was thus predicated upon the elaboration of nitrile/ester 126 to N-tosyllactam/olefin cyclization precursor 138 (Scheme 39). We hoped that metathesis of 138 would afford tricyclic enesulfonamide intermediate 139 which contains the A/B/D-ring subunit of myrioneurinol. We expected that cleavage of the sulfonyl group from nitrogen would induce tautomerization of enesulfonamide 139 to endocyclic imine 140. Since, the α-alkylation of imines via 1-azaallyl anion formation is well documented,42 we hoped that metallation of 140 followed by treatment with an appropriate electrophile would accomplish the necessary C9,11 bond formation necessary for the eventual installation of the 1,3-oxazine C-ring. Examination of molecular models of 1-azaallyl anion 141 suggested that the approach of the electrophile would favor a trajectory leading to an equatorial disposition of the C11-substituent. We further theorized that reduction of imine 142 should occur from the less-hindered convex face, thus establishing the proper C10-stereochemistry for elaboration of piperidine 143 to myrioneurinol.

Scheme 39. Rainier Metathesis Strategy for Myrioneurinol B-Ring Closure.

H H H O CN O CN Rainier CN metathesis CO2Me 10 H H 9 N N Bn Ts N Ts

126 138 139

H H CN CN deprotect base

N H N H

140 141

[H-] H H CN CN - H X OR [H ] 11 11 9 10 9 N H OR N H OR H H H

142 143

4.2.3. Preparation of N-Tosyllactam/Terminal Olefin Cyclization Precursor

4.2.3.1. Lactam Nitrile System

In order to prepare the requisite cyclization precursor for the pivotal Rainier metathesis reaction, nitrile ester 126 was first converted to N-methoxy-N-methylamide 144 in moderate yield using a combination of N,O-dimethylhydroxylamine hydrochloride and dimethylaluminum chloride (Scheme 40).33 Chemoselective reduction of amide 144 with lithium aluminum hydride at -40 ºC furnished aldehyde 145 in excellent yield.34 We were surprised to discover that Wittig olefination of 145 with methylenetriphenylphosphorane resulted only in ca. 5% yield of the desired terminal olefin 147. Various alternative methylenation strategies for 145 were explored including

Peterson olefination and treatment with the Tebbe-Petasis reagent. Eventually, Julia-Kocienski olefination of aldehyde 145 with easily prepared phenyltetrazoylmethyl sulfone 146 was found to provide olefin 147 in a more acceptable (and unoptimized) 32% yield.43 However, we were disappointed to discover that during the removal of the benzyl protecting group from the lactam nitrogen of 147 via dissolving metal reduction with sodium in liquid ammonia at -78 ºC, concomitant loss of the nitrile functionality resulted leading to olefin 148.44

Scheme 40. Attemped Elaboration of Nitrile Ester 126 to Rainier Metathesis Cyclization Precursor 138.

H H Me O CN O CN Me(OMe)NH2Cl N LiAlH4 CO2Me OMe o H Me2AlCl H THF, -40 C N N O Bn CH2Cl2 Bn 93% 0 °C-rt, 73%

126 144

Ph MeO S H 2 N H H O CN N CN Na/NH N O 3 O CHO N Et2O o H -78 C N 146 H Bn N Bn N H LiHMDS, THF/HMPA rt, 32% 145 147 148

4.2.3.2. Methoxymethyl (MOM) Ether System

The low yields observed for the olefination in the nitrile series and our failure to successfully cleave the benzyl protecting group from 147 forced us to revisit the oxime cleavage of Michael adducts 123a/b. We were pleased to discover that a reductive deoximation method recently developed in our laboratory employing titanium (IV) chloride and zinc metal dust at 0 ºC

57 cleanly converted the aldoxime E/Z-mixture 123a/b to aldehyde 149 in moderate yield (Scheme

41).45 Subsequent reduction of aldehyde 149 with one equivalent of sodium borohydride at 0 ºC led to the isolation of α-carbomethoxylactone 150, which results from translactonization by the intermediate C7-hydroxymethyl group resulting from reduction of the aldehyde. Krapcho decarboxylation of 150 using lithium chloride in refluxing DMSO/water then furnished γ-lactone

151 in excellent yield.40

Scheme 41. Elaboration of Oximes 123a/b to Lactone 151

OH H H NaBH N TiCl , Zno CHO 4 O 4 o O MeOH THF, 0 C 0 oC CO2Me CO2Me H CO2Me 63% HCO2Me 81% N Bn N Bn 123a/b 149

O LiCl O H H O O DMSO/H2O O 155-160 oC O CO Me H 2 N 90% H Bn N Bn 150 151

Chemoselective reduction of γ-lactone 151 with DIBAL-H provided a ca. 3:1 diastereomeric mixture of γ-lactols 152 in good yield (Scheme 42). Wittig olefination of lactol mixture 152 with excess methylenetriphenylphosphorane furnished the desired terminal olefin 153 in a yield much improved over that observed for the methylenation in the nitrile series (Cf. Scheme

40). The C7-hydroxymethyl group in 153 was then protected as the methoxymethyl (MOM) ether

154 in excellent yield. Dissolving metal reduction of N-benzyllactam 154 with sodium metal and

58 liquid ammonia at -78 ºC cleanly furnished N-H lactam olefin 155, which was treated with

LiHMDS followed by p-toluenesulfonyl chloride to furnish N-tosyllactam 156 in excellent yield.

Scheme 42. Elaboration of Lactone 151 to Rainier Metathesis Cyclization Precursor 156

O O DIBAL-H O H H Ph3PMeBr THF OH O o O n-BuLi, THF -78 C 0 oC H N 83% H 68% Bn N Bn 151 152 dr ~3:1

OH MOMCl OMOM H DIEA H Na/NH O o O 3 0 C Et2O CH2Cl2 -78 oC H H N Bn 92% N Bn 92% 153 154

OMOM OMOM H H TsCl O O LiHMDS THF, 0 oC H H N N H 88% Ts 155 156

4.2.3.3. Rainier Metathesis of N-Tosyllactam 156.

With the requisite N-sulfonyllactam terminal olefin Rainier metathesis cyclization precursor 156 in hand, we began to explore the conditions required to effect this pivotal transformation. Gratifyingly, subjection of 156 to the metathesis conditions outlined by Rainier provided the desired tricyclic ensulfonamide 157 in ca. 30% unoptimized yield (Scheme 43, entry

1).41d Since a small amount of the undesired acyclic enesulfonamide side product 158 resulting from the insertion of the reduced titanium ethylidene formed from 1,1-dibromoethane was also

59 detected, we reasoned that increasing the concentration of cyclization precursor 156 might ameliorate this problematic side reaction. Indeed, tripling the concentration of lactam olefin 156 improved the yield of tricycle 157 to a more synthetically useful 55%, with none of the acyclic side product 158 detected by TLC or NMR analysis of the crude mixture (entry 2).

Scheme 43. Preliminary Studies on Rainier Metathesis Reaction of 156

o TiCl4, Zn , PbCl2 OMOM Br2HCCH3 OMOM OMOM H TMEDA, THF H H Me O o CH2Cl2, 55 C + H H N N Me Ts N Ts Ts 156 157 158

entry concentration (M) result

1 0.003 157 (30%) + 158* 2 0.009 157 (55%)

*yield not determined due to complex mixture

4.2.3.4. Attempted Elaboration of N-Ts Enesulfonamide 157.

Rather than trying to optimize the Rainier metathesis of lactam olefin 156 at this stage, we instead decided to attempt to further elaborate tricycle 157. Since cleavage of the tosyl protecting group from nitrogen was necessary for the tautomerization of enesulfonamide 157 to the endocyclic imine 159, various conditions were explored to deprotect the tricyclic substrate

(Scheme 44). Unfortunately, enesulfonamide 157 was resistant to a variety of standard tosyl group cleavage methods including treatment with lithium or sodium naphthalenide (entries 1-2) and

60 dissolving metal reduction in liquid ammonia at -78 ºC (entries 3-4). In each case, extensive decomposition of the starting material was observed.

We hypothesized that these strongly reducing conditions might be incompatible with the enesulfonamide moiety and thus also investigated several milder detosylation protocols.

Unfortunately, a mild aqueous samarium diiodide-mediated procedure,46a sonication of 157 with magnesium turnings in anhydrous methanol,46b and treatment of 157 with potassium diphenylphosphide46c were all unsuccessful in furnishing any endocyclic imine 159.

Scheme 44. Attempted Desulfonylation of Enesulfonamide 157

OMOM OMOM H H

conditions

N Ts N 157 159

entry conditions result

1 Nao, naphthalene, THF, -78 oC D

2 Lio, naphthalene, THF, -78 oC D o o 3 Na , NH3, Et2O, -78 C D o o 4 Li , NH3, Et2O, -78 C D o 5 SmI2, H2O, 0 C NR o 6 Mg , MeOH, sonication D o 7 KPPh2, THF, -78 C D*

*small amount of unidentified side product

4.2.4. N-SES-Lactam System

Since we were unable to cleave the tosyl group from the enesulfonamide nitrogen in tricycle 157, an alternative cyclization precursor for the pivotal Rainier metathesis reaction containing a more labile 2-trimethylsilylethylsulfonyl (SES) protecting group for the lactam nitrogen was prepared.47 Thus, treatment of N-H lactam olefin 155 with SES chloride48 cleanly furnished the N-SES lactam olefin 160 in good yield. We were pleased to discover that subjection of 160 to our optimized metathesis reaction conditions for tosyllactam 157 provided the desired tricyclic N-SES enesulfonamide 161 in excellent 83% yield. Unfortunately, enesulfonamide 161 could not be desulfonylated using any of the existing fluoride-mediated protocols including treatment with CsF,47a TBAF,47b TAS-F,47c and HF-pyridine complex.

Scheme 45. Rainier Metathesis of N-SES Lactam Olefin 160

OMOM OMOM H SESCl H O LiHMDS O THF, 0 oC H H N N H 78% SES 155 160

o TiCl4, Zn , PbCl2 Br HCCH OMOM OMOM 2 3 H H TMEDA, THF o CH2Cl2, 55 C 9 N H 83% N SES 161 159

We also briefly examined the possibility of utilizing the weakly nucleophilic character of enesulfonamides 157 and 161 to effect C9-functionalization.49 However, both compounds were

62 resistant to halogenation with elemental bromine and N-chlorosuccinimide,50a hydroboration, acylation with various acyl halides,50b Vilsmier-Haack formylation,50c and Simmons-Smith cyclopropanation.50d In each case, either decomposition or recovery of the starting material was observed.

Although we had demonstrated that the pivotal Rainier metathesis of N-sulfonyllactam olefins 156 and 160 could accomplish the desired B-ring formation, our failure to elaborate the tricyclic products 157 and 161 forced us to abandon this route to myrioneurinol.

4.3. Allyl Silane/N-Sulfonyliminium Aza-Sakurai Strategy

4.3.1. Background: Weinreb Synthesis of the Sarain A Core Structure

Some time ago, the Weinreb laboratory had successfully employed an intramolecular variant of the Sakurai reaction in a pivotal stereoselective carbon-carbon bond formation step in the synthesis of the core structure 170 of the unusual marine alkaloid sarain A (171) (Scheme 46).51

In order to prepare the requisite cyclization precursor 167, Weinreb and coworkers had first treated

N-benzyllactam aldehyde 162 with vinylmagnesium bromide to furnish a diastereomeric mixture of allylic alcohols 163. Alcohols 163 were then acylated with acetic anhydride to furnish allyl acetates 164, in order to improve the nucleofugicity of the hydroxyl group. The acetate diastereomeric mixture 164 was next treated with a trimethylsilylcuprate reagent generated in situ, according to the method of Fleming and coworkers,52 which provided allyl silane 165 as an inconsequential mixture of (E)- and (Z)-olefin geometric isomers. It should be noted that Weinreb and coworkers determined that only the N-sulfonyllactam 167, as opposed to the N-benzyl protected substrate 165, could be partially reduced with diisobutylaluminum hydride (DIBAL-H)

63 to afford a diastereomeric mixture of hemiaminals 168. Thus, the N-benzyl protecting group on lactam 165 was removed via dissolving metal reduction with sodium and liquid ammonia at -78

ºC to afford N-H lactam 166, which was in turn protected as the N-tosyl derivative 167. Upon reduction of 167 with DIBAL-H, it was discovered that treatment of the resulting mixture of hemiaminals 168 with the Lewis acid iron (III) chloride effected the desired stereoselective six- membered ring closure adjacent to the nitrogen. Weinreb and coworkers hypothesized that this interesting cyclization likely involved the highly electrophilic N-sulfonyliminium ion intermediate

169 which is attacked by the π-system of the pendant allyl silane moiety that occupies a quasi- equatorial position in the chair-like conformation shown, resulting in the observed stereochemistry for tricycle 170.

Scheme 46. Pivotal Aza-Sakurai Cyclization in Weinreb Route to Sarain A Core

O O O Bn H Bn MgBr H Bn (TMS)2(CN)Li2Cu H o N o N BnN N THF, 0 C to rt BnN THF: HMPA, -25 C RN H H 50% H H H OR H CHO 162 SiMe3 Ac2O, Et3N 163 R = H o 165 R = Bn (50%) DMAP, CH2Cl2 Na , NH3 35% (2 steps) 164 R = Ac THF, -78 oC 166 R = H (95%) TsCl, LiHMDS o THF, 0 C 167 R = Ts (71%)

DIBAL-H SiMe3 OH Bn CH2Cl2 H FeCl3, CH2Cl2 H o N -78 C to rt TsN -78 oC to rt 61% H NBn H NBn 93% H Ts N Ts H N H 168 H H H 169 170 SiMe3

O H N N HO H H HO H sarain A (171)

We recognized the fundamental similarity of this transformation with the desired C9,10 bond formation to construct the cis-DHQ in the myrioneurinol system and thus sought to explore this B-ring closure strategy further (vide infra).

4.3.2. Third Generation Myrioneurinol Retrosynthesis

Due to the failure of our studies on the Rainier metathesis strategy for B-ring closure, we explored the possibility of accomplishing the pivotal C9,10 bond formation in the myrioneurinol total synthesis using a related allyl silane/N-sulfonyliminium aza-Sakurai reaction. This strategy was predicated upon our ability to elaborate nitrosoalkene Michael adducts 123a/b to the appropriate aza-Sakurai cyclization precursor (Scheme 47). Partial reduction of the N- sulfonyllactam carbonyl in 172 with DIBAL-H would furnish a mixture of hemiaminal diastereomers 173, which upon treatment with an appropriate Lewis acid would dehydrate to afford N-sulfonyliminium intermediate 174. We anticipated that 174 would cyclize via the conformation shown where the incipient B-ring would be chair-like and the allyl silane moiety would occupy a quasi-equatorial position leading to tricycle 175 which contains the desired C9,10 relative configuration for elaboration to the natural product.

Scheme 47. Aza-Sakurai Approach to Forming the Myrioneurinol B-Ring

OH H H H R R O N O OH DIBAL-H CO2Me SiMe3 SiMe3 HCO2Me N N N Bn Ts Ts

123a/b 172 173

R = CN, CH2OMOM

H H Lewis R H R Acid SiMe 3 10 9 N N Ts TsH 174 175

4.3.3. Preparation of Cyclization Precursor

4.3.3.1. Attempted Allyl Silane Formation via Fleming Cuprate Methodology in Nitrile

System

At the outset of our studies on the intramolecular aza-Sakurai reaction, the successful oxime cleavage method for converting 123a/b into aldehyde 149 (Cf. Scheme 41) had not yet been discovered. Therefore, the preliminary investigative work toward allyl silane/sulfonyllactam cyclization precursor 172 was performed from nitrile aldehyde 145 (Cf. Scheme 40). Towards this end, aldehyde 145 was first treated with vinylmagnesium bromide to furnish allyl alcohols 176 in moderate yield (Scheme 48). Acylation of 176 with acetic anhydride then furnished the desired acetate mixture 177 in good yield. Disappointingly, acetates 177 did not undergo the desired conversion to the allyl silane 179 when subjected to the Fleming silylcuprate methodology.52a A related trimethylsilylcuprate addition to the corresponding allylic mesylates 178, prepared from alcohol 176 in good yield, was similarly unsuccessful in generating any of the desired allyl silane

179.52b

Scheme 48. Attempted Fleming Silylcuprate Additions to Derivatives of Aldehyde 145

H H MgBr O CN O CN CHO THF, rt H H OR N Bn N Bn

145 dr ~ 4:1

Ac2O, Et3N 176 R = H DMAP, CH2Cl2 73% (2 steps) 177 R = Ac

and

MsCl, Et3N 176 R = H o CH2Cl2, 0 C 76% (2 steps) 178 R = Ms

H (TMS)2(CN)Li2Cu CN o O THF, HMPA, -25 C SiMe3 177 or 178 H N Bn 179

4.3.3.2. Attempted Allyl Silane Formation in Methoxymethyl (MOM) Ether-Protected

System

Having developed the sequence to convert nitrosoalkene Michael adducts 123a/b to γ- lactone 151 (Cf. Scheme 41), we decided to explore the elaboration of this compound to the requisite precursor for the aza-Sakurai reaction. Towards this end, lactone 151 was first ring opened to N-methoxy-N-methylamide 180 using N,O-dimethylhydroxylamine hydrochloride and dimethylaluminum chloride in good yield (Scheme 49).33 Since immediate protection of the C7- hydroxymethyl group of 180 was necessary to prevent reversion to γ-lactone 151, the alcohol was converted to the methoxymethyl (MOM) ether 181 in good yield. At this stage, chemoselective

68 reduction of the N-methoxy-N-methylamide moiety in 181 with lithium aluminum hydride at -40

ºC furnished aldehyde 182.34

Scheme 49. Elaboration of Lactone 151 to Aldehyde 182

O OR H O H O O Me(OMe)NH2Cl O

H Me2AlCl H N N Bn N CH2Cl2 Bn Me OMe 151 0 °C-rt MOMCl 180 R = H (86%) DIEA THF, 0 °C 181 R = MOM (80%)

OMOM H LiAlH4 O THF, -40 °C CHO H N Bn

182

Addition of vinylmagnesium bromide to aldehyde 182 provided a mixture of allyl alcohol diastereomers 183 in good yield (Scheme 50). Alcohols 183 were then converted to the corresponding acetates 184 in excellent yield via acylation with acetic anhydride. We were again disappointed to discover that acetates 184 failed to undergo the Fleming trimethylsilylcuprate addition to afford allyl silane 187.52a Moreover, attempts to prepare the corresponding mesylate

185 from alcohols 183 resulted instead in the isolation of vinylic furan 186 which presumably arises via in situ methoxymethyl group cleavage followed by intramolecular displacement of the mesylate.

Scheme 50. Attempted Elaboration and Fleming Silylcuprate Addition in MOM Ether Series.

OMOM OMOM H MgBr H O O THF, rt CHO H H 58% N OR N Bn Bn dr ~ 10:1 182 183 R = H

Ac2O, Et3N o DMAP, CH2Cl2, 0 C 184 R = Ac (91%) H O O

183 R = H H N MsCl, Et3N Bn o NaHCO3, CH2Cl2, 0 C 186 185 R = Ms

(TMS) (CN)Li Cu OMOM 2 2 H THF, HMPA, -25 oC O SiMe3 184 H N Bn 187

4.3.3.3. Seyferth-Wittig Homologation of Aldehyde 182

Since acetate mixture 184 was unreactive toward the Fleming silylcuprate addition protocol, the search for an alternative allyl silane formation method became necessary.

Examination of the synthetic work on the sarain A core revealed that attempted homologation of aldehyde 162 (Cf. Scheme 46) with the Seyferth-Wittig reagent using 2- trimethylsilylethyltriphenylphosphonium iodide (SETPPI),53 had been attempted but was unsuccessful in generating allyl silane 165.

Nevertheless, we reasoned that perhaps this method might work for the desired homologation of aldehyde 182 in the myrioneurinol route. We were pleased to discover that treatment of 182 with five equivalents of the Seyferth-Wittig reagent, generated via treatment of

SETPPI with phenyllithium at a room temperature, led to formation of allyl silane 187 as an inconsequential ca. 2.5:1 Z/E mixture of olefin geometric isomers (Scheme 51). With allyl silanes

187 finally in hand, the benzyl protecting group on the lactam nitrogen was removed in good yield using dissolving metal reduction with sodium in liquid ammonia at -78 ºC to afford the rather unstable N-H lactam 188. Immediate sulfonylation of 188 via treatment with LiHMDS followed by p-toluenesulfonyl chloride afforded the requisite N-tosyllactam allyl silane cyclization precursor 189 for the proposed intramolecular aza-Sakurai reaction in high yield.

Scheme 51. Seyferth-Wittig Homologation of Aldehyde 182

OMOM H H OMOM PPh3 I O O Me3Si CHO PhLi, THF, rt SiMe H 3 N N Bn 74% (2 steps) Bn

182 187

H Na/NH3 O OMOM Et2O -78 °C SiMe3 N R

LiHMDS 188 R = H (79%) TsCl, THF DMAP 189 R = Ts (87%)

4.3.4. Aza-Sakurai Reaction of N-Tosyllactam/Allyl Silane 189.

The pivotal intramolecular allyl silane/N-sulfonyliminium aza-Sakurai reaction of 189 was next addressed. In the sarain A work, partial reduction of sulfonyllactam 167 with DIBAL-H was utilized to afford the chromatographically-isolable hemiaminals 168 as a diastereomeric mixture

(Cf. Scheme 46).51a Accordingly, we were pleased to discover that treatment of 189 with fifteen equivalents of DIBAL-H at -78 ºC resulted in complete consumption of the starting material and the emergence of two new spots on the reaction TLC, as well as the correct molecular ion peak for hemiaminal 190 upon mass spectrometric analysis (Scheme 52). However, the yields of 190 upon aqueous workup and flash column chromatographic purification on silica gel were very low (<5%).

Moreover, treatment of the presumed purified hemiaminal mixture 190 with anhydrous iron (III) chloride at -78 ºC, followed by gradual warming to room temperature, conditions which had been successful in the sarain A route, led only to decomposition of the starting material.

Scheme 52. Attemped Aza-Sakurai Cyclization of Allyl Silane 189 Using Conditions from Sarain A Work

H H O OMOM DIBAL-H OH OMOM -78 oC SiMe3 SiMe3 N Ts <5% N Ts 189 190

FeCl3 H CH2Cl2 H OMOM -78 oC to rt

N Ts H 191

Since the isolation of the hemiaminals 190 appeared to be problematic, it was decided to attempt to perform the partial reduction and the cyclization in one synthetic operation. To our delight, treatment of 189 with fifteen equivalents DIBAL-H at -78 ºC, followed by addition of anhydrous iron (III) chloride and gradual warming to 0 ºC over two hours and an aqueous workup, provided proton NMR evidence for the formation of a single diastereomeric compound possessing the correct molecular weight (as determined by LRMS) for tricyclic olefin 191 (Scheme 53, entry

1). The reaction appeared to be approximately 40% complete, with hemiaminals 190 comprising the remainder of the mixture. Encouraged by this result, in an attempt to drive the reaction to completion, another trial was performed in which the reaction mixture was allowed to warm to room temperature (entry 2). However, we were disappointed to observe extensive decomposition under these conditions via TLC and NMR analysis. The optimal reaction temperature range for the aza-Sakurai cyclization of 189 was eventually discovered to be -78 to ca. 5 ºC (entry 3).

Careful monitoring of the temperature was essential to the reproducibility of the procedure, as was immediate aqueous quenching of the mixture when the temperature had reached 5 ºC. In this manner, tricyclic olefin 191 could be consistently isolated in yields greater than 70% even on a several hundred milligram scale.

Scheme 53. Optimization of the 'One Pot' Aza-Sakurai Cyclization of 189

H DIBAL-H H H O OMOM OMOM OMOM CH2Cl2 OH H -78 oC SiMe3 SiMe3 + N then FeCl N N Ts 3 Ts Ts H temperature 189 190 191

entry temperature result (% yield) 1 -78 oC to 0 oC 190 (~30) + 191 (~20) 2 -78 oC to rt D 3 -78 oC to 5 oC 191 (78%)

D = decomposition

4.3.5. Confirmation of the C9,10 Stereochemistry of Tricycle 191

A single diastereomer of tricyclic olefin 191 was produced in the aza-Sakurai cyclization which was determined to possess the correct C9,10 relative configuration for elaboration to myrioneurinol. Two-dimensional NMR study of tricycle 191 revealed strong 1H-1H NOESY correlations between H10 with H6, H16ax, H14ax, and H8ax suggesting a syn-facial disposition for these hydrogens (Figure 5). Moreover, a strong NOESY correlation between H9 with H7, H4ax and H2ax provided strong evidence that these signals were disposed to the same face. Since no such correlation was observed between H9 and H10, and the aforementioned correlations were consistent with those in the NOESY spectrum of natural myrioneurinol,54 we were confident that tricycle 191 contained the five contiguous stereocenters in the correct relative configuration for the alkaloid.

H 15 16 H H H 14 17 H 3 4 5 H 6 H N H 2 10 7 OMOM H Ts 18 H H 9 H H 8 H

Figure 5. NOESY Correlations for Tricycle 191 (H H)

CHAPTER 5: COMPLETION OF THE MYRIONEURINOL SYNTHESIS

5.1. Attempted Elaboration of N-Ts Tricyle 191

With the advanced tricyclic intermediate 191 containing all five contiguous stereocenters and the A/B/D-rings of the alkaloid secured, the installation of the 1,3-oxazine C-ring was next addressed in order to complete the total synthesis of the alkaloid. Thus, the vinyl group in tricycle

191 was cleaved ozonolytically using a two step reductive workup first involving treatment of the ozonide with triphenylphosphine overnight, followed by reduction of the crude intermediate aldehyde with sodium borohydride to furnish alcohol 192 in excellent yield (Scheme 54). At this stage, removal of the N-tosyl group from alcohol 192 to afford free piperidine 193 was attempted using a variety of methods. Strongly reducing conditions including treatment with either sodium or lithium naphthalenide (entries 1-2), dissolving metal reduction with either sodium or lithium metal in liquid ammonia at -78 ºC (entries 3-4), and treatment with freshly-prepared sodium amalgam (entry 5) each led to extensive decomposition of the starting material. Milder desulfonylation methods such as the sonication of 192 with magnesium turnings in anhydrous methanol46b (entry 6) and treatment with aqueous samarium diiodide46a (entry 7) were likewise unsuccessful.

Scheme 54. Ozonolytic Cleavage with Reductive Workup of Olefin 191 and Attemped Desulfonylation of 192

H H H H OMOM 1) O , CH Cl H OMOM H OMOM 3 2 2 conditions -78 °C; PPh3 OH OH N 2) NaBH4 N H N Ts H MeOH, 0 °C Ts H H 191 92% 192 193

entry conditions result

1 Nao, naphthalene, THF, -78 oC D 2 Lio, naphthalene, THF, -78 oC D o o 3 Na , NH3, Et2O, -78 C D o o 4 Li , NH3, Et2O, -78 C D 5 Na-Hg, MeOH, rt D 6 Mgo, MeOH, sonication, rt D

7 SmI2, THF, pyrrolidine, H2O, rt NR 8 Red-Al, PhMe, reflux D

D = decomposition; NR = no reaction

Heating alcohol MOM ether 192 at 50 ºC in 6 N aqueous HCl in THF cleanly removed the methoxymethyl protecting group, providing diol 194 in quantitative yield (Scheme 55). However, diol 194 proved equally resistant to desulfonylation utilizing a number of the aforementioned methods, with decomposition being observed in the majority of cases.

Scheme 55. Removal of the Methoxymethyl Protecting Group from sulfonamide 192 and Attempted N-Ts Cleavage

H H 6 N HCl OH H H OMOM H N-Ts H OH THF/H2O cleavage 50 oC OH OH OH N N H N Ts H 100% Ts H H 192 194 195

5.2. Alternative Protecting Groups for the Lactam Nitrogen

5.2.1. N-SES-Lactam System

Since the inability to remove the sulfonyl protecting group from the nitrogen of tricycles

192 and 194 presented a serious obstacle to the completion of the total synthesis of myrioneurinol, it was decided to evaluate the feasibility of performing the aza-Sakurai reaction on N- sulfonyllactam substrates bearing more easily cleaved protecting groups. Towards this end, the N-

SES lactam allyl silane precursor 196 was prepared from N-H lactam 188 in moderate yield

(Scheme 56a).47,48 Subjection of 196 to the optimized conditions for the cyclization of N-Ts lactam

189 provided a small amount of the desired N-SES tricyclic olefin 197 along with what appeared to be hemiaminals 198. Attempted desulfonylation of tricycle 197 utilizing the fluoride sources

CsF or TBAF at elevated temperatures led only to decomposition or recovery of the starting material (Scheme 56b).

Scheme 56. Studies on Aza-Sakurai Cyclization of N-SES Series

a) Preparation and Cyclization of N-SES Lactam/Allyl Silane 196

H O OMOM H O OMOM LiHMDS, SES-Cl SiMe o 3 THF, 0 C to rt SiMe N 3 H N 73% SES 188 196

DIBAL-H H OMOM H CH2Cl2 H OMOM -78 oC OH + SiMe3 then FeCl N 3 SES N SES warm to ~5 oC 197 198 27% 41%

b) Attempted Desulfonylation of Tricycle 197

H OMOM conditions H 197 N H

entry conditions result 1 CsF, DMF, rt to 95 oC D 2 TBAF, THF, reflux NR

5.2.2 N-Nosyllactam System

Cyclization precursor 199 containing the 4’-nitrobenzenesulfonyl (nosyl) protecting group on nitrogen was prepared from N-H lactam 188 in good yield (Scheme 57). However, attempted partial reduction/cyclization of 199 using both the optimized method developed for N-tosyllactam

55 189 as well as a related Sc(OTf)3-mediated protocol resulted in the formation of a complex mixture of products, none of which was consistent with the desired tricyclic olefin 200.

Scheme 57. Synthesis and Attempted Cyclization of N-Ns Substrate 199

H H O OMOM O OMOM LiHMDS, NsCl o SiMe3 THF, 0 C to rt SiMe3 N N H 80% Ns 188 199

H OMOM conditions H

N Ns

200

entry conditions result

o o 1 DIBAL-H, CH2Cl2, -78 C, then FeCl3 warm to ~5 C D

o 2 DIBAL-H, CH2Cl2, -78 C, aqueous quench then FeCl3, D o o CH2Cl2, -78 C to 0 C o 3 DIBAL-H,CH2Cl2, -78 C, aqueous quench then Sc(OTf)3, unidentified SP o CH2Cl2, -78 C to rt

D = decomposition; SP = side product

5.2.3. Acid-Labile Sulfonamides

The t-butylsulfonyl (Bus) protecting group is orthogonal to the majority of other sulfonyl groups for nitrogen, requiring strong acid for cleavage rather than reductive conditions.56 Thus, the preparation of a cyclization precursor 201 containing an N-Bus lactam was also attempted

(Scheme 58a). However, the two-step process for N-Bus group installation involving treatment of

80 the N-H lactam 188 with t-butylsulfinyl chloride followed by chemoselective oxidation of the resulting sulfinamide to the sulfonamide appeared to be incompatible with the rather delicate allyl silane moiety in 188.

A cyclization precursor 202 containing another acid-labile sulfonyl protecting group,

2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (pbf),57 was prepared successfully from N-H lactam 188 in moderate yield. However, perhaps due to steric reasons, N-pbf lactam 202 failed to cyclize to tricycle 203 in the desired manner leading instead to a complex mixture of products.

Scheme 58. Attempted aza-Sakurai Cyclizations with Acid Labile Sulfonamides

A) Attempted N-Bus Protection of 188

H O OMOM 1) t-BuSOCl H o O OMOM LiHMDS, THF, 0 C O SiMe3 SiMe3 S = Bus N H N o Bus 2) mCPBA, CH2Cl2, 0 C O 188 201

B) N-pbf Protection and Attempted Cyclization of 202

H pbfCl, LiHMDS H DIBAL-H H O OMOM O OMOM CH Cl OMOM THF, DMAP 2 2 H -78 oC 0 oC to rt SiMe3 SiMe3 N N H N pbf pbf 63% then FeCl3 o 188 202 warm to ~5 C 203

Me Me O Me pbfCl Me ClO2S Me

5.2.4. Attempted Cyclization of N-Cbz Lactam

We also briefly examined the possibility of performing an allyl silane/N-acyliminium aza-

Sakurai reaction58 of N-Cbz lactam cyclization precursor 204 which was prepared via treatment of

N-H lactam 188 with benzyl chloroformate in acceptable yield (Scheme 59). However, treatment of N-acyllactam 204 with DIBAL-H did not provide any evidence of partial reduction of the lactam carbonyl at -78 ºC. After gradual warming to room temperature followed by an aqueous quench, evidence of the N-H lactam 188 and benzyl alcohol was observed in the NMR of the crude mixture, suggesting that deacylation of N-Cbz lactam 204 was the primary mode of reactivity.

Scheme 59. Attempted N-Acyliminium Aza-Sakurai Reaction of 204

H O OMOM n-BuLi, CbzCl H O OMOM THF, -78 oC to rt SiMe3 SiMe3 N H 58% N Cbz 188 204

DIBAL-H H OMOM CH2Cl2 H -78 oC

N Cbz then FeCl3 warm to ~5 oC 205

5.3. N-Tosyllactam System Revisted

Since the intramolecular aza-Sakurai cyclization of sulfonamide 189 was by far the highest yielding and most reproducible (vide supra), we decided to revisit the desulfonylation of the N- tosyl series. The protection of the C7-hydroxymethyl group as a methoxymethyl (MOM) ether had

82 been necessary throughout the entire sequence to prevent undesired side reactions from occurring.

We therefore wondered whether the free C9-hydroxymethyl was somehow interfering with the desulfonylation of tricycles 192 and 194.

To verify this hypothesis, tricyclic alcohol 192 was protected as the bis-methoxymethyl ether 206 in good yield (Scheme 60). The cleavage of the N-tosyl group from 206 was first attempted using magnesium metal turnings in anhydrous methanol under sonication46b (entry 1) providing what appeared to be a trace amount of the desired product 207 upon mass spectrometric analysis of the crude mixture. However, we were unable to drive this rather sluggish reaction to completion without decomposing the posited N-H piperidine 207 (entry 2). We reasoned that perhaps subjecting bis-MOM ether 206 to more strongly reducing conditions for a very brief period of time might be more successful in cleaving the sulfonamide. To our delight, subjection of 206 to dissolving metal reduction with lithium metal in liquid ammonia at -78 ºC for just one minute followed by an immediate quench at that temperature with solid ammonium chloride cleanly furnished free piperidine 207 in good yield (entry 3).

Scheme 60. MOM-Protection of Alcohol 192 and Desulfonylation of 206

MOMCl H H H OMOM DIPEA H OMOM 7 THF, 0 °C 7

9 OH 9 OMOM N 80% N Ts H Ts H

192 206

H H OMOM conditions 7 9 OMOM N H H

207

entry conditions result

1 Mgo, MeOH, rt, 1h SM + 207 (trace) 2 Mgo, MeOH, 40 oC, 4h SM + 207 (trace) + D 3 Lio, NH , Et O, -78 oC, 1 min 207 (81%) 3 2

5.4. Endgame: Closure of the 1,3-Oxazine C-Ring

With free piperidine 207 finally in hand, the final tasks remaining in the total synthesis of myrioneurinol were the cleavage of the two methoxymethyl (MOM) ethers and formation of the

1,3-oxazine C-ring. We recognized that it might be feasible to directly utilize the MOM-protected

C9-hydroxymethyl group to install the C-ring, since the methylene of the protecting group could serve as a formaldehyde surrogate for C13 of the alkaloid.

It was discovered that stirring N-H piperidine 207 with 6 N aqueous HCl in THF at room temperature provided a mixture of compounds that were identified via mass spectrometry as unreacted starting material, MOM-protected myrioneurinol 208, along with a trace amount of the natural product itself (Scheme 61, entry 1). To our delight, simply warming the reaction mixture

84 to 50 ºC accomplished the desired 1,3-oxazine ring formation with concomitant deprotection of the C7-hydroxymethyl group providing the racemic alkaloid 19 in good yield (entry 2). This synthetic material had proton and carbon NMR spectra (including 2D spectra) identical to those of the natural material isolated by Bodo and coworkers.54

Scheme 61. Completion of the Myrioneurinol Total Synthesis

H H H OMOM 6 N HCl H OR THF/H2O OMOM N H conditions N O H H

207 208 R = MOM (±)-19 R = H

entry conditions result 1 rt, 1 h 208 + (±)-19 (trace) 2 50 oC, 1 h (±)-19 (75%)

5.5. Concluding Remarks

In summary, we have completed the first total synthesis of the tetracyclic antimalarial alkaloid (±)-myrioneurinol in twenty-seven steps starting from commercial materials and in 1.8% overall yield (Scheme 62).23 Three highly diastereoselective reactions were utilized as pivotal steps including: (1) an IMA of an N-Cbz lactam/(E)-α,β-unsaturated ester to construct the spirocyclic

A/D-ring subunit with the correct C5,6 relative configuration for the alkaloid (2) a malonate enolate umpolung conjugate addition to a transient nitrosoalkene intermediate derived from an α- chloro-O-silyloxime to install the requisite functionality at C7 and (3) an allyl silane/N-

85 sulfonyliminium aza-Sakurai reaction of a sulfonyllactam to install the B-ring and attendant C9,10 stereocenters within the cis-DHQ scaffold.

The hypothesized position of myrioneurinol at the nexus of the biosynthetic pathways of the Myrioneuron and Nitraria alkaloids, as well as its challenging structure containing five contiguous stereocenters (including the C5-spiranic carbon), motivated us to design and carry out a total synthesis of this metabolite. It is our hope that the chemistry developed and utilized herein will stimulate further research in the somewhat underexplored field of Myrioneuron alkaloid synthesis and might benefit organic synthesis in general. In particular, the nitrosoalkene umpolung solution to the intractable C7-functionalization problem has the potential to find broader application to other systems that are likewise unreactive toward classical enolate chemistry. We anticipate that this total synthesis, which showcases the utility of nitrosoalkene conjugate addition chemistry, along with other work both past and ongoing in the Weinreb laboratory, will allow this useful methodology to play a prominent role in modern organic synthesis.

Scheme 62. Overall Final Synthetic Route to (±)-Myrioneurinol

n-BuLi O3, CH2Cl2 n-BuLi (2 equiv.) THF, -78 °C -78 °C; PPh3 THF, 0 °C CbzCl -78 °C-rt N O N O N O H Br H 89% Cbz 90% N O Cbz (2 steps) CHO

H TiCl4, Et3N CO Me CO2Me 2 (EtO)2POCH2CO2Me CH2Cl2 LiCl, DBU, MeCN, rt O 0 °C-rt O Cbz 82% N N R

R = Cbz (86%) H2, EtOAc 10% Pd-C R = H (98%) BnBr, Ag2O, TBAI CaSO4, rt R = Bn (73%)

Me(OMe)NH2Cl LiAlH4 pyrrolidine H O H H Me2AlCl, CH2Cl2 Me THF CHO CHCl3, 0 °C N 0 °C-rt N -40 °C 4Å MS O O O OMe 90% 91% Bn 100% Bn N Bn N N

LiHMDS, THF -78 oC H OTBS Cl CHO TBSONH2 H CO Me 1) NCS, 65 °C PPTS Cl N 2 Et O, CHCl CO Me 2 3 O CH2Cl2, rt 2 Bn O 2) HOAc, H2O N 85% then TBAF N Bn 82% -78 oC to 0 oC dr = 2.2:1 dr ~ 2.2:1 93%

OH O H H NaBH H N TiCl , Zno CHO 4 O O 4 o O MeOH O THF, 0 C 0 oC CO2Me CO2Me CO2Me HCO2Me 63% HCO2Me 81% H N Bn N Bn N Bn

~5:1 E/Z

LiCl O OR H O H DMSO/H2O o O O 155-160 C Me(OMe)NH2Cl O 90% H Me AlCl H N 2 N N Bn CH2Cl2 Bn Me OMe 0 °C-rt MOMCl R = H (86%) DIEA THF, 0 °C R = MOM (80%)

H LiAlH OMOM OMOM 4 PPh3 I O H Me3Si THF O -40 °C PhLi, THF, rt SiMe3 CHO N H 74% (2 steps) Bn N Bn

H H Na/NH O OMOM DIBAL-H 3 H OMOM Et2O CH2Cl2 1) O3, CH2Cl2 -78 °C o SiMe3 -78 C -78 °C; PPh3 N R N H then FeCl3 Ts 2) NaBH4 warm to 5 oC MeOH, 0 °C LiHMDS R = H (79%) 78% TsCl, THF DMAP R = Ts (87%)

H H H Li/NH OMOM 6 N HCl OH H OMOM 3 H THF/H O H Et2O 2 -78 °C 50 °C OR OMOM N O N 81% N H 75% Ts H H H

(±)-myrioneurinol MOMCl R = H (92%, 2 steps) DIPEA THF, 0 °C R = MOM (80%)

CHAPTER 6. EXPERIMENTAL SECTION

General Methods. All non-aqueous reactions were carried out in oven- or flame-dried glassware under an atmosphere of argon. All reagents were purchased from commercial vendors and used as recieved, unless otherwise specified. Anhydrous tetrahydrofuran (THF), dichloromethane (CH2Cl2), diethyl ether (Et2O), and acetonitrile (MeCN) were obtained from a solvent purification system. Reactions were stirred magnetically and monitored by thin layer chromatography (TLC) with 250 μm EMD 60 F254 precoated silica gel plates. Flash chromatographic separations were performed using silica gel (240-400 mesh). Proton and carbon-

13 NMR chemical shifts are reported relative to chloroform for 1H and 13C NMR (δ 7.24 and 77.0, respectively). High resolution mass spectra were recorded on a time-of-flight (TOF) mass spectrometer.

N O Bn O O 50

3-(4-(1,3-Dioxolan-2-yl)butyl)-1-benzylpiperidin-2-one (50). n-Butyllithium (2.5 M in hexanes, 1.25 mL, 3.12 mmol) was added to diisopropylamine (0.42 mL, 2.92 mmol) at 0 ºC and the resulting light yellow gel was diluted with anhydrous THF (0.1 mL) and stirred for 45 min at that temperature. This solution of LDA was added dropwise at -78 ºC to a stirred solution of 1- benzylpiperidin-2-one (48, 509 mg, 2.7 mmol) in dry THF (5 mL). The mixture was warmed to 0

ºC and stirred for 1 h. Neat 2-(4-iodobutyl)-1,3-dioxolane (49, 2.07 g, 8.1 mmol) was added

89 dropwise, the mixture was warmed to rt and stirred overnight. The mixture was diluted with saturated NH4Cl (aq) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (gradient 20% to 50% EtOAc/hexanes) to

1 afford lactam 50 (416 mg, 49%) as a clear colorless gum: H NMR (400 MHz, CDCl3) δ 7.15-7.26

(m, 5H), 4.78 (t, J = 4.6 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 4.51 (d, J = 10.4 Hz, 1H), 3.89-3.91

(m, 2H), 3.76-3.77 (m, 2H), 3.11 (t, J = 5.9 Hz, 2H), 2.28-2.29 (m, 1H), 1.89-1.93 (m, 2H), 1.19-

13 1.62 (m, 10H); C NMR (75 MHz, CDCl3) δ 173.1, 137.9, 128.9, 128.3, 127.6, 104.9, 65.2, 50.7,

+ 47.8, 41.9, 34.2, 32.4, 27.5, 26.9, 24.5, 22.0; HRMS-ES+ (C19H28NO3) calcd 318.2069 (MH ), found 318.2054.

N O Bn CHO 51

5-(1-Benzyl-2-oxopiperidin-3-yl)pentanal (51). To a solution of lactam 50 (416 mg, 1.3 mmol) in THF (5 mL) was added 1 N HCl (aq) (5 mL) and the mixture was stirred at rt for 6 h.

Saturated NaHCO3 (aq) was added and the mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford aldehyde 51 (355 mg, 100%) as a clear colorless gum that was used in the

1 subsequent step without further purification: H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.22-7.33

(m, 5H), 4.62 (d, J = 14.6 Hz, 1H), 4.53 (d, J = 14.6 Hz, 1H), 3.19 (dd, J = 7.3, 4.9 Hz, 2H), 2.45

(t, J = 1.7 Hz, 2H), 2.33-2.34 (m, 1H), 1.89-2.04 (m, 2H), 1.81-1.89 (m, 1H), 1.66-1.70 (m, 3H),

13 1.42-1.56 (m, 4H); C NMR (100 MHz, CDCl3) δ 202.7, 172.5, 137.5, 128.5, 128.0, 127.3, 50.3,

-1 47.4, 43.7, 41.4, 31.7, 26.6, 26.5, 22.1, 21.7; IR (neat) 1724, 1605 cm ; HRMS-ES+ (C17H24NO2) calcd 274.1807 (MH+), found 274.1803.

CO2Me O N Bn 52

Methyl 7-(1-Benzyl-2-oxopiperidin-3-yl)hept-2-enoate (52). To a stirred suspension of anhydrous lithium chloride (81 mg, 1.9 mmol) in dry MeCN (15 mL) at rt was added methyl diethylphosphonoacetate (0.34 mL, 1.9 mmol) and DBU (0.24 mL, 1.8 mmol). A solution of aldehyde 51 (440 mg, 1.61 mmol) in dry MeCN (5 mL) was added dropwise over 5 min. The resulting cloudy suspension was stirred for 24 h at rt, then diluted with saturated NH4Cl (aq). The reaction mixture was extracted with EtOAc (3 x 50 mL) and the combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (25% EtOAc/hexanes) to afford (E)-α,β-unsaturated ester 52

1 (477 mg, 90%) as a clear colorless gum: H NMR (400 MHz, CDCl3) δ 7.15-7.26 (m, 5H), 6.89-

6.96 (m, 1H), 5.75 (d, J = 15.7 Hz, 1H), 4.55 (d, J = 14.6 Hz, 1H), 4.47 (d, J = 14.6 Hz, 1H), 3.66

(s, 3H), 3.11-3.14 (m, 2H), 2.27-2.29 (m, 1H), 2.16 (q, J = 6.9 Hz, 2H), 1.20-1.76 (m, 10H); 13C

NMR (75 MHz, CDCl3) δ 172.9, 167.5, 149.9, 137.9, 128.9, 128.3, 127.6, 121.3, 51.7, 50.7, 47.7,

+ 41.9, 32.5, 32.1, 28.4, 27.2, 26.8, 22.1; HRMS-ES+ (C20H28NO3) calcd 330.2069 (MH ), found

330.2070.

H CO2Me O N Bn 53

Methyl 2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)acetate (53). Method A. To a stirred solution of (E)-α,β-unsaturated ester 52 (215 mg, 0.65 mmol) in anhydrous THF (7 mL) was added dropwise freshly prepared LDA (1.7 M in THF, 0.45 mL, 0.78 mmol) at -78 ºC. The resulting bright yellow reaction mixture was slowly warmed to rt over 24 h then diluted with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (gradient 10% to 30% EtOAc/hexanes) to

1 afford spirocycle 53 (41 mg, 19%) as a light yellow gum: H NMR (400 MHz, CDCl3) δ 7.15-7.25

(m, 5H), 4.66 (d, J = 14.5 Hz, 1H), 4.36 (d, J = 14.5 Hz, 1H), 3.59 (s, 3H), 3.08-3.12 (m, 2H), 2.69

(t, J = 10.7 Hz, 1H), 2.12 (dd, J = 14.4, 3.2 Hz, 1H), 1.96 (dd, J = 14.5, 10.6 Hz, 1H), 1.05-1.75

13 (m, 12H); C NMR (100 MHz, CDCl3) δ 175.3, 173.6, 138.1, 128.9, 128.4, 127.6, 52.0, 51.1,

47.5, 46.2, 39.9, 37.8, 34.9, 27.2, 26.0. 23.4, 20.9, 19.7; IR (neat) 1733, 1675, 1172 cm-1; HRMS-

+ ES+ (C20H28NO3) calcd 330.2069 (MH ), found 330.2065.

Method B. To a stirred solution of the N-H lactam 63 (11.68 g, 48.7 mmol) in benzyl bromide (120 mL) was added silver (I) oxide (32.91 g, 146 mmol), tetra-n-butylammonium iodide

(18.25 g, 48.7 mmol) and anhydrous calcium sulfate (33.90 g, 244 mmol). The reaction flask was covered with aluminum foil and the mixture was stirred at rt for 44 h. The mixture was filtered through a Celite pad, which was washed with Et2O, and the total filtrate was concentrated in vacuo.

The residue was purified by flash column chromatography on silica gel (gradient 100% hexanes to 30% EtOAc/hexanes) to afford the N-Bn lactam ester 53 as a greenish gum (11.59 g, 73%). This material had spectroscopic data identical to that prepared by Method A.

N O H O O 58

3-(4-[1,3]Dioxolan-2-yl-butyl)-piperidin-2-one (58). To a stirred solution of valerolactam (57, 250 mg, 2.52 mmol) in THF (10 mL) at -78 ºC was added dropwise n- butyllithium (2.5 M in hexanes, 2.1 mL, 5.25 mmol) and the mixture was warmed to 0 ºC for 1 h.

Iodoacetal 49 (955 mg, 3.73 mmol) was added dropwise and the reaction mixture was stirred at 0

ºC for 3 h then diluted with saturated aqueous NH4Cl. The mixture was extracted with CH2Cl2 (3 x 50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 25% to 100% EtOAc/hexanes) to afford lactam acetal 58 (135 mg, 24%) as a

1 yellowish solid: H NMR (300 MHz, CDCl3) δ 6.33 (br s, 1H), 4.85 (t, J = 4.7 Hz, 1H), 3.84-3.97

13 (m, 4H), 3.27-3.30 (m, 2H), 2.11-2.24 (m, 1H), 1.41-1.91 (m, 12H); C NMR (75 MHz, CDCl3)

δ 175.5, 105.0, 104.9, 65.2, 42.8, 41.3, 34.2, 31.9, 27.4, 26.5, 24.5, 21.8.

N O Cbz O O 59

3-(4-[1,3]Dioxolan-2-yl-butyl)-2-oxopiperidine-1-carboxylic Acid Benzyl Ester (59).

To a stirred solution of lactam acetal 58 (135 mg, 0.59 mmol) in THF (2 mL) at -78 ºC was added n-butyllithium (2.5 M in hexanes, 0.283 mL, 0.71 mmol) and the mixture was stirred at that temperature for 1 h. Benzyl chloroformate (0.168 mL, 1.18 mmol) was added dropwise and the mixture was stirred for 1 h at -78 ºC, then warmed to 0 ºC for 1 h. Saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc (3 x 25 mL), the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified via flash column chromatography on silica gel (25% EtOAc/hexanes) to afford N-

Cbz lactam acetal 59 (140 mg, 65%) as a clear oil: (300 MHz, CDCl3) δ 7.29-7.43 (m, 5H), 5.26

(s, 2H), 4.83 (t, J = 4.8 Hz, 1H), 3.78-3.93 (m, 4H), 3.55-3.61 (m, 1H), 2.21-2.37 (m, 1H), 1.40-

13 1.87 (m, 13H); C NMR (75 MHz, CDCl3) δ 174.6, 154.7, 136.0, 128.9, 128.5, 128.3, 104.9, 68.8,

65.3, 46.4, 44.1, 34.2, 31.4, 27.3, 26.3, 24.4, 22.0.

N O Cbz CHO 60

Benzyl 2-Oxo-3-(5-oxopentyl)piperidine-1-carboxylate (60) Method A. A solution of

N-Cbz lactam acetal 59 (140 mg, 0.39 mmol) in THF (5 mL) and 1 N HCl(aq) (5 mL) was stirred for 4 h at rt. The mixture was extracted with EtOAc (2 x 25 mL) and the combined organic layers

94 were washed with 1 M NaHCO3(aq), brine, dried over anhydrous MgSO4, then concentrated in vacuo to afford aldehyde 60 (124 mg, 100%) as a clear gum that was used in the subsequent step without further purification. This material had spectroscopic data identical to that prepared by

Method B.

Method B A solution of N-Cbz lactam 67 (17.37 g, 55.1 mmol) in dry CH2Cl2 (500 mL) was cooled to -78 °C and ozone was bubbled through the reaction mixture for 1 h until a light blue coloration was achieved. The mixture was then purged with argon for 5 min followed by the portionwise addition of triphenylphosphine (17.36 g, 66.2 mmol). The reaction mixture was warmed to rt over 6 h and then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column chromatography on silica gel (gradient 25% to 40% EtOAc/hexanes) to

1 afford aldehyde 60 (15.86 g, 90%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 9.70-

9.75 (m, 1H), 7.31-7.45 (m, 5H), 5.27 (s, 2H), 3.69-3.82 (m, 1H), 3.47-3.67 (m, 1H), 2.42-2.47

13 (m, 3H), 1.62-1.88 (m, 5H), 1.23-1.49 (m, 5H); C NMR (75 MHz, CDCl3) δ 203.0, 174.5, 154.6,

135.9, 129.0, 128.6, 128.5, 68.8, 46.4, 44.0, 31.2, 26.9, 26.3, 22.4, 21.9, 21.4; HRMS-ES+

+ (C18H24NO4) calcd 318.1705 (MH ), found 318.1696.

CO2Me O N Cbz 61

(E)-Benzyl 3-(Hex-5-en-1-yl)-2-oxopiperidine-1-carboxylate (61). Anhydrous LiCl

(2.63 g, 62.0 mmol) was flame-dried under a stream of argon and then suspended in dry MeCN

(420 mL) to which was added methyl diethylphosphonoacetate (11.0 mL, 62.2 mmol) and DBU

(7.9 mL, 56.9 mmol) at rt. A solution of aldehyde 60 (16.43 g, 51.8 mmol) in dry MeCN (150 mL) was added dropwise over 1 h and the resulting cloudy white reaction mixture was stirred for 48 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude material was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to provide (E)-

1 α,β-unsaturated ester 61 (15.83 g, 82%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ

7.29-7.72 (m, 5H), 6.97 (dt, J = 15.6, 7.0 Hz, 1H), 5.83 (d, J = 15.6 Hz, 1H), 5.29 (s, 2H), 3.80-

3.89 (m, 1H), 3.65-3.75 (m, 4H), 2.36-2.48 (m, 1H), 2.21 (q, J = 7.2 Hz, 2H), 1.81-1.95 (m, 4H),

13 1.28-1.52 (m, 6H); C NMR (75 MHz, CDCl3) δ 174.6, 167.5, 154.7, 149.8, 135.9, 129.0, 128.7,

128.4, 121.5, 68.8, 51.8, 46.4, 44.2, 32.4, 31.3, 28.4, 27.0, 26.4, 22.0; HRMS-ES+ (C21H28NO5) calcd 374.1967 (MH+), found 374.1958.

H CO2Me O N Cbz 62

Benzyl 7-(2-Methoxy-2-oxoethyl)-1-oxo-2-azaspiro[5.5]undecane-2-carboxylate (62).

TiCl4 (10.1 mL, 91.4 mmol) and dry Et3N (12.7 mL, 91.4 mmol) were dissolved in dry CH2Cl2

(275 mL) at 0 °C and the resulting deep maroon solution was stirred for 15 min. A solution of (E)-

α,β-unsaturated ester 61 (16.95 g, 45.5 mmol) in dry CH2Cl2 (120 mL) was added dropwise over

10 min and the reaction mixture was subsequently stirred at rt for 1 h. Saturated NaHCO3 (aq) was carefully added at 0 °C, the mixture was stirred for 30 min and then extracted with CH2Cl2 (4 x

250 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to afford a yellow oil that was purified by flash chromatography on silica gel (gradient 20% to 35% EtOAc/hexanes) to give spirocyclic ester 62 (14.58 g, 86%) as a light yellow gum: 1H

NMR (300 MHz, CDCl3) δ 7.28-7.41 (m, 5H), 5.23 (s, 2H), 3.66-3.79 (m, 1H), 3.55-3.62 (m, 4H),

2.65 (t, J = 9.6 Hz, 1H), 2.22 (dd, J = 12.4, 2.9 Hz, 1H), 2.02 (dd, J = 18.9, 7.7 Hz, 1H), 1.56-1.86

13 (m, 9H), 1.19-1.26 (m, 2H), 1.09 (q, J = 9.6 Hz, 1H); C NMR (75 MHz, CDCl3) δ 177.4, 173.2,

155.0, 136.0, 128.9, 128.4, 128.3, 68.7, 51.9, 49.4, 47.5, 39.8, 37.4, 35.6, 27.3, 25.8, 24.2, 20.9,

+ 20.2; HRMS-ES+ (C21H28NO5) calcd 374.1967 (MH ), found 374.1968.

H CO2Me O N H 63

Methyl 2-(1-Oxo-2-azaspiro[5.5]undecan-7-yl)acetate (63). To a stirred solution of spirocyclic ester 62 (14.57 g, 39.1 mmol) in EtOAc (150 mL) was added 10% palladium on carbon

(20% w/w, 2.91 g). The reaction flask was purged and filled with hydrogen gas at 1 atm (supplied via two balloons). The resulting suspension was stirred for 36 h at rt, then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated in vacuo to afford the

N-H lactam 63 (9.21 g, 98%) as a slightly yellowish gum which was used in the next step without

1 further purification: H NMR (300 MHz, CDCl3) δ 6.56 (br s, 1H), 3.26 (s, 3H), 3.23-3.25 (m,

2H), 2.62 (t, J = 10.7 Hz, 1H), 2.23 (dd, J = 14.5, 3.2 Hz, 1H), 2.05 (dd, J = 14.6, 10.7 Hz, 1H),

13 1.25-1.87 (m, 11H), 1.06 (q, J = 13.1 Hz, 1H); C NMR (75 MHz, CDCl3) δ 177.7, 173.5, 51.9,

45.7, 42.5, 39.4, 37.7, 34.6, 26.8, 25.9, 23.2, 20.7, 19.7; HRMS-ES+ (C13H22NO3) calcd 240.1600

(MH+), found 240.1579.

HO H

O H N 64

7-(2-Hydroxyethyl)-2-azaspiro[5.5]undecan-1-one (64). To a stirred suspension of

LiAlH4 (20 mg, 0.40 mmol) in anhydrous THF (1 mL) at 0 °C was added dropwise N-H lactam 63

(25 mg, 0.10 mmol) as a solution in THF (1 mL) over 5 min. The reaction mixture was stirred for

4 h at 0 °C, then carefully quenched with MeOH. The mixture was diluted with 1 N HCl (aq) and extracted with CHCl3 (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to provide alcohol 64 as a white crystalline solid. The crude alcohol 64 was recrystallized from a minimal amount of refluxing Et2O/MeOH to afford clear prisms that were suitable for X-ray analysis (17 mg, 82%): 1H NMR (300 MHz,

CDCl3) δ 6.24 (br s, 1H), 3.57 (t, J = 5.9 Hz, 2H), 3.22-3.31 (m, 2H), 2.80 (br s, 1H), 2.18-2.29

13 (m, 1H), 1.07-1.98 (m, 14H); C NMR (75 MHz, CDCl3) δ 179.7, 61.0, 42.6, 38.4, 36.7, 34.6,

-1 30.1, 28.0, 26.3, 22.6, 20.8, 19.3; IR (neat) 3290, 1636, 1049 cm ; HRMS-ES+ (C12H22NO2) calcd

212.1651 (MH+), found 212.1670.

N O Cbz 67

Benzyl 3-(Hex-5-en-1-yl)-2-oxopiperidine-1-carboxylate (67). To a stirred solution of valerolactam (57, 6.12 g, 61.7 mmol) in dry THF (250 mL) was added n-butyllithium (2.5 M in hexanes, 52 mL, 129.6 mmol) at 0 °C. The resulting yellowish-orange solution was stirred at 0 °C for 1 h and then 6-bromohex-1-ene (10.00 g, 61.7 mmol) was added rapidly in one portion. The reaction mixture was stirred for 1 h and was gradually warmed to rt. Brine was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 250 mL).

The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to provide lactam 66 as a yellowish solid.

The crude lactam 66 was dissolved in dry THF (250 mL), n-butyllithium (2.5 M in hexanes,

27.2 mL, 67.9 mmol) was added at -78 °C and the reaction mixture was stirred for 30 min. Benzyl chloroformate (13.3 mL, 92.6 mmol) was added dropwise and the resulting bright yellow solution was slowly warmed to rt over 1 h. Saturated NH4Cl (aq) was added and the mixture was extracted with ethyl acetate (3 x 250 mL). The organic phase was washed with brine and dried over anhydrous MgSO4. The solution was concentrated in vacuo to afford a viscous yellowish oil that was purified by flash column chromatography on silica gel (15% EtOAc/hexanes) to yield N-Cbz

1 lactam 67 (17.37 g, 89%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 7.29-7.48 (m,

5H), 5.76-5.89 (m, 1H), 5.30 (s, 2H), 4.94-5.05 (m, 2H), 3.81-3.89 (m, 1H), 3.67-3.75 (m, 1H),

13 2.41-2.45 (m, 1H), 1.72-2.12 (m, 6H), 1.28-1.59 (m, 6H); C NMR (75 MHz, CDCl3) δ 174.8,

154.8, 139.2, 136.0, 129.0, 128.6, 128.4, 114.9, 68.9, 46.5, 44.3, 34.1, 31.4, 29.3, 26.9, 26.2, 21.8;

HRMS-ES+ (C19H26NO3) calcd 316.1913 (MH+), found 316.1909.

O N Cbz 72

3-Hex-5-enyl-2-oxopyrrolidine-1-carboxylic Acid Benzyl Ester (72). To a stirred solution of 2-pyrrolidinone (70, 500 mg, 5.9 mmol) in THF (10 mL) at 0 ºC was added n- butyllithium (2.5 M in THF, 4.9 mL, 12.4 mmol) and the mixture was stirred for 1 h. To the resulting orange-red solution was added 6-bromo-1-hexene (952 mg, 5.9 mmol) in one portion and the mixture was stirred for 1 h at 0 ºC. Brine was added and the mixture was extracted with CH2Cl2

(3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford lactam 71 as a yellowish gum.

To a solution of crude lactam 71 in THF (10 mL) was added n-butyllithium (2.5 M in hexanes, 2.61 mL, 6.5 mmol) at -78 ºC and the mixture was stirred for 1 h at that temperature.

Benzyl chloroformate (1.52 mL, 10.6 mmol) was added dropwise and the mixture was stirred at -

78 ºC for 1 h, then warmed to rt. Saturated NH4Cl (aq) was added and the mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified via flash column chromatography on silica gel (gradient 10% to 20% EtOAc/hexanes) to afford N-Cbz lactam 72 as

1 a clear gum (318 mg, 18%): H NMR (300 MHz, CDCl3) δ 7.19-7.33 (m, 5H), 5.55-5.76 (m, 1H),

13 5.12 (s, 2H), 4.85-5.01 (m, 2H), 4.01 (m, 2H), 1.29-2.12 (m, 11H); C NMR (75 MHz, CDCl3) δ

175.4, 155.3, 140.6, 128.7, 127.3, 114.2, 69.5, 48.2, 33.5, 33.2, 30.2, 29.6, 27.2, 25.4, 20.4, 19.4.

100

CHO O N Cbz 73

2-Oxo-3-(5-oxopentyl)-pyrrolidine-1-carboxylic Acid Benzyl Ester (73). A solution of

N-Cbz lactam 72 (318 mg, 1.1 mmol) in dry CH2Cl2 (10 mL) was cooled to -78 °C and ozone was bubbled through the reaction mixture for 5 min until a light blue coloration was achieved. The mixture was then purged with argon for 5 min followed by the portionwise addition of triphenylphosphine (278 mg, 1.2 mmol). The reaction mixture was warmed to rt over 4 h and then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column chromatography on silica gel (gradient 20% to 35% EtOAc/hexanes) to afford aldehyde 73 (254

1 mg, 79%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 9.63-9.69 (m, 1H), 7.25-7.43 (m,

5H), 5.21 (s, 2H), 3.91-3.95 (m, 2H), 2.49-2.58 (m, 2H), 1.29-2.22 (m, 9H); 13C NMR (75 MHz,

CDCl3) δ 200.3, 176.5, 155.6, 140.9, 129.0, 128.6, 127.5, 68.5, 48.4, 44.0, 33.2, 27.9, 26.3, 22.4,

21.4.

CO2Me O N Cbz

3-(6-Methoxycarbonyl-hex-5-enyl)-2-oxopyrrolidine-1-carboxylic Acid Benzyl Ester

(74). Anhydrous LiCl (90 mg, 2.1 mmol) was flame-dried under a stream of argon and then suspended in dry MeCN (10 mL) to which was added methyl diethylphosphonoacetate (0.22 mL,

1.3 mmol) and DBU (0.16 mL, 1.2 mmol) at rt. A solution of aldehyde 73 (254 mg, 1.06 mmol)

101 in dry MeCN (5 mL) was added dropwise over 5 min and the resulting cloudy white reaction mixture was stirred for 48 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude material was purified by flash column chromatography on silica gel (20%

EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 74 (213 mg, 56%) as a clear colorless oil: 1H

NMR (300 MHz, CDCl3) δ 7.31-7.69 (m, 5H), 6.87 (dt, J = 15.4, 7.2 Hz, 1H), 5.76 (d, J = 15.3

13 Hz, 1H), 5.21 (s, 2H), 3.90-3.99 (m, 2H), 1.25-2.30 (m, 14H); C NMR (75 MHz, CDCl3) δ 176.6,

165.0, 155.7, 146.8, 136.0, 129.1, 128.7, 128.3, 122.5, 69.8, 50.8, 48.4, 44.3, 32.1, 31.7, 28.2, 27.1,

22.0.

O NCbz 79

3-Hex-5-enyl-2-oxoazepane-1-carboxylic Acid Benzyl Ester (79). To a stirred solution of caprolactam (77, 1.00 g, 8.8 mmol) in THF (40 mL) at 0 ºC was added n-butyllithium (2.5 M in THF, 7.40 mL, 18.5 mmol) and the mixture was stirred for 1 h. To the resulting yellowish solution was added 6-bromo-1-hexene (1.28 mL, 9.3 mmol) in one portion and the mixture was stirred for 1 h at 0 ºC. Brine was added and the mixture was extracted with CH2Cl2 (3 x 50 mL).

The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford lactam

78 as a yellowish gum.

102

To a solution of the crude lactam 78 in THF (40 mL) was added n-butyllithium (2.5 M in hexanes, 3.91 mL, 9.7 mmol) at -78 ºC and the mixture was stirred for 30 min at that temperature.

Benzyl chloroformate (2.21 mL, 15.5 mmol) was added dropwise and the mixture was stirred at -

78 ºC for 20 min, then warmed to rt for 2 h. Saturated NH4Cl (aq) was added and the mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified via flash column chromatography on silica gel (10% EtOAc/hexanes) to afford N-Cbz lactam 79 as a clear

1 gum (790 mg, 27%): H NMR (300 MHz, CDCl3) δ 7.19-7.37 (m, 5H), 5.66-5.79 (m, 1H), 5.19

(s, 2H), 4.84-4.96 (m, 2H), 3.30 (dd, J = 14.9, 10.5 Hz, 1H), 2.52-2.57 (m, 1H), 1.98 (q, J = 6.6

13 Hz, 2H), 1.15-1.85 (m, 13H); C NMR (75 MHz, CDCl3) δ 177.2, 154.9, 139.1, 136.1, 128.8,

128.4, 128.1, 114.8, 68.7, 46.6, 45.7, 34.1, 32.9, 31.1, 29.4, 28.5, 28.4, 27.3.

O NCbz CHO 80

2-Oxo-3-(5-oxopentyl)-azepane-1-carboxylic Acid Benzyl Ester (80). A solution of N-

Cbz lactam 79 (790 mg, 2.40 mmol) in dry CH2Cl2 (35 mL) was cooled to -78 °C and ozone was bubbled through the reaction mixture for 25 min until a light blue coloration was achieved. The mixture was then purged with argon for 5 min followed by the portionwise addition of triphenylphosphine (755 mg, 2.88 mmol). The reaction mixture was warmed to rt over 4 h and then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column chromatography on silica gel (gradient 20% to 35% EtOAc/hexanes) to afford aldehyde 80 (470

103

1 mg, 58%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H), 7.16-7.34 (m, 5H),

5.16 (s, 2H), 4.21 (dd, J = 15.1, 3.8 Hz, 1H), 3.31 (dd, J = 15.2, 10.6 Hz, 1H), 2.52-2.57 (m, 1H),

13 2.30 (t, J = 7.2 Hz, 2H), 1.11-1.87 (m, 11H); C NMR (75 MHz, CDCl3) δ 202.9, 177.1, 154.9,

136.1, 128.8, 128.2, 128.1, 68.7, 46.4, 45.7, 44.0. 32.9, 31.1, 28.5, 28.3, 27.3, 22.5.

CO2Me O N Cbz 81

3-(6-Methoxycarbonylhex-5-enyl)-2-oxoazepane-1-carboxylic Acid Benzyl Ester (81).

Anhydrous LiCl (75 mg, 1.77 mmol) was flame-dried under a stream of argon and then suspended in dry MeCN (10 mL) to which was added methyl diethylphosphonoacetate (0.29 mL, 1.67 mmol) and DBU (0.22 mL, 1.54 mmol) at rt. A solution of aldehyde 80 (470 mg, 1.40 mmol) in dry MeCN

(4 mL) was added dropwise over 5 min and the resulting cloudy white reaction mixture was stirred for 22 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude material was purified by flash column chromatography on silica gel (gradient 10% to 20%

EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 81 (390 mg, 72%) as a clear colorless gum:

1 H NMR (300 MHz, CDCl3) δ 7.19-7.40 (m, 5H), 6.90 (dt, J = 15.7, 7.0 Hz, 1H), 5.76 (dt, J =

15.6, 1.4 Hz, 1H), 5.22 (s, 2H), 4.28 (dd, J = 15.1, 3.9 Hz, 1H), 3.65 (s, 3H), 3.36 (dd, J = 14.8,

10.2 Hz, 1H), 2.55-2.59 (m, 1H), 2.15 (q, J = 6.8 Hz, 2H), 1.20-1.86 (m, 12H); 13C NMR (75 MHz,

104

CDCl3) δ 177.2, 167.4, 154.9, 149.8, 136.0, 128.9, 128.5, 128.2, 121.3, 51.7, 46.6, 45.8, 32.9, 32.4,

31.1, 28.6, 28.5, 28.3, 27.4.

N O Cbz 87

2-Oxo-3-pent-4-enylpiperidine-1-carboxylic Acid Benzyl Ester (87). To a stirred solution of valerolactam (57, 1.00 g, 10.1 mmol) in dry THF (50 mL) was added n-butyllithium

(2.5 M in hexanes, 8.9 mL, 22.2 mmol) at 0 °C. The resulting yellowish-orange solution was stirred at 0 °C for 1 h and then 5-bromopent-1-ene (1.65 g, 11.1 mmol) was added rapidly in one portion.

The reaction mixture was stirred for 1 h and was gradually warmed to rt. Brine was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL).

The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to provide lactam 86 as a yellowish solid.

The crude lactam 86 was dissolved in dry THF (25 mL), n-butyllithium (2.5 M in hexanes,

4.4 mL, 11.1 mmol) was added at -78 °C and the reaction mixture was stirred for 30 min. Benzyl chloroformate (2.1 mL, 15.2 mmol) was added dropwise and the resulting bright yellow solution was slowly warmed to rt over 1 h. Saturated NH4Cl (aq) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with brine and dried over anhydrous

MgSO4. The solution was concentrated in vacuo to afford a viscous yellowish oil that was purified by flash column chromatography on silica gel (15% EtOAc/hexanes) to yield N-Cbz lactam 87

1 (2.07 g, 68%) as a clear oil: H NMR (300 MHz, CDCl3) δ 7.33-7.48 (m, 5H), 5.76-5.90 (m, 1H),

105

5.30 (s, 2H), 4.95-5.06 (m, 2H), 3.80-3.89 (m, 1H), 3.66-3.75 (m, 1H), 2.39-2.49 (m, 1H), 1.75-

13 2.13 (m, 7H), 1.45-1.57 (m, 4H); C NMR (75 MHz, CDCl3) δ 174.7, 154.7, 138.9, 135.9, 128.9,

128.5, 128.3, 115.1, 68.8, 46.5, 44.2, 34.2, 31.1, 26.7, 26.3, 22.0.

N O CHO Cbz 88

2-Oxo-3-(4-oxobutyl)-piperidine-1-carboxylic acid Benzyl Ester (88). A solution of N-

Cbz lactam 87 (2.07 g, 6.8 mmol) in dry CH2Cl2 (75 mL) was cooled to -78 °C and ozone was bubbled through the reaction mixture for 20 min until a light blue coloration was achieved. The mixture was then purged with argon for 5 min followed by the portionwise addition of triphenylphosphine (2.14 mg, 8.16 mmol). The reaction mixture was warmed to rt over 2 h and then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to afford aldehyde 88 (1.31

1 g, 64%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.30-7.44 (m, 5H),

5.26 (s, 2H), 3.78-3.87 (m, 1H), 3.63-3.71 (m, 1H), 2.37-2.55 (m, 3H), 1.41-2.08 (m, 8H); 13C

NMR (75 MHz, CDCl3) δ 202.7, 174.3, 154.5, 135.9, 128.9, 128.5, 128.4, 68.8, 46.4, 44.2, 44.1,

30.9, 26.3, 22.0, 20.0.

106

CO2Me O N Cbz 89

3-(5-Methoxycarbonylpent-4-enyl)-2-oxopiperidine-1-carboxylic Acid Benzyl Ester

(89). Anhydrous LiCl (90 mg, 2.1 mmol) was flame-dried under a stream of argon and then suspended in dry MeCN (12 mL) to which was added methyl diethylphosphonoacetate (0.35 mL,

1.9 mmol) and DBU (0.25 mL, 1.8 mmol) at rt. A solution of aldehyde 88 (500 mg, 1.7 mmol) in dry MeCN (4 mL) was added dropwise over 5 min and the resulting cloudy white reaction mixture was stirred for 24 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude material was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 89 (395 mg, 67%) as a clear colorless gum: 1H NMR (300

MHz, CDCl3) δ 7.27-7.41 (m, 5H), 6.94 (dt, J =15.7, 7.0 Hz, 1H), 5.80 (dt, J = 15.6, 1.5 Hz, 1H),

5.23 (s, 2H), 3.75-3.83 (m, 1H), 3.67 (s, 3H), 3.55-3.66 (m, 1H), 2.34-2.45 (m, 1H), 2.17 (q, J =

13 5.2 Hz, 2H), 1.42-1.99 (m, 8H); C NMR (75 MHz, CDCl3) δ 174.3, 167.4, 154.5, 149.3, 135.9,

128.9, 128.4, 128.2, 121.6, 68.7, 51.7, 46.3, 44.0, 35.3, 31.0, 26.4, 25.9, 21.9.

107

CO2Et

Me O N Cbz 93

3-(6-Ethoxycarbonylhept-5-enyl)-2-oxopiperidine-1-carboxylic Acid Benzyl Ester

(93). To a stirred solution of triethyl 2-phosphonopropionate (0.41 mL, 1.9 mmol) in THF (10 mL) at -78 ºC was added solid KHMDS (347 mg, 1.7 mmol) in one portion. The mixture was stirred for 30 min at -78 ºC, then aldehyde 60 (500 mg, 1.6 mmol) in THF (5 mL) was added dropwise.

The mixture was warmed to rt over 3 h, diluted with saturated NH4Cl (aq), and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous

MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (20% EtOAc/hexanes) to afford enoate 93 (177 mg, 29%) as a ~2.5:1

1 inseparable mixture of (E)- and (Z)-olefin geometric isomers: H NMR (300 MHz, CDCl3) δ 7.24-

7.39 (m, 5H), 6.69 (t, J = 7.4 Hz, 1H), 5.86 (t, J = 7.2 Hz, 1H), 5.21 (s, 2H), 4.11 (q, J = 7.3 Hz,

2H), 3.62-3.84 (m, 2H), 2.27-2.45 (m, 2H), 2.12 (q, J = 7.0 Hz, 2H), 1.71-1.98 (m, 5H), 1.25-1.44

(m, 6H), 1.21 (t, J = 6.5 Hz, 3H).

CO2Me

O N Cbz 94

3-(6-Methoxycarbonylnona-5,8-dienyl)-2-oxopiperidine-1-carboxylic Acid Benzyl

Ester (94). To a stirred solution of 2-(diethoxyphosphoryl)-pent-4-enoic acid methyl ester (90 mg,

0.38 mmol) in THF (2 mL) at -78 ºC was added in one portion solid KHMDS (78 mg, 0.40 mmol).

108

The mixture was stirred for 30 min at -78 ºC, then aldehyde 60 (131 mg, 0.41 mmol) as a solution in THF (1 mL) was added dropwise. The mixture was warmed to rt and stirred overnight then saturated NH4Cl (aq) was added. The mixture was extracted with EtOAc (3 x 20 mL), the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo.

The crude material was purified via flash column chromatography on silica gel (10%

EtOAc/hexanes) to afford enoate 94 (81 mg, 47%) as a ~4.2:1 inseparable mixture of (E)- and (Z)-

1 olefin geometric isomers: H NMR (360 MHz, CDCl3) 7.30-7.47 (m, 5H), 6.85 (t, J = 7.5 Hz, 1H),

5.93 (t, J = 7.2 Hz, 1H), 5.75-5.87 (m, 1H), 5.29 (s, 2H), 4.97-5.04 (m, 2H), 3.81-3.86 (m, 1H),

3.68-3.75 (m, 4H), 3.08 (d, J = 5.9 Hz, 2H), 3.01 (d, J = 5.8 Hz, 2H), 2.40-2.44 (m, 1H), 2.21 (d,

13 J = 7.2 Hz, 2H), 1.79-2.06 (m, 9H), 1.37-1.65 (m, 9H); C NMR (90 MHz, CDCl3) 174.2, 168.1,

154.3, 143.9, 143.2, 135.5, 135.4, 130.0. 129.7, 128.6, 128.5, 128.2, 128.1, 128.0, 128.0, 116.1,

115.0, 68.4, 64.4, 51.7, 51.3, 46.0, 43.8, 42.0, 38.3, 31.6, 30.9, 30.8, 30.6, 29.5, 29.4, 28.7, 28.4,

26.9, 26.7, 26.0, 25.9, 22.7, 21.6, 19.1, 14.1, 13.7.

O O

O N Cbz 97

2-Oxo-3-[5-(2-oxo-dihydropyran-3-ylidene)-pentyl]-piperidine-1-carboxylic Acid

Benzyl Ester (97) A stirred solution of phosphonolactone 96 (188 mg, 0.80 mmol) and 18-crown-

6 (1.05 g, 3.9 mmol) in THF (18 mL) was cooled to -78 ºC and KHMDS (1 M in THF, 0.86 mL,

0.86 mmol) was added dropwise. The mixture was stirred for 30 min at -78 ºC, then aldehyde 60

(241 mg, 0.76 mmol) was added dropwise as a solution in THF (5 mL). The reaction mixture was

109 allowed to slowly warm to rt over 3 h, then saturated NH4Cl (aq) was added. The mixture was extracted with Et2O (3 x 25 mL) and the combined organic layers were washed with water then brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product (which contained a ~3:2 mixture of (Z)- and (E)-olefin geometric isomers) was purified via flash column chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to furnish the desired (E)-

1 olefin 97 (57 mg, 19%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 7.33-7.45 (m, 5H),

7.05 (tt, J = 5.1, 2.2 Hz, 1H), 5.29 (s, 2H), 4.32 (dd, J = 5.2, 5.1 Hz, 2H), 3.81-3.89 (m, 1H), 3.60-

3.74 (m, 1H), 2.53 (t, J = 5.7 Hz, 2H), 2.38-2.44 (m, 1H), 2.18 (q, J = 7.1 Hz, 2H), 1.78-2.08 (m,

13 6H), 1.39-1.58 (m, 6H); C NMR (75 MHz, CDCl3) δ 174.6, 167.1, 154.6, 146.7, 135.9, 129.1,

128.7, 128.5, 126.0, 69.0, 68.9, 46.4, 44.2, 31.3, 28.5, 27.2, 26.4, 24.1, 23.1, 22.0.

CO2Et

CO2Et N O Cbz 99

2-[5-(1-Benzyloxycarbonyl-2-oxopiperidin-3-yl)-pentylidene]-malonic Acid Diethyl

Ester (99). To a solution of aldehyde 60 (250 mg, 0.79 mmol) in dry PhH (10 mL) was added diethyl malonate (0.14 mL, 0.95 mmol), piperidine (0.015 mL, 0.15 mmol) and HOAc (2 drops, cat). The mixture was heated at reflux for 3 h, then cooled to rt and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with 1 M HCl (aq), brine, dried over anhydrous

MgSO4, and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (10% EtOAc/hexanes) to afford enedioate 99 (330 mg, 91%) as a

1 clear colorless oil: H NMR (400 MHz, CDCl3) δ 7.30-7.43 (m, 5H), 6.96 (t, J = 7.9 Hz, 1H), 5.26

110

(s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.82 (ddd, J = 12.8, 7.5, 5.0 Hz, 1H),

3.67 (ddd, J = 12.4, 7.0, 5.3 Hz, 1H), 2.38-2.45 (m, 1H), 2.30 (q, J = 7.4 Hz, 2H), 2.00 (sex, J =

6.3 Hz, 1H), 1.79-1.91 (m, 3H), 1.33-1.54 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz,

13 3H); C NMR (100 MHz, CDCl3) δ 174.5, 168.8, 165.9, 164.3, 154.6, 149.4, 135.9, 129.2, 128.9,

128.6, 128.4, 68.8, 61.6, 46.3, 44.1, 31.2, 29.9, 28.7, 27.1, 26.4, 22.0, 14.5.

N O

O O Me

Me 101

3-Hex-5-enyl-2-oxopiperidine-1-carboxylic Acid 2-Isopropyl-5-methylcyclohexyl

Ester (101). To a stirred solution of N-H lactam 66 (1.83 g, 10.1 mmol) in THF (25 mL) at -78 ºC was added dropwise n-butyllithium (2.5 M in hexanes, 4.40 mL, 11.1 mmol) and the reaction mixture was stirred for 30 min at that temperature. (-)-Menthyl chloroformate (3.21 mL, 15.2 mmol) was added dropwise and the mixture was warmed to rt over 1 h. Saturated NH4Cl (aq) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified via flash column chromatography on silica gel (gradient 5% to 7.5% EtOAc/hexanes) to afford (-)-menthyl carbamate 101 (2.47 g, 67%) as a clear colorless oil: 1H NMR (300 MHz,

CDCl3) δ 5.74-5.82 (m, 1H), 4.98 (dp, J = 13.2, 1.1 Hz, 1H), 4.91 (dp, J = 8.6, 1.0 Hz, 1H), 4.71

(tt, J = 10.5, 2.4 Hz, 1H), 3.73-3.79 (m, 1H), 3.61-3.67 (m, 1H), 2.34-2.43 (m, 1H), 1.66-2.12 (m,

9H), 1.01-1.54 (m, 12H), 0.90 (d, J = 4.7 Hz, 6H), 0.78 (d, J = 5.2 Hz, 3H); 174.6, 154.6, 154.5,

111

139.2, 114.8, 77.7, 47.2, 46.32, 46.28, 44.22, 44.19, 41.14, 41.10, 34.6, 34.0, 31.9, 31.3, 31.31,

31.26, 29.2, 26.84, 26.81, 26.45, 26.36, 26.33, 26.29, 23.60, 23.58, 22.4, 22.1, 22.0, 21.3. 21.2,

16.5.

N O CHO O O Me

Me 102

2-Oxo-3-(5-oxopentyl)-piperidine-1-carboxylic Acid 2-Isopropyl-5-methylcyclohexyl

Ester (102). A solution of (-)-menthyl carbamate 101 (1.0 g, 2.8 mmol) in dry CH2Cl2 (25 mL) was cooled to -78 °C and ozone was bubbled through the reaction mixture for 10 min until a light blue coloration was achieved. The mixture was then purged with argon for 5 min followed by the portionwise addition of triphenylphosphine (866 mg, 3.3 mmol). The reaction mixture was warmed to rt over 2 h and then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column chromatography on silica gel (gradient 10% to 15% EtOAc/hexanes) to afford

1 aldehyde 102 (979 mg, 100%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 9.78 (t, J =

1.7 Hz, 1H), 4.74 (tdd, J = 10.8, 4.4, 2.0 Hz, 1H), 3.75-3.84 (m, 1H), 3.64-3.69 (m, 1H), 2.47 (td,

J = 7.2, 1.7 Hz, 2H), 2.35-2.44 (m, 1H), 2.12 (br d, J = 12.1 Hz, 1H), 1.39-2.06 (m, 17H), 0.98-

13 1.16 (m, 2H), 0.92 (d, J = 5.7 Hz, 6H), 0.79 (d, J = 6.9 Hz, 3H); C NMR (75 MHz, CDCl3) δ

203.0, 174.5, 154.4, 77.8, 47.3, 46.3, 46.3, 44.1, 44.04, 44.01, 41.2, 41.1, 34.6, 31.9, 31.21, 31.16,

26.97, 26.94, 26.5, 26.42, 26.38, 23.65, 23.62, 22.43, 22.40, 22.37, 22.2, 22.1, 21.29, 21.26, 16.60,

16.56.

112

CO2Me Me Me O N O

103 Me

3-(6-Methoxycarbonylhex-5-enyl)-2-oxopiperidine-1-carboxylic Acid 2-Isopropyl-5- methylcyclohexyl Ester (103). Anhydrous LiCl (160 mg, 3.7 mmol) was flame-dried under a stream of argon and then suspended in dry MeCN (15 mL) to which was added methyl diethylphosphonoacetate (0.58 mL, 3.3 mmol) and DBU (0.42 mL, 3.0 mmol) at rt. A solution of aldehyde 102 (979 mg, 2.75 mmol) in dry MeCN (9 mL) was added dropwise over 5 min and the resulting cloudy white reaction mixture was stirred for 24 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude material was purified by flash column chromatography on silica gel (10% EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 103 (814

1 mg, 70%) as a clear colorless oil: H NMR (300 MHz, CDCl3) δ 6.84 (dt, J = 15.6, 7.0 Hz, 1H),

5.71 (dt, J = 15.7, 1.5 Hz, 1H), 4.61 (tdd, J = 10.9, 4.3, 2.0 Hz, 1H), 3.52-3.72 (m, 2H), 3.61 (s,

3H), 2.20-2.32 (m, 1H), 2.11 (q, J = 6.5 Hz, 2H), 1.51-2.06 (m, 10H), 1.20- 1.47 (m, 9H), 0.84-

13 0.98 (m, 2H), 0.82 (d, J = 6.8 Hz, 6H), 0.67 (d, J = 7.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ

174.3, 167.2, 154.4, 154.3, 149.6, 121.3, 77.6, 51.6, 47.2, 46.2, 46.1, 44.1, 44.0, 41.1, 41.0, 34.5,

32.3, 31.7, 31.13, 31.07, 28.4, 26.9, 26.8, 26.5, 26.3, 26.2, 23.6, 23.5, 22.3, 22.1, 22.0, 21.13,

21.10, 16.5, 16.4.

113

H H CO2Me MeO2C Me Me Me Me O O N O O N

O O 104a Me Me 104b

7-Methoxycarbonylmethyl-1-oxo-2-azaspiro[5.5]undecane-2-carboxylic Acid 2-

Isopropyl-5-methylcyclohexyl Ester (104a/b). TiCl4 (0.153 mL, 1.35 mmol) and dry Et3N (0.190 mL, 1.35 mmol) were dissolved in dry CH2Cl2 (6 mL) at 0 °C and the resulting deep maroon solution was stirred for 5 min. A solution of (E)-α,β-unsaturated ester 103 (284 mg, 0.68 mmol) in dry CH2Cl2 (5 mL) was added dropwise and the reaction mixture was slowly warmed to rt over

3 h. Saturated NaHCO3 (aq) was carefully added, the mixture was stirred for 30 min and then extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried over anhydrous

MgSO4 and concentrated in vacuo to afford a reddish oil that was purified by flash chromatography on silica gel (10% EtOAc/hexanes) to give spirocyclic ester 104a/b (165 mg, 66%) as a light

1 yellow gum in a 1:1 diastereomeric mixture: H NMR (300 MHz, CDCl3) δ 4.71 (td, J = 10.8, 4.4

Hz, 1H), 3.72-3.78 (m, 1H), 3.64 (s, 3H), 3.52-3.62 (m, 1H), 2.59-2.71 (m, 1H), 2.25-2.30 (m,

1H), 1.07-2.09 (m, 30H), 0.89-0.93 (m, 11H), 0.79 (d, J = 5.2, 3H), 0.77 (d, J = 5.2 Hz, 3H); 13C

NMR (75 MHz, CDCl3) δ 177.5, 177.4, 173.3, 173.2, 154.9, 154.7, 77.9, 77.8, 53.8, 51.9, 49.4,

49.3, 47.3, 47.2, 41.1, 40.3, 39.8, 37.4, 37.3, 35.6, 35.2, 35.1, 34.6, 32.0, 31.8, 27.4, 26.7, 26.4,

25.8, 24.4, 24.1, 23.9, 23.6, 23.1, 22.4, 21.3, 21.1, 21.05, 20.99, 20.4, 20.3, 16.9, 16.5, 14.5.

114

O O P EtO O Me EtO Ph Me 106

(Diethoxyphosphoryl)-acetic Acid 2-(1-Methyl-1-phenylethyl)-cyclohexyl Ester (106).

To a stirred solution of diethoxyphosphorylacetyl chloride (265 mg, 1.2 mmol) in dry CH2Cl2 (4 mL) at 0 ºC was added dropwise (+)-TCC alcohol (105, 250 mg, 1.2 mmol) as a solution in dry

CH2Cl2 (2 mL) followed by Et3N (0.16 mL, 1.2 mmol). The mixture was warmed to rt and stirred overnight, then saturated NH4Cl (aq) was added. The mixture was extracted with Et2O (3 x 25 mL) and the combined organic layers were washed with brine and dried over anhydrous MgSO4 then concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (50% EtOAc/hexanes) to afford (+)-TCC phosphonoester 106 (213 mg, 47%) as a clear gum:

1 H NMR (300 MHz, CDCl3) δ 7.22-7.29 (m, 4H), 7.07-7.13 (m, 1H), 4.78 (td, J = 10.3, 4.6 Hz,

1H), 3.91- 4.12 (m, 4H), 2.34 (dd, J = 21.3, 14.4 Hz, 1H), 1.99-2.11 (m, 2H), 1.79-1.92 (m, 2H),

13 1.66-1.70 (m, 2H), 1.02-1.29 (m, 16H); C NMR (75 MHz, CDCl3) δ 165.5, 165.4, 152.2, 128.3,

125.7, 125.4, 75.8, 62.8, 62.7, 51.1, 39.9, 35.1, 33.4, 29.6, 27.1, 26.3, 24.9, 23.6, 16.7, 16.6.

Me Me O Ph O

O N Cbz 107

3-{6-[2-(1-Methyl-1-phenylethyl)-cyclohexyloxycarbonyl]-hex-5-enyl}-2- oxopiperidine-1-carboxylic Acid Benzyl Ester (107). To a stirred solution of (+)-TCC phosphonoester 106 (50 mg, 0.13 mmol) in dry THF (2 mL) at -78 ºC was added in one portion

115 solid KHMDS (27 mg, 0.13 mmol) and the mixture was stirred at that temperature for 30 min. A solution of aldehyde 60 (40 mg, 0.13 mmol) in dry THF (0.5 mL) was added dropwise and the mixture was allowed to warm to rt overnight. Saturated NH4Cl (aq) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (15% EtOAc/hexanes) to afford (E)-α,β-unsaturated ester

1 107 (23 mg, 32%) as a clear gum: H NMR (300 MHz, CDCl3) δ 7.12-7.47 (m, 10H), 6.50 (dt, J

= 11.7, 5.3 Hz, 1H), 5.25 (s, 2H), 4.79-4.85 (m, 1H), 3.65-3.89 (m, 2H), 2.22-2.45 (m, 1H), 1.09-

2.10 (m, 28H).

H CO2Me OMe N 110

(1-Methoxy-2-azaspiro[5.5]undec-1-en-7-yl)-acetic Acid Methyl Ester (110). To a solution of N-H lactam 63 (90 mg, 0.38 mmol) in dry CH2Cl2 (2 mL) was added freshly distilled methyl trifluoromethanesulfonate (0.054 mL, 0.47 mmol) and the mixture was stirred for 8 h at rt.

Saturated Na2CO3 (aq) was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to furnish imidate 110 (96 mg, 100%) as a light brownish gum which was used without further

1 purification: H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.45-3.60 (m, 4H), 3.25-3.33 (m, 1H),

13 2.46-2.57 (m, 1H), 2.05-2.12 (m, 2H), 1.31-1.75 (m, 12H); C NMR (75 MHz, CDCl3) δ 173.9,

167.0, 52.7, 51.9, 47.4, 42.6, 39.3, 37.4, 34.2, 26.8, 26.2, 23.9, 20.8, 20.4; HRMS-ES (m/z): [M +

116

+ H] calcd for C14H23NO3, 254.3413; found, 254.3419.

H CHO

O N H 111

2-(1-Oxo-2-azaspiro[5.5]undecan-7-yl)acetaldehyde (111). To a stirred solution of N-H lactam 63 (355 mg, 1.48 mmol) in dry CH2Cl2 (35 mL) at -78 °C was added dropwise DIBAL-H

(1.5 M in PhMe, 2.96 mmol, 2.0 mL) over 5 min. The reaction mixture was stirred for 2 h at -78

°C, carefully quenched with MeOH, then warmed to rt. An equal volume of saturated aqueous potassium sodium tartrate solution was added and the mixture was stirred at rt for 1 h. The mixture was separated and the aqueous layer extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% CH2Cl2/Et2O + 1%

1 MeOH) to furnish the aldehyde 111 as a clear gum (208 mg, 67%): H NMR (300 MHz, CDCl3)

δ 9.63-9.67 (m, 1H), 6.37 (br s, 1H), 3.25-3.48 (m, 2H), 2.72-2.80 (m, 1H), 2.31 (ddd, J = 17.1,

3.5, 1.6 Hz, 1H), 1.91 (ddd, J = 15.0, 9.1, 3.7 Hz, 1H), 1.67-1.98 (m, 6H), 1.04-1.66 (m, 6H); 13C

NMR (75 MHz, CDCl3) δ 203.0, 177.7, 47.3, 45.8, 42.5, 37.1, 34.5, 27.4, 26.1, 23.3, 20.6, 19.6;

-1 + IR (neat) 1720, 1645 cm ; HRMS-ES+ (C12H20NO2) calcd 210.1494 (MH ), found 210.1495.

117

H N O N H

112

7-(E)-2-(Pyrrolidin-1-yl)vinyl)-2-azaspiro[5.5]undecan-1-one (112). To a stirred solution of aldehyde 111 (50 mg, 0.24 mmol) in CHCl3 (1 mL) at 0 °C was added 4Å molecular sieves (300 mg) and pyrrolidine (0.29 mmol, 0.024 mL). The reaction mixture was stirred for 1.5 h at 0 °C, then filtered through a Celite pad and concentrated in vacuo to give pyrrolidinoenamine

112 as a white solid that was used without further purification (63 mg, 100%). A small sample (ca.

5 mg) of enamine 112 was recrystallized from Et2O to afford clear prisms that were suitable for

1 X-ray analysis: H NMR (300 MHz, CDCl3) δ 6.08-6.19 (m, 2H), 3.95 (dd, J = 13.8, 7.6 Hz, 1H),

13 2.85-3.25 (m, 6H), 2.62-2.73 (m, 1H), 1.11-2.05 (m, 16H); C NMR (75 MHz, CDCl3) δ 178.6,

136.9, 100.2, 49.6, 47.4, 43.8, 42.7, 34.3, 28.1, 26.3, 25.2, 23.5, 20.8, 20.4; HRMS-ES+

+ (C16H27N2O) calcd 263.2123 (MH ), found 263.2131.

H O Me N O OMe N Bn 114

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-N-methoxy-N-methylacetamide

(114). To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (10.16 g, 105.7 mmol) in dry CH2Cl2 (300 mL) at 0 °C was added dropwise dimethylaluminum chloride (1 M in hexane, 105.7 mL, 105.7 mmol). The reaction mixture was warmed to rt and stirred for 2 h. A solution of N-Bn lactam 53 (11.59 g, 35.2 mmol) in dry CH2Cl2 (60 mL) was added and the mixture

118 was stirred for 24 h at rt. An equal volume of saturated aqeuous potassium sodium tartrate solution was added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous layer extracted with CH2Cl2 (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This material was purified via flash column chromatography on silica gel (50% EtOAc/hexanes) to afford N-methoxy-N-

1 methylamide 114 (11.34 g, 90%) as a light yellow gum: H NMR (300 MHz, CDCl3) δ 7.21-7.31

(m, 5H), 4.68 (d, J = 14.6 Hz, 1H), 4.46 (d, J = 14.6 Hz, 1H), 3.65 (s, 3H), 3.16-3.27 (m, 5H), 2.75

13 (br s, 1H), 2.27 (m, 1H), 2.12 (m, 1H), 1.10-1.94 (m, 12H); C NMR (75 MHz, CDCl3) δ 175.4,

138.2, 128.9, 128.3, 127.6, 61.6, 51.1, 47.7, 46.3, 39.6, 35.6, 35.1, 32.6, 27.2, 26.1, 23.5, 20.9,

+ 19.7; HRMS-ES+ (C21H31N2O3) calcd 359.2335 (MH ), found 359.2335.

H CHO

O N Bn 115

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)acetaldehyde (115). To a stirred solution of N-methoxy-N-methylamide 114 (11.34 g, 31.7 mmol) in dry THF (300 mL) at -40 °C was added lithium aluminum hydride (4.79 g, 126.6 mmol) in portions over 5 min. The resulting dark grey suspension was stirred for 1 h at -40 °C, then carefully diluted with methanol followed by 1 N NaOH (aq). The mixture was warmed to rt and additional 1 N NaOH (aq) solution was added.

The mixture was extracted with EtOAc (4 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified via flash column chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to

119

1 afford aldehyde 115 (8.62 g, 91%) as a waxy yellowish solid: H NMR (300 MHz, CDCl3)  9.61

(dd, J = 3.7, 1.6 Hz, 1H), 7.17-7.34 (m, 5H), 4.67 (d, J = 14.5 Hz, 1H), 4.37 (d, J = 14.5 Hz, 1H),

3.05-3.21 (m, 2H), 2.78-2.86 (m, 1H), 2.15 (ddd, J = 14.4, 3.6, 1.5 Hz, 1H), 2.04 (ddd, J = 14.5,

10.3, 3.8 Hz, 1H), 1.65-2.00 (m, 7H), 1.34-1.64 (m, 6H), 1.17 (qd, J = 12.5, 4.2 Hz, 1H); 13C NMR

(75 MHz, CDCl3)  203.3, 175.3, 137.9, 129.1, 128.4, 127.8, 51.2, 47.6, 47.4, 46.2, 37.7, 34.8,

+ 27.7, 26.1, 23.5, 20.8, 19.6; HRMS-ES+ (C19H26NO2) calcd 300.1964 (MH ), found 300.1956.

H Cl CHO

O N Bn 117

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-chloroacetaldehyde (117). To a stirred solution of aldehyde 115 (8.62 g, 28.8 mmol) in dry CHCl3 (175 mL) at 0 °C were added powdered 4Å molecular sieves (38.2 g) and pyrrolidine (2.82 mL, 34.5 mmol). The reaction mixture was stirred for 1.5 h at 0 °C, then filtered through a pad of Celite, which was washed with dry Et2O (1 x 50 mL) and dry CH2Cl2 (2 x 50 mL) to afford a solution of (E)-pyrrolidinoenamine

116: 1H NMR (obtained on a sample of crude material after concentration in vacuo) (300 MHz,

CDCl3) δ 7.23-7.36 (m, 5H), 6.20 (d, J = 13.7 Hz, 1H), 5.13 (d, J =14.7 Hz, 1H), 4.12 (d, J = 14.7

Hz, 1H), 3.96 (dd, J = 13.6, 7.8 Hz, 1H), 3.02-3.23 (m, 2H), 2.92-3.01 (m, 4H), 2.80-2.88 (m, 1H),

13 1.14-1.93 (m, 16H); C NMR (75 MHz, CDCl3) δ 176.2, 138.2, 136.9, 128.8, 128.4, 127.4, 100.2,

51.3, 49.4, 47.9, 44.6, 34.5, 28.6, 26.5, 25.3, 23.9, 21.1, 20.4.

120

To the above stirred CHCl3/Et2O solution of enamine 116 (10.14 g, 28.8 mmol) was added

N-chlorosuccinimide (3.81 g, 28.5 mmol) in one portion. The reaction mixture was heated at reflux for 30 min and then stirred at rt for 5 h. Aqueous acetic acid (10% v/v) was added and the resulting biphasic mixture was stirred for 30 min. The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with 1 N HCl (aq), saturated NaHCO3 (aq), and brine, dried over anhydrous MgSO4 and then concentrated in vacuo. The resulting brownish oil was purified by flash column chromatography on silica gel (gradient 7.5% to 15% EtOAc/hexanes) to afford α-chloroaldehyde 117 (7.84 g, 82%) as an inseparable ~2.2:1 mixture of C7-diastereomers:

1 H NMR (300 MHz, CDCl3) δ 9.37 (d, J = 4.8 Hz, 1H), 9.30 (d, J = 3.6 Hz, 1H), 7.21-7.35 (m,

5H), 5.05 (d, J = 14.7 Hz, 1H), 4.93 (d, J = 14.5 Hz, 1H), 4.72 (s, 1H), 4.22 (d, J = 14.5 Hz, 1H),

3.98-4.04 (m, 2H), 3.87 (dd, J = 8.4, 4.8 Hz, 1H), 2.98-3.31 (m, 4H), 1.22-2.04 (m, 9H); 13C NMR

(75 MHz, CDCl3) δ 194.4, 193.9, 175.3, 175.2, 137.7, 137.7, 129.0, 128.9, 128.7, 128.4, 127.4,

127.3, 68.3, 66.3, 65.8, 65.7, 51.4, 51.0, 47.4, 47.1, 46.3, 45.3, 43.9, 43.6, 35.5, 35.4, 25.9, 25.8,

25.1, 24.1, 23.5, 23.1, 20.7, 20.6, 19.6, 19.2, 15.7; HRMS-ES+ (C19H25NO2Cl) calcd 334.1574

(MH+), found 334.1574.

OTBS H Cl N

O N Bn 122

(E)-2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-chloroacetaldehyde O-(tert-

Butyldimethylsilyl)oxime (122). To a stirred solution of α-chloroaldehyde 117 (~2.2:1 C7- diastereomeric mixture, 7.84 g, 23.54 mmol) in dry CH2Cl2 (110 mL) was added O-TBS-

121 hydroxylamine (6.85 g, 47.08 mmol), powdered 4Å molecular seives (650 mg), and PPTS (1.00 g, 3.97 mmol). The reaction mixture was stirred for 24 h at rt, then filtered through a pad of Celite which was washed with CH2Cl2. The combined filtrate was concentrated to afford a colorless oil that was purified by flash column chromatography on silica gel (gradient 2.5% to 5%

EtOAc/hexanes) to provide the O-TBS-oxime 122 as a separable ~2.2:1 mixture of diastereomers

1 (9.25 g total, 85%): H NMR (300 MHz, CDCl3) δ (major) 7.48 (d, J = 9.3 Hz, 1H), 7.19-7.36 (m,

5H), 5.53 (d, J = 15.0 Hz, 1H), 4.35 (t, J = 9.3 Hz, 1H), 3.63 (d, J = 15.0 Hz, 1H), 3.10-3.21 (m,

2H), 2.74-2.86 (m, 1H), 2.20-2.25 (m, 1H), 1.13-2.05 (m, 11H), 0.98 (s, 9H), 0.23 (s, 3H), 0.21 (s,

3H); 1H NMR (minor) δ 7.18-7.65 (m, 5H), 7.04 (d, J = 8.8 Hz, 1H), 5.09-5.18 (m, 2H), 3.86 (d,

J = 14.7 Hz), 3.01-3.13 (m, 2H), 2.74-2.80 (m, 1H), 2.17-2.31 (m, 1H), 1.16-1.87 (m, 11H), 0.95

13 (s, 9H), 0.22 (s, 3H), 0.19 (s, 3H); C NMR (75 MHz, CDCl3) δ (major) 175.4. 155.0, 138.2,

129.0, 128.1 127.6, 62.7, 51.0, 47.1, 46.8, 46.1, 35.3, 26.4, 25.8, 25.4, 22.4, 20.9, 19.4, 18.4, -4.5,

-4.8; (minor) 175.3, 153.3, 137.8, 128.9, 128.1, 127.6, 53.8, 51.0, 47.1, 46.9, 46.2, 35.3, 26.3, 25.8,

25.5, 22.3, 20.9, 19.3, 18.4, -4.7, -4.9; HRMS-ES+ (C25H40N2O2SiCl) (major) calcd 463.2548

(MH+), found 463.2551; (minor) calcd 463.2548 (MH+), found 463.2543.

OH H O N CO2Me HCO2Me N Bn

123a/b

Dimethyl-2-((E/Z)-1-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-

(hydroxyimino)ethyl)malonate (123a/b). To a stirred solution of dimethyl malonate (1.21 mL,

122

10.6 mmol) in dry THF (60 mL) at -78 °C was added dropwise LiHMDS (1 M in THF, 10.6 mL,

10.6 mmol) and the resulting yellow solution was stirred for 30 min at that temperature. A solution of O-TBS-oxime 122 (~2.2:1 mixture of C7-diastereomers, 4.10 g, 8.9 mmol) in dry THF (30 mL) was added dropwise over 5 min followed by the dropwise addition of TBAF (1 M in THF, 17.7 mL, 17.7 mmol) over 5 min. The reaction mixture was immediately warmed to 0 °C via transfer to an ice bath and stirred for 4 h at that temperature. The mixture was diluted with saturated NH4Cl

(aq) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give an oil that was purified by flash chromatography on silica gel (10% Et2O in CH2Cl2) to afford oximes 123a/b (~5:1 mixture of E- and Z-oxime geometric isomers, 3.66 g, 93%) as a white solid. The geometric isomers 123a (E) and 123b (Z) (~5 mg of solid from column fractions near the beginning and end of the elution, respectively) were each recrystallized from a minimal amount of Et2O via slow evaporation to afford clear prisms that were analyzed by X-ray crystallography. All attempts to purify a sufficient quantity of the minor isomer (123b) by chromatography for NMR analysis were unsuccessful: 1H

NMR (300 MHz, CDCl3) (major (123a)) δ 7.72-7.77 (m, 2H), 7.23-7.36 (m, 5H), 4.80 (d, J = 14.6

Hz, 1H), 4.39 (d, J = 14.6 Hz, 1H), 3.90 (d, J = 5.6 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.14-3.31

(m, 2H), 2.79-2.86 (m, 1H), 2.55 (dt, J = 13.1, 3.2 Hz, 1H), 1.06-1.93 (m, 12H). 13C NMR (75

MHz, CDCl3) (major (123a)) δ 175.2, 169.1, 168.9, 152.6, 137.8, 129.0, 128.4, 127.7, 55.7, 53.1,

52.7, 51.1, 47.8, 47.4, 44.1, 42.2, 35.1, 26.5, 25.1, 23.1, 20.8, 19.5; HRMS-ES+ (C24H33N2O6)

(mixture) calcd 445.2339 (MH+), found 445.2342.

123

H O CN CO2Me HCO2Me N Bn 125

Dimethyl 2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)(cyano)methyl)malonate

(125). To a stirred solution of oximes 123a/b (284 mg, 0.64 mmol) in dry CH2Cl2 (8 mL) were added CuSO4·5H2O (100 mg), Et3N (0.16 mL, 1.54 mmol), and pyridine (0.51 mL, 6.4 mmol).

DCC (158 mg, 0.77 mmol) was then added in one portion and the reaction mixture was stirred for

14 h at rt, and diluted with 1 N HCl (aq). The mixture was extracted with CH2Cl2 (3 x 50 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to provide nitrile 125 (263 mg, 96%) as a white waxy solid: 1H NMR

(300 MHz, CDCl3) δ 7.21-7.61 (m, 5H), 4.57 (dd, J = 19.4, 14.5 Hz, 2H), 3.83 (s, 3H), 3.82 (s,

3H), 3.77 (d, J = 5.9 Hz, 1H), 3.16-3.33 (m, 2H), 3.07 (dd, J = 7.8, 1.2 Hz, 1H), 2.51 (dd, J = 12.1,

13 3.1 Hz, 1H), 2.04-2.15 (m, 1H), 1.32-1.94 (m, 11H); C NMR (75 MHz, CDCl3) δ 174.3, 167.4,

166.7, 137.7, 129.1, 128.3, 127.8, 119.2, 54.3, 53.7, 53.4, 51.3, 47.8, 47.5, 42.0, 34.8, 34.5, 26.0,

-1 24.7, 23.5, 20.6, 19.2; IR (neat) 2242, 1741, 1625, 1201 cm ; HRMS-ES+ (C24H31N2O5) calcd

427.2233 (MH+), found 427.2215.

124

H O CN CO2Me H N Bn 126

Methyl 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-3-cyanopropanoate (126). To a stirred solution of nitrile 125 (2.22 g, 5.2 mmol) in DMSO (50 mL) and H2O (25 mL) was added

LiCl (2.21 g, 52.1 mmol) and the reaction mixture was heated at 155 °C for 24 h, and then cooled to rt. The mixture was extracted with EtOAc (3 x 200 mL) and the combined organic layers were washed with H2O, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to

1 furnish ester 126 (1.41 g, 73%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 7.18-7.32

(m, 5H), 4.64 (d, J = 14.5 Hz, 1H), 4.44 (d, J = 14.5 Hz, 1H), 3.71 (s, 3H), 3.14-3.25 (m, 2H), 2.80

(dd, J = 10.6, 3.6 Hz, 1H), 2.75 (dd, J = 26.0, 10.6 Hz, 1H), 2.59 (dd, J = 14.6, 3.5 Hz, 1H), 2.40

13 (dd, J = 12.8, 3.6 Hz, 1H), 1.23-2.07 (m, 12H); C NMR (75 MHz, CDCl3) δ 174.3, 170.2, 137.3,

128.2, 127.9, 127.4, 120.7, 52.1, 50.9, 47.2, 47.1, 43.6, 37.6, 34.4, 30.5, 25.6, 23.8, 22.9, 20.2,

-1 + 18.7; IR (neat) 2239, 1739, 1623, 1203 cm ; HRMS-ES+ (C22H29N2O3) calcd 369.2178 (MH ), found 369.2188.

125

H O CN

H OH N Bn

127

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-4-hydroxybutanenitrile (127). To a stirred suspension of LiBH4 (21 mg, 0.95 mmol) in dry THF (3 mL) at rt was added dropwise a solution of ester 126 (250 mg, 0.68 mmol) in dry THF (5 mL). The reaction mixture was stirred for 15 h at rt and diluted with brine. The mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (40% EtOAc/hexanes) to afford alcohol 127 (203 mg, 88%)

1 as a clear gum: H NMR (300 MHz, CDCl3) δ 7.20-7.37 (m, 5H), 4.77 (d, J = 14.5 Hz, 1H), 4.37

(d, J = 14.5 Hz, 1H), 3.84-3.93 (m, 1H), 3.61-3.72 (m, 1H), 3.49-3.59 (m, 1H), 3.21-3.36 (m, 2H),

13 2.53-2.59 (m, 2H), 1.30-2.18 (m, 14H); C NMR (75 MHz, CDCl3) δ 176.3, 137.2, 129.2, 128.3,

128.0, 122.6, 59.0, 51.6, 47.7, 47.6, 40.4, 34.7, 30.2, 26.1, 23.5, 23.1, 20.7, 18.8; HRMS-ES+

+ (C21H29N2O2) calcd 341.2229 (MH ), found 341.2219.

H O CN

H OMs N Bn

128

Methanesulfonic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-propyl

Ester (128). To a stirred solution of alcohol 127 (28 mg, 0.085 mmol) in dry CH2Cl2 (1.5 mL)

126 was added Et3N (0.022 mL, 0.17 mmol) and methanesulfonyl chloride (0.015 mL, 0.17 mmol).

The reaction mixture was stirred for 3 h at rt and then 1 N HCl (aq) was added. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (35% EtOAc/hexanes) to afford mesylate 128 (23 mg, 64%)

1 as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 7.21-7.63 (m, 5H), 4.69 (d, J = 14.6 Hz,

1H), 4.30-4.47 (m, 3H), 3.16-3.36 (m, 2H), 3.05 (s, 3H), 2.54 (td, J = 7.6, 1.3 Hz, 1H), 2.43 (ddd,

13 J = 14.9, 3.3, 1.3 Hz, 1H), 2.05-2.13 (m, 3H), 1.36-1.98 (m, 11H); C NMR (75 MHz, CDCl3) δ

174.8, 137.6, 129.2, 128.2, 127.9, 121.1, 67.3, 51.3, 47.6, 47.4, 43.6, 37.8, 34.8, 32.4, 30.9, 30.1,

26.1, 24.0, 23.3, 20.7, 19.1.

H O CN

H CN N Bn

129

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-pentanedinitrile (129). To a stirred solution of mesylate 128 (23 mg, 0.055 mmol) in dry MeCN (1 mL) was added 4Å molecular seives (100 mg) and Et4NCN (60 mg, 0.39 mmol). The reaction mixture was heated at 60 °C for

15 h then cooled to rt and passed through a pad of Celite that was washed with EtOAc. The total filtrate was washed with 1 M NaHCO3 (aq) and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (20% EtOAc/hexanes) to afford dinitrile 129 (20 mg, 99%) as a clear gum: 1H NMR (300

MHz, CDCl3) δ 7.23-7.37 (m, 5H), 4.77 (d, J = 14.5 Hz, 1H), 4.38 (d, J = 14.5 Hz, 1H), 3.23-

127

13 3.38 (m, 2H), 2.35-2.60 (m, 4H), 1.22-2.13 (m, 14H); C NMR (75 MHz, CDCl3) δ 174.7, 137.6,

129.1, 128.4, 127.9, 120.6, 118.7, 51.5, 47.7, 47.5, 43.6, 34.5, 33.6, 28.9, 26.0, 24.2, 23.3, 20.6,

19.1, 15.8.

H O CN

H OH N H

131

4-Hydroxy-2-(1-oxo-2-azaspiro[5.5]undecan-7-yl)butanenitrile (131). Liquid ammonia

(ca. 10 mL) was condensed at -78 °C and Na metal (83 mg, 3.6 mmol) was added until the reaction had developed a deep purple coloration. A solution of alcohol 127 (122 mg, 0.36 mmol) in dry

Et2O (10 mL) was added dropwise, the reaction mixture was stirred for 45 min, and then quenched by the addition of solid NH4Cl (~200 mg). The mixture was warmed to rt, saturated NH4Cl (aq) was added, and the resulting biphasic mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo.

The crude product was purified by flash chromatography on silica gel (gradient 5% to 10%

MeOH/EtOAc) to afford N-H lactam alcohol 131 (76 mg, 87%) as a white solid: 1H NMR (300

MHz, CDCl3) δ 6.15 (br s, 1H), 3.82-3.93 (m, 1H), 3.71 (dt, J = 12.3, 4.9 Hz, 1H), 3.28-3.46 (m,

2H), 2.66 (dd, J = 10.2, 4.9 Hz, 1H), 2.45 (dd, J = 12.6, 3.4 Hz, 1H), 2.07-2.15 (m, 1H), 1.24-2.06

13 (m, 14H); C NMR (75 MHz, CDCl3) δ 178.6, 122.4, 59.1, 47.3, 42.5, 40.7, 34.8, 34.5, 30.2, 26.1,

+ 23.3, 23.1, 20.6, 18.8; HRMS-ES+ (C14H23N2O2) calcd 251.1760 (MH ), found 251.1752.

128

H O CN

H OMs N H

132

3-Cyano-3-(1-oxo-2-azaspiro[5.5]undecan-7-yl)propyl Methanesulfonate (132). To a stirred solution of N-H lactam alcohol 131 (76 mg, 0.31 mmol) in dry CH2Cl2 (5 mL) at rt was added Et3N (0.083 mL, 0.62 mmol) and MsCl (0.047 mL, 0.37 mmol) and the mixture was stirred for 4 h at that temperature. The reaction mixture was diluted with brine and extracted with CH2Cl2,

(3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5%

1 MeOH/EtOAc) to furnish mesylate 132 (92 mg, 91%) as a clear gum: H NMR (300 MHz, CDCl3)

δ 6.61 (br s, 1H), 4.28-4.43 (m, 2H), 3.23-3.36 (m, 2H), 3.07 (s, 3H), 2.59 (td, J = 7.8, 1.3 Hz, 1H),

2.28 (ddd, J = 12.7, 3.5, 1.2 Hz, 1H), 2.03-2.10 (m, 3H), 1.20-1.88 (m, 11H); 13C NMR (75 MHz,

CDCl3) δ 177.1, 121.0, 67.5, 47.0, 43.3, 42.3, 37.8, 34.6, 32.4, 30.9, 26.0, 23.8, 23.1, 20.5, 19.0;

+ HRMS-ES+ (C15H25N2O4S) calcd 329.1535 (MH ), found 329.1536.

H O CN

H CN N H 130

2-(1-Oxo-2-azaspiro[5.5]undecan-7-yl)pentanedinitrile (130). To a solution of mesylate

132 (92 mg, 0.28 mmol) in dry MeCN (10 mL) was added Et4NCN (308 mg, 1.96 mmol) and 4 Å molecular seives (100 mg). The reaction mixture was heated at 60 °C for 12 h and cooled to rt.

129

The mixture was filtered through a Celite pad which was rinsed with EtOAc. The combined filtrate was washed with 1 M NaHCO3 (aq) and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting orange oil was purified by flash column chromatography on silica gel (40%

1 EtOAc/Et2O) to afford dinitrile 130 (71 mg, 97%) as a yellowish gum: H NMR (300 MHz, CDCl3)

 6.59 (br s, 1H), 3.30-3.41 (m, 2H), 2.49-2.68 (m, 3H), 2.29 (dd, J = 12.8, 2.9 Hz, 1H), 1.18-2.13

13 (m, 19H); C NMR (75 MHz, CDCl3) δ 177.1, 120.5, 118.7, 47.0. 43.2, 42.4, 34.4, 33.6, 29.0,

-1 26.0, 24.0, 23.2, 20.5, 19.0, 15.8; IR (neat) 2242, 2159, 1649 cm ; HRMS-ES+ (C15H22N3O) calcd

260.1763 (MH+), found 260.1750.

H CN OMe N CN

133

2-(1-Methoxy-2-azaspiro[5.5]undec-1-en-7-yl)pentanedinitrile (133). To a stirred solution of dinitrile 130 (7.5 mg, 0.029 mmol) in dry CH2Cl2 (1 mL) was added methyl trifluoromethanesulfonate (0.0144 mL, 0.087 mmol) and the reaction mixture was stirred for 10 h at rt. CH2Cl2 was added and the mixture was washed with 1 M NaHCO3 (aq) and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (40% EtOAc/Et2O) to afford methyl imidate 133

1 (6.3 mg, 79%) as a clear gum: H NMR (850 MHz, CDCl3) δ 3.64 (s, 3H), 3.62 (dd, J = 16.7, 3.6

Hz, 1H), 3.44 (pentet, J = 7.7 Hz, 1H), 2.58-2.62 (m, 1H), 2.51-2.54 (m, 1H), 2.44 (dd, J = 9.0,

8.9 Hz, 1H), 2.15 (dd, J = 12.5, 3.3 Hz, 1H), 2.05-2.08 (m, 1H), 2.02 (dt, J = 9.8, 3.9 Hz, 1H), 1.92

(pentet, J = 7.3 Hz, 1H), 1.88 (br d, J = 13.2 Hz, 1H), 1.80 (br d, J = 13.7 Hz, 1H), 1.72-1.75 (m,

130

1H), 1.61-1.68 (m, 5H), 1.57-1.59 (m, 1H), 1.51 (qt, J = 9.7, 3.9 Hz, 1H), 1.36 (qt, 13.2, 4.2 Hz,

13 1H); C NMR (212.5 MHz, CDCl3) δ 165.1, 120.0, 118.1, 52.6, 46.8, 43.3, 43.1, 33.8, 33.0, 28.8,

+ 25.8, 23.7, 23.5, 20.2, 19.5, 15.5; HRMS-ES+ (C16H24N3O) calcd 274.1919 (MH ), found

274.1906.

H Me O CN N OMe H O N Bn

144

3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-N-methoxy-N-methyl- propionamide (144). To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (260 mg, 2.7 mmol) in dry CH2Cl2 (300 mL) at 0 °C was added dropwise dimethylaluminum chloride

(1 M in hexane, 2.7 mL, 2.7 mmol). The reaction mixture was warmed to rt and stirred for 2 h. A solution of ester 126 (200 mg, 0.54 mmol) in dry CH2Cl2 (5 mL) was added and the mixture was stirred for 24 h at rt. An equal volume of saturated aqeuous potassium sodium tartrate solution was added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous layer was extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This material was purified via flash column chromatography on silica gel (50% EtOAc/hexanes) to afford N-methoxy-N-

1 methylamide 144 (183 mg, 85%) as a light yellow gum: H NMR (300 MHz, CDCl3) δ 7.18-7.37

(m, 5H), 4.89 (d, J =14.6 Hz, 1H), 4.25 (d, J = 14.5 Hz, 1H), 3.71 (s, 3H), 3.14-3.38 (m, 4H), 2.91-

3.09 (m, 2H), 2.64 (dd, J = 15.8, 3.6 Hz, 1H), 2.49 (dd, J = 12.7, 3.2 Hz, 1H), 1.05-2.18 (m, 13H).

131

H O CN CHO H N Bn

145

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-4-oxobutyronitrile (145). To a stirred solution of N-methoxy-N-methyl amide 144 (60 mg, 0.15 mmol) in dry THF (10 mL) at -40 °C was added LiAlH4 (23 mg, 0.61 mmol) in one portion. The reaction mixture was stirred for 30 min at that temperature then quenched via dropwise addition of MeOH followed by 1 N NaOH (aq).

CH2Cl2 (50 mL) and an equal volume of saturated aqueous potassium sodium tartrate solution were added and the mixture was stirred overnight at rt. The organic layer was washed with brine, dried over anhydrous MgSO4 then concentrated in vacuo. The crude material was purified via flash column chromatography on silica gel (40% EtOAc/hexanes) to afford aldehyde 145 (50 mg, 93%)

1 as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H), 7.21-7.37 (m, 5H), 4.68 (d,

J = 14.5 Hz, 1H), 4.44 (d, J = 14.5 Hz, 1H), 3.22-3.33 (m, 2H), 2.97 (dd, J = 17.1, 9.7 Hz, 1H),

2.85 (ddd, J = 8.4, 4.2, 1.1 Hz, 1H), 2.71 (dd, J = 17.0, 4.1 Hz, 1H), 2.41 (dd, J = 12.9, 2.7 Hz,

13 1H), 2.05-2.09 (m, 1H), 1.36-1.94 (m, 12H); C NMR (75 MHz, CDCl3) δ 198.0, 174.7, 137.6,

129.1, 128.3, 127.9, 120.9, 51.5, 47.7, 47.6, 46.9, 44.1, 34.7, 27.8, 26.0, 24.2, 23.2, 20.6, 19.1.

132

H O CN

H N Bn

147

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-pent-4-enenitrile (147). To a stirred solution of aldehyde 145 (123 mg, 0.33 mmol) in dry THF (4 mL) and HMPA (0.13 mL) at rt was added phenyltetrazoylmethyl sulfone 146 (78 mg, 0.35 mmol) followed by the dropwise addition of LiHMDS (1 M in THF, 0.66 mL, 0.66 mmol). The reaction mixture was stirred at rt for 20 min then diluted with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (10%

EtOAc/hexanes) to afford olefin 147 (36 mg, 32%) as a clear colorless gum: 1H NMR (300 MHz,

CDCl3) δ 7.22-7.35 (m, 5H), 5.78-5.87 (m, 1H), 5.18-5.23 (m, 2H), 4.58 (s, 2H), 3.23-3.28 (m,

13 2H), 2.33-2.48 (m, 4H), 2.01-2.11 (m, 2H), 1.11-1.91 (m, 10H); C NMR (75 MHz, CDCl3) δ

174.9, 137.9, 134.0, 129.1, 128.4, 127.9, 121.8, 118.9, 51.5, 47.8, 47.6, 44.1, 37.5, 34.7, 30.1, 26.0,

24.0, 23.6, 29.8, 19.3.

H O CHO CO2Me HCO2Me N Bn 149

Dimethyl 2-(1-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-oxoethyl)malonate

(149). To a stirred solution of the aldoxime E/Z isomer mixture 123a/b (1.06 g, 2.4 mmol) in dry

133

THF (34 mL) at 0 °C was added Zn metal dust (1.58 g, 23.9 mmol) followed by the dropwise addition of TiCl4 (1.37 mL, 11.9 mmol). The reaction mixture was stirred at 0 °C for 10 min, then carefully quenched with saturated NaHCO3 (aq). The mixture was filtered through a sintered glass frit and the filter cake was washed with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to yield a yellow oil that was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to give aldehyde 149 (651 mg, 63%) as a white fluffy solid:

1 H NMR (300 MHz, CDCl3) δ 9.92 (s, 1H), 7.23-7.35 (m, 5H), 4.60 (d, J = 14.5 Hz, 1H), 4.50 (d,

J = 14.5 Hz, 1H), 3.93 (d, J = 7.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.21-3.35 (m, 2H), 2.86 (dt,

J = 7.7, 2.1 Hz, 1H), 2.70 (dt, J = 13.3, 2.5 Hz, 1H), 2.02-2.16 (m, 1H), 1.26-1.89 (m, 11H); 13C

NMR (75 MHz, CDCl3) δ 202.9, 174.8, 169.5, 169.0, 137.8, 129.2, 128.3, 127.8, 53.7, 53.4, 53.1,

52.5, 51.2, 47.6, 47.5, 43.9, 34.8, 26.7, 24.7, 24.6, 20.8, 19.5; IR (neat) 1734, 1627 cm-1; HRMS-

+ ES+ (C24H32NO6) calcd 430.2230 (MH ), found 430.2235.

O H O O CO Me H 2 N Bn 150

Methyl 4-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-oxotetrahydrofuran-3- carboxylate (150). To a stirred solution of aldehyde 149 (1.18 g, 2.7 mmol) in MeOH (60 mL) and CH2Cl2 (5 mL) at 0 °C was added NaBH4 (102 mg, 2.7 mmol) in one portion. The reaction mixture was stirred at 0 °C for 5 min and then diluted with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried

134 over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to afford α-carbomethoxylactone 150

1 (879 mg, 81%) as a white crystalline solid: mp 110-112 ºC; H NMR (300 MHz, CDCl3) δ 7.22-

7.35 (m, 5H), 5.34 (d, J = 14.6 Hz, 1H), 4.50 (t, J = 8.6 Hz, 1H), 4.02 (t, J = 9.3 Hz, 1H), 3.87 (s,

3H), 3.77 (d, J = 10.1 Hz, 1H), 3.69 (d, J = 14.7 Hz, 1H), 3.15-3.20 (m, 2H), 3.02 (pentet, J = 8.4

13 Hz, 1H), 2.58-2.62 (m, 1H), 1.28-2.09 (m, 12H); C NMR (75 MHz, CDCl3) δ 174.9, 173.0,

168.9, 137.9, 129.0, 128.2, 127.8, 71.5, 53.6, 51.3, 50.8, 47.1, 45.9, 44.8, 41.1, 35.2, 26.2, 24.8,

-1 22.5, 20.5, 18.8; IR (neat) 1764, 1727, 1617, 1149 cm ; HRMS-ES+ (C23H30NO5) calcd 400.2124

(MH+), found 400.2118.

O H O O

H N Bn 151

2-Benzyl-7-(5-oxotetrahydrofuran-3-yl)-2-azaspiro[5.5]undecan-1-one (151). To a solution of α-carbomethoxylactone 150 (879 mg, 2.2 mmol) in DMSO (45 mL) and H2O (16 mL) was added LiCl (4.59 g, 110.0 mmol) and the reaction mixture was heated in an oil bath at 155-

160 °C for 24 h (additional water was added periodically to maintain the solvent). The mixture was cooled to rt, brine was added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give a yellowish oil that was purified by flash column chromatography on silica gel

(gradient 20% to 30% EtOAc/hexanes) to furnish butyrolactone 151 (676 mg, 90%) as a white

1 crystalline solid: mp 136-139 ºC; H NMR (400 MHz, CDCl3) δ 7.24-7.36 (m, 5H), 5.02 (d, J =

135

14.4 Hz, 1H), 4.41 (t, J = 7.3 Hz, 1H), 4.12 (d, J = 14.5 Hz, 1H), 3.94 (t, J = 8.8 Hz, 1H), 3.17-

3.24 (m, 2H), 2.42-2.53 (m, 3H), 2.18 (dd, J = 16.0, 6.7 Hz, 1H), 1.97 (dt, J = 13.8, 3.2 Hz, 1H),

13 1.11-1.89 (m, 11H); C NMR (100 MHz, CDCl3) δ 177.7, 175.4, 137.4, 129.1, 128.6, 127.9, 73.2,

51.3, 47.7, 45.7, 44.5, 39.5, 35.5, 33.3, 30.1, 25.9, 23.6, 20.7, 19.5; IR (neat) 1765, 1609, 1188 cm-

1 + ; HRMS-ES+ (C21H28NO3) calcd 342.2069 (MH ), found 342.2068.

O H OH O

H N Bn 152

2-Benzyl-7-(5-hydroxytetrahydrofuran-3-yl)-2-azaspiro[5.5]undecan-1-one (152). To a stirred solution of butyrolactone 151 (97 mg, 0.28 mmol) in dry THF (10 mL) at -78 °C was added dropwise DIBAL-H (1 M in THF, 2.8 mmol, 2.8 mL) over 20 min. The reaction was quenched with MeOH at -78 °C, warmed to rt and an equal volume of CH2Cl2 and saturated aqueous potassium sodium tartrate solution were added. The mixture was stirred for 1 h, and was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% Et2O/CH2Cl2) to afford the lactol 152 (80 mg, 83%)

1 as a ~4:1 mixture of C9-diastereomers: H NMR (400 MHz, CDCl3) δ (mixture) 7.23-7.33 (m,

5H), 5.35-5.38 (m, 1H), 4.88-4.93 (m, 1H), 3.95-4.31 (m, 1H), 3.71-3.94 (m, 1H), 3.47-3.55 (m,

13 1H), 3.21-3.32 (m, 2H), 2.30-2.52 (m, 3H), 1.18-2.03 (m, 14H); C NMR (75 MHz, CDCl3) δ

(major) 176.0, 137.8, 128.9, 128.7, 127.7, 99.2, 73.2, 51.4, 47.8, 46.1, 44.8, 39.7, 37.9, 35.6, 27.4,

26.3, 23.5, 21.0, 19.6; (minor) 176.9, 137.4, 129.0, 128.7, 127.9, 99.5, 71.3, 51.4, 47.7, 44.2, 42.2,

136

+ 39.7, 38.1, 35.6, 30.1, 27.3, 23.5, 20.9, 19.4; HRMS-ES+ (C21H30NO3) calcd 344.2226 (MH ), found 344.2236.

OH H O

H N Bn 153

2-Benzyl-7-(1-hydroxypent-4-en-2-yl)-2-azaspiro[5.5]undecan-1-one (153). To a stirred suspension of MePPh3Br (recrystallized from THF/CH2Cl2, 1.22 g, 3.18 mmol) in dry THF

(15 mL) at 0 °C was added n-butyllithium (1.6 M in hexanes, 2.1 mL, 3.2 mmol) and the resulting yellow orange solution was stirred for 30 min at 0 °C. A solution of lactol 152 (218 mg, 0.64 mmol) in dry THF (13 mL) was added dropwise over ca. 5 min and the mixture was slowly warmed to rt over 12 h. The mixture was diluted with saturated NH4Cl (aq) then extracted with EtOAc (3 x

50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to furnish terminal olefin 153 (169 mg, 77%) as a clear gum: 1H NMR

(400 MHz, CDCl3) δ 7.24-7.33 (m, 5H), 5.81-5.92 (m, 1H), 4.98-5.10 (m, 2H), 4.68 (d, J = 14.5

Hz, 1H), 4.47 (d, J = 14.5 Hz, 1H), 3.51-3.59 (m, 2H), 3.16-3.28 (m, 2H), 2.42 (dt, J = 9.7, 3.2 Hz,

1H), 2.24-2.28 (m, 1H), 2.10-2.13 (m, 1H), 1.87-1.96 (m, 1H), 1.19-1.86 (m, 13H); 13C NMR (75

MHz, CDCl3) δ 176.4, 138.5, 137.9, 128.8, 128.5, 127.7, 116.4, 64.0, 51.4, 47.8, 47.4, 44.2, 43.8,

+ 37.4, 35.8, 26.9, 24.5, 24.2, 21.2, 19.6; HRMS-ES+ (C22H32NO2) calcd 342.2433 (MH ), found

342.2431.

137

OMOM H O

H N Bn 154

2-Benzyl-7-(1-methoxymethoxy)pent-4-en-2-yl)-2-azaspiro[5.5]undecan-1-one (154).

To a stirred solution of terminal olefin alcohol 153 (181 mg, 0.53 mmol) in dry CH2Cl2 (20 mL) at 0 °C was added DIEA (0.41 mL, 2.65 mmol) and MOMCl (0.14 mL, 1.59 mmol). The mixture was stirred for 28 h at rt, then diluted with 1 M NaHCO3 (aq). The mixture was extracted with

CH2Cl2 (3 x 50 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (10% EtOAc/hexanes) to furnish MOM ether 154 (189 mg, 93%) as

1 a clear oil: H NMR (300 MHz, CDCl3) δ 7.24-7.31 (m, 5H), 5.81-5.95 (m, 1H), 5.01-5.11 (m,

2H), 4.67 (d, J = 14.5 Hz, 1H), 4.56 (s, 2H), 4.49 (d, J = 14.5 Hz, 1H), 3.57 (dd, J = 9.8, 4.0 Hz,

1H), 3.31-3.39 (m, 4H), 3.13-3.24 (m, 1H), 2.42 (dt, J = 12.8, 3.0 Hz, 1H), 2.21-2.28 (m, 1H),

13 1.84-1.96 (m, 1H), 1.16-1.83 (m, 14H); C NMR (75 MHz, CDCl3) δ 175.7, 138.2, 137.4, 128.9,

128.5, 127.5, 116.4, 96.9, 69.0, 55.6, 51.3, 47.9, 47.8, 44.3, 40.3, 38.1, 35.5, 26.8, 24.2, 23.3, 21.2,

+ 19.7; HRMS-ES+ (C24H36NO3) calcd 386.2695 (MH ), found 386.2687.

OMOM H O

H N H 155

7-(1-(Methoxymethoxy)pent-4-en-2-yl)-2-azaspiro[5.5]undecan-1-one (155). Liquid ammonia (ca. 25 mL) was condensed at -78 °C and Na metal (113 mg, 4.91 mmol) was added until

138 the reaction had developed a deep purple coloration. A solution of MOM ether 154 (189.4 mg,

0.491 mmol) in dry Et2O (10 mL) was added dropwise and the mixture was stirred for 1 h. Solid

NH4Cl was added and the mixture was warmed to rt. Brine was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (gradient 50% to 75% Et2O/CH2Cl2) to provide N-H lactam

1 155 (127 mg, 88%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 5.81-5.95 (m, 2H),

5.01-5.11 (m, 2H), 4.59-4.63 (m, 2H), 3.60 (dd, J = 9.8, 3.9 Hz, 1H), 3.27-3.41 (m, 6H), 2.23-2.34

13 (m, 3H), 1.11-2.01 (m, 13H); C NMR (75 MHz, CDCl3) δ 178.0, 137.3, 116.5, 97.1, 69.0, 55.7,

43.9, 42.8, 40.3, 38.1, 35.3, 30.1, 26.7, 24.0, 23.0, 21.1, 19.7; HRMS-ES+ (C17H30NO3) calcd

296.2226 (MH+), found 296.2238.

OMOM H O

H N Ts 156

7-(1-Methoxymethoxy)pent-4-en-2-yl)-2-tosyl-2-azaspiro[5.5]undecan-1-one (156).

To a stirred solution of N-H lactam 155 (127 mg, 0.43 mmol) in dry THF (15 mL) at 0 °C was added LiHMDS (1 M in THF, 1.3 mL, 1.3 mmol) and the mixture was stirred for 1 h at that temperature. TsCl (278 mg, 1.3 mmol) was added and the reaction mixture was stirred for 20 h at rt. 1 M NaHCO3 (aq) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20%

139

EtOAc/hexanes) to furnish N-tosyllactam 156 (170 mg, 88%) as a white solid: 1H NMR (300 MHz,

CDCl3) δ 7.89 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 4.2 Hz, 2H), 5.35-5.48 (m, 1H), 4.82-4.92 (m, 2H),

4.52-4.54 (m, 2H), 4.16-4.21 (m, 1H), 3.59-3.68 (m, 1H), 3.43 (dd, J = 9.9, 4.4 Hz, 1H), 3.24-3.35

(m, 4H), 2.43 (s, 3H), 2.12 (dt, J = 9.8, 3.2 Hz, 1H), 1.05-1.93 (m, 15H); 13C NMR (75 MHz,

CDCl3) δ 176.5, 144.9, 136.8, 136.7, 129.6, 129.1, 116.5, 97.0, 68.5, 55.7, 50.3, 47.5, 44.6, 40.3,

37.5, 35.7, 26.4, 23.8, 23.4, 22.0, 21.0, 20.5; HRMS-ES+ (C24H39N2O5S) calcd 467.2580

+ (MNH4 ), found 267.2585.

OMOM H

N Ts 157

7-((Methoxymethoxy)methyl)-4-tosyl-2,3,4,6,7,7a,8,9,10,11-decahydro-1H- benzo[e]quinoline (157). TiCl4 (0.37 mL, 3.3 mmol) was dissolved in dry CH2Cl2 (6 mL) at 0 °C followed by the addition of dry THF (1.7 mL, 19.3 mmol) and TMEDA (2.8 mL, 19.3 mmol). The reaction mixture was stirred for 20 min at rt, followed by the addition of activated Zn dust (washed with 1 N HCl (aq), acetone, then dried in vacuo at 100 ºC for 24 h) (468 mg, 7.2 mmol) and PbCl2

(104 mg, 0.38 mmol). The mixture was stirred for 5 min at rt and a solution of N-tosyllactam 156

(45 mg, 0.1 mmol) and Br2CHCH3 (0.41 mL, 4.5 mmol) in dry CH2Cl2 (3 mL) was added dropwise.

The reaction mixture was heated at 55 °C for 30 min, and cooled to 0 °C, treated with saturated

K2CO3 (aq) (0.8 mL) and stirred for 30 min. The resulting yellowish mixture was filtered through a sintered glass frit that was washed with CH2Cl2. The combined filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (15% EtOAc/hexanes) to afford

140

1 enesulfonamide 157 (23 mg, 55%) as a white solid: H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 8.3

Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.56 (dd, J = 5.9, 2.7 Hz, 1H), 4.60 (s, 2H), 4.00 (dd, J = 11.6,

4.1 Hz, 1H), 3.35-3.58 (m, 6H), 2.96 (td, J = 4.2, 3.5 Hz, 1H), 2.11-2.20 (m, 1H), 1.20-2.10 (m,

13 17H); C NMR (213 MHz, CDCl3) δ 144.6, 142.8, 138.8, 129.5, 127.2, 120.1, 96.7, 69.9, 65.9,

55.3, 50.2, 46.7, 39.4, 32.5, 32.2, 29.8, 29.7, 28.0, 26.3, 22.3, 21.5, 20.6, 20.6; HRMS-ES+

+ (C23H34NO4S) calcd 420.2209 (MH ), found 420.2217.

OMOM H O

H N SES 160

7-(1-Methoxymethoxy)pent-4-en-2-yl)-2-((2-trimethylsilyl)ethyl)sulfonyl-2- azaspiro[5.5]undecan-1-one (160). To a stirred solution of N-H lactam 155 (45 mg, 0.15 mmol) in dry THF (5 mL) at 0 °C was added LiHMDS (1 M in THF, 0.45 mL, 0.45 mmol) and the mixture was stirred for 1 h at that temperature. SES-Cl (0.087 mL, 0.45 mmol) was added and the reaction mixture was stirred for 24 h at rt. 1 M NaHCO3 (aq) was added and the mixture was extracted with

EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous

MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to furnish N-sulfonyllactam 160 as a clear

1 colorless gum (55 mg, 78%): H NMR (300 MHz, CDCl3) δ 5.73-5.87 (m, 1H), 5.01-5.07 (m, 2H),

4.57 (s, 2H), 3.94-3.97 (m, 1H), 3.46-3.57 (m, 3H), 3.35-3.40 (m, 4H), 2.13-2.33 (m, 3H), 0.88-

13 1.97 (m, 19H), 0.04 (s, 9H); C NMR (75 MHz, CDCl3) δ 178.1, 136.8, 131.7, 127.9, 117.0, 97.1,

141

68.6, 55.7, 51.4, 50.6, 47.5, 44.2, 40.7, 37.9, 36.2, 26.4, 26.4, 24.1, 23.2, 21.1, 20.5, -1.6; HRMS-

+ ES+ (C22H45N2O5SSi) calcd 477.2818 (MNH4 ), found 477.2849.

OMOM H

N SES 161

7-((Methoxymethoxy)methyl)-4-(2-trimethylsilyl)ethyl)sulfonyl)-

2,3,4,6,7,7a,8,9,10,11-decahydro-1H-benzo[e]quinoline (161). TiCl4 (0.37 mL, 3.3 mmol) was dissolved in dry CH2Cl2 (4 mL) at 0 °C followed by the addition of dry THF (1.7 mL, 19.3 mmol) and TMEDA (2.7 mL, 19.3 mmol). The reaction mixture was stirred for 20 min at rt, followed by

the addition of activated Zn dust (washed with 1 N HCl (aq), acetone, then dried in vacuo at 100 ºC for 24 h) (468 mg, 7.2 mmol) and PbCl2 (104 mg, 0.38 mmol). The mixture was stirred for 5 min at rt, and a solution of N-sulfonyllactam 160 (43 mg, 0.1 mmol) and Br2CHCH3 (0.41 mL, 4.5 mmol) in dry CH2Cl2 (2 mL) was added dropwise. The reaction mixture was heated at 55 °C for

30 min, cooled to 0 °C, then treated with saturated K2CO3 (aq) (0.5 mL) and stirred for 30 min. The resulting yellowish mixture was filtered through a sintered glass frit that was washed with CH2Cl2.

The combined filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (15% EtOAc/hexanes) to afford enesulfonamide 161 (33 mg, 83%) as a clear gum: 1H NMR

(300 MHz, CDCl3) δ 5.72 (dd, J = 6.3, 2.0 Hz, 1H), 4.61 (s, 2H), 3.96 (dd, J = 11.9, 4.5 Hz, 1H),

3.55 (dd, J = 9.4, 4.1 Hz, 1H), 3.36-3.40 (m, 4H), 2.95-3.07 (m, 3H), 0.79-2.29 (m, 18H), 0.06 (s,

13 9H); C NMR (75 MHz, CDCl3) δ 145.2, 121.6, 97.1, 70.2, 55.7, 51.0, 50.2, 47.2, 33.0, 32.8,

142

30.3, 30.1, 28.5, 26.7, 22.7, 21.1, 20.9, 10.9, -1.56; HRMS-ES+ (C21H40NO4SSi) calcd 430.2447

(MH+), found 430.2453.

H O CN

H OH N Bn

176

2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-4-hydroxyhex-5-enenitrile (176). To a stirred solution of aldehyde 145 (50 mg, 0.14 mmol) in dry THF (5 mL) at rt was added vinylmagnesium bromide (1 M in THF, 0.56 mL, 0.56 mmol) and the reaction mixture was stirred for 15 min then quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x

25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (25% EtOAc/hexanes) to afford allylic alcohol 176 as a separable ~4:1 mixture of

1 diastereomers (23 mg total, 45%): H NMR (300 MHz, CDCl3) δ (major) 7.23-7.35 (m, 5H), 5.81-

5.94 (m, 1H), 5.33 (dt, J = 17.2, 1.3 Hz, 1H), 5.14 (dt, J = 11.7, 1.4 Hz, 1H), 4.63 (d, J =14.4 Hz,

1H), 4.49 (d, J = 14.5 Hz, 1H), 4.17 (br s, 1H), 3.21-3.36 (m, 2H), 2.52-2.68 (m, 2H), 1.95-2.13

(m, 1H), 1.27-1.94 (m, 14H); (minor) δ 7.23-7.35 (m, 5H), 5.81-5.94 (m, 1H), 5.35 (dt, J = 17.2,

1.4 Hz, 1H), 5.15 (dt, J = 13.7, 1.4 Hz, 1H), 4.88 (d, J = 14.4 Hz, 1H), 4.28 (d, J = 14.5 Hz, 1H),

4.05 (br. s, 1H), 3.21-3.36 (m, 2H), 2.52-2.68 (m, 2H), 1.95-2.13 (m, 1H), 1.27-1.94 (m, 14H); 13C

NMR (75 MHz, CDCl3) (major) δ 175.6, 140.5, 137.5, 129.1, 128.4, 127.9, 122.2, 115.4, 71.5,

51.5, 47.7, 47.6, 43.7, 40.2, 34.7, 31.9, 26.0, 23.9, 23.2, 20.7, 19.0; (minor) δ 176.5, 139.7, 137.0,

129.2, 128.3, 128.0, 122.6, 115.5, 68.3, 51.4, 47.6, 47.5, 40.4, 38.9, 30.1, 29.9, 26.1, 23.4, 23.0,

20.7, 18.7.

143

H O CN

H OAc N Bn

177

Acetic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-1-vinylpropyl

Ester (177). To a stirred solution of allylic alcohol diastereomeric mixture 176 (17 mg, 0.046 mmol) in dry CH2Cl2 (1.5 mL) at rt was added acetic anhydride (0.013 mL, 0.14 mmol), Et3N

(0.0195 mL, 0.14 mmol), and DMAP (ca. 0.5 mg, cat.). The reaction mixture was stirred at rt for

2 h then diluted with brine. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined organic fractions were dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (15% EtOAc/hexanes) to afford allyl acetates 177 (13.8 mg, 73%) as an inseparable ~4:1 diastereomeric mixture: 1H NMR (300 MHz,

CDCl3) δ 7.22-7.36 (m, 5H), 5.74-5.92 (m, 1H), 5.23-5.43 (m, 3H), 4.41-4.78 (m, 2H), 4.00-4.02

(m, 1H), 3.18-3.33 (m, 2H), 2.25-2.48 (m, 2H), 1.28-2.08 (m, 16H).

H O CN

H OMs N Bn

178

Methanesulfonic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-1- vinylpropyl Ester (178). To a stirred solution allylic alcohol diastereomeric mixture 176 (69 mg,

0.15 mmol) in dry CH2Cl2 (2.5 mL) at rt was added methanesulfonyl chloride (0.024 mL, 0.17 mmol) and Et3N (0.038 mL, 0.29 mmol). The reaction mixture was stirred for 3 h then brine was

144 added. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (25% EtOAc/hexanes) to furnish allylic mesylate 178 (30

1 mg, 47%) as an inseparable ~4:1 diastereomeric mixture: H NMR (300 MHz, CDCl3) δ 7.19-

7.35 (m, 5H), 5.78-5.92 (m, 1H), 5.17-5.60 (m, 3H), 4.30-4.89 (m, 2H), 2.08-3.20 (m, 6H), 2.15-

2.54 (m, 3H), 1.23-2.04 (m, 12H).

OH H O O H N N Bn Me OMe

180

3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-4-hydroxy-N-methoxy-N- methylbutanamide (180). To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride

(2.57 g, 29.7 mmol) in dry CH2Cl2 (25 mL) at 0 °C was added dropwise dimethylaluminum chloride (0.9 M in heptane, 33.0 mL, 29.7 mmol) and the resulting mixture was stirred for 2 h at rt. A solution of butyrolactone 151 (676 mg, 2.0 mmol) in dry CH2Cl2 (10 mL) was added dropwise and the reaction mixture was stirred for 24 h at rt. The mixture was diluted with an equal volume of saturated aqueous potassium sodium tartrate solution and the resulting biphasic mixture was stirred for 1 h at rt. The aqueous layer was extracted with CH2Cl2 (3 x 100 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo.

The crude product was purified via flash column chromatography on silica gel (gradient 50% to

1 100% Et2O/CH2Cl2) to afford amide alcohol 180 (681 mg, 86%) as an off-white fluffy solid: H

NMR (300 MHz, CDCl3) δ 7.15-7.39 (m, 5H), 4.78 (d, J = 14.6 Hz, 1H), 4.38 (d, J = 14.6 Hz,

145

1H), 4.10 (br s, 1H), 3.70-3.74 (m, 4H), 3.47-3.54 (m, 1H), 3.15-3.29 (m, 5H), 1.28-2.81 (m, 16H);

13 C NMR (75 MHz, CDCl3) δ 176.0, 175.4, 138.0, 129.1, 128.2, 127.6, 65.4, 61.8, 51.2, 47.9, 47.7,

46.2, 40.3, 35.4, 32.6, 26.9, 23.6, 23.3, 21.2, 20.7, 19.5; HRMS-ES+ (C23H35N2O4) calcd 403.2597

(MH+), found 403.2600.

OMOM H O O H N N Bn Me OMe

181

3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-N-methoxy-4-(methoxymethoxy)-N- methylbutanamide (181). To a stirred solution of amide alcohol 180 (681 mg, 1.7 mmol) in dry

CH2Cl2 (20 mL) at 0 °C was added MOMCl (0.75 mL, 8.5 mmol) and DIEA (2.62 mL, 16.9 mmol).

The reaction mixture was stirred for 24 h at rt, then diluted with saturated NaHCO3 (aq), and extracted with EtOAc (3 x 100 mL). The combined extract washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting crude oil was purified via flash column chromatography on silica gel (gradient 20% to 100% Et2O/CH2Cl2) to afford MOM ether 181 (596

1 mg, 80%) as a light yellow gum: H NMR (300 MHz, CDCl3) δ 7.19-7.29 (m, 5H), 4.85 (d, J =

14.6 Hz, 1H), 4.51 (s, 2H), 4.20 (d, J = 14.6 Hz, 1H), 3.64 (s, 3H), 3.56 (dd, J = 15.9, 5.6 Hz, 1H),

3.44-3.50 (m, 1H), 3.29 (s, 3H), 3.07-3.20 (m, 5H), 2.59-2.78 (m, 1H), 2.31-2.42 (m, 2H), 1.10-

13 2.06 (m, 13H); C NMR (75 MHz, CDCl3) δ 175.9, 138.1, 128.9, 128.3, 127.5, 97.0, 69.1, 61.6,

55.7, 50.9, 47.4, 44.6, 37.3, 35.9, 35.5, 32.7, 30.7, 26.8, 23.7, 23.6, 21.1, 19.5; HRMS-ES+

+ (C25H39N2O5) calcd 447.2859 (MH ), found 447.2870.

146

OMOM H O CHO H N Bn

182

3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-4-(methoxymethoxy)butanal (182).

To a stirred solution of MOM ether 181 (596 mg, 1.3 mmol) in dry THF (50 mL) at -40 °C was added lithium aluminum hydride (169 mg, 5.4 mmol) in one portion and the resulting suspension was stirred for 1 h at that temperature. Methanol was added carefully followed by 1 N NaOH (aq), the mixture was warmed to rt and further diluted with brine. The reaction mixture was extracted with Et2O (3 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford aldehyde 182 as a clear colorless gum that

1 was used in the next step without further purification: H NMR (300 MHz, CDCl3) δ 9.57 (dd, J =

3.4, 1.8 Hz, 1H), 7.22-7.33 (m, 5H), 4.63 (d, J = 14.4 Hz, 1H), 4.43-4.54 (m, 3H), 3.64 (dd, J =

9.7, 3.8 Hz, 1H), 3.21-3.33 (m, 6H), 2.42-2.49 (m, 2H), 2.32-2.37 (m, 1H), 1.08-2.01 (m, 13H);

13 C NMR (75 MHz, CDCl3) δ 203.2, 175.6, 137.9, 128.9, 128.5, 127.7, 96.8, 69.7, 55.8, 51.4, 49.1,

47.8, 45.0, 36.7, 35.3, 30.7, 26.7, 23.9, 23.1, 21.0, 19.4; HRMS-ES+ (C23H34NO4) calcd 388.2488

(MH+), found 388.2490.

147

OMOM H O

H OH N Bn

183

2-Benzyl-7-(3-hydroxy-1-methoxymethoxymethylpent-4-enyl)-2- azaspiro[5.5]undecan-1-one (183). To a stirred solution of aldehyde 182 (85 mg, 0.22 mmol) in dry THF (5 mL) at rt was added vinylmagnesium bromide (1 M in THF, 1,1 mL, 1.1 mmol) and the reaction mixture was stirred for 5 min then quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to afford allylic alcohol 183 as a

1 separable ~10:1 mixture of diastereomers (57 mg total, 58%): H NMR (300 MHz, CDCl3) (major)

δ 7.23-7.52 (m, 5H), 5.90 (ddd, J = 17.1, 9.4, 4.6 Hz, 1H), 5.24-5.34 (m, 2H), 5.04 (dt, J = 10.5,

1.7 Hz, 1H), 4.77 (d, J = 14.5 Hz, 1H), 4.55-4.59 (m, 2H), 4.42 (d, J = 14.5 Hz, 1H), 4.19 (br s,

1H), 3.67 (dd, J = 9.5, 2.3 Hz, 1H), 3.31 (s, 3H), 3.16-3.28 (m, 3H), 2.62 (dd, J = 13.1, 2.9 Hz,

13 1H), 1.95-2.03 (m, 1H), 1.06-1.87 (m, 14H); C NMR (75 MHz, CDCl3) (major) δ 177.1, 142.1,

137.7, 129.0, 128.4, 127.7, 113.3, 96.9, 73.4, 70.8, 55.7, 51.4, 48.4, 47.8, 44.4, 41.5, 40.3, 35.6,

26.8, 24.3, 21.9, 21.1, 19.2.

148

OMOM H O

H OH N Bn

184

Acetic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-4-methoxymethoxy-1- vinylbutyl Ester (184). To a stirred solution of the major diastereomer of allylic alcohol 183 (10.0 mg, 0.024 mmol) in dry CH2Cl2 (0.5 mL) at rt was added acetic anhydride (0.004 mL, 0.036 mmol),

Et3N (0.015 mL, 0.12 mmol), and DMAP (ca. 0.5 mg, catalytic amount). The reaction mixture was stirred at rt for 12 h, then diluted with brine. The mixture was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo.

The crude residue was purified by flash column chromatography on silica gel (15%

EtOAc/hexanes) to afford allyl acetate 184 (10.2 mg, 91%) as a clear gum: 1H NMR (300 MHz,

CDCl3) δ 7.22-7.32 (m, 5H), 5.78 (ddd, J = 16.8, 12.9, 6.7 Hz, 1H), 5.45 (q, J = 6.5 Hz, 1H), 5.30

(d, J = 17.2 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 4.95 (d, J = 14.6 Hz, 1H), 4.58 (s, 2H), 4.20 (d, J

= 14.5 Hz, 1H), 3.63 (dd, J = 10.0, 3.5 Hz, 1H), 3.33 (s, 3H), 3.03-3.30 (m, 2H), 2.43 (dt, J = 10.1,

3.0 Hz, 1H), 2.05 (s, 1H), 1.09-2.04 (m, 18H).

OMOM H O SiMe3 H N Bn 187

2-Benzyl-7-(E/Z)-1-(methoxymethoxy)-6-(trimethylsilyl)hex-4-en-2-yl)-2- azaspiro[5.5]undecan-1-one (187). To a stirred solution of 2- trimethylsilylethyltriphenylphosphonium iodide (2.66 g, 5.4 mmol) in dry THF (35 mL) at rt was

149 added dropwise PhLi (1.8 M in dibutyl ether, 3.05 mL, 5.5 mmol). The resulting deep crimson solution was stirred at rt for 5 min, then a solution of aldehyde 182 (519 mg, 1.3 mmol) in dry

THF (5 mL) was added dropwise. The reaction mixture was stirred for 12 h at rt and diluted with saturated NH4Cl (aq). The mixture was extracted with Et2O (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 8% to 10%

EtOAC/hexanes) to afford allylsilane 187 (470 mg, 74%) as an inseparable ~2.2:1 mixture of E/Z-

1 olefin isomers: H NMR (300 MHz, CDCl3) δ 7.21-7.35 (m, 5H), 5.25-5.54 (m, 2H), 4.79 (d, J =

14.5 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.56 (s, 2H), 4.48 (d, J = 14.4 Hz, 1H), 4.38 (d, J = 14.5

Hz, 1H), 3.58 (dd, J = 9.8, 4.1 Hz, 1H), 3.48-3.52 (m, 1H), 3.32-3.38 (m, 4H), 3.10-3.27 (m, 2H),

2.41 (dt, J = 12.8, 2.4 Hz, 1H), 2.05-2.28 (m, 2H), 1.11-1.97 (m, 16H), 0.01 (s, 9H), 0.001 (s, 9H);

13 C NMR (75 MHz, CDCl3) δ 175.9, 175.8, 138.3, 138.2, 129.7, 128.9, 128.9, 128.6, 128.5, 128.3,

127.5, 126.9, 126.7, 126.0, 119.8, 115.9, 55.6, 55.6, 51.3, 51.2, 48.0, 47.9, 47.8, 47.7, 44.7, 44.6,

40.8, 40.6, 36.8, 35.6, 35.4, 30.8, 29.8, 26.9, 26.8, 24.3, 24.1, 23.6, 23.3, 23.3, 21.3, 21.2, 19.8,

+ 19.7, 18.9, -1.3, -1.4; HRMS-ES+ (C28H46NO3Si) calcd 472.3247 (MH ), found 472.3272.

H O OMOM

SiMe3 N Ts

189

7-(E/Z)-1-(Methoxymethoxy)-6-(trimethylsilyl)hex-4-en-2-yl)-2-tosyl-2- azaspiro[5.5]undecan-1-one (189). Anhydrous ammonia (15 mL) was condensed into a flask at

-78 °C and Na metal (158 mg, 6.9 mmol) was added portionwise until the mixture had developed

150 a dark blue color. A solution of N-Bn lactam/allylsilane E/Z mixture 187 (324 mg, 0.69 mmol) in anhydrous Et2O (15 mL) was added dropwise and the reaction mixture was stirred at -78 °C. When the reaction was determined to be complete via TLC (about 2 h), solid NH4Cl was added in one portion and the mixture was warmed to rt. Additional Et2O and brine were added, and the layers were separated. The aqueous layer was extracted with Et2O (3 x 50 mL), the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (10% Et2O/CH2Cl2) to afford unstable

N-H lactam 188 (inseparable mixture of E/Z-olefin geometric isomers) (207 mg, 79%) as a clear

1 colorless gum: H NMR (300 MHz, CDCl3) δ 5.84 (br s, 1H), 5.34-5.50 (m, 2H), 4.60 (s, 2H), 3.59

(dd, J = 9.7, 3.9 Hz, 1H), 3.28-3.41 (m, 5H), 2.14-2.32 (m, 3H), 0.87-1.97 (m, 16H), 0.00 (s, 9H),

-0.002 (s, 9H).

To a stirred solution of N-H lactam 188 (207 mg, 0.54 mmol) in dry THF (30 mL) at 0 °C was added dropwise LiHMDS (1 M in THF, 1.63 mL, 1.6 mmol) and the mixture was stirred for

30 min at that temperature. TsCl (509 mg, 2.7 mmol) and DMAP (20 mg, 0.16 mmol) were added and the reaction mixture was stirred for 11 h at rt. The mixture was then diluted with saturated

NaHCO3 (aq) and extracted with Et2O (3 x 50 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 10% to 20% EtOAc/hexanes) to afford N- tosyllactam 189 (inseparable mixture of E/Z-olefin geometric isomers) (251 mg, 87%) as a clear

1 colorless gum: H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 10.4 Hz, 2H), 7.30 (d, J = 12.7 Hz, 2H),

5.15-5.40 (m, 1H), 4.80-4.98 (m, 1H), 4.52-4.61 (m, 2H), 4.13-4.19 (m, 1H), 3.62-3.72 (m, 1H),

3.45 (dd, J = 9.9, 4.7 Hz, 1H), 3.33-3.38 (m, 3H), 3.24 (dd, J = 8.4, 7.1 Hz, 1H), 2.37 (s, 3H),

13 1.93-2.11 (m, 1H), 0.75-1.94 (m, 16H), -0.02 (s, 9H), -0.03 (s, 9H); C NMR (75 MHz, CDCl3) δ

151

176.6, 176.5, 144.7, 144.6, 136.9, 136.7, 131.9, 130.8, 129.5, 129.0, 129.0, 128.6, 127.0, 126.2,

125.3, 96.9, 96.9, 68.8, 68.3, 55.7, 55.7, 50.6, 50.2, 47.5, 47.5, 45.1, 44.6, 40.7, 40.6, 36.2, 35.6,

35.6, 30.7, 30.5, 30.1, 29.6, 26.5, 26.4, 24.0, 23.7, 23.2, 23.1, 22.1, 22.0, 21.1, 21.1, 20.6, 20.5,

+ 18.7, -1.4, -1.5; HRMS-ES+ (C28H46NO5SiS) calcd 536.2866 (MH ), found 536.2877.

H H OMOM

N Ts H 191

9-((Methoxymethoxy)methyl)-1-tosyl-11-vinyldodecahydro-1H-benzo[e]quinoline

(191). To a stirred solution of N-tosyllactam 189 (50 mg, 0.095 mmol) in dry CH2Cl2 (20 mL) at -

78 °C was added dropwise DIBAL-H (1 M in PhMe, 1.4 mL, 1.4 mmol). The reaction mixture was stirred for 45 min, then anhydrous FeCl3 (150 mg, 0.95 mmol) was added in one portion and the mixture was warmed to 5 ºC over 1.5 h (formation of a slightly turbid green solution indicated that the reaction had gone to completion). An equal volume of saturated aqueous potassium sodium tartrate solution was added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous layer was extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (8:1:1 hexanes/CH2Cl2/Et2O) to afford tricycle 191

1 (33 mg, 78%) as a clear colorless gum: H NMR (850 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H),

7.23 (d, J = 8.1 Hz, 2H), 5.50-5.55 (m, 1H), 4.86 (dd, J = 17.0, 1.1 Hz, 1H), 4.63 (dd, J = 10.1, 1.6

Hz, 1H), 4.60 (d, J = 6.5 Hz, 1H), 4.58 (d, J = 6.5 Hz, 1H), 3.60 (dd, J = 13.8, 5.3 Hz, 1H), 3.48-

3.50 (m, 2H), 3.35-3.38 (m, 4H), 2.91 (td, J = 13.5, 3.4 Hz, 1H), 2.75-2.79 (m, 1H), 2.42-2.47 (m,

152

1H), 2.41 (s, 3H), 2.18 (br d, J = 13.9 Hz, 1H), 1.85 (dt, J = 13.2, 3.7 Hz, 1H), 1.74 (br d, J = 13.9

Hz, 2H), 1.66-1.70 (m, 2H), 1.54-1.61 (m, 5H), 1.49 (br d, J = 13.3 Hz, 1H), 1.41 (br d, J = 13.9

Hz, 1H), 1.22- 1.33 (m, 7H), 1.14 (ddd, J = 25.6, 12.9, 3.9 Hz, 1H), 0.97 (td, J = 13.3, 3.0 Hz, 1H);

13 C NMR (75 MHz, CDCl3) δ 142.7, 141.6, 139.4, 129.4, 127.3, 115.2, 97.0, 70.6, 66.4, 55.6, 47.8,

40.5, 39.9, 37.5, 36.9, 35.7, 34.4, 26.7, 23.5, 21.9, 21.1, 20.3, 20.1; HRMS-ES+ (C25H38NO4S) calcd 448.2522 (MH+), found 448.2536.

H H OMOM

OH N TsH 192

9-((Methoxymethoxy)methyl)-1-tosyldodecahydro-1H-benzo[e]quinolin-11- yl)methanol (192). Ozone gas was bubbled through a stirred solution of tricyclic alkene 191 (33 mg, 0.074 mmol) in dry CH2Cl2 (10 mL) at -78 °C for 5 min until a blue color was observed. PPh3

(58 mg, 0.22 mmol) was added to the reaction mixture which was subsequently warmed to rt over

10 h. The mixture was diluted with MeOH (4 mL), cooled to 0 °C, and NaBH4 (20 mg, 0.53 mmol) was added in one portion. The reaction mixture was stirred for 5 min then diluted with an equal volume of saturated NH4Cl (aq) solution causing two layers to form. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to afford tricyclic

1 alcohol 192 (30 mg, 91%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.3

Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 4.60 (q, J = 6.6 Hz, 2H), 3.90 (dd, J =12.1, 2.8 Hz, 1H), 3.70

153

(br d, J = 14.4 Hz, 1H), 3.34-3.52 (m, 7H), 2.98-3.12 (m, 1H), 2.44 (s, 3H), 2.15 (br t, J = 10.0

13 Hz, 1H), 1.91 (dd, J = 9.8, 3.9 Hz, 1H), 0.52-1.69 (m, 16H); C NMR (75 MHz, CDCl3) δ 143.4,

138.7, 129.9, 127.3, 97.1, 70.8, 63.4, 55.7, 47.8, 40.9, 37.6, 35.9, 35.8, 35.1, 32.9, 30.1, 26.5, 23.5,

+ 21.9, 21.0, 19.9, 19.9; HRMS-ES+ (C24H38NO5S) calcd 452.2471 (MH ), found 452.2445.

H H OH

OH N Ts H 194

[9-Hydroxymethyl-5-(toluene-4-sulfonyl)-5-azatricyclo[8.4.0.01,6]tetradec-7-yl]- methanol (194). To a stirred solution of MOM-ether 192 (5 mg, 0.011 mmol) in THF (0.5 mL) was added 6 N HCl (aq) (0.25 mL) and the mixture was heated at 50 ºC for 1.5 h and then cooled to rt. Saturated NaHCO3 (aq) was added and the mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (40% to

1 75% Et2O/CH2Cl2) to afford diol 194 as a clear gum (4.5 mg, 100%): H NMR (400 MHz, CDCl3)

δ 7.72 (d, J = 6.7 Hz, 2H), 7.28 (d, J = 7.1 Hz, 2H), 3.91 (dd, J =12.2, 2.7 Hz, 1H), 3.67-3.73 (m,

2H), 3.43-3.49 (m, 2H), 2.98-3.09 (m, 2H), 2.44 (s, 3H), 2.14-2.19 (m, 1H), 1.88 (dd, J = 9.8, 4.2

Hz, 1H), 1.12-1.75 (m, 16H), 0.66 (t, J = 12.9 Hz, 1H).

154

H O OMOM

SiMe3 N SES 196

7-(1-Methoxymethoxymethyl-5-trimethylsilanylpent-3-enyl)-2-(2-trimethylsilanylethanesulfonyl)-2-azaspiro[5.5]undecan-1-one (196). To a stirred solution of N-H lactam 188

(38 mg, 0.10 mmol) in dry THF (2 mL) at 0 °C was added dropwise LiHMDS (1 M in THF, 0.30 mL, 0.30 mmol) and the mixture was stirred for 30 min at that temperature. SESCl (0.100 mL,

0.50 mmol) was added and the reaction mixture was stirred for 12 h at rt. The mixture was then diluted with saturated NaHCO3 (aq) and extracted with Et2O (3 x 50 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 5% to 7%

EtOAc/hexanes) to afford N-SES lactam 196 (inseparable mixture of E/Z-olefin geometric

1 isomers) (40 mg, 73%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 5.04-5.54 (m, 2H),

4.59 (s, 2H), 3.95-3.98 (m, 1H), 3.37-3.63 (m, 5H), 3.37 (s, 3H), 0.96-2.34 (m, 20H), 0.07 (s, 9H),

13 0.01 (s, 9H); C NMR (75 MHz, CDCl3) δ 178.2, 178.0, 129.1, 127.6, 126.0, 125.2, 69.0, 68.4,

55.8, 51.4, 50.9, 50.6, 47.5, 44.6, 44.4, 41.3, 41.2, 36.9, 36.4, 36.1, 30.8, 30.7, 30.1, 26.6, 26.5,

24.3, 24.0, 23.6, 23.3, 23.1, 21.2, 20.6, 18.9, 10.5, -1.3, -1.4, -1.6.

H H OMOM

N SES

197 155

9-Methoxymethoxymethyl-5-(2-trimethylsilanylethanesulfonyl)-7-vinyl-5-azatricyclo[8.4.0.01,6]tetradecane (197). To a stirred solution of N-SES lactam 196 (10.0 mg, 0.018 mmol) in dry CH2Cl2 (4 mL) at -78 °C was added dropwise DIBAL-H (1 M in PhMe, 0.28 mL,

0.28 mmol). The reaction mixture was stirred for 45 min, then anhydrous FeCl3 (28 mg, 0.18 mmol) was added in one portion and the mixture was warmed to 5 ºC over 1.5 h (formation of a slightly turbid green solution indicated that the reaction had gone to completion). An equal volume of saturated aqueous potassium sodium tartrate solution was added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (8%

EtOAc/hexanes) to afford tricycle 197 (2.2 mg, 27%) as a clear colorless gum: 1H NMR (300

MHz, CDCl3) δ 5.64-5.76 (m, 1H), 5.13 (dd, J = 17.1, 1.3 Hz, 1H), 4.99 (dd, J = 11.8, 1.8 Hz, 1H),

4.62 (dd, J = 8.0, 1.5 Hz, 2H), 3.41-3.50 (m, 3H), 3.35-3.40 (m, 6H), 2.81-3.14 (m, 4H), 2.35-2.40

+ (m, 1H), 0.89-1.95 (m, 15H), 0.045 (s, 9H); HRMS-ES+ (C23H44NO4SSi) calcd 458.2760 (MH ), found 458.2810.

H O OMOM

SiMe3 N Ns 199

7-(1-Methoxymethoxymethyl-5-trimethylsilanylpent-3-enyl)-2-(4-nitrobenzenesulfonyl)-2-azaspiro[5.5]undecan-1-one (199). To a stirred solution of N-H lactam 188

156

(57 mg, 0.15 mmol) in dry THF (4 mL) at 0 °C was added dropwise LiHMDS (1 M in THF, 0.45 mL, 0.45 mmol) and the mixture was stirred for 30 min at that temperature. Solid 4- nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol) was added and the reaction mixture was stirred for 14 h at rt. The mixture was then diluted with saturated NaHCO3 (aq) and extracted with Et2O (3 x 20 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 10% to 40% EtOAc/hexanes) to afford N-Ns lactam 199 (mixture of E/Z-olefin

1 geometric isomers) (60 mg, 72%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 8.35 (d,

J = 9.2 Hz, 2H), 8.22 (d, J = 7.0 Hz, 2H), 5.19-5.39 (m, 1H), 4.77-4.86 (m, 1H), 4.54-4.56 (m,

2H), 4.18-4.26 (m, 1H), 3.60-3.75 (m, 1H), 3.23-3.49 (m, 5H), 1.09-1.99 (m, 21H), 0.0062 (s, 9H);

13 C NMR (75 MHz, CDCl3) (major) δ 177.1, 150.8, 145.5, 130.4, 127.6, 124.8, 124.2, 97.1, 68.8,

55.8, 50.8, 47.8, 45.1, 44.4, 41.2, 35.8, 30.6, 26.4, 23.8, 23.0, 21.0, 20.5, 18.9, -1.48.

H O OMOM

SiMe3 N pbf 202

7-(1-Methoxymethoxymethyl-5-trimethylsilanyl-pent-3-enyl)-2-(2,2,4,6,7- pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl)-2-aza-spiro[5.5]undecan-1-one (202). To a stirred solution of N-H lactam 188 (68 mg, 0.18 mmol) in dry THF (3 mL) at 0 °C was added

157 dropwise LiHMDS (1 M in THF, 0.34 mL, 0.34 mmol) and the mixture was stirred for 30 min at that temperature. Solid 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (97 mg,

0.34 mmol) and DMAP (6.3 mg, 0.05 mmol) were added and the reaction mixture was stirred for

14 h at rt. The mixture was then diluted with saturated NaHCO3 (aq) and extracted with Et2O (3 x

25 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 10% to 15% EtOAc/hexanes) to afford N-pbf lactam 202 (mixture of E/Z-olefin

1 geometric isomers) (62 mg, 63%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 5.22-

5.49 (m, 1H), 4.66-4.93 (m, 1H), 4.56-4.62 (m, 2H), 4.06-4.10 (m, 1H), 3.72-3.80 (m, 1H), 3.47-

3.61 (m, 1H), 3.38 (s, 3H), 3.20-3.27 (m, 1H), 3.01 (br s, 2H), 2.59 (d, J = 2.5 Hz, 3H), 2.50 (s,

13 3H), 2.11 (s, 3H), 0.83-2.10 (m, 24H), -0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 177.0, 176.9,

160.61, 160.58, 140.3, 140.2, 136.9, 136.6, 128.9, 128.72, 128.65, 128.2, 127.0, 125.9, 125.4,

125.3, 118.2, 118.1, 97.12, 97.10, 87.30, 87.28, 69.4, 69.0, 55.72, 55.69, 50.6, 50.5, 46.0, 45.9,

44.8, 44.7, 43.5, 40.5, 40.2, 35.2, 35.0. 34.8, 30.5, 30.2, 29.11, 29.06, 29.0, 26.5, 26.4, 24.1, 23.9,

23.4, 23.1, 22.9, 21.1, 21.0, 20.20, 20.17, 20.09, 19.61, 19.57, 18.8, 17.9, 17.8, 13.2, 12.8, 12.7, -

1.3, -1.4.

H O OMOM

SiMe3 N Cbz 204

7-(1-Methoxymethoxymethyl-5-trimethylsilanylpent-3-enyl)-1-oxo-2- azaspiro[5.5]undecane-2-carboxylic Acid Benzyl Ester (204). To a stirred solution of N-H

158 lactam 188 (57 mg, 0.15 mmol) in dry THF (4 mL) at -78 °C was added dropwise n-butyllithium

(1.6 M in hexanes, 0.11 mL, 0.18 mmol) and the mixture was stirred for 10 min at that temperature.

Benzyl chloroformate (0.10 mL, 0.75 mmol) was added and the reaction mixture was warmed to rt and stirred for 1 h. The mixture was then diluted with saturated NH4Cl (aq) and extracted with

Et2O (3 x 20 mL). The combined organic extract was washed with brine, dried over anhydrous

MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (gradient 15% to 25% EtOAc/hexanes) to afford N-Cbz lactam 204

(mixture of E/Z-olefin geometric isomers) (35 mg, 58%) as a clear colorless gum: 1H NMR (300

MHz, CDCl3) δ 7.35-7.54 (m, 5H), 5.29-5.41 (m, 1H), 5.21 (s, 2H), 4.78-4.90 (m, 1H), 4.53-4.55

(m, 2H), 4.12-4.23 (m, 1H), 3.63-3.79 (m, 1H), 3.33-3.49 (m, 6H), 1.14-2.15 (m, 20H), 0.003 (s,

9H).

H H OMOM

OMOM N Ts H

206

9,11-bis((Methoxymethoxy)methyl)-1-tosyldodecahydro-1H-benzo[e]quinoline (206).

To a stirred solution of alcohol 192 (24.3 mg, 0.053 mmol) in dry CH2Cl2 (2 mL) at 0 °C was added MOMCl (20 μL, 0.22 mmol) and DIEA (70 μL, 0.44 mmol). The reaction mixture was stirred overnight at rt then diluted with saturated NaHCO3 (aq) solution. The aqueous layer was

159 extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash column chromatography on silica gel (15% EtOAc/hexanes) to afford bis-MOM ether 206 (22 mg,

1 80%) as a clear colorless gum: H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.28 (d, J

= 6.9 Hz, 2H), 4.60 (q, J = 6.6 Hz, 2H), 4.47 (q, J = 6.4 Hz, 2H), 3.69 (dd, J = 13.5, 3.6 Hz, 1H),

3.38-3.53 (m, 3H), 3.37 (s, 3H), 3.30 (s, 3H), 3.15 (t, J = 9.4 Hz, 1H), 2.97 (td, J = 11.9, 3.5 Hz,

13 1H), 2.30-2.43 (m, 4H), 2.05-2.18 (m, 2H), 0.86-1.76 (m, 15H); C NMR (75 MHz, CDCl3) δ

142.9, 139.2, 129.7, 127.3, 97.0, 97.0, 70.7, 70.5, 63.9, 55.6, 55.5, 47.9, 40.6, 37.6, 35.6, 34.6,

34.3, 34.1, 30.7, 30.1, 26.7, 23.6, 21.8, 21.1, 20.3, 20.1; HRMS-ES+ (C26H45N2O6S) calcd

+ 513.2998 (MNH4 ), found 513.3034.

H H OMOM

OMOM N H H

207

9,11-bis((Methoxymethoxy)methyl)dodecahydro-1H-benzo[e]quinoline (207).

Anhydrous ammonia (ca.7.5 mL) was condensed into a flask at -78 °C and Li metal (25 mg, 3.5 mmol) was added until a blue color persisted. A solution of bis-MOM ether 206 (68 mg, 0.136 mmol) in dry Et2O (8 mL) was added dropwise and the mixture was stirred for 1 min at -78 °C, then quenched with NH4Cl (s) at that temperature. The reaction mixture was warmed to rt, diluted with CH2Cl2, filtered through a sintered glass frit, and concentrated in vacuo. The crude product

160 was purified via flash column chromatography on silica gel (gradient 1:1 Et2O/CH2Cl2 to

1:1:0.1:0.01 Et2O/CH2Cl2/MeOH/TEA) to afford tricyclic amine 207 (37 mg, 81%) as a clear

1 colorless gum: H NMR (400 MHz, CDCl3) δ 4.64 (q, J = 6.4 Hz, 2H), 4.58 (q, J = 6.6 Hz, 2H),

3.68 (dd, J = 9.8, 4.4 Hz, 1H), 3.57 (dd, J = 9.7, 6.8 Hz, 1H), 3.48 (dd, J = 9.5, 3.5 Hz, 1H), 3.38

(s, 3H), 3.34 (s, 3H), 3.18 (br d, J = 12.2 Hz, 1H), 2.92-2.97 (m, 1H), 2.75 (br d, J = 13.2 Hz, 1H),

2.70 (br d, J = 11.6 Hz, 1H), 2.43-2.55 (m, 1H), 1.87-1.98 (m, 2H), 0.81-1.86 (m, 15H); 13C NMR

(75 MHz, CDCl3) δ 97.1, 97.0, 72.7, 69.8, 65.8, 56.4, 55.8, 46.7, 39.5, 35.1, 34.2, 32.3, 32.1, 30.1,

+ 26.2, 23.1, 20.4, 18.2, 17.7; HRMS-ES+ (C19H36NO4) calcd 342.2644 (MH ), found 342.2649.

H H OH

N O H (±)-19

Racemic Myrioneurinol ((±)-19). To a stirred solution of tricyclic amine 207 (36.9 mg,

0.11 mmol) in THF (25 mL) was added 6 N HCl (aq) (14 mL). The reaction mixture was heated at

50 °C for 90 min and then cooled to rt. The mixture was and basified with Na2CO3 (aq) to a pH of

>10. The mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with a small amount of brine, dried over anhydrous MgSO4, and concentrated in vacuo.

The crude product was purified via flash column chromatography on silica gel (gradient 66% to

100% Et2O/CH2Cl2) to afford racemic myrioneurinol ((±)-19, 22 mg, 75%) as a clear colorless

1 gum: H NMR (850 MHz, CDCl3) δ 4.47 (d, J = 10.2 Hz, 1H), 4.42 (d, J = 10.2 Hz, 1H), 3.91 (dd,

161

J = 11.1, 4.3 Hz, 1H), 3.64 (dd, J = 11.1, 4.3 Hz, 1H), 3.48 (dd, J = 10.2, 6.0 Hz, 1H), 3.28 (td, J

= 13.6, 4.3 Hz, 1H), 3.21 (t, J = 11.1 Hz, 1H), 2.67 (dd, J = 11.9, 5.1 Hz, 1H), 2.49 (br d, J = 12.8

Hz, 1H), 2.46 (qt, J = 12.8, 4.3 Hz), 2.28 (d, J = 11.1 Hz, 1H), 1.74-1.80 (m, 2H), 1.68 (br d, J =

13.6 Hz, 1H), 1.59 (dd, J = 12.8, 2.6 Hz, 1H), 1.56 (dt, J = 12.8, 3.4 Hz, 2H), 1.48-1.53 (m, 2H),

1.35-1.45 (m, 2H), 1.24-1.30 (m, 1H), 1.20 (qd, J = 12.8, 3.4 Hz, 1H), 1.14 (td, J = 11.1, 2.6 Hz,

13 1H), 0.87 (td, J = 14.5, 3.4 Hz, 1H), 0.80 (q, J = 11.9 Hz, 1H); C NMR (150 MHz, CDCl3, APT)

δ 86.8 (CH2), 73.6 (CH2), 69.6 (CH), 65.4 (CH2), 47.7 (CH), 45.0 (CH2), 37.1 (CH), 36.3 (C), 34.4

(CH2), 31.1 (CH2), 27.2 (CH), 26.7 (CH2), 23.1 (CH2), 20.5 (CH2), 20.5 (CH2), 19.8 (CH2); IR

-1 + (neat) 3399, 1028 cm ; HRMS-ES+ (C16H28NO2) calcd 266.2120 (MH ), found 266.2132.

162

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VITA

Anthony J. Nocket

Anthony J. Nocket was born in 1987 and raised in Schuylkill Haven, Pennsylvania. After graduation from Blue Mountain High School in 2005, he attended Franklin and Marshall College where he earned his B.A. (magna cum laude) in chemistry in 2009. His undergraduate research under the supervision of Professor Phyllis A. Leber focused upon the synthesis and thermal study of model compounds to probe the thermal [1,3] sigmatropic rearrangement of bicyclic vinylcyclobutane derivatives. These substrates were shown to undergo some degree of the cyclopropylcarbinyl to homoallylic (CPC) radical clock rearrangement, thus providing ‘indirect’ evidence of singlet diradical intermediates in this pathway. In the fall of 2009, he joined the laboratory of Steven M. Weinreb at Penn State where he completed the first total synthesis of the tetracyclic antimalarial alkaloid myrioneurinol in racemic form. Upon completion of his graduate studies, Anthony will seek employment in the pharmaceutical industry.