New Methodologies for the Asymmetric Syntheses of Amines and Nitrogen Heterocycles from Enantiopure Sulfinimines

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NEW METHODOLOGIES FOR THE ASYMMETRIC SYNTHESES OF AMINES

AND NITROGEN HETEROCYCLES FROM ENANTIOPURE

SULFINIMINES (N-SULFINYL IMINES)

A Dissertation

Submitted to

The Temple University Graduate Board

In Partial Fulfillment

of the Requirement for the Degree

DOCTOR OF PHILOSOPHY

Hui Qiu

January, 2012

Examining Committee Member:

Dr. Franklin A. Davis,

Department of Chemistry, Temple University

Dr. Rodrigo B. Andrade,

Department of Chemistry, Temple University

Dr. Chris Schafmeister,

Department of Chemistry, Temple University

Dr. Kevin Cannon

Department of Chemistry, Pennsylvania State University

Hui Qiu

2012

ii ABSTRACT

New methodologies for the asymmetric syntheses of amines and nitrogen

heterocycles from enantiopure sulfinimines (N-sulfinyl imines)

By Hui Qiu

Doctor of Philosophy

Temple University, January, 2012

Doctoral Advisory Committee Chair: Professor Franklin A. Davis, Ph.D.

The objective of this research was to development new methodologies for the asymmetric syntheses of amine and natural products from enantiopure sulfinimines (N- sulfinyl imines). In this context, new methods was devised for the asymmetric synthesis of 2,5-cis and trans-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates, prepared by an intramolecular metal carbenoid N-H insertion from a sulfinimine derived

-amino -diazo -ketophosphonate. Horner-Wadsworth-Emmos reaction of the 3-oxo pyrrolidine 2-phosphonates and aldehydes provided Pyrrolidine enones. Hydrogenation

(Pd/H2) of the pyrrolidine enones gave cis-2,5-disubstituted pyrrolidines. Luche reduction the pyrrolidine enones followed by a TFA-NaBH3CN mediated hydroxy

iii directed reduction provided the 2,5-trans products. (+)-Preussin, a potent antiviral and antitumor agent was prepared in 9 steps in 28% overall yield from the sulfinimine.

An acid catalyzed intramolecular Mannich cyclization of a sulfinimine-derived N- sulfinyl syn--methyl -amino ketones was employed for the asymmetric synthesis of

2,3,5,6-tetrasubstituted piperidinones. The -amino ketones were prepare by treatment of prochiral lithium Weinreb amide enolates with enantiopure (E)-N-(4-

(benzyloxy)butylidene)-2,4,6-triisopropylbenzenesulfinamide. This new methodology was highlighted in the first asymmetric synthesis of the poison frog alkaloid (-)- indolizidine 221T.

By manipulation of water concentration in tetrahydrofuran, syn- and anti-2,3- diamino esters were prepared by treatment of the lithium enolate of N-

(diphenylmethylene) glycine ethyl ester with sulfinimines. Anhydrous THF afforded enantiopure syn-2,3-diamino esters with a syn/anti selectivity of better than 25:1. In a

THF-H2O the anti-2,3-diamino esters were formed. The mechanism involves the generation of H2O-LDA species in the formation of enolate which inhibited the retro-

Mannich fragmentation in the diamino ester species. (SR,2S,3R)-(-)-Ethyl-2-(N,N- dibenzylamino)-3-N-(p-toluenesulfinyl)amino-pent-4-enoate was employed in an improved total synthesis of the anti-tumor antibiotic (-)-agelastatin A.

A series of N-sulfinyl aza-Morita-Baylis-Hillman products were prepared by addition of vinylaluminum and N-methylmorpholine-N-oxide reagents to enantiopure N-

(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines from the least hindered direction via a non-chelation control mechanism. Hydrogenation of the these acrylates with a rhodium(I) catalyst afforded anti--substituted--amino esters with a

iv anti/syn selectivity of better than 17:1. This new methodology is useful for the asymmetric synthesis of anti--alkyl--amino esters, which are valuable chiral building blocks for the preparation of biologically active nitrogen-containing natural products.

v ACKNOWLEDGEMENTS

There are so many people I need thank for their help during my study at Temple

University. I know it is impossible to mention all of the names here, I would like to express my gratitude to all of them.

First of all, I would like to thank my advisor Dr. Franklin A. Davis. Without his help and guidance, I have no chance to finish my Ph.D. study. As a professional researcher, Dr. Davis taught me to do my chemistry carefully, creatively and happily. He always encourages me to challenge myself to be the best. Besides knowledge in chemistry, he also teaches me many other things about life, family. From him, I learned

“chemistry comes first, but family is even more important.” All of these are truly valuable for me.

I would also like thank my committee members Dr. John R. Williams, Dr.

Andrade, who have given me support all the way. Dr. Kevin Cannon, who was once my instructor of “organic synthesis”, taught me many advanced knowledge of chemistry, which is really helpful in my later research in chemistry. Dr. Andrade, who is really nice, illustrated the mechanism to me with patience whenever I ask him questions. Dr. John R.

Williams is a very good instructor. What he taught in his class about total synthesis is truly necessary for me to accumulate knowledge of different reactions. Other faculty should be recognized includes Dr. Alfred Findeisen for his nice work as the organic chemistry laboratory coordinator.

Also I have deep gratitude to my colleagues at department of chemistry, especially Dr. Junyi Zhang, Dr. Minsoo Song who worked as a postdoctoral fellow and mentored my research and my friends Dr. Yongzhong Wu, Dr. Bin Yang, Dr.

vi Ramachandar Tokalo, Dr. Dr. He Xu (Leo), Dr. Kerisha Bowen, Dr. Jianghe Deng, Dr.

Paul Gaspari, Dr. Naresh Theddu, Mr. Yanfeng Zhang, Mr Venkata Velvadapu, Mr.

Narendra V. Gaddiraju and Mr. Peng Xu.

I would also like to thank my wife, Jing Chai, without your encouragement, my road would be much more difficult with no doubt. My parents, Xianzhu Li and Zhangfa

Qiu, thanks for letting me know the importance of education and providing me the opportunity of studying in USA.

Life is just like climbing different mountains. The milestone I have reached today is just the beginning of another climb.

vii

TABLE OF CONENTS

Page

ABSTACT………………………………………………………………………………iii

ACKNOWLEDGEMENTS ………………...……………………………………….....vi

LIST OF TABLES…………………………………………………….………………...xi

LIST OF FIGURES…………………………………………………………...... xiii

CHAPTER

1. ASYMMETRIC SYNTHESIS OF TRANS-2,5-DISUBSTITUTED

PYRROLIDINES.

1.1. Introduction………………………………………………………...... 1

1.2. Cyclization (SN2)……………………………………………………………...2

1.2.1. Intramolecular cyciliztion………………………………………...... 2

1.2.2. Intermolecular cyclization reaction…………………………………..5

1.2.2.1. Halides as leaving groups……………………………….....5

1.2.2.2. 1,4-diol derivatives as leaving groups………………………..6

1.2.2.3. Miscellaneous examples…………………………………...7

1.3. Cyclization (SN2’)………………………………………………………….....8

1.4. Aza-Michael reaction…………………………………………………….....10

1.5. Radical cyclization………………………………………………………...14

1.6. Iodocyclization…………………………………………………………….14

1.7. Metal catalyzed cyclization………………………………………………....16

1.8. 1, 3 Dipolar reaction……………………………………………………..….20

viii 2. ASYMMETRIC SYNTHESIS OF TRANS- OR CIS-2,5-DISUBSTITUTED

PYRROLIDINES.

2.1. Indroduction……………………………………………………………….26

2.2. Present study. …………………………………………………………...... 28

2.2.1. Previous syntheses of (+)-preussin………………………………...29

2.2.2. Total synthesis (+)-preussin and its analogs……………………… 31

2.2.2.1. Synthesis of (+)-3-oxo pyrrolidine 2-phosphonate………..31

2.2.2.2. Synthesis of (+)-preussin and cis-2,5-disubstituted pyrrol..32

2.2.2.3. Synthesis of trans-2,5-disubstituted pyrrolidines derivatives

of (+)-preussin………………………………………..34

3. ASYMMETRIC SYNTHESIS AND UTILIZATION OF POLYSUBSTITUTED

PIPERIDINE AS BUILDING BLOCKS.

3.1. Introduction……………………………………………………………. 36

3.2. Present study……………………………………………………………39

3.2.1. Synthesis of cis -alkyl--amino ketone…………………………..40

3.2.2. Synthesis of 2,3,4,5-tetrasubstitutued piperidine via Mannich

r e a c t i o n … … … … … … … … … … … … … … … … … … … … . 4 1

3.2.3. Total synthesis of (-)-221T…………….…………………………..44

4. ASYMMETRIC SYNTHESIS AND UTILIZATION OF ANTI- AND SYN-2,3-

DIAMINO ESTERS.

4.1. Introduction……………………………………………………………….48

4.2. Present study……………………………………………………………...51

4.2.1. Synthesis of syn-2,3-diamino ester from sulfinimines (N-sulfinyl

ix imines…………..…………………………………………………..51

4.2.2. Mechanism exploration...... 54

4.2.3. Total synthesis of (-)-agelastatin A from sulfinimine-derived syn-,-

diamino ester……………………………………………………57

5. SYNTHESIS OF ANTI-LKYL-AMINO ESTERS.

5.1. Indroduction……………………………………………………………….62

5.2. Previous syntheses of -substituted -amino esters from sulfinimine…..62

5.3. Present study………………………………………………………………65

5.3.1. Synthesis of -alkyl -amino ester from enantiopure sulfinimine...65

5.3.1.1. Synthesis of -amino-acrylate via aza-Morita-Baylis-

Hillman (MBH) reaction……………………………...65

5.3.1.2. Hydrogenation of aza-MBH adducts with organometallic

catalysts………………………………………………...69

6. EXPERIMENTAL SECTION……………………………………………………..72

REFERENCE…………………………………………………………………………131

x LIST OF TABLES

Table 1.1. Intramolecular cyclizations between amines and tosylates……………….7

Table 1.2. SN2’cyclizations of 59 catalyzed by Iridium complex…………………...10

Table 1.3. aza-Michael cyclizations of (-)-68 in the presence of bases…………….12

Table 1.4. Asymmetric synthesis of 106a-b by Yb catalyzed cyclizations………...18

Table 1.5. 1,3-Dipolar reactions between 119 and alkene 120……………………..20

Table 1.6. 1,3-Dipolar reactions of 124 with dipolarophiles 125a,b……………….21

Table 1.7. Three components 1,3-dipolar reactions catalyzed by rhodium complex.23

Table 3.1. Synthesis of syn/anti--alkyl--amino ketone (-)-219 and (-)-220 from

Weinreb amide 218 and sulfinimine (-)-217………………………...39

Table 3.2. Synthesis of piperidine (-)-224 from (-)-221………………………...….42

Table 3.3. Transformation of (+)-226 to (+)-227 under reaction different condition

……………………………………………………………………….44

Table 4.1. Selectively deprotection of N-sulfinylimidazolidines 243a-c………….49

Table 4.2. Reactions between sulfinimine (+)-241 and glycine ester enolate 250....53

Table 4.3. Additional reactions for mechanism exploration………………….……54

Table 4.4. Reaction of anti-251a and syn-252a with bases at -78 oC for 1.5 h…... 55

Table 4.5. Conversion of (-)-266 to (-)-267 using 10 equiv of Cs2CO3……..……..59

Table 5.1. Synthesis of -substituted -amino esters from sulfinimines (+)-273a..62

Table 5.2. Synthesis of -Substituted -Amino Weinreb Amides………………..63

Table 5.3. Synthesis of -amino-acrylate (+)-282 and (+)-288 via aza-Morita-

Baylis- Hillman (MBH) reaction………………………………………65

Table 5.4. Reactions of vinylaluminum reagent with sulfinimines (+)-273b and (+)

xi 273d………………………………………………………………..…..68

Table 5.5. Reactions of -substituted vinylaluminum reagents to sulfinimines (-)-

273b and (-)-273d…………………….……………..…………………69

Table 5.6. Hydrogenation of aza-MBH adducts with organometallic

catalysts………………………………………..………...... 70

Table 5.7. Hydrogenation of products of aza-MBH reactions with catalyst

289…………………………………………………………………….71

xii LIST OF FIGURES

Figure 1.1. Natural products containing trans-2,5-disubstituted pyrrolidine moiety……1

Figure 1.2. Natural compounds synthesized by Kibayashi’s group……………………..2

Figure 1.3. Compounds synthesized by intramolecular cyclization……….…………….4

Figure 1.4. Ligands used in the reaction……………………….……………………….10

Figure 1.5. Proposed iridium complex structure……………………..……………….10

Figure 1.6. Possible mechanism of iodocyclization reaction…………………………..14

Figure 1.7. Transition state of iodocyclization...... 16

Figure 1.8. Structures of (102) and (+)-103...... 17

Figure 1.9. Transition states of the dipolar cyclization reactions………………………21

Figure 1.10. Ruthenium complex used in the reaction……………………..…………23

Figure 1.11. Natural compounds synthesized from chiral azomethines………………..24

Figure 2.1. Synthesis of primary amine from p-tolenesulfinimine (N-sulfinyl imine)...25

Figure 2.2. Sulfinamides synthesized from (2R,4S,5R)-141…………………………....27

Figure 2.3. Proposed transition state in the formation of pyrrolidine 162…………...30

Figure 2.4. Transition state for the NH carbenoid insertion reaction…………………..31

Figure 2.5. Mechanism of hydroxyl-directed hydride transfer…………………………33

Figure 3.1. Piperidine alkaloids having therapeutic potentials………………….……35

Figure 3.2. Some indolizidines isolated from frogs of Dendrobatidae family……… 35

Figure 3.3. Result for the NOE analysis of piperidinone (-)-224………………….…43

Figure 3.4. Mechanism for generation of pyrrole (+)-227 from indolizidine (+)-226.45

Figure 4.1. Drug and drug candidates containing ,-diamino ester and its derivative

…………………………………………………………………………...47

xiii Figure 5.1. Molecules having the -amino acids structure……………………………..61

Figure 5.2. Retrosynthetic approach to -alkyl--aminoesters………………………...64

Figure 5.3. Structure of acrylate 283…………………………………………………...66

Figure 5.4. Model to explain the selectivity in the formation of acrylate (+)-288……..67

Figure 5.5. Structure of vinylaluminium reagent 286…………………………………..67

Figure 5.6. Structures of catalyst 289………………………………………………...70

xiv CHAPTER 1

ASYMMETRIC SYNTHESIS OF TRANS-2,5-DISUBSTITUTED

PYRROLIDINES

1.1. Introduction.

trans-2,5-Disubstituted pyrrolidines are important chiral auxiliaries in asymmetric synthesis.1-4 They have been widely used in alkylation, condensation reactions,5 Claisen rearrangement reactions,6 and [2+2]/[4+2] cycloadditions.7,8

These heterocycles also exist in numerous natural products, including (-)-securinine,

(-)-bulgecinine and (+)-casuarine (Figure 1.1).9-18

Figure 1.1. Natural products containing trans-2,5-disubstituted pyrrolidine moiety.

Two methods are commonly used for the synthesis of trans-2,5-disubstitutend pyrrolidines. One begins with construction of the pyrrolidine ring from acyclic compounds, the other method starts with a five-member aza-heterocycle, such as 1,2- dihydropyrrole,19 oxazolidine,20 cyclic iminium ions derived from pyroglutamic acid,21-34 and commercially available pyrrolidines.35-39 Besides these two methods, 4- member aza-heterocycles are also used for this purpose.40-43 This chapter will focus on the synthesis of pyrrolidine from acyclic compounds.

1.2. Cyclization (SN2).

1.2.1. Intramolecular cyclization.

Formation of trans-2,5-disbustituted pyrroldines via intramolecular cyclization has been reported in the preparation of several bioactive natural products (Scheme

1.1). One example is (-)-197B(8), synthesized by Kibayashi (Scheme 1.2).44,45

1 Treatment of the chiral diol (5S,8S)-2, derived from epoxide (S,S)-(-)-1, with thionyl chloride followed by an oxidation afforded sulfonate (4S,7S)-(+)-3 in 77% yield.

Nucleophilic opening of the sulfate ring with LiN3 and a subsequent tosylation formed a 1:1 mixture of the azides 6 and 7 (92% yield). Without purification, hydrogenation of azides 6 and 7 followed by an intramolecular cyclization provided (-)-197B (8) in

91% yield. The same methodology was employed to prepare other pyrrolidines, such as (+)-195B,46 (-)-223AB, (-)-239AB and (-)-239CD47 (Figure 1.2).

Scheme 1.1

R 2 R LG 2 N NH2 R1 R1 H

R1, R2 can be alkyl, Ar. LG=leaving grouop, for example OTs, Br

Scheme 1.2

O OH SOCI2. Et3N, CH2Cl2; then NalO4. RuCl3, Acetonitrile-H2O O OH 77% (S,S)-(-)-1 (5S,8S)-2

LiN3,DMF,then N3 TsCl, Et3N, DCM O O S (6S,9R)-4 O O H2SO4,THF 91% N3 (4S,7S)-(+)-3 92%

OH (5S,8R)-5

OTs (6S,9R)-4/(5S,8R)-5=1:1

N 3 Pd/C, MeOH (6S,9R)-6 n-C5H11 N n-C4H9 91% H N3 8 (-)-197B OTs (5S,8R)-7 (6S,9R)-6/(5S,8R)-7=1:1

2 Figure 1.2. Natural compounds synthesized by Kibayashi’s group.

Intramolecular cyclization was also applied to the total synthesis of (-)- condonopsinine (14) by Takabe and co-workers (Scheme 1.3).48 A reaction of p- methoxyphenylmagnesium bromide with 9 afforded a liable pyrrolidine 10, which was stereoselectively reduced to two alcohols 11 and 12 in a 95:5 ratio. Mesylation of the major isomer 11 and a sequential intramolecular cyclization in the presence of t-

BuOK provided a tetrasubstituted pyrrolidine 13 in 92% yield. Deprotection of the benzyl group and a following LAH reduction afforded (-)-condonopsinine (14).

Scheme 1.3

Besides those examples, tetrasubstituted alkaloid broussonetine C (-)-15, a potent -galactosidase and -mannosidase inhibitor,49 was also synthesized by Yoda in 1999 (Figure 1.3).50 Later, in 2004, Holt reported a formal synthesis of (-)- bulgecinine 16.51,52 Koert’s group accomplished the synthesis of oligoprrolidines (+)-

17 and in the same year, and polyhydroxylated aza-sugar L-DMDP (-)-18 was prepared by Fleet et al.53,54

Figure 1.3. Compounds synthesized by intramolecular cyclization.

In most cases, the leaving groups in intramolecular cyclizations are a halide or tosylate group. In 2004, Han reported the total synthesis of polyhydroxylated pyrrolidines involving an intramolecular cyclization between a nitrogen atom and an epoxide (Scheme 1.4).55 A Sharpless epoxidation of the key allylic alcohol 19 produced epoxide 20 and pyrrolidine 24, which was assumed to be formed by an intramolecular cyclization from the unstable epoxide 21. Treatment of epoxide 20 with trifluoroacetic acid provided a ring-closure product 22 in 82% yield.

Deprotection of the p-methoxy phenyl group in 22 and 24 with cerium ammonium nitrate, followed by the cleavage of Boc group under acidic condition afforded pyrrolidines 23 and 25 both in 76% yield.

4 Scheme 1.4

1.2.2. Intermolecular cyclization.

Unlike intramolecular cyclization, in which the leaving groups and amines are in the same molecule (Scheme 1.1), in an intermolecular cyclization, they are from different ones (Scheme 1.5).

Scheme 1.5

1.2.2.1. Halides as the leaving groups.

In 1989, Ridley and O’Neill observed that when meso dimethyl-2,5- dibromoadipate (26a) was treated with potassium bromide, a mixture of isomers

(2S,5S)-27 and (2R,5R)-28 was obtained in 76% yield.56,57 Later Yamamoto58 and

Aggarwal,59 respectively, synthesized 2,5-trans-pyrrolidines (S,S,S)-(-)-29 and

(S,R,R)-30 with poor selectivity (Scheme 1.6).

5 Scheme 1.6

NH Br Br Br Br 2 H KBr/DMF Ph (S)-27 CO2Me CO Me CO Me CO Me 2 + 2 + 2 CO2Me o 80 C, 2-3h CO2Me CO2Me CO2Me K2CO3/tulene, 20h Br Br Br Br meso-26a (2S,5S)-27 (2R,5R)-28 meso-26

19% 76%

MeO C CO2Me + 2 N MeO2C N CO2Me H H + cis-31 (42%) Ph Ph (S, S, S)-(-)-29 (30%) (S, R, R)-30 (28%)

meso-Dibromoadipate’s acid derivative 26b reacted with chiral alcohol (R)-32, in the presence of DCC and DMAP, affording a mixture of diastereomers (2S,5R)-33 and (2R,5S)-34, which underwent an intermolecular cyclization with benzylamine to provide a mixture of trans pyrrolidines (-)-35 and (+)-36 in 51% combined yield

(Scheme 1.7).60

Scheme 1.7

1.2.2.2. 1,4-Diol derivatives as leaving groups.

A few syntheses of 2,5-trans-disubstituted pyrrolidines started with meso diols because most syntheses of these heterocycles began with optically active diols.61 For example, Marzi reported the synthesis of pyrrolidine 41 from chiral diol (2S,5S)-37.62

Benzylation of the primary alcohol followed by tosylation afforded a fully protected alcohol 39. A subsequent intermolecular cyclization with benzylamine provided N-

6 benzyl pyrroldine 40 as a single isomer. Selective N-debenzylation of 40 was accomplished via a palladium hydroxide catalyzed hydrogenation, producing pyrrolidine 41 in 90% yield (Scheme 1.8).

Scheme 1.8

Several other syntheses of 2,5-trans disubstituted pyrrolidines by intermolecular cyclization of tosylates and amines are listed in Table 1.1 (Scheme 1.9).

Good to excellent selectivity was observed for different R, R’ and R1 groups (Table

1.1, entry 4 and 5). The lowest yield (50%) was obtained when a chiral amine was used (Table 1.1, entry 4). If it was replaced by a benzyl amine, a much higher yield

(75%) was reported (Table 1.1, entry 3).

Scheme 1.9

OTs NH R R 2 1 R' N R R' OTs R1

7 Table 1.1 Intramolecular cyclizations between amines and tosylates.63-67

Entry R R’ Amine Product Yield(%) Selectivitya 1 OTBDMS OTBDMS BnNH2 TBDMSO OTBDMS 90 95:5 N Bn (2R,5R)-42

b 2 OBn OBn BnNH2 BnO OBn 52 91:9 N Bn (2R,5R)-43

b 3 Me Me BnNH2 75 98:2/99:1 N Bn (2R,5R)-44 4 Me Me (R)- 50 single N Ph(CH3)CHNH2 isomer Ph (2S,5S,S)-45

5 n-C5H11 n-C4H9 BnNH2 90 single n-C H n-C H 5 11 N 4 9 isomer Bn (2S,5S)-46 a d.r. if not specificly noted. b e.r.

1.2.2.3. Miscellaneous cyclizations.

A synthesis of trans-2,5-disubstituted pyrrolidine from (2R)-2-t-

butoxycarbonylamino-3-phenylsulfonyl-1-(2-tetrahydropyranyloxy) propane (R)-48

was described by Sasaki.68 Reaction of the anion generated from (R)-48 with glycidyl

tosylate (S)-47 in the presence of n-BuLi produced a mixture of 2,3,5-trisubstituted

pyrrolidine 49. Deprotection of THP group in 49 with pyridinium p-toluenesulfonate

and subsequent desulfonylation gave a mixture of pyrrolidines 51. Jones oxidation of

this mixture followed by esterification with diazomethane afforded pyrrolidine

(2S,5S)-52 and its diastereomer (2S,5R)-53 in a 96:4 ratio (Scheme 1.10).

8 Scheme1.10

1.3. Cyclization (SN2’).

Scheme 1.11

Similar to the SN2 reaction, an SN2’ reaction also starts with a nucleophilic attack of an electrophilic carbon and ends with expelling a leaving group. But unlike

3 an SN2 reaction, in which the attacked carbon is often sp hybridized and directly

2 connected to the leaving group, in a SN2’ reaction this carbon is an sp and located at the -position of the leaving group (Scheme 1.11). Only a limited number of studies on the synthesis of 2,5-trans pyrrolidine via SN2’ cyclization have been reported. In

69 2005, a SN2’ cyclization catalyzed by Ag(I) was reported by Yamamoto. Cross

Metathesis of unsaturated carboxylic ester (S)-54 with allylic chloride (55) afforded ester (S,E)-56. An SN2’ cyclization of 56, catalyzed by AgOTf gave a 4:1 unseparable mixture of pyrrolidine (2S,5S)-57 and (2S,5R)-(-)-58 (Scheme 1.12).

9 Scheme 1.12

O Cl O o 55 , Grubbs(II) cat. n-BuLi, -78--15 C OMe Cl OMe then AgOTf, THF, NHBoc DCM, 40oC NHBoc rt, 2.5 h (S)-54 67% (S,E)-56 77%

CO Me CO Me N 2 + N 2 Boc Boc (2S,5S)-57 (2S,5R)-(-)-58

Helmchen’s group reported a synthesis of pyrrolidine (2R,5R)-60 with an

70,71 iridium-catalyzed SN2’ cyclization of diester 59 and benzylamine (Scheme 1.13).

It is believed that the ligand couples with the iridium metal forming a chiral complex, which interacts with benzylamine, facilitating the asymmetric SN2’ reaction between the nitrogen atom and the allylic carbonate 59 (Figure 1.4). In the five ligands tested, excellent dr’s, ee’s, and moderate to good yields were observed. Ligand E, which replaced the original aromatic ring in A to a saturated ring performed best in selectivity (Table 1.2, entry 6). The lowest dr values were obtained with ligand A and

B, which gave highest yields (Table 1.2, entry 1-3). On the contrary, ligand C and D, which have the naphthalene and diphenylmethylene groups, rather than a phenyl ring, afforded a hightly superior ratio but lower yields (Table 1.2, entry 4-5).

Scheme 1.13

Figure 1.4. Ligands used in the reaction.

Ar Ar

O P Ir O

Figure 1.5. Proposed iridium complex structure.

a 70,71 Table 1.2. SN2’cyclizations of 59 catalyzed by Iridium complex.

Entry Ligand time (h) yield (%)b drc ee(%)d 1 A 9 79 91:9 99 2 A 2 82 92:8 99 3 B 2 76 95:5 >99 4 C 0.5 57 95:5 >99 5 D 1 50 96:4 >99 6 E 1 59 97:3 >99 aAll reactions were carried out on a 0.5 mmol scale using 1.3 equiv. of nucleophile, 4 mol % [Ir(COD)Cl]2, 8 mol% of ligand and 2 h of activation with TBD (16 mol%). bCombined yield of isolated products. cRatio of isomers (2R,5R)-60 and (2R,5S)-61 were determined by 1H NMR analysis on crude reaction mixtures. dDetermined by HPLC.

1.4. Aza-Michael reaction

Scheme 1.14

EWG

R N NH2 EWG 1 R1 H

R1 can be alkyl, Ar. EWG=electron withdrawing groups, for example carboxylic ester

11 In aza-Michael reactions, the most widely used Michael acceptors are ,- unsaturated carboxylic esters.72 One example is the synthesis of pyrrolidine (2S,5S)-

(-)-65, the precursor of cyclic ketone (1R,3aS,6S)-(-)-67 (Scheme 1.15).73 Reduction of lactam (S)-62 with LiBEt3H followed by a Horner-Wadsworth-Emmons reaction provided conjugated carboxylate ester (S)-63 in 70% yield. This ester was transformed to a pyrrolidine mixture 64 via an aza-Michael cyclization and reduced with LiBH4 to give pyrrolidine (2S,5S)-(-)-65 and its diasteromer (2S,5R)-(-)-66 with good selectivity (95:5).

Scheme 1.15

o CO2Et 1) LiBEt3H, THF, -100 C O 2) NaH, THF, EtO C 2 o (EtO)2POCH2CO2Et LiBH4,Et2O, 0 C N H N Boc N Boc CO2tBu 70% Boc CO2tBu CO2tBu

(S)-62 (S)-63 64 H HOH C HOH2C 2 N + N CbzHN Boc Boc CO Me CO tBu O 2 CO2tBu 2 (2S,5S)-(-)-65 (2S,5R)-(-)-66 (1R,3aS,6S)-(-)-67 95 : 5

Recently, a synthesis of trans-2,5-disubstituted pyrrolidine via an Aza-

Michael reaction was reported by Schneider. Here it was noticed that the diastereoselectivity of aza-Michael reactions could be controlled by the choice of base

(Scheme 1.16). Treatment of carbamate (-)-68 with KOt-Bu gave the cis pyrrolidine

(+)-70 as the major isomer with a diastereoselectivity of 94:6 (Table 1.3, entry 1).

With NaOEt the trans diastereomer (-)-69 was obtained as the major product in 90% yield (Table 1.3, entry 2). Moreover, treatment of pyrrolidine (-)-69 with KOt-Bu in

DMF/THF furnished its cis isomer (+)-70 in high selectivity. But when the cis isomer

(+)-70 was subjected to the same conditions, there was no detectable change in the dr.

When both of these two pyrrolidines were treated with NaOEt, only the unchanged

12 substrate was recovered. These observations imply that trans pyrrolidine (-)-69 is the kinetic product, which was formed faster than thermodynamic product (+)-70. When both were treated with KOt-Bu, a stronger base than NaOEt, deprotonation led to an intermediate 71 via a retro aza-Michael reaction. A sequential aza-Michael cyclization afforded the thermodynamic 2,5-cis product. Apparently, NaOEt is not strong enough to deprotonate these pyrrolidines (Scheme 1.17).

Scheme 1.16

Table 1.3. aza-Michael cyclizations of (-)-68 in the presence of bases.74

Base Solvent T (oC) t (min) 69:70a Yieldb

KOtBu DMF/THF(2:1) -78 40 6:94 88

NaOEt DMF/THF(2:1)-78 40 >95:5 90

aDetermined by 1H NMR spectroscopy. bYield of isolated product after flash column chromatography.

Scheme 1.17

13 In addition to ,-unsaturated carboxylate esters, enantiopure sulfoximides have also been used as Michael acceptors. Reggelin reported a study on the formation of pyrrolidine (+)-77 from sulfoximide 72.75 Deprotonation of 72 with n-BuLi followed by transmetallation with titanium species 73 and addition of -amino aldehyde 74 afforded titanium intermediate 75. After deprotection of Fmoc group with peperidine, a sequential aza-Michael cyclization produced pyrrolidine 76.

Protection of nitrogen atom with Boc and removal of the sulfoximide by SmI2 gave the pyrrolidines 77 as the major isomer. The best trans/cis ratio thus obtained is greater than 96:4. The total yields for these six-step syntheses are 33% (Scheme 1.18).

Scheme 1.18

1.5. Radical cyclization.

Although several syntheses of trans-2,5-disubstituted pyrrolidines using radical cyclization methods have been reported, only a few of them are asymmetric.

A possible reason is the challenge of controlling the selectivity.

In 2000, Lee reported the synthesis of (-)-223AB (82), in which a radical cyclization was employed as the key step to form the pyrrolidine ring.76 From tosylate (R)-78, a SN2 reaction with phenylselenide followed by a Michael reaction

14 provided a mixture of E/Z isomers of (R)-79 in 86% yield. Exposure of this mixture to AIBN and tributyltin hydride afforded trans-(2S,5R)-80 and the corresponding 2,5- cis isomer 81 in 3:1 ratio (Scheme 1.19)

Scheme 1.19

Ses=2-(trimethylsilyl)ethanesulfonyl

1.6. Iodocyclization.

Iodocyclization hasn’t been widely used in the syntheses of trans-2,5- disubstituted pyrrolidines. However, an advantage of this strategy lies in that the iodide product can be a useful building block. The mechanism involves an iodiranium ring formation and a subsequent ring-opening by a nucleophile (Figure

1.6). Takano in 1989 discovered that homoallylic amine (S)-(-)-83 can react with iodine in aqueous acetonitrile to provide a labile pyrrolidine (2S,5S)-87.77 In the proposed mechanism, it was suggested that the iodocyclization initiated a nucleophilic opening of the iodiranium species 84 followed by the formation of an oxazolium intermediate 86, which was quickly hydrolysis to pyrroldine (2S,5S)-87. Due to the low stability of this compound, it was transformed to the carbamate (2S,5S)-(-)-88

(Scheme 1.20).

Figure 1.6. Possible mechanism of iodocyclization reaction.

Scheme 1.20

The scope of iodocyclization chemistry was expanded by Knight and coworkers.78 In 2001, this group demonstrated that a 5-endo-trig iodocyclization of

E-homoallylic sulfonamide (2S,3R,E)-88 in the presence of potassium carbonate can give a good yield of pyrrolidine (2S,3R,4S,5S)-89 (Scheme 1.21).

Scheme 1.21

In 2006, a concise synthesis of the bioactive natural compound (-)-197B (93) was reported by Davis and coworkers, in which the key step is the formation of a trans-2,5-disubstituted-pyrrolidine via iodocyclization.79 From -amino aldehyde (S)-

90, a Wittig reaction afforded a mixture of homoallylic sulfonamide isomers 91 with an E/Z ratio 54:46. Irradiation of this mixture 91 at 300 nm in the presence of 2.0 equiv of PhSSPh improved the E:Z ratio from 54:46 to 85:15 with a 84% yield.

Iodocyclization of the irradiated mixtures 91 formed iodopyrrolidine (2R,3S,5R)-(+)-

92, the precursor of (-)-197B (93) in 82% yield along with the Z-homoallylic

16 sulfonamide (Scheme 1.22). The stereoselectivity of E-homoallylic sulfonamide was explained as arising via a chair-like transition state. Because of the A1,3 strain of the transition state in TS-A, the energy of TS-B is less. This results in the lack of activity of Z-homoallylic sulfonamide (Figure 1.7).

Scheme 1.22

Figure 1.7. Transition state of iodocyclization.

1.7. Metal involved cyclizations.

About 40 years ago, cyclization of 2,5-trans-disubstituted pyrrolidines via

80 aminomercuration in the presence of HgCl2 was studied by Perie. In 1981, Harding developed a related cyclization method in which HgCl2 was replaced by Hg(OAc)2

(Scheme 1.23).81,82 It was proposed that the cyclization catalyzed by Hg underwent a chair-like transition state (Scheme 1.24). The adoption of a trans configuration was because putting both the R and methyl group on equatorial positions were more favorable. With Harding’s protocol, Danishefsky synthesized pyrrolidine (3S,8aS)-97

83 from the chiral homoallylicamine (S)-94. Reaction of (S)-94 with Hg(OAc)2 gave pyrrolidine (2R,5S)-95, which was subjected to the conditions of reductive coupling

17 reaction to afford the corresponding ester (2R,5S)-96. Hydrogenation of ester

(2R,5S)-96 produced the final product (3S,8aS)-97 in 85% yield (Scheme 1.25).

Scheme 1.23

COR E R 1) Hg(OAc)2 N R H N 2) NaBH , E+ 4 COR

Scheme 1.24

COR R N H R N HgX COR

Scheme 1.25

Hg(OAc)2,THF NaBH4,C2H3COOMe N N H HgOAc NHCbz Cbz 41% for two steps Cbz C2H4CO2Me (S)-94 (2R,5S)-95 (2R,5S)-96

H Pd/C,EtOH N 85% O (3S,8aS)-97

Based on Harding’s aminomercuration methodology, Schlessinger and

Takahata, respectively, prepared several 2,5-trans dialkylpyrroldines.84,85 The procusor (2R,5S)-(+)-100 for (+)-197B (101), a bioactive compound extracted from toxic frogs, was also prepared. The synthesis started with an amidomercuration of carbamate (S)-98 in the presence of NaBr. Following reductive oxygenation86 of organomercurial bromide 99 resulted in pyrrolidine (2R,5S)-(+)-100 in 56% yield

(Scheme 1.26). Besides (+)-197B (101), the 2,5-trans disubstituted pyrroldine in (+)- xenovenine (102) and its derivative (3S,5R,7aS)-(+)-103 were also prepared (Figure

1.8).87

18 Scheme 1.26

H H

N N

C7H15 6

(+)-xenovenine (102) (3S,5R,7aS)-(+)-103

Figure 1.8. Structures of (102) and (+)-103.

In addition to mercury, ytterbium was also used in the synthesis of pyrrolidines. One example was reported by Kerr and coworkers in 2008 (Scheme

1.27).88 With a Yb(III) catalyzed tandem ring opening followed by N-alkylation of the E-oxime ether (R)-104a-b afforded a series of pyrrolo-isoxazolidines 105a-b in high selectivity (Table 1.4, entry 2). Hydrogenation of 105a-b under acidic conditions provided pyrolidines 106 a-b in quantitative yields (Table 1.4, entry 1-2).

Scheme 1.27

19 Table 1.4. Asymmetric synthesis of 106a-b by Yb catalyzed cyclizations.88

Entry Substrate % Yield of 105 a/ Product % Yield

eeb

O HO 1 N 98 (105a)/single 98 H CO Me MeO C 2 H Ph 2 - + Cl H2N 104a isomer H Ph CO2Me CO Me 2 106a

O b HO 2 N 75 (105b)/ 99 H CO Me MeO C 2 H 2 - + Cl H2N 104b H CO2Me CO2Me

106b aIsolate yield of single diastereomer. Isomeric ratio determined by 1H NMR analysis of crude mixture. bee>99%.

1.8. 1,3-Dipolar cycloadditions.

1,3-Dipolar cycloadditions are reactions between 1,3-dipoles and

dipolarophiles. Azomethine ylides are one kind of 1,3-dipoles, which consist of a

nitrogen atom and two terminal sp2 carbons and has been used to build up

pyrrolidines (Scheme 1.28).89 Most dipolarophiles of azomethine ylides are

substituted alkenes.

Scheme 1.28

R' R' R'' R2 R4 R'' diplolarophile R1 R4 R N R 1 5 R2 N R5 R3 R3 1,3-dipolar One example of synthesis of pyrrolidines from an azomethine ylide was

reported by Williams.90 Azomethine ylide (5S,6R)-108, prepared from amino lactone

(5S,6R)-107 and propioaldehyde, was treated with dimethyl maleate (109) in the

20 presence of p-toluenesulfonic acid to afford bicyclic lactones (+)-110 and (+)-111.

Hydrogenation of the lactone (+)-111 produced pyrrolidines (+)-112 in 94% yield

(Scheme 1.29).

Scheme 1.29

A similar chiral building block (R)-113 was developed by Harwood to synthesize the stabilized azomethine, for example (R)-114.91 When azomethine ylide

(R)-114 was reacted with N-methyl maleimide (115), tricyclic lactones (+)-116 and

(+)-117 were formed with 38% and 15% yields, respectively (Scheme 1.29).

Scheme 1.30

O O O H H H H Ph N Ph Ph H N N Ph N + PhCHO, C6H6 Ph N _ O 115 Ph N + Ph N 2 6 H H Molecular Sieve H H H O H H O O O O O O O O O (R)-113 (R)-114 (2R,6R,7S,8R,9R)-(+)-116 (2R,6R,7R,8S,9R)-(+)-117 38% 15% Besides the above building blocks, 4(S)-phenylimidazolinium ylide 119, which was prepared from dihydro imidazole (S)-118, was also used for the synthesis of trans-2,5-disubstituted pyrrolidines.92,93 The reactions of ylide (S)-119 and a variety of alkenes 120 produced major and minor isomers 121a-e and 122a-e (Scheme

21 1.31). It turned out that when Y is a nitrile group, low yields of major isomers were always obtained (Table 1.5, entry 1-2). The highest yield (71%) was observed when a conjugated ketone was used as the dipolarophile (Table 1.5, entry 5). The selectivity results from a more favorable endo adduct, which can be explained with the proposed transition state (Figure 1.9).

Scheme 1.31

Bn Bn Bn Bn H C=CR Y N 2 2 N N N BrCH2CO2R 120 H H R2 + R2 + N DBU, THF, Ph N Ph N Y Ph N Y Ph _ Reflux RO C 2 CO2R CO2R (S)-118 (S)-119 121a-e 122a-e

Table 1.5. 1,3-Dipolar reactions between 119 and alkene 120.92,93

R R1 R2 Y Yield of Yield of 121a(%) 122a(%) 1 Me H Me CN 24(41) 3(5) 121a 122a 2 t-Bu H Me CN 27(22) 4(3) 121b 122b 3 t-Bu H H CO2Me 59(49) 3(2) 121c 122c 4 t-Bu H H SO2Ph 33 121d 5 t-Bu H H COMe 71 121e a Value in brackets indicates using the corresponding R isomer of the dipolar.

Figure 1.9. Transition states of the dipolar cyclization reactions.

22 The iminium ions in all of the chiral azomethine ylides discussed above are

either connected with or are in a cyclic system. In 1998, Enders developed a non-

cyclic azomethine ylide.94 He demonstrated that azomethine (4S,5S)-124, prepared

from chiral amine (4S,5S)-(+)-123 and benzaldehyde, can react with different alkenes

125a-b to afford mixtures of exo and endo cycloadducts 126a-c and 127a-c (Table

1.6). However, the selectivity of this non-cyclic ylide is poor giving the two isomers

in a ratio of 2:1. The endo-adducts 127a-c were the major isomers with one exception

(Table 1.6, entry 2) (Scheme 1.32).

Scheme 1.32

Table 1.6. 1,3-Dipolar reactions of 124 with dipolarophiles 125a,b.94

a Alkene R1 exo Product endo product % yield of de (diploarophile) product(exo:endo)b MeO2C MeO2C CO2Me MeO2C CO2Me 1 CO2Me CO2Me 86(43:57) >96% 125a MeO2C N Ph MeO2C N Ph Ph Ph

OO OO

exo-(+)-126a endo-(+)-127a

MeO2C MeO2C CO2Me MeO2C CO2Me 2 CO2Me C6H5 83(65:35) >96% 125a Ph N Ph Ph N Ph Ph Ph

OO OO

exo-(+)-126b endo-(+)-127b NC NC CN NC CN 3 CN CO2Me 91(30:70) >96% 125b MeO2C N Ph MeO2C N Ph Ph Ph

OO OO

exo-(+)-126c endo-(+)-127c a Determined by 1H NMR. bDetermined by HPLC. All the isomers can be separated by chromatography or pre-HPLC.

23 In 2003, Che discovered that a ruthenium catalyzed three component coupling reaction of α-diazo esters 129 with N-benzylidene imines 128 and alkenes 130a-e can furnish pyrrolidines (2R,5R)-131a-e with excellent diastereoselecitivity (Scheme

1.33).95 In all cases, with the exception of the reaction with acrolein (Table 1.7, entry

1), yields are around 60% or lower, especially when disubstituted alkenes were used

(Table 1.7, entry 5). This lowest yield may result from an increased steric bulkiness associated with the disubstituted alkene, which could decrease the reaction rate.

Scheme 1.33

Table 1.7. 1,3-Dipolar reactions catalyzed by ruthenium complex.95

a R1 Dipolarophile Product Yield 1 Ph 91b

130a

131a 2 PMB 63 b

130b

131b 3 PMB 57 b

130c

131c 4 PMB 61 b

130d

131d 5 PMB 45

130e

131e a Reaction conditions: catalyst/128/129/130=0.001:2:1:4 in DCM. b The first four reaction were undertaken at room temperature. The last ones were undertaken at 50oC.

Cl Cl

Cl Cl N CO N Ru N N Cl Cl

Cl Cl

RuII(TDCPP)(CO)

Figure 1.10. Ruthenium complex used in the reaction.

As shown in the above examples, 1,3-dipolar cycloadditions are a simple and efficient way to form 2,5-trans disubstituted pyrrolidines. It has been used to synthesize a number of optically active natural products including (-)- spirotryprostatin-A (132), (-)-spirotryprostatin B (133), ADE fragment of nakadomarin A (Figure 1.11).96-98

O O Boc N N N N N O O O H H CO2Me H N HN HN O

OMe ADE fragment of (-)-spirotryprostatin A (132) (-)-spirotryprostatin B (133) nakadomarin A

Figure 1.11. Natural compounds synthesized from chiral azomethines.

25 CHAPTER 2

ASYMMETRIC SYNTHESIS OF TRANS/CIS-2,5-DISUBSTITUTED

PYRROLIDINES

2.1. Introduction.

p-Toluenesulfinimine (N-Sulfinyl Imine) is a new type of chiral imine building block, which was first developed by Davis, et al in 1992 (Figure 2.1). The electron- withdrawing p-toluenesulfinyl group not only activates the imine bond for nucleophilic addition, but also stabilizes the negative charge on the nitrogen after the addition avoiding epimerization of the newly-generated chiral center. Due to the powerful stereodirecting effect of the chiral sulfinyl group, a highly diastereomeric sulfinamide species can often be obtained. Moreover, simply treating the sulfinamide with hydrogen chloride will cleave the sulfinyl group and provide a chiral primary amine. This versatile building block has been quite widely used in the synthesis of amine derivatives and bioactive natural products.99

Figure 2.1 Synthesis of primary amine from p-tolenesulfinimine (N-sulfinyl imine).

Two methods have been developed to prepare (S)-(+)-p-toluenesulfinimine

(136) (Scheme 2.1).100,101 The initial one-pot procedure (Method A) involves treatment of the Anderson reagent (S)-134 with LiHMDS followed by an aldehyde or ketone to afford sulfinimine product. In the optimized procedure (Method B), the intermediate sulfinamide (S)-135 was isolated and Ti(OEt)4 was used as a Lewis acid and dehydrating reagent in the sulfinimine formation. Method B gives better yields because the menthol by-product in Method A does not need to be removed.

26 Besides p-toluenesulfinamide, Ellman and co-workers synthesized tert- butanesulfinamide (R)-140 via an asymmetric oxidation of di-tert-butyl disulfide 137 with hydrogen peroxide, vanadyl acetylacetonate [VO(acac)2] and a sequential reaction with lithium amide. The pure enantiomer (R)-140 can be separated by crystallization (Scheme 2.2).102-104 Compared to tert-butanesulfinamide, p- toluenesulfinamide is more UV detectable, while tert-butanesulfinamide has the advantage of increased nucleophilicity and diastereoselectivity.

Scheme 2.1

O S O 1) Li HM 2) D (S)-134 RC S O H HO Method A , C S sF N R 1) LiHMDS 2) Sat. NH4Cl 87% (S)-136 Et) 4 (O Ti O O, CH Method B S R NH2

(S)-135

Scheme 2.2

t-Bu H OH

t-Bu OH

t-Bu (S)-138

Additionally, more hindered sulfinamides have been prepared from N- sulfonyl-1,2,3-oxathiazolidine-2-oxide species by Senanayake and co-workers.105 For example, sulfinamide (R)-143 can be readily produced from reactions of a (1R,2S)-1-

27 N-tosyl-aminoindanol derived (2R,4S,5R)-141 with Grignard reagent and lithium amide (Scheme 2.3). Several sulfinamides have been syntheized via this protocol

(Figure 2.2).

Scheme 2.3

Ms Ms N O NH O O S RMgBr, THF LiNH2/NH3 S S O -78--10oC O R or NaHMDS H2N R -78oC 141 142 (R)-143

O O O O S S NH2 S NH S NH2 2 NH2

(R)-143a (R)-143b (R)-143c (R)-143d

Figure 2.2. Sulfinamides synthesized from (2R,4S,5R)-141.

2.2. Present study.

cis-and trans-2,5-Disubstituted pyrroldines, commonly found in numerous bioactive products, are promising drug candidates or lead compounds for the treatment of cancer and other diseases.9-18 (+)-Preussin (144) is one alkaloid in this large pyrrolidine family. It was first isolated from fermentation broths of A. ochracceus ATCC 22947 and is a powerful antifungal agent, and potent against several tumor cell lines. Moreover, because it can also inhibit -1 programmed ribosomal frame shifting and virus propagation, it could also play a role in the field of

HIV treatment.106 So far there are 29 publications on the asymmetric synthesis of preussin.107-134

The major objective of the present study was to develop new methodology for the asymmetric synthesis of preussin and its analogs from enantiopure sulfinimines.

The retro analysis shows a proposed route for (+)-preussin (Scheme 2.4). The key

28 intermediate is 3-oxopyrrolidine 2-phosphonates 146, which should be readily synthesized from N-sulfinyl -amino -ketophosphonates 147 via an NH carbenoid insertion reaction. Enone 145 is prepared via a Horner-Wadsworth-Emmons (HWE) reaction of phosphonates 146 and an aldehyde. Finally, different hydride transfer protocols will be explored to prepare (+)-preussin (144).

Scheme 2.4

2.2.1. Previous syntheses of (+)-preussin.

In 2004, Davis and Deng reported a concise synthesis of (+)-preussin (Scheme

2.5).133 From sulfinimine (R)-(-)-149, two sequential sodium enolate addition reactions provided N-sulfinyl -amino -ketoester (-)-151. Replacement of the sulfinyl group with a Boc group and reducing the double bonds afforded N-Boc - amino -ketoester (+)-153. On treatment of (+)-153 with 4- carboxybenzenesulfonylazide (4-CBSA) in the presence of Et3N, -keto -diazoester

(+)-154 was obtained in 94% yield (Scheme 2.5). Treatment (+)-154 with 5 mol%

Rh2(OAc)4 in DCM gave the 3-oxo proline derivative (2S,5R)-155 as a single diastereoisomer. Due to its poor stability, without purification, the crude 155 was directly subjected to a one-pot reduction mediated by LAH to produce the desired dihydroxy N-methyl pyrrolidine (-)-156 in 61% isolated yield. Selective iodination of the primary alcohol in (-)-156 with 4 equiv. of I2, Ph3P and imidazole followed by a

29 reaction with 10 equiv. Ph2CuLi afforded (+)-preussin (144) in 41% yield for the two steps. The overall yield for this synthesis is 23% from -amino -ketoester (+)-153.

Scheme 2.5

In 2006, another concise total synthesis of (+)-preussin was reported by Wolfe

(Scheme 2.6).134 The synthesis started with reaction of t-butylsulfinimine (R)-157 with allylmagnesium bromide to afford sulfinamide 158 as a single isomer. After replacement of the sulfinyl group with Boc and oxidative cleavage of the double bond in the presence of ozone, a copper catalyzed vinyl addition reaction provided a mixture of alcohol 160 with a 3:1 ratio. The hydroxyl group in the major isomer

(3S,5R)-160 was then protected with TBS to afford key intermediate 161, which was converted to pyrrolidine (2S,3S,5R)-162 in the presence of Pd(OAc)2, DPE-Phos and

PhBr (Figure 2.3). Finally, a reduction with LAH followed by deprotection of the

TBS group under basic condition produced (+)-pressuin (144) in 96% ee. The overall

30 yield for this synthesis is 12%. The advantage of this strategy lies in that it can be easily applied to synthesis of derivatives of (+)-preussin, which has been demonstrated by the author in the article.

Scheme 2.6

+ C9H19 + OTBS Boc Ar Pd OR N C9H19 N Boc Ph H H (2S,3S,5R)-162 R=TBS

Figure 2.3. Proposed transition state in the formation of pyrrolidine 162.

2.2.2. Total synthesis of (+)-preussin and its analogs.

2.2.2.1. Synthesis of (+)-3-oxo pyrrolidine 2-phosphonate.

The synthesis of (+)-3-oxo pyrrolidine 2-phosphonate (2S,5R)-(+)-179 was based on a methodology developed earlier by the Davis’ group (Scheme 2.7).135 The synthesis began with the preparation of N-sulfinyl -amino ester (Rs,S)-(-)-150 from sulfinimine (R)-149, which was derived from sulfinamide (R)-135. Reacting the - amino ester (Rs,S)-(-)-150 with the lithium enolate of dimethyl methylphosphonate in

31 THF afforded N-sulfinyl -amino -ketophosphonate (Rs,S)-(-)-163 in 80% yield.

Subsequent cleavage of the sulfinyl group under acidic condition, and protection of the free amine with a Boc group followed by a hydrogenation afforded (S)-(+)-165.

This material was readily converted to the -diazo phophonate (S)-(+)-166 with 2.0 equiv of NaH and 0.99 equiv. 4-acetamidobenzenesulfonyl azide (4-ABSA). The byproduct, 4-acetamidobenzenesulfonamide, precipitated from the CHCl3 solution and was removed by filtration. Finally, treatment of the -diazo compound (S)-(+)-

166 with 4mol % Rh2(OAc)4 in DCM furnished the corresponding 3-oxo pyrrolidine

2-phosphonates (2R,5R)-(+)-167 in 81% isolated yield (Scheme 2.7). The selectivity for the NH carbenoid insertion may be explained by transition states TS-1 ( favored) and TS-2, in which the phosphonate may compete with the metal carbenoid group for the axial position, leading to the major cis and minor trans products (Figure 2.4).

Scheme 2.7

O O n-C H O O 5 11 CH COOCH p-Tolyl S CH P(O)(OMe) S 3 3 NH O 3 2 S p-Tolyl N p-Tolyl NH2 NaHMDS n-BuLi Ti(OEt)4 C H 9 15 C5H11 OMe (R)-(-)-135 77%(R)-(-)-149 80% (Rs,S)-(-)-150 80%

O S p-Tolyl NH O O Boc Boc TFA/MeOH NH O O Pd/C, H2 NH O O OMe OMe OMe P MeOH C H OMe (Boc)2O/Et3N P P 5 11 C9H15 OMe C9H19 OMe 87% (Rs,S)-(-)-163 (S)-(+)-164 95% (S)-(+)-165

O Boc NH O O Rh (OAc) , DCM 1) NaH, THF OMe 2 4 P 2) 4-ABSA C9H19 N P(OMe) C9H19 OMe 2 Boc O 81% N2 81% (S)-(+)-166 (2S,5R)-(+)-167

O S p-Tolyl N C9H19 (R)-149A

Figure 2.4. Transition state for the NH carbenoid insertion reaction.

It is important to note that in order to achieve high selectivity (>25:1) in the formation of N-sulfinyl -amino ester, it was necessary to react the sodium enolate with unsaturated sulfinamide (R)-149 instead of (R)-149A, although an extra hydrogenation step was needed to reduce the double bond. The enhanced selectivity may attribute to the rigid structure of the conjugated double bond in (R)-149, making one face of the imine bond more favorable for the enolate addition.

2.2.2.2. Synthesis of (+)-preussin and cis-2,5-disubstituted pyrrolidines.

With the key intermediate (2S,5R)-(+)-167 in hand, a Horner-Wadsworth-

Emmons reaction (HWE) reaction with benzaldehyde or p-methoxybenzaldehyde produced crude enones (2S,5R)-(-)-168a and (2S,5R)-(+)-168b in 85 and 70% yield, respectively (Scheme 2.14). Due to the instability of these enones, without purification, the enones were directly used in the next hydrogenation step to afford cis-2,5-disubstituted 3-oxo pyrrolidines (2S,5R)-(+)-169a and (2S,5R)-(+)-169b. An

LAH mediated one pot reduction produced (+)-preussin (144) and its cis derivative

(2S,5R)-(+)-170 (Scheme 2.8). The formation of 3S configuration can be explained with a delivery of hydride from the less hindered top face. The analytical data

(HRMS, 1H NMR, 13C NMR and rotation) of (+)-144 were consistent with the reported values.136

33 Scheme 2.8

O O O R R NaH, PhCHO Pd/C, MeOH C H N P(OMe) C9H19 N C9H19 N 9 19 2 or DBU, LiCl, rt Boc O 4-MeOPhCHO Boc Boc (2S,5R)-(+)-167 (R)-(-)-168a R=Ph 85% (2S,5R)-(+)-169a R=Ph 78% (R)-(+)-168b R=4-MeOPh 70% (2S,5R)-(+)-169b R=4-MeOPh 80%

OH R LAH, THF C9H19 N reflux CH3 (2S,3S,5R)-(+)-144 R=Ph 83% (2S,3S,5R)-(+)-170 R=4-MeOPh 70%

2.2.2.3. Synthesis of trans-2,5-disubstituted pyrrolidines derivatives of

(+)-preussin.

To prepare the unknown 2,5-trans analogs of (+)-preussin, (R)-168a and (R)-

168b were reduced to the corresponding cis-allylic alcohols (3S,5R)-171a and

(3S,5R)-171b. Due to a stability issue, both of them were subsequently converted to the trans-2,5-disubstituted pyrrolidine alcohols (2S,3S,5R)-172a and (3S,5R)-172b

137,138 with TFA-NaBH3CN. The selectivity can be explained by a hydroxyl-directed hydride transfer mechanism, in which the reducing reagent was first coupled with the oxygen atom in C3-OH rendering the hydride delivered only from the bottom face of the pyrrolidine ring (Figure 2.5). The attempt to reduce the N-Boc group in pyrrolidines 172 to N-methyl group with LAH was not successful obviously due to the increased steric hindrance caused by the 2,5-trans configuration. The proton NMR data of 172a and 172b clearly showed the existence of rotamers, which was a solid evidence for the formation of a 2,5-trans configuration. Finally, a reductive amination protocol afforded trans analogs (2S,3S,5R)-173a and (2S,3S,5R)-173b in 70 and 81% yields, respectively (Scheme 2.9).

Figure 2.5. Mechanism of hydroxyl-directed hydride transfer.

Scheme 2.9

O OH OMe

. NaBH CN TFA R NaBH4 CeCl3 7H2O 3 C H C9H19 N 9 19 N MeOH -45oC Boc Boc

(R)-(-)-168a R=Ph (3S,5R)-(+)-171a R=Ph (R)-(+)-168b R=4-MeOPh (3S,5R)-(+)-171b R=4-MeOPh

OH OH 1) TFA, DCM R R C9H19 N 2) HCHO, C9H19 N Boc NaCH3CN, CH3 HOAc, ACN (2S,3S,5R)-(-)-172a R=Ph 60% (2S,3S,5R)-(-)-173a R=Ph 70% (2S,3S,5R)-(-)-172b R=4-MeOPh 61% (2S,3S,5R)-(-)-173b R=4-MeOPh 81%

In summary, the asymmetric synthesis of (+)-preussin (144) was accomplished in 10 steps (7 operations) in 15% overall yield from sulfinimine (-)-135, and is one of the most efficient syntheses to date. A highlight of this new methodology lies in its potential versatility for the preparation a wide scope of both cis and trans-2,5- pyrrolidines from a common phosphonate intermediate.

35 CHAPTER 3

ASYMMETRIC SYNTHESIS AND UTILIZATION OF POLYSUBSTITUTED

PIPERIDINE AS BUILDING BLOCKS

3.1. Introduction.

Piperidines are a common moiety found in numerous of bioactive natural products (Figure 3.1).139-155 Among them, there is a specific family of more than 800 alkaloids, which were isolated from the skins of Dendrobatidae poison frogs by Daly et al.156 These alkaloids are interesting targets to be synthesized due to their unique proprieties and therapeutic potential as drug candidates (Figure 3.2). For example (-)-

1-epi-207I (181), (-)-235B’ (189) were found to be selective and non-competitive blockers of 42 nicotinic acetylcholine receptors.142

Figure 3.1. Piperidine alkaloids having therapeutic potentials.

Figure 3.2. Some indolizidines isolated from frogs of Dendrobatidae family.

36 Several strategies have been employed to prepare the piperidine core in these alkaloids. A straightforward one is from a six member lactam ring. This was utilized by Toyooka and Nemoto in their synthesis of (-)-203A (178) (Scheme 3.1).145,157

After protection of the nitrogen atom in cyclic lactam (-)-192, a sequential triflate formation, a palladium catalyzed carbonylation, and a Michael addition afforded piperidine (-)-196. The carboxylic ester group in piperidine 196 was then reduced to give alcohol (+)-197 in 92% yield. Swern oxidation and a HWE reaction provided an

,-unsaturated ester species 198. Hydrogenation of 198 followed by a trimethylaluminum-catalyzed cyclization led to the precursor of (-)-203A (178)- piperidine intermediate (-)-199. Indolizidines (-)-205A (179), (-)-207A (180), (-)-

231C (186), (-)-233D (187) and (-)-235B (188) were also synthesized with the same strategy.158,159

Scheme 3.1

LiHMDS, H n-BuLi, CbzCl H Comins' reagent H O N O N THF, -78 to -40oC TfO N o H OTBDPS THF, -78 to 0 C Cbz OTBDPS Cbz OTBDPS (S)-(-)-192 86% (S)-(-)-193 91% (S)-(-)-194

H Me

Pd(Ph3P)4, CO H Me2CuLi, Et2O H super-H MeO C N o MeO C N o MeOH, Et3N, DMF 2 -78 to -10 C 2 THF, 0 C Cbz OTBDPS Cbz OTBDPS 78% (S)-(-)-195 99% (2R,3R,6S)-(-)-196 92%

H H Me Me 1) 20% Pd(OH)2/C, H 1) Swern Oxidation H MeOH, rt N EtO2C N 2) NaH, (EtO)2P(O)CH2CO2Et 2) Me3Al, DCM OH Cbz OTBDPS Cbz OTBDPS 97% (2R,3R,6S)-(+)-197 (2R,3R,6S)-198

H Me H H N N OTBDPS O (5S,8R,8aS)-(-)-199 (-)-203A 178

37 Acyclic compounds can also been used to prepare piperidine alkaloids. One example is the synthesis of trans-(-)-209D (184), in which the key piperidine ring was synthesized via a Grubbs catalyst involved ring closing metathesis (Scheme 3.2).160

Nucleophilic reaction between epoxide (+)-200 and allylic amine provided a labile aminodiol 201, which was protected with a Boc group to afford diol 202. The amino diol diene was subjected to ring closing metathesis using Grubbs I catalyst to give tetrahydropiperidine (+)-203 in 72% yield.

Scheme 3.2

Boc O NH2 NH N Boc2O OH OH NaHCO , MeOH OH LiClO4, ACN 3 OH OH (2R,3R)-(+)-200 (2S,3S)-201 60% two steps (2S,3S)-202

C5H13 Boc N Grubbs I cat. N DCM OH OH 72% H

(2S,3S)-(+)-203 trans-(-)-209D 184

A novel strategy involving a Mannich cyclization reaction was employed by

Davis and co-workers in their synthesis of (-)-209B (182).161 In this study -amino ketal (-)-205, was prepared from sulfinimine (-)-204. A condensation reaction between aldehyde 206 and -amino ketal (-)-205 afforded crude imine species 207, which was treated with anhydrous TsOH to give piperidine (-)-208 as a single isomer.

Two subsequent hydrogenations catalyzed by Pd/C and Pd(OH)2/C respectively and a

Ph3P/CBr4/Et3N mediated cyclization provided the indolizidine (-)-209 in good yield.

Transformation of the ketal group to a thioketal followed by a desulfurization formed

(-)-209B (182). This protocol also led to the synthesis of (+)-241D (191) (Scheme

3.3).

38 Scheme 3.3

OBn

OBn N NH2 O O O O 206 O O TsOH S p-Tolyl N C5H11 75oC MgSO4, DCM

(Rs)-(-)-204 (R)-(-)-205 (R)-207 61% for two steps

O O 1) Pd/C, H O O S S 2 HS SH , BF3.OEt2

2) Pd(OH)2/C, H2 3) Ph3P, CBr4, Et3N n-C5H11 N n-C H N n-C5H11 N H 5 11 OBn 74% 92% (2S,3S,6R)-(-)-208 (2S,3S,6R)-(-)-209 (2S,3S,6R)-(-)-210

Ra-Ni, EtOH

n-C5H11 N 75% (-)-209B 182

3.2. Present study.

(-)-221T (211) is one alkaloid in the same family as those piperidine alkaloids mentioned above, but bearing a more complicated 5,6,8-trisubstituted indolizidine core. This indolizidine has never been prepared. The goal of this research is to develop methodology for the asymmetrically synthesize (-)-221T and its derivatives.

The retro analysis shows a proposed synthesis route (Scheme 3.4). The key 2,3,5,6- tetrasubstituted piperidinone intermediate 212 is constructed via an acid-catalyzed intramolecular Mannich cyclization with imine species 213.162-164 Imine 213 is anticipated to be readily prepared from a Davis’ sulfinimine derived N-sulfinyl - alkyl -amino ketone 214.

39 Scheme 3.4

3.2.1. Synthesis of syn -alkyl--amino ketone.

The chiral sulfinimine (-)-217 was synthesized from sulfinamide (+)-216 in quantitative yield (Scheme 3.5).101 When sulfinimine (-)-217 was added into lithium Weinreb amide enolate of N-methoxy-N-methylpropylamide (218) in THF, the syn- and anti--alkyl--amino Weinreb amides (-)-219 and (-)-220 were obtained.

Efforts were made to optimize the syn/anti selectivity and are summarized in Table

3.1. The best selectivity (5.1:1) was obtained when the enolate concentration was

0.12 M and LiHMDS were used (Table 1 entry 3). Switching the base from LiHMDS to LDA resulted in a almost the same ratio (5.0:1) (Table 1, entry 4). With the required Weinreb amide (-)-219 in hand, it was treated with of n-butylmagnesium chloride in THF to produce cis -alkyl--amino ketone (-)-221 in 91% yield.

Scheme 3.5

40 Table 3.1. Synthesis of syn/anti--alkyl--amino ketone (-)-219 and (-)-220 from

Weinreb amide 218 and sulfinimine (-)-217.165

Base Solvent Enolate Ratio of two Concentration diastereomersa LiHMDS THF 0.35M 4.3:1 LiHMDS THF 0.25M 4.9:1 LiHMDS THF 0.12M 5.1:1 LDA THF 0.12M 5.0:1 a All the reactions were run at -78oC, with the enolate:sulfinimine = 1:1.

3.2.2. Synthesis of 2,3,4,5-tetrasubstitutued piperidine via a Mannich reaction.

With the key intermediate syn--alkyl--amino ketone (-)-221 in hand, the next step was to synthesize piperidine (-)-224, which can be achieved by a deprotection step, imine formation, and a subsequent Mannich cyclization reaction

(Scheme 3.6). To optimize the yield of (-)-224 and simplify the procedure, different reaction protocols were explored (Table 3.2). It turned out that all attempts to purify the deprotected amine (+)-222 were difficult due to its stability. Furthermore, the synthesis of (-)-224 from a purified amine 222 didn’t provide a significantly higher yield than that from crude amine 222 (Table 3.2, entry 2, 4). Therefore, the crude amine (+)-222 was carried on to imine formation. The use of Ti(OEt)4 as a catalyst in this step was beneficial to decreasing the amount of aldehyde and slightly increased the yield compared to when no catalyst was used (Table 3.2, entry 3,5). In the presence of Ti(OEt)4, the imine species (3R,4S)-223 was smoothly formed from crude amine 222. Some efforts were made to purify the labile imine product 223 via chromatography to minimize the possible side reactions caused by the impurities. It was later found to be troublesome due to its poor stability. The crude imine 223 was

41 only purified by a short-pad of Celite to filter away the inorganic impurity and carried on to the next step immediately. The best reaction conditions for the intramolecular

Mannich cyclization was to heat the imine 223 with 2.0 equiv anhydrous p- toluenesulfonic acid at 75 oC for 8 h (Table 3.2, entry 7). This one-pot protocol afforded the desired 2,3,5,6-tetrasubstituted piperidinone (-)-224 in 51% yield from (-

)-221. It’s worth noting that the use of anhydrous p-toluenesulfonic acid, the temperature, and time are all critical for high yields. The use of anhydrous p- toluenesulfonic acid and a reaction temperature lower than 75 oC resulted in an uncomplete reaction and low yields (Table 3.2, entry 1). Lower yields were also observed when the reaction time was longer or shorter than 8 h (Table 3.2, entry 6, 8).

Scheme 3.6

Table 3.2. Synthesis of piperidine (-)-224 from (-)-221.165

Imine formation Mannich reaction Catalyst Aldehyde / Reaction T(oC) Yield of 223 Catalyst Solvent T(oC) Reaction Yield of 224 catalyst/ 222 time (h) (equiv.) Time (h) (from 222) . 1 N/A 10/0/1 4 0-rt No separation 2.0 TsOH H2O PhH rt-50 109 44%+16%(SM) 2 N/A 30/0/1 3 0-rt No separation 2.0 TsOH Toluene 75 16 42% from 221 Pure amine was isolated 3 N/A 30/0/1 3 0-rt 61% from 222 2.0 TsOH Toluene 75 16 44% from 221 Pure imine was used in Mannich Reaction 4 N/A 30/0/1 3 0-rt No separation 2.0 TsOH Toluene 75 16 40% from 221 One pot reaction 5 Ti(OEt)4 10/5/1 3 0-rt 63% from 221 2.0 TsOH Toluene 75 16 48% from 221 Pure imine was used in Mannich Reaction 6 Ti(OEt)4 10/5/1 3 0-rt No separation 2.0 TsOH Toluene 75 16 41% from 221 One pot reaction 7 Ti(OEt)4 10/5/1 3 0-rt No separation 2.0 TsOH Toluene 75 8 51% from 221 One pot

reaction

8 Ti(OEt)4 10/5/1 3 0-rt No separation 2.0 TsOH Toluene 75 7 49% from 221 One pot

reaction

43 The absolute stereochemistry of 2,3,5,6-tetrasubstituted piperidinone (-)-224 was confirmed by the NOE analysis (Figure 3.3). The observed NOE between the Hb and proton of methyl group at C3 indicated a cis relationship between them. The NOE between Ha and proton of the terminal methyl group at C5 also revealed a cis relationship between Ha and the propyl group. Both of these confirmed the stereocenter at C5 is 5S.

Similarly, the correlations between the Hd and He, implied a cis relationship between these two protons, which signified the configuration of C6 to be 6S. This result was further confirmed by a cis relationship between Hb and alkenyl group, based on the NOE between Hb and Hc.

O CH3 Hb Ha CH3 3S 2R Hc BnO N H Hd He

Figure 3.3. Result for the NOE analysis of piperidinone (-)-224.

3.2.3. Total synthesis of (-)-221T.

The next stage of the total synthesis was N-allylation of the piperidinone (-)-224 with allyl bromide to afford the diene (+)-225 in 72% yield (Scheme 3.7). When diene

(+)-225 was heated with Grubbs I catalyst in DCM at 40 oC for 18 h, a blue colored byproduct 227 was unexpectedly formed in 62% yield. After careful analysis of the spectral data, this blue compound was identified as pyrrole (+)-227, which was confirmed by four protons appearing at  6.5 ppm and d 6.0 ppm, respectively. The desired indolizidine

(+)-226 was obtained in less than 10% yield.

44 Scheme 3.7

O O Br Na2CO3, Grubbs I catalyst BnO N EtOH, 75oC, 16 h BnO N DCM H 72%

(2R,3S,5S,6S,E)-(-)-224 (2R,3S,5S,6S,E)-(+)-225

O O

+ BnO N BnO N

(5R,6S,8S,8aS)-(+)-226 (3R,4S)-(+)-227 <10% 62%

It’s suspected that the pyrrole 227 was transformed from the desired indolizidine

226 and this transformation may be catalyzed by the high temperature and catalyst. To confirm this hypothesis, a mixture of indolizidine (+)-226 and pyrrole 227 was stirred at

40 oC in DCM for 16 h. The ratio of indolizidine (+)-226 to pyrrole 227 changed from

7:1 to 5:1 (Table 3.3, entry 1). When the same reaction mixture was subjected the RCM condition with Grubbs I catalyst the ratio decreased from 7:1 to 1:6 (Table 3.3, entry 2).

Finally, when a mixture of (+)-226 and 227 was heated at 80 oC in benzene, the ratio was changed from 12:1 to 4:1 (Table 3.3, entry 3). Grubbs I catalyst and a reaction temperature above 80 oC catalyzed the rearrangement of indolizidine 226 to pyrrole 227.

A mechanism, which involves a retro-Mannich reaction followed by pyrrole ring formation was suggested to explain this unexpected transformation (Figure 3.4).

Table 3.3. Transformation of (+)-226 to (+)-227 under reaction different conditions.165

Entry Ratio of (+)-226/(+)-227 before Reaction Ratio of (+)-226/(+)-227 the reaction conditions after the reaction 1 7:1 40oC, DCM 5:1 2 7:1 Grubbs I 1:6 catalyst, 40oC, DCM 3 12:1 80oC, toluene 4:1

Figure 3.4. Mechanism for generation of pyrrole (+)-227 from indolizidine (+)-226.

Finally by lowing the reaction temperature and reducing the reaction time, the yield of was increased to 69%. Because indolizidine (+)-226 was still contaminated by the blue pyrrole and was difficult to purified, the crude mixture was hydrogenated using

Pd/C in MeOH to furnish a saturated indolizidine (-)-228 in 60% yield for two steps

(Scheme 3.8).

Scheme 3.8

O O O Br 1) Grubbs II cat. rt, 2.5 h Na2CO3, 2) Pd/C, H , MeOH, rt, 2 h BnO N EtOH, 75oC, 16 h BnO N 2 BnO N H 60% for two steps 72%

(2R,3S,5S,6S,E)-(-)-224 (2R,3S,5S,6S,E)-(+)-225 (5R,6S,8S,8aS)-(-)-228

With the formation of indolizinone (-)-228, efforts were next directed to the removal of the carbonyl group (Scheme 3.9). Reduction with NaBH4 afforded a mixture of alcohols in quantitative yield. With Barton deoxygenation protocol, the alcohols were treated with NaH, followed by CS2 and MeI to afford an S-methyl carbonodithioate intermediate 229. Reaction of 229 with AIBN and n-Bu3SnH provided (-)-230 in 55% yield.166

The next step in the synthesis of indolizidine (-)-221T is removal of the benzyl group and proved to be challenging. Exposure of benzyl protected alcohol (-)-230 to

BCl3 resulted in decomposition. Hydrogenation of (-)-230 with Pd(OH)2 gave the desired

46 o alcohol (-)-231 in 62% yield at 50 C under 40 bar H2-atmosphere. The requirement of high temperature and high pressure may be attributed to the lone-pair electron on the nitrogen, which may have poisoned the catalyst. Transformation of the tertiary amine in

(-)-230 to the corresponding salt could avoid this problem. Hydrogenation of (-)-230 in the presence of TFA went smoothly at rt and 1 atm H2 to provided alcohol (-)-231 in 79% yield. Finally, a Swern oxidation followed by a Wittig reaction (Ph3PCH3/n-BuLi) installed the methylene group, completing the first total synthesis of (5R,6R,8R,9S)-(-)-

5,9Z-Indolizidine 221T (211) .

Scheme 3.9

O O S AIBN, n-Bu SnH, o 3 1) NaBH4, MeOH, 0 C Toluene, 85oC N 2) NaH, CS2, MeI, THF N N rt 55% for three steps BnO BnO BnO

(5R,6S,8S,8aS)-(-)-228 (5R,6S,8S,8aS)-229 (5R,6S,8S,8aS)-(-)-230

Pd(OH)2/C, TFA 1) Swern Oxidation N N MeOH, H , rt 2 2) Ph3PCH3, n-BuLi HO THF, 0oC 79% (5R,6S,8S,8aS)-(-)-231 76% for two steps (-)-221T 211

In summary, the first total synthesis of alkaloid (5R,6R,8R,9S)-(-)-5,9Z- indolizidine 221T (211) was accomplished in 15 steps with a 4.4% overall yield. The key

2,3,5,6-tetrasubstituted piperidine was constructed via a novel intramolecular Mannich cyclization using anhydrous TsOH as the catalyst. This intramolecular Mannich cyclization protocol can also be applied to synthesize piperidine moieties in other alkaloids.

47 CHAPTER 4

ASYMMETRIC SYNTHESIS AND UTILIZATION OF ANTI- AND SYN-2,-

DIAMINO ESTERS

4.1. Introduction.

,-Diamino esters and their derivatives are important compounds because they are present as a fundamental residue in numbers of natural products.167 Many of these natural products are biologically active, such as bleomycin A2 (232) and (-)-agelastatin A

(233), which have been shown to have potent antitumor properties and are potential drug candidates.168,169 Even more, some important drugs on market also contain this moiety, such as the cardiovascular drug imidapril (234) and the orally bioavailable HIV protease inhibitor indinavir (235) (Figure 4.1).170,171 Furthermore, ,-diamino esters are valuable building blocks in the total syntheses of bioactive natural products.172-174

Figure 4.1. Drug and drug candidates containing ,-diamino ester and its derivatives.

48 Two basic approaches have been applied to synthesize ,-diamino esters. The key reactions in these two approaches are C-C bond formation and C-N bond formation, respectively. An example of the first approach is shown in Scheme 4.1. Catalyzed by a complex of CuClO4 and oxazoline ligand 240, the enolate generated from ester 236 reacted with N-sulfonyl imine 237 to provide syn-,-diamino ester (-)-238 with moderate selectivity. Hydrolysis followed by protection of the free amino group with

175 Boc2O gave a highly enantiopure syn-,-diamino ester (+)-239 (Scheme 4.1).

Scheme 4.1

NHTs N CO Me Ts CO Me NHTs 2 N 10 mol% L-CuClO4 Ph 2 1) HCl-Et2O + CO2Me 10 mol% Et N, -20o C N Ph Ph Ph Ph Ph 3 2) Boc2O, Na2CO3 THF-4A MS NHBoc Ph 94% syn:anti=79:21 94% syn:anti=77:23 236 237 ee (syn)=97% (-)-(2S,3R)-238 ee (syn)=97% (+)-(2S,3R)-239

N PAr2 L=

Ar=2,4,6-Me3C6H2 240

Enantiopure sulfinimines (+)-241a-c were employed by Viso’s group to synthesize a series of a,-diamino esters.167 Addition of lithiated imino esters 242 in the

. presence of BF3 Et2O to sulfinimines (+)-241a-c afforded enantiopure 2-carbomethoxy-

N-sulfinylimidazolidines (+)-243a-b and (-)-243c, respectively (Scheme 4.2). From imidazolidines (+)-243a,b and (-)-243c, enantiopure syn-N-sulfinyl-,-diamino esters

(+)-244a-c or ,-diamino esters (+)-245a-c can be selectively produced by choosing different acids and solvents. It’s observed the deprotection reaction of imidazolidines was conducted in a nucleophilic solvent MeOH would simultaneous removal of the

49 aminal and sulfinyl moieties to afford the unprotected ,-diamino esters (+)-245a-c

(Table 4.1, entry 1,3,5). Replacement of MeOH with a non-nucleophilic solvent THF would preserve the sulfinamide moiety, providing the N-sulfinyl diamino ester (+)-244a- c in modest to good yields (Table 4.1, entry 2,4,6).

Scheme 4.2

Table 4.1. Selectively deprotection of N-sulfinylimidazolidines 243a-c.167

Entry R Method Yield of (+)- Yield of (+)- 244a-c(%) 245a-c(%) a 1 Ph H3PO4/MeOH 59 b 2 H3PO4/THF 72 20 c 3 p-FC6H4 TFA/MeOH 61 b 4 H3PO4/THF 76 c 5 Ph(CH2)2 TFA/MeOH 11 61 b 6 H3PO4/THF 81 a b c H3PO4, THF/MeOH/H2O (6:3:1), 0 °C. H3PO4, THF/H2O (7:3), 0 °C to rt. TFA, MeOH, rt, 4-14 h.

The C-N formation strategy to optically active syn- and anti-,-diamino acids or the derivatives normally begins with a chiral amino acid. Then the second amino group is introduced by replacement of a group in the molecule with azide via an SN2 reaction.

50 A subsquential hydrogenation of this azide compound would provide an ,-diamino product. In 2000, Lee and co-workers prepared -diamino ester (+)-249, utilizing a C-

N bond formation strategy.176 Replacement of the acetyl group in (-)-246 with a Boc group, followed by a Mitsunobu reaction with hydrazoic acid afforded azide (-)-248. A subsequent hydrogenation transformed azide (-)-248 into anti-,-diamino ester (+)-249

(Scheme 4.3).176

Scheme 4.3

O O O

NH O O NH O O NH O 1) HCl, MeOH, reflux PPh3, HN3, DEAD H2, Pd/C, EtOAc i OiPr OiPr O Pr 2) Boc2O, TEA, 0 oC-rt OH OH N3

(-)-(2R,3S)-246 87% (2R,3S)-247 90% (2S,3S)-248 99%

O NH O

OMe

NH2

(+)-(2S,3S)-249

In addition to the examples mentioned above, there are many other synthetic routes reported.167 However, considering the importance of a,-diamino acids as key structural units of biologically active compounds and valuable synthetic intermediates, development of new and efficient synthetic routes for these molecules will still be attractive.

4.2. Present study.

The goal of this research is to develop a methodology for the asymmetric synthesis of anti and syn-,-diamino ester from enantiopure p-toluenesulfinimines.

51 4.2.1. Asymmetric Synthesis of anti/syn-2,3-diamino ester from sulfinimines

(N-sulfinyl imines).

In 2004, Davis and coworkers developed a new one-pot methodology for the asymmetric synthesis of anti-2,3-diamino ester (-)-251a involving addition of the prochiral lithium enolates of N-(diphenylmethylene)-glycine ethyl ester (250) to (S)-(+)-

N-(benzylidene)-p-toluenesulfinamide (+)-241a (Scheme 4.4).172 However, in later studies, this result was not reproducible. In this study treatment of the lithium enolate generated from glycine ester 250 in the presence of LDA with p-toluenesulfinimine (+)-

241a in anhydrous THF, which is either from the solvent system (made by Glass

Contour) or from fresh bottles purchased from Aldrich, VWR, EMD Serono, afforded a mixture of all four isomers. However, when the same reaction was conducted in THF from an opened bottle (Acros), a highly diastereomerically pure diamino ester species was formed. This product was confirmed to be anti-2,3-diamino ester (-)-251a by comparing the rotation and the NMR data with the literature values.172 Some efforts were then spent to explore the possible reason for these different selectivities. Generally speaking, a big difference between THF from a fresh bottle and an opened bottle is the water concentration in them. Following this clue, it was finally discovered that the different selectivity in the reaction of sulfinimine (+)-241a and glycine ester 250 was connected with the water concentration in THF. Later, to determine the water concentration in THF favoring the formation of anti-2,3-diamino ester (-)-251a, hydrous

THF solutions were prepared by addition of different amounts of water into anhydrous

THF from the solvent system (made by Glass Contour in Irvine, CA). The water concentration in these hydrous THF was determined by Karl Fisher titration method

52 (coulometric Karl Fisher Titrator, Model 275 KF, Denver Instrument). These results are showed in Table 4.2. It’s observed that when the water/LDA ratio is below 0.5, no selectivity was obtained (Table 4.2, entry 1 and 2). When the ratio was increased to 0.7, the anti-(-)-251/syn-(+)-252 ratio dramatically increased to 16:1 (Table 4.2, entry 3). The highest ratio of 33:1 was obtained if the ratio reaches 1.09. The same selectivity can be maintained even when the H2O/LDA ratio jumped to 4:1 although the yield dropped to

60% (Table 4.2, entry 5-7). Similar results were also observed for different sulfinimines

(+)-241b,d,f bearing electron withdrawing or donating groups on the phenyl ring (Table

4.2, entry 8-10). Replacement of water with MeOH resulted a 10:1 selectivity if

MeOH:LDA = 1.5:1 (Table 4.2, entry 11). But when a more bulky t-butanol was used, the selectivity dropped to nearly 1:1 (Table 4.2, entry 12).

. In the continuous efforts to asymmetric synthesize syn-,-diamino esters, a former protocol developed by Davis and Deng was first tested.172 Treatment of sulfinimine (+)-241a and (+)-241b with 5.0 equiv of prochiral lithium enolate of glycine ester 250 at the concentration of 0.14M, respectively, yielded syn-,-diamino ester (+)-

252a and (+)-252b with high selectivities (Table 4.2, entry 13, 15). However, when the reaction in entry 13 was repeated in a hydrous THF, all four isomers were detected (Table

4.2, entry 14). The absolute configuration of syn-,-diamino ester (+)-252a was confirmed by transforming it into a product with known configuration, which is outlined in Scheme 4.5. Diamino ester (+)-252a was reacted with TFA to give the deprotected diamine (-)-243. Heating this diamine (-)-243 with 1,1-carbonyldiimidazole (CDI) provided imidazolidinone (-)-254 in 45% yield. The rotation and NMR data of

53 imidazolidinone (-)-254 are consistent with the literature values.177 In this way, the absolute stereochemistry of (+)-252a-b was fully established.

Scheme 4.4

O O Ph N O S S NH O NH O S N Ph CO2Et 250 R OEt + R OEt R o LDA, THF, -78 C N N

Ph Ph Ph Ph

(S)-(+)-241 (SS,2S,3S)-(-)-251a-d (SS,2R,3S)-(+)-252a-d

a: R=Ph a: R=Ph a: R=Ph b: R=4-CF3 phenyl b: R=4-CF phenyl b: R=4-CF phenyl d: R=4-Chloro phenyl 3 3 c: R=4-Chloro phenyl e: R=4-MeO phenyl c: R=4-Chloro phenyl d: R=4-MeO phenyl d: R=4-MeO phenyl

Table 4.2. Reactions between sulfinimine (+)-241 and glycine ester enolate 250.178 R Enolate Con. Water:Base dr (251:252)a Yield (%) b 1 Ph 0.02M 0 1:1 2 0.02M 0.5:1 1:1 b 3 0.02M 0.7:1 16:1 80 4 0.02M 0.98:1 25:1 86 5 0.02M 1.09:1 33:1 86 6 0.02M 3.1:1 33:1 78 7 0.02M 3.9:1 33:1 60 8 4-Chloro phenyl 0.02M 1.9:1 25:1 80 9 4-CF3 phenyl 0.02M 2.0:1 25:1 87 10 4-MeO phenyl 0.02M 1.9:1 25:1 85 11c Ph 0.02M 1.5:1 10:1 b 12d 0.02M 1.5:1 1:1.3 b 13 0.14M 0 1:33 86 14 0.14M 2.0:1 1:1 b 15 4-CF3 phenyl 0.14M 0 1:25 85 a ratio was determined by crude HNMR data. bNo pure isomer was obtained. cMeOH was used instead of water.

Scheme 4.5

54 4.2.2. Mechanistic exploration.

To better understand these observations, a series of additional experiments were conducted (Table 4.3). LDA reacts with H2O to give LiOH and diisopropylamine.

However, under the same reaction condition, when LDA was replaced by the same equivalents of LiOH, no reaction happened (Table 4.3, entry 1). Before addition of

o glycine ester 250, if the LDA-THF-H2O solution is warmed up from -78 C to rt and immediately cooled back to -78 oC, anti-,-diamino ester (-)-251a was obtained in 38% yield (Table 4.3, entry 2). However, if before addition of glycine ester 250, the LDA-

o o THF-H2O solution is warmed up from -78 C to rt for 10 min then cooled back to -78 C, no anti-,-diamino ester (-)-251a was obtained (Table 4.3, entry 3). From these

o observations, it’s reasonable to assume that at -78 C, LDA may coexist with H2O for some time. Based on the existing observations, there is another possibility that a complex of LDA-LiOH-diisopropylamine could exist, which was the active base species.179

Table 4.3. Additional reactions for mechanism exploration.178

Entry Enolate Con. Water:base (-)-251a:(+)-252a a Yield(%) 1b 0.02M 2:1 ----- 0 2c 0.02M 2:1 33:1 38 3d 0.02M 2:1 ----- 0 a Determined by proton NMR of crude mixture. bLiOH was used instead of LDA. cThe - 78 C water-THF-LDA solution was warmed to rt and immediately cooled back to -78 C prior to addition of glycine ester 250. dThe -78 C water-THF-LDA solution was warmed to rt for 10 min and cooled back to -78 C prior to addition of glycine ester 250.

More experiments were conducted to determine whether these products are formed under kinetic or thermodynamic control (Table 4.4). When anti-(-)-251a was treated with 1.1 equiv. LDA at -78 oC in anhydrous THF, the chiral centers isomerized

55 and all four isomers were obtained with the retro-Mannich products (S)-(+)-N-

(benzylidene)-p-toluenesulfinamide (+)-241a and N-(diphenylmethylene)-glycine ethyl ester 250 (Table 4.4, entry 1). Replacement of anhydrous solvent with hydrous THF gave the recovered starting materials anti-(-)-251a along with 10% yield of sulfnimine

(+)-241a and glycine ester 250, respectively (Table 4.4, entry 2). Similar results were obtained on treatment of the syn-diamino ester 252a under the same reaction conditions.

All four isomers were detected in the presence of LDA in anhydrous THF, but with H2O-

LDA, syn-252a was recovered in 80% yield in addition to retro-Mannich products, sulfinime and glycine ester (Table 4.4, entry 3, 4). The most stunning observation is when anti-2,3-diamino ester 251a was treated with 5.0 equiv. of the lithium enolate of glycine ester 250, syn-252a was isolated in 86% yield (Table 4.4, entry 5). But the same reaction in the presence of 1.1 equiv. enolate provided all four isomers (Table 4.4, entry

6). Similar reactions of this enolate with syn-252a only afforded the recovered starting material (Table 4.4, entries 7 and 8).

Table 4.4. Reaction of anti-251a and syn-252a with bases at -78 oC for 1.5 h.178

Entry a Diamino ester LDA (equiv. to diamino ester) Products[Yields (%)]

1 anti-251a LDA (1.1:1) Four isomers[80], (+)- 241a[9], 250[9] 2 anti-251a LDA (1.1:1)b anti-251a [77], (+)- 241a[10], 250[10] 3 syn-252a LDA (1.1:1) Four isomers[86], (+)- 241a[6], 250[6] 4 syn-252a LDA (1.1:1)b syn-252a [80], (+)- 241a[10], 250[10] 5 anti-251a LDA-250 (5:1) syn-252a [82] 6 anti-251a LDA-250 (1.1:1) Four isomers [84] 7 syn-252a LDA-250 (5:1) syn-252a[84] 8 syn-252a LDA-250 (1.1:1) syn-252a[90] a b Water-free THF used unless otherwise noted. H2O:LDA=2.5:1.

56 To explain these novel results, the reasonable assumption is that the reaction between the Z-enolate 255 and sulfinimine (S)-(+)-241a gave the anti-2,3-diamino ester anion anti-256, which is in equilibrium with the chelated anti-258 and kinetically favored

(Scheme 4.5). Similarly, the syn-2,3-diamino ester anion syn-257 is in equilibrium with chelated syn-259. It is thermodynamically favored over anti-258 due to its less steric hindered trans configuration of the phenyl and ester groups.180 In anhydrous THF with

1.1 equiv of LDA, the retro-Mannich reaction of anti-256 or syn-257 regenerates (+)-

241a and enolate 255 to form all four 2,3-diamino ester isomers on reaction of anti-(-)-

251a or syn-(+)-252a, respectively. Retro-Mannich fragmentations of sulfinimine- derived sulfinamide products are usually not observed because the N-sulfinyl group stabilizes anions at nitrogen.181 However, the steric hindrance in sulfinimine-derived sulfinamide and the stability of Z-enolate 255 may favor this fragmentation. In hydrous

THF with 1.1 equiv of LDA, the anion of anti-256 or syn-257 was stabilized by the H2O-

LDA species, so only small amount of products from retro-Mannich reaction were formed. For the same reason, when the enolate 255 was generated in H2O-THF solution and reacted with sulfinimine (+)-241a, the anion anti-256 was also stabilized by H2O-

LDA species and the anti-2,3-diamino ester (-)-251a was obtained on workup. In the presence of 5.0 equiv enolate 255 in anhydrous THF, retro-Mannich fragmentation of anti-(-)-251a gives a mixture of sulfinimine (+)-241a and 5.0 equiv enolate 250, which then reacted with each other to form the thermodynamically favored syn-2,3-diamino ester (+)-252a on workup.

Scheme 4.6

O Ph O Ph S Li S Li p-Tolyl N N Ph p-Tolyl N N Ph

Ph CO2Et Ph )(CO2Et syn-259 anti-258

O H O S O p-Tolyl N Ph S S p-Tolyl N O (S)-(+)-241a p-Tolyl N O Retro-Mannich Retro-Mannich + Ph OEt Ph OEt Li O N N Ph N OEt Ph Ph Ph Ph Ph 255 syn-257 anti-256

H O aq. NH4Cl 2

O O S S p-Tolyl NH O p-Tolyl NH O

Ph OEt Ph OEt N N

Ph Ph Ph Ph syn-(+)-252a anti-(-)-251a (thermodynamic) (kinetic)

4.2.3. Total synthesis of (-)-agelastatin A from sulfinimine-derived syn-,- diamino ester.

(-)-Agelastatin A (233) is an alkaloid having unique tetracyclic structure. It was first isolated from the Coral Sea sponge Agelas dendromorpha by Pietra et al. in 1993.182

This interesting alkaloid not only shows significant antitumor activity against several tumor cell lines, but also selectively inhibits the glycogen synthase kinase-3, which also makes it a potential lead compound for the treatment of Alzheimer’s disease.183,184

Attracted by these properties, considerable effort has been aimed at the asymmetric synthesis of this alkaloid. So far, more than 10 groups have accomplished this

58 goal.172,173,185-199 In 2009, based on the original synthesis route,177 the Davis’ group reported an optimized total synthesis of (-)-agelastatin A (233) from the sulfinimine- derived syn-,-diamino ester (-)-260 (Scheme 4.7). The reaction conditions for several steps with modest and low yields were modified. The total yield was increased from formerly 9% to 23%. To date, this optimized synthesis of (-)-agelastatin A is the most efficient one with 11 steps under eight operations.

Scheme 4.7

O S N CH 3 O HO N O S Br p-Tolyl NH O H NH (R)-(-)-260 N H OEt + NH NBn H 2 Bn N O (S ,2S,3R)-(-)-262 2 R CO Et (-)-Agelastatin A 2 261 233

This total synthesis commenced with preparation of acrolein-derived sulfinimine

(-)-260. Treatment of the sulfinimine (-)-260 with 5.0 equiv. lithium enolate of ethyl

(dibenzylamino) acetate 261 provided the syn-,-diamino ester (-)-262 in 73% yield

(Scheme 4.8). The syn-,-diamino ester (-)-262 was treated with the lithium N,O- dimethylhydroxylamine-THF solution to give the corresponding Weinreb amide (-)-263 in 89% yield. Cleavage of the sulfinyl group afforded a crude amine, which was directly reacted with pyrrole-2-carboxylic acid in the presence of HBTU and DIPEA to generate amide (+)-264 in 88% isolated yield for the two steps. A Grignard reaction with allymagnesium bromide provided a γ-unsaturated ketone intermediate, which was isomerized to diene (-)-265 with Et3N. Ring closing metathesis catalyzed by Grubbs (II) catalyst provided the 4,5-diamino cyclopenten-2-enone (-)-266 in 87% yield.

Scheme 4.8

H O O O H 5.0equiv. Ti(OEt)4 S O S Bn2N CO2Et 261 p-Tolyl NH S p-Tolyl N p-Tolyl NH2 DCM, rt CO2Et 5.0 equiv. LDA, Et2O, (R)-(+)-135 (R)-(+)-260 -78oC NBn2 95% 73% (SR,2S,3R)-(-)-262

O Me S 1) TFA, MeOH, 0oC MeO N O LiN(OMe)Me p-Tolyl NH O THF, -78oC OMe 2) N NBn2 Me N CO2H 89% NBn2 NH H N HBTU, DIPEA, CH3CN, H rt O (SR,2S,3R)-(-)-263 88% (2S,3R)-(+)-264

O MgBr, THF, O Grubbs2nd Catalyst 1) 0oC DCM, rt NBn NBn 2 2) TEA, EtOH, rt 2 NH NH N N H H O 2 steps 85% O 87% (3R,4S)-(-)-265 (1R,5S)-(-)-266

The Michael addition of 4,5-diamino cyclopenten-2-enone (-)-266 was unexpectedly tricky (Scheme 4.9). Treatment of enone (-)-266 with 10 equivalents of

Cs2CO3 in MeOH, gave the desired ring closure product (-)-267 in 68% yield, however, control of the reaction time was critical (Table 4.5, entry 1). It was found that reaction times longer than 16 min resulted in formation of the retro-Michael product cyclopentenone (-)-268 and decomposition (Table 4.5, entry 2). It’s reasoned that the fast reaction rate is connected with the high concentration of basic carbonate anion in MeOH.

By switching the solvent to less polar tetrahydrofuran, the reaction became much easier to control and (-)-268 was not observed. However, the reaction did not go completion.

The highest yield obtained was 66% with recovery of 26% of enone (-)-266. Increasing the reaction time failed to improve the yield and decomposition products were observed

60 (Table 4.5, entry 4). So the recovered (-)-266 was re-subjected to the same reaction condition, resulting in an additional 15% of (-)-267. Thus a combined yield of 81% was finally realized.

Scheme 4.9

O O O Bn Bn Cs CO , solvent, rt N + N NBn2 2 3 N N NH Bn Bn N NH NH H 2 O O O (1R,5S)-(-)-266 (3S,3aR,9aR)-(-)-267 (R)-(-)-268

200 Table 4.5. Conversion of (-)-266 to (-)-267 using 10 equiv of Cs2CO3.

entry Solvent Time (h) Products (% isolated yield) 1 MeOH 0.27 (-)-267 (68); (-)-268 (trace) 2 2 (-)-267 (0); (-)-268 (46)a 3 THF 2 (-)-267 (66); (-)-268 (26) 4 4 (-)-267 (66); (-)-268 (20)a a Decomposition products observed.

Synthesis of the precursor debromo agelastatin A (-)-269 from cyclic enone (-)-

267 required trapping the primary amine intermediate with methyl isocyanate after removal of the benzyl protecting group (Scheme 4.10). However, with the original reaction condition, a significant amount of N-benzyl debromo agelastatin A (-)-270 was obtained (32%)along with debromo agelastatin A (-)-269 in 43% yield. It was speculated that this is because of a slower reaction rate of debenzylation compared to the trapping reaction by methyl isocyanate. Then raising the reaction rate of the deprotecting step by increasing the amount of catalyst may inhibit the formation of N-benzyl debromo

61 agelastatin A (-)-270. So the original 0.08 equiv of 10% Pd/C was switched to 6.5 equiv of 30% Pd/C. Under these new reaction conditions, debromo agelastatin A (-)-269 was obtained in 70% yield. Less than 10% of byproduct (-)-270 was obtained. Finally, treatment of debromo agelastatin A (-)-269 with 1,3-dibromo-5,5-dimethylhydantoin

(271)201 in MeOH-THF (1:2) provided the final product (-)-agelastatin A in 94% yield.

Compared to NBS, 1,3-dibromo-5,5-dimethylhydantoin (271) not only gave a much higher yield (70% vs 91%), but also simplified the procedure. Moreover, unlike NBS,

1,3-dibromo-5,5-dimethylhydantoin is quite stable at room temperature and can be used without any purification.

Scheme 4.10

Me Me O HO HO N O N O Bn N Pd/C, MeNCO, THF NH N N N + N Bn Bn NH H2, rt, 12 h NH NH

O O O (3S,3aR,9aR)-(-)-267 (-)-269 (-)-270

0.08 equiv.10%Pd/C 47% 32%

6.5 equiv. 30%Pd/C 70% 10%

Me HO N O Br THF, rt NH N NH

O (-)-agelastatin A 233 O Br N 91% O N Br 271

O Br N 70% O

In summary, an improved synthesis of the novel marine alkaloid (-)-agelastatin A

(233) has been accomplished by employing THF to optimize the Michael addition, (-)-

62 266 to (-)-267, increasing the efficiency of the N-benzyl deprotection step by using excess 30% Pd-C, (-)-267 to (-)-269, and employing 1,3-dibromo-5,5-dimethylhydantoin

271 to brominate (-)-269. The result was 11 steps (eight operations) with an overall yield of 23% from the sulfinimine.

63 CHAPTER 5

ASYMMETRIC SYNTHESIS OF TRANS--ALKYL -AMINO ESTERS

5.1. Introduction.

The asymmetric synthesis of optically pure -amino acids and derivatives continues to be an important area of study because of their valuable biological properties and their utility as chiral building blocks. Many molecules having this moiety show antibiotic and antitumor activities, such as (-)-cispentacin (272), a new antibiotic compound isolated from the culture broth of a Bacillus cereus strain, and antitumor molecule taxol (273) (Figure 5.1).202 Furthermore, due to their similarity in structure to

-amino acids, -amino acids also have applications in an increasing range of therapeutic areas.203 For these reasons, many methods have been developed for the synthesis of - amino acids.99,202,204,205 However, only a few methods result in enantiopure acyclic - substituted -amino acids and their derivatives.206-208

O OH Bz NH2 NH O

O O CO2H OH OH OBz OAc (-)-cispentacin 272 Taxol 273

Figure 5.1. Molecules having the -amino acids structure.

5.2. Previous syntheses of -substituted -amino esters from sulfinimines.

As valuable building blocks, sulfinimines have been employed by several groups to prepare -substituted -amino esters. A strategy to prepare -substituted -amino esters is the addition of prochiral enolates to sulfinimines. An early example was reported by Ellman in 2002 (Scheme 5.1).205 The reaction between titanium enolates of

-substituted esters 274a-c and a variety of N-t-butylsulfinyl imines 273a-d provided the

64 corresponding -substituted -amino esters 275a-e in high yields and diastereoselectivities (Table 5.1). The best diastereoselectivity (95:3:2:0) was observed when methyl propionate 274a (R2 = Me) was reacted with sulfinimine (+)-273c (R1 = i-

Bu) (Table 5.1, entry 2). Switching from methyl propionate 274a (R2 = Me) (Table 5.1, entries 1-3) to esters 274b (R2 = Bn) and 274b (R2 = 4-MeOBn) resulted in lower yields and decreased stereoselectivities (Table 5.1, entries 4-5).

Scheme 5.1

Table 5.1. Synthesis of -substituted -amino esters from sulfinimines (+)-273a-d.205

entry t- -substituted Yield dr butylsulfinimine esters (%) 1 (+)-273a 274a 96 92:7:1:0a 2 (+)-273c 274a 81 95:3:2:0a 3 (+)-273d 274a 85 88:12:0:0b 4 (+)-273b 274b 67 90:10:0:0a 5 (+)-273a 274c 65 83:17:0:0a a Diastereomeric ratios determined through peak integration from HPLC analysis of filtered, crude reaction mixtures. b Diastereomeric ratios determined through 1H NMR integration of crude reaction mixtures; the other two isomers were not observed.

The addition of prochiral Weinreb amide enolates to sulfinimines was explored by

Davis and coworkers (Scheme 5.2).207 Addition of the prochiral Weinreb amide enolate of N-methoxy-N-methylpropylamide (277) to sulfinimine (+)-241a (Z = 4-MePh) gave syn isomer (+)-278a as the major product in good selectivity, regardless of the base and

65 solvent employed (Table 5.2, entries 1-4). However, all four diastereoisomers were detected and they were not separable by conventional chromatography. It should be noted that when KHMDS was employed, no reaction was observed and starting materials were recovered (Table 5.2, entry 5). Switching from p-toluenesulfinamine (+)-241a to the more bulky t-butylsulfinimine (-)-273d (Z = t-butyl) results in no reaction and recovery of the starting material (Table 5.2, entry 6). Weinreb amide enolate addition to the N-(2,4,6-mesitylsulfinyl) imine (+)-276a (Z = 2,4,6-Me3C6H2) and the N-(2,4,6- triisopropylphenylsulfinyl) imine (+)-276b (Z = 2,4,6-i-Pr3C6H2) provided the corresponding syn-diasteromers in 68% and 76% isolated yields, respectively (Table 5.2, entries 7-8).

Scheme 5.2

207 Table 5.2. Synthesis of -Substituted -Amino Weinreb Amides.

entry sulfinimine base solvent yield (%)a drb 1 (+)-241a LiHMDS THF 99 87:13:<1:trace 2 THF:Et2O (1:1) 35 93:7:trace 3 NaHMDS THF 67 91:6:3:0 4 Et2O 99 73:17:9:1 5 KHMDS THF NR 6 (-)-273d LiHMDS THF NR 7 (+)-276a LiHMDS THF 99 (68)c 96:4:0:0 8 (+)-276b LiHMDS THF 74 (76)c 92:5:3:0 a yields of all diastereomers b Diastereomeric ratios determined through 1H NMR integration of crude reaction mixtures. c yields of syn-278 diastereomers

66 Another way to form -substituted -amino esters is via the stereoselective reduction of the double bond in sulfinimine-derived -(aminoalkyl) acrylates (aza-

Morita-Baylis-Hillman) adducts. Several groups have reported studies on the synthesis of sulfinimine-derived -(aminoalkyl) acrylates.200,201,209 For example, from p- toluenesulfinimine (+)-241a, Aggarwal prepared (Ss,R)-methyl 2-[phenyl(p- toluenesulfinylamino)methyl]-acrylate (+)-282 and (Ss,S)-Methyl 2-[phenyl(p-

209 toluenesulfinylamino)methyl]-acrylate (-)-283 with a ratio of 18:82 (Scheme 5.3).

Scheme 5.3

5.3. Present study.

The goal of this study is to develop new methodology for the asymmetric synthesis of -substituted -amino esters from enantiopure sulfinimines. The retrosynthetic approach is given in Figure 5.2. It was planned to synthesize the key intermediate -(aminoalkyl) acrylates (aza-Morita-Baylis-Hillman) adducts from sulfinimines, which on catalytic asymmetric hydrogenation would give to the desired - substituted -amino esters.

O O S S Z NH O Z NH O O H S R OEt R OEt Z N R

R' R' a-alkyl-b-amino ester Aza-Morita-Baylis-Hillman Sulfinimine adduct

Figure 5.2. Retrosynthetic approach to -alkyl--aminoesters.

67 5.3.1. Synthesis of -alkyl -amino ester from enantiopure sulfinimines.

5.3.1.1. Synthesis of -amino-acrylate via the aza-Morita-Baylis-Hillman

(MBH) reaction.

The synthesis of -alkyl -amino ester started with treatment of (S)-(+)-N-

(benzylidene)-p-toluenesufinamide (241a) with vinylaluminium reagents 286 (R = Et) or

287 (R = Me) prepared according to Ramachandran's protocol, in which the vinylaluminium reagents were synthesized from DIBAL, -acetylenic esters and 4- methylmorpholine N-oxide (NMO) (Scheme 5.4).210 To obtain a high yield of acrylate adduct (Ss,R)-(+)-288, 3.0 equiv ethyl propiolate 284, 4.5 equiv DIBAL and 6.0 equiv

NMO were required, otherwise, the yield dropped to 19% (Table 5.3, entry 2). In this way, a yield of 65% was obtained along with good selectivity (7:1) (Table 5.3, entry 2).

It was also observed that the selectivity was not sensitive to either the sulfinimine concentration or the addition of Lewis acids (Table 5.3, entries 3-5). Switching from ethyl propiolate 284 to methyl propiolate 285 resulted in slightly better selectivity, but the yield dropped from 65% to 32% (Table 5.3, entry 6).

Scheme 5.4

O H S p-Tolyl N Ph O S NMO, DIBAL, (i-Bu) Al CO R (+)-241a, p-Tolyl NH O CO R 2 2 2 THF, 0oC Ph OR 284: R = Et 285: R = Me 286: R = Et 287: R = Me (Ss,R)-(+)-288: R = Et (Ss,R)-(+)-282: R = Me

68 Table 5.3. Synthesis of -amino-acrylate (+)-282 and (+)-288 via aza-Morita-Baylis- Hillman (MBH) reaction.211

entry NMO:DIBAL:Alkyne alkyne catalyst product dr a yield(%)b [dr] c (equiv) 1 2.0:1.5:1.0 284 (+)-288 9:1 17 2 6.0:4.5:3.0 284 (+)-288 7:1 65 f [20:1] c 3d 6.0:4.5:3.0 284 (+)-288 6:1 65 f [20:1] c 4e 6.0:4.5:3.0 284 (+)-288 7:1 60 f [20:1] c f c 5 6.0:4.5:3.0 284 Zn(OTf)2 (+)-288 8:1 63 [20:1] 6 6.0:4.5:3.0 285 (+)-282 8:1 32 f [28:1] c a Determined by 1H NMR on the crude reaction mixture. b Combined yield of two isomers unless otherwise noted. c Dr of purified major isomers, determined by 1H NMR of on purified major isomers. d Compared to entry 1, the concentration of sulfinimine was doubled. e.Compared to entry 1, the concentration of sulfinimine was decreased by 50%. f Isolate yields of major isomers.

To confirm the absolute configuration of acrylate (+)-288 and its analog (Ss,R)-

(+)-282, (+)-288 was converted into products with known absolute stereochemistry.

Hydrogenation of acrylate (+)-288 with cationic rhodium complex 289 gave a 22:1

mixture of diastereoisomers with isolation of the major diastereoisomer (Ss,2R,3S)-(+)-

290 in 88% yield (Scheme 5.5). Oxidation with m-CPBA followed by hydrolysis

provided the known acid (2R,3S)-(-)-293.212,213 The acid was treated with DCC/4-

pyrrolidinopyridine to give known lactam (3R,4S)-(-)-294. Both the rotation and the 1H

NMR spectra of acid (-)-293 and lactam (-)-294 were consistent with the reported

values.212 In this way, the absolute configurations of (Ss,R)-(+)-288 and (Ss,R)-(+)-282

were established.

O S p-Tolyl NH O

Ph OMe

(Ss,S)-(-)-283

Figure 5.3. Structure of acrylate 283.

69 Scheme 5.5

The observed selectivity in the formation of (+)-288 can be explained by a non- chelation control model in which the vinylaluminum species 286 adds to sulfinimine (+)-

241a from its less hindered side to generate a new chiral centre (Figure 5.3).214 The presence of NMO, which acts as a ligand to the aluminum species, may interrupt the chelation between the aluminum species and the sulfinyl oxygen preventing the formation a chelated transition state.215

Figure 5.4. Model to explain the selectivity in the formation of acrylate (+)-288.

(i-Bu)2Al CO2R

286: R = Et

Figure 5.5. Structure of vinylaluminium reagent 286.

70 With the optimized conditions, several additional reactions were done to explore the scope of the methodology with other sulfinimines (Scheme 5.6). When t- butylsulfinimine (+)-273d (R2 = Ph) was subjected to the original reaction conditions, no reaction was observed. However, utilization of ZnBr2 as the catalyst led to a 41% yield of an inseparable mixture of diasteromers with poor 73:27 selectivity (Table 5.4, entries

1-2). Increasing the temperature to 45 oC and extending the reaction time provided 12:1 selectivity. Chromatographic separation of the reaction mixture afforded a single isomer

(-)-295 in low yield (38%) (Table 5.4, entries 3-4). When the reaction temperature was raised to 70 oC, a 65% yield of acrylate (-)-295 was obtained without loss of selectivity

(Table 5.4, entry 5). Switching from t-butylsulfinimine (+)-273d (R = Ph) to (+)-273b (R

= Et) led to poorer selectivity (8:1) and the yield of the isolated major diasteromer (-)-296 was less than 50% (Table 5.4, entries 6-7). Finally, the reaction between methyl propiolate 285 and sulfinimine (+)-273d (R = Ph) provided the corresponding acrylate (-

)-297 in 44% yield and a dr of 65:1 after purification. A higher yield (58%) was obtained when the amount of vinylaluminum reagents as doubled (Table 5.4, entries 8-9).

Scheme 5.6

O S NH O NMO, DIBAL, CO R 2 1 THF, 0oC, then R2 OR1

284: R1 = Et O H (SR,S)-(-)-295: R1 = Et, R2 = Ph 285: R1 = Me - S (SR,S) (-)-296: R1 = Et, R2 = Et N R2 - (SR,S) (-)-297: R1 = Me, R2 = Ph

(+)-273d: R2 = Ph (+)-273b: R2 = Et

71 Table 5.4. Reactions of vinylaluminum reagent with sulfinimines (+)-273b and (+)-

273d.211 entry alkyne, equiv sulfinimine temp,oC dr a product,yield(%)b (NMO:DIBAL:Alkyne) (h) [dr]c 1 284: R = Et, (6.0:4.5:3.0) (+)-273d 25 (7) NR NR 2 284: R = Et, (6.0:4.5:3.0) (+)-273d 25 (23) 3:1 (-)-295, 41b, d 3 284: R = Et, (6.0:4.5:3.0) (+)-273d 45 (7) NR NR 4 284: R = Et, (6.0:4.5:3.0) (+)-273d 45 (18) 12:1 (-)-295, 38e [99:1] c 5 284: R = Et, (6.0:4.5:3.0) (+)-273d 70 (18) 12:1 (-)-295, 65e [99:1] c 6 284: R = Et, (6.0:4.5:3.0) (+)-273b 70 (18) 8:1 (-)-296, 41b 7 284: R = Et, (12.0:9.0:6.0) (+)-273b 70 (15) 8:1 (-)-296, 46b 8 285: R = Me, (6.0:4.5:3.0) (+)-273d 70 (18) 8:1 (-)-297, 44e [65:1] c 9 285: R = Me,(12.0:9.0:6.0) (+)-273d 70 (18) 8:1 (-)-297, 58e [65:1] c a Determined by 1H NMR on the crude reaction mixture. b Combined yield of two isomers unless otherwise noted. c Dr of purified major isomers, determined by 1H NMR of on d e purified major isomers. ZnBr2 was added as Lewis acid catalyst. Isolate yields of major isomer.

The addition of -substituted propiolate 299 (R2 = Ph) derived vinylaluminum

reagents to p-toluenesulfinimine (+)-241a (R = Ph) was next explored. However,

chromatography failed to separate a pure diastereoisomer. Switching from p-

toluenesulfinimine (+)-241a to t-butylsulfinimine (+)-273b (R1 = Et) provided the major

isomer (-)-300 as a 6.2:1 mixture of diastereoisomers. The major diastereoisomer (-)-300

was isolated in 35% yield with a dr of greater than 92:1 (Table 5.7, entry 1). Similar

results were also observed when sulfinimine (+)-273d (R1 = Ph) was reacted with -

substituted propiolates 298 (R2 = Me) and 299 (R2 = Ph), respectively (Table 5.3, entries

2-3).

72 Scheme 5.7

NMO,DIBAL,R CO Et O 2 2 O S S N 298, R2 = Me NH O 299, R2 = Ph H R1 R1 OEt THF, 0 to 70oC (+)-273b: R1 = Et R2 (+)-273d: R1 = Ph (-)-300: R1 = Et, R2 = Ph (-)-301: R1 = Ph, R2 = Me (-)-302: R1 = Ph, R2 = Ph

Table 5.5. Reactions of -substituted vinylaluminum reagents to sulfinimines (-)-273b and (-)-273d. 211 entry sulfinimine Alkyne time (h) dr a product, yield(%) b (NMO:DIBAL:Alkyne) [dr] c d c 1 (+)-273b 299: R2 = Ph (6.0:4.5:3.0) 15 6.2:1 (-)-300, 35 [92:1] d c 2 (+)-273d 298, R2 = Me (6.0:4.5:3.0) 18 7:1 (-)-301, 71 [90:1] d c 3 (+)-273d 299, R2 = Ph (6.0:4.5:3.0) 18 7:1 (-)-302, 73 [32:1] a Determined by 1H NMR on the crude reaction mixture. b Combined yield of two isomers. c Dr of purified major isomers, determined by 1H NMR of on purified major isomers. d Isolate yields of major isomers.

5.3.1.2. Hydrogenation of aza-MBH adducts with organometallic catalysts.

The reduction of the aza-MBH adducts to -substituted -amino acids was next examined. When rhodium complex 289 was treated with acrylate (Rs,S)-(-)-295 at 1 atm of H2 for 48 h, selectivity of >1:21 and a high isolated yield of the major diastereomer

(Rs,S)-(-)-306 (>81%) were obtained (Table 5.6, entry 3). For the reduction of the methyl ester derivative (SR,S)-(-)-296 with catalyst 289, similar syn/anti ratio (1:25) and an isolated yield of (Rs,S)-(-)-307 (83%) were observed (Table 5.6, entry 4). However, when R1 is an ethyl group, the hydrogenation afforded a 1:9 mixture of inseparable diastereoisomers (Table 5.6, entry 5)

73 Scheme 5.8

O O O S S S NH O NH O H2 NH O R2 + R2 R2 R1 O R1 O R1 O

- (S ,2R,3S)-(-)-303 (S ,2S,3S)-306 (SR,S) (-)-295: R1 = Ph, R2 = Et R R - (S ,2R,3S)-(-)-304 (S ,2S,3S)-307 (SR,S) (-)-296: R1 = Ph, R2 = Me R R - (S ,2R,3S)-(-)-305 (S ,2S,3S)-308 (SR,S) (-)-297: R1 = Et, R2 = Et R R

Table 5.6. Hydrogenation of aza-MBH adducts with organometallic catalysts.211

entry acrylate catalyst/loading time (h), temp syn:anti Product, o a (mol%) atm of H2 ( C) yield (%)

1 (-)-295 289/7.5 48, 1 25 1:21 (-)-306, 83 2 (-)-296 289/7.5 48, 1 25 1:25 (-)-307, 81 3 (-)-297 289/7.5 48, 1 25 1:9 (-)-308, 77b a yield of isolated major isomer. b Combined yield of two isomers.

Ph Ph P Rh+ P + BF4 Ph Ph

289

Figure 5.6. Structures of catalyst 289.

Based on the results in Table 5.6, the rhodium complex 289 was used to reduce the other aza-MBH adducts (Scheme 5.9). These results were summarized in Table 5.7.

Due to the steric hindrance associated with substituents on the double bond, no reaction of acrylate (-)-301 (R1 = Ph, R2 = Me) was detected at 1 atm of H2 (Table 5.7, entry 1).

When the pressure of H2 was increased to 25 atm, -alkyl--amino ester (-)-312 was formed as a 1:20 mixture of diastereomers with isolation of the major diastereomer in

81% yield (Table 5.7, entry 2). For -amino-acrylate (-)-300 (R1 = Et, R2 = Ph) and (-)-

302 (R1 = Ph, R2 = Ph), similar results were obtained (Table 5.7, entries 3-4).

74 Scheme 5.9

O O O S S S NH O H2 NH O NH O + Et Et Et R1 O R1 O R1 O

R2 R2 R2 - (Rs,S) (-)-300: R1 = Et, R2 = Ph (Rs,2S,3R)-(-)-309 (Rs,2R,3R)-(-)-312 - (Rs,S) (-)-301: R1 = Ph, R2 = Me (Rs,2S,3R)-(-)-310 (Rs,2R,3R)-(-)-313 - (Rs,2S,3S)-(-)-311 (Rs,2S,3R)-(-)-314 (Rs,S) (-)-302: R1 = Ph, R2 = Ph

Table 5.7. Hydrogenation of products of aza-MBH reactions with catalyst 289.

211

entry acrylate atm of H2 time (h) solvent syn:anti product, yielda(%) 1 (-)-301 1 48 DCM ------2 (-)-301 25 72 DCE 1:20 (-)-310, 81 3 (-)-300 25 72 DCE 1:20 (-)-309, 79 4 (-)-302 25 72 DCE 1:17 (-)-311, 79 a yield of isolated major isomer. b Combined yield of two isomers. ccatalyst loading 7.5mol% at 25oC

In summary, new methodology was developed for the preparation of N-sulfinyl acrylates (aza-Morita-Baylis-Hillman adducts) with good selectivities and moderate to good yields by reaction of vinylaluminum NMO reagents with sulfinimines (N-sulfinyl imines). Hydrogenation of the aza-MBH adducts with rhodium metal catalyst afford anti--substituted N-sulfinyl--amino esters with excellent selectivities. This new methodology is useful to prepare versatile building block anti--alkyl--amino esters in the synthesis of more complex compounds.

75 CHAPTER 6

EXPERIMENTAL SECTION

General Procedures. Reagents and solvents were purchased from Sigma-

Aldrich Company or Acros Organics and used without additional purification unless otherwise mentioned. Anhydrous tetrahydron Furan (THF), diethyl ether (Et2O), toluene

(PhMe) and methylene chloride (DCM) were purified by filtration on a Glass Contour

Solvent Dispensing System. Melting points were recorded on a Mel-Temp equipment.

Optical rotations were masured on a Perkin-Elmer 341 polarimeter. Infrared spectra were measured on a Perkin-Elmer 1600 FTIR spectrometer. 1H, 13C and 15P NMR spectra were measured with Varian 300MHz NMR, Bruker 400MHz or GE Omega 500MHz spectrometer. High resolution mass spectra (HRMS) were measured by the Departement of Chemistry at Drexel University. Column chromatography was performed on silica gel,

Merck grade 60 (230-400 mesh). TLC plates were visualized with UV, in an iodine chamber, or with phosphomolybdic acid, unless noted otherwise.

Water-THF solution was prepared with the following procedure

In a 50-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed 32-mL THF from Glass Contour

Solvent Dispensing System, which has a water concentration of 0 ppm. Add 29-uL of water (HPLC grade, from Fisher) to the flask via a syringe. Stir the solution for 5 min and water concertration in THF is measure the water concentration with Karl Fisher Titrator.

Store the flask in a desiccator.

(SR,1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-methylbenzenesulfinate

(134),100 (S) or (R)-p-toluenesulfinamide (135),101 (R)-(+)-2,4,6-

76 trimethylbenzenesulfinamide (143b),105 (R)-(+)-2,4,6-triisopropylbenzenesulfinamide

(216),105 (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (241a),101 (S)-4-methyl-N-(4-

(trifluoromethyl)benzylidene)benzenesulfinamide (241b),101 (S)-N-(4- chlorobenzylidene)-4-methylbenzenesulfinamide (241d),101 (S)-N-(4- methoxybenzylidene)-4-methylbenzenesulfinamide (241e),101 were prepared according to literature procedure.

O S p-Tolyl N C9H15

(R)-(-)-N-(2,4-Decaylidene)-p-toluenesulfinamide (149). In an oven-dried, 250- mL one necked, round-bottomed flask equipped with a magnetic stirring bar was placed

E,E-2,4-decadienal (3.6 mL, 20 mmol) in CH2Cl2 (100 mL). Titanium (IV) ethoxide (22 mL, 100 mmol) and (R)-(-)-p-toluenesulfinamide (2.83 g, 18.2 mmol) were added and the reaction mixture was stirred at rt for 12h. At this time, the reaction was quenched by addition of ice-H2O (40 mL) and filtered through Celite. The organic phase was washed with brine (20 mL), dried (Na2SO4), and concentrated. Flash chromatography (30%

EtOAc/hexanes) afforded 4.47 g (77%) of 149 as an oil. Spectral properties were consistent with literature values.133

p-Tolyl S NH O

C5H11 OMe

(Rs,S)-(-)-Methyl-3-N-(p-toluenesulfinyl)amino-3-dodeca-4,6-dienoate(150).

In an oven-dried, 500-mL one necked, round-bottomed flask equipped with a magnetic

77 stirring bar, rubber septum and an argon balloon was placed NaHMDS (18 mL, 1.0M solution in THF) in ether (200 mL) and the solution was cooled to -78oC. Anhydrous methyl acetate (1.5 mL, 18 mmol) was added dropwise and the reaction mixture was stirred at -78oC for 50 min. In another 100-mL round-bottom flask was placed 149 (3.5 g, 12.2 mL) in ether (50 mL). The solution was transferred to the 500-mL, round-flask containing NaHMDS and anhydrous methyl acetate via cannula at -78oC. The reaction

o mixture was stirred at -78 C for 4 h and quenched at this temperature with sat. NH4Cl solution (20 mL), and warm to rt. After diluted with H2O (20 mL), the aqueous phase was washed with EtOAc (2×50 mL) and the combined organic phase were washed with brine (30 mL), dried (Na2SO4), and concentrated. Flash chromatography (50%

20 EtOAc/hexanes) afforded 3.53 g (80%) of 150 as an colorless oil. [] D = -105.0 (c 1.32,

133 CHCl3). Spectral properties were consistent with literature values.

O S p-Tolyl NH O O OMe P OMe

Dimethyl (Rs,S,5E,7E)-(-)-4-(4-methylphenylsulfinamido)-2-oxotrideca-5,7- dienyl-phosphonate (163). In an oven-dried, 500-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed n-

BuLi (2.5 M in cyclohexane, 26.5 mL, 66.0 mmol) in THF (185 mL) and the solution was cooled to -78 oC. To the solution, dimethyl methylphosponate (7.0 mL, 66.0 mmol) was added dropwise by syringe. After 15 min, the mixture was transferred to an oven- dried, 500-mL one necked, round-bottomed flask containing the 150 (3.0 g, 8.25 mmol) in THF (180 mL) -78oC. After the stirring the solution at -78oC for 2 h, the reaction was

78 quenched with sat. NH4Cl solution (20 mL) at this temperature, and warm to rt. After diluted with H2O (20 mL), the aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phase were washed with brine (30 mL), dried (Na2SO4), and concentrated. Flash chromatography (EtOAc) afforded 3.00 g (80%) of 163 as an oil.

20 [] D = -86.7 (c 0.655, CHCl3) ; IR (neat): 3188, 1715, 1257 (P=O), 1032 (POC), 811

-1 1 cm ; H NMR (CDCl3)  0.89 (t, J = 6.8 Hz, 3 H), 1.26-1.38 (m, 6 H), 2.07 (dd, J = 6.8

2 Hz, J = 13.6 Hz, 2 H), 2.41 (s, 3 H), 2.97 ( d, J = 5.6 Hz, 2 H), 3.06 (d, J HCP = 22.8 Hz, 2

3 3 H), 3.74 (d, J HCOP = 3.6 Hz, 3 H), 3.77 (d, J HCOP = 3.6 Hz, 3 H), 4.32 (m, 1 H), 4.68 (d, J

= 6.4 Hz, 1 H), 5.58 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 5.73 (m, 1 H), 6.00 (dd, J = 10.0

Hz, J = 14.8 Hz, 1 H), 6.25 (dd, J = 10.4 Hz, J = 14.8 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 2 H),

13 1 7.58 (d, J = 8.0 Hz, 2 H); C NMR  14.3, 21.7, 22.8, 29.2, 31.7, 32.9, 41.7 (d, J cp =

2 127 Hz), 50.3, 52.9, 53.4(d, J cop = 6.5 Hz), 125.8, 129.4, 129.7, 129.9, 133.5, 136.9,

2 31 141.7, 142.7, 200.3 (d, J ccp = 5.8 Hz). P NMR (CDCl3)  21.89. HRMS calcd. for

C22H35NO5PS (M + H): 546.1974. Found 546.1971.

O O NH O O OMe P OMe

Dimethyl (S, 5E, 7E)-(+)-2-oxo-N-(tert-butoxycarbonyl)-4-amino-trideca-5,7- dienyl-phosphonate (164). In an oven-dried, 500-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed

163 (2.25 g, 4.95 mmol) in anhydrous methanol (85 mL). The solution was cooled to 0 oC and TFA (1.90 mL, 24.7 mmol) was added via syringe. The reaction mixture was slowly warmed to rt and stirred for 2 h before concentration. At this time, THF (100 mL)

79 o was added to the flask and the solution was cooled to 0 C in an ice bath, NEt3 (4.1 mL,

29.7 mmol), DMAP (60 mg, 0.49 mmol), di-tert-butyl dicarbonate (6.0 mL, 6.0 mmol,

1.0M in THF) were added in sequence. The reaction was stirred at 0 oC for 3 h, quenched by addition of H2O (40 mL), and extracted with Et2O (80 mL) and EtOAc (2×80 mL), and the combined organic phase were washed with brine (30 mL), dried (Na2SO4), and concentrated. Flash chromatography (67% EtOAc/hexanes) afforded 1.80 g (87%) of

20 164 as an light yellow oil. [] D = 11 (c 2.2, CHCl3); IR (neat): 3306, 1715, 1518, 1366,

-1 1 1253 (P=O), 1172, 1034 (POC), 990 cm ; H NMR (CDCl3)  0.85 (t, J = 6.8 Hz, 3 H),

1.24-1.35 (m, 6 H), 1.40 (s, 9 H), 2.01 (qt, J = 7.2 Hz, J = 14.0 Hz, 2 H), 2.80-3.20 ( m, 4

3 H), 3.74 (s, 3 H), 3.76 (d, J HCOP = 0.4 Hz, 3 H), 4.50 (m, 1 H), 5.05 (br.s., 1 H), 5.49 (dd,

J = 6.0 Hz, J = 15.2 Hz, 1H), 5.64 (m, 1 H), 5.93 (dd, J = 10.8 Hz, J = 15.2 Hz, 1 H),

6.08 (dd, J = 10.0 Hz, J = 15.2 Hz, 1 H),; 13C NMR  14.3, 22.8, 28.7, 29.2, 31.7, 32.9,

1 2 41.7 (d, J cp = 126.8 Hz), 49.0, 53.36, 53.45(2 x d, J cop = 6.3 Hz), 80.0, 129.5, 129.7,

31 131.7, 136.3, 155.4, 200.4. P NMR (CDCl3)  22.17. HRMS calcd. for C20H37NO6P

(M + H): 418.2359. Found 418.2357.

O O NH O O OMe P OMe

Dimethyl (R)-(+)-2-oxo-N-(tert-Butoxycarbonyl)-4-amino-2-oxo-tridecyl- phosphonate (165). In an oven-dried, 250-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an H2 balloon was placed 164

(1.23 g, 2.95 mmol) and 10% Pd/C (0.22 mg, 0.20 mmol) in anhydrous methanol (100 mL). The solution was evacuated and then filled with H2, and this sequence was repeated

80 5 times and was stirred for 12 h at rt. The catalyst was removed by filtration through

Celite and the filtrate was concentrated. Flash chromatography (50% EtOAc/hexanes)

20 afforded 1.18 g (95%) of 165 as an light yellow oil. [] D = 36.0 (c 0.47, CHCl3).

Spectral properties were consistent with literature values.216

O O NH O O OMe P OMe N2

Dimethyl-(R)-(+)-1-diazo-2-oxo-N-(tert-butyloxycarbonyl)-4-amino-tridecyl- phosphonate (166). In an oven-dried, 250-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed

NaH (60% in mineral oil, 0.21 g, 5.15 mmol), which was washed by petroleum ether (10 mL). After removal of the petroleum ether by syringe, the flask was placed under vacuum for 2 min, and THF (25 mL) was added by syringe. In another 100-mL, round- bottom flask was placed 165 (1.10 g, 2.59 mmol) and 4-acetamidobenznesulfonyal amide

(0.58 g, 2.46 mmol) in THF (62 mL). The solution was transferred to the 250-mL, round- flask containing NaH and THF via cannula at rt. After stirring for 1 h, the reaction mixture was quenched by addition of sat. NH4Cl solution (20 mL), extracted with Et2O

(80 mL) and EtOAc (2×80 mL), and the combined organic phase were washed with brine

(30 mL), dried (Na2SO4), and concentrated. Flash chromatography (50%

20 EtOAc/hexanes) afforded 0.94 g (81%) of 166 as an light yellow oil. [] D = 18.0 (c

0.745, CHCl3). Spectral properties were consistent with literature values.

81 O

C9H19 N P(OMe)2 Boc O

Dimethyl (2S,5R)-(+)- N-(tert-butyloxycarbonyl)-3-oxo-5-nonyl-pyrrolidine-2- phosphonate (167). In an oven-dried, 250-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, and an argon balloon was placed diazophosphonate 166 (0.90g, 2.0 mmol), rhodium (II) acetate dimmer (35 mg, 0.08

o mmol, 4 mol%) in CH2Cl2 (60 mL). The reaction mixture was stirred for 16 h at 35 C.

At this time, the solution was washed with H2O (2×15 mL) and extracted with CH2Cl2

(2×30 mL). The combined organic phase were washed with brine (10 mL), dried

(Na2SO4), and concentrated. Flash chromatography (25% EtOAc/hexanes) afforded 0.68

20 g (81%) of 167 as an light yellow oil. [] D = 44.8 (c 2.31, CHCl3). Spectral properties were consistent with literature values.216

Ph C9H19 N Boc one isomer

(5R)-(-)-tert-Butyl 2-benzylidene-5-nonyl-3-oxopyrrolidine-1-carboxylate

(168a). In a 100 mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaH (60% in mineral oil, 0.060 g, 1.50 mmol), which was washed by petroleum ether (5 mL). After removal of the petroleum ether by syringe, the NaH was placed under vacuumed for 2 min, THF (15 mL) was added by syringe, and the solution was cooled to 0 C. In a 50 mL round- bottom flask was placed (+)-167 (0.414 g, 0.99 mmol) and benzaldehyde (0.116 g, 1.09

82 mmol) in THF (25 mL) and the solution was transferred to the 100 mL round-bottom flask containing the NaH via cannula. After stirring the reaction mixture at 0 C for 1 h, sat. aqueous NH4Cl (5 mL) was cautiously added. After dilution with H2O (5 mL) the solution was extracted with Et2O (20 mL) and EtOAc (2  20 mL). The combined organic phases were washed with brine (5 mL), dried (MgSO4), and concentrated. Flash

20 chromatography (EtOAc: hexane, 1:1) afforded 0.336 g (85%) of a yellow oil. []D -

-1 1 3.0 (c 0.3, CHCl3); IR (neat) 3405, 1722 cm ; H NMR (CDCl3)  0.78 (t, J = 6.9 Hz, 3

H), 1.16-1.21 (m, 14 H), 1.31-1.44 (m, 1 H), 1.49 (s, 9 H), 1.64-1.68 (m, 1 H), 2.19 (dd, J

= 1.3 Hz, J = 17.6 Hz, 1 H), 2.64 (dd, J = 9.2 Hz, J = 17.6 Hz, 1 H), 4.29-4.34 (m, 1 H),

13 7.17-7.48 (m, 5 H); C NMR (CDCl3)  14.5, 23.0, 25.6, 28.7, 29.6 (2 C), 29.81, 29.88,

32.2, 36.0, 41.5, 54.5, 81.9, 122.8, 128.0, 128.2, 130.3, 132.1, 134.6, 152.9, 199.0.

Because of the instability of this compound it was not possible to obtain an HRMS.

Ph C9H19 N Boc

(2S,5R)-(+)-tert-Butyl 2-Benzyl-5-nonyl-3-oxopyrrolidine-1-carboxylate

(169a). In a 100 mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, and rubber septum was placed (-)-168a (0.14 g, 0.35 mmol) and Pd/C (10%,

0.040 g) in MeOH (20 mL). A hydrogen balloon was attached and the reaction mixture was stirred for 16 h at rt. At this time the solution was filtered through Celite®, washed with MeOH (2  10 mL), Et2O (10 mL), and concentrated. Flash chromatography

20 (EtOAc:hexane, 1:9) afforded 0.099 g (70%) of a colorless oil. [] D +92.4 (c 1.2,

-1 1 CHCl3); IR (neat) 2926, 1711 cm ; H NMR (CDCl3)  0.77 (t, J = 6.9 Hz, 3 H), 0.93-

83 1.20 (m, 16 H), 1.40 (s, 9 H), 1.81 (d, J = 18.8 Hz, 1 H), 2.51 (dd, J = 9.6 Hz, J = 18.6

Hz, 1 H), 3.06-3.12 (m, 2 H), 3.91 (br.s., 1 H), 4.09 (br.s., 1 H), 6.97 (d, J = 6.7 Hz, 2 H),

13 7.09-7.13 (m, 3 H); C NMR (CDCl3)  14.5, 23.0, 26.5, 28.8, 29.61, 29.66, 29.7, 29.8,

32.2, 36.2, 42.7, 54.4, 64.8, 80.6, 127.1, 128.6, 130.7, 137.4, 155.0, 213.9. HRMS calcd for C25H39NO3Na (M+Na) 424.2828. Found 424.2833.

Ph C9H19 N CH3

(+)-Preussin

(2S,3S,5R)-(+)-2-Benzyl-1-methyl-5-nonyl-pyrrolidin-3-ol (144) (Preussin). In a 50 mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, reflux condenser and argon balloon was placed (+)-169a (0.030 g, 0.075 mmol) in Et2O (10 mL). LiAlH4 (1.0 M in Et2O, 0.45 mL, 0.45 mmol) was added and the mixture was refluxed for 16 h. A second portion of LiAlH4 (1.0 M in Et2O, 0.45 mL, 0.45 mmol) was added, the solution was refluxed for another 5 h, and cooled to 0 C. At this time sat. aqueous Na2SO4 solution (1 mL) was cautiously added, the solution was stirred at rt for

1 h, and filtered. The mixture was extracted with Et2O (20 mL) and EtOAc (2  20 mL), the combined organic phases were washed with brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (EtOAc:hexane, 1:1) afforded 0.020 g (83%) of a

20 136 20 1 colorless oil; [] D +33.3 (c 1.0, CHCl3) [lit. [] D +31.5 (c 1.0, CHCl3)]; H NMR

(CDCl3)  0.79 (t, J = 7.0 Hz, 3 H), 1.19-1.23 (m, 16 H), 1.33-1.38 (m, 1 H), 1.62-1.67

(m, 1 H), 2.07-2.14 (m, 2 H), 2.20-2.22 (m, 1 H), 2.28 (s, 3 H), 2.79-2.81 (m, 2 H), 3.73

84 13 (br.s., 1 H), 7.11-7.15 (m, 1 H), 7.20-7.24 (m, 4 H); C NMR (CDCl3)  14.5, 23.1, 26.7,

29.7, 29.9, 30.0, 30.3, 32.3, 34.0, 35.3, 38.9, 39.6, 66.2, 70.8, 73.9, 126.5, 128.8, 129.7,

139.7.

O OMe

C9H19 N Boc

(R)-(+)-2-(4-methoxybenzylidene)-3-oxo-5-nonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (168b). In an oven-dried, 100-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, and an argon balloon was placed 167 (0.66 g, 1.57 mmol) and LiCl (0.132 g, 3.14 mmol) in CH3CN (100 mL). To the soluction was added DBU (0.24 mL, 1.57 mmol) and 4-methoxylbenzoaldehyde (0.24 mL, 1.88 mmol) at 0 oC. After stirring for 16 h, the reaction mixture was quenched by addition of sat. NH4Cl solution (10 mL), extracted with Et2O (20 mL) and EtOAc (2×20 mL), and the combined organic phase were washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography (25% EtOAc/hexanes) afforded 0.47 g (71%) of

20 168b as a yellow oil. [] D = 21.7 (c 0.30, CHCl3); IR (neat): 2926, 1731 , 1697, 1607,

-1 1 1390, 1252, 1175, 1139, 826 cm ; H NMR (CDCl3)  0.86 (t, J = 6.4 Hz, 3 H), 1.25-

1.60 (m, 25 H), 2.27 (d, J = 17.6 Hz, 1 H), 2.74 (dd, J = 9.2 Hz, J = 18 Hz, 1H), 3.81 (s, 3

H), 4.40 (m, 1H), 6.83 (d, J = 8.4 Hz, 1 H), 7.25 (s, 1H), 7.28(d, J=7.2 Hz,

2H),13CNMR

. HRMS is not available because the compound is not stable.

O OMe

C9H19 N Boc

(2S,5R)-(+)-2-(4-methoxybenzyl)-3-oxo-5-nonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (169b). In an oven-dried, 25-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an H2 balloon was placed 168b

(0.106 g, 0.247 mmol) and 10% Pd/C (60 mg, 0.054 mmol) in anhydrous methanol (6 mL). The solution was evacuated and then filled with H2, and this sequence was repeated

5 times and was stirred for 12 h at rt. The catalyst was removed by filtration through

Celite and the filtrate was concentrated. Flash chromatography (10% EtOAc/hexanes)

20 afforded 0.082 g (80%) of 169b as a light yellow oil. [] D = 81.9 (c 0.165, CHCl3); IR

-1 1 (neat): 1751, 1696, 1512, 1390, 1248, 1176, 1154cm ; H NMR (CDCl3)  0.89 (t, J =

6.8 Hz, 3 H), 0.93-1.36 (m, 16 H), 1.51 (s, 9H), 1.94 (d, J = 18.0 Hz, 1 H), 2.65 (m, 1H),

3.12 (m, 2H), 3.77 (s, 3 H), 4.05 ( b.s. 1H), 4.15 (b.s. 1H), 6.78 (d, J =8.8 Hz, 2 H), 7.00

(d, J =8.4 Hz, 2 H); 13C NMR  14.4, 23.0, 26.5, 28.8, 29.60, 29.67, 29.8, 29.9, 32.3,

36.4, 42.8, 54.4, 55.6, 64.9, 77.6, 80.5, 114.1, 129.5, 131.6, 155.0, 159.0, 214.0. HRMS calcd. for C26H41NO4 (M): 431.3036. Found 431.3028.

86 OH OMe

C9H19 N CH3

(2S,3S,5R)-(+)-2-(4-methoxybenzyl)-1-methyl-5-nonyl-pyrrolidin-3-ol (170).

In an oven-dried, 25-mL one necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and argon balloon was placed 169b (0.080 g, 0.186 mmol) in Et2O (26 mL). At this time, LiAlH4 (1.0M in THF, 1.11 mL, 1.11 mmol) was added and the mixture was refluxed for 16 h before another LiAlH4 (1.0M in THF, 1.11 mL,

1.11 mmol) was added. After refluxed for another 5 h, the reaction mixture was quenched by sat. Na2SO4 solution and stirred at rt for 1 h. The mixture was then filtered and extracted with Et2O (20 mL) and EtOAc (2×20 mL), and the combined organic phase were washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) afforded 0.045 g (70%) of 170 as a colorless oil.

20 -1 1 [] D = 24.0 (c 0.95, CHCl3); IR (neat): 3431, 1751, 1512, 1246 cm ; H NMR (CDCl3)

 0.88 (t, J = 7.2 Hz, 3 H), 1.15-1.33 (m, 15 H), 1.40 (ddd, J =14Hz, J =6.4 Hz, J =2.0

Hz 1H), 1.70(m, 1H), 1.89 (d, J = 9.2 Hz, 1 H), 2.05-2.24 (m, 3H), 2.32(s, 3H), 2.79(m,

2H), 3.78 (s, 4 H), 6.83 (d, J =6.4 Hz, 2 H), 7.21 (d, J =6.4 Hz, 2 H); 13C NMR  14.5,

23.0, 26.6, 29.6, 29.93, 29.98, 30.0, 30.2, 32.3, 35.4, 39.0, 39.7, 55.6, 66.1, 70.9, 74.1,

114.2, 130.6, 131.9, 158.2. HRMS calcd. for C22H37NO2 (M+H): 348.2903. Found

348.2890.

(2R,3S,5R)-(-)- tert-Butyl 2-Benzyl-3-hydroxy-5-nonyl-pyrrolidine-1- carboxylate (172a). In a 25 mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (-)-168a (0.145 g,

. 0.36 mmol) and CeCl3 7H2O (0.54 g, 1.45 mmol) in MeOH (10 mL). The solution was

o stirred at rt for 30 min before NaBH4 (0.055 g, 1.45 mmol) was added at 0 C. After stirring at this temperature for 30 min, H2O (10 mL) was added and the solution was extracted with EtOAc (3  10mL). The combined organic phases was washed with brine

(10 mL), dried (Na2SO4), and concentrated to give a crude product. To the crude product was added CH2Cl2 (25 mL), and NaBH3CN (0.091 g, 1.45 mmol). The solution was stirred at rt for 5 min, cooled to -45 oC, and trifluoroacetic acid (0.195 mL, 2.5 mmol) was added. After stirring at this temperature for 30 min, the aqueous sat. NaHCO3 (10 mL) was added, the solution was warmed to rt and extracted with EtOAc (3  10 mL).

The combined organic phases were washed with brine, dried (Na2SO4), and concentrated.

Chromatography (hexanes:EtOAc = 10:1) gave 0.087 g (61% from 172a) of a colorless

23 -1 1 oil. [] D -3.4 (c 0.99, CHCl3); IR (neat) 3465, 1685, 1394 cm ; H NMR (CDCl3)

(two sets of signals are observed due to rotamers)  0.87 (t, J = 7.0 Hz, 3 H), 1.26 (m, 15

H), 1.51 (m, 10 H), 1.75 (m, 1 H), 1.95 and 2.18 ( total 2 H, 2 sets of m), 2.40 (m, 1 H),

3.13 and 3.25 ( total 1H, 2 sets of dd, J = 13.0, 3.0 Hz, J = 14.0, 2.5 Hz), 3.62 and 3.76

(total 1H, 2 sets of t, J = 9.8 Hz, J = 8.0 Hz), 3.93 and 4.01 (total 1H, 1dd and 1d, J =

10.5, 2.5 Hz, J = 6.5 Hz,), 4.15 (d, J = 4.0 Hz, 1 H), 7.21 (m, 5 H); 13C NMR (75 MHz,

CDCl3) (two sets of signals are observed due to rotamers) 14.2, 22.7, 26.8, 26.9, 27.0,

88 28.4, 28.5, 28.7, 29.3, 29.4, 29.5, 29.6, 29.7, 29.9, 31.9, 34.1, 34.8, 35.0, 35.4, 38.9, 45.0,

58.3, 58.4, 68.7, 68.9, 74.0, 74.5, 79.4, 79.6, 126.4, 126.6, 128.5, 128.6, 128.7, 129.2,

129.5, 129.7, 138.5, 154.1. HRMS (FAB) calcd for C25H41NO3Na (M+Na) 426.2984.

Found 426.2971.

(2R,3S,5R)-(-)-2-Benzyl-1-methyl-5-nonyl-pyrrolidin-3-ol (173a). In a 25 mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 172a (0.02 g, 0.047 mmol) and trifluoroacetic acid (0.4 mL) in CH2Cl2 (1.6 mL). The solution was stirred at rt for 30 min, concentrated, and acetonitrile (3 mL) was added. Aqueous formaldehyde (37 wt%, 0.2 mL), NaBH3CN

(0.023 g, 0.37 mmol), and CH3COOH (0.018 mL) were added and the solution was stirred at rt for 4 h. At this time aqueous sat. NaHCO3 (5 mL) was added and the solution was extracted with EtOAc (3  10 mL). The combined organic phases were dried

(Na2SO4), filtered, and concentrated. Chromatography (hexanes:EtOAc, 1:1) gave 0.011

23 g (70 %) of a colorless oil. [] D -62.1 (c 0.51 , CHCl3); IR: 3465, 2923, 2855, 1685,

-1 1 1394 cm ; H NMR (500 MHz, CDCl3) (two sets of signals are observed due to rotamers)  0.89 (t, J = 7.0 Hz, 3 H), 1.28 (m, 15 H), 1.53 (dd, J = 14.3, 5.2 Hz, 1 H),

1.70 (m, 1 H), 2.0 (brs, 1 H), 2.20 (dd, J = 13.5, 11.0 Hz, 1 H), 2.39 (ddd, J = 15.0, 8.0,

6.5 Hz, 1 H), 2.46 (s, 3 H), 2.68 (m, 1 H), 2.98 (dd, J = 13.5, 4.2 Hz, 1 H), 3.16 (dd, J =

10.5, 4.0 Hz, 1 H), 3.91 (t, J = 6.25 Hz, 1 H), 7.18 (m, 3 H), 7.29 (m, 2 H); 13C NMR (75

MHz, CDCl3) (two sets of signals are observed due to rotamers) 14.2, 22.8, 26.3, 29.4,

89 29.6, 29.7, 30.0, 31.6, 32.0, 33.7, 35.1, 38.9, 61.3, 73.4, 73.9, 126.1, 128.6, 129.1, 139.4.

HRMS (FAB) calcd for C21H36NO (M+H) 318.2797. Found 318.2802.

OH OMe

C9H19 N Boc

(3S,5R,E)-(+)-2-(4-methoxybenzylidene)-3-hydroxy--5-nonyl-pyrrolidine-1- carboxylic acid tert-butyl ester(171b). In an oven-dried, 50-mL one necked, round- bottomed flask equipped with a rubber septum, a magnetic stirring bar, and an argon balloon was placed 168b (0.350 g, 0.82 mmol) and CeCl3.7H2O (1.25 g, 3.28 mmol) in

MeOH (20 mL). The reaction was stirred at rt for 30 min before NaBH4 (0.15 g, 3.28 mmol) was added at 0 oC. After stirring for another 30 min, the mixture was quenched by

H2O (10 mL), extracted with Et2O (10 mL) and EtOAc (2×10 mL), and the combined organic phase were washed with brine (50 mL), dried (Na2SO4), and concentrated. The

20 crude product was used immediately in the next step without purification. [] D = 36.0

-1 1 (c 0.47, CHCl3); IR (neat): 3418, 1699, 1386, 1252, 1174, 1142, 864 cm ; H NMR

(CDCl3)  0.88 (t, J = 6.6 Hz, 3 H), 1.20-1.35 (m, 15 H), 1.54 (s, 9 H), 1.60-2.00 (m, 4

H), 3.80 (s, 3 H), 4.03 (m, 1 H), 5.00 (m, 1 H), 6.86 (dd, J = 2.0 Hz, J = 6.8 Hz, 2 H),

7.24 (s, 1 H),7.34 (dd, J = 8.4 Hz, 2 H); HRMS is inaccessible due to its instability.

90 OH OMe

C9H19 N Boc

(2R,3S,5R)-(-)-2-(4-methoxybenzyl)-3-hydroxy-5-nonyl-pyrrolidine-1- carboxylic acid tert-butyl ester (172b). In an oven-dried, 100-mL one necked, round- bottomed flask equipped with a rubber septum, a magnetic stirring bar, and an argon balloon was placed crude 171b and NaBH3CN (0.32 g, 5.0 mmol) in CH2Cl2 (40 mL).

The solution was stirred at rt for 10 min before it was cooled to -45 oC. and TFA ( 0.66 mL, 8.47 mmol) was added. The reaction was stirred at this temperature for 50 min and quenched with aqueous NaHCO3 solution (40 mL). The solution was extracted with Et2O

(10 mL) and EtOAc (2×10 mL), and the combined organic phase were washed with brine

(50 mL), dried (Na2SO4), and concentrated. Flash chromatography (20%

EtOAc/hexanes) afforded 0.21 g (61% for two reduction steps) of 172b as a colorless oil.

20 -1 1 [] D = -17.2 (c 0.43, CHCl3); IR (neat): 3423, 1667, 1512, 1393, 1247 cm ; H NMR

(CDCl3) (two sets of signals are observed due to rotamers)  0.87 (m, 3 H), 1.24-1.38

(m, 15 H), 1.50(s, 4H), 1.54 (s, 5H), 1.70(s, 0.51H), 1.75(s, 0.49H), 1.92(m, 1.39H),

2.16(m, 0.61H), 2.36(m, 1H), 3.04(dd, J = 2.0 Hz, J = 13.6 Hz, 0.51H), 3.16(dd, J = 2.0

Hz, J = 13.2 Hz, 0.49H), 3.59(t, J = 10.0 Hz, 0.47H), 3.73(t, J = 10.0Hz, 0.53H), 3.79(s,

3H), 3.87(d, J = 8.4Hz, 0.57H), 3.95(d, J = 7.2Hz, 0.43H), 4.13(d, J = 4.4 Hz, 1H),

6.83(m, 2H), 7.08(m, 2H); ); 13C NMR  14.4, 23.0, 27.2, 29.0, 29.7, 29.8, 29.9, 30.1,

32.3, 34.4, 35.2, 35.4, 35.8, 36.8, 38.1, 55.6, 58.7, 69.2, 74.5, 74.9, 79.7, 114.4, 130.5,

130.7, 154.4, 158.6. HRMS calcd. for C26H43NO4Na (M + Na): 456.3090. Found

456.3070.

OH OMe

C9H19 N CH3

(2R,3S,5R)-(-)-2-(4-methoxybenzyl)-1-methyl-5-nonyl-pyrrolidin-3-ol (173b).

In an oven-dried, 5-mL one necked, round-bottomed flask equipped with a rubber septum, a magnetic stirring bar, and an argon balloon was placed crude 172b (0.021 mg,

0.05 mmol) and TFA (0.42 mL, 5.2 mmol) in CH2Cl2 (1.7 mL). The solution was stirred at rt for 30 min before it was concentrated. The residue was sissolved in CH3CN (3.3 mL) and to the resulting solution was added aqueous formaldehyde (37 wt%, 0.22 mL),

NaBH3CN (0.025 g, 0.4 mmol) and CH3COOH (0.018 mL). After stirring at rt for 4 h, the reaction was quenched with aqueous NaHCO3 (5 mL) and extracted with Et2O (10 mL) and EtOAc (2×10 mL), and the combined organic phase were washed with brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography (67% EtOAc/hexanes)

20 afforded 0.014 g (81%) of 173b as a colorless oil. [] D = -50.0 (c 0.47, CHCl3); IR

-1 1 (neat): 3351, 1512, 1246,821 cm ; H NMR (CDCl3)  0.87 (t, J = 6.4 Hz, 3 H), 1.27

(m, 15 H), 1.54 (dd, J = 3.2 Hz, J = 14.0 Hz, 1H), 1.70 (m, 1 H), 2.20 (m, 2 H), 2.40 (m,

1H), 2.47 (s, 3H), 2.71 (m, 1H), 2.94 (dd, J = 4.0 Hz, J = 13.2 Hz, 1H), 3.15 (dd, J = 4.0

Hz, J = 10.4 Hz, 1H), 3.78 (s, 3H), 3.92 (d, J = 6.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2 H),

7.06 (d, J = 8.8 Hz, 2 H); 13C NMR  14.4, 23.0, 26.6, 29.7, 29.9 , 30.0, 30.3, 31.2, 32.2,

33.7, 35.4, 39.2, 55.6, 61.8, 73.8, 74.3, 114.5, 130.3, 131.4, 158.4. HRMS calcd. for

C22H38NO2 (M + H): 348.2903. Found 348.2916.

(R)-(-)-N-(3-(Benzyloxy)propylidene)-2,4,6-triisopropylbenzenesulfinamide

(217). In a 1000 mL, oven-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed (R)-(+)-2,4,6- triisoproyplphenylsulfinamide (3.56 g, 13.3 mmol), 3-benzyloxypropanal (2.30 g, 14.0 mmol) in DCM (200 mL). The mixture was cooled to 0 C, and Ti(OEt)4 (13.8 mL, 66.5 mmol) was added. The solution was warmed up to rt and stirred for 4h. At this time, the mixture was diluted with DCM (300 mL). Then 13.8 mL water was dropwise added into the vigorly stirred mixture. The sticky mixture was filtered through Celite pad, washed it with CH2Cl2 (100 mL). The combined organic layers were concentrated. Flash

20 chromatography (20% Et2O/hexane) provided 5.44 g (99%) of a colorless oil. [] D -

-1 1 139.1 (c 0.83, CHCl3); IR (neat) 2961, 2867, 1083 cm ; H NMR (CDCl3)  8.40 (t, J =

4.8 Hz, 1H), 7.30 (m, 5H), 7.07 (s, 2H), 4.53 (s, 2H), 3.76 (m, 4H), 2.86 (m, 3H), 1.25

13 (m, 21H); C NMR (CDCl3)  165.9, 152.8, 149.7, 138.0, 134.5, 128.5, 127.8, 123.0,

73.3, 66.3, 36.8, 34.5, 27.9, 24.5, 24.0, 23.8 (one carbon can’t be identified due to overlap). HRMS calcd for C25H36NO2S (M+H) 414.2467. Found 414.2450.

O S TIPP NH O OMe BnO N

(RS,2S,3R)-(-)-N-Methoxy-N,2-dimethyl-3-(2,4,6-

93 triisopropylphenylsulfinamido)-5-benzyloxypentanamide (219). In a 100 mL, oven- dried, single-neck round-bottomed flask equipped with a magnetic stirring bar, rubber septum was placed LiHMDS (13.85 mL, 13.85 mmol, 1.0 M solution in THF) under argon and a solution of N-methoxy-N-methylpropylamide (218) (1.62 g, 13.85 mmol) in

THF (40.0 mL) was added at -78 C via cannula, then stirred for 2 h at -78 C. To the reaction mixture, was added a solution of sulfinimine 217 (2.29 g, 5.54 mmol) in THF

(16.0 mL) at -78 C. The reaction mixture was stirred at this temperature for 1 h and quenched with sat. aqueous NH4Cl (10 mL) at -78 C, warmed up to rt, and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (2 x 20 mL), dried (MgSO4), and concentrated. Chromatography (50% Et2O/hexanes) provided

20 2.26 g (77%) of a colorless oil as a major isomer. Major isomer: [] D -27.6 (c 0.975,

-1 1 CHCl3); IR (neat) 2961, 2869, 1652, 1079 cm ; H NMR (CDCl3)  7.32 (m, 5H), 7.05

(s, 2H), 5.16 (d, J = 8.0 Hz, 1H), 4.45 (s, 2H), 3.95 (bs, 2H), 3.74 (m, 4H), 3.57 (m, 3H),

3.20 (s, 3H), 2.87 (m, 1H), 2.14 (m, 1H), 2.03 (m, 1H), 1.28 (d, J = 6.6 Hz, 3 H), 1.23 (m,

13 18 H); C NMR (CDCl3)  176.1, 151.6, 147.4, 138.8, 138.6, 128.4, 127.6, 127.5, 123.0,

73.0, 67.8, 61.6, 56.9, 40.5, 34.4, 32.0, 31.3, 28.5, 24.4, 24.3, 23.9, 13.6. HRMS calcd for C30H47N2O4S (M+H) 531.3257. Found 531.3280.

O S TIPP NH O OMe BnO N

(RS,2R,3R)-(-)-N-Methoxy-N,2-dimethyl-3-(2,4,6- triisopropylphenylsulfinamido)-5-benzyloxypentanamide (220). Chromatography

94 (50% Et2O/hexanes) provided 0.529 g (18%) of a colorless oil as a minor isomer. Minor

20 -1 1 isomer: [] D -48.6 (c 1.05, CHCl3); IR (neat) 2961, 2869, 1653, 1457 cm ; H NMR

(CDCl3)  7.29 (m, 5H), 7.05 (s, 2H), 4.90 (d, J = 8.4 Hz, 1H), 4.51 (d, J = 2.4 Hz, 2H),

4.02 (bs, 2H), 3.80 (m, 1H) 3.65 (m, 2H), 3.52 (s, 3H), 3.11 (m, 4H), 2.86 (m, 1H), 2.16

13 (m, 1H), 1.96 (m, 1H), 1.23 (m, 21H); C NMR (CDCl3)  166.6, 151.6, 147.4, 139.2,

138.6, 128.6, 128.0, 127.8, 123.1 73.4, 67.7, 61.5, 58.6, 40.2, 34.5, 33.8, 32.5, 28.6, 24.8,

24.4, 24.0, 15.1. HRMS calcd for C30H46N2O4SNa (M+Na) 531.3257. Found 531.3280.

O S TIPP NH O

BnO

(-)-N-[(Rs,3R,4S)-1-(benzyloxy)-4-methyl-5-oxononan-3-yl]-2,4,6- triisopropylbenzenesulfinamide (221). In a 25 mL, flame-dried, single-necked round- bottomed flask equipped with a magnetic stirring bar, rubber septum was placed Weinreb amide 219 (2.07 g, 3.95 mmol) in THF (50 mL). To the solution was added n- butylmagnesium chloride (19.7 mL, 39.5 mmol, 2.0 M solution in THF) at 0 C via syringe and the resulting mixture was stirred for 2 h at rt. The reaction mixture was quenched by sat. aq. NH4Cl (5 mL) at 0 C and extracted with Et2O (2 x 50 mL). The organic layers were dried (MgSO4), and concentrated. Chromatography (50%

20 Hexanes/EtOAc) provided 1.89 g (91%) of product as a colorless oil. [] D -42.6 (c

-1 1 0.47, CHCl3); IR (neat) 2960, 2869, 1700, 1457 cm ; H NMR (CDCl3)  7.30 (m, 5H),

7.04 (s, 2H), 5.20 (d, J = 8.8 Hz, 1H), 4.42 (s, 2H), 3.90 (bs, 2H), 3.66 (m, 1H), 3.51 (m,

2H), 3.23 (m, 1H), 2.86 (dq, J = 6.8 Hz, 1H), 2.48 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H),

95 13 1.22(m, 23 H), 0.90 (t, J = 7.4 Hz, 3H),; C NMR (CDCl3)  213.9, 151.1, 146.8, 138.2,

137.9, 127.9, 127.1, 127.0, 122.5, 72.6, 67.0, 56.9, 50.0, 41.0, 33.9, 31.7, 28.0, 25.2, 23.9,

23.8, 23.3, 21.9, 13.5, 13.3. HRMS calcd for C32H50NO3S (M+H) 528.3511. Found

528.3487. Crude compound can be directly used in the next step.

BnO N H

(2R,3S,5S,6S,E)-(-)-2-(2-(Benzyloxy)ethyl)-3-methyl-6-(prop-1-enyl)-5- propylpiperidin-4-one (224). In a 250 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon ballon was placed sulfinamide 221 (1.71 g, 3.24 mmol) in anhydrous MeOH (103 mL). The solution was cooled to 0 C. And HCl (6.5 mL, 12.98 mmol, 2.0 M solution in Et2O) was added via syringe and the resulting mixture was stirred for 20 min. at 0 C. The reaction mixture was neutralized to pH 9 by aq. NaOH at 0 C. The mixture was extracted with

DCM (2 x20 mL). The combined organic layers were brined, dried and concentrated.

The crude compound was used in the next step without further purification. In a 250 mL, oven-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed residue from last step in anhydrous

CH2Cl2 (52 mL). To the solution was added crotonaldehyde (2.76 mL, 32.5 mmol) and

Ti(OEt)4 (3.31 mL, 16.25 mmol) at 0 C via syringe. The resulting mixture was stirred for 3 h at rt before it was diluted with DCM (100 mL) and quenched by dropwise addition of sat. NaHCO3 solution (6.62 mL) into the vigorly stirred mixture. The sticky

96 mixture was filtered through Celite pad, washed it with CH2Cl2 (100 mL). The combined solution was washed with brine, dried (MgSO4) and concentrated. The crude imine product was carried to the next step without further purification. In a 250 mL, oven-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed unhydrous TsOH (1.04 g, 6.48 mmol). A solution of crude imine from last step in anhydrous Toluene (103 mL) was added via a cannula into the flask containing TsOH. After the transfer, the mixture was warmed up to 75 C and stirred for 8 h before it was cooled to rt, diluted with Et2O (20 mL) and quenched with sat. aq. NaHCO3 until the PH of the water layer is larger than 7. The water layer was extracted with DCM (2 x10 mL). The combined organic layers were brined, dried

(MgSO4) and concentrated Chromatography (10% EtOAc/hexanes) provided 0.545 g

20 (51%) of a yellow oil as major compound. [] D -5.7 (c 0.667, CHCl3); IR (KBr) 3343,

-1 1 2958, 1707, 1455 cm ; H NMR (CDCl3)  7.24 (m, 5H), 5.57 (dq, J = 6.4, 15.2 Hz, 1H),

5.41 (ddq, J = 1.6, 8.4, 15.2 Hz, 1H), 4.48 (m, 2H), 3.65 (m, 1H), 3.59 (m, 1H), 2.97 (dd,

J = 8.4, 10.2 Hz, 1H), 2.61 (ddd, J = 2.4, 8.6, 10.8 Hz, 1H), 2.27 (ddq, J = 1.1, 6.4, 10.8,

1H), 2.16 (ddd, J = 1.1, 6.5, 10.2, 1H), 1.95 (m, 1H), 1.74 (m, 1H), 1.69 (dd, J = 1.6, 6.4

Hz, 3H), 1.61 (m, 1H), 1.36 (m, 1H), 1.16 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H), 0.85 (t, J =

7.2 Hz, 3H), NH proton could be partially overlapped with peak at 2.27; 13C NMR

(CDCl3)  211.3, 138.4, 132.7, 128.6, 128.5, 127.8, 127.5, 73.2, 68.7, 65.3, 62.6, 55.9,

50.9, 34.0, 27.6, 21.2, 17.9, 14.6, 10.3. HRMS calcd for C21H32NO2 (M+H) 330.2433.

Found 330.2428.

97 NH2 O BnO

(3R,4S)-(+)-3-amino-1-(benzyloxy)-4-methylnonan-5-one (222).

Chromatography (5% MeOH/CH2Cl2, 0.5% Et3N) provided 95% of product as a colorless

20 -1 1 oil. [] D +32.6 (c 0.35, CHCl3); IR (neat) 3386, 2933, 2870, 1705 cm ; H NMR

(CDCl3)  7.31 (m, 5 H), 4.50 (s, 2 H), 3.59 (m, 2 H), 3.26 (dt, J = 4.8, 8.4 Hz, 1 H), 2.56

(dq, J = 4.8 ,6.8 Hz, 1 H), 2.45 (m, 2 H), 1.63 (m, 2 H), 1.52 (m, 2 H), 1.28 (m, 4 H), 1.06

13 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.4 Hz, 3 H); C NMR (CDCl3)  214.6, 138.7, 128.7,

127.98, 127.95, 73.4, 68.5, 51.8, 50.4, 42.1, 35.9, 26.1, 22.7, 14.2, 10.7. HRMS calcd for

C17H28NO2 (M+H) 278.2120. Found 278.2111.

BnO N

(2R,3S,5S,6S,E)-(+)-1-Allyl-2-(2-(benzyloxy)ethyl)-3-meth yl-6-(prop-1-enyl)-

5-propylpiperidin-4-one (225). In a 50 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed piperidone 224 (0.465 g, 1.413 mmol) in absolute EtOH (40 mL). To the solution was added unhydrous Na2CO3 (2.15 g, 21.21 mmol) and allyl bromide (1.21 mL, 14.13 mmol) sequentially at rt and the reaction mixture was stirred for 15 h at 70 C. The reaction mixture was cooled to rt and filtered through Celite pad washing it with DCM, and organic layers were concentrated. Water (5 mL) was added to the concentrated residue and the solution was extracted with DCM (2 x 20 mL). The combined organic

98 phases were brined, dried (MgSO4) and concentrated. Chromatography (10%

20 Et2O/hexanes) provided 0.376 g (72%) of product as a yellow oil. [] D +14.5 (c 0.75,

-1 1 CHCl3); IR (KBr) 2960, 2871, 1716, 1455 cm ; H NMR (CDCl3)  7.31 (m, 5H), 5.77

(m, 1H), 5.50 (dq, J = 6.4, 15.0 Hz, 1H), 5.27 (ddq, J = 1.6, 9.4, 15.0 Hz, 1H), 5.11 (m,

1H), 5.08 (s, 1H), 4.51 (s, 2H), 3.64 (dd, J = 7.2, 7.2 Hz, 2H), 3.47 (dd, J = 6.0, 16.0 Hz,

1H), 3.29 (dd, J = 7.0, 16.0 Hz, 1H), 2.96 (dd, J = 9.4, 9.4 Hz, 1H), 2.59 (m, 1H), 2.47

(dq, J = 6.4, 7.2, 1H), 2.25 (m, 1H), 2.05 (m, 1H), 1.91 (m, 1H), 1.71 (dd, J = 1.6, 6.4 Hz,

3H), 1.60 (m, 1H), 1.31 (m, 1H), 1.14 (m, 2H), 1.05 (d, J = 6.4 Hz, 3H), 0.84 (t, J = 6.8

13 Hz, 3H); C NMR (CDCl3)  211.9, 138.7, 133.7, 132.8, 128.9, 128.5, 127.7, 117.7,

73.3, 69.6, 66.6, 64.1, 53.4, 51.6, 48.0, 30.9, 28.6, 21.1, 17.8, 14.5, 12.5 (one unsaturated carbon can’t be identified due to overlap). HRMS calcd for C24H36NO2 (M+H) 370.2746.

Found 370.2747.

N O

BnO

20 (+)-1-(Benzyloxy)-4-methyl-3-(1H-pyrrol-1-yl)nonan-5-one (227). [] D +1.5

-1 1 (c 0.733, CHCl3); IR (neat) 3446, 3031, 2958, 2870, 1716 cm ; H NMR (CDCl3)  7.23

(m, 5H), 6.5 (t, J = 2.2 Hz, 2H), 6.0 (t, J = 2.0 Hz, 2H), 4.29 (s, 2H), 4.24 (ddd, J = 3.6,

10.1, 12.1 Hz, 1H), 3.25 (m, 1H), 2.94 (m, 2H), 2.12 (m, 2H), 1.81 (m, 2H), 1.23 (m,

13 2H), 1.05 (d, J = 7.6 Hz, 3H), 1.02 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H); C NMR (CDCl3) 

213.1, 138.2, 128.4, 127.7, 127.6, 119.4, 108.0, 73.2, 66.3, 58.8, 51.8, 42.4, 32.8, 25.2,

22.0, 14.5, 13.8. HRMS calcd for C21H29NO2 (M+) 327.2198. Found 327.2207.

99 O

BnO N

(5R,6S,8S,8aS)-(-)-5-[2-(Benzyloxy)ethyl]-6-methyl-8-propyl- hexahydroindolizin-7(1H)-one (228). In a 250 mL, oven-dried, single-necked round- bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed piperidone 224 (0.340 g, 0.92 mmol) in anhydrous CH2Cl2 (49 mL).

To the solution was added Grubbs’ 2nd generation catalyst (0.078 g, 0.092 mmol) and stirred for 2.5 h at rt. The reaction mixture was concentrated and dicrectly applied to a short-pad silica gel column. 33.3% Et2O/hexanes was used to collect the crude product.

The collected blue color solution was concentrated and carried to the next step without further purification because it’s not stable. In a 50 mL, oven-dried, single-necked round- bottomed flask equipped with a magnetic stirring bar, rubber septum was placed the crude compound obtained before in anhydrous MeOH (15 mL). To the solution was added 5 % Pd/C (0.408 g, 120 wt%) at rt. The mixture was evacuated and filled with H2, and this sequence was repeated for 5 times. The reaction mixure was stirred for 2 h at rt under H2-atomosphere (1 atm, H2-filled balloon). The mixture was filtered through

Celite pad washing it with Et2O (20 mL) and concentrated. Chromatography (25%

20 EtOAc/hexanes) provided 0.181 g (60%) of product as a colorless oil. [] D -12.0 (c

-1 1 0.28, CHCl3); IR (neat) 3031, 2957, 2870, 2786 cm ; H NMR (CDCl3)  7.27 (m, 5H)

4.48 (s, 2H), 3.63 (ddd, J = 1.6, 7.2, 7.4 Hz, 2H), 3.20 (ddd, J = 2.4, 8.4, 8.8 Hz, 1H),

2.43 (ddq, J = 1.2, 6.4, 8.4, 1H), 2.24 (m, 1H), 2.0 (m, 6H), 1.80 (m, 1H), 1.68 (m, 2H),

1.54 (m, 1H), 1.37 (m, 1H), 1.15 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H), 0.80 (t, J = 7.2 Hz,

100 13 3H); C NMR (CDCl3)  211.7, 138.6, 128.5, 127.6, 127.56, 73.1, 69.6, 66.3, 66.1, 55.3,

50.7, 47.2, 31.4, 30.2, 28.2, 21.4, 21.2, 14.6, 10.7. HRMS calcd for C21H32NO2 (M+H)

330.2433. Found 330.2418.

BnO N

(5R,6R,8R,8aS)-(-)-5-(2-(Benzyloxy)ethyl)-6-methyl-8-prop yl- octahydroindolizine (230). In a 50 mL, oven-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed

228 (0.110 g, 0335 mmol) in anhydrous MeOH (11.5 mL). To the solution was added

NaBH4 (0.101 g, 1.338 mmol) at 0 C and the resulting mixture was stirred for 2 h at the same temperature under argon. The reaction mixture was concentrated and diluted with water (3 mL), then extracted with Et2O. The combined organic layers were dried

(MgSO4) and concentrated. The crude alcohol was carried to the next step without further purification. In a 50 mL, oven-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed

NaH (0.160 g, 2.007 mmol) in unhydrous petroleum ether (2 mL). The mixture was gently stirred for 30 seconds, and the petroleum ether was taken away by a syringe. The sticky mixture was evacuated for 2 mins and filled with argon, and this sequence was repeated for 2 times. To the mixture was added THF (5.6 mL) at rt followed by a solution of crude residue from last step in THF (5.6 mL). The solution was stirred for 1 h at rt and was added CS2 (0.120 mL, 2.007 mmol) then stirred for another 2h at the same temperature. To the mixture was added MeI (0.208 mL, 3.35 mmol) and stirred for 16 h

101 at rt. The reaction was quenched with H2O (2 mL), diluted with Et2O (20 mL) and washed with water (3 x 3 mL). The organic phases were combined, washed with brine, dried (MgSO4), and concentrated. In a 25 mL, oven-dried, single-necked round- bottomed flask equipped with a magnetic stirring bar, rubber septum and an argon balloon was placed AIBN (0.0275 g, 0167 mmol). A solution of crude residue of last step in unhydrous benzene (1.4 mL) was added via a cannula. The mixture was warmed up to 85C followed by slowly addition of a solution of n-Bu3SnH in benzene (1.4 mL) using syringe drive over 3.5 h. The reaction mixture was stirred for another 30 min at the same temperature before it was cooled to rt and concentrated under reduced pressure.

Chromatography (10% Et2O/hexanes -> 50% Et2O/hexanes) provided 0.058 g (55% for 3

20 -1 1 steps) of a colorless oil. [] D -61.7 (c 0.12, CHCl3); IR (neat) 3020, 2956, 2869cm ; H

NMR (CDCl3)  7.22 (m, 5H), 4.51 (s, 2H), 3.59 (dd, J = 7.8, 7.8 Hz, 2H), 3.18 (ddd, J =

1.2, 8.4, 8.8 Hz, 1H), 1.05 – 1.95 (m, 15H), 0.98 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.87

13 (t, J = 7.0 Hz, 3H), 0.65 (m, 1H); C NMR (CDCl3)  138.9, 128.4, 127.6, 127.5, 73.0,

70.5, 67.5, 67.4, 52.2, 40.8, 40.5, 35.7, 34.8, 31.0, 29.2, 21.0, 19.8, 18.7, 14.5. HRMS calcd for C21H34NO (M+H) 316.2640. Found 316.2650.

HO N

2-((5R,6R,8R,8aS)-(-)-6-Methyl-8-propyl-octahydroindolizin -5-yl)ethanol

(231). In a 10 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar was placed indolizine 230 (0.055 g, 0.174 mmol) in anhydrous THF

(6.8 mL) and MeOH (2.4 mL). To the solution was added 20% Pd(OH)2/C (0.551 g,

102 1000 wt%) and TFA (0.215 mL, 2.79 mmol). The mixture was evacuated for 30 seconds and filled with hydrogen, and this sequence was repeated for 5 times. The mixture was stirred for 28 h at rt under 1atm H2 (hydrogen balloon). The reaction mixture was filtered through Celite pad and washed it with EtOH (20 mL). The combined solution was washed with 5 mL sat. NaHCO3 solution. This procedure was repeated for several times until the water layer’s PH>7. Prep. TLC (6% MeOH/CH2Cl2) provided 0.0308 g (79%)

20 -1 1 of a yellow oil. [] D -56.2 (c 1.04, CHCl3); IR (neat) 3394, 2956, 2870, 2781 cm ; H

NMR (CDCl3)  3.98 (dt, J = 2.8, 11.6 Hz, 1H), 3.66 (m, 1H), 3.61 (broad t, J = 8.0 Hz,

1H), 2.14 (m, 1H), 2.00 (m, 2H), 1.87 (m, 3H), 1.68 (m, 4H), 1.24 (m, 5H), 1.00 (m, 1H),

0.90 (d, J = 6.4 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H), 0.72 (q, J = 11.9 Hz, 1H); 13C NMR

(CDCl3)  71.0, 68.3, 59.9, 52.7, 40.3, 39.8, 35.5, 31.9, 29.1 (2C), 20.6, 19.7, 18.7, 14.5.

HRMS calcd for C14H28NO (M+H) 226.2171. Found 226.2173.

Alkaloid (-)-221T (211). In a 5 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar and argon balloon was placed DMSO (0.036 mL, 0.512 mmol) in CH2Cl2 (1.9 mL). The solution was cooled to -78 C. To the solution was added (COCl)2 (0.030 mL, 0.341 mmol). After stirring for 30 min at, a solution of (-)-231 (25.6 mg, 0.114 mmol) in CH2Cl2 (1.9 mL) was added dropwise over

10 min using syringe pump. After stirring for 30 min at -78 C, the reaction mixture was quenched with Et3N (0.095 mL, 0.683 mmol) and slowly warmed up to rt in 15 min. The

103 mixture was diluted with CH2Cl2 (5 mL), washed with sat. aq. NaHCO3 (2 x 5 mL). The organic layer was brined, dried (MgSO4) and concentrated. This crude aldehyde was subjected directly to the next step. In a 5 mL, oven-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar and an argon balloon was placed 5-

(methylsulfonyl)-1-phenyl-1H-tetrazole (0.036 g, 0.137 mmol) in THF (1.4 mL). The solution was cooled to -78 C. To the solution was added NaMHDS (0.137 mL, 0.137 mmol, 1.0M in THF). The mixture was stirred at -78 C for 1 h before a solution of crude aldehyde in THF (1.0 mL) was added via a cannula at -78 C. The reaction mixture was stirred for 30 min at -78 C, slowly warmed up to -20C, stirred for another

1 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (3 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Prep. TLC (6% MeOH/CH2Cl2, <1% Et3N)

20 provided 0.0096 g (38% for 2 steps) of a light yellow oil. [] D -28.0 (c 0.35, CHCl3);

-1 1 IR (KBr) 2956, 2870, 2781 cm ; H NMR (CDCl3)  6.05 (m, 1H), 5.21 (d, J = 9.5 Hz,

1H), 5.18 (s, 1H), 3.96 (m, 1H), 2.80 (m, 1H), 2.67 (m, 2H), 2.54 (m, 1H), 2.30 (m, 5H),

2.02(m, 1H), 1.92 (m, 2H), 1.15 – 1.43 (m, 4H), 1.07 (m, 1H), 0.01 (d, J = 6.5 Hz, 3H),

13 0.90 (t, J = 7.0 Hz, 3H); C NMR (CDCl3)  133.9, 119.2, 73.5, 70.7, 52.5, 39.1, 37.5,

35.2, 34.0, 33.8, 30.0, 27.2, 20.2, 19.3, 14.6. HRMS calcd for C15H28N (M+H) 222.2222.

Found 222.2221.

104 O S NH O

Ph OEt N

Ph Ph

(Ss,2S,3S)-(+)-Ethyl-2-N-(Diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)- amino-3-phenylpropanoate (251a). In a 25-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed LDA

(0.13 mL, 1.5 M Lithium diisopropylamide mono(tetrahydrofuran) solution from

Aldrich) in THF (water concentration is 600 ppm) (5 mL) at -78 oC. In a second 10-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed N-(diphenylmethylene) glycine ethyl ester (250) (0.053 g,

0.2 mmol) in THF (water concentration is 600 ppm) (5 mL) and cooled down to -78 oC and then transfer to LDA solution via cannula at -78 oC. The mixture was stirred at -78 oC for 60 min and at this temperature (s)-(+)-N-(benzylidene)-p-toluenesulfinamide

(241a) (0.030 g, 0.123 mmol) in THF (water concentration is 600 ppm) (2 mL) at -78 oC was added dropwise via cannula. The reaction mixture was stirred for 90 min, quenched by addition of sat. aq. NH4Cl (5 mL), and slowly warm up to rt. The aqueous phase was separated, and extracted with EtOAc (3 X 10 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4) and concentrated. Chromatography (20%

20 EtOAc in Hexanes) afforded 0.055 g (86%) of clear oil. [] D = -64.1 (c 1.2, CHCl3) [lit

20 177 1 [] D = -63.0 (c 1.1,CHCl3)] ; H NMR (CDCl3) 1.13 (t, J = 7.0 Hz, 3 H), 2.37 (s, 3

H), 4.06 (m, 2 H), 4.39 (d, J = 7.0 Hz, 1 H), 5.00 (t, J = 6.0 Hz, 1 H), 5.33 (d, J = 7.0 Hz,

1 H), 6.88 (d, J = 6.5 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.25 (m, 11 H), 7.60 (m, 4 H);

105 13 C NMR 14.4, 21.8, 60.9, 61.7, 70.6, 125.9, 128.2, 128.4, 128.6, 128.8, 129.0, 129.2,

129.3, 129.9, 131.0,136.2, 138.9, 139.6, 141.7, 142.8.

(S s ,2S,3S)-(+)-ethyl-2-((diphenylmethylene)amino)-3-phenyl-3 –

-(trifluoromethyl)phenylsulfinamido)propanoate (251b), (Ss,2S,3S)-(+)-Ethyl-2-N

(Diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)-amino-3-p-chloro- phenylpropanoate (251c), (Ss,2S,3S)-(+)-Ethyl-2-N-(Diphenylmethyleneamino)-3-N-

(p-toluenesulfinyl)-amino-3-p methoxylphenylpropanoate (251d) were synthesized with the same precedure to prepare ( S s ,2S ,3S )-(+)-Ethyl-2-N -

(Diphenylmethyleneamino)-3-N -(p -toluenesulfinyl)-amino-3- phenylpropanoate (251a).

(Ss,2S,3S)-ethyl-2-((diphenylmethylene)amino)-3-phenyl-3-

(trifluoromethyl)phenylsulfinamido)propanoate (251b). The title compound 0.059 g

(87%) was prepared with (S)-(+)-N-(benzylidene)-p-trifluromethyl-phenylsulfinamide

20 (241b) (0.037 g, 0.12 mmol) as a clear oil. [] D - 4.9 (c 0.55, CHCl3); IR (neat): 3200,

-1 1 3058, 1734, 1619 cm ; H NMR (CHCl3) 1.09 (t, J = 7.0 Hz, 3 H), 2.37 (s, 3 H), 4.01

(m, 2 H), 4.38 (d, J = 6.3 Hz, 1 H), 4.94 (t, J = 6.0 Hz, 1 H), 5.34 (d, J = 6.6 Hz, 1 H),

13 6.87 (m, 2 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.30-7.57 (m, 14 H); C NMR  14.3, 21.7,

60.1, 61.7, 70.1, 125.5, 125.8, 127.9, 128.5, 128.6, 128.9, 129.3, 129.9, 130.4, 131.2,

106 132.7, 136.0, 139.3, 141.8, 142.2, 143.4, 169.9, 173.3. HRMS calcd. For C32H30N2O3SF3

(M + H): 579.1929. Found. 579.1938.

O S NH O

Cl Ph OEt N Ph Ph

(Ss,2S,3S)-(+)-Ethyl-2-N-(Diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)- amino-3-p-chloro-phenylpropanoate (251c). The title compound 0.053 g (78%) was prepared with (S)-(+)-N-(benzylidene)-p-chloro-phenylsulfinamide (241d) (0.037 g, 0.12

20 mmol) as a clear oil. [] D -14.0 (c 0.655, CHCl3); IR (neat): 3233, 1733, 1624, 1491,

-1 1 1091 cm ; H NMR (CHCl3) 1.11 (t, J = 6.8, Hz, 3 H), 2.37 (s, 3 H), 4.04 (m, 2H), 4.34

(d, J = 6.4 Hz, 1 H), 4.91 ( t, J = 6.0 Hz, 1 H), 5.24 (d, J = 6.0 Hz, 1 H), 6.88 (dd, J = 2.0

13 Hz, J = 7.6 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 7.28-7.54 (m, 14 H); C NMR 14.3,

21.7, 60.0, 61.8, 70.2, 125.8, 128.0, 128.4, 128.7, 128.8, 129.2, 129.9 130.3, 131.1, 134.1,

136.1, 137.6, 139.4, 141.7, 142.5, 170.1, 173.0. HRMS calcd. for C31H30N2O3SCl (M +

H): 545.1666. Found 545.1668.

O S NH O

MeO Ph OEt N

Ph Ph

(Ss,2S,3S)-(+)-Ethyl-2-N-(Diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)- amino-3-p methoxylphenylpropanoate (251d). The title compound 0.056 g (80%) was

107 prepared with (S)-(+)-N-(benzylidene)-p-chloro-phenylsulfinamide (241e) (0.036 g, 0.12

20 mmol) as a clear oil. [] D -31.4 (c 0.335, CHCl3); IR (neat): 3271, 1734, 1512, 1250,

-1 1 702 cm ; H NMR (CHCl3) 1.12 (t, J = 7.2, Hz, 3 H), 2.36 (s, 3 H), 3.78 (s, 3H), 4.04

(dd, J = 7.2 Hz, J = 14.1 Hz, 2 H), 4.33 (d, J = 6.6 Hz, 1 H), 4.93 ( t, J = 6.0 Hz, 1 H),

5.20 (d, J = 5.4 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 2 H), 6.89 (m, 2 H), 7.19 -7.53 (m, 14 H);

13C NMR  14.4, 21.7, 55.6, 60.4, 61.6, 70.6, 114.0, 125.8, 128.2, 128.4, 128.7, 129.1,

129.3 129.8, 130.2, 130.8, 130.9, 136.3, 139.7, 141.5, 143.0, 159.6, 170.5, 172.6. HRMS calcd. for C32H32N2O4S (M + H): 541.2161. Found 541.2163.

O S NH O

Ph OEt N

Ph Ph

(Ss,2R,3S)-(-)-Ethyl-2-N-(Diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)- amino-phenylpropanoate (252a). In a 50-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed N-

(diphenylmethylene)glycine ethyl ester (250) (0.302 g, 1.13 mmol), in water-free THF

(8mL). The solution was cooled to -78 oC and LDA (0.56 mL, 2.0 M in heptane/tetrahydrofuran/ethylbenzene from Aldrich) was added dropwise. The red brown solution was stirred at -78 oC; the color slowly changed to yellow within 40 min and the solution became slightly turbid. After stirring for 60 min, (S)-(+)-241a (0.055 g, 0.23 mmol) in anhydrous THF (1.6 mL) at -78 oC was added dropwise via cannula. The reaction mixture was stirred at -78 oC for 30 min, quenched by addition of sat. aqueous

108 NH4Cl (3 mL), stirred for 5 min, and warmed to rt. The phases were separated and the aqueous phase was extracted with EtOAc (3 X 5 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated. Chromatography

20 (20% EtOAc in hexanes) afforded 0.099 g (86%) of a clear oil; [] D +182 (c 0.4,

1 CHCl3); IR (neat): 3281, 3058, 1738, 1093 cm-1; H NMR (CHCl3) 1.12 1.18 (t, J = 7.2

Hz, 3 H), 2.42 (s, 3 H), 4.13 (m, 2 H), 4.18 (d, J = 3.6 Hz, 1 H), 5.08 (m, 1 H), 5.75 (d, J

= 7.2 Hz, 1 H), 6.50 (d, J = 7.2 Hz, 2 H), 7.20-7.60 (m, 18 H); 13C NMR  14.4, 21.7,

60.9, 61.8, 71.3, 126.2, 127.5, 127.8, 127.9, 128.4, 128.59, 128.64, 128.88, 129.26,

129.79, 131.05, 136.17, 139.09, 140.75, 141.48, 142.67, 169.80, 173.08. HRMS calcd.

C31H30N2O3SLi (M + Li): 517.2137. Found. 517.2146.

(SS,2R,3S)-(+)-Ethyl-2-N-(diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)- amino-3-(4-trifluoromethylphenyl)propanoate (252b) was synthesized with the same procedure to prepare (Ss,2R,3S)-(-)-Ethyl-2-N-(Diphenylmethyleneamino)-3-N-(p- toluenesulfinyl)-amino-phenylpropanoate (252a).

O S NH O

F3C Ph OEt N

Ph Ph

(SS,2R,3S)-(+)-Ethyl-2-N-(diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)-

20 amino-3-(4 trifluoromethylphenyl)propanoate (252b). Colorless oil, 87% yield; [] D

+135 (c 1.0, CHCl3); IR (neat): 3267, 1734, 1619 cm-1; 1H NMR (CDCl3) δ 1.19 (t, J

109 =7.2 Hz, 3 H), 2.44 (s, 3 H), 4.14 (m, 3 H), 5.02 (m, 1 H), 5.95 (d, J = 7.5 Hz, 1 H), 6.47

(d, J = 7.2 Hz, 2 H), 7.20-7.60 (m, 18 H); 13C NMR δ 14.4, 21.7, 60.1, 62.0, 70.9, 125.5,

126.1, 127.3, 127.9, 128.1, 128.5, 128.7, 129.1, 129.2, 129.5, 129.9, 131.3, 135.9, 138.8,

141.8, 145.2, 169.5, 173.5. HRMS calcd. For C32H30N2O3SF3 (M+H): 579.1929. Found.

579.1932.

O S p-Tolyl N

(R) -(-)-N-(Propylidine)-p-toluenesulfinamide (260). In a 50-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed p-toluenesulfinamide (+)-135 (0.618 g, 5.0 mmol), DCM (10 mL), acrolein (0.380 mL, 5.5 mmol), and Ti(OEt)4 (5.2 mL, 25.0 mmol) respectively. The solution was stirred for 8 h at rt, quenched with ice-H2O (5 mL), and filtered. The white predicate was washed with DCM (3 X 10 mL), and the aqueous phase was separated and extracted with DCM (3 X 5 mL). The combined organic phases were washed with brine

(15 mL), dried (Na2SO4), and concentrated. Chromatography (10% EtOAc/hexane)

20 afforded 0.687 g (86%) of a yellow oil; [] D = -796 (c 1.1, CHCl3); IR (neat): 2923,

-1 1 1577, 1096, 810 cm ; H NMR (CHCl3)  2.43 (s, 3H), 6.03 (S, 1 H), 6.07 (d, J = 6.9

Hz, 1 H), 6.68 (m, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.59 (d, J = 7.8 Hz, 2 H), 8.39 (d, J =

9.3 Hz, 1 H); 13C NMR  21.4, 124.6, 129.9, 132.2, 134.6, 141.4, 141.9, 162.0.

110 O S p-Tolyl NH

CO2Et N Bn Bn

(SR,2S,3R)-(-)-Ethyl-2-(N,N-dibenzylamino)-3-N-(p-toluenesulfinyl)amino- pent-4-enoate (262). In a 25-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 261 (3.3 g, 11.6

o mmol), Et2O (8.0 mL). The solution was cooled to 0 C. In a second 100-mL, one- necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed LDA (5.8 mL, 2.0 M in cyclohexane/heptane/benzene from

Aldrich) and Et2O (30.0 mL). The solution of 261 was added via a double-end needle at -

78 oC. The yellow-orange solution was stirred for 30 minutes at this temperature and

o sulfinimine (+)-260 (0.450g, 2.33 mmol) in Et2O (6.0 mL) was added dropwise at -78 C.

The solution was stirred at this temperature, monitored by TLC for completion (about 30 min), and quenched by addition of sat. aq. NH4Cl (10 mL). The solution mixture was warmed to rt and the aqueous phase was separated and extracted with EtOAc (3 X 10 mL). The combined organic phases were washed with brine (15 mL), dried (Na2SO4), and concentrated. Chromatography (5% and then 10% EtOAc/hexane) afforded 0.810 g

20 (73%) of a yellow oil; [] D = -121.4 (c 1.7, CHCl3); IR (neat): 3229, 1734, 1465, 1094

-1 1 cm ; H NMR (CHCl3)  1.35 (t, J = 7.0 Hz, 3 H), 2.48 (s, 3 H), 3.17 (d, J = 10.5 Hz, 1

H), 3.30 (d, J = 13.0 Hz, 2 H), 3.95 (d, J = 13.0 Hz, 2 H), 4.27 (m, 2 H), 4.38 (dd, J = 7.5

Hz, J = 10.5 Hz, 1 H), 5.15 (s, 1 H), 5.30 (m, 1 H), 5.45-5.57 (m, 2 H), 7.12-7.23 (m, 10

H), 7.32 (d, J = 8.0 Hz , 2 H), 7.56 (d, J = 8.0 Hz , 2 H); 13C NMR  14.8, 21.7, 53.4,

54.4, 60.8, 64.6, 122.0, 125.4, 127.5, 128.6, 129.6, 134.7, 138.2, 141.4, 143.2, 168.8 (one

111 carbon miss due to the overlap in the aromatic region). HRMS calcd. for

C28H32N2O3SNa (M + Na): 499.2031. Found: 499.2041.

O S p-Tolyl NH O OMe N N Me Bn Bn

(SR,2S,3R)-(-)-3-N-(p-Toluenesulfinyl)amino-2-(dibenzylamino)-N-methoxy-

N-methylpent-4-enamide (263). In a 50-mL, one-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (-)-262 (0.530 g, 1.1 mmol) in THF (10 ml) and the solution was cooled to -78 oC. In a separate 100- mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed N,O-dimethylhydroxylamine hydrochloride (0.542 g, 5.56 mmol) in THF (35 mL). The solution was cooled to -78 oC and n-BuLi (7.0 mL,

1.6 M in hexane) was added via syringe. The reaction mixture was warmed to rt, stirred for 20 min, and cooled to -78 oC. At this time the -78 oC solution of (-)-262 was slowly added via a double-end needle to the lithium N,O-dimethylhydroxylamine solution. The reaction mixture was stirred, monitored for completion by TLC (10 min), and quenched

o at -78 C by addition of sat. aqueous NH4Cl (10 mL). The solution was warmed to rt and the aqueous phase was separated and extracted with EtOAc (3 X 10 mL). The combined organic phases were washed with brine (15 mL), dried (Na2SO4), and concentrated.

20 Chromatography (30% EtOAc/hexane) afforded 0.488 g (89%) of a yellow oil; [] D = -

-1 1 18.6 (c 0.8, CHCl3); IR (neat): 3229, 3028, 1653, 1453, 1092 cm ; H NMR (CHCl3) 

2.48 (s, 3 H), 3.26 (s, 3 H), 3.30 (d, J = 14.0 Hz, 2 H), 3.46 (s, 3 H), 3.73 (d, J = 10.5 Hz,

112 1 H), 4.04 (d, J = 14.0 Hz, 2 H), 4.79 (dd, J = 8.0 Hz, J = 10.5 Hz, 2 H), 5.32 (m, 2 H),

5.49 (m, 1 H), 5.59 (m, 1 H), 7.17 (m, 10 H), 7.35 (d, J = 8.0 Hz , 2 H), 7.61 (d, J = 8.0

Hz, 2 H); 13C NMR  21.7, 31.8, 53.9, 54.2, 60.0, 61.6, 121.8, 125.4, 127.2, 128.4,

129.4, 129.6, 135.0, 139.2, 141.4, 143.4, 169.5. HRMS calcd. for C28H34N3O3S(M + H):

492.2321. Found 492.2314.

N NH O H OMe N N Me Bn Bn

N-[(2S,3R)-(+)-1-(N-Methoxy-N-methylcarbamoyl)-1-(dibenzylamino)but-3- en-2-yl]]-1H-pyrrole-2-carboxamide (264). In a 100-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed

MeOH (30 mL), (-)-263 (0.440 g, 0.9 mmol), and TFA (0.345 mL, 4.5 mmol) was added at 0 oC. The reaction mixture was stirred for 2 h at rt and concentrated. The residue was dissolved in DCM (30 mL), and sat aqueous NaHCO3 was used to adjust solution to pH to ~7. The aqueous phase was separated and extracted with EtOAc (3 X 8 mL) and the organic phases were combined, washed with brine (15 mL), dried (Na2SO4), and concentrated. The flask containing the residue was then equipped with a magnetic stirring bar, rubber septum, and argon balloon. CH3CN (20 ml), 2-pyrrole carboxylate acid (0.110 g, 0.99 mmol) was added to the flask, followed by HBTU (0.390 g, 1.03 mmol), and

DIPEA (0.611 mL, 4.5 mmol). The reaction was stirred at rt for 8 h, diluted with EtOAc

(40 mL), and the organic phase was washed with Na2CO3 (15 mL), H2O (10 mL), and 1

N HCl (10 mL). The organic phase was then washed with brine (15 mL), dried

113 (Na2SO4), and concentrated. Chromatography (20% EtOAc/hexane) afforded 0.381 g

o o 20 (94%) of a white solid, mp 74.5 C-75.5 C; [] D = +131.6 (c 0.6, CH3OH); IR (neat):

-1 1 3406, 3253, 1646, 742 cm ; H NMR (CHCl3)  3.34 (s, 3 H), 3.44 (d, J = 14.0 Hz, 2

H), 3.53 (s, 3 H), 3.86 (d, J = 10.5 Hz, 1 H), 4.05 (d, J = 14.0 Hz, 2 H), 5.02 (m, 1 H),

5.16 (m, 1 H), 5.35 (m, 1 H), 5.68 (m, 1 H) 6.35 (m, 1 H), 6.42 (m, 1 H), 6.64 (s, 1 H),

6.98 (s, 1 H), 7.26 (m, 10H), 9.82 (b, 1 H); 13C NMR  31.9, 51.1, 54.4, 59.8, 61.6, 109.1,

109.9, 117.8, 122.1, 126.2, 127.4, 128.6, 129.4, 136.2, 139.8, 161.4, 169.8. HRMS calcd. for C26H30N4O3Na (M + Na): 469.2216. Found 469.2227.

O Bn N Bn NH

O NH

N-(-)-[(E,3R,4S)-4-(dibenzylamino)-5-oxoocta-1,6-dien-3-yl]]-1H-pyrrole-2- carboxamide (265). In a 50-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed compound (+)-264

(0.350 g, 0.78 mmol) in THF (20 mL) and allylmagnesium bromide (3.14 mL, 1.0 M in ether) was added at 0 oC. The reaction mixture was stirred for 20 min and quenched with

o sat. aqueous NH4Cl (5 mL) at -78 C. The solution was warmed to rt and the aqueous phase was separated and extracted with EtOAc (3 X 6 mL). The organic phase was washed with brine (10 mL), dried (Na2SO4), and concentrated. The residue was dissolved in EtOH (30 mL), placed in a 50-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon. To the solution was added Et3N (4 mL), and the reaction mixture was stirred for 12 h and concentrated.

114 Chromatography (EtOAc:hexane 1:5) afforded 0.285 g (85%) of a yellow solid, mp

o 20 124.5-125.5 C; [] D = -30.3 (c 1.1, CHCl3); IR (neat): 3365, 3232, 1650, 1562, 742

-1 1 cm ; H NMR (CHCl3)  1.99 (d, J = 6.5 Hz, 3 H), 3.49 (d, J = 14.0 Hz, 2 H), 3.67 (d, J

= 10.5 Hz, 1 H), 3.98 (d, J = 14.0 Hz, 2 H), 5.15 (m, 2 H), 5.30 (m, 1 H), 5.72 (m, 1 H),

6.33 (m, 3 H), 6.62 (m, 1 H), 6.82 (m, 1 H), 6.98 (m, 1 H), 7.23 (m, 10 H), 9.98 (b, 1 H);

13C NMR  18.8, 50.0, 54.6, 65.7, 109.0, 110.0, 118.1, 122.0, 126.3, 127.7, 128.8, 129.3,

132.8, 136.0, 139.2, 144.7, 161.0, 198.0. HRMS calcd. for C27H29N3O2Na(M + Na):

450.2157. Found 450.2165.

O Bn N Bn H N NH

N-(-)-[(1R,5S)-5-(dibenzylamino)-4-oxocyclopent-2-enyl]]-1H-pyrrole-2- carboxamide (266). In a 250-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (-)-264 (0.150 g, 0.35 mmol) and Grubbs 2nd generation catalyst (0.030 g, 10 mol%) in DCM (75 mL). The reaction mixture was refluxed for 12 h and concentrated. Chromatography (1:4

o 20 EtOAc/hexane) afforded 0.116 g (87%) of a yellow solid, mp 85.5-86.5 C; [] D = -

-1 1 147.4 (c 0.25, CHCl3); IR (neat): 3265, 1717, 1646, 1333 cm ; H NMR (CHCl3)  3.45

(d, J = 4.0 Hz, 1 H), 3.46 (d, J = 14.0 Hz, 2 H), 3.88 (d, J = 10.5 Hz, 1 H), 5.48 (m, 1 H),

6.07 (d, J = 8.7 Hz, 1 H), 6.20 (d, J = 6.0 Hz, 1 H), 6.29 (s, 1 H), 6.52 (s, 1 H), 7.02 (s, 1

H), 7.27 (m, 5 H), 7.38 (m, 5 H); 10.22 (b, 1 H); 13C NMR  51.5, 52.3, 70.3, 110.1,

115 110.3, 122.7, 125.3, 127.5, 128.6, 129.1, 134.8, 139.2, 160.4, 161.1, 205.4. HRMS calcd. for C24H23N3O2Na(M + Na): 408.1688. Found 408.1699.

Bn N N Bn NH

(-)-(3S,3aR,9aR)-3-(dibenzylamino)-3a,4-dihydro-1H- cyclopenta[e]pyrrolo[1,2-a]pyrazine-2,5(3H,9aH)-dione (267). In a 100-mL, one- necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (-)-266 (0.64 g, 1.68 mmol) in THF (60 mL) and Cs2CO3 (5.48 g, 16.8 mmol) was added. The reaction mixture was stirred at rt for 3 h, then filtered and concentrated. Chromatography (1:1 EtOAc/hexane) afforded 0.42 g (66%) of (-)-267 as off white solid and 0.16 g of (-)-266. To the recovered (-)-266 (0.16 g, 0.42 mmol) in

THF (15 mL), Cs2CO3 (1.37 g, 4.2 mmol) was added. The solution was stirred at rt for 2 h, then filtered and concentrated. Chromatography (1:1 EtOAc/hexane) afforded 0.096 g

(15%) of an off white solid and combined with above product give 81% as overall yield.

o 20 -1 1 mp 195 C dec; [] D = -10.2 (c 0.28, CHCl3); IR (neat): 3854, 1653, 1350 cm ; H

NMR (CHCl3)  2.63 (dd, J = 6.0 Hz, J = 19.2 Hz, 1 H), 2.97 (d, J = 19.2 Hz, 1 H), 3.51

(d, J = 11.7 Hz, 1 H), 3.89 (m, 1 H), 3.94 (s, 4 H), 4.68 (t, J = 6.0 Hz, 1 H), 6.26 (m, 1

H), 6.48 (d, J = 3.3 Hz, 1 H), 6.71 (m, 1 H), 6.91 (m, 1 H), 7.27 (m, 10 H); 13C NMR 

43.0, 50.3, 54.4, 56.4, 69.7, 111.2, 115.3, 122.4, 123.7, 127.9, 128.9, 138.7, 158.9, 211.2

(one carbon is absent due to the ring strain or overlap in aromatic region). HRMS calcd. for C24H23N3O2Na(M + Na): 408.1688. Found 408.1699.

116

Me HO N O NH N NH

(-)-(5aS,5bS,8aS,9aR)-8a-hydroxy-8-methyl-5,5a,5b,6,8,8a,9,9a- octahydroimidazo[4',5':4,5]cyclopenta[1,2-e]pyrrolo[1,2-a]pyrazine-4,7-dione (269).

In a 10-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, an outlet and inlet stopcock equipped with a H2 filled balloon, and a rubber septum was placed THF (10 mL), (-)-267 (0.130 g, 0.337 mmol), and 10% Pd/C (1.30 g, 1.21 mmol).

The solution was evacuated and then filled with H2, and this sequence was repeated 5 times. Methyl isocyanate (0.201 mL, 3.370 mmol) was added via a syringe to the flask in one shot. The reaction mixture was stirred for 12 h at rt, the catalyst was removed by filtration through Celite and the filtrate was concentrated. Preparative TLC (1:9

MeOH/DCM) afforded 0.065 g (70%) of (-)-269 as an off-white solid, mp 243.5-244.5 o 3 o 20 3 20 C [lit mp 244-245 C]; [] D = -66.2 (c 0.21, MeOH) [lit. [] D = -68.4 (c 0.4,

-1 1 MeOH)]; IR (neat): 3281, 2849, 1653, 1559 cm ; H NMR (CD3OD)  2.27 (dd, J =

13.0 Hz, J = 10.5 Hz, 1 H), 2.62 (dd, J = 6.0 Hz, J = 13.0 Hz, 1 H), 2.78 (s, 3 H), 3.79 (d,

J = 1.0 Hz, 1 H), 3.99 (dd, J = 1.0 Hz, J = 6.0 Hz, 1 H), 4.63 (m, 1 H), 6.21 (dd, J = 2.5

Hz, J = 4.0 Hz, 1 H), 6.87 (dd, J = 1.5 Hz, J = 4.0 Hz, 1 H), 7.01 (dd, J = 2.5 Hz, J = 1.5

Hz, 1 H); 13C NMR  24.2, 41.6, 55.6, 62.8, 68.0, 95.8, 111.0, 115.4, 122.9, 125.6,

161.3, 162.0.

117 Me HO N O N N Bn NH

(-)-(5aR,5bS,8aS,9aR)-6-benzyl-8a-hydroxy-8-methyl-5,5a,5b,6,8,8a,9,9a- octahydroimidazo[4',5':4,5]cyclopenta[1,2-e]pyrrolo[1,2-a]pyrazine-4,7-dione (270).

Chromatography (1:9 MeOH/DCM) afforded 0.030 g (24%) of an off-white solid, mp

o 20 -1 1 105.0 C dec; [] D = -57.9 (c 0.29, CHCl3); IR (neat): 3279, 2925, 1653, 1525 cm ; H

NMR (CHCl3)  2.26 (dd, J = 13.0 Hz, J = 10.5 Hz, 1 H), 2.62 (dd, J = 6.0 Hz, J = 13.0

Hz, 1 H), 2.84 (s, 3H), 3.67 (d, J = 1.0 Hz, 1 H), 3.94 (dd, J = 1.0 Hz, J = 6.0 Hz, 1 H),

4.39 (d, J = 15.0 Hz, 1 H), 4.58 (m, 1 H), 4.59 (d, J = 15.0 Hz, 1 H), 6.19 (m, 1 H), 6.83

(m, 1 H), 6.97 (m, 1 H), 7.26 (m, 1 H), 7.32 (m, 4 H); 13C NMR  25.5, 41.8, 48.4, 55.1,

59.4, 72.2, 93.1, 111.4, 116.2, 121.6, 124.9, 128.6, 129.0, 129.6, 137.8, 159.0, 161.0.

HRMS calcd. for C19H21N4O3(M + H): 353.1614. Found 353.1629.

Me HO N O Br NH N NH

(-)-Agelastatin A (233). In a 25-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed MeOH (5 mL),

THF (10 mL), (-)-269 (0.026 g, 0.099 mmol). Cool the solution to -78 oC. 1,3-dibromo-

5,5-dimethylhydantoin (DBDMH) 271 (0.014 g, 0.049 mmol) was added. The reaction solution was stirred at this temperature for 2 h then warm up to rt and stirred for 12 h.

118 The solution mixture was concentrated and purified by preparative TLC (1:4

20 MeOH/EtOAC) afforded 0.031g (91%) of an off-white solid. [] D = -62.2 (c 0.18,

MeOH) [lit.188 -65.5 (c 0.5, MeOH); lit.217: -59.3 (c 0.13, MeOH)]; IR (neat): 3289, 2917,

-1 1 1657, 1564 cm ; H NMR (CHCl3)  2.08 (dd, J = 12.5 Hz, J = 12.5 Hz, 1 H), 2.62 (dd,

J = 6.0 Hz, J = 13.5 Hz, 1 H), 2.79 (s, 3H), 3.87 (s, 1 H), 4.07 ( J = 5.5 Hz, 1 H), 4.58 (m,

1 H), 6.30 (J = 4.5 Hz, 1 H), 6.89 (J = 4.5 Hz, 1 H); 13C NMR  24.6, 40.4, 54.8, 62.6,

67.8, 96.1, 107.6, 114.2, 116.4, 124.6, 161.5, 161.8.

(Ss,R)-(+)-Ethyl 2-[phenyl(p-toluenesulfinylamino)methyl]acrylate (288). In a

5 mL, heat-gun dried, single-necked round bottom flask equipped with a magnetic stirring bar and rubber septum was placed NMO (0.174 g, 1.48 mmol) in anhydrous THF

(2 mL). To the stirring solution was added DIBAL (1.12 mL, 1.0 M in THF) at 0 oC and the mixture was stirred at this temperature for 1 h before ethyl propiolate (0.076 mL, 0.74 mmol) was added. The mixture was stirred for 2 h at 0 oC, followed by the addition of a solution of (S)-(+)-N-benzylidene-p-toluenesulfinamide (241a) (0.060g, 0.246 mmol) in

THF (2 mL). The mixture was warmed up to rt, stirred for 4 h before quenching with

NaKC4H4O6. H2O (6 mL), diluted with EtOAc (5 mL), and vigorously stirred for 30 min, extracted with EtOAc (3 X 5 mL). The organic layer was brined, dried (MgSO4) and concentrated. Prep. TLC (50% Hexane/Ethyl Acetate) provided 55.0 mg (65%) of

119 20 colorless oil as a major isomer. (dr >20:1). [] D = +30.0 (c 0.28, CHCl3); IR (neat):

-1 1 3204, 1711, 1053 cm ; H NMR (CDCl3)  1.20 (t, J = 6.8 Hz, 3H), 2.39(s, 3H),

4.13(qt, J = 7.2 Hz, 2H), 4.93 (d, J = 7.2 Hz, 1H), 5.35(d, J = 7.2 Hz, 2H), 6.03(d, J = 0.8

Hz, 1H), 6.47(s, 1H), 7.20-7.28(m, 7H), 7.61(d, J = 6.4 Hz, 2H); 13C NMR  14.5, 21.7,

58.4, 61.3, 126.0, 127.2, 127.4, 128.0, 128.9, 129.9, 140.5, 141.6, 141.8, 166.0 (one carbon can’t be identified due to overlap). HRMS calcd. for C19H22NO3S(M+H):

344.1320. Found 344.1327.

(Ss,R)-(+)-Methyl 2-[phenyl(p-toluenesulfinylamino)methyl]acrylate (282).

Prep. TLC (50% Hexane/Ethyl Acetate) provided 19.5 mg (32%) of colorless oil as a

20 major isomer. (dr >28:1). [] D = +32.5 (c 0.415, CHCl3); IR (neat): 3228, 1720, 1053

-1 1 cm ; H NMR (CDCl3)  2.39(s, 3H), 3.70(s, 3H), 4.95(d, J = 6.8 Hz, 1H), 5.35(d, J =

7.2 Hz, 2H), 6.04(s, 1H), 6.47(s, 1H), 7.20-7.28(m, 7H), 7.61(d, J = 6.4 Hz, 2H); 13C

NMR  21.7, 52.3, 58.3, 126.0, 127.3, 127.5, 128.0, 128.9, 129.9, 140.3, 141.3, 141.7,

141.8, 166.5. HRMS calcd. for C18H19NO3SNa(M+Na) 352.0983. Found 352.0990.

O S NH O

Ph O

120 Ethyl (Rs,2S)-(-)-2-(phenyl(tert-butylsulfinyl amino)methyl)acrylate (295). In a 25 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum was placed NMO (0.606 g, 5.16 mmol) in THF (6 mL). To the stirring solution was added DIBAL (3.9 mL, 1.0 M solution in CH2Cl2) at 0 °C and the mixture was stirred for 30 min. Ethyl propiolate (284) (0.264 mL, 2.59 mmol) was added via syringe, and the mixture was stirred for 1 h at 0 °C, followed by the addition of a soution of (R)-(+)-N-benzylidene-t-butylsulfinamide (273d) (0.180 g, 0.864 mmol) in anhydrous THF (6 mL). The mixture was heated to 67 °C and stirred for 15 h. The reaction mixture was cooled to rt and quenched with sat. aqueous NaKC4H4O6H2O

(Rochell salt) (5 mL), diluted with EtOAc (5 mL), vigorously stirred at rt. The organic phase was dried (MgSO4) and concentrated. Flash chromatography (25%

EtOAc/hexanes) provided 0.174 g (65%) of a colorless oil as a single diastereomer based

1 20 -1 on crude H NMR. [] D -1.4 (c 0.933, CHCl3); IR (KBr) 3233, 2980, 1717, 1061 cm ;

1 H NMR (CDCl3)  7.26 (m, 5H), 6.45 (s, 1H), 5.99 (s, 1H), 5.49 (d, J = 4.4 Hz, 1H),

4.12 (t, J = 7.0 Hz, 2H), 3.76 (d, J = 4.8 Hz, 1H), 1.25 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H);

13 C NMR (CDCl3)  166.0, 141.6, 140.7, 129.1, 128.3, 127.9, 126.8, 61.3, 59.8, 56.5,

30.7, 23.0, 14.4. HRMS calcd for C16H24NO3S (M+H) 310.147691. Found 310.1472.

O S NH O

Ph O

121 Methyl (Rs,2S)-(-)-2-(phenyl(tert-butylsulfinyl amino)methyl)acrylate (297).

Flash chromatography (25% Et2O/hexanes) provided 0.062 g (44%) of a colorless oil as a

1 20 single diastereomer based on crude H NMR. [] D -9.9 (c 0.87, CH2Cl2); IR (KBr)

-1 1 3236, 1722, 1060 cm ; H NMR (CDCl3)  7.26 (m, 5H), 6.45 (d, J = 0.8 Hz, 1H), 5.99

(t, J = 0.8 Hz, 1H), 5.48 (d, J = 4.4 Hz, 1H), 4.12 (t, J = 7.0 Hz, 2H), 3.73 (d, J = 4.4 Hz,

13 1H), 3.67 (s, 3H), 1.23 (s, 9H); C NMR (CDCl3)  166.0, 141.3, 140.5, 129.1, 128.4,

127.8, 127.5, 127.0, 61.3, 59.7, 56.5, 52.2, 23.0. HRMS calcd for C15H22NO3S (M+H)

296.1319. Found 296.1320.

(RS,3S)-(-)-Ethyl 3-(1,1-Dimethylethylsulfinamido)-2-methylenepentanoate

(296). Flash chromatography (40% EtOAc/hexanes) provided 55% of a colorless oil: IR

20 (neat) 3212, 1718 cm-1; [] D -39.6 (c 1.26, CHCl3); 1H NMR (CDCl3) δ 6.26 (s, 1H),

5.27 (s,1H), 4.22 (m, 2H), 4.04 (dt, J ) 6.8 Hz, 1H), 3.68 (d, J = 6.8 Hz,1H), 1.86 (m,

2H), 1.31 (t, J ) 6.8 Hz, 3H), 1.19 (s, 9H), 0.93 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3)

δ 166.4, 141.3, 126.3, 61.2, 60.1, 56.1, 29.1, 22.9, 14.5, 11.3. HRMS calcd for

C12H24NO3S (M + H) 262.1477. Found 262.1455.

O S NH O

122 Ethyl (Z)-Ethyl (Rs,2S)-(-)-2-(ethyl(tert-butylsulfinylamino) methyl)-3- phenylacrylate(300). Flash chromatography (50% EtOAc/hexanes) provided 0.124 g

20 (35%) of a colorless oil as a major isomers (dr=92:1). [] D -36.3 (c 0.84, CHCl3); IR

-1 1 (KBr) 3211, 1722, 1225, 1061cm ; H NMR (CDCl3)  7.22 (m, 5H), 6.77 (s, 1H), 4.07

(m, 3H), 3.47 (d, J = 5.2 Hz, 1H), 1.98 (m, 1H), 1.83 (m, 1H), 1.20 (s, 9H), 1.06 (t, J =

13 7.2 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H); C NMR (CDCl3) major isomer:  161.3, 128.3,

127.9, 127.3, 121.3, 121.2, 121.1, 58.8, 55.3, 53.7, 48.7, 21.9, 15.5, 6.7, 3.7. HRMS calcd for C18H28NO3S (M+H) 338.1790. Found 338.1781.

O S NH O

Ph O

(Z)-Ethyl (Rs,2S)-(-)-2-(phenyl(tert-butylsulfinylamino)methyl) but-2-enoate (301).

Flash chromatography (33% EtOAc /hexanes) provided 0.181 g (71%) of a colorless oil

20 as a major isomers (dr=90:1). [] D -24.8 (c 0.29, CHCl3); IR (KBr) 3214, 3030, 2959,

-1 1 2869, 1717 cm ; H NMR (CDCl3) major isomer:  7.25 (m, 5H), 6.35 (qt, J =7.3 Hz,

1H), 5.34 (d, J = 6.0 Hz, 1H), 4.09 (m, 2H), 3.85 (d, J = 6.4 Hz, 1H), 2.05 (dd, J = 0.8,

13 7.2 Hz, 1H), 1.23 (s, 9H), 1.15 (t, J = 7.0 Hz, 3H); C NMR (CDCl3)  166.7, 141.0,

138.8, 133.8, 128.7, 127.8, 127.4, 61.9, 60.5, 56.2, 22.8, 15.7, 14.2. HRMS calcd for

C17H26NO3S (M+H) 324.163341. Found 324.1649.

123 O S NH O

Ph O

(Z)-Ethyl (Rs,2R)-(-)-2-(phenyl(tert-butylsulfinylamino)methyl) -3-phenylacrylate

(302). Flash chromatography (25% EtOAc/hexanes) provided 0.240 g (73%) of a

20 colorless oil as a major isomers (dr=32:1). [] D -41.0 (c 1.05, CHCl3); IR (KBr) 3211,

-1 1 3029, 2979, 2868, 1734, 1225 cm ; H NMR (CDCl3) major isomer:  7.38 (m, 2H), 7.28

(m, 3H), 7.20 (m, 5H), 6.94 (s, 1H), 5.45 (d, J = 5.6 Hz, 1H), 4.00 (m, 2H), 3.91 (d, J =

13 6.0 Hz, 1H), 1.27 (s, 9H), 0.97 (t, J = 7.0 Hz, 3H); C NMR (CDCl3)  168.1, 139.9,

135.7, 135.4, 134.9, 128.8, 128.6, 128.5, 128.3, 128.2, 127.7, 62.7, 60.9, 56.4, 22.8 (3C),

13.7. HRMS calcd for C22H28NO3S (M+H) 386.178991. Found 386.1805.

O S NH O

Ph O

(Ss,2R,3S)-(+)-ethyl 2-methyl-3-(4-methylphenylsulfinamido)-3- phenylpropanoat (290). In an oven-dried, 25 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an H2 balloon was placed (+)-

288 (0.040 g, 0.117 mmol) and RuBIPHOS Complex 289 (0.0062 g, 0.0088 mmol) in anhydrous DCM (5.0 mL). The solution was evacuated and then filled with H2, and this sequence was repeated 5 times and was stirred for 48 h at rt. Prep. TLC (50%

EtOAc/hexanes) afforded 0.0352 g (88%) of colorless oil as a major isomer (dr > 24:1).

124 20 -1 1 [] D = +33.6 (c 0.645, CHCl3); IR (neat): 3206, 1730, 1090, 1053 cm ; H NMR

(CDCl3)  1.46 (d, J = 6.8 Hz, 3H), 1.21(t, J = 7.2 Hz, 3H), 2.32(s, 3H), 2.88(quint, J =

7.6 Hz, 1H), 4.13(qt, J = 7.2 Hz, 2H), 4.50 (t, J = 7.6 Hz, 1H), 5.06(d, J = 7.2 Hz, 1H),

7.11(m, 4H), 7.19-7.23(m, 3H), 7.43(d, J = 8.0 Hz, 2H); 13C NMR  14.5, 15.8, 21.6,

46.9, 60.4, 61.1, 126.1, 127.3, 127.9, 129.0, 129.5, 141.1, 141.4, 142.0, 175.0. HRMS calcd. for C19H23NO4SNa(M+Na) 368.1304. Found 368.1296.

O S NH O

Ph O

(SR,2S,3R)-(-)-ethyl 2-methyl-3-(4-methylphenylsulfinamido)-3 phenylpropanoate (306). Chromatograpy (50% EtOAc/hexanes) afforded 0.112 g (83%)

20 of colorless oil as a major isomer (dr > 21:1). [] D = -20.6 (c 0.18, CHCl3); IR (neat):

-1 1 3584, 3256, 2979, 2734, 1734 cm ; H NMR (CDCl3)  7.24 (m, 2H), 4.39 (d, J = 8.4

Hz, 1H), 4.05 (q, J = 6.1 Hz, 2H), 3.89 (d, J = 8.0 Hz, 1H), 2.86 (dq, J = 7.0, 8.6 Hz, 1H),

13 1.17 (t, J = 7.2 Hz, 3H), 1.11 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H); C NMR (CDCl3) 

174.9, 140.4, 128.9, 128.2, 127.4, 63.1, 60.8, 56.4, 46.8, 22.7, 15.2, 14.3. HRMS calcd for C16H26NO3S (M+H) 312.163341. Found 312.1625.

O S NH O

Ph O

125 (Rs,2S,3R)-methyl 3-(1,1-dimethylethylsulfinamido)-2-methyl-3- phenylpropanoate (307). Prep. TLC (50% EtOAc/hexanes) afforded 0.0263 g (73%) of

20 colorless oil as a major isomer (dr > 33:1). [] D = -17.6 (c 0.38, CHCl3); IR (neat):

-1 1 3237, 1737, 1057 cm ; H NMR (CDCl3)  7.26-7.37 (m, 5H), 4.45 (t, J = 7.6 Hz, 1H),

3.88 (d, J = 8.1 Hz, 1H), 3.66 (s, 3H), 2.96 (m, 1H), 1.17 (s, 9H), 1.04 (d, J = 7.2 Hz,

13 3H); C NMR (CDCl3)  175.5, 140.5, 129.2, 128.5, 127.6, 63.5, 60.4, 56.6, 54.1, 46.9,

22.7, 15.4. HRMS calcd for C15H24NO3S (M+H) 298.1477. Found 298.1475.

(RS,2S,3S)-(-)-Ethyl-2-methyl-3-(tert-butylsulfinylamino)pentanoate (308).

20 Preparative TLC (50% EtOAc/hexane) afforded 0.0255 g (55%) of a colorless oil: [] D

-31.46 (c 0.06, CHCl3); IR (neat) 3280, 1732, 1462, cm-1; 1H NMR (CDCl3) δ 4.06

(m, 2H), 3.62 (d, J =12 Hz, 1H), 3.29 (m, 1H), 2.69 (m, 1H), 1.72 (m, 1H), 1.26 (t, J =

7.2 Hz, 3H) 1.23 (s, 9H), 1.19 (d, J ) 7.2 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H); 13C NMR

(CDCl3) δ 174.9, 61.3, 60.4, 56.2, 43.4, 27.37, 22.7, 14.7, 14.2, 10.0. HRMS calcd for

C12H26NO3S (M + H) 264.1633. Found 264.1613.

O S NH O

Ph O

(Rs,S)-(-)-ethyl 2-((R)-(1,1- dimethylethylsulfinamido)(phenyl)methyl)butanoate (310). In an oven-dried, 25 mL

126 one-necked, round-bottomed flask equipped with a magnetic stirring bar were placed (-)-

301 (0.0302 g, 0.093 mmol) and rhodium complex 289 (0.005 g, 0.007 mmol) in 1,2- dichloroethane (4.5 mL). The solution was placed in a high-pressure vessel (Series 4650

2.50 Inch Inside Diameter HP/HT from Parr Instrument Company). The vessel was tightly closed and was filled with H2 until the inner pressure reached 25 atm at which time it was evacuated and refilled with H2 to 25atm. This sequence was repeated three times. The reaction mixture was stirred at 25 atm of H2 for 72 h at rt, at which time the solution was concentrated. Preparative TLC (50% EtOAc/hexanes) afforded 0.0241 g

20 (81%) of a colorless oil. [] D -44.4 (c 0.41, CHCl3); IR (neat) 3216, 1732, 1052 cm-1;

1H NMR (CDCl3) δ 7.30 (m, 5H), 4.60 (dd, J ) 7.6, 7.6 Hz, 1H), 3.95 (q, J ) 7.2 Hz,

2H), 3.66 (d, J = 7.6 Hz, 1H), 2.80 (m, 1H), 1.63 (m, 2H), 1.20 (s, 9H), 1.04 (t, J = 7.2

Hz, 3H), 0.92 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 173.0, 140.6, 128.6, 128.0,

127.3, 61.7, 60.4, 56.5, 54.2, 22.7, 22.1, 14.0, 11.9. HRMS calcd for C17H28NO3S (M+

H) 326.1790. Found 326.1782.

O S NH O

(Rs,2S,3S)-ethyl 2-benzyl-3-(1,1-dimethylethylsulfinamido)pentanoate (309).

Prep. TLC (50% EtOAc/hexanes) afforded 0.0153 g (77%) of colorless oil as a major

20 -1 1 isomers (dr>25:1). [] D = -27.7 (c 0.51, CHCl3); IR (neat): 3228, 1731, 1053 cm ; H

NMR (CDCl3) major isomer  7.10-7.27 (m, 5H), 4.00(qt, J = 7.6 Hz, 2H), 3.66 (m, 1H),

127 3.23 (d, J = 7.6 Hz, 1H), 2.96 (m, 2H), 2.85(m, 1H), 1.77(m, 1H), 1.62(m, 1H), 1.20 (s,

13 9H), 1.10(t, J = 8.1 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H) ; C NMR (CDCl3)  173.2, 139.2,

128.8, 128.5, 126.4, 60.4, 59.8, 56.2, 52.0, 34.1, 26.8, 22.9, 14.1, 10.4. HRMS calcd for

C18H29NO3SNa (M+Na) 362.1766. Found 362.1761.

O S NH O

Ph O

(Rs,S)-(-)-ethyl 2-((R)-(1,1- dimethylethylsulfinamido)(phenyl)methyl)butanoate (311). Prep. TLC (50%

EtOAc/hexanes) afforded 0.0171 g (79%) of colorless oil as a major isomer (dr > 20:1).

20 -1 1 [] D = -19.5 (c 0.565, CHCl3); IR (neat): 3221, 1730, 1052 cm ; H NMR (CDCl3) 

7.20-7.40 (m, 10H), 4.66 (t, J = 7.2 Hz, 1H), 3.81 (qt, J = 7.6 Hz, 2H), 3.20 (m, 1H),

13 3.06 (m, 1H), 2.92 (m, 1H), 1.23(s, 9H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (CDCl3) 

172.3, 140.0, 138.8, 128.8, 128.6, 128.4, 128.1, 127.3, 126.4, 61.9, 60.3, 56.5, 54.6, 35.0,

22.6, 13.7. HRMS calcd for C22H29NO3SNa (M+Na) 410.1765. Found 410.1751

Ts NH O

Ph O

(2R,3S)-(-)-ethyl 2-methyl-3-(4-methylphenylsulfonamido)-3- phenylpropanoate (292). In an oven-dried, 10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and an Argon balloon was placed

(+)-290 (0.028 g, 0.081 mmol) in anhydrous DCM (3.0 mL). The mixture was cooled to

128 0oC, m-CPBA (0.056 g, 0.243 mmol, 75% wt) was added in one portion. The solution was then warmed up to rt, and stirred for 1.5 h before quenching with sat. Na2S2O3 solution (10 mL). The solution was stirred for 10 min, extracted with DCM (2 x 5 mL).

The combined organic layer was washed with sat. NaHCO3 solution (2 x 5 mL), brined, dried (MgSO4), concentrated. Prep. TLC (50% EtOAc/hexanes) afforded 0.0242 g (87%)

20 -1 1 of colorless oil. [] D = -43.0 (c 1.085, CHCl3); IR (neat): 3279, 1733, 1161 cm ; H

NMR (CDCl3)  1.10-1.15(m, 6H), 2.31(s, 3H), 2.79(quint, J = 6.4 Hz, 1H), 4.01(qt, J =

7.2 Hz, 2H), 4.50 (dd, J = 6.0 Hz, J = 8.4 Hz, 1H), 5.96(d, J = 8.8 Hz, 1H), 6.99-7.01(m,

2H), 7.05(d, J = 8.4 Hz, 2H),7.09-7.15(m, 3H), 7.48(d, J = 8.0 Hz, 2H); 13C NMR  14.3,

15.8, 21.7, 46.3, 60.5, 61.2, 126.9, 127.3, 127.7, 128.6, 129.5, 138.4, 139.4, 143.1, 174.9.

HRMS calcd. for C19H22NO4S(M+H): 362.1426. Found 362.1419.

(2S,3R)-(+)-2-methyl-3-(4-methylphenylsulfonamido)-3-phenylpropanoic acid (293). In an oven-dried, 10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, rubber septum was placed 292 (0.066 g, 0.182 mmol) and LiOH monohydrate ( 0.0308 mg, 0.728 mmol) in THF (14 mL) and H2O (0.5 mL). The mixture was refluxed for 16 h at 67oC, cooled to rt, and concentrated. The residue was diluted with DCM (10 mL), washed with 1N HCl until PH<2. The solution was stirred for 10 min, extracted with DCM (3 x 5 mL). The combined organic layer was brined, dried (MgSO4), and concentrated. Chromatography (50% EtOAc/hexanes)

129 20 afforded 0.0448 g (75%) of colorless oil. [] D = +28.5 (c 0.575, EtOAc); IR (neat):

-1 1 3263, 1712, 1160 cm ; H NMR (CDCl3)  1.17(d, J = 6.8 Hz, 3H), 2.29(s, 3H),

2.87(quint, J = 6.8 Hz, 1H), 4.50 (dd, J = 7.2 Hz, J = 8.8 Hz, 1H), 6.20(d, J = 9.2 Hz,

1H), 7.01-7.03(m, 4H), 7.09-7.14(m, 3H), 7.47(m, 2H); 13C NMR  15.7, 21.7, 46.1,

60.5, 127.1, 127.3, 127.9, 128.7, 129.5, 138.0, 138.9,143.3, 178.6. HRMS calcd. for

C17H20NO4S(M+H): 334.1113. Found 334.1126. Spectrum and rotation is consistent with reported ones.218,219

Ph Ts N

(3S,4R)-(+)-3-methyl-4-phenyl-1-tosylazetidin-2-one (294). In an oven-dried,

10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum was placed 293 (0.0223 g, 0.067 mmol) DCC (0.017 mg, 0.0804 mmol) and 4- pyrrolidinopyridine in DCM (2.5 mL). The mixture was refluxed for 16 h at rt, filtered through Celite. The filtrate was washed with water (3.0 mL), 5% aqueous HOAc (3 mL), and water (3 mL). The combined organic layers were brined, dried (MgSO4), and concentrated. Prep. TLC (25% EtOAc/hexanes) afforded 0.0165 g (80%) of colorless oil.

20 -1 1 [] D = +104 (c 0.575, EtOAc); IR (neat): 1794, 1361, 1168 cm ; H NMR (CDCl3) 

1.34(d, J = 7.6 Hz, 3H), 2.42(s, 3H), 3.16(m, 1H), 4.60 (d, J = 3.2 Hz, 1H), 7.20-7.31(m,

7H), 7.62(dd, J = 3.2 Hz, J = 6.4 Hz, 2H); 13C NMR  12.8, 22.0, 55.0, 65.4, 126.9,

127.8, 129.2, 129.3, 130.1, 136.1, 136.5, 145.4, 167.9. HRMS calcd. for

C17H18NO3S(M+H): 316.1007. Found 316.1013. (Spectrum and rotation is consistent with reported ones.218

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