University Microfilms International 300 N

INFORMATION TO USERS

This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted.

The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction.

1. The sign or “target” for pages apparently lacking from the document photographed is “Missing Page(s)”. If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure complete continuity.

2. When an image on the film is obliterated with a round black mark, it is an indication of either blurred copy because of movement during exposure, duplicate copy, or copyrighted materials that should not have been filmed. For blurred pages, a good image of the page can be found in the adjacent frame. If copyrighted materials were deleted, a target note will appear listing the pages in the adjacent frame.

3. When a map, drawing or chart, etc., is part of the material being photographed, a definite method of “sectioning” the material has been followed. It is customary to begin filming at the upper left hand corner of a large sheet and to continue from left to right in equal sections with small overlaps. If necessary, sectioning is continued again—beginning below the first row and continuing on until .complete.

4. For illustrations that cannot be satisfactorily reproduced by xerographic means, photographic prints can be purchased at additional cost and inserted into your xerographic copy. These prints are available upon request from the Dissertations Customer Services Department.

5. Some pages in any document may have indistinct print. In all cases the best available copy has been filmed.

University Microfilms international 300 N. Zeeb Road Ann Arbor, Ml 48106 8526189

Hong, Won-Pyo

TOTAL SYNTHESIS OF ( + /-)-LYTHRANCEPINE-ll

The Ohio State University Ph.D. 1985

University Microfilms International 300 N. Z eeb Road, Ann Arbor, Ml 48106 TOTAL SYNTHESIS OF <*>-LYTHRANCEPINE-II

DISSERTATION

Presented in Partial Fulfillment of the

Requirements for the Degree Doctor of Philosophy

in the Graduate School of

The Ohio State University

Won-Pyo Hong, B.S., M.S

The Ohio State University

1985

Reading Committee: Approved by:

Dr. David J. Hart

Dr. Gideon Fraenkel

Dr. John S. Swenton Advisor

Department of Chemistry To My Parents

Soon-Kyung Hong and Hee-Kyung Kim Hong ACKNOWLEDGEMENTS

I wish to express my gratitude to Professor David J.

Hart for his invaluable advice, support, friendship, and contagious enthusiasm for chemistry throughout this endeavor. His role as an advisor and his interest in my career goals are deeply appreciated. I also wish to express my gratitude to Professor Eun Lee in Seoul

National University for his initial enthusiasm for organic chemistry. I should say the works in this thesis could not have been achieved without numerous help from others. I would like to thank all the members of the Hart group, past and present, for their numerous discussions and encouragement, especially Drs. Y.-M. Tsai, J.-K.

Choi, and Mr. D.-C. Ha. I am also grateful to Mr. R.

Weisenberger for mass spectra, Drs. C. Cottrell and B.

Chenera for 500 MHz *H- and l^C-NMR spectra, Mr. C.

Engelman for l^C-NMR spectra, Mr. D. Burnett for 200 MHz

3-H-NMR spectra, Mr. J. R. Wermer for FT-IR spectra, and

Dr. J.-J. Lee for helpful discussions of COSY spectroscopy.

iii VITA

July 11, 1953 ...... Born, Pusan, Korea

1977...... B.S. (Chemistry), Seoul National University, Seoul, Korea

1979...... M.S. (Organic Chemistry), Seoul National University, Seoul, Korea

19S0 - 1982 ...... Teaching Associate, Department of Chemistry The Ohio State University, Columbus, Ohio

1982 - present ...... Research Associate, Department of Chemistry The Ohio State University, Columbus, Ohio

PUBLICATIONS

1. Lee, E.; Hong, W.-P. "Studies on Biogenetic-type Synetheis of Natural Products (I). Synthesis and Reactions of Methyl 3-Hydroxymethylorsellinate" K9E§§Q Chenu Soc^, 1979, 23, 30.

2. Lee, E.; Hong, W.-P.; Ko, S. Y. "Fluoride-assisted Acetylation of Alcohols and Phenols" Bui1^ Korean Chem^ Soc^, 1980, 1, 144.

3. Hart, D. J.; Hong, W.-P. "Lythraceae Alkaloids: Total Synthesis of (+)-Lythrancepine-II" Qrg*. C h e m 1985, 50, 0000.

iv CONTRIBUTED PAPER

1. Hart, D. J.; Hong, W.-P. "Total Synthesis of <+)- Lythrancepine-II" The 17th Central Regional Meeting of the American Chemical Society, Akron, 1985.

FIELD OF STUDY

Major Field: Organic Chemistry

v TABLE OF CONTENTS

ACKNOWLEDGEMENTS ...... iii

VITA ...... iv

TABLE ...... viii

LIST OF FIGURES ...... ix

LIST OF SCHEMES ...... x

I. ISOLATION AND STRUCTURE DETERMINATION OF LYTHRACEAE ALKALOIDS ...... 1

A. Introduction ...... 1

B. Classification and Isolation of Lythraceae Alkaloids ...... 3

C. Type D Lythraceae Alkaloids: Structure Determination of the Lythrancine and Lythrancepine Groups ...... 5

II. MODEL STUDIES FOR LYTHRANCEPINE ALKALOID SYNTHESIS ...... 10

A. Stereochemistry at C-l, C-3, AND C-5 (N-Acyliminium Ion Cyclizations) ...... 12

B. Introduction of the C-9 Sidechain (Eschenmoser Sulfide Contraction) ...... 25

III. AN APPROACH TO THE SYNTHESIS OF LYTHRANCEPINE ALKALOID VIA BIARYL INTERMEDIATES ...... 38

IV. TOTAL SYNTHESES OF <+)-LYTHRANCEPINE-II AND (■♦•) - LYTHRANCEPINE-III ...... 50

vi V. EXPERIMENTAL

BIBLIOGRAPHY LIST OF TABLE

Table

1. Reduction of ketone 55

viii LIST OF FIGURES

ix LIST OF SCHEMES

Schemes page

I ...... 8

II...... 11

III...... 13

IV...... 13

V ...... 14

VI ...... 15

VII...... 17

VIII...... 18

IX...... 19

X ...... 20

XI ...... 21

XII...... 23

XIII...... 25

XIV...... 27

XV ...... 28

XVI...... 30

XVII...... 31

XVIII...... 33

x 34

74 xi X XX

88 IIAXXXX

98 ...... IAXXXX

S8 ...... AXXXX

£8 ...... AIXXXX

...... IZXXXX CHAPTER I: ISOLATION AND STRUCTURE DETERMINATION OF

LYTHRACEAE ALKALOIDS

A. Introduction

The objective of this research was the total synthesis of lythrancepine-II (4), a structurally interesting quinolizidine metacyclophane Lythraceae alkaloid which has yet to undergo pharmacological evaluation. To provide the reader with some perspective, a brief introduction describing the classification and isolation of Lythraceae alkaloids will be presented here.

An overview of the structure determination of quinolizidine metacyclophane Lythraceae alkaloids will also be presented.

Brief references to the Lythraceae alkaloids have appeared in Volumes X, XII, and XIV of "The Alkaloids"1 and a short review on the alkaloids from Lythrum ancega was published in Japan.2 Two major reviews on the

Lythraceae alkaloids have appeared, one covering mainly structure elucidation^ and the other covering a considerable amount of synthesis as well as structure elucidation.4 1 2

Plants of the Lythraceous family are moderately well

distributed in different regions of the world, from the

tropics to the temperate zones, and are especially abundant in Latin America. The family consists of 22 genera composed of about 500 species, including several economically important species of the genera Heimia,

^2 9 d£ordia, Lafoensia, Lythrum, Cuphea, Ammannia, Cuphea,

and Lawsonia. One reason for the early

investigation of the Lythraceous plants was the pronounced but mild psychoaomimetic effect displayed by the Heimia salicifolia. This plant has been used as a medicine against bronchitis, dysentery, indigestion, and syphilis, and is used by women after delivery to close the womb and to cure inflammation of the womb. Lythrum salicaria L. has been used in case of diarrhoea and dysentery as a Chinese drug, 'qian qu cai'.

At present forty-three alkaloids have been

identified in Lythraceous plants. These alkaloids were detected only in the aerial parts of the plants. The structures of most of these bases have been established using chemical and spectroscopic data and/or X-ray analysis. 3

>OH HO,

OMe OMe

Type A: Decinine Type B: Vertaline Type C: Lythranidine

H HO

OAc

Me OH Me< MeO OH OMe

4 5

Type D: Lythrancepine-II Type E: Abresoline

Figure 1

B. Classification and Isolation of Lythraceae Alkaloids

Lythraceae alkaloids have been classified according to five structural types by Fujita and his coworkers,5*6 representative examples of which are shown in Figure 1. The first isolation of the Lythraceae alkaloids from Decodon verticillatus (L) Ell was reported by Ferris in 1962.7 Ferris isolated several lactonic biphenyl alkaloids (type A: decinine, decodine, verticillatine, decamine, and vertine) and lactonic ether alkaloids (type B: decaline, and vertaline). This report was followed by isolation of other lactonic alkaloids from Heimia salicifglia Link and Otto (type A: lythrine, lyfoline, and vertine; type B: heimine) by Schwarting and his coworkers® and from Heimia mytifolia Cham and Schl.

(type A: lythrine and vertine) and Heimia salicifglia

(type A: lythrine) by Douglas and his coworkers.9 in

1967, Fujita and his coworkers isolated three piperidine metacyclophane alkaloids from Lythrum ancegs Makino (type

C: lythranine, lythranidine, and lythramine).10 The fourth structural variant of the Lythraceae alkaloids, quinolizidine metacyclophanes, were isolated by Fujita and his coworkera^ from Lythrum anceps in 1971 (type

D: lythrancines I-VII and lythrancepines I-III) and by

Ferris*2 from Lythrum lanceolatum in 1973 (type

D: lythrumine and monoacetyllythrumine). Finally, Rother and SchwartinglS isolated several simple phenylquinolizidine alkaloids (type E: demethyllasubine-I and demethyllasubine-II) from young seedlings of Heimia salicifglia plants in 1974. This report was followed by the isolation of other simple phenylquinolizidine alkaloids from Heimia salicifolia (type E: 5 demethoxyabresoline and 10-epidemethoxyabresoline) by

Rother and Schwarting14 and fro* aubcoatato (type

E: laaubine-I and II, subcosine-I and II) by Fujita and his coworkera.6 Theae alkaloids (type E) were absent in extracts of plants obtained at later atagea of growth, suggesting this type of alkaloid is an intermediate in the biosynthesis of macrocylic Lythraceae alkaloids.

Several of the type A, B, C and E alkaloids have been synthesized. The synthesis of the type D alkaloids, however, has never been achieved.15 This thesis will describe the first total synthesis of the type D alkaloids, lythrancepine-II (4) and lythracepine-III

(14). Therefore, the structure determination of the

lythrancine and lythrancepine groups of Lythraceae

alkaloids will be reviewed in following section.

C. Type D Lythraceae Alkaloids: Structure Determination

of the Lythrancine and Lythrancepine Groups

Ten alkaloids containing a cis-quinolizidine ring

system and a biphenyl group, i.e. lythrancine-I (6), -II

(7), -III (8), -IV (9), -V (10), -VI (11), -VII (12), and

lythrancepine-I (13), -II (4), and -III (14), belong to the type D family of Lythraceae alkaloids. All of these 6

6 Rl=r2=r3=H 10 Rl=R2=Ac 13 Rl=R2=H

7 r1=r2=H , r 3=Ac 11 R*=Ac, R2=H 4 Rl=H, r 2=Ac

S Rl=R3=Ac, R2=H 12 Rl=H, R2=Ac 14 R1=R2=Ac

9 r !=r 2=r 3=a c

Figure 2 alkaloids were isolated from Lythrum anceps. These compounds are shown in Figure 2.18 All of these type D

Lythraceae alkaloids have methoxyl groups at C-17 and C-

21 and share a common skeleton. Lythrancine-type alkaloids (6-12) have hydroxyl or acetoxyl groups at C-3,

C-4, and C-ll. Lythrancines 7-9 and lythrancines 10-12 are epimeric at C-3. Lythrancepines 13, 4, and 14 are C-4 deoxy derivatives of lythrancines 6, 7, and 8 (9), respectively. Because the structural relationship between the lythrancine and lythrancepine groups is so close, their structure determinations are interrelated. 7

The structures of these alkaloids were initially established using a combination of spectral techniques and chemical correlations.The first confirmation that these assignments were correct came in 1974 when Sim and his coworkers reported X-ray structure of lythrancine-IV

(9) and the 3-0-p-bromobenzenesulfonate of lythrancine-II

<7>.20 Rather than presenting the complex arguments originally used to establish the structures of lythrancepines I-III, this X-ray data will be used as the starting point to convince the reader of the correctness of structures 13, 4, and 14. First, acetylation of lythrancine-II (7) with acetic anhydride in pyridine at room temperature (2 h) furnished lythrancine-III (6), whereas acetylation at 110°C for 3 h gave lythrancine-IV

(9) as shown in Scheme I. Hydrolysis of lythrancine-II

(7) with 1 X methanolic potassium hydroxide <25°C, 2 h) yielded lythrancine-I (6). As expected, lythrancine-I (6) gave lythrancine-III (8) on acetylation with acetic anhydride in pyridine at room temperature. The structural relationship between the lythrancine and lythrancepine groups was established by lithium aluminum hydride reduction of the CC4)-tosylate of lythrancine-III (8) and acetylation of the product to give lythrancepine-III (14) and its C-3 epimer. Hydrolysis of lythrancepine-III (14) with 1 X methanolic potassium hydroxide (25°C) gave the 8

lythrancepine-I (13) and Identical treatment of

lythrancepine-II (4) also gave 13. Acetylation of

lythrancepine-II <4> with acetic anhydride in pyridine

(25^0, 5 h) gave lythrancepine-III (14) and identical treatment of lythrancepine-I (13) also gave 14. Thus, from the relationships established by these acetylation and hydrolysis studies, the structures and absolute

stereochemistry of 6-9, 13, 4, and 14 are on firm ground.

Scheme I

Lythrancine-I KOH Lythrancine-II 6 7

Ac20, A c 20, Py, r1 Py, 110°C

Lythrancine-III Lythrancine-IV 8 9

l.TsCl, Py 2 .LAH 3.Ac20, Py, rt

Ac 20, Py, rt Lythrancepine-III Lythrancepine-II 14 4

Lythrancepine-I 13 The structures and stereochemistry of lythrancine-V,

-VI, and -VII were elucidated by analysis of NMR and mass spectra and by comparison with those of lythrancine-IV

<9>.19

Although all structures of type D Lythraceae alkaloids were established as described above, no X-ray analysis of a lythrancepine group alkaloid has been carried out. Thus, the following syntheses of 4 and 13 provide additional proof of the structures of the lythrancepine group of Lythraceae alkaloids. CHAPTER II: MODEL STUDIES FOR LYTHRANCEPINE ALKALOID

SYNTHESIS

Several total syntheses of lactonic Lythraceae alkaloids (type A and B) have been reported. Most of these syntheses use Mannlch reactions of pelletlerine

(15) with substituted benzaldehydes,21 biaryls,22 or diaryl ether&23 to assemble the quinolizidine moiety. For example, Hanaoka and his coworkers21 condensed pelletlerine (15) with G-bromoveratraldehyde (16) and obtained a 5:2 ratio of quinolizidine derivatives 17 and

18, respectively (Equation 1). None of the '‘pelletlerine" syntheses of type A and B Lythraceae alkaloids are highly stereoselective.

H H

NaOH (eq.1)

OMe OMe

15 16 17 18

As mentioned before, no syntheses of the

10 11 quinolizidine metacyclophane alkaloids (type D) have been reported. Recently, Hart and Kanai developed an efficient and highly stereoselective synthesis of the lactonic alkaloid vertaline (2).24 Their approach to this type B

Lythraceae alkaloids differs from all previous approaches most notably by passing through C-9 functionalized intermediates. Thus, it was hoped that this route could be adapted to the synthesis of type D Lythraceae alkaloids.

The general plan for adapting this chemistry to type

D Lythraceae alkaloid synthesis is outlined antithetically in Scheme II. Methods for the preparation

Scheme II H R^O

20 19

23 22 21 12 of compounds such aa 21 from 22 and 23 had been developed during the previoualy mentioned ayntheeia of vertaline <2).

Thus, the four major problema which had to be addreaaed were:

1) Adjustment of stereochemistry at C-3 (21— *>20),

2) Attachment of the C-9 aidechain with control of

stereochemistry.

3) Establiahing the stereochemistry at C-ll, and

4) Closure of the macrocylic ring.

Before attempting a total synthesis of the lythrancepine alkaloids, some model atudiee addressing the firat two problema were performed. This chapter will focua on these studies, but first, an overview of the N-acyliminium ion chemistry leading to the synthesis of compounds of type

21 will be presented.

A. Stereochemistry at C-l, C-3, and C-5

Ion Cyclizations)

Although acyclic N-acyliminium ions have been used in synthesis for several decades, the chemistry of cyclic

N-acyliminium ions received little attention until

Speckamp and his coworkers began their studies.25 jn

1971, Speckamp developed a facile entry to cyclic N- acyliminium ion precursors 26 via pH controlled sodium 13 borohydride reduction of cyclic imides 24 in ethanol

(Scheme III).26 He proceeded by studying a series of

Scheme III

T* NaBH^ T EtOH X N ^ O HCl OX ^ N ^ O H HC1 I I R R

24 25 26 intramolecular cyclization reactions of N-acyliminium ions with built-in olefins.27 a relavant example is shown in Scheme IV. Treatment of ethoxy lactam 27 with formic

Scheme IV

HCOOH

27 28

HCO- H"

30 29 acid gave 29 (90 *) and 30 (10 X> in nearly quantitative 14 yield with high stereoselectivity. A reasonable explanation of the stereochemical course of this reaction involves initial ionization of 27 to afford cyclic N- acyliminium ion 28 followed by anti-periplanar addition of an electrophile-nucleophile pair across the olefin via a transition state in which the 2-aza-l,5-hexadiene unit resembles a chair-like conformation. In large part due to the pioneering work of Speckamp, this N-acyliminium ion initiated olefin cyclization has been documented as a potent tool in alkaloid synthesis.28

Although Speckamp delineated several stereochemical features of these reactions, the effect of asymmetric centers on their stereochemical course was not explored until the current decade. In 1980, Hart found that asymmetric centers alpha to the nitrogen can excert profound influence over the stereochemistry of N- acyliminium ion cyclization.29 t 0 evaluate the effect of this chiral center on the stereochemical course of N-

SchemeV

OH H HOCO OH a,b

31 32 33 a. glutarimide, DEAD, Ph3P b. DIBAL-H c. HC00H 15 acyliminium ion cyclizationa In a conformationally nonblaaed aystem, carbinolamide 32 was prepared as outlined in Scheme V. Treatment of 32 with formic acid gave cyclization product 33 (64 X) and only small amounts

<2-5 X) of substances stereoiaomeric to 33 at C-3. A possible explanation of this observation is shown in

Scheme VI. The N-acyliminium ion derived from 32 cyclizes via a chair-like conformation in which the incipient C-l substituent occupies an axial site, in contrast to the equatorial orientation of substituents usually observed in olefin cyclizations and other reactions whose transition-state geometries resemble chair cyclohexane.30

This unusual observation can be attributed to the strong unfavorable a <1'3) strain between the amide carbonyl and the phenyl group in the transition-state leading to the

C-l isomer 36.31

Scheme VI

HOCO

36 0 33 16

In summary, two factors seem to be responsible for stereoselectivity in this N-acyliminium ion cyclization.

First, the cyclization of carbinolamide 32 most likely proceeds through an N-acyliminium ion which can adopt chair conformations like 34 and 35. Second, the development of a severe A <3-'3) interaction in 34 may force the C-l substituent to occupy an axial position as shown in conformation 35. It is emphasized that these two factors are believed to be responsible for the stereochemical course of all N-acyliminium cyclizations performed during the lythrancepine alkaloid syntheses described herein.

Before presenting the lythrancepine model studies, one more piece of background information will be presented. During the course of executing the aforementioned total synthesis of the vertaline (2), a need arose to convert benzaldehyde 16 to homoallylic amine 37 (Equation 2).24 After several conventional procedures for accomplishing this task met with failure.

CHO 2 Br (eq.2)

OMe OMe OMe

16 37 17 a convenient route was found by adding an organometalllc reagent to an N-silyl Imlne which prepared by a modification of a procedure developed by Wannagat and

R o c h o w . 3 2 Thus, treatment of aldehyde 16 with a slight excess of lithium hexamethyldisilazide in tetrahydrofuran gave the corresponding N-silyl imine. Addition of a slight excess of allylmagnesium bromide gave an excellent yield <97 X) of amine 37 after an aqueous workup and purification. This was the first report of an organometallic adding to an N-silyl imine. Although this method is limited to nonenolizable carbonyl compounds,33 it is extremely valuable in the early stages of the synthesis of lythrancepine alkaloids.

Scheme VII CHO H HOCO.,

OMe

38 OMe 39 Problem

H RO H RO

Problem 2

C02Et

OMe OMe 41 40 18

Keeping in mind the general plan outlined in Scheme

II, it waa decided to examine the first two problems described above as outlined in Scheme VII. Treatment of commercially available p-anisaldehyde (38) with 1.2 equivalents of lithium hexamethyldisilazide in tetrahydrofuran followed by addition of 1.22 equivalents of ethereal allylmagnesium bromide at 0°C gave an amine

43 in 87 * yield after an aqueous workup and distillation as shown in Scheme VIII. As mentioned above, this reaction

Scheme VIII

NSiMe

b,c

OMe

a. LiHMDS b. CH2=CHCH2MgBr c. H20 sequence presumably proceeds via initial formation of N- silyl imine 42 followed by addition of the organometallic reagent. To maximize the yield, the silyl imine intermediate 42 was not purified or fully characterized.

The formation of 42, however, was established by crude proton NMR which showed the silyl imine proton as a singlet at 8 8.90 as well as no aldehyde proton due to 36 at 8 9.87. 19

Amine 43 was converted to amide 44 using the excellent method of Weinreb.34 Thus, sequential treatment of amine 43 in dichloromethane with trimethylaluminum35 and methyl 5,5-dimethoxypentanoate (22) gave amide 44 in

98 x yield as shown in Scheme IX. The methyl 5,5- dimethoxypentanoate (22) was prepared from dimethyl

Scheme IX

1. AlMe

OMe 43 44

Me2OC NaOMe co 2 MeO.C 45 46 47

H C (OMe)3 p-TsOH

OMe NaCl OMe wet DMF 0 OMe Me02C

22 48 20 malonate (45) and acrolein (46) using the known procedure of Stevens3& in an overall 22 X yield.

Treatment of amide 44 with formic acid in dichloromethane (25°C, 3 h) gave a mixture of four products. The major product was quinolizinone 39 (66 X") with the expected stereochemistry. In addition, isomeric formate 50 (3.3 X) and an equal mixture of olefins 49 (14

X) were obtained (Scheme X). Several aspects of this

Scheme X MeO OMe HOCO

HC00H

OMe OMe 39 HOCO-[3R] 44 50 HOCO-[3S1 cyclization reaction are notable. The conversion of 44 to

49, 39, and 50 presumably proceeds via initial acetal hydrolysis, C-N bond formation to give a carbinol amide such as 51, dehydration to give an N-acyliminium ion 52, and cyclization (Scheme XI). No products derived from 0- alkylation of the amide 44 (e.g. amine 43), were obtained. It is also noted that the subsequent iminium ion cyclization (52— ►49, 39 and 50) proceeds with very clean stereochemistry at C-l and C-5. All of the 2 1 quinolizinone products (49, 39, and 50) have the same stereorelationship predicted by the transition-state model proposed for such iminium ion cyclizations.29 Scheme XI MeO .OMe

49 + 39 4- 50 OMe

44 The stereochemical assignments for 39 and 50 were made primarily on the basis of proton NMR analysis (Figure 3)

OMe

HOCO

OMe 39

HOCO. OMe

HOC

OMe

50 Figure 3 2 2

Both 39 and 50 have sharp doublets at 6 6.24 and 5 5.85, respectively, due to H-l. The coupling constants for H-l

4.5 Hz). The large coupling constants suggest that both

H-3 and H-5 are axially disposed in 39. The appearance of a quintet (J=3.5 Hz) at S 5.13 in 50 confirmed the equatorial nature of H-3 in this minor product.

Adjustment of the stereocenter at C-3 in the major formate 39 was performed in a straightforward manner as shown in Scheme XII. Treatment of the formate 39 alone with sodium hydroxide in aqueous methanol gave alcohol 53 in 94 X yield. However, after confirming the iminium ion cyclization stereochemistry, the mixture of 49, 39, and

50 was hydrolyzed directly with sodium hydroxide for practical purposes. Thus, treatment of amide 44 on a moderate scale <21.3 g; 66.2 mmol) with formic acid <2 h,

25°C) followed by hydrolysis gave an inseparable mixture of alcohols 53 and 54 in 67 X overall yield from amide 44 as well as a mixture of olefins 49 in 11 X yield. It was possible to crystallize about 80 x of alcohols 53 and 54 directly from the crude hydrolysis products using ethyl 23 Scheme XII

HOCO HO

CrO NaOH 3

OMe OMe OMe 39 HOCO-[3R] 53 HO-[3R] 55 50 HOCO-[3S] 54 HO-[3S] LiEt3BH or K-sec-BUjBH

HO AcO-

OMe OMe OMe 56 57 54 HO-[3Sj 53 HO-[3R] acetate-hexane. The mother liquor was separated easily by column chromatography over silica gel. Chromatographic separation of 49, 39, and 50 prior to hydrolysis was complicated by their similar mobilities on silica gel.

The mixture of alcohols 53 and 54 was treated with

Jones reagent in acetone to give ketone 55 in 74 X yield as well as recovered alcohols 53 and 54 in 19 X yield.

Oxidation of alcohols 53 and 54 with pyridinium chlorochromate in dichloromethane3& did not improve the

yield of 55. Two bulky reducing agents, lithium

triethylborohydride

sec-butylborohydride (K-Selectride),3^b were chosen for

converting rigid ketone 55 to the desired axial alcohol

54. The resulting inseparable alcohols 54 and 53 were

treated with acetic anhydride, triethylamine, and a

catalytic amount of 4-dimethylaminopyridine40 to give a

separable mixture of acetates 56 and 57. The results are

shown in Table I. The table shows that the lithium

Table I: Reduction of ketone 55*

Reducing agents Yield of alcohols Yield of acetates Ratio 53 and 54 56 and 57 56:57

K-sec-Bu3 BH 98 * 83 X 6.6:1

LiEt3BH 99 * 87 X 9.5:1

• Both reactions were performed in tetrahydrofuran at

- 78° C

triethylborohydride is slightly superior to potassium tri-sec-butylborohydride in terms of stereoselectivity.

Thus, lithium triethylborohydride was used in all subsequent reactions involving reduction of a C-3 k e t o n e . 41 As expected, the C-3 proton in axial acetate 56 appeared as a quintet

Having established the appropriate stereochemistry at C-l, C-3, and C-5, we turned to introduction of the C-

9 sidechain as described in the next section.

B. Introduction of the C-9 Sidechain (Eschenmoser

Sulfide Contraction)

This section will describe introduction of the C-9 sidechain via an Eschenmoser sulfide contraction^^ Qnd the establishment of the C-9 stereochemistry <40— ^41 in

Scheme V I I ) . Lactam 5 6 , with appropriate stereochemistry at carbons 1, 3, and 5, was converted to thiolactam 58 using the excellent method developed by Lawesson and his coworkers43 (Scheme X I I I ) . A mixture of 0.5 equivalents

Scheme XIII AcO AcO,

Lawesson1s

reagent 59 OMe OMe 56 58 of 2,4-bis<4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-

2,4-disulfide CLawesson's reagent (59)] and lactam 56 in toluene gave thiolactam 58 in a nearly quantitative yield. Lawesson's reagent (59) was prepared from anisole 2 6

OMe 155°C |) + p4s 10 (eq.3) 6 s 59 and phosphorus pentasulfide in 72 * yield (Equation 3).

It was found that H-l in thiolactam 58 was more than 1 ppm downfield from H-l in lactam 56 by proton NMR analysis. Thus, the H-l proton in lactam 56 appeared at

8 6.08 but that in thiolactam 58 was at 8 7.35, even lower than the aromatic protons. The differences between 58 and

56 may arise from the position of the sulfur in the third row of the periodic table. The higher atomic number of 0 sulfur causes an increased covalent radius (0: 0.74 A; S: O 1.04 A), larger polarizability, and a decreased tendency to form double bonds with second row elements. In terms of the valence bond theory, this leads to a stronger contribution due to polar resonance structures

(60) in thioamides than in amides (Figure 4 ).44

Figure 4

This electronic effect is probably responsible for the downfield shift of H-l in thiolactam 58. 27

The next step involved introduction of the sidechain at the C-9 position. The Eschenmoser sulfide contraction,42 in which a thioamide is converted into a vinylogous urethane, seemed to be a viable method.

Surprisingly, initial attempts to introduce a C-9 carbethoxymethylidene group from thiolactam 58 met with failure. For example, sequential treatment of thiolactam

56 with ethyl iodoacetate and triphenylphosphine- triethylamine at room temperature gave lactam 56 in 74 X yield and only 12 X of vinylogous urethane 61 (Scheme XIV).

Scheme XIV u H

C 02Et

AcO

OMe OMe

56 62 28

Variations of solvents and

the use of reagents such as ethyl bromoacetate and

iodoacetonitrile did not improve the yield of desired

products. For example, identical treatment of thiolactam

58 with iodoacetonitrile gave lactam 56 in 50 H yield and enamino nitrile 62 in 23 ft yield. Before discussing the solutions to the problem of lactam formation, the

Scheme XV AcO AcO

C0,Et

OMe OMe

AcO

OMe

AcO AcO

COjEt Ph tP C 02E1

OMe OMe

66 61 probable mechanism of the sulfide contraction should be

explained (Scheme XV). The first step of this sequence

involves thiolactam S-alkylation. This step may be

reversible. For example, Ireland and Brown showed that

heating thioiminium salt 66 with ester 67 in

acetonitrile give a 1:1 mixture of salts 66 and 66

(Equation 4 ).45 The second step of the reaction involves

C 02Et I S 'CO,i-Pr /^ N (C H 3)2 + ,CH2CCV - Pr L © + ICH2C0 2Et .© 32 ^ N ( C H 3), (eq.4) ' I0 66 67 68 63 sequential deprotonation, episulfide formation, and removal of sulfur by the thiophilic triphenylphosphine.

To identify the problem, a series of experiments were performed. First, it was shown that thiolactam alkylation was not the problem. Thus, thiolactam 58 was treated with excess methyl iodide in a mixture of diethyl ether and dichloromethane at room temperature to give salt 69 in 80 X yield as a pale yellow solid. This material was easily characterized by iH-NMR and IR spectroscopy. This hygroscopic salt 69 was then treated with sodium borohydride in methanol to give amine 71 in 92 X yield.

Identical treatment of thiolactam 58 with

iodoacetonitrile in diethyl ether gave salt 70 in 85 X 30 yield. Reduction with sodium borohydride gave amine 71 in

98 * yield (Scheme XVI). These experiments showed that thioiminium salt formation was not a problem and showed that such ions were susceptable to nucleophilic attack.46

Scheme XVI

AcO AcO

CH_ I ©

OMe OMe 58 69

ICH2CN NaBH,

AcO AcO,

NaBH,

CH2CN

OMe OMe 70 71 Since it appeared that the deprotonation or sulfur scavenging steps may be the problem, proton NMR studies were performed at room temperature. Thus, a solution of pure thioiminium ion 70 in chloroform was placed in an

NMR tube and 1.2 equivalents of triphenylphosphine was 31 added. No change in the NMR spectrum of 70 was observed.

However, addition of 1.2 equivalents of DABCO to the mixture caused an immediate change.47 The NMR spectrum clearly showed disappearance of doublets at 6 4.35

(J=18.9 Hz) and 5 5.10

Scheme XVII

AcO AcO

OMe OMe 70 72

h 2o

AcO AcO

OMe OMe 56 62 32

doublet, at 5 4.50 (H-5) in 70 and the appearance of multiplete at 6 5.35, 4.90, and a ainglet at 6 3.20

suggested that salt 70 had probably been converted to enamine 72: S 3.20 (SCH2 CN), 3.90

3), and 5.35

should account for charge neutralization by deprotonation

of thioiminium ion 70 to ketene N,S-acetal 72. Therefore,

it appears that base kinetically deprotonates 70 at C-8 rather than the carbon bonded directly to sulfur. Aqueous workup then converts 72 to lactam 56, perhaps via salt 70

(Scheme XVII).

Several examples of enamine formation in sulfide contractions have been reported. For example, Ireland and

Brown found that attempted sulfide contraction of salt 73

led only to thiophene 74 presumably via enamine formation from the salt 73 (Equation 5 ).45 After completion of these

(eq.5)

73 74 studies, Rapoport and his coworkers also found that sulfide contraction of thiolactam 75 produced a-alkylated thiolactam 80 and lactam 78 in 2-10 x and 5-18 X yields, respectively, as side products depending on reaction 33

conditions (Scheme XVIII).48

Scheme XVIII

t-Bu02C"'\N/■ O ^n 0 I Bzl

t-Bu02C"'^N^^/- O - -co’Me 2 78 I Bzl

81 r \ t t-BuOjC'^MAs^^co^Me ' L Bzl

t-B u 0 2C'"\N K ^S____ ^t-BuOjC'^N^S^^CQ^e 77 Bzl Bzl J

75 76 r^ C Q ,M e t-Bu02C"'C§As/ \ c . ^ I 2 I— Bzl t-Bu02C"'SNAs 79 I Bzl

Since it was clear that competitive deprotonation at

C-8 was causing the problems, conditions were sought to deprotonate the methylene sidechain. It was reasoned that the pKa's of DABCO-HI and the C-8 and SCH2 CN positions of salt 70 might be close enough that deprotonation of 70 adjacent to sulfur might occasionally take place under forcing conditions. It was anticipated that such a deprotonation might then lead to episulfide formation and 34

irreversible removal of sulfur by the thiophilic

triphenylphosphine. Thus, salt 70 was warmed under reflux

with triphenylphosphine and DABCO. A dramatic improvement

in the yield of enamino nitrile 62 was observed. Overall,

treatment of thiolactam 58 with iodoacetonitrile gave 62

in 70 X yield. Similarly, treatment of thiolactam 62 wi^.i

ethyl bromoacetate in a mixture of tetrahydrofuran and

diethyl ether for 2 days followed by the addition of

triphenylphosphine and DABCO under reflux for 5 min gave

vinylogous urethane 61 in 65 X yield.

With the sidechain carbons introduced, attention was turned to fixing the C-9 stereochemistry. Reduction of vinylogous urethane 61 with sodium cyanoborohydride49 at pH 4 gave amino ester 82 (77 X) with the desired stereochemistry at C-9. None of the C-9 diastereomer was obtained (Scheme XIX). This step should not pass without

Scheme XIX

AcO. AcO.

NaBH3CN

C 02Et pH 4 C 02Et

OMe OMe 61 82 comment. Since the C-9 isomer of amino ester 82 was not isolated in this model study and some other relevant experiments were performed later, an explanation of thiB 35 stereoselective reduction will be deferred until chapter

IV (vide infra). However, evidence for the assignment of structure 82 is presented here. Proton NMR analysis of amino ester 82 suggests that it adopts a cis-fused chair- chair conformation. For example, 200 MHz NMR analysis of amino ester 82 showed a 9-line triplet of triplets (J=11.2,

11.2, 5.0, and 5.0 Hz) at 5 4.75-5.20 for H-3. This indicates that the A-ring of 82 is in a conformation in which this hydrogen is axially disposed. An analysis of

H-9 suggested that it was equatorially disposed. Thus, independent irradiation of the C-10 protons <5 2.28 and

6 2.75) caused H-9 (6 3.20) to collapse to a broad doublet

Since a large coupling to the axial hydrogen on C-8 was not observed, this suggested that H-9 was equatorially disposed. These NMR experiments are consistent with structure 82 in the aforementioned cis-fused chair-chair conformation. Some other experiments were performed to ensure that the stereochemical assignment at C-9 and the identification of H-9 in the NMR were correct. The amino ester 82 was converted to C-10 deuterated hydroxy ester

83 upon treatment with excess methyl alcohol-d and sodium methoxide under reflux in 81 x yield. The resulting hydroxy ester 83 was converted to acetate 84 (63 X) as shown in Scheme XX. 200 MHz proton NMR analysis of 36 Scheme XX

AcO, HO AcO

MeOD Py

D C0>Me DMAP CO,Me

OMe OMe OMe

82 83 84

acetate 84 clearly showed a doublet of doublets at 6 4.02

and a broad doublet at 6 3.16

which is equatorially disposed. Finally, the structure of

amino ester 82 was proven by X-ray analysis of a crystal

grown from methanol (Figure 5).5* 37

It. is int.ereBt.ing that only upon formation of amino ester 82 does the quinolizidine skeleton release the severe 1,3-diaxial interaction between the C-l aryl group and C-3 substituents. All quinolizidine structures up to vinylogous urethane 61 and enamino nitrile 62 adopt conformations corresponding to 50 in Figure 3. After release of the 1,3-diaxial interaction, amino ester 82, for the first time, affords a quinolizidine with the cis- fused conformation 82a shown in Figure 6.

^ COzEt AcO

C 0 2Et AcO

OMe

Figure 6

In summary, the model studies established methods for controlling all the stereochemistry from C-l to C-9 and provided a method for introducing a carbon-carbon bond at the lactam carbonyl group (C-9). The next two chapters will present synthetic approaches to <+>- lythrancepine-II itself. CHAPTER III. AN APPROACH TO THE SYNTHESIS OF LYTHRANCEPINE

ALKALOID VIA BIARYL INTERMEDIATES

The first approach to <+)-lythrancepine-II started with a biaryl system. The synthetic plan is shown in

Scheme XXI.

Scheme XXI

CHO CHO CHO OMe NH OMe OMe OMe OMe OMe OMe CHO

85 86 87

PhCH.O HOCO OMe

OMe OMe OMe OMe

OMe OMe CHO

91 89 3S CO.Et C02Et OAc OAc OAc MeO MeO . MeO 92 93

OAc •SPh

OH Me eO MeO

4 96 95 We began with the known biaryl 86.^2 A mixture of aniaaldehyde (38), iodine monochloride, and acetic acid under gentle reflux gave 3-iodoanisaldehyde (85) in 71 X yield. A mixture of 85 and copper p o w d e r ^ 3 Was heated at

210-220°C to give biaryl 86 in 78 X yield.

Monoacetalization of dialdehyde 86 gave a atatiatical mixture of producta aa ahown in Scheme XXII.

Therefore, a mixture of dialdehyde 86, 1 equivalent of neopentylglycol, and a catalytic amount of p- tolueneaulfonic acid monohydrate in benzene gave an easily separable mixture of monoacetal 87 (50 X) , diacetal 97 (16 *>, and starting dialdehyde 86 (21 X).

Obviously diacetal 97 could be recycled by hydrolysis to give monoacetal 87. This was performed by stirring a mixture of diacetal 97 and 1 N aqueous sulfuric acid in acetone to give monoacetal 87 (42 X), dialdehyde 86 (29

X> , and starting diacetal 97 (25 X) using TLC to monitor the reaction progress. Further experiments were performed to verify the statistical formation of acetals in this biaryl system. A mixture of dialdehyde 86, 1 equivalent of 1,3-propanedithiol, and a catalytic amount of

Scheme XXII

CHO 41 phosphorous oxychloride In chloroform also gave an easily separable mixture of monothioacetal 98 <35 x>, dithioacetal 99 <25 X) , and 25 X of starting dlaldehyde

Conversion of monoacetal 87 to amide 89 was stralghtfoward. Thus, sequential treatment of nonoaldehyde 87 with 1.3 equivalents of lithium hexamethyldisilazide followed by the addition of 1.3 equivalents ethereal allylmagnesium bromide gave amine 88

<85 X). Treatment of 88 with trimethylaluminum54 and methyl 5,5-dimethoxylpentanoate <22)36 in sequence gave amide 89 in 94 x yield as shown in Scheme XXI. 34

Treatment of amide 89 with formic acid in dichloromethane for 2 h gave five products: 86 <4 x), 100

<36 X), 101 <9 X), 90 <43 X), and 102 <7 X). Products 86 and 100 are unlike those formed in the model study

90) in this biaryl system is more complicated from a mechanistic standpoint than as depicted in Scheme X.

Therefore, several points will be described here. First, as shown in Scheme XXIII, hydrolysis of the cyclic acetal took place during the cyclization. This is not surprising as it is known that electron donating aryl groups accelerate acetal hydrolysis.55 in addition, acetal 42

Scheme XXIII

HOCO

OMe HCOOH OMe

CHO OMe CHO 89 86 90 HOCO-[3R] 102 HOCO-[3S]

OMe +

OMe CHO 101 migration <89— *-100) waa obaerved. Apparently, hydrolyaia of dimethylacetal 89 givea an aldehyde which undergoea carbinolamide formation and cyclization or ketalization with neopentylglycol to give 100. Thia acetal ia aomewhat resistant to hydrolyaia due to the gem-dimethyl effect,55 but will aerve aa an intermediate in the bicycloannelation. Thia waa ahown by treating pure iaolated amide 100 with formic acid for 24 h to give olefin 101 (15 X), formate 90 (53 X), and isomeric formate 102 (2 X ). The formation of dialdehyde 86 can be explained as follows. In 1981, during the course of a synthesis of gephyrotoxin 2 2 3 AB,S6 Hart and Tsai discovered that an N-acyl-2-aza-Cope rearrangements? was underlying an N-acyliminium ion cyclization. They found that treatment of hydroxy lactam 103 with formic acid- dichloromethane (25°C, 10 h) gave a 60 X yield of formate

104, and trace amounts of isomeric formate 105, and olefins 106 as expected (Scheme XXIV). But it was quite a

Sc he me XXIV

HOCO, HHHOCO. H

104 105 106

HCOOH-CH2Cl2 OH

CF3COOH-CH2Cl2-Et3SiH surprise when none of the cyclized product was detected upon treatment of hydroxy lactam 103 with a mixture of trifluoroacetic acid-dichloromethane-triethylsilane

(25°C, 5 min). Instead, a separable 3:5 mixture of lactams 107 and 100 was obtained in a 73 X yield. Also, treatment of 103 with formic acid-dichloromethane- triethylsilane (25°C, 10 h) gave cyclized formate 104 (29

X) in addition to a 3:5 mixture of lactams 107 and 108 respectively (42 X). The observations outlined above suggest that treatment of carbinolamide 103 with acid gives N- acyliminium ion 109 which rearranges to ion 110, presumably via a 2-aza-Cope process as shown in Figure

7. Reduction products 107 and 108 apparently result from a trapping of N-acyliminium ions 109 and 110 by triethylsilane. In addition, it was found that the ratio

Figure 7 of lactams 107 and 108 did not vary with the reaction media. This suggested that an equilibrium mixture of 109 45 and 110 was rapidly established, followed by slower secondary processes such as reduction and/or cyclization.

In trifluoroacetic acid, reduction was faster than cyclization. In the presumably more nucleophilic formic acid media, cyclization and reduction took place at comparable rates. This was the first example of a hetero-

Cope rearrangement in an N-acyliminium ion system.58

Thereafter, Hart and Yang studied the 2-aza-Cope rearrangements in detail and applied it to the synthesis of pyrrolizidine alkaloids.59*60 it was also found that there appears to be little difference in the behavior of the five- and six-membered ring iminium ions. Therefore, it is presumed that dialdehyde 86 is the result of 2-aza-

Cope rearrangement of the initially formed N-acyliminium

Scheme XXV

112 CHO 111

86 46 ion 111 t.o an ion 112, followed by hydrolysis (Scheme

XXV). This was the first isolation of the aldehyde portion resulting from hydrolysis of an iminium ion formed in an N-acyl-2-aza-Cope rearrangement.

Continuing with the synthesis, formate 90 was hydrolyzed to alcohol 113 with sodium hydroxide in aqueous methanol (96 *) and resulting alcohol 113 was treated with neopentylglycol and a catalytic amount of g- toluenesulfonic acid monohydrate to give acetal 114 (100 *>

Scheme XXVI

HOCO

Cl ho o h OMe NaOH OMe H

CHO CHO 90 113 DMSO, (C 0C 1)., Et3N 1 I

114 + 113 + OMe + OMe

OMe OMe HO 116 115 47

Oxidation of alcohol 114 using a Swern oxidation, however, aroused some troubles.61 Sequential treatment of alcohol 114 with oxalyl chloride and dimethyl sulfoxide in dichloromethane followed by the addition of triethylamine gave ketone 115 in variable yields (20-96

*). When yields were low, starting alcohol 114, hydrolyzed alcohol 113, and/or hydrolyzed ketone 116 were obtained (Scheme XXVI). Because alkyl methylthiomethyl ether

118 (the common side-product of Moffatt type oxidations resulting from a Pummerer-type rearrangement) was not isolated, recovery of alcohol 114 results from only partial conversion of alcohol to its alkoxysulfonium salt

117 before addition of triethylamine (Scheme XXVII).

Scheme XXVII

o o r § ©>» Me,SO ♦ CtCCCI [Me2SCICI J

r ’r'c h o h 114

,CH c s TE— (M e^O CH Rtfci) ♦ HCI I I H CH2 117

RfRzCH0®* CH^CHZ 115 I R'r'c HOH ♦ rV c HOCH.SCH j 114 118 48

Acetal hydrolysis should be resulted from protonation by hydrogen chloride produced in this Swern oxidation.

Although hydrolysis of acetal 113 and 116 and recovery of alcohol 114 may be explained as above, it is still uncertain that what factors may influence the yield.

Ketone 115 was converted to an inseparable mixture of alcohols 119 and 114 with lithium triethylborohydride

Scheme XXVIII

OMe OMe OMe

OMe OMe

114 119 115 I NaH, /PhCH2Br

PhCHzO.

OMe HCl OMe

OMe

CHO

120 91 (72 X) and resulting mixture of alcohols was treated with benzylbromide and sodium hydride to give mainly axial

benzyl ether 91 (44 X) as well as recovered alcohols (15

X). No attempt was made to isolate the benzyl ether

isomeric to 91. Hydrolysis of the acetal was also a problem during the aqueous workup of this reduction.

Finally, the acetal 91 was hydrolyzed by hydrochloric acid in aqueous acetone to give aldehyde 120 in 87 X yield (Scheme XXVIII).

The next steps in this approach would have been adjustment of the aldehyde oxidation state, introduction of the C-10 carbethoxymethylidene group, and conversion of enamino ester 93 to /?-amino ester 94. This was to be followed by the synthesis of the 0-ketosu If oxide 95, activation of hydroxyl group, high dilution cyclization of the intermediate tosylate, and reduction of the phenyl sulfinyl group. The synthesis of lythrancepine-II (4) was then to be completed by reducing 9G, acetylation, and removing the blocking group. However, due to difficulties associated with the acetal protecting group and solubility problems encountered with several of the intermediates, an alternative route was pursued. This route, which revolves around construction of the biaryl via an intramolecular Ullmann reaction, will be the subject of the next chapter. CHAPTER IV. TOTAL SYNTHESES OF <£)-LYTHRANCEPINE-II

AND <♦)-LYTHRANCEPINE-III

The next approach to lythrancepine-II la outlined antithetically in Scheme XXIX. In the final atage of thia

Scheme XXIX H HO

OAc

> OAc

OMe ieO 121 OMe

MeO OMe

MeO O OMe OMe 22 123 122 synthesis, we envisioned the 13-membered ring closure via an intramolecular biaryl coupling. The C-9 aubstituent in

121 would be introduced by the Eachenmoaer aulfide

50 51 contraction. The synthesis of lactam 122 was anticipated to be quite stralghtfoward according to the procedures established In the model study. This synthetic strategy has several advantages. First of all. It avoids the problem of acetal hydrolysis which occurred in the scheme using biaryl systems (chapter III>. Second, if introduction of the entire C-9 aidechain succeeds, the scheme is convergent. Lastly, the basic strategy allows for functional group differentiation in all rings and should allow the synthesis of all other members of type D

Lythraceae alkaloids, even the lythrum alkaloids (see ref. IS, i and ii).

Before describing the synthesis, it is noted that all the conformations of intermediates are identical to the corresponding structures prepared in the model study up to amino ester 82. To avoid repetition, the details of the chemistry will only be mentioned on occasion.

The synthesis began with m-iodoanisaldehyde (85) which had already been prepared for the synthesis of the biaryl 8 6 . It is noted that the proton NMR spectrum of 85 clearly showed a doublet at 5 6.93 for ArHs with J=9 Hz

<2££li2 coupling), a doublet of doublets at 6 7.84 for ArH& with J=9, 2 Hz (ortho and meta couplings), and a doublet at 6 8.27 for ArH2 with J*2 Hz (meta coupling). All compounds in this synthesis exhibited this aromatic NMR pattern as long as they maintained the 3-iodo-4- 52 methoxyphenyl moiety. Sequential treatment of m-

iodoaniealdehyde (85) with lithium hexamethyldieilazide and allylmagneaium bromide gave homoallylic amine 123 (76

X) along with 9 X of reduced amine 43. The crude proton

NMR of the ailyl imine intermediate analogoua to 42 ahowed no reduction of the iodophenyl moiety by lithium hexamethyldieilazide. Thua, a poaaible explanation for the formation of amine 43 may be metal-halogen exchange between the aryl iodide and Grignard reagent followed by protonation during the aqueoua workup. In fact, the yield of amine 43 waa 9 X only if a alight exceaa (1.05 equivalenta) of allylmagneaium bromide waa uaed. The uae of larger amounta of the Grignard reagent increaaed the yield of 43.

Sequential treatment of amine 123 with trimethylaluminum and eater 22 gave amide 124 in 96 X yield.54 Treatment of amide 124 with formic acid in dichloromethane <2 h, 25QC) gave formate 126 (48 X) , iaomeric formate 127 (5 X), inaeparable alcohola 126 and

129 (22 X), olefina 125 (9 X), and m-iodoaniaaldehyde

(85) (11 X). Formate 126 could be cryatallized directly from the mixture of crude cyclized producta in 38 X yield

(Scheme XXX). The olefin mixture 125 waa cryatallized from ethyl acetate to give a aingle iaomer by 13C-NMR apectroacopy. Thia iaomer waa tentatively aaaigned at the ^2»3-iaomer based on 1 H-NMR and mass spectral data. 3-H

NMR of olefin mixture 125 showed approximately a 3:1 ratio of the A2'3-isomer and A^'^-isomer, respectively

Scheme XXX

CHO 1.LiHMDS 2.CH2=CHCH2MgBr

3.H20

1.AlMe

CHO OMe HCOOH — Y o OMeOh

OMe

124

R 126 R=H0C0-[3R] + 127 R=H0C0-[3S] 128 R=H0-[3R] 129 R=H0-[3S] OMe

Both formates (126 and 127) and both alcohols

(126 and 129) are useful as synthetic intermediates. 54

Treatment of the mixture of formates 126 and 127 with

Scheme XXXI

HOCO HO

NaOH

OMe OMe

126 HOCO- [ 3R ] 128 HO- [ 3R ] 127 HOCO- [ 3 S ] 129 HO- [ 3 S ]

DMSO, Et.N (C0C1) 3

AcO HO

AC 2 O LiEt3BH

OMe OMe OMe 130 131 129 HO-[3S] + 128 HO-[3R] AcO. AcO

Lawesson1s reagent

59 OMe OMe 132 133 sodium hydroxide in aqueoua methanol gave alcohols 1 2 8 and 1 3 0 in 95 X yield. These alcohols, together with the alcohols produced during the cyclization, were converted to ketone 1 2 9 in 99 X yield using a Swern oxidation.61 It

is noted that the Swern oxidation gave ketone 1 3 0 almost quantitatively, unlike ketoacetal 1 1 5 (Chapter III).

Ketone 1 3 0 was reduced at -78°C with lithium triethylborohydride to give a mixture of alcohols 1 2 9 and

1 2 8 (100 X) and the resulting inseparable mixture of 1 2 9 and 1 2 8 was treated with acetic anhydride, triethylamine, and a catalytic amount of 4-dimethylaminopyridine to afford a separable mixture of acetate 1 3 2 (84 X) along with 7.5 X of isomeric acetate 1 3 1 (Scheme XXXI).

Having established the appropriate stereochemistry at C-l, C-3, and C-5, we turned to introduction of the

C-9 sidechain. Treatment of lactam 1 3 2 with Lawesson's r e a g e n t 4 3 gave easily crystal1izable thiolactam 1 3 3 in 98

X yield. Treatment of thiolactam 1 3 3 with ethyl iodoacetate in tetrahydrofuran (25°C, 2 days) gave a quantitative yield of crystalline salt 1 3 4 . It is noted that ethyl iodoacetate is much more efficient than ethyl bromoacetate in thia reaction. Also using excess electrophile shortened the reaction time considerably.

Treatment of salt 1 3 4 with triphenylphosphine and DABC0 in chloroform under reflux gave vinylogous urethane 1 3 5

(76 X) . I t should be mentioned that formation of 1 3 5 from 56 the salt 134 required a longer reaction time than formation of 61 from 64. TLC analysis of the reaction mixture after 1 0 min showed considerable amounts of lactam 132. The crude proton NMR, however, showed no peaks due to lactam 132, suggesting the existence of an equilibrium between iminium ion and enamine as mentioned before. The formation of lactam presumably occurs only on the TLC plate or upon aqueous workup of the reaction media. Reduction of vinylogous urethane 135 at pH 4 with

Scheme XXXII H H AcO AcO

ICH2C02Et

OMe OMe

133 134

DABCO, Ph3P

AcO AcO.

NaBH3CN

pH 4 OMe OMe 136 CH2C02Et-[9R] 137 CH2C02Et-[ 9S] 135 57 sodium cyanoborohydride49 gave amino ester 137 <94 X) and

5 X of isomeric amino ester 136 <25°C, 30 min) (Scheme

XXXII).

Sequential treatment of thiolactam 133 with 5 equivalents of iodoacetonitrile in a mixture of tetrahydrofuran and diethyl ether <25°C, 3 days) followed by the addition of triphenylphosphine and DABCO under reflux <20 min) gave enamino nitrile 138 in 79 X yield.

Reduction of enamino nitrile 138 at pH 4 with sodium cyanoborohydride gave 84 X of amino nitrile 140 and 8 X

SchemeXXXIII

H H AcO AcO

1. ICH2CN CN 2.DABCO, Ph3P

OMe OMe

133 138

H AcO 58

of isomeric amino nitrile 139 (25°C, 10 min) (Scheme

XXX1I1). Thus, as expected, the chemistry developed in

Chapter II translated well to this system.

Attention was next turned to introduction of the entire C-9 sidechain. This required the preparation of «-

bromoketone 1 5 0 . This was accomplished in 8 steps from p- hydroxybenzaldehyde ( 1 4 1 ) as outlined in Scheme XXXIV.

Treatment of 1 4 1 with malonic acid and pyridine gave cinnamic acid 1 4 2 (44 X) .62 Reduction of 1 4 2 with 5 X palladium on chacoal gave hydrocinnamic acid 1 4 3 (89 X ).

Acid 1 4 3 was treated with potassium iodide and iodine in ammonium hydroxide to give monoiodide 1 4 4 in 46 X yield

(25°C, 2 h) along with a trace of diiodide.63 Treatment of hydroxyhydrocinnamic acid 1 4 4 with excess diazomethane

(25°C, 2 days) gave ester 1 4 5 in 90 X y i e l d . 63 Methyl ester 1 4 5 was hydrolyzed with sodium hydroxide in aqueous methanol (25°C, 3 h) to give acid 1 4 6 in 99 X yield.

Treatment of acid 1 4 6 with thionyl chloride under reflux

(30 min) gave acid chloride 1 4 7 (100 X) and slow addition of acid chloride 1 4 7 to excess diazomethane at 0°C gave diazoketone 1 4 8 (99 X ).64 Hydrogen chloride was passed through a solution of diazoketone 1 4 9 in diethyl ether to give chloromethylketone 1 4 9 (76 X ) and identical treatment of 1 4 8 with hydrogen bromide gave bromomethylketone 1 5 0 in 72 X y i e l d . 65 iodomethylketone 1 5 1 was prepared by treating chloromethylketone 1 4 9 with sodium 59 Scheme XXXIV

COjH CHO

Pd/C

Py OH

141 142

KI c o 2h

NaOH CH„N

OMe OMe OH

146 145 144 | SOC1,

HC1

OMe OMe OMe 147 148 149 HBr Nal

OMe OMe OMe

150 152 151 60 iodide in acetone in 89 X y i e l d . ^

Initially, iodomethylketone 151 was used as the electrophile in the preparation of the required thioiminium salt. However, iodomethylketone 151 was slowly reduced to methylketone 152, causing complications.

Bromomethylketone 150 did not reduce to methylketone 152 under the same conditions and was quite suitable for use.

Sequential treatment of thiolactam 133 with 2 equivalents of a-bromoketone 150 in chloroform (25°C, 3 days) followed by the addition triphenylphosphine and DABCO under reflux (30 min) gave a single product in 6 8 X yield

(Scheme XXXV). However, spectroscopic data suggested this material was not the desired enamino ketone 154. For example, IR spectrum showed no carbonyl absorption bands due to a vinylogous amide. The proton NMR spectrum was so complicated that it was very difficult to characterize the exact structure. However, critical information was provided by the mass spectrum and 13C-NMR spectrum. First of all, the parent ion did not match that required by structure 154. Instead of m/e 729 required by 154, the parent ion appeared at m/e 743, consistant with the molecular formula C2 9 H3 1 NO4 I2 S. The 13C-NMR spectra (broad band and off resonance) clearly showed the presence of 6 methylenes and 1 0 quaternary carbons, inconsistant with the 7 methylenes and 9 quaternary required by 154.

Finally, the UV spectrum gave a Amax at 227 nm 61 inconsistent with the Xmax 327 nm <7r-ir« band) calculated by 1 5 4 using Woodward's rules. It waa concluded from these spectral data that the product obtained from the attempted sulfide constraction was, in fact, thiophene 1 5 5 . This structure agrees with all spectral data including the parent peak of 743

. Also all fragmentation patterns were in accord with the assigned structure 1 5 5 . It was mentioned in Chapter II that Ireland and B r o w n ^ S had obtained thiophene 7 4 when 7 3 was heated with triethylamine in methanol. In this case, the phenyl ring in 7 3 apparently increases the acidity of the /?-thioamide protons enough such that deprotonation occurs there in preference to the acetate methylene group. In the case of salt 1 5 3 , formation of thiophene 1 5 5 presumably results from competitive deprotonation at C-S protons to give the corresponding enamine followed by nucleophilic attack at the ketone carbonyl group. It is notable that although salt 1 3 4 undoubtedly gives enamine, no closure to a thiophene-like structure was observed. Presumably, the decreased electrophilicity of the ester carbonyl is responsible for elimination of this undesired reaction.

In a similar fashion, this reaction with bromoacetone& 7 gave thiophene 1 5 8 in 65 X yield. Scheme XXXV

DABCO, Ph3P

DABCO 63

The disappointing results with 150 forced us to adopt a procedure which involved stepwise introduction of the C-9 sidechain. Since this required the use of carbanion chemistry (vide infra), adjustment of the C-3 blocking group was required. Thus, a mixture of alcohols

129 and 128 obtained from lithium triethylborohydride reduction of 130, was treated with sodium hydride and benzyl bromide in DMF to afford a separable mixture of benzyl ether 122 (66 X) and 159 (10 X) as shown in Scheme

XXXVI. Treatment of lactam 122 with Lawesson's reagent^3

Scheme XXXVI

HO PhCH20

NaH

OMe OMe

128 ♦ 129 159 +

PhCH20.

Lawesson's reagent 59 OMe OMe

160 122 64 gave thiolactam 160 (10 min, 98 X) . At this point, it is worth mentioning additional data which is consistent with the downfield shift of H-l in thiolactams as described in chapter II. Lawesson and his coworkers®® have intensively studied the 13C-NMR of thiolactams. A linear relation between the chemical shifts of the thiocarbonyl group of the thioamides and carbonyl group of the corresponding amides has.been found by a least square linear regression analysis (Equation 6 ). According to this equation,

8 (C=S> = 1.60 x <5 (C=0) - 72.3 (eq.6)

the calculated chemical shift of C-9 of thiolactam 160 is

5 199.1 (chemical shift of C-9 of lactam 122 is 8 169.6) which is quite close to the observed value of 8 201.0. It was suggested that the shifts may partly result from different inductive effects of the thioamide group operating through bonds and from the considerably higher dipole moment of thioamides operating through space relative to amides. It is noted that the a-carbons attached to the nitrogen are also shifted downfield in

160 (chemical shifts at C-l: 8 48.3 for lactam 122,

8 57.3 for thiolactam 160: chemical shift at C-5: 5 47.1 for 122, 8 50.4 for 160).

Treatment of thiolactam 160 with 10 equivalents of ethyl iodoacetate in chloroform (25°C, 24 h) followed by 65 the addition of DABCO and triphenylphosphine under reflux, gave enamino ester 161 in 92 * yield. Reduction of 161 at pH 4 with sodium cyanoborohydride (25°C, 10 nin) gave amino esters 162 (68 X) and 163 (10 X ) (Scheme

XXXVII). Reduction of 161 with Adams' catalyst (Pt02> in acetic acid gave 51 * of amino eater 162 and 27 X of iodide-reduced amino ester analogous to 162 (58 psi, 90 min) .

At this point, a plausible reason for the good stereoselectivity observed in the iminium ion reduction

Scheme XXXVII

1 .ICHoC0oEt C 0 2Et 2.DABCO, Ph^P

OMe OMe

160 161

pH 4 PhC H ,0

CO, Et C 02Et

OMe OMe

162 163 (161— ►162 and 163) ahould be presented. Initially, it was felt that 162 would be the thermodynamically most stable reduction product and that an equilibrium might be established between 162 and 163 via an elimination- addition process after reduction took place. Although this is a resonable suggestion, it is not the case as subjecting 162 and 163 to the reduction reaction conditions did not cause their interconversion.

Therefore, the partitioning of 161 between 162 and 163 is kinetically controlled. In rationalizing the observed results, it is assumed that iminium ion 164, derived from protonation of 161, is the species undergoing reduction.

Proton NMR spectra of iminium salts 64, 69, 70, 134, 153, and 156 suggest the C-l and C-3 substituents in 164 are axially disposed. Thus, in discussing the addition of hydride to 164, two formations, 164a and 164b, must be considered as shown in Scheme XXXVIII. It has been suggested that stereoelectronic features govern the course of addition of nucleophiles to iminium ions.

Bohlmann and his coworkers&9 have shown that the 67 borohydride reduction of iminium salts of type 167 gave products 168 in preference to its isomer 169 (Equation 7).

This results, and others,70 suggest that a stereoelectronic requirement in iminium ion reductions is maintenance of maximum orbital overlap between the developing nitrogen lone pair and incoming nucleophile. Applying this principle to the case in hand suggests that there are four possible transition states in the reduction of 164 where maximum orbital overlap can be maintained with respect to the attacking hydride reagent and the developing lone pair on nitrogen, resulting in products where the sp3-hybridized orbitals generated are anti- coplanar. Two of these, 165 (path a; si-face attack) and

166 (path c; re-face attack), require boat-like transition states and are probably kinetically disfavored.71 Before discussing the remaining two possibilities, path b (re-face attack) and path d (si- face attack), the relative stabilities of conformations

164a and 164b will be discussed. Although the conformation of the B-rings in 164a and 164b are drawn as half-chairs, there may be some differences in the case of

164a. Because of the adjacent rigid chair-like A-ring, C-

6 cannot move as much as expected when C-7 is flip- floping to interconvert both possible half-chair conformations in the B-ring. Thus, in 164a, the B-ring should have an envelope-like conformation72a j.n order to Scheme XXXVIII

PhCH2o k ^ I ^COjEt / W T ° PHCH.01JH

? A

^ 162a O * ,, '

P ath a P ath b

\ P ath a - M s

164a

P ath b 165

Me P ath d

,© P a th c

166 164 b P ath c P ath d

OMe

PhCH2cj| PhCH ,0 PhCH

CO,Et C02Et 163 b place C -6 at an equatorial position of rigid A-ring, In

164b, however, the B-ring can adopt a true half-chair conformation. Hence 164b seems to be more favorable than conformation 164a. However path d clearly suffers from an unfavorable 1,3-diaxial interaction developing between the C-l phenyl group and the incoming nucleophile

(hydride ion). In addition, the most obvious changes that occur on introduction of a heteroatom into a six-membered ring have to do with bond lengths and bond angles. O Carbon-nitrogen bond lengths <1.47 A) are shorter than 0 the carbon-carbon bond length of 1.54 A. The C-N-C bond angle is somewhat smaller than the C-C-C angle in cyclohexane. So, nitrogen containing heterocyclic rings

(e.g. piperidine) are somewhat more puckered than cyclohexane itself. Applying this concept to conformations 164a and 164b, and considering the exocyclic ^N=C double bond to A-ring, this ring might also contain a little bit of envelope character to compensate for increasing C(l)-N-C(5) angle resulting from the exocyclic double bond. As a result, the phenyl substituent and C(2)-C<3) bond should rotate little bit clockwise. Keeping in mind the shorter bond lengths of

C <1)-N and ^N=C,7 2b this result suggests that path d suffers from a stronger interaction between the incoming nucleophile and the phenyl group than expected and path b might not suffer from an interaction between the 70 nucleophile and C

In summary, rather than the relative stability of conformations 164a and 164b, the sterically more favorable transition state which satisfies the stereoelectronic control requirements leads to the product. As mentioned before, assuming that 162 and 163 will prefer to adopt chair-chair conformations, an evaluation of all possible conformers indicates that 162c should be the thermodynamically most possible reduction product.7 3 In fact, proton NMR analyses of 162 and 163 proved that 162 and 163 adopt the conformations of 162c and 163a respectively.7 4

To complete the introduction of the C-9 sidechain, some /3-keto sulfone chemistry was examined.75 it was hoped that methyl phenyl sulfone could be used as a one carbon synthon to link 162 and a 3-iodo-4-methoxybenzyl group.

Therefore, the model study outlined in Scheme XXXIX was performed. Sequential treatment of methyl phenyl sulfone

1707& with sodium hydride in DMSO <65°C, 30 min) and a solution of ethyl caproate (171) in tetrahydrofuran gave

/3-keto sulfone 172 in 84 X yield.7 7 £-Keto sulfone 172 was treated with sodium hydride in DMSO (25°C, 50 min) 71

followed by benzyl chloride 173?B (25°C, 2 h) to give a-

aubstituted-0-keto aulfone 174 in 43 X yield.79 Reduction of aulfone 174 waa performed with aluminum amalgam in 10

X aqueoua tetrahydrofuran (reflux, 3 h) to give ketone

175 in 71 x yield.Thia model atudy aeemed to give a resonable way of introducing the C-9 aidechain. Becauae we were aware that the conditione ueed in the reductive cleavage of aulfone might alao reduce an aryl iodide, a

Scheme XXXIX

PhS02 CH3 + CH3(CH2)4C02Et

170 171

NaH

OMe 173 o CH3(CH2)4C C H S 0 2Ph

O CH, Al-Hg CH3(CH2)4CCH2CH. OMe

OBzl OMe 175 174 model atudy uaing 3-iodo-4-methoxybenzyl chloride (177) in place of 173 waa performed (Scheme XXXX). 3-Iodo-4- 72 methoxy-benzaldehyde (85) was reduced with sodium borohydride to give alcohol 176 in 96 * yield (25°C, 10 min). Treatment of alcohol 176 with thionyl chloride and pyridine (25°C to reflux, 3 h) gave benzyl chloride 177 in 70 X yield. /3-Ketosulfone 172 was treated with sodium hydride in DMSO (25°C, 1 h) followed by benzyl chloride

177 <25°C, 30 h> to give a-substituted-/?-keto sulfone 178 in 63 X yield along with 24 X of recovered /3-keto sulfone

Scheme XXXX CHO H ri

NaBH4 soci2

OMe OMe OMe 177 85 176 j NaH, 172

CH2 O

179 OMe

178

172. Sulfone 178 could also be prepared by sequential treatment of /3-keto sulfone 172 with potassium t-butoxide in t-butanol <60°C, 30 min) and a solution of benzyl 73 chloride 177 in tetrahydrofuran (60°C, 36 h) in 75 X yield.®! The reductive cleavage of aulfone 178 waa firat performed with aluminum-amalgam. However, treatment of aulfone 178 with aluminum-amalgam in 10 X aqueous tetrahydrofuran under reflux <1 h) gave 8 8 X of ketone

179 in which the aryl iodide had also been reduced.

Several other methods for desulfonylation were examined.

For example, zinc-acetic acid (25°C to reflux, 24 h)®2 gave no desulfonylation product but the aryl iodide waa reduced. Sodium amalgam (3 *) in the presence of diaodium hydrogen phosphate in methanol (25°C, 2 h ) ® 3 gave doubly reduced product 179. W-2 Raney-nickel in ethanol®**

(reflux, 24 h) gave only aryl iodide reduction. These disappointing results forced us to look for different coupling process which would circumvent aryl iodide cleavage during removal of the activating substituent.

The next possibility was the Horner-Wadsworth-

Emmons reaction.®5 Avoiding model studies, sequential treatment of 2 . 2 equivalents of dimethyl methylphosphonate with 2 equivalents of butyllithium (0°C, 15 nin) followed by 1 equivalent of ester 162 (0°C, 75 min) gave /3-ketophosphonate 180 in 99 X yield after an aqueous workup (Scheme XXXXI).®® /?-Ketophosphonate 180 was then treated with sodium hydride in DME (25°C, 1 h) followed by 3-iodo-4-methoxybenzaldehyde (85) (25°C, 6 h> to give a ,/?-unsaturated ketone 181 in 81 X yield. 74

Scheme XXXXI

CH,P(0)(OMe) P(OMe)

OMe OMe

162 180 1 .NaH, 2.85

OMe

181

The next step in the ayntheaia required reduction of the unsaturated ketone moiety in 161 without touching the aryl iodides. As a matter of course, appropriate model studies were performed. Treatment of aldehyde 65 with 1- triphenylphosphoranylidene-2 -propanone (182)87 in dichloromethane (25°C, 48 h) gave a,/?-unsaturated ketone

183 in 8 6 % yield (Scheme XXXXII). The next objectives of this model study were the selective 1,2- or 1,4-reduction of the enone system. First, attempts were made to obtain 75

Scheme XXXXII

CHO

S o + Ph.P-%>A v OMe 182 85 OMe 183

Et_SiH 10 eq CF-COOH CF-COOH

OH OH

NaOH HN=NH

OMe OMe OMe

185 187 186

the 1,4-reduction product 184. However, moat popular 1,4- reduction methods such as catalytic hydrogenations and dissolving metal redutions were not used since both might be expected to also reduce the aryl iodide moiety.

Reduction of 183 with sodium borohydride in pyridine8 8 or copper(I) bromide with sodium bis-(2 -methoxyethoxy>- aluminum hydride (RED-AL)®® met with failure, giving poor regioeelectivity. It had been reported that treating an a,/3-unsaturated ketone with triethylsilane (1 equivalent) and trifluoroacetic acid (10 equivalents) would afford the saturated carbonyl compound.91 However, treatment of ketone 183 with 1 equivalent of triethylsilane and 10 equivalents of trifluoroacetic acid in chloroform gave a mixture of saturated ketone 184 and starting ketone 183

(reflux, 40 h ) . With 8 equivalents of triethylsilane and

11 equivalents of trifluoroacetic acid, ketone 183 was converted to trifluoroacetate 185 in 79 X yield (reflux,

2 h). This trifluoroacetate 185 was easily converted to saturated alcohol 187 upon treatment with 3 N aqueous sodium hydroxide in methanol in 96 X yield (25°C, 5 min).

Direct conversion of ketone 183 to saturated alcohol 187 was also performed with 3 equivalents of triethylsilane and 16 equivalents of trifluoroacetic acid (reflux, 2 h) followed by basic workup with 3 N aqueous sodium hydroxide in 95 X y i e l d . ^2

Although this reduction was potentially suitable for use in the lythrancepine-II synthesis, the presence of a benzylic amine in the real system caused some worries.

Thus, selective 1,2-reduction of unsaturated ketone 183 was also attempted. Treatment of ketone 183 with 1.2 equivalents of lithium triethylborohydride^® in 77 tetrahydrofuran gave unsaturated alcohol 186 quantitatively (0°C, 10 min). The unaaturated alcohol 186 was reduced to saturated alcohol 187 with diimide, generated from p-toluenesulfonylhydrazide and sodium acetate, in 87 X yield (reflux, 5 h).^3 other methods for the generation of diimide such as hydrazine hydrate with sodium metaperiodate and copper(II) sulfate^ or potassium azodicarboxylate with acetic acid$5 could not be adopted for the reduction of unaaturated alcohol 186.

The former method gave alcohol 187 along with material in which the iodide hod also been reduced in about a 3:5 ratio. The latter method gave only a low yield of alcohol

187. Moreover, it was suspected that acidic conditions might hurt the amino moiety of actual compound 181.

These results led us to use lithium triethylborohydride rather than triethylsilane. It was hoped that metal hydride reduction of ketone 181 might show some diastereoselectivity due to chelation between the metal (Li+), nitrogen lone pair of quinolizidine skeleton, and carbonyl group. Treatment of a ,/3- unsaturated ketone 181 with 2 equivalents of lithium triethylborohydride in a mixture of tetrahydrofuran and dichloromethane gave an easily separable mixture of allylic alcohols 188 (71 x') and 189 (25 X , 0°C, 30 min) as shown in Scheme XXXXIII. As expected, it was difficult to characterize the stereochemistry at C-ll in 188 and 78

Scheme XXXXIII

OMe

OMe OMe

181 OH 189 OMe

OMe

OH HN=NH OMe 188

OMe

OMe 190

189. An extremely tentative assignment, however, was made on the basis of TLC mobilities. The Rf values for 188,

181, and 189 (silica gel; ethyl acetate-hexane, 1 :1 ) were 0.57, 0.50, and 0.14, respectively. The unusually low polarity of alcohol 188 may be explained by intramolecular hydrogen bonding^ between the C-ll hydroxy group and nitrogen lone pair as shown in Figure

8 . Both alcohols 188 and 189 could adopt conformations

OMe

188

P hC H p

OMe

189

OMe Figure 8 80

in which the hydroxyl and amino groups are

intramolecularly hydrogen bonded. However, in 188, the C-

11 alkenyl sidechain is pseudo-equatorially disposed

whereas in 189, the C-ll alkenyl sidechain is paeudo-

axially disposed and experiences more severe steric

interaction with the C-l aryl group. As a result, it was

anticipated that 188 should have more intramolecular

hydrogen bonding than 189 and therefore be less polar

than 189. It is on this basis that stereochemistry was

originally assigned. This reduction might also have been

expected to give 188 as the major product based on a

chelation controlled reduction. Perhaps the lithium

coordinates with both the nitrogen lone-pair and a non

bonded carbonyl oxygen lone-pair. This locks 181 into a conformation where the incoming triethylborohydride

should potentially attack the re-face rather than the si-

face which is relatively hindered by the H-5 axial

proton. Although TLC analysis and spectroscopic arguments allowed us to make a tentative C-ll stereochemical assignment at this point, proof of stereochemistry waa obtained at the next stage of the synthesis.

The major alcohol 188 was reduced with diimide generated from p-toluenesulfonylhydrazide and sodium

acetate in aqueous DME to afford saturated alcohol 190 in

92 X yield (reflux, 4 h) . The IR spectrum of 190 like,

188, showed no sharp free hydroxyl stretching band and 8 1 only showed a broad hydrogen bonded hydroxyl stretching band around 3100 cm~l. The structure of alcohol 190 was firmly extablished by X-ray crystallographySl also showed hydrogen bonding between the C-ll hydroxyl group and nitrogen lone-pair (Figure 9).

Figure 9

Alcohol 190 was acetylated with acetyl anhydride, triethylamine, and a catalytic amount of 4- dimethylaminopyridine (25°C, 3 days) to give acetate 121 in 85 % yield. With the entire C-9 sidechain in place, we 82 were set for the critical biaryl construction. Synthetic procedures for the preparation of biaryls by the classical Ullmann reaction have, in recent years, been

supplanted by the use of zerovalent nickel to effect the

reductive coupling of aryl halides under homogeneous conditions. The original method, discovered by Semmelhack and his coworkers, used the isolable albeit air-sensitive bis<1 ,5 -cyclooctadiene)nickel<0 ).^7 Their studies were extended to intramolecular biaryl coupling especially using tetrakis(triphenylphosphine)nickel(0) (191) under high dilution conditions.36 In addition, it had been reported that this method had been used to prepare the biphenyl unit in a model study for the synthesis of the alkaloid protostephanine.59 This result suggested that a tertiary amine might not interfere with such a coupling.

Fresh 191 was prepared using a classical method from anhydrous bis(2,4-pentanedionato)nickel, triphenyl phosphine, and triethylaluminum and stored in a dry box

(Equation 8 ).100 This reddish brown solid 191 could be

Ni(CHjCOCH COCH3)2 + 2Et3AI + 4Ph3P

(Ph3p)«Ni + 2(C5H70 2 )AIEt2 + 2 C2H, (eq. 8)

191 S3 stored for a long time in a fairly well equipped dry box but became inactive upon exposure to oxygen. Treatment of

121 with 1.5 equivalents of 191 in DMF (S mM concentration of 121) at 55°C for 48 h gave the long- awaited biaryl 192 in 20-25 X yield along with 12 X of reduction product 193 (Scheme XXXXIV). The structure 192

Schem e XXXXIV H

OMe

190 PhCHp OMe

OAc

OMe

121 191

PhCH20 OAc OMe

OAc Mei eO OMe 192 193 84 was apparent from spectral data. In particular, the aromatic region was identical to the patterns reported for type D Lythraceae alkaloids. Although this reaction gave poor mass balance, no intensive attempt was made to optimize the yield of biaryl 192.

All that remained to complete the synthesis was removal of the benzyl group from the C-3 oxygen. Cleavage of this benzyl ether by hydrogenolysis was anticipated to be simple. However, initial attempts to cleave benzyl ether 192 with 10 X palladium on charcoal in 95 x aqueous ethanol gave no reaction. A variety of conditions were tried with no success. The reason why 192 was resistant to hydrogenolysis in the presence of palladium on charcoal is still uncertain. This surprising result induced us to perform some model studies (Scheme XXXXV).

First, treatment of benzyl ether 162 with 10 X palladium on charcoal in ethyl acetate <75 psi, 24 h) gave no hydrogenolysis product, only benzyl ether 194 was obtained confirming that palladium was not a good choice of catalyst. Treatment of benzyl ether 162 with W-4 Ra-Ni in ethanol1 0 1 '1 0 2 gave 61 X of piperidine 195 <1 atm, 48 h), the product of benzyl ether and benzylic C-N bond cleavage.1 0 3

We next moved to non-catalytic methods using a slightly different model system. Some methods such as dissolving metals (Na/NHg), DDQ, lithium aluminum 85

Scheme XXXXV

Ph CHjO

C 0 2Et

PhCH 20 OMe Pd/C 194

CO,Et H H W-4 OMe Ra-Ni 162 COzEt

OMe

195

hydride, electrolytic reduction or oxidation, free radical bromination-hydrolyeis, or oxidation-hydrolysis were felt to be unusable for cleavage of benzyl ether

192 due to the presence of sensitive functional groups in

192.104 a new model compound was prepared as shown in

Scheme XXXXVI. Alcohols 5 3 and 5 4 (mainly 5 4 ) were converted to benzyl ether 196 with benzyl bromide and sodium hydride in DMF <25°C, 6 h) in 48 % yield after

separation by chromatography. Treatment of lactam 196 with lithium aluminum hydride gave amine 197 in 94 x 8 6

Scheme XX XXVI

NaH

O Me OMe

53 HO-[3R] 196 54 HO-[3S] LAH

BBr

OMe OMe

198 197 yield (reflux, 1 h). A variety of benzyl ether cleavage conditions such as catalytic transfer hydrogenations <10

X palladium on charcoal with 1,4-cyclohexadiene in ethanol at 25°Cl05 or io X palladium on charcoal with cyclohexene in ethanol under reflux^O^ ) , boron trifluoride etherate with ethanethiol in dichloromethane

(25°C, 24 h),107 triraethylsilyl chloride with sodium iodide in acetonitrile <50°C, 12 h>,108 and trimethylsilyl iodide in chloroform <25°C, 24 h>109 met with failure giving sluggish reactions at best. At long last, cleavage of benzyl ether 197 was accomplished using

3 equivalents of boron tribromide in dichloromethane

<0°C, 15 min) giving 198 in 65 * yield.We were still concerned that treatment of benzyl ether 192 with boron tribromide might destroy the acetoxy group because it had been reported that boron trihalides will cleave carboxylic esters to the corresponding alkyl halides.m

Nonetheless, treatment of acetate 121 with 2 equivalents of boron tribromide in dichloromethane at 0°C for 3 min followed by an aqueous workup showed that cleavage of the benzyl ether might be faster than reaction of the acetate. This result encouraged us to attempt the cleavage of benzyl ether 192 using similar conditions.

Thus, sequential treatment of benzyl ether 192 with 4 equivalents of boron tribromide in dichloromethane at 0°C for 3 min followed by aqueous workup gave <+)- lythrancepine-II, in 54 yield (Scheme XXXXVII).

Unlike the reaction conditions for benzyl ethers 197 and

1 2 1 , excess boron tribromide was needed in this case, presumably because oxygens could coordinate with boron tribromide. Even though the yield of this reaction was not extremely high, no side products were isolated and TLC analysis of the reaction mixture showed only a single spot due to <+)-4. The synthetic (+)-lythrancepine-II (4) was identical to an authentic sample of < + )- Scheme XXX XVII

PhCH,0. HO

OAc BBr. OAc

eO leO 192

Py AcO

OAc

Mei eO

lythrancepine-II kindly provided by Professor Fujitall2

(TLC, FT-IR, mass spectrum, 500 MHz ^H-NMR). Further proof of structure was obtained by acetylation of ( + )-4 with acetic anhydride in pyridine <25°C, & h, 64 X) to give

FT-IR, mass spectrum, 500 MHz iH-NMR). A J-Resolved 2D ^H-NMR spectrum11^ was taken for the <+)-l4 and consequently, most of the chemical shifts and coupling constants of (0-4 and <0-14 were Identified. These spectra as well as those of natural <+)-lythrancepine-II and -III are shown in Figures 10 and 11 respectively.

In conclusion, we have completed the first total synthesis of a member of the largest structural family of

Lythraceae alkaloids. The synthesis required 18 steps from anisaldehyde and proceeds in approximately 1 * overall yield. The synthetic scheme allowed us to synthesize all three members of lythrancepine alkaloids as shown in Figure 1 (Chapter I). Furthermore, the basic strategy should allow the synthesis of all other members of this family of Lythraceae alkaloids. h 2o

r ,• » ...-..-p., r~i T- T T • • r * • a . :i l.n r.n l.C» u.o 8.0 6.0 I «-M Figure 10a. 1H NMR Spectrum of (+)-Lythrancepine-II (4) (CDCl3, 500 MHz) HO,

OAc

Mei eO

HzO

t 1 -’T-’ T* •*~1 ’ 1 T’ 8.0 6.0 5 .0 4.U 3. U 2 .0 1. 0 0.0 PPM CO Figure 10b. H NMR Spectrum of (+)-Lythrancepine-II (4) (CDCl^, 500 MHz) MtATI LTIHRPfltEiMNi Figure 11a. NMR Spectrum of (+)-Lythrancepine-III (+)-Lythrancepine-III of Spectrum NMR 11a. Figure 1 7.0 I \ AcO eO OAc r- *- r *t- T T 't ifti tl;.!; ?.o (14) HzO CC^ 50 MHz) 500(CDCl^, l.U o.n >r T PPH Figure lib. NMR Spectrum of (+)-Lythrancepine-III (+)-Lythrancepine-III of Spectrum NMR lib. Figure oJ uJ ii Jk lu Jo Jo k r W u .0 7 AcO 6.0 eO l j OAc A .0 5 . -j--.-. 4.0 HHK .0 3 (14) ■ I" ■'“ 2.0 CC^ 500MHz) (CDCl^, .^iniu<)|fb-l r’u Jt jStejl

PPM V. EXPERIMENTAL

All melting points were taken with a Thomas-Hoover capillary melting point apparatus and are uncorrected. nuclear magnetic resonance spectra were recorded on

Varian Associates EM-360 <60 MHz), Brucker NR-80 (80

MHz), Varian Associates EM-390 <90 MHz), Bruker WP-200

(200 MHz), or Bruker AM-500 <500 MHz) spectrometers and are reported in parts per million from internal tetramethylsilane on the 6 scale. Data are reported as follows: chemical shift [multiplicity

CHCHC0Me=ArHs or ArHs', CHCHC0Me=ArH& or ArHg'. 13c nuclear magnetic resonance spectra were recorded on a

Bruker WP-80 <20.11 MHz), Bruker WP-200 <50.28 MHz),

Nicolet NT-300 <75.42 MHz), or Bruker AM-500 <125.69 MHz) spectrometers and are reported in parts per million from internal tetramethylsilane. NMR data are reported as 95 follows: chemical shift, [multiplicity (s=singlet, d=doublet, t=triplet, q=quartet), interpretation]. Host

13c NMR spectra were recorded as Broad-Band or DEPT

(Distortionless Enhancement by Polarization Transfer) spectra. Thiophene 155 is the only compound whose multiplicities were determined via off-resonance techniques. Infrared spectra were taken with Perkin-Elmer

457, Perkin-Elmer 263B, or Mattson Cygnus 25 FT-IR instruments. Mass spectra were recorded on AEI-MS9,

Kratos DS-55, or Kratos MS-30 instruments at an ionization energy of 70 eV. Samples on which exact masses were measured exhibited no significant peaks at m/e values greater than those of the parent. The parent ions of some amines and a few other compounds were too small for exact mass measurements to be obtained and the parent ions of some compounds which have molecular weights of greater than 700 were beyond calibration to get exact masses. In these cases, the fragmentation patterns were in accord with the assigned structures. Laser desorption

Fourier transform mass spectrometry was performed for 161 using a Nicolet FT/MS-1000 and Tachisto 215 G TEA CO2 laser doped with KBr to supply K+ without calibration.

Combustion analyses were performed by Micro-Analysis,

Inc., Wilmington, DE.

Solvents and reagents were dried and purified prior to use when deemed necessary: acetic anhydride (distilled 97 from P2055; tetrahydrofuran and diethyl ether (distilled from sodium metal); dichloromethane and chloroform

(passed through activity I alumina or distilled from

CaH2 >; benzene, dimethoxyethane, dimethylformamide, toluene, and triethylamine (distilled from CaH2 >; methanol (distilled from magnesium methoxide), dimethyl sulfoxide (distilled from CaH2 at reduced pressure). All reaction temperatures refer to those of the reaction mixture unless indicated otherwise. Reactions requiring an inert atmosphere were run under a blanket of argon or nitrogen. Formic acid (98 X) was used in all cyclizations. 61 X of Oil dispersion of sodium hydride was used without washing it. Most reactions were followed by thin layer chromatography over silica gel or alumina using EM Laboratories glass-backed 0.25-mm thick precoated silica gel 60 F-254 plates or EM Laboratories glass-backed 0.25-mm thick precoated aluminum oxide 60 F-

254 plates. Column chromatography was performed over EM

Laboratories silica gel 60 (70-230 mesh) or Woelm neutral alumina. Preparative thin layer chromatography was performed over EM Laboratories glass-backed 2.0-mm thick precoated silica gel 60 F-254 plates or EM Laboratories glass-backed 0.5-mm thick precoated silica gel 60 F-254 plates. Medium pressure liquid chromatography (MPLC) was performed over EM Laboratories Lobar columns using an FMI RPSY lab pump. Rotary diak chromatography (chromatotron) waa performed over EH Laboratoriea allica gel PF-254 with

CaSC>4 1/2 H2 O type 60 platea uaing an FMI RP G-150 lab pump. Ethyl acetate and n-hexane, uaed aa eluenta in column chromatography, were diatilled prior to uae. Order of experimental liata generally followed their echeme aa well aa numbera of compounda.

4-A»ino-4-(4-methoxyphenyl)-l-butene <43). To a

aolution of 10.1 mL (47.7 mmol) of

1,1,1,3,3,3,-hexamethyldieilazane

in 12 mL of tetrahydrofuran waa

added 28.3 mL <43.9 mmol) of 1.55 M

n-butyllithium in hexane with

cooling in an ice bath. The

aolution waa atirred for 1 0 min and

5.0 g <36.7 mmol) of p-methoxybenzaldehyde waa added via ayringe with cooling in an ice bath. The mixture waa atirred at room temperature for 1 h followed by addition of 61.5 mL <44.9 mmol) of 0.73 M ethereal allylmagneaium bromide with cooling in an ice bath. The resulting mixture waa stirred for 20 min at room temperature, poured carefully into 100 mL of saturated aqueous ammonium chloride, and extracted with three 100-mL portions of diethyl ether. The combined organic layers were washed with 100 mL of saturated aqueous sodium chloride and 100 mL of water, dried

(Na2 S0 4 >, and concentrated in vacuo. The residue was distilled to give 5.63 g (87 X) of amine 43 as a colorless oil: bp 84-85QC at 0.5 mrnHg; IR 3370,

1608 cm-1; NMR (CDClg) 6 1.50 , 2.30-2.55

2H, CH2 CH=>, 3.80 , 3.85

ArCHN), 4.95-5.25 (m, 2H, =CH2 >, 5.50-6.00 (m, 1H, =CH>,

6.85 (d, J=9 Hz, 2H, ArH), 7.28

CH2CH=CH2» 100), 121 (47), 93 (8 ); exact mass calcd for

CsHiqNO (Mi‘-CH2 CH=CH2 ) ffi/e 136.0763, found m/e 136.0762.

N-[1-(4-Methoxyphenyl)but-3-en-l-yl3-5,5-dimethoxypentanamide (44). To a solution of 5.93 g (33.5 mmol) of

amine 43 in 40 mL of

dichloromethane at room

OMe temperature was added 27.0 mL (40.2 mmol) of OMe 1.49 M trimethyl-

OMe aluminum in heptane

under nitrogen. The 44 solution was stirred for 30 min followed by addition of 5.90 g (33.5 mmol) of methyl 5,5-dimethoxypentanoate (22) in 5 mL of dichloromethane. The resulting solution was warmed under reflux for 2 0 h, cooled to room temperature, poured into

50 mL of 1 N aqueous sodium hydroxide, and extracted with five 80-mL portions of dichloromethane. The organic layers were washed with three 100-mL portions of saturated aqueous sodium chloride, dried (MgS0 4 ), and concentrated in vacuo. The residual pale yellow solid was chromatographed over 150 g of silica gel (eluted with ethyl acetate-hexane, 7:3) to give 10.5 g <98 X) of amide

44 as a pale yellow oil which solidified upon standing for several weeks in the refrigerator: mp 50-51°C; IR

3425, 1650 cm"l; NMR (CDCI3 ) 5 1.55-1.80

CH2 CH2 C(OMe)2 > » 2 .1 0 -2 . 3 5

Hr, 2 H, CH2 C-), 3.30

ArOCH3 >, 4.25-4.40

=CH2 and ArCHN), 5.45-6.05 (m, 2H, =CH and NH), 6.82

J =9 Hr, 2H, ArH), 7.20

(3), 280 (8 ), 249 (7), 248 (42), 176 (5), 145 (10), 136

(100), 71 (59); exact mass calcd for C1 7 H2 4 NO3

rel-<4R,9aS)-4-<4-Methoxyphenyl)-1,6,7,8,9,9a- hexahydrophenyl-4H-quinolirin-6-one (49), rel-(2R,4R,9a5)-

Formyloxy-4-<4-methoxyphenyl)octahydro-4H-quinolirin-6- 101 o n m (39), and rel-(2S,4R,9aS)-2-Formyloxy-4-(4-*ethoxyphenyl)octahydro-4H-quinolizin-6-one (50). To a solution

H H M HOCO,, HOCO

OMe OMe OMe

49 39 50 of 512 mg (1.60 mmol) of amide 44 in 6 mL of dichloromethane at room temperature was added 16 mL of

98 X formic acid. The solution was stirred at room temperature for 3 h, neutralized with saturated aqueous sodium bicarbonate, extracted with three 50-mL portions of dichloromethane, washed with three 50-mL portions of saturated aqueous sodium bicarbonate, dried (MgS0 4 >, and concentrated in vacuo. The resulting mixture was chromatographed over a Lobar size B column (eluted with ethyl acetate-hexane, l:l> to give 56 mg (14 X) of a mixture of isomeric olefins 49, 319 mg (66 X) of formate

39, and 16 mg (3.3 X) of isomeric formate 50 as colorless oils.

Isomeric olefins 49: IR (CH2 CI2 ) 1650 cm“l; NMR

(CCI4 ) S 1.35-2.65 (m, 8 H, CH2 ), 3.30-3.80 (m with s at

3.72, 4H, OCH3 and NCH), 5.70-5.98 (m, 2H, CH=CH), 6.00- 102

6.22 (broad a, 1H, ArCHN), 6.68 (d, J=9 Hz, 2H, ArH),

7.25 (d, J=9 Hz, 2H, ArH); mass spectrum, m/e (relative intensity) 257 (M+, 100), 242 (5), 228 (4), 160 (27); exact mass calcd for C 1 6 H1 9 NO2 m/e 257.1416, found m/e

257.1423.

Formate 39: IR (CH2 CI2 ) 1719, 1633 cm"!; NMR (CCI4 )

8 1.20-2.90 (m, 10H, CH2 ), 3.15-3.55 (m, 1H, NCH), 3.75

(s, 3H, OCH3 ), 4.85-5.45 (broad m, 1H, CO2 CH), 6.23

(broad d, J=4.5 Hz, 1H, ArCHN), 6.85 (d, J=9 Hz, 2H,

ArH), 7.20 (d, J=9 Hz, 2H, ArH), 8.03 (s, 1H, HCO2 ); mass spectrum, m/e (relative intensity) 303 (M+, 100), 302

(12), 288 (1), 274 (1), 258 (8 ), 256 (23), 161 (10); exact mass calcd for C 1 7 H2 1 NO4 m/e 303.1470, found m/e

303.1477.

Isomeric formate 50: NMR (CCI4 ) 8 1.50-2.70 (m, 10H,

CH2 ). 3.70 (s, 3H, OCH3 ), 3.55-3.85 (m, 1H, NCH), 5.13

(qu, J=3.5 Hz, 1H, CO2 CH), 5.85 (dd, 1H, ArCHN), 6.65

(d, J=9 Hz, 2H, ArH), 6.92 (d, J=9 Hz, 2H, ArH), 7.50 (s,

1H, HCO2 ); mass spectrum, m/e (relative intensity) 303

(M*, 100), 302 (13), 288 (3), 274 (8 ), 258 (15), 256

(22), 161 (16); exact mass calcd for C3.7 H2 1 NO4 m/e

303.1470, found m/e 303.1477.

rel-(2R,4R,9aS)-2-Hydroxy-4-(4-methoxyphenyl)- octahydro-4H-quinolizin-6-one (53). To a solution of 299 103

mg CO.958 mmol) of formate 39 in 7

H mL of methanol at room temperature

was added 0.95 mL of 3 N aqueous

sodium hydroxide. The mixture was

stirred at room temperature for 1

OMe h, poured into 30 mL of saturated

53 aqueous sodium bicarbonate, and

extracted with three 30-mL portions of dichloromethane. The organic extract was washed with three 50-mL portions of brine, dried (MgS0 4 ), and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate-hexane to give 254 mg

(94 *) of alcohol 53 as a white solid: mp 131°C; IR

(CHCI3 ) 3592 (sharp), 3400 (broad), 1627 cm“l; NMR

(CDCI3 ) 6 1.25-2.90 (m with s at 2.05, 11H, CH2 and OH),

3.10-3.60 (broad m, 1H, 0CH), 3.70-4.20 (broad m with s at 3.80, 4H, NCH and OCH3 ), 6.18 (broad d, J=4 Hz, 1H,

ArCHN), 6.85 (d, J=9 Hz, 2H, ArH), 7.00 (d, J=9 Hz, 2H,

ArH); mass spectrum, m/e (relative intensity) 275 (M*,

100), 274 (51), 257 (5), 245 (4), 161 (25), 150 (43), 135

(45); exact mass calcd for C 1 6 H2 1 NO3 m/e 275.1521, found m/e 275.1530.

rel-<4R,9aS>-4-(4-Methoxyphenyl)octahydro-4H- quinolizin-2,6-dione (55). To a solution of 200 mg (0.73 104

mmol) of alcohol 53 in 5 mL of

H acetone, cooled in an ice bath O was added 0.33 mL (0.66 mmol) of

Jones reagent <2.66 M) . The

mixture was stirred for 2 0 min

with cooling in an ice bath OMe followed by dilution with 20 mL 55 of dichloromethane. The organic

layer was washed with four 50-mL portions of water, dried

4 ), and concentrated in vacuo. The residue was chromatographed over 5 g of silica gel (eluted with ethyl acetate) to give 37 mg <19 X) of starting alcohol 53 and

147 mg (74 X) of ketone 55 as a colorless oil: IR

1715, 1635 cm-*; NMR

CH2 >, 3.20-3.80

7.08 (d, J=9 Hz, 2H, ArH); mass spectrum, m/e (relative

intensity) 273

149 (24), 134 (30); exact mass calcd for C 1 6 H1 9 NO3 m/e

273.1365, found m/e 273.1372.

rel-<2S,4R,9aS)-2-Hydroxy-4-(4-methoxyphenyl)- octahydro-4H-quinolizin-6-one (54), rel-<2S,4R,9aS)-2-

Acetoxy-4-<4-*ethoxyphenyl)octahydro-4H-quinolizin-6-one

(56), and rel-(2R,4R,9aS)-2-Acetoxy-4-(4-*ethoxyphenyl>- 105 octahydro-4H-qu±nolizin-6-one (57). Method A. To a

HO AcO

OMe OMe OMe

54 56 57 solution of 1.36 g <4.97 nmol) of ketone 55 in 25 mL of tetrahydrofuran was added 6 mL <6.0 mmol) of 1 M lithium triethylborohydride in tetrahydrofuran with cooling in a dry ice bath under nitrogen. The mixture was stirred for

1 h with cooling in a dry ice bath, hydrolyzed with 1.5 mL of water at room temperature, and oxidized with 2 mL of 30 H hydrogen peroxide followed by stirring at room temperature for 3 h. The aqueous layer was saturated with potassium carbonate and the organic layer was concentrated in vacuo to give 1.36 g <99 *i) of an inseparable mixture of alcohol 54 and isomeric alcohol 53 as a white solid.

To a solution of 1.36 g <4.95 mmol) of alcohols 53 and 54 in 5 mL of dichloromethane was added 0.93 mL <9.S4 mmol) of acetic anhydride, 0.69 mL <4.95 mmol) of triethylamine and a catalytic amount of 4- dimethylaminopyridine. The mixture was atirred vigorously 106 at. room temperature for 5 h, diluted with 100 mL of dichloromethane, washed with three 30-mL portions of aqueous saturated sodium bicarbonate and two 50-mL portions of 1 N aqueous hydrochloric acid, dried (MgS0 4 ), and concentrated in vacuo. The residual pale yellow solid was chromatographed over 30 g of silica gel (eluted with ethyl acetate) to give 1.23 g (79 X) of acetate 56 as a white solid and 0.11 g (8.3 X) of isomeric acetate 57 as a pale yellow oil.

Method B. To a solution of 205 mg (0.75 mmol) of ketone 55 in 4 mL of tetrahydrofuran was added 0.95 mL

(0.95 mmol) of 1 M potassium tri-sec-butylborohydride in tetrahydrofuran with cooling in a dry ice bath under nitrogen. The mixture was stirred for 1 h with cooling in a dry ice bath, hydrolyzed with 0.2 mL of water at room temperature, and oxidized with 0.4 mL of 30 X hydrogen peroxide followed by stirring at room temperature for 2 h. The aqueous layer was saturated with potassium carbonate and the organic layer was concentrated in vacuo to give 203 mg (98 X) of mixture of alcohol 54 and isomeric alcohol 53 as a white solid.

To a solution of 200 mg (0.73 mmol) of alcohols 53 and 54 in 2 mL of dichloromethane was added 1.5 mL (15.9 nmol) of acetic anhydride, 1.0 mL (7.17 mmol) of triethylamine and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred vigorously at room 107

temperature for 1 h, and concentrated In vacuo. The

reaidue was diluted with 20 mL of dichloromethane, washed with three 20-mL portions of saturated aqueous sodium

bicarbonate and two 20-mL portions of 1 N aqueous hydrochloric acid, dried (MgS0 4 >, and concentrated in vacuo. The residual pale yellow solid mixture was chromatographed over a Lobar size B column (eluted with ethyl acetate) to give 167 mg <72 ss) of acetate 56 and 25 mg <11 *) of isomeric acetate 57.

Acetate 56: mp 74.5°C; IR (CH2C12) 1732, 1610 cm'l;

NMR

CH2 ), 3.80 (s, 3H, OCH3 ), 3.85-4.10

(sharp qu, J=3.5 Hz, 1H, AcOCH), 6.08 (broad d, J=7 Hz,

1H, ArCHN) 6.90

2H, ArH); mass spectrum, m/e (relative intensity) 317

(33), 134 (16); exact mass calcd for C1QH2 3 NO4 m/e

317.1627, found m/e 317.1636.

Isomeric acetate 57: IR (CH2C12) 1732, 1630 cm-*;

NMR (CDCI3 ) 6 2.40-2.70 (m with s at 2.02, 13H, CH2 and

CH3 CO2 ) 3.10-3.60

5.30 (broad m, 1H, ArOCH), 6.25 (broad d, J=4.5 Hz, 1 H,

ArCHN), 6.85 (d, J=9 Hz, 2H, ArH), 7.20 (d, J=9 Hz, 2H,

ArH); mass spectrum, m/e (relative intensity) 317

100), 302 (2), 258 (11), 257 (21), 256 (60), 134 (18); 108 exact, mass calcd for C 1 3 H2 3 NO4 m/e 317.1627, found m/e

317.1636.

rel-<2S,4R,9aS)-2-Acetoxy-4-(4-methoxyphenyl)- octahydro-4H-quinolizin-6-thione <58). A mixture of 785

mg <1.94 mmol) of 2,4-bis(4-

methoxyphenyl)-l,3-dithia-2,4- AcO diphosphetane-2 ,4-disulfide

(Lawesson's reagent, 59) and 1.23

g (3.89 mmol) of lactam 56 in 50

mL of toluene was warmed at 100°C O M e for 10 min. The mixture was 58 stirred at room temperature for additional 1 0 min and chromatographed directly over 1 2 0 g of silica gel

171.5-172°C ; IR 1732 cm"!; NMR

6 1.60-2.20

CH3 CO2 ), 2.85

J-10.2, 5.8 Hz, 2H, CH2 CS), 3.82

J=8 .5 Hz, 2H, ArH), 7.10

J=4.5 Hz, 1H, ArCHN); mass spectrum, m/e

(12), 149 <100), 57 <44), 49 <49); exact mass calcd for 109

C 1 8 H2 3 NO3 S m/e 333.1399, found m/e 333.1406.

Anal. Calcd for C1 8 H2 3 NO3 S: C, 64.84; H, 6.95.

Found: C, 64.72; H, 7.06.

rel-(2S,4R,9aS)-2-Acetoxy-6(E)-(carbethoxymethylidene)-

4- <4-methoxyphenyl > octahydro-4H-quinolizine (61). To a

solution of 620 mg (1 . 8 6

H mmol) of thiolactam 58 in AcO 10 mL of tetrahydrofuran

and 2 mL of diethyl ether

C 0 2Et was added 931 mg (5.57

OMe mmol) of ethyl bromoacetete. The resulting 61 solution was stirred at room temperature under nitrogen for 48 h, and concentrated in vacuo to give a yellow oil 64 which was dissolved in 4 mL of dry chloroform and returned to the original reaction vessel.

To the resulting solution was added 500 mg (1.90 mmol) of triphenylphosphine and 313 mg (2.79 mmol) of

1,4-diazabicyclo[2,2,23octane at room temperature. The solution was stirred under reflux for 5 min, concentrated in vacuo, and chromatographed directly over a Lobar size

B column (eluted with ethyl acetote-hexane, 2:3) to give

469 mg (65 ft) of vinylogous urethane 61 as a yellow foam: IR 1730, 1675, 1550 cm“l; NMR 6 1.15

J =8 Hz, 3H, CO2 CH2 CH3 ), 1.50-3.40

CH2 and CH3C02>, 3.80

NCH and CO2 CH2 CH3 ), 4.55

AcOCH and ArCHN), 6.90

Hz, 2H, ArH); mass spectrum, m/e (relative intensity) 387

(M+, 48), 342 (16), 327 (16), 326 (49), 300 (23), 254

(40), 240 (29), 239 (100), 160 (22), 84 (37); exact mass calcd for C2 2 H2 9 NO5 m/e 387.2046, found m/e 387.2055.

rel-(2S,4R,9aS)-2-Acatoxy-6(E)-(cyanomethylidene)-

4-(4-methoxyphenyl)octahydro-4H-quinolizine (62). To a

solution of 248 mg (0.745

mmol) of thiolactam 58 in 10

mL of tetrahydrofuran and 2

mL of ether was added 692 mg

(4.14 mmol) of iodoacetonitrile

and the resulting solution

was stirred at room temperature

under nitrogen for 36 h. The precipitate was collected, washed with 5 mL of diethyl ether, and dried in vacuo to give 346 mg (93 as) of iminium salt 70 as a yellow solid.

To a solution of 323 mg (0.646 mmol) of iminium salt

70 in 5 mL of chloroform was added 187 mg (0.713 mmol) of Ill triphenylphosphine and 80 mg <0.713 mmol) o£ 1,4- diazabicyclo[2,2,23 octane at room temperature. The aolution was atirred under reflux for 2 h and concentrated in vacuo. The resulting yellow oil was chromatographed directly over a Lobar size B column

(eluted with ethyl acetate-hexane, 2:3) to give 153 mg

(70 X) of enamino nitrile 62 as a pale yellow oil: IR

(CHCI3 ) 2197, 1732, 1568 cm"l; NMR (CDCls) S 1.45-2.90

J=9 Hz, 2H, ArH), 7.05

239 (15), 160 (37), 159 (16), 121 (25), 8 6 (47), 84

(100), 49 (25); exact mass calcd for C2 0 H2 4 N2 O3 m/e

340.1787, found m/e 340.1796.

rel-<2S,4R,9aS)-2-Acetoxy-4-<4-mothoxyphenyl)-6 - methylthio-1,2,3,4,7,8,9,9a-octahydroquinolizinium iodide

<69). To a solution of 188 mg (0.565 mmol) of thiolactam

58 in 1.5 mL of diethyl ether and 2 mL of dichloromethane was added 0.2 mL (3.22 mmol) of methyl iodide dropwise at room temperature. The mixture was stirred at room temperature under nitrogen for 36 h. The resulting precipitate was collected, washed with 2 mL of diethyl ether. 112

and recrystallized from

dichloromethane to give AcO 214 mg (80 Js> of Balt 69

as an amorphous white CH solid: mp 175°C (dec.);

OMe IR (CH2Cl2> 1738 cm"l;

NMR (CDCI3 ) 6 1.78 (s, 69 3H, CH3 CO2 ), 1.80-2.65

(m, 8 H , CH2 ), 2.95 (s, 3H, SCH3 ), 3.30-3.60 (m, 2H,

CH2 CS), 3.80 (s, 3H, OCH3 ), 4.20-4.55 (broad d, J=10 Hz,

1H, NCH), 5.18 (qu, J=3 Hz, 1H, AcOCH), 5.86 (t, 1H,

ArCHN), 6.95 (d, J=9 Hz, 2H, ArH), 7.18 (d, J=9 Hz, 2H,

ArH) .

ral-(2S,4R,9aS)-2-Acetoxy-4-(4-mathoxyphenyl)- octahydro-4H-quinolizine (71). To a solution of 41 mg

(0.086 mmol) of salt 69 in 1

AcO, mL of methanol was added 12

mg (0.32 mmol) of sodium

borohydride with cooling in

an ice bath. The cooled

O M e mixture was stirred for 10

min followed by stirring at 71 room temperature for 2.5 h.

To the mixture was added 0. 5 mL of 3 N aqueous 113 hydrochloric acid. The solution was stirred for 5 min, basified to pH 10 with 10 * aqueous sodium hydroxide, and extracted with three 1 0 -mL portions of dichloromethane.

The organic extract was washed with 10 mL of brine, two

10-mL portions of water, dried (Na2 S0 4 ), and concentrated in vacuo to give 24 mg <92 X) of amine 71 as a colorless oil, homogeneous by TLC (silica gel; ethyl acetate): IR

1725 crn-1; NMR 6 0.50-2.90

2.00, 15H, CH2 and CH3C02>, 3.20-3.50

5.25 (broad m, 1H, AcOCH), 6.82

7.30

(7), 161 (100), 160 (13); exact mass calcd for C 1 8 H2 5 NO3 m/e 303.1834, found m/e 303.1842.

Ethyl Crel-<2S,4R,6S,9aS)-2-acetoxy-4-<4-methoxyphenyl)- octahydro-4H-quinolizin-6-yl)acetate (82). To a solution

of 190 mg <0.491 mmol) of

AcO vinylogous urethane 61 in

2.5 mL of methanol was

added a trace of bromo- C 0 2Et cresol green followed O M e by 46 mg (0.732 mmol)

82 of sodium cyanoborohydride. A 1.06 N methanolic hydrochloric acid (0.64 mL) was added dropwise until the reaction mixture maintained a yellow color. The resulting mixture was stirred at room temperature for 1 0 min, neutralized with 1 N aqueous

sodium hydroxide, and extracted with three 20-mL portions of dichloromethane. The combined organic layers were

dried

82 as a white solid: mp 106-107°C (methanol); IR

1730 cm-1; NMR (CDC1 3 ) 5 0.85-2.10

Hz and s at 2.00, 16H, CH2 , CO2 CH2 CH3 , and CH3 CO2 ), 2.25

9.3 Hz, 1H, CH2 C0 2 Et), 3.10-3.25

3.42-3.56

3H, ArCHN and CO2 CH2 CH3 ), 4.75 <9-line dddd, J=11.2,

11.2, 5.0, 5.0 Hz, 1H, AcOCH), 6.80 (d, J=9 Hz, 2H, ArH),

7.20

intensity) 389

(100), 279 (8 ), 242 (40), 149 (40), 134 (21); exact mass calcd for C2 2 H3 1 NO5 m/e 389.2202, found m/e 389.2207.

Hethyl Cirel- <2S,4R,6S,9aS) -2-Hydroxy-4- (4-methoxyphenyl>octahydro-4H-quinolizin-6-yl3 C2,2-2h 3 acetate

(83). To a solution of 140 mg (0.360 mmol) of amino 115

ester 82 in 1 mL of methyl

H alcohol-d was added 195 mg HO (3.60 mmol) of sodium

methoxide under nitrogen. The

mixture was stirred under

O M e reflux for 12 h and concentrated in vacuo. The 83 residue was treated with 3 mL of water and extracted with five 10-mL portions of dichloromethane. The combined organic layers were washed with three 10-mL portions of brine and 10 mL of water, dried

(81 JO of hydroxy ester 83 as a yellow oil. This material was used in subsequent reaction without purification: NMR

(CDCl3 > 6 0.80-2.18 (m, 10H, CH2 >, 2.20 (s, 1H, OH), 3.12

(sharp m, 1H, CHCD2 C0 Ac), 3.30-4.10 (m, 3H, NCH, 0CH, and

ArCHN), 3.62 (s, 3H, CO2 CH3 ), 3.80 (s, 3H, OCH3 ), 6.79

(d, J= 9 Hz, 2H, ArH), 7.15 (d, J= 9 Hz, 2H, ArH).

Methyl Crel-(2S,4R,6S,9aS)-2-Acetoxy-4-(4-*ethoxyphenyl)octahydro-4H-quinolizin-6-yl][2,2-^Hlacetate (84).

To a solution of 98 mg (0.293 mmol) of alcohol 83 in 1.5 mL of dichloromethane was added 1.0 mL (10.6 mmol) of acetic anhydride, 0.5 mL (3.60 mmol) of triethylamine, and a catalytic amount of 4-dimethylaminopyridine. The 116

mixture was stirred at H AcO room temperature for 2 h

and diluted with 5 mL of

dichloromethane. The

excess solvent and

O M e reagents were removed in

vacuo and the resulting 84 residue was chromatographed over 20 g of activity I alumina (eluted with ethyl acetate-hexane, 1:1) to give 69 mg <63 *) of acetate 84 as a pale yellow oil: NMR (CDCI3 ) 5 0.80-2.20

J=2 .6 Hz, 1H, CHCD2 COAC), 3.40-3.70

4H, NCH and CO2 CH3 ), 3.80 (s, 3H, OCH3 ), 4.02 (dd, J=12,

3 Hz, 1H, ArCHN), 4.80-5.25

Hz, 2H, ArH), 7.19 (d, J=9 Hz, 2H, ArH); mass spectrum, m/e (relative intensity) 377 (M*, 5), 334 (1), 318 (10),

302 (100); exact mass calcd for C2 1 H2 7 D2 NO5 m/e 377.2171, found m/e 377.2180.

3-Iodo-4-*«thoxybenzaldehyde (85).52 To a stirred solution of 150 g <0.924 mol) of iodine monochloride in

160 mL (2.80 mol) of acetic acid was slowly added 110 g

(0.808 mol) of p-anisaldehyde (38) at room temperature.

The mixture was warmed under gentle reflux for 3 h (oil 117

bath temperature waa 120-140°C>

The mixture was cooled to room CHO temperature and poured into 1 N

aqueous sodium hydroxide

carefully. The resulting solids O M e were collected and dissolved in

85 500 mL of dichloromethane. The solution was washed with five 200-mL portions of water, dried (MgS0 4 ), and concentrated in vacuo. The residual yellow solid waa recrystallized from methanol to give 150 g (71 J4) of 85 as a pale yellow solid: mp 105-107°C

(lit.52 104-106°C>; IR (CHCI3 ) 1685, 1588, 1487 cm"l; lH

NMR (CDCI3 ) 5 3.95 (s, 3H, OCH3 ), 6.93 (d, J=9 Hz, 1H,

ArH5 >, 7.84 (dd, J=9, 2 Hz, 1H, ArH6 >, 8.27 (d, J=2 Hz,

1H, ArH2 >» 9.83 (s, 1H, CHO); mass spectrum, m/e

(relative intensity) 262 (M*, 100), 261 (63), 233 (4),

218 (3), 203 (4), 106 (2), 91 (2), 63 (7); exact mass calcd for CSH7 O2 I Oi/© 261.9489, found m/e 261.9496.

5,5'-Dlformyl-2,2'-dimethoxybiphenyl (86).52 a mixture of 23.0 g (87.8 mol) of iodobenzene 85 and 23.0 g of copper powder53 was heated at 210-220°C with mechanical stirring for 4 h. The mixture was cooled to room temperature, diluted with 300 mL of benzene, and filtered. The resulting filtrate was concentrated in vacuo and subjected to flash

chromatography over 1 0 0 g of CHO silica gel (eluted with

ethyl acetate) to afford

crude product which

CHO recrystallized from methanol to give 9.21 g <78 >«) of 86 biphenyl product 8 6 as a white solid: mp 134^0 (lit.52 134-136°C); IR

1690, 1600, 1500 cm”!; *H NMR (CDCI3 ) 5 3.84

OCH3 ), 7.04

ArH), 9.88

(85), 57 (97), 55 (100); exact mass calcd for CJ.6 H 1 4 O4 m/e 270.0888, found m/e 270.0968.

3- [2/-Mathoxy-5'-(5",5,,-di*ethyl-l,,,3,,-dioxacyclohex-2M-yl)phenyl)anisaldehyde (87) and 2,2'-

Dimethoxy-5,5'-bi»<5",5"-dimethyl-1",3"-dioxacyclohax-2"- yl)biphenyl (97). A mixture of 5.77 g (21.4 mmol) of dialdehyde 8 6 , 2.23 g (21.4 mmol) of neopentylglycol, and a catalytic amount of p-toluenesulfonic acid monohydrate in 70 mL of benzene was warmed under reflux for 5 h with removal of water via a Dean-Stark trap. The mixture was cooled to room temperature, washed sequentially with 40 119

mL of 1 N aqueouB sodium CHO O M e hydroxide, 20 mL of brine, and four 30-mL portions of

water, dried (MgS0 4 ), and

concentrated in vacuo. The

residual solid was

87 chromatographed over 1 0 0 g

of silica gel (eluted with

ethyl acetate-hexane, 3:7)

O M e to give 1.21 g (21 X) of

starting aldehyde 8 6 , 3.80 g O M e (50 X) of monoacetal 87, and

1.51 g (16 X) of diacetal 97

as white solids. 97 Monoacetal 87: mp 179-180°C (MeOH-CH2 Cl2 >J IR

(CH2 Cl2 > 1685, 1600 cm“l; *H NMR (CDCl3 > 6 0.78 (s, 3H,

CH3 >, 1.26 (s, 3H, CH3 ), 3.62 (3 , 2H, OCH2 C), 3.68 (s,

2H, OCH2 C), 3.71 (s, 3H, 0 CH3 >, 3.79 (s, 3H, OCH3 ), 5.33

(s, 1H, ArCH), 6.85-7.95 (m, 6 H, ArH), 9.83 (s, 1H, CHO); mass spectrum, m/e (relative intensity) 356 (M+, 70), 355

(46), 325 (9), 270 (100), 269 (50), 255 (48); exact mass calcd for C2 1 H2 4 O5 m/e 356.1617, found m/e 356.1632.

Anal. Calcd for C2 1 H2 4 O3 : C, 70.77; H, 6.79. Found:

C, 71.07; H, 7.15.

Diacetal 97: mp 65°C; IR (CH2 CI2 ) 1600 cm-!; *H NMR

(CDCI3 ) 6 0.76 (s, 6 H, CH3 >, 1.28 (s, 6 H, CH3 ), 3.66 (s. 1 2 0

4H, QCH2 >, 3.72 (s, 10H, OCH2 and OCH3 ), 5.36 (6 , 2H,

ArCH), 6.93

ArH); mass spectrum, m/e (relative intensity) 442 (M-'',

97), 441 (65), 411 (12), 386 (6 ), 356 (65), 355 (100),

327 (28), 270 (91), 115 (71); exact mass calcd for

C26H34°6 442.2356, found m/e 442.2354.

3- C2'-Methoxy-5'- < 1", 3"-dithiacyclohex-2,,-y 1) - phenyl)anisaldehyde (98) and 2,2'-Dimethoxy-5,5'- bis(l“,3,,-dithiacyclohex-2"-yl)biphenyl (99). A mixture

of 207 mg (0.767 mmol) of CHO dialdehyde 8 6 , 83 mg (0.767 mmol)

of 1 ,3-propanedithiol, and a

catalytic amount of phosphorous

oxychloride in 2 mL of chloroform

was stirred at room temperature 98 for 4 h under nitrogen. The

mixture was partitioned between

20 mL of saturated aqueous sodium

bicarbonate and 20 mL of

dichloromethane. The aqueous

layer was extracted with two 2 0 -

mL portions of dichloromethane

99 and the combined organic layers were dried

Monothioacetal 98: mp 148°C; IR (CH2 CI2 ) 1680 cm-1; lH NMR 5 1.70-2.40

4 H , SCH2 > » 3.68 (s , 3H, 0CH2>, 3.78 (s, 3H, OCH3 ), 5.12

360

Dithioacetal 99: IR 1600 cm"l; lH NMR

(CDCI3 ) S 1.60-2.20

SCH2 >, 3.75 (s , 6 H, OCH3 ), 5.12

J=9 Hz, 2H, CH2 C0 Me), 7.20-7.50

(13), 302 (54); exact mass calcd for C2 2 H2 6 O2 S4 m/e

450.0817, found m/e 450.0826.

4-A»ino-4-(4-methoxy-3-C2'-mothoxy-5'-(S'^S"- dimethyl-l,,,3,,-dioxacyclohex-2"-yl>phenyl] phenyl) -1- butena (8 8 ). To a solution of 6.20 mL <29.4 mmol) of 122

1,1,1,3,3,3-

hexamethyldiailazane in 10 NH mL o£ tetrahydrofuran was OMe added 18.4 mL (29.4 mmol) of

OMe 1.60 M n-butyllithium in hexane with cooling in an

ice bath under argon. The

solution was stirred for 5

min and 8.05 g (22.6 mmol) of aldehyde 87 in 50 mL of tetrahydrofuran was added dropwise via syringe with cooling in an ice bath. The mixture was stirred at room temperature for 1 h followed by addition of 43 mL (29.3 mmol) of 0.58 M ethereal allylmagnesium bromide with cooling in an ice bath. The resulting mixture was stirred for 10 min with cooling followed by an additional 1 h at room temperature. The solution was poured into 100 mL of saturated aqueous ammonium chloride and extracted with three 80-mL portions of diethyl ether. The combined organic layers were washed with 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, and two 100-mL portions of water, dried

(Na2 S0 4 ), and concentrated in vacuo. The residue was chromatographed over 1 2 0 g of silica gel (eluted with ethyl acetate-methanol, 8:1) to give 7.63 g (85 X) of amine 8 8 as a pale yellow oil: IR (CCI4 ) 3385, 1605 cm-*; lH NMR (CDCI3 ) S 0.78 (s, 3H, CH3 ), 1.38 (s, 3H, CH3 ) 123

1.75 (s, 2H, NH2>, 2.25-2.53 Cm, 2H, CH2 C=), 3.63 (s, 2H,

0CH2>. 3.70 (s, 5H, OCH3 and 0CH2>, 3.72

3.70-4.10 Cm, 1H, CHN), 4.95-5.20 Cm, 2H, =CH2 >, 5.35 Cs,

1H, ArCH), 5.50-5.85 Cm, 1H, =CH>, 6.82-7.52 Cm, 6 H,

ArH); mass spectrum m/e Crelative intensity) 396 CM+-H,

6 ), 380 C7), 356 C100), 270 C37); exact mass calcd for

C2 4 H3 0 NO4 CM+-H) m/e 396.2167, found m/e 396.2143.

N-{1 -(4-Methoxy-3-12'-methoxy-5'-<5",5"-dimethyl-

1" ,3*,-dioxacyclohex-2**-yl > phenyl3 phenylJbut-3-en-l-yl} -

5,5-dimethoxypentanamide (89). To a solution of 13.53 g

C34.1 mmol) of amine 8 8 'Y ^ Y ° Me in 10 mL of dichloro OMe methane was added OMe 17.0 mL C40.1 mmol) of 2.36 M trimethylaluminum54

in hexane at room

temperature under

89 nitrogen. The solution was stirred for 30 min followed by addition of 6.00 g

(34.1 mmol) of methyl 5,5-dimethylpentanoate (22). The resulting solution was warmed under reflux for 60 h, cooled to room temperature, and poured into 50 mL of 1 N aqueous sodium hydroxide. The aqueous layer was extracted with four 100-mL portions of dichloromethane and the 124 combined organic layers were washed with 200 mL o£ brine and two 200-mL portions o£ water, dried (MgS0 4 >, and concentrated in vacuo. The residue was chromatographed over 150 g of silica gel (eluted with ethyl acetate) to give 17.39 g <94 ?«) o£ amide 89 as a white solid: mp 74-

750C; IR (CCI4 ) 3320, 1645 cm"!; lH NMR (CDClg) S 0.76

(s, 3H, CH3 ), 1.26 (s, 3H, CH3 ), 1.48-1.75

CH2 CH2 C(OMe)2 ), 1.94-2.25 , 2.48

Hz, 2H, CH2 C=>, 3.21 (s, 6 H, <0CH3>2>» 3.59-3.65 (two s,

4H, <0CH2>2>» 3-60 , 3.63

4.15-4.35 2>, 4.78-5.30

=CH2 >, 5.28 (s, 1H, ArCH), 5.40-6.05

6.60-7.50 (m, 6 H, ArH); mass spectrum, m/e (relative intensity) 541

(100), 75 (18), 56 (15).

5,5'-D±£ormyl-2,2'-dimethoxybipheny1 (8 6 ), rel-

(4R,9aS) -4- C3' - <5,,-For*yl-2,,-methoxyphenyl>-4' -methoxyphenyl)-l,6,7,8,9,9a-hexahydro-4H-quinolizin-6-one (101), rel- (2R,4R,9aS) -2-Formyloxy-4- 13' - (5,,-for*yl-2M-*ethoxyphenyl)-4'-methoxyphonyl)octahydro-4H-quinolizin-6-ona

(90), and rel-(2S,4R,9aS)-2-For*yloxy-4-t 3 ' - (5,,-£or*yl-

2"-methoxyphonyl)-4'-methoxyphonyl)octahydro-4H-quinolizin-

6 -one (102). To a solution o£ 645 mg (1.19 mmol) of amide 125

HOCO CHO

OMe OMe OMe

OMe OMe OMe CHO CHO CHO

90 86 101

89 in 6 mL of dichloro

HOC1 methane at room

temperature was added 18

OMe mL of 98 9i formic acid. The solution was stirred OMe at room temperature for CHO 26 h and the excess 102 formic acid and dichloromethane were removed in vacuo <0.5 mmHg) at room temperature. The resulting dark oil was diluted with 100 mL of dichloromethane, washed with four 40-mL portions of saturated aqueous sodium bicarbonate and two 30-mL portions of water, dried (MgS0 4 >, and concentrated in vacuo. The resulting mixture was chromatographed over a

Lobar size B column (eluted with ethyl acetate-hexane,

1:1) to give 14 mg (4.3 90 of dialdehyde 8 6 as a yellow solid, 70 mg <15 90 of a mixture of isomeric olefins 101 126 as a white foam, 323 mg <62 5t> of formate 90 as a white foam, and 44 mg <8.5 *) of isomeric formate 102 as a white foam.

Dialdehyde 8 6 : IR, *H NMR, and mass spectra agreed with those reported elsewhere

Olefins 101: IR 1700, 1640 cm"l; *H NMR

8 1.65-2.75 , 3.60-3.90

CH=CH), 6.28

< s, 1H, CHO).

Formate 90: mp 75-80°C; IR , 3.30-3.90

5.45

ArCHN), 6.80-7.95

<100); exact mass calcd for C2 5 H2 7 NO6 m/e 437.1831, found m/e 437.1851.

Isomeric formate 102: *H NMR

10H, CH2 )» 3.45-3.90

J=6 , 2 Hz, 1H, ArCHN), 6.72-7.85

HCO2 H and ArH), 9.80

rel-(2R,4R,9aS)-4-13'-<5M-Forwyl-2"-methoxyphenyl)-

4'-methoxyphonyl!-2-hydroxyoctahydro-4H-quinolizin-6-ona

(113). A mixture of 520 mg <1.19 mmol) of formate 90 in

10 mL of methanol and 3 H mL of 3 N aqueous sodium

hydroxide was stirred at

room temperature for 5

min. The solution was

concentrated in vacuo and

the residual crude solid

was dissolved in 30 mL of dichloromethane, washed with two 20-mL portions of saturated aqueous sodium bicarbonate and two 20-mL portions of water. The solution was dried (MgSO**) , concentrated in vacuo, and chromatographed over 50 g of silica gel (eluted with ethyl acetate) to give 465 mg (96

X) of alcohol 113 as a white solid: mp 235-237°C; IR

(CH2 CI2 ) 3610 (sharp), 3400 (broad), 1695, 1633 cm"l; lH

NMR (CDC1 3 ) 6 1.25-2.80

(m, 1H, OCH), 3.60-3.90

7H, two OCH3 and NCH), 6.15 (broad d, J=8 Hz, 1H, ArCHN),

6.80-7.90 (m, 6 H, ArH), 9.83 (s, 1H, CHO); mass spectrum, m/e (relative intensity) 409 (M+, 31), 408 (15), 294 (6 ),

268 (7), 98 (25), 69 (50), 55 (90), 41 (100); exact mass calcd for C2 4 H2 7 NO5 m/e 409.1882, found m/e 409.1922. 1 28

r m l - <2R,4R,9aS)-2-Hydroxy-4-(4'-methoxy-3'-[2"- m«thoxy-5,,-<5"’ ,5"* -dimethyl-l"* ,3*" -dioxacyclohex-^"’ - yl)phenyl]phenyl)octahydro-4H-quinolizin-6-on* (114). A

mixture of 200 mg <0.489

mmol) of aldehyde 113,

102 mg <0.978 mmol) of

OMe neopentylglycol and a

catalytic amount of p- OMe toluenesulfonic acid

monohydrate in 20 mL of

benzene was warmed under 114 reflux for 1.5 h with water removal using an additional funnel which contained 0 4 A molecular sieves in a small thimble. The mixture was cooled to room temperature, excess solid sodium bicarbonate was added, the solution was dried , and concentrated in vacuo. The residue was chromatographed over a 2 mm thick silica gel rotary disk

3420

(broad), 1635, cm"1; *H NMR 5 0.87

1.30 » 2.80

OH), 3.20-4.20 ,

3.70

1H, ArCH), 6.12 (broad d, J= 8 Hz, 1H, ArCHN), 6.70-7.50 (m, 6 H, ArH); mass spectrum, m/e (relative intensity) 495

(M+, 37), 409 (53), 408 (100), 268 (12), 57 (40), 56

(46), 55 (6 8 ), 41 (91); exact mass calcd for C2 9 H3 7 NO6 m/e 495.2613, found m/e 495.2648.

rel-(4R,9aS> -4- t4' -Methoxy-3' - C2,,-*ethoxy-5"-(5,M ,5”*

-dinethyl-1"' ,3’" -dioxacyclohex-2"* -yl) phenyl] phenyl)- octahydro-4H-quinolizin-2,6-dione (115). To a stirred

solution of 2 mL of

dichloromethane and 0.5 mL

(5.73 mmol) of oxalyl

chloride was added a OMe solution of 0.8 mL (11.5

OMe mmol) of dimethyl sulfoxide in 1 mL of dichloromethane

over a 5 min period at -70°C

under nitrogen. The mixture 115 was stirred for 30 min and a solution of 1.37 g (2.77 mmol) of alcohol 114 in 3 mL of dichloromethane was added within 5 min. Stirring was continued for an additional 1 h and 1.5 mL (10.8 mmol) of triethylamine was added. The reaction mixture was stirred for 5 min and then allowed to warm to room temperature.

The resulting yellow gelatinous mixture was partitioned between 5 mL of water and 4 mL of dichloromethane and the 130 aqueous layer was extracted with three 30-mL portions of dichloromethane. The combined organic layers were washed with 10 mL of brine and 10 mL of water, dried (MgS0 4 ), and concentrated in vacuo. The resulting yellow foam was chromatographed over 50 g of silica gel (eluted with ethyl acetate) to give 1.17 g <86 X) of ketone 115 as a white foam: IR 1720, 1647 cm'l; *H NMR (CDCI3 ) 5

0.80 , 1.28 , 1.50-3.00

CH2 >, 3.40-3.90 , 3.72

, 3.76

ArCH), 6.52 (broad d, J=7 Hz, 1H, ArCHN), 6.75-7.55

6 H, ArH); mass spectrum, m/e (relative intensity) 493

(22), 165 (11); exact mass calcd for C2 9 H3 5 NO6 m/e

493.2465, found m / e 493.2498.

rel-(2S,4R,9aS)-2-Hydroxy-4-(4'-methoxy-3'- t2"- methoxy-5*’-(5"* ,5*" -dimethyl-1*” ,3"* -dioxacyclohex-2"’ - yl)phenyl]phenyl)octahydro-4H-quinolizin-6-one (119). To a solution of 1.04 g (2.11 mmol) of ketone 115 in 15 mL of tetrahydrofuran was added 2.50 mL <2.50 mmol) of 1 M lithium triethylborohydride in tetrahydrofuran with cooling in a dry ice bath under nitrogen. The cooled mixture was stirred for 1 h hydrolyzed with 0.5 mL of water, allowed to warm to room temperature, and oxidized 131

H with 0.5 mL of 30 * HO hydrogen peroxide

followed by stirring at

room temperature for 1 h

The aqueous layer was

saturated with potassium

carbonate and the organic

layer was concentrated in 119 vacuo. The resulting oil was chromatographed over 40 g of silica gel (eluted with ethyl acetate) to give 754 mg <72 *e) of a mixture of alcohols 114 and 119 as a white foam: IR (CHCI3 ), 3590

(sharp), 3430 (broad), 1620 cm"!; lH NMR (CDCI3 ) 6 0.76

0CH2>, 3-78 , 3.80

5.30

6 H, ArH).

rel-<2S,4R,9aS>-2-Benzyloxy-4-(4'-methoxy-3'- 12"- methoxy-5"-<5"* , 5 ,,• -dimethyl-1"* ,3"* -dioxacyclohex-2"* - yl)phenyl]phenyl)octahydro-4H-quinolizin-6-one (91). To a solution of 104 mg (0.210 mmol) of alcohol 119 in 2 mL of tetrahydrofuran was added 25 mg <0.630 mmol) of sodium hydride in a single portion at room temperature. The mixture was stirred for 2 PhCH.O h followed by addition of

108 mg <0.632 mmol) of OMe benzyl bromide. The

resulting mixture was OMe stirred under reflux for

4 h, cooled, treated with

10 mL of water, and 91 extracted with three 2 0 - mL portions of dichloromethane. The combined organic

layers were washed with two 10-mL portions of brine and

10 mL of water, dried , and concentrated in vacuo.

The residual yellow oil was chromatographed over a Lobar size A column (eluted with ethyl acetate) to give 16 mg

(15 X) of starting alcohol 119 and 54 mg <44 *) of benzyl ether 91 as a pale yellow oil: IR (CCI4 ) 1650 cm'l;

NMR (CDC1 3 ) 6 0.80 (s, 3H, CH3 ), 1.28 (s, 3H, CH3 ), 1.44-

2.80

3.68, 12H, two OCH3 , two OCH2 , NCH, and BzOCH), 4.32 (d,

J = 1 2 Hz, 1H, ArCH2 >, 4.40 (d, J = 1 2 Hz, 1H, ArCH2 )» 5.28

7.50 (m, 11H, ArH); mass spectrum, m/e (relative intensity) 585

493 (3), 408 (21), 91 (41); exact mass calcd for

C3 6 H4 3 NO6 ffi/e 585.3091, found m/e 585.3052. 133

rel-<2S,4R,9aS)-2-Benzyloxy-4-[3'-<5"-£or*yl-2"- methoxyphenyl > -4' -methoxyphenylD octahydro-4H-quinolizin-

S-one (120). A mixture of 199 mg <0.340 mmol) of acetal

91 and 10 drops of 1 N PhCH,0^ Z - ^ aqueous hydrochloric acid

in 7 mL of acetone was

OMe stirred at room

temperature for 3 h.

Solvent was removed in CHO vacuo and the resulting 120 oil was diluted with 30 mL of dichloromethane, washed with two 30-mL portions of water, dried , and chromatographed over a Lobar size B column (eluted with ethyl acetate) to give 146 mg

<87 ?t) of aldehyde 120 as a white foam: mp 65-67°C;

NMR - 3.40-4.20

4.31 (broad s, 2H, ArCH2 >, 5.95

(m, 11H, ArH), 9.75

(relative intensity) 499

(5), 408 (14), 392 (11), 391 (10), 91 (100); exact mass calcd for C3 1 H3 3 NO5 m/e 499.2359, found m/e 499.2329.

4-Amino-4-<3-iodo-4-methoxyphenyl)-1-butene (123) and

4-Amino-4-<4-methoxyphenyl)-1-butene (43). To a solution 134

of 21.1 mL (100.2 mmol) of

1,1,1,3,3,3,-hexamethyl-

disilazane in 20 mL of

tetrahydrofuran was added

70.6 mL (100.2 mmol) of 1.42

M n-butyllithium in hexane

with cooling in an ice bath.

The solution was stirred for

10 min and a solution of

25.0 g (95.4 mmol) of 3-

iodo-4-methoxybenzaldehyde

(85) in 100 mL of

tetrahydrofuran was added via syringe with cooling in an ice bath. The mixture was stirred at room temperature for 1 h followed by addition of 139 mL (100.2 mmol) of 0.72 M ethereal allylmagnesium bromide with cooling in an ice bath. The resulting mixture was stirred for 10 min, carefully poured into 2 0 0 mL of saturated aqueous ammonium chloride, and extracted with two 150-mL portions of dichloromethane. The combined organic phases were washed with 100 mL of saturated aqueous ammonium chloride and two 100-mL portions of water, dried (MgS0 4 ), and concentrated in vacuo. The residual pale red oil was chromatographed over 500 g of silica gel (eluted with 10 % ammonium hydroxide in 135

methanol-chloroform, 1:30) to give 21.4 g (74 JO of amine

123 as a yellow oil and 1.52 g (9 JO of reduced amine 43

as a yellow oil.

Iodoamine 123: IR (CC14 ) 3390, 3320, 1595 cm'l; *H

NMR S 1.32 (a, 2H, NH2 >, 2.15-2.40 ,

3.70-3.90 Cm with s at 3.82, 4H, OCH3 and ArCHN), 4.85-

5.20 (m, 2H, = CH2 >, 5.45-5.95 (broad m, 1H, =CH), 6.70

(d, J=9 Hz, 1H, ArHs), 7.39 (dd, J=9, 2 Hz, 1H,

ArH&),7.78 (d, J=2 Hz,lH, ArH2); mass spectrum, m/e

(relative intensity) 302 (M+-H, 3), 287 (2), 262 (100), > 247 (9), 219 (3); exact mass calcd for C1 1 H 1 3 ONI (M+-H)

m/e 302.0042, found m/e 302.0032.

Reduced amine 43: IR, ^H-NMR, and mass spectra

agreed with those reported elsewhere (vide supra).

N-[1-(3-Iodo-4-methoxyphenyl>but-3-en-l-yll-5,5-dimethoxypentanamide <124). To a solution of 18.3 g (60.4

mmol) of amine 123 in 60

mL of dichloromethane

at room temperature was

added 38.5 mL (90.6

mmol) of 2.36 M OMe trimethylaluminumS4 in

124 heptane under nitrogen The solution was stirred for 30 min followed by addition of 11.7 g (68.4 mmol) of methyl 5,5-dimethoxypentanoate (22). The resulting solution was warmed under reflux for 2 0 h, cooled to room temperature, poured into 50 mL 1 N aqueous sodium hydroxide, and extracted with two 200-mL portions of dichloromethane. The combined organic extracts were washed with two 200-mL portions of 1 N aqueous hydrochloric acid and two 200-mL portions of water, dried

, and concentrated in vacuo to give 26 g (96 ss) of amide 124 as a yellow oil, homogeneous by TLC (silica gel chloroform-10 % ammonium hydroxide in methanol, 7:1).

This material was used in subsequent reactions without purification: IR (CCI4 ) 3300, 1650 cm-*; *H NMR (CDCI3 )S

1.50-1.85 (m, 4H, CH2 CH2 C(OMe)2 >, 2.15-2.35 (m, 1H,

COCH2 ), 2.55 (t, J = 6 Hz, 2H, CH2 CO, 3.32 (s, 6 H,

(0CH3)2>» 3.83 (s, 3H, ArOCHg), 4.25-4.45 (m, 1H,

HC(OMe)2 ^ p 5.03 (m, 1H, ArCHN), 5.10-5.25 (m, 2H, =CH2 ),

5.45-5.90 (m, 1H, CH=), 6.38 (d, 1H, NH), 6.80 (d, J=9

Hz, 1H, ArHs), 7.25 (dd, J=9, 2 Hz, 1H, ArH&), 7.70 (d,

J=2 Hz, 1H, ArH2 ); mass spectrum, m/e (relative intensity) 416 (M+-0Me, 5), 415(9), 406 (16), 375 (12),

374 (73), 330 (2), 302 (6 ), 261 (3), 214 (3), 145 (32),

113 (29), 106 (7), 91 (5), 75 (26), 71 (100), 63 (3); exact mass calcd for C1 7 H2 3 O3 NI (M+-0Me) m/e 416.0723, found m/e 416.0660. 137

3-Iodo-4-methoxybenzaldehyde (85), rel-(4R,9aS)-

1,6 ,7,8 ,9,9a-Hexahydro-4-<3-±odo-4-methoxypheny1>-4H-quinolizin-6 -one (125), rel-(2R,4R ,9aS)-2-Formyloxy-4-(3- iodo-4-methoxyphenyl)octahydro-4H-quinolizin-6-one (126), rel-<2S,4R,9aS)-2-Forayloxy-4-<3-iodo-4-methoxyphenyl)- octahydro-4H-quinolizin-6-one <127), and rel-<4R,9aS)-2-

Hydroxy-4-<3-iodo-4-*ethoxyphenyl)octahydro-4H-quinolizin-

6 -one (128+129). To a solution of 26 g (58.2 mmol) of

HOCO,, CHO

OMe °M e 10

®5 125 126

amide 124 in 100 mL of

dichloromethane at room

HOCO temperature was added 300 mL

of 98 X formic acid. The

solution was stirred at room

temperature for 2 h, and

OMe concentrated in vacuo. The

<127 residual dark oil was

diluted with 200 mL of 13a

dichloromethane, washed with H HO three 100-mL portions of

saturated aqueous sodium

bicarbonate and two 100-mL

portions of water, dried OMe (MgS0 4 >, and concentrated in

128 + 129 vacuo. The resulting mixture was crystallized from methanol to give 9.4 g (38 X) of formate 126 as a white solid. The residue was chromatographed over a Lobar size

C column (eluted with ethyl acetate-hexane, 1:1) to give

1.65 g (11 X) of 3-iodo-4-methoxybenzaldehyde (85) as a yellow solid, 2.05 g (9.2 X) of a mixture of isomeric olefins 125 as a white solid, 1.70 g (10 X) of additional formate 126 as a pale yellow foam, 1.15 g (4.6 X) of

isomeric formate 127 as a yellow foam, and 5.06 g (22 X) of a mixture of isomeric alcohols 128 and 129 as white solids.

Benzaldehyde 85: IR, NMR, and mass spectra agreed with those reported elsewhere (vide supra).

A2>3 Olefin 125: mp 136.5-138.5°C (EtOAc); IR

(CHCI3 ) 1625 cm-1; *H NMR (CDCl3 > 6 1.50-2.60 (m, 8 H,

CH2 >» 3.50-3.80 (m, 1H, NCH), 3.88 (s, 3H, OCH3 ), 5.65-

6 . 1 0 (m. 2H, CH=CH), 6.22 (broad s, 1H, ArCHN), 6.78 (d,

J=9 Hz, 1H, ArHs>, 7.45 (dd, J=9, 2 Hz, 1H, ArH&), 7.82 139

(d, J = 2 Hz, 1H, ArH2 >; 13C NMR

32.4, 32.9 , 51.5 (C-

1 ), 56.3 , 85.7 (Ar3 ), 110.7 (Ars>, 126.4 (Ar6 >,

126.1 (C-3), 129.9 (C-2), 135.0 (Ari), 139.0 , 157.4

(Ar; mass spectrum, m/e (relative intensity) 383 (M+, 100), 368 (6 ), 354 (2), 340 <2), 326

(3), 312 (4), 150 (6 ); exact mass calcd for C 1 6 H 1 3 NO2 I m/e 383.0378, found m/e 383.0383.

Anal. Calcd for C 1 6 H 1 0 NO2 I: C, 50.13; H, 4.74. Found:

C, 50.47; H, 4.70.

Formate 1 2 6 : mp 162-163QC; IR

1; lH NMR (CDC13 ) 8 1.50-2.85 (m, 10H, CH2 >, 3.25-3.60

(m, 1H, NCH), 3.84

CO2 CH), 6.25 (broad d, J=4.5 Hz, 1H, ArCHN), 6.78 (d, J=9

Hz, 1H, ArHs), 7.25 (d, J=9 Hz, 1H, ArHfe), 7.60 (broad s,

1H, ArH2 >» 8.03 (s, 1H, HCO2 ); mass spectrum, m/e

(relative intensity) 429 (M*, 100), 414 (1), 385 (1), 384

(9), 383 (9), 356 (3), 328 (4), 302 (3), 256 (14); exact mass calcd for C 1 7 H2 0 NO4 I m/e 429.0438, found m/e

429.0458.

Anal. Calcd for C 1 7 H2 0 NO4 I ‘ C, 47.57; H, 4.70.

Found: C, 47.12; H, 4.28.

Isomeric formate 127: mp 48-50°C; IR (CHC13) 1725,

1635 cm~l; lH NMR (CDC13 > 8 1.60-2.90 (m, 10H, CH2 >,

3.60-3.90 (m with s at 3.80, 4H, NCH and 0CH3 ) 5.00-5.30

(qu, J=3 Hz, 1H, CO2 CH), 5.90 (dd, J=6 , 3 Hz, 1H, ArCHN), 6.70 (d, J=9 Hz, 1H, ArHs>, 7.05 (dd, J=9, 2 Hz,

1H, ArHg), 7.48 , 7.68

HC02>; mass spectrum, m/e (relative intensity) 429 (M+,

100), 428 (15), 414 (7), 385 (4), 383 (35), 356 (6), 328

(7), 302 (3), 286 (8), 271 (1), 256 (11), 159 (8), 97

(1); exact mass calcd for C 1 7 H2 0 NO4 I m/e 429.0438, found m/e 429.0444.

rel-<2R,4R,9aS>-2-Hydroxy-4-(3-iodo-4-methoxyphenyl)- octahydro-4H-quinolizin-6-one (128). To a solution of

10.55 g (24.6 mmol) of formate

126 in 70 mL of methanol at room

temperature was added 4 mL of 3

N aqueous sodium hydroxide. The

mixture was stirred at room

temperature for 1 h. The OMe reaction mixture was 128 concentrated in vacuo, diluted with 200 mL of dichloromethane, washed with two 100-mL portions of 1 N aqueous hydrochloric acid and two 200-mL portions of water, dried (MgS0 4 ), and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate-dichloromethane to give 9.4 g (95 X) of alcohol

128 as a white solid: mp 158-160°C; IR (CH2 CI2 ) 3600

(sharp), 3390 (broad), 1620 cm~l; *H NMR (CDCI3 ) 8 1.20- 141

2.70 (m, 10H, CH2 >, 3.05-3.50 (m, 1H, OCH) , 3.55-3.95 (m with s at 3.75, 5H, OH, CHN, and OCH3 ), 6.10 (broad d,

J=4 Hz, 1H, ArCHN), 6 . 6 8 , 7.05

(broad d, J=9 Hz, 1H, ArH6 ># 7.60 (broad s, 1H, ArH2>; mass spectrum, m/e (relative intensity) 401 (Mi', 100),

400 (39), 384 (7), 383 (3), 356 (6 ), 328 (10), 274 (48); exact mass calcd for C 1 6 H2 0 NO3 I m/e 401.0483, found m/e

401.0523.

Anal. Calcd for C1 6 H2 0 NO3 I : C, 47.90; H, 5.02. Found:

C, 48.15; H, 4.68.

rel-(4R,9aS)-4-(3-Iodo-4-methoxyphenyl)octahydro-

4H-quinolizin-2,6-dione (130). To a stirred solution of 60

mL of dichloromethane and 2.4

mL (27.5 mmol) of oxalyl

chloride was added a solution

of 3.9 mL (54.9 mmol) of

dimethyl sulfoxide in 15 mL of

dichloromethane at -50°C to OMe -60°C under nitrogen. The 130 reaction mixture was stirred for 2 min and a solution of 10 g (25.0 mmol) of alcohol

128 in 30 mL of dichloromethane was added within 5 min.

Stirring was continued for an additional 30 min and 17.4 mL (125 mmol) of triethylamine was added. The reaction 142

mixture was stirred for 5 min and then allowed to warm to room temperature. Water (50 mL) was added and the aqueous

layer was extracted with three 100-mL portions of dichloromethane. The organic layers were combined, washed with three 100-mL portions of brine and 100 mL of water, dried (HgS0 4 >, and concentrated in vacuo to give white solid which was recrystallized from ethyl acetate to give

9.9 g <100 X) of ketone 130 as a white solid: mp 136-

137°C; IR (CH2 CI2 ) 1725, 1640 cm"!; NMR 8 1.45-

3.10 , 3.38-3.80

OCH3 ), 6.45 (dd, J=6 , 3 Hz, 1H, ArCHN), 6.78

IH, ArHs), 7.20 (dd, J=9, 2 Hz, 1H, ArH6 >, 7.65 (d, J=2

Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity)

399

399.0291.

Anal. Calcd for C1 6 H 1 8 NO3 I: C, 48.14; H, 4.54.

Found: C, 48.58; H, 4.53.

rel-<2S,4R,9aS)-2-Hydroxy-4-<3-±odo-4-»ethoxyphenyl)- octahydro-4H-quinolizin-6-one (129). To a solution of

II.9 g (30.0 mmol) of ketone 130 in 150 mL of tetrahydrofuren was added 40.0 mL (40.0 mmol) of 1 M lithium triethylborohydride in tetrahydrofuran with cooling in a dry ice bath under nitrogen. The mixture was 143

stirred for 50 min, hydrolyzed H HO with 1 mL of water, allowed to worm to room temperature, and

oxidized with 1 mL of 30 X

hydrogen peroxide followed by

OMe stirring at room temperature 10 for 3 h. The aqueous layer was 129 saturated with potassium carbonate and the organic layer was concentrated in vacuo to give a pale yellow oil. The residual yellow oil was chromatographed over 250 g of silica gel (eluted with ethyl acetate-methanol, 95:5) to give 11.9 g <100 of a mixture of alcohol 129 and isomeric alcohol 128 as a pale yellow foam.

Alcohol 129: IR

1620 em-1; lH NMR S 1.25-2.70 (m, 10H, CH2 ),

3.10-3.50 (m, 1H, 0HC), 3.65-4.20

NCH, OH, and OCH3 ), 5.75 (broad s, 1H, ArCHN), 6.75 (d,

J=9 Hz, 1H, ArHs), 7.18

(broad s , 1H, ArH2 ); 13C NMR (CDC1 3 ) 6 17.9, 29.1, 32.7,

34.2, 39.8 (C-2, C-4, C-6 , C-7, and C-8 ), 46.5 (C-5),

48.6 (C-l), 56.1 (C-10), 64.0 (C-3), 85.7 (Ar3 >, 110.5

(Ars), 127.1 , 135.1 (Ari), 136.9

(Ar4 ), 169.8 (C-9); mass spectrum, m/e (relative intensity) 401

356 (11), 328 (13), 274 (16), 260 (7); exact mass calcd 144

for C 1 6 H2 0 NO3 I m/e 401.0483, found m/e 401.0488.

rel-(2S,4R,9aS)-2-Acetoxy-4-(3-iodo-4-methoxyphenyl)-

octahydro-4H-quinolizin-6-one (132) and rel-(2R,4R,9aS)-2-

Acetoxy-4-(3-iodo-4-»ethoxyphenyl)octahydro-4H-quinolizin-

8 -one (131). To a solution of 3.00 g <7.47 mmol) of

alcohols 128 and 129 in 30 mL of

dichloromethane was added 14.1

AcQ mL (149 mmol) of acetic

anhydride, 10.4 mL (74.7 mmol)

of triethylamine, and a

catalytic amount of 4- OMe dimethylaminopyridine. The

132 mixture was stirred vigorously at room temperature for 5 h,

diluted with 30 mL of AcO dichloromethane. The excess

solvent and reagents were

removed in vacuo and the

resulting residue was diluted OMe with 150 mL of dichloromethane, 131 washed with three 100-mL

portions of saturated aqueous sodium bicarbonate and two

100-mL portions of brine, dried (MgS0 4 ), and concentrated

in vacuo. The residual pale yellow foam was chromatographed o,ver a Lobar size C column (eluted with 145 ethyl acetate-hexane, 9:1) to give 2.77 g (84 X) of acetate 132 as a white foam and 0.24S g (7.4 x) of isomeric acetate 131 as a white solid.

Acetate 132: IR (CCl4 > 1740, 1645 cm'l; *H NMR

(CDCI3 ) 6 1.50-2.90 (m with s at 1.68, 13H, CH2 and

CO2 CH3 ), 3.65-4.00 (m with s at 3.88, 4H, NCH and OCH3 ),

5.10 (sharp qu, J=3 Hz, 1H, AcOCH), 6.00 (broad d, J=5

Hz, 1H, ArCHN), 6.75 (d, J=9 Hz, 1H, ArHs), 7.10 (dd,

J=9, 2 Hz, 1H, ArHfc>, 7.55 (d, J=2 Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity) 443 (M+, 100), 398

(10), 384 (10), 383 (32), 382 (56), 356 (18), 354 (14),

328 (8 ), 256 (54); exact mass calcd for C 1QH2 2 NO4 I m/e

443.0588, found m/e 443.0586.

Isomeric acetate 131: mp 153-154°C (CCI4 ); IR

(CH2 CI2 ) 1730, 1630 cm-1; *H NMR (CDCI3 ) 6 1.35-2.85 (m with s at 2.08, 13H, CH2 and CO2 CH3 ), 3.20-3.55 (m, 1H,

NCH), 3.88 (s, 3H, OCH3 ), 4.75-5.20 (broad m, 1H, AcOCH),

6.23 (broad d, J=4.5 Hz, 1H, ArCHN), 6.78 (d, J=9 Hz, 1H,

ArH5 ), 7.23 (broad d, J=9 Hz, 1H, ArHg)* 7.65 (broad s,

1H, ArH2 ); mass spectrum, m/e (relative intensity) 443

(M+, 100), 398 (8 ), 384 (9), 383 (27), 382 (48), 356

(17), 354 (16), 328 (8 ), 256 (83); exact mass calcd for

C 1 8 H2 2 NO4 I m/e 443.0588, found m/e 443.0577.

rel-(2S,4R,9aS)-2-Acetoxy-4-(3-iodo-4-m*thoxyphenyl>- octahydro-4H-quinolizin-6-thione (133). A mixture o£

0.933 g <2.31 mmol) of 2,4-

bis(4-methoxyphenyl)-1 ,3- AcO 11,12 dithia-2 ,4-diphosphetane-2,4-

disulfide (Lawesson's reagent,

59) and 2.05 g (4.62 mmol) of

lactam 132 in 40 mL of toluene OMe 10 was warmed at 110°C under

133 nitrogen for 6 min. The mixture was cooled to room temperature, concentrated in vacuo, and chromatographed over 150 g of silica gel (eluted with ethyl acetate-haxane, 1:1) to give 2.10 g (99 fc) of thiolactam 133 as a yellow foam which was crystallized from dichloromethane-methanol to give 1.91 g (90 *«) of

133 as a pale yellow solid: mp 164-164.5°C; IR (CH2 CI2 )

1735, 1240 cm"l; lH NMR (CDCI3 ) 6 1.60-2.95 (m with s at

1.85, 11H, CH2 and CO2 CH3 ), 3.20 (t, 2H, CH2 CS), 3.80-

4.10 (m with s at 3.88, 4H, NCH and OCH3 ), 5.15 (qu J=3

Hz, 1H, AcOCH), 6.85 (d, J=9 Hz, 1H, ArHs), 7.15 (d, J=9

Hz, 1H, ArH6 ), 7.30 (m, 1H, ArCHN), 7.65 (d, J=2 Hz, 1H,

ArH2 >; 13C NMR (CDCl3 ) 5 17.7, 29.2, 29.8, 37.5, 42.5 (C-

2, C-4, C-6 , C-7, and C-8 ), 21.0 (C-12), 50.0 (C-5), 56.3

(C-10 and C-l), 67.1 (C-3), 85.7 (Ar3 ), 110.7 (Ars),

126.7 (Ar&) , 132.0 (Arj.), 136.8 (Ar2 >, 156.8

(C-ll), 201.4 (C-9); mass spectrum, m/e (relative intensity) 461 (M++2, 3), 459 (M+, 37), 427 (2), 399 (2), 147

398 (4), 366 (100), 300 (1), 272 (38), 239 (16); exact mass calcd for C 1 8 H2 2 NO3 SI m/e 459.0360, found m/e

459.0319.

Anal. Calcd for C 3.8 H2 2 NO3 SI: C, 47.07; H, 4.83.

Found: C, 46.84; H, 4.69.

rel-(2S,4R,9aS)-2-Acetoxy-4-<3-iodo-4-methoxyphenyl)-

6 - < carbethoxymethy 1 thio ) -1 ,2 ,3,4,7,8 ,9,9a-octahydroqui.no- lizinlum Iodide (134). To a solution of 200 mg (0.436

mmol) of thiolactam 133

AcO in 4 mL of tetrahydrofuran was

added 0.52 mL (4.36

mmol) of ethyl

OMe iodoacetate (63) in

a single portion. The 134 mixture was stirred at room temperature under nitrogen for 2 days in the dark. The resulting precipitate was collected and washed with 2 mL of tetrahydrofuran to give 293 mg (100 *) of salt 134 as an amorphous white solid: mp 169°C (dec) ; 3-H

NMR (CDCI3 ) 8 1.30 (t, J=7 Hz, 3H, CO2 CH2 CH3 ), 1.70-3.15

(m with s at 1.89, 11H, CH2 and CO2 CH3 ), 3.40-3.65 (m,

2H, CH2 CS), 3.92 (s, 3H, OCH3 ), 4.10-4.60 (m, 1H, NCH),

4.30 (q, J=7 Hz, 2H, CO2 CH2 CH3 ), 4.65 (d, J = 4 Hz, 2H, 148

SCH2 C0 2 Et), 5.20 (sharp m, 1H, AcOCH), 5.98 (sharp m, 1H,

ArCHN), 6.95 (d, J=9 Hz, 1H, ArHs), 7.40 (broad d, J=9

Hz, 1H, ArH&), 7.68 (d, J=2 Hz, 1H, ArH2 >.

rel-(2S,4R,9aS)-2-Acetoxy-6(E>- (carbethoxymethy11dene)-4 -

(3-iodo-4-methoxyphenyl)octahydro-4H-quinolizine (135). To

a solution of 293 mg

(0.436 mmol) of salt 134 AcO, in 5 mL of chloroform

was added 137 mg (0.523

C 0 2El mmol) of triphenyl-

phosphine and 59 mg OMe (0.523 mmol) of 1,4- 135 diazabicyclo[2 ,2 ,2 ]octane at room temperature. The solution was stirred under reflux for 40 min, concentrated in vacuo, and chromatographed directly over 25 g of silica gel (eluted with ethyl acetate-hexane, 1:1) to give 169 mg (76 *) of vinylogous urethane 135 as a yellow foam: IR (CH2 CI2 )

1735, 1680, 1550 cm'l; *H NMR (CDCI3 ) 6 1.15 (t, J=7 Hz,

3H, CO2 CH2 CH3 ), 1.50-2.62 (m with s at 1.67, 11H, CH2 and

CO2 CH3 ), 2.96-3.42 (m, 2H, C=CCH2 >, 3.75-3.90 (m with s at 3.86, 4H, NCH and OCH3 ), 3.98 (12-line m, 2H,

OCH2 CH3 ), 4.55 (s, 1H, =CH), 5.00 (qu, J=4 Hz, 2H, AcOCH and ArCHN), 6.78 (d, J=9 Hz, 1H, ArHs), 7.06 (dd, J=9, 2 Hz, 1H, ArH&>, 7.55 I mass spectrum m/e (relative intensity) 513 (M+, 60), 466 (10), 452

(32), 453 (10), 408 (11), 380 (26), 365 (100), 350 (8 ),

326 (8 ); exact mass calcd for C2 2 H2 8 NO5 I m/e 513.1005, found m/e 513.0969.

Ethyl [rel-(2S,4R,6S,9aS)-2-acetoxy-4-(3-iodo-4- methoxyphenyl)octahydro-4H-quinolizin-6-y13 acetate (137) and Ethyl [rel-(2S,4R,6 R,9aS)-2-acetoxy-4-(3-iodo-4- methoxyphenyl>octahydro-4H-quinoliz±n-6-yl3acetate (136)

H H AcO AcO

CO.Et

OMe OMe

137 136

To a solution of 100 mg (0.195 mmol) of vinylogous urethane 135 in 3 mL of methanol was added a trace of bromocresol green followed by 18 mg (0.292 mmol) of sodium cyanoborohydride. A solution of 1 N methanolic hydrochloric acid (0.4 mL) was added dropwise until the reaction mixture maintained a yellow color. After 30 min stirring at room temperature, the resulting solution was 150

neutralized with 1 N aqueous sodium hydroxide,

concentrated in vacuo, and chromatographed over 35 g of

activity I alumina (eluted with ethyl acetate-hexane,

2:3) to give 94 mg (94 X) of amino ester 137 as a white foam and 5 mg (5 of isomeric amino ester 136 as a yellow oil.

Amino ester 137: IR (CHCI3 ) 1725 cm'l; lH NMR

(CDCI3 ) 5 1.26 (t, J=7 Hz, 3H, CO2 CH2 CH3 ), 1.40-2.10 (m with s at 2.00, 13H, CH2 and CO2 CH3 ), 2.25 (dd, J=14.0,

7.0 Hz, 1H, CHC02Et>, 2.75 (dd, J=14.0, 9.7 Hz, 1H,

CHC0 2 Et> 3.20 (m, 1H, CHCH2 CQ2 Et), 3.51 (broad d, J=13

Hz, 1H, NCH), 3.88 (s, 3H, OCH3 ), 3.95-4.30 (m, 3H, ArCHN and CO2 CH2 CH3 ), 5.02 (septet, J=5 Hz, 1H, AcOCH), 6.75

(d, J=9 Hz, 1H, ArHs), 7.20 (dd, J=9, 2 Hz, 1H, ArH&),

7.65 (d, J=2 Hz, 1H, ArH2 ).

Isomeric amino ester 136: IR (CHCI3 ) 1725 cm~l; ^H

NMR (CDCI3 ) 6 1.15 (t, 3H, CO2 CH2 CH3 ), 1.40-2.00 (m with s at 1.82, 13H, CH2 and CH3 CO2 ), 2.00-2.40 (m, 2 H,

CH2C02Et), 3.15 (m, 1H, CHCH2C02Et), 3.45 (m, 1H, NCH),

3.88 (s, 3H, OCH3 ), 4.0 (q, J=7 Hz, 2H, CO2 CH2 CH3 ), 4.25

(sharp m, 1H, ArCHN), 5.00 (sharp m, 1H, ArOCH), 6.75

(d, 1H, ArHs), 7.25 (m, 1H, ArHfe), 7.90 (d, J=2 Hz, 1H,

ArH2>•

rel-<2S,4R,9aS)-2-Acetoxy-6-cyano»ethylidene-4-(3- 151 iodo-4-methoxyphenyl>octahydro-4H-quinolizine (138). To a

solution of 130 mg <0.283

mmol) of thiolactam 133 in 2

mL of tetrahydrofuran and

0.5 mL of diethyl ether was

added 236 mg <1.42 mmol) of

iodoacetonitrile and the OMe resulting solution was

138 stirred under argon at room temperature for 3 days. The resulting precipitate was collected, washed with 5 mL of diethyl ether, and dried in vacuo to give 152 mg <86 fc) of crude iminium salt as a yellow solid: mp 179°C

To a solution of 134 mg <0.215 mmol) of the salt in

2 mL of chloroform was added 89 mg <0.340 mmol) of triphenylphosphine and 38 mg <0.340 mmol) of 1,4- diazabicycloC2,2,2]octane at room temperature under argon. The mixture was stirred under reflux for 20 min and concentrated in vacuo. The resulting yellow oil was chromatographed directly over 2 0 g of silica gel

133) of enamino nitrile 138 as a pale yellow oil: IR

2195, 1735, 1570 cm"l; lH NMR

3.00

1H, =CH), 3.70-4.00

4.65 (t, J = 4.5 Hz, 1H, ArCHN), 5.00

AcOCH), 6.80 , 7.05 (brood d, J = 9

Hz, 1H, ArH6), 7.55

408 (1), 407 (10), 406 (45), 405 (100), 380 (1), 378 (6),

365 (28), 238 (3); exact mass calcd for C2 0 H2 3 N2 O3 I m/e

466.0748, found m/e 466.0797.

[rel-(2S,4R,6S,9aS)-2-Acetoxy-4-(3-iodo-4-n»ethoxyphenyl)octahydro-4H-quinolizin-6-yl3acetonitrile (140) and

[rel-(2S,4R,6R,9aS)-2-Acetoxy-4-(3-iodo-4-methoxyphenyl)- octahydro-4H-quinolizin-6-yl3acetonitrile (139). To a

AcO AcO

CN CN

OMe OMe

solution of 79 mg (0.170 mmol) of enamino nitrile 138 in

2 mL of methanol was added 16 mg (0.255 mmol) of sodium cyanoborohydride followed by addition of a trace of bromocresol green at room temperature. A solution of 1 N methanolic hydrochloric acid (0.3 mL) was added dropwise 153 until the reaction mixture maintained a yellow color.

After 10 min stirring at room temperature, the resulting solution was neutralized, with 1 N aqueous sodium hydroxide and concentrated in vacuo. The resulting deep blue oil was chromatographed over 1 -mm thick rotary disk over silica gel (eluted with ethyl acetate-hexane, 2:3) to give 67 mg <64 30 of amino nitrile 140 as a white foam and £ mg (8 K) of isomeric amino nitrile 139 as a colorless oil.

Amino nitrile 140: IR 2245, 1725 cm‘l;

NMR (CDC1 3 ) 5 1.00-2.15

CO2 CH3 ), 2.35 (dd, J= 14, 7 Hz, 1H, CHCN), 2.75 (dd, J=14,

9 Hz, 1H, CHCN), 3.15 (m, 1H, CHCH2 CN), 3.35 (broad d,

J=13 Hz, 1H, NCH), 3.88 (s, 3H, OCH3 ), 3.95 (dd, J = 10, 3

Hz, 1H, ArCHN), 5.00 (broad m, 1H, AcOCH), 6.82 (d, J=9

Hz, 1H, ArHs), 7.40 (broad d, J = 9 Hz, 1H, ArH6 > » 7.78

(broad s, 1H, ArH2 >; mass spectrum, m/e (relative intensity) 468 (M+, 2), 428 (100), 427 (2), 407 (2), 368

(37); exact mass calcd for C2 0 H2 5 N2 O3 I 468.0911, found m/e 468.0937.

Isomeric amino nitrile 139: IR (CHCI3 ) 2245, 1725 cml; *H NMR (CDCI3 ) 5 1.10-2.40 (m with s at 1.81, 15H,

CH2 , CH2 CH3 , and CH2 CN) 2.85 (m, 1H, CHCH2 CN), 3.45

(broad t, J=8 Hz, 1H, NCH), 3.88 (s, 3H, OCH3 ), 4.13 (m,

1H, ArCHN), 5.00 (sharp qu, J=3 Hz, 1H, ArOCH), 6.75 (d,

J=9 Hz, 1H, ArHs), 7.25 (m, 1H, ArH&), 7.95 (d, J=2 Hz, 154

1H, ArH2 >; mass spectrum, m/e (relative intensity) 428

C 1 8 H2 3 NO3 I

p-Hydroxycinnamic acid (142).62 To a solution of 61

g (0.50 mol) of p-hydroxybenzaldehyde

(141) and 52 g (0.50 mol) of malonic

acid in 200 mL of benzene was added 6

mL of pyridine. The mixture was

stirred under reflux using a Dean-

Stark trap for 6 h until water was no

longer produced. The resulting

percipitate was collected, washed with 150 mL of ice-cold benzene, and recrystallized from methanol to give 35.7 g (44 X) of cinnamic acid 142 as a pale yellow solid: mp 217QC (lit.62 mp 210-212OC); IR

(KBr) 3250, 2920, 1680 cm “1; *H NMR (DMS0-d6) S 6.32 (d,

J=15 Hz, 1H, ArC=CH), 6.83 (d, J=9 Hz, 2H, ArH), 7.50 (d,

J=9 Hz, 2H, ArH), 7.55 (d, J=15 Hz, 1H, ArCH=), 10.0-12.1

(broad s, 2H, OH and CO2 H); mass spectrum, m/e (relative intensity) 164 (M+, 100), 163 (35), 147 (36), 135 (10),

123 (12), 95 (18); exact mass calcd for C9 HSO3 m/e

164.0473, found m/e 164.0455. 155

p-Hydroxyhydrocinna»ic acid (143).114 To a solution

of 16.5 g (101 mmol) of p-

COjH hydroxycinnamic acid (142) in 300 mL

of 1 N aqueous sodium hydroxide was

slowly added 1.6 g of 5 X palladium on

charcoal. The mixture was agitated in OH a Parr hydrogenation apparatus under 143 an initial pressure of 55 psi of hydrogen for 20 h. The resulting mixture was filtered through Celite and the filtrate was acidified with 25 mL of concentrated hydrochloric acid to crystallize 13.4 g

(89 X) of hydrocinnamic acid 143 as colorless needles: mp

127°C (lit.114 mp 128-129°C); IR (KBr) 3390, 2950

(broad), 1670 cm'l; lH NMR (Acetone-dg) 6 2.30-3.00 (m,

4H, CH2 CH2 >, 6 . 6 8 (d, J=9 Hz, 2H, ArH), 7.08 (d, J=9 Hz,

2H, ArH), 9.60 (s, 2H, OH and CO2 H); mass spectrum, m/e

(relative intensity) 166 (M+, 41), 121 (3), 107 (100), 91

(7), 79 (4), 78 (3), 77 (15); exact mass calcd for

C9 H 1 0 O3 m/e 166.0630, found m/e 166.0629.

4~Hydroxy-3-iodohydrocinnamic acid (144).63 To a solution of 18.7 g (0.113 mol) of p-hydroxyhydrocinnamic acid (143) in 1.5 L of concentrated ammonium hydroxide was added a solution of 8 6 g (o.51S mol) of potassium iodide and 27 g (0.106 mol) of iodine dissolved in 200 mL of water over a 1 h period at room

temperature. The reaction mixture was

stirred for additional 1 h,

concentrated in vacuo, and acidified OH with 300 mL of 1 N aqueous

144 hydrochloric acid. The resulting dark oil layer was extracted with three 200-mL portions of diethyl ether, washed with 100 mL of brine and 100 mL of water, dried (MgS0 4 ), and concentrated in vacuo. The residual dark red solid was chromatographed over 350 g of silica gel (eluted with ether-chloroform, 1:9) to give

15.1 g (46 X) of monoiodide 1 4 4 as a white solid: mp 106-

110°C (lit.63 mp 112-11300; IR (KBr> 3390

(sharp), 3040 (broad), 1670 cm“l; *H NMR (Acetone-dg)

5 2.40-3.00 (m, 4H, CH2CH2 ), 6 . 8 8 (d, J=9 Hz, 1H, ArHs),

7.10 (dd, J=9, 2 Hz, 1H, ArH0 ), 7.60 (d, J=2 Hz, 1H,

ArH2>, 8.95 (broad s, 2H, OH and CO2 H); mass spectrum, m/e (relative intensity) 292 (M+, 55), 247 (8 ), 233

(100), 120 (4), 106 (11); exact mass calcd for C9 H9 O3 I m/e 291.9596, found m/e 291.9606.

Methyl 3-iodo-4-methoxyhydrocinnamate (145).63 To a solution of 13.5 g (46 mmol) of 4-hydroxy-3-iodohydrocinnamic acid ( 1 4 4 ) in 40 mL of diethyl ether was added a solution of excess diazomethane prepared from 22 g (103 157

mmol) of N-methyl-N-nitroso-g-

CCKMe tol uenesulf onamide in diethyl ether

dropwlse with cooling in an ice bath.

The resulting yellow solution was

OMe stirred in a water bath for 2 days at room temperature. Several drops of 145 acetic acid was added and the reaction mixture was concentrated in vacuo. The resulting yellow oil was chromatographed over a Lobar size C column

(eluted with ethyl acetate-hexane, 1:3) to give 13.3 g

(90 X) of ester 145 as a pale yellow oil which solidified in the freezer: mp 34-35°C (lit.63 mp 42-43°C); IR

(CHCI3 ) 1728 cm-1; *H NMR (CCI4 ) 6 2.38-2.95 (m, 4H,

CH2 CH2 >, 3.60 (s, 3H, CO2 CH3 ), 3.80 (s, 3H, OCH3 ), 6.65

(d, J=9 Hz, 1H, ArHs), 7.08 (dd, J=9, 2 Hz, 1H, ArHfe),

7.57 (d, J=2 Hz, 1H, ArH2>? mass spectrum m/e (relative intensity) 320 (M+, 75), 289 (1), 261 (3), 260 (30), 246

(100); exact mass calcd for C1 1 H 1 3 O3 I m/e 319.9906, found m/e 319.9926.

3-Iodo-4-methoxyhydrocinnamic acid (146). To a solution of 13.3 g (41.4 mmol) of methyl ester 145 in 30 mL of methanol was added 70 mL of 1 N aqueous sodium hydroxide in a single portion at room temperature. The mixture was stirred under reflux for 3 h, concentrated in vacuo, and acidified with 10 mL of

concentrated hydrochloric acid. The

resulting precipitate was collected,

washed with 50 mL of water, and dried

in the air to give 12.5 g <99 >«) of

acid 146 as a white solid: mp 102-

103°C; IR 2930 (broad), 1710 cm-1; lH NMR (CDClg) 5 2.50-3.00

(s, 3H, OCH3 ), 6.73

J=9, 2 Hz, 1H, ArHfe), 7.60 » 11.10

306

3-Iodo-4-methoxyhydrocinnamoyl chloride (147). A

solution of 1.38 g (4.52 mmol) of

acid 146 in 30 mL (413 mmol) of

thionyl chloride was warmed at

45°C for 45 min and refluxed for

30 min in sequence. The resulting OMe solution was concentrated in 147 vacuo to give 1.46 g (100 fc) of acid chloride 147 as a yellow oil. This material was used in subsequent reactions without purification: IR (CH2 CI2 )

1799 cm-1; 1h NMR (CC1 4 ) 8 2.70-3.25

3.81 (s, 3H, 0 CH3 >, 6.70

J=9, 2 Hz, 1H, ArHg), 7.59 (d, J=2 Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity) 288 (M^-HCl, 1), 260

(4), 247 (100); exact mass calcd for C 1 0 H9 O2 I (M+-HC1) m/e 287.9647, found m/e 287.9642.

l-Diazo-4-(3-iodo-4-methoxyphanyl)-2 -butanona (148). To

a solution of excess diazomethane

in diethyl ether prepared from

5.0 g (48.5 mmol) of N-methyl-N-

nitrosourea was added a solution

of 1.46 g (4.50 mmol) of acid

chloride 147 in 20 mL of diethyl

ether dropwise with cooling in an ice bath. The residual diazomethane was destroyed by adding several drops of acetic acid. The solution was concentrated in vacuo to give 1.47 g (99 X) of diazoketone 148 as a pale yellow oil. This material was used in subsequent reactions without purification: IR

(CCI4 ) 2120, 1740 cml; *H NMR (CCI4 ) S 2.40-2.95 (m, 4H,

CH2CH2>, 3.82 (s, 3H, OCH3 ), 5.18 (s, 1H, CHN2 >, 6.65 (d,

J=9 Hz, 1H, ArHs), 7.08 (dd, J=9, 2 Hz, 1H, ArH6 >» 7.55

(d, J=2 Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity) 330 (M% 2), 302 (31), 279 (8 ), 261 (2), 260

(8 ), 248 (9), 247 (100), 232 (2), 175 (6 ), 134 (2); exact 160 mass calcd for C 1 1 H1 1 O2 N2 I m/e 329.9866, found m/e

329.9924.

l-Chloro-4-(3-iodo-4-methoxyphenyl>-2-butanona

(149). Through a solution of 1.47 g <4.46 mmol) of

diazoketone 148 in 20 mL of diethyl

ether was passed excess hydrogen

chloride, generated from ammonium

chloride and concentrated sulfuric

acid, over a 1 0 min period at room

OMe temperature. The resulting cloudy

solution was concentrated in vacuo and 149 chromatographed over a Lobar size B column (eluted with ethyl acetate-hexane, 1:4) to give

1.14 g (76 *) of chloromethylketone 149 as a yellow oil which solidified on standing: mp 56.5-57.5QC (CH2 CI2 - hexane); IR (CHCl3 > 1720 cm~l; *H NMR (CCI4 ) 8 2.78 (s,

4H, CH2 CH2 )/ 3.80 (s, 3H, OCH3 ), 3.92 (s, 2H, CH2 CI),

6.65 (d, J=9 Hz, 1H, ArHs), 7.07 (dd, J=9, 2 Hz, 1H,

ArH&), 7.55 (d, J=2 Hz, 1H, ArH2 ); mass spectrum, m/e

(relative intensity) 340 (M++2, 17), 338 (M+, 50), 303

(7), 302 (1), 289 (12), 261 (2), 247 (100), 176 (3), 162

(6 ), 134 (9), 120 (2); exact mass calcd for C n H i 2 0 2 3^ClI m/e 337.9571, found m/e 337.9544.

Anal. Calcd for C n H i 2 0 2 3 5 ClI: C, 39.02; H, 3.57. 161

Found: C, 38.87; H, 3.68.

l-Bromo-4-<3-iodo-4-*athoxyphenyl)-2-butanona (150) .

Through a solution o£ 4.2 g <12.7

mmol) of diazoketone 148 in 50 mL of

diethyl ether was passed excess

hydrogen bromide for 10 min at room

temperature. The resulting solution

O M e was concentrated in vacuo and

chromatographed directly over 1 0 0 g of 150 silica gel (eluted with ethyl acetate- hexane, 3:7) to give 4.36 g <89 *) of bromomethylketone

150 as a yellow oil which crystallized from carbon tetrachloride to give 3.49 g <72 %) of 150 as a yellow solid: mp 46-4800; IR 1720 cm“l; lH NMR

2.65-3.00

3H, OCH3 ), 6.65

Hz, 1H, ArHfc), 7.55 (d, J=2 Hz, 1H, ArH2 ); mass spectrum, m/e (relative intensity) 384

<80), 302 <5), 247 (100), 176 <17), 134 <60); exact mass calcd for CliHi2 0 2 ^BrI ni/e 381.9065, found m/e 381.9092.

l-Iodo-4-<3-iodo-4-methoxyphenyl)-2-butanone (151).

To a solution of 148 mg <0.989 mmol) of sodium iodide in 10 mL of acetone wae added 223 mg

(0.659 mmol) of chloromethylkatone

149 in a single portion at room

temperature. A precipitate of sodium

O M e chloride began to form immediately. The reaction mixture was stirred at 151 room temperature for 40 min, warmed under reflux for 45 min, and cooled to room temperature.

The solution was filtered and the collected solid was washed with 10 mL of cold acetone. The combined filtrates were concentrated in vacuo. The residual yellow oil was diluted with 50 mL of chloroform, washed sucessively with

30 mL of dilute aqueous sodium thiosulfate and two 30-mL portions of water, dried (MgS0 4 ), and concentrated in vacuo. The residual yellow oil was chromatographed over

40 g of silica gel (eluted with ethyl acetate-hexane,

1:4). to give 252 mg (89 90 of iodomethylketone 151 as a pale yellow oil which crystallized from carbon tetrachloride: mp 48-4900; IR (CH2 CI2 ) 1719 cm -1; *H NMR

(CDCI3 ) 6 2.65-3.10 (m, 4H, CH2 CH2 ), 3.68 (s, 2H, CH2 I),

3.80 (s, 3H, OCH3 ), 6 . 6 8 (d, J=9 Hz, 1H, ArHs), 7.08 (dd,

J=9, 2 Hz, 1H, ArH6 >, 7.55 (d, J=2 Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity) 430 (M*, 13), 303

(100), 302 (5), 261 (2), 260 (10) 247 (50), 176 (13), 162

(2), 134 (39), 120 (2); exact mass calcd for C 3.1 H1 2 O2 I2 m/e 429.8924, found m/e 429.8915. 163

ral-(1R,3S,4aS)-3-Acetoxy-l-<3-iodo-4-methoxyphenyl)-

7- C2- <3-iodo-4-methoxyphenyl )ethyl3 -9-thiacyclopenta-6a,7- dlenylC2,3,-h3octahydro-lH-quinolizine (155). To a solution

of 250 mg <0.545 mmol)

H of thiolactam 133 in 2 17, 16 H mL of chloroform was ar°"e added 417 mg <1.089

mmol) of l-bromo-4-<3-

iodo-4-methoxypheny1)-2-

butanone (150) in a

single portion. The mixture was stirred at room temperature under argon for 3 days in the dark. Triphenylphosphine (143 mg; 1.09 mmol) and 122 mg <1.09 mmol) of 1,4-diazabicyclo[2,2,23 octane were added in a single portion at room temperature. The solution was stirred under reflux for 30 min. concentrated in vacuo, and chromatographed directly over

1 0 0 g of silica gel (eluted with ethyl acetate-hexane.

1:4) to give 270 mg (66 X) of amino thiophene 155 as a pale green solid: mp 65-78°C; IR (CH2C12) 1732 cm"!; lH

NMR (CDC1 3 ) 8 1.45-2.60 (m with s at 1.68, 11H, CH2 and

CO2 CH3 ), 2.60-2.85 , 3.75-3.90

Hz, 1H, ArHs

rel-(1R,3S,4aS)-3-Acetoxy-l-(3-iodo-4-methoxyphenyl)-

7-[2-(3-iodo-4-*ethoxyphenyl)ethyl]-9-thiacyclop#nta-6a,7-

dienyl(2,3,-h)octahydro-lH-quinolizine <155). To a solution

of 250 mg (0.545 mmol)

of thiolactam 133 in 2 AcO 17, 16 OMe mL of chloroform was 15 added 417 mg (1.069

mmol) of l-bromo-4-(3-

iodo-4-methoxyphenyl)-2- OMe 14 155 butanone (150) in a single portion. The

mixture was stirred at room temperature under argon for 3

days in the dark. Triphenylphosphine (143 mg; 1.09 mmol)

and 122 mg (1.09 mmol) of 1,4-diazabicycloC2,2,23 octane

were added in a single portion at room temperature. The

solution was stirred under reflux for 30 min,

concentrated in vacuo, and chromatographed directly over

1 0 0 g of silica gel (eluted with ethyl acetate-hexane,

1:4) to give 270 mg (66 X) of amino thiophene 155 as a

pale green solid: mp 65-78QC; IR (CH2 CI2 ) 1732 cm“l; lH

NMR (CDCI3 ) 6 1.45-2.60 (m with s at 1.68, 11H, CH2 and

CO2 CH3 ), 2.60-2.85 (m, 4H, ArCH2 CH2 ># 3.75-3.90 (m with s

at 3.85, 7H, NCH and two OCH3 ), 4.55 (m, 1H, ArCHN), 5.15

(qu, J=3 Hz, 1H, AcOCH), 6.05 (s, 1H, SCH), 6.74 (d, J=9

Hz, 1H, ArHs (ArH5 ')), 6.76 (d, J=9 Hz, 1H, ArHs' 165

were added in a single portion

H at room temperature. The AcO 15,14 solution was stirred under

reflux for 30 min

concentrated in vacuo, and

chromatographed directly over OMe 13 50 g of silica gel (eluted 158 with ethyl acetate-hexane

1:4) to give 176 mg (65 X) of amino thiophene 158 as a pale green solid: mp 67-72° (dec.); IR (CCI4 ) 1738 cm“l; lH NMR (CDCI3 ) S 1.40-2.65 (m with two s at 1.68 and

2.05, 14H, CH2 , CH3 , and C0 2 CH3 >, 3.70-3.90 (m with s at

3.84, 4H, NCH and OCH3 ), 4.55 (t, J=*4.5 Hz, 1H, ArCHN) ,

5.15 (qu, J=3 Hz, 1H, AcOCH), 6.05 (s, 1H, SCH), 6.75 (d,

J=9 Hz, 1H, ArHs), 7.25 , 7.75

(d, J=2 Hz, 1H, ArH2 ); 13C NMR (CDCI3 ) 6 14.8 (C-12),

20.8 (C-15), 20.8, 27.7, 32.8, 34.0 (C-2, C-4, C-6 , and

C-7), 48.4 (C-5), 56.3 (C-13), 58.4 (C-l), 67.9 (C-3),

85.7 (Ar3 ), 105.0 (C-10), 110.5 (Ars), 115.4 (C-8 ), 128.0

(Ar&), 135.7 (Arx), 136.3 (C-ll), 138.0 (C-2), 149.1 (C-

9), 156.8 (Ar4 ), 170.4 (C-14); mass spectrum, m/e

(relative intensity) 499 (M++2, 6 ), 497 (M+ , 95), 437

(8 ), 436 (4), 370 (3), 151 (100); exact mass calcd for

C2 1 H2 4 NO3 IS m/e 497.0516, found m/e 497.0512. 166

£•1-(2S,4R,9aS)-2-Banzyloxy-4-<3-iodo-4-methoxyphenyl)- octahydro-4H-quinolizin-6-on® <122> and rol-<2R,4R,9aS)-

2-Benzyloxy-4-<3-iodo-4-*athoxyphanyl)octahydro-4H- quinolizin-6 -one (159). To a solution of 1.00 g (2.05

nmol) of alcohols 128 and 129

in 7 mL of dimethylformamide

was added 294 mg <7.47 mmol)

of sodium hydride in a single

portion at room temperature.

The mixture was stirred for OMe 10 1 h followed by addition of

122 1.28 g (7.47 mmol) of benzyl

bromide over a 5 min period.

PhCH20 The resulting mixture was

stirred at room temperature

for 36 h, concentrated in

vacuo, diluted with 100 mL OMe of dichloromethane. and

159 washed with 100 mL of brine.

The aqueous layer was extracted with three 100-mL portions of dichloromethane and the combined organic layers were washed with two 100-mL portions of brine and

100 mL of water, dried

Lobar size C column (eluted with ethyl acetate-hexane.

3:2) to give 801 mg (65 fc) of benzyl ether 122 as a 167 yellow foam and 121 mg (10 X) of isomeric benzyl ether

159 as a yellow foam.

Benzyl ether 122: IR (CHCI3 ) 1625 cm"l ; *H NMR

(CDCI3 ) 6 1.30-2.68 (m, 10H, CH2 ) , 3.60-4.00

3.72, 5H, NCH, BzOCH, and 0 CH3 >, 4.23 ,

5.80 (broad d, J=5 Hz, 1H, ArCHN), 6.60 (d, J=9 Hz, 1H,

ArHs), 6.75-7.35 (m, 6 H, ArHs and ArH), 7.68 (broad s,

1H, ArH2 >; 13C NMR (CDCI3 ) 6 18.3, 29.6, 31.4, 32.9, 37.4

(C-2, C-4, C-6 , C-7, and C-8 ), 47.1 (C-5), 48.3 (C-l),

56.1 (C-10), 69.7 (C-ll>, 71.2 (C-3), 85.7 (Ar3 >, 110.5

(Ars>, 126.7 (Ar3 ' and Ars'>, 127.0 (Ar2 ' and Ars'),

127.9 (Ar4 ^ and Ar&) , 135.4 (Ari), 136.8 (Ar2 > , 138.1

(Ari'), 156.3 (Ar4 ), 169.6 (C-9); mass spectrum, m/e

(relative intensity) 491 (M+ , 71), 400 (19), 384 (10),

383 (6 ), 286 (7), 256 (7), 91 (100), 65 (10); exact mass calcd for C2 3 H2 6 NO3 I m/e 491.0951, found m/e 491.0951.

Isomeric benzyl ether 159: IR (CHCI3 ) 1620 cm-*; ^H

NMR (CDCI3 ) 6 1.10-2.70 (m, 10H, CH2 ), 2.95-3.35 (m, 1H,

NCH), 3.35-3.75 (m, 1H, BzOCH), 3.80 (s, 3H, OCH3 ), 4.47

(s, 2H, ArCH2 )* 5.99 (broad d, J=4.5 Hz, 1H, ArCHN), 6.60

(d, J=9 Hz, 1H, ArH5 ), 6.95 (broad d, J=9 Hz, 1H, ArHs),

7.30 (broad s, 5H, ArH), 7.42 (broad s, 1H, ArH2); mass spectrum, m/e (relative intensity) 491 (M+, 58), 463 (2),

400 (33), 384 (7), 383 (5), 372 (2), 356 (8 ), 326 (3),

286 (5), 256 (6 ), 97 (5), 91 (100), 69 (14), 65 (15); 168 exact mass calcd for C2 3 H2 6 NO3 I m/e 491.0951, found m/e

491.0994

ggl-C2S,4R,9aS)-2-Banzyloxy-4-(3-lodo-4-mathoxyphenyl)- octahydro-4H-quinolizin-6-thione (160). A mixture of

461 mg Cl.14 mmol) of 2,4-

bis(4-methoxyphenyl)-1,3-

dithia-2,4-diphosphetane-

2,4-disulfide (Lawesson's

reagent 59) and 801 mg Cl.63

OMe nmol) of lactam 122 in 10 mL 10 of toluene was warmed at 160 105°C under nitrogen for 10 min. The mixture was cooled to room temperature, concentrated in vacuo, and chromatographed over 100 g of silica gel Celuted with ethyl acetate-hexane, 3:7) to give 810 mg C98 X) of thiolactam 160 as a white solid, which was recrystallized from dichloromethane-methanol to give 793 mg C96 JO of 160 as a colorless solid: mp 175-

176°C; IR CCHCI3 ) 1255 cm~l; NMR CCCI4 ) 8 1.50-2.80

Cm, 8 H, CH2 >f 3.12 Cm, 2H, CH2 CS), 3.70-4.15 Cm with s at

3.80, 5H, NCH, ArOCH, and OCH3 ), 4.35 Cs, 2H, ArCH2 >,

6.74 Cd, J=9 Hz, 1H, ArHs), 6.95-7.40 Cm, 7H, ArHg,

ArCHN, and ArH), 7.78 Cd, J=2 Hz, 1H, ArH2); 13C NMR

CCDCI3 ) 8 17.8, 29.4, 31.1, 38.0, 42.7 CC-2, C-4, C-6 , C-

7, and C-8 ), 50.4 CC-5), 56.4 CC-10), 57.3 CC-1), 70.4 169

(C-ll), 71.5 (C-3), 85.0 (Ar3 >, 110.7 (Ars), 127.1 (Ar6 >,

127.3

(Ar4 '), 133.2 , 137.4 CAr2 > , 138.2 (Ari'), 156.9

CAr4 >, 201.0

(62), 384 (1), 383 (1), 380 (16), 367 (7), 348 (5), 240

(4), 91 (100), 65 (12); exact mass calcd for C2 3 H2 6 NCD2 IS m/e 507.0723, found m/e 507.0773.

Anal. Calcd for C2 3 H2 6 NO2 IS: C, 54.43; H, 5.17.

Found: C, 54.10; H, 4.93.

rel-(2S,4R,9aS)-2-Benzyloxy-6(E)-(carbethoxymethylidene)-

4-(3-iodo-4-methoxyphenyl)octahydro-4H-quinolizine (161). To

a solution of 180 mg

(0.355 mmol) of P h C H z0 thiolactam 160 in 3 mL

of chloroform was added

0.42 mL (3.55 mmol) of

OMe ethyl iodoacetate (63) 14 in a single portion. The 161 mixture was stirred at room temperature under argon in the dark for 24 h.

Triphenylphosphine (186 mg; 0.71 mmol) and 478 mg (4.26 mmol) of 1 ,4-diazabicyclo[2 ,2 ,2 ]octane were added in a single portion at room temperature. The solution was stirred under reflux for 1 h, concentrated in vacuo, and chromatographed directly over 40 g of silica gel (eluted with ethyl acetate-hexane, 3:7) to give 183 mg <92 X) of vinylogoua urethane 161 as a yellow foam: IR

1675, 1550 cm"l; *H NMR 6 1.16

CO2 CH2 CH3 ), 1.40-2.50 , 3.05-3.35

CH2 >r 3.60-4.20 , 4.45 ,

4.82

ArHs), 6.90-7.35

1H, ArH2 >; 13C NMR (CDClg) 6 14.6 (C-13), 17.3, 28.4,

29.8, 34.2, 38.1 (C-2, C-4, C-6 , C-7, and C-8 ), 48.2

5), 55.1 (C-12), 56.3 (C-14), 58.2 (C-l), 70.0 (C-15),

71.4 (C-3), 84.5 (C-10), 86.2

(Ars>, 127.1 , 127.3

128.2 (Ar4 '), 134.5 (Ari), 136.9 , 138.2 (Ari'),

156.8 (Ar4 ), 162.0 (C-9), 169.0 (C-ll); mass spectrum, m/e (relative intensity) 561 (M+, 54), 546 (2), 532 (2),

518 (1), 516 (10), 488 (6 ), 470 (1), 454 (3), 453 (2),

434 (2), 425 (1), 424 (3), 409 (1), 408 (3), 380 (5), 366

(2), 365 (7), 91 (100), 65 (9); exact mass calcd for

C2 7 H3 2 NO4 I m/e 561.1368, found m/e 561.1367.

Ethyl Crel-<2S,4R,6S,9aS)-2-benzyloxy-4-<3-iodo-4- methoxyphenyl)octahydro-4H-quinolizin-6-y13 acetate (162) 171 and Ethyl Cral-C2S,4R,6 R ,9aS>-2-benzyloxy-4-( 3- iodo*ethoxyphenyl)octahydro-4H-quinolizin-6-yll acatata

<163). To a solution of 293 mg (0.522 mmol) of vinylogous

H urethane 161 in a mixture Ph CH2a of 5 mL of methanol and

5 mL of tetrahydrofuran

C 02Et was added a trace of 12,13 bromocresol green OMe 14 followed by 6 6 mg (1.04

162 mmol) of sodium

cyanoborohydride. A

1.06 N methanolic

hydrochloric acid

CO.Et solution (1.0 mL) was added dropwise until

OMe the reaction mixture

163 maintained a yellow color. After stirring for 10 min at room temperature, the resulting solution was neutralized with 1 N aqueous sodium hydroxide and extracted with three 20-mL portions of dichloromethane. The combined organic layers were dried (MgS0 4 ), concentrated in vacuo, and chromatographed over 40 g of activity I alumina (eluted with ethyl acetate-hexane, 2:3) to give 259 mg (88 &) of amino ester

162 as a yellow foam and 30 mg (10 *e) of isomeric amino ester 163 as a yellow oil. 172

Amino ester 162: IR (CH2 Cl2 > 1725 cm"!; lH NMR

S 1.18 (t, J=7 Hz, 3H, CO2 CH2 CH3 ), 1.40-2.20 (m,

10H, CH2 >, 2.25 (4-line dd, J=13, 6.5 Hz, 1H, CH2 C0 2 Et),

2.75 (4-line dd, J=13, 9.3 Hz, 1H, CH2 C0 2 Et>, 3.10-3.25

(m, 1H, CHCH2 C0 2 Et), 3.32-3.75

3.80

CO2 CH2CH3 ), 4.50 (d, J=12 Hz, 2H, ArCH2 >, 4.53 (d, J=12

Hz, 1H, ArCH2 )>, 6.75

(m, 6 H, ArHs and ArH), 7.70 (broad s, 1H, ArH2 ); ^ C nhr

(CDCI3 ) 6 14.4 (C-13), 20.5, 20.8, 24.0, 37.3, 37.5 (C-2,

C-4, C-6 , C-7, and C-8 ), 42.9 (C-10), 50.0 (C-5), 51.1

(C-9), 56.4 (C-14), 57.3 (C-l), 60.0 (C-12), 69.6 (C-15),

71.9 (C-3), 85.7 (Ar3 ), 111.0 (Ars), 127.5 (Ar6 , Ar2', and Ars'), 128.3 (Ar3 ' and Ars'), 128.4 (Ar4 '), 138.4

(Ar2 ), 138.8 (Ari'), 144.0 (Ari), 157.3 (Ar4 ), 172.1 (C-

11); mass spectrum, m/e (relative intensity) 563 (M+, 2),

476 (99), 475 (2), 457 (21), 456 (2), 369 (3), 384 (3),

368 (19), 330 (5), 91 (100), 65 (5); exact mass calcd for

C2 7 H3 4 NO4 I m/e 563.1534, found m/e 563.1397.

Isomeric amino ester 163: IR (CH2 CI2 ) 1725 cm“l; lH

NMR (CDCI3 ) 5 1.18 (t, J=7 Hz, 3H, CO2 CH2 CH3 ), 1.40-2.05

(m, 11H, CH2 and CH2 C0 2 Et), 2.20-2.35 (m, 1H, CH2 C0 2 Et),

3.05-3.15 (m, 1H, CHCH2C02Et), 3.35-3.50 (m, 1H, NCH),

3.70-3.78 (m, 1H, BzOCH), 3.85 (s, 3H, OCH3 ), 4.00 (q,

J - 7 Hz, 2H, CO2 CH2 CH3 ), 4.15-5.18 (m with d at 4.18, J=12 173

Hz, 2H, ArCHN and ArCH2 >, 4.22 ,

6.65

(broad s, 1H, ArH6 ), 7.84 (broad s, 1H, ArH2 ) ; jjmp

(CDCI3 > 6 14.2 (C-13), 24.3, 29.9, 31.6, 37.2, 38.8 (C-2,

C-4, C-6 , C-7, and C-8 ), 40.0 (C-10), 53.7 (C-5), 56.1

(C-9), 56.4 (C-14), 57.1 (C-l), 60.3 (C-12), 69.3 (C-15),

71.4 (C-3), 85.5 (Ar3 ), 110.5 (Ars), 127.3 (Ar6 ), 127.6

(Ar2 '» Ar3 ', Ars', and Arfe'), 128.9 (Ar4 '), 138.7 (Ari and Ari'), 139.9 (Ar2), 156.9 (Ar4 ), 172.1 (C-ll); mass spectrum, m/e (relative intensity) 563 (M’*', 2), 476 (58),

475 (24), 457 (3), 369 (8 ), 368 (25), 330 (3), 91 (100),

65 (8 ); exact mass calcd for C2 7 H3 4 NO4 I m/e 563.1524, found m/e 563.1567.

2-0xoheptyl phenyl sulfone (172). A mixture of 3.12 g

(2 0 . 0 mmol) of methyl

0 ® phenyl sulfone (170)

and 785 mg (20.0 mmol) 0 of sodium hydride 172 in 10 mL of dimethyl sulfoxide was warmed at 65°C with stirring over a 30 min period. The resulting mixture was cooled to room temperature and diluted with 10 mL of tetrahydrofuran. A solution of 1.44 g (10.0 mmol) of ethyl caproate (171) in

5 mL of tetrahydrofuran was added and the mixture was heated to 65°C with stirring for 1 h. The resulting

mixture was cooled, poured into ice cold 1 N aqueous

hydrochloric acid, and extracted with four 50-mL portions

of chloroform. The combined organic layers were washed

with two 100-mL portions of saturated aqueous sodium

bicarbonate, two 100-mL portions of brine, and 100 mL of

water, dried (MgS0 4 ), and concentrated in vacuo. The

resulting pale yellow oil was chromatographed over 150 g

of silica gel (eluted with ethyl acetate-hexane, 3:7) to

give 2.13 g <84 *) of /8-keto sulfone 172 as a white

solid: mp 38-40°C; IR 1720, 1323, 1152 cm~l; *H

NMR (CCI4 ) 8 0.85 Ct, J=5 Hz, 3H, CH3 ), 0.90-1.85

3 >, 2.60

COCH2 SO2 ), 7.30-8.10

(relative intensity) 211 < n + - C H 2CH 2CH 3 2), 198 (43), 183

(4), 141 (6 6 ), 99 (75), 77 (100), 55 (5); exact mass calcd for C 1 0 H 1 1 O3 S

1-(3-Benzyloxy-4-methoxy)benzyl-2-oxoheptyl phenyl sulfone (174). A mixture of 77 mg (1.97 mmol) of sodium hydride and 500 mg (1.97 mmol) of /3-keto sulfone 172 in 3 mL of dimethyl sulfoxide was stirred for 50 min at room temperature. To the resulting yellow mixture was added a solution of 569 mg <2.17 mmol) of 3-benzyloxy-4- methoxybenzyl chloride (173) in 3

mL of dimethyl sulfoxide and

stirred at room temperature for 2

h. The solution was concentrated

in vacuo and partitioned between OCH.Ph OMe 50 mL of cold 1 N aqueous hydrochloric acid and 100 mL of 174 chloroform. The organic layer was washed with 50 mL of brine and 50 mL of water, dried

(MgS0 4 >, and concentrated in vacuo. The residual yellow oil was chromatographed over 80 g of silica gel (eluted with ethyl acetate-hexane, 3:7) to give 401 mg (43 X) of

«-substituted-/3-keto sulfone 174 as a white 6 olid: mp 74-

78°C; IR (CH2 CI2 ) 1722, 1310, 1138 cm"!; *H NMR (CDCI3 ) 6

0.76 (t, J=5 Hz, 3H, CH3 ), 0.70-1.60 (m, 6 H, (CH2 >3 >,

1.70-2.75 (m, 2H, CH2 CO), 2.75-3.30 (m, 2H, CHCH2 Ar),

3.78 (s, 3H, OCH3 ), 4.10-4.45 (m, 1H, COCHSO2 ), 5.02 (s,

2H, 0 CH2 Ar>, 6.35-6.75 (m, 3H, ArH), 7.10-7.95 (m, 10H,

ArH); mass spectrum, m/e (relative intensity) 480 (M+,

9), 339 (18), 248 (3), 99 (6 ), 91 (100), 77 (4), 55 (4); exact mass calcd for C2 8 H3 2 O5 S m/e 480.1971, found m/e

480.1925.

1-(3-Benzyloxy-4-methoxyphenyl)-4-octanona (175).

Aluminum foil (750 mg) was cut into rectangular strips 176

(10 cm x 1 cm) and

immersed all at once in a

CH3(CH2)4CCH2CH2 OCHj 2 X aqueous solution (100

O C H 2Ph mL) of mercuric chloride

for 15 sec. The strips

175 were rinsed with absolute methanol and diethyl ether in sequence and cut immediately with scissors into pieces, approximately 1 cm2, directly into a solution of

400 mg (0.830 mmol) of /3-keto sulfone 174 in 30 mL of 10

* aqueous tetrahydrofuran. The reaction mixture was stirred under reflux at 65°C for 3 h and cooled to room temperature. The solution was filtered and the collected solid was washed with 30 mL of tetrahydrofuran. The combined filtrates were concentrated in vacuo, diluted with 70 mL of dichloromethane, washed with two 30-mL portions of water, dried (MgS0 4 ), and concentrated in vacuo. The residual yellow oil was chromatographed over

40 g of silica gel (eluted with ethyl acetate-hexane,

1:4) to give 201 mg (71 X) of ketone 175 as a white solid: mp 67.5-69°C; (CH2 Cl2 > 1709 cm~l; *H NMR (CC14 ) 6 0.80

(t, J=5 Hz, 3H, CH3 ), 0.80-1.60 (m, 6 H, (CH2 )3 >, 2.18 (t,

J=7 Hz, 2H, CH2 CO), 2.58 (sextet, J =6 Hz, 4H,

C0 CH2 CH2 Ar), 3.84 (s, 3H, OCH3 ), 4.95 (s, 2H, CH2 A D ,

6.65 (broad s, 3H, ArH), 7.10-7.45 (m, 5H, ArH); mass spectrum, m/e (relative intensity) 340 (M+, 16), 249 (4), 177

Anal. Calcd for C2 2 H2 8 O3 ! C, 77.61; H, 8.29. Found:

C, 76.94; H, 8.21.

3-Iodo-4-methoxybenzyl alcohol (176).115 To a solution

of 5.0 g <19.1 mmol) of 3-iodo-4-

methoxybenzaldehyde <85) in 30 mL

of ethanol and 15 mL of

tetrahydrofuran was added 361 mg OMe <9.50 mmol) of sodium borohydride

176 in a single portion at room temperature under argon. The solution was stirred for 10 min and 10 mL of acetone was added. The solution was stirred for 10 min, 30 mL of water was added, and the mixture was concentrated in vacuo until a white solid appeared in the aqueous layer. The solid was collected and washed with 20 mL of cold water to give 4.83 g <96 ft) of alcohol 176. This material was used in subsequent reactions without purification: mp 77-79°C

84°C); IR

OCH3 ), 4.58 (s, 2H, CH2 AD, 6.69

7.28

ArH2 >; mass spectrum, m/e

100), 263 <14), 247 (22), 233 <5), 218 <1), 203 (1), 137

(7); exact mass calcd for C8 H9 O2 I ffi/g 263.9647, found m/e

263.9631.

3-Iodo-4-*ethoxybenzyl chloride <177).To a

solution of 4.5 g <17.0 mmol) of

alcohol 176 in 15 mL of

dichloromethane was added 2.59 g I <32.8 mmol) of pyridine with OMe cooling in an ice bath. Thionyl

chloride <4.09 g, 34.4 mmom) was added at a rate such that the temperature did not exceed

35°C. The mixture was stirred with cooling in an ice bath for 10 min, at room temperature for 1 h, and finally warmed under reflux for 2 h. The resulting mixture was diluted with 50 mL of dichloromethane and neutralized with 50 mL of 1 N aqueous hydrochloric acid. The aqueous layer was extracted with three 50-mL portions of dichloromethane and the combined organic layers were washed with 50 mL of 1 N aqueous hydrochloric acid, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of brine, and two 50-mL portions of water, dried

1600 cm-1; lH NMR 8 3.85 (s, 3H, OCH3 ),

4.45 (s, 2H, CH2 A D , S.70 (d, J=9 Hz, 1H, ArHs), 7.27 (d d, J=9, 2 Hz, ArHfe), 7.74 ; moss spectrum, m/e (relative intensity) 284 (M++2, 12), 282

281.9295.

1-<3-Iodo-4-*ethoxy)benzyl-2-oxoheptyl phenyl sulfone (178). A mixture of 62 mg (1.57 mmol) of sodium

hydride and 400 mg (1.57

mmol) of /?-keto sulfone CH 3(CHz)4CCH-S 172 in 3 mL of dimethyl c h 2 o sulfoxide was stirred for

1 h at room temperature.

OMe A solution of 444 mg

(1.57 mmol) of benzyl 178 chloride 177 in 3 mL of dimethyl sulfoxide was added and the mixture was stirred at room temperature for 30 h. The resulting mixture was partitioned between 100 mL of chloroform and 50 mL of 1 N aqueous hydrochloric acid. The aqueous layer was extracted with two 70-mL portions of chloroform. The combined organic layers were washed with three 50-mL portions of brine, dried (MgS0 4 ), and concentrated in 180 vacuo. The resulting yellow oil was chromatographed over

SO g of silica gel (eluted with ethyl acetate-hexane,

3:7) to give 105 mg <24 X) of recovered 177 and 496 mg

<63 X) of a-substituted /J-keto sulfone 178 as a pale yellow oil: IR 1720, 1308, 1146 cm"l; lH NMR

(CCI4 ) 5 0.78

3 >, 1.85-3.20

3H, OCH3 ), 4.32

J=9 Hz, 1H, ArHs), 6-92

» 7.40-7.85

247 <27), 99 (40), 77 (100), 71 <47); exact mass calcd for C2 1 H2 5 O4 SI m/e 500.0519, found m/e 500.0557.

1-<4-Methoxyphenyl)-4-octanone (179). Aluminum foil

<800 mg) was cut into

rectangular strips <10 cm O .---- - || / — \ x 1 cm) and immersed all CH ,(CH 2)4CCH*CH2-

2 X aqueous solution of 179 mercuric chloride for

15 sec. The strips were rinsed with absolute methanol and diethyl ether in sequence and cut immediately with scissors into pieces, approximately 1 cm2 , directly into a solution of 370 mg <0.740 mmol) of /3-keto sulfone 178 181 in 30 mL of 10 k aqueous tetrahydrof uran. The reaction mixture was stirred under reflux at 65°C for 1 h and cooled. The solution was filtered and the collected solid was washed with 30 mL of tetrahydrofuran. The combined filtrates were dried (MgS0 4 ), and concentrated in vacuo.

The residual yellow oil was chromatographed over 70 g of silica gel (eluted with ethyl acetate-hexane, 3:20) to give 153 mg <88 «) of ketone 179 as a yellow oil: IR

1705 cm-1; *H NMR (CCI4 ) 8 0.88 (t, J=5 Hz, 3H,

CH3 ), 0.90-1.70 3 >, 2.23

CH2 CO>, 2.66 (sextet, J= 6 Hz, 4H, C0 CH2 CH2 Ar), 3.71

3H, OCH3 ), 6.72

2H, ArH); mass spectrum, m/e (relative intensity) 234

234.1584.

1-trel-<2S,4R,6S,9aS)-2-Benzyloxy-4-<3-iodo-4-methoxyphenyl)octahydro-4H-quinolizin-6-yll-3-(dimethoxyphosphi- nyl)-2-propanone (180). To a solution of 60 mg <0.49 mmol) of dimethyl methylphosphonate in 2 mL of tetrahydrofuran was added 0.36 mL (0.44 mmol) of 1.22 M n-butyllithium in hexane over 2 min period with cooling in an dry ice-acetone bath under nitrogen. The mixture was stirred for 15 min followed by addition of 124 mg 182

(0 . 2 2 mmol) of ester

162 in 1 mL of

PhC H jO tetrahydrofuran over a

5 min period. The

resulting mixture was P(0M e) 13,14 stirred for 75 min,

warmed to room

temperature, and poured

into 30 mL of diethyl ether. The organic layer was washed with 20 mL of saturated aqueous ammonium chloride and two 30-mL portions of water, dried (Mg5 0 4 >, and concentrated in vacuo. The residue was chromatographed over 40 g of silica gel (eluted with 10 % ammonium hydroxide in methanol-chloroform, 1:14) to give 141 mg (99 9£) of @- ketophosphonate 180 as a yellow oil: IR(CH2 Cl2 ) 1710,

1050 cm“l; lH NMR (CDCI3 ) 5 0.85-2.25 (m, 10H, CH2 ), 2.50

(dd, J=17.5, 9.3 Hz, 1H, CHCOCH2 P ) > 2.85-3.25 (m, 4H,

CHCOCH2 P, CHCH2 CO, and OCCH2 P)» 3.40-3.90 (m, 2H, NCH and

BzOCH), 3.68 (d, J=ll, 2 Hz, 3H, P(0 )0 CH3 ), 3.82 (d,

J=ll, 2 Hz, 3H, P(0 )0 CH3 ), 3.82 (s, 3H, OCH3 ), 3.80-4.00

(m, 1H, ArCHN), 4.50 (s, 2H, ArCH2 ), 6.78 (d, J=9 Hz, 1H,

ArHs), 7.10-7.45 (m, 6 H, ArH& and ArH), 7.68 (d, J=2 Hz,

1H, ArH2 ); 13C NMR (CDCI3 ) 8 20.4, 21.1, 24.0, 37.5, 42.4

(C-2, C-4, C-6 , C-7, and C-8 ), 40.4 (C-10), 45.7 (C-12), 183

50.1

(C-13)), 56.3 (C-15), 57.0 (C-l), 69.6 (C-16), 71.6 (C-

3), 86.1 (Ar3 ), 111.0 (Ars), 127.4 (Ar&, Ar2'» and Ar^'),

128.3 , 138.2

(Ar2 >, 138.7 (Ari'), 157.4 , 200.8 and 201.1 Cd, C-

11); mass spectrum, m/e (relative intensity) 476 (M+-

CH2 C0 CH2 P(0 ) (0 Me)2 i. 7), 4 7 5 (8 ), 368 (5 ), 294 (1 0 0 ), 293

(67), 279 (6 ); exact mass calcd for C2 3 H2 7 NO2 I (M+-

CH2 COCH2 P (0)(OMe)2 ) m/e 476.1088, found m/e 476.1060.

4-[rel-(2S,4R,6S,9aS)-2-Benzyloxy-4-<3-iodo-4-methoxyphenyl>octahydro-4H-quinolizin-6-yl3-1-(3-iodo-4-*ethoxyphenyl)-l-buten-3-one (181). To a solution of 10.3 mg

(0.262 mmol) of

H sodium hydride in 1 mL

of dimethoxyethane was OMe added a solution of 140

mg (0.218 mmol) of /?-

ketophosphonate 180 in 2 OMe 15 mL of dimethoxyethane 181 under argon at room temperature. The resulting solution was stirred for 1 h followed by addition of 58 mg (0.218 mmol) of 3-iodo-

4-methoxybenzaldehyde (85) in 2 mL of dimethoxyethane.

The reaction mixture was stirred for 6 h, diluted with 20 mL of dichloromethane, concentrated in vacuo, and chromatographed over 30 g of silica gel (eluted with 10 ammonium hydroxide in methanol-chloroform, 1:30) to give

138 mg <81 so of a,-unsaturated ketone 181 as a white solid: mp 2 0 1 .5-202°C ; IR (CH2 CI2 ) 1680,

1650, 1600, 1590 cm'l; NMR & 0.80-2.25

10H, CH2 >, 2.60 (dd, J=13, 6 Hz, 1H, CHC0CH=), 3.05 (dd,

J=13, 8 Hz, 1H, CHC0CH=), 3.20-3.30

3.45-3.70

3.80-3.95

6.45

6.83

Hz, 1H, ArH2 >, 7.95

(CDC13) 8 20.5, 21.1, 24.2, 37.5, 42.7, (C-2, C-4, C-6 ,

C-7, and C-8 ), 43.8 (C-10), 50.3 (C-5), 51.6 (C-9), 56.3

(C-14 (C-15)), 56.4 (C-15 (C-14)), 57.3 (C-l), 69.7

16), 71.8 (C-3), 85.8

110.9 (Ars

(Ars')>» 127.5 (Ars' (Ars>» Ar3 ", and Ars"), 128.3

138.2

), 140.0 (C-13), 157.1 (Ar4

(Ar4 )), 199.0 (C-ll); mass spectrum, m/e (relative intensity) 476

(30), 287 (26), 264 (100), 247 (39), 160 (40); exact mass calcd for C3 4 H3 7 NO4 I2 K (M++K) m/e 816.0451, found m/e

815.5460.

Anal. Calcd for C3 4 H3 7 NO4 I2 : C, 52.53; H, 4.80.

Found: C, 52.33; H, 4.89.

1-(3-Iodo-4-methoxyphenyl)-l-buten-3-one (183). To a

solution of 3.00 g (11.5 mmol) of

3-iodo-4-methoxybenzaldehyde (85)

in 10 mL of dichloromethane was

added 3.64 g (11.5 mmol) of 1-

triphenylphosphoranylidene-2 - OMe propanone (182) in a single

portion The mixture was stirred at room temperature for 2 days, concentrated in vacuo, and chromatographed over 1 2 0 g of silica gel (eluted with ethyl acetate-hexane, 1:4) to give 2.97 g (86 X) of <*,/?- unsaturated ketone 183 as a white solid: mp 80-81°C; IR

(CH2 CI2 ) 1690, 1670, 1610, 1595, 980 cm"l; *H NMR (CDCI3 )

6 2.32 (s, 3H, CH3 ), 3.91 (s, 3H, OCH3 ), 6.58 (d, J=16 Hz,

1H, C0CH=), 6.80 (d, J=9 Hz, 1H, ArHs), 7.35 (d, J=16 Hz,

1H, ArCH=), 7.48 (dd, J=9, 2 Hz, 1H, ArH&), 7.95 (d, J=2

Hz, 1H, ArH2 ); 13C NMR (CDCI3 ) 6 27.6 (CH3 ), 56.5 (OCH3 ),

8 6 . 6 (Ar3 ), 110.8 (Ars), 125.9 (Ar6 >» 129.1 (Ari), 130.0

(CH=CHC0), 139.1 (Ar2 ), 141.2 (HC=CHC0), 159.8 (Ar4 ), 1 86

197.8 (C=0); mass spectrum, m/e (relative intensity) 302

(M+, 99), 287 (6 6 ), 272 (2), 271 (6 ), 259 (13), 175 (9),

160 (100), 145 (11), 144 (2), 132 (10), 117 (6 ), 89 (15); exact mass calcd for C 1 1 H 1 1 O2 I m/e 301.9801, found m/e

301.9803.

3-Cl-(3-Iodo-4-methoxyphenyl)3butyl trifluoroacetate

(185). To a solution of 302 mg (1.00 mmol) of <*,/?-

unsaturated ketone 183 in 6 mL of

F,C CCX chloroform was added 930 mg

(8 . 0 0 mmol) of triethylsilane and

0.85 mL (11.0 mmol) of

trifluoroacetic acid in sequence

at room temperature. The reaction

mixture was stirred under reflux for 2 h, cooled to room temperature, and concentrated in vacuo. The resulting yellow oil was diluted with 30 mL of chloroform, washed with two 30-mL portions of saturated aqueous sodium bicarbonate, 30 mL of brine, and two 30-mL portions of water, dried (MgS0 4 >, and concentrated in vacuo. The residual colorless oil was chromatographed over 80 g of silica gel (eluted with ethyl acetate- hexane, 1:3) to give 319 mg (79 fc) of trifluoroacetate

185 as a colorless oil: IR (CH2 CI2 ) 1778 cm“l; NMR

(CDCI3 ) 5 1.38 (d, J=7 Hz, 3H, CH3 ), 1.70-2.20 (m, 2H, 187

CH2 CHOCOCF3 ), 2.30-2.70 Cm, 2 H, ArCH2 >, 3.80

OCH3 ), 5.05 (sextet, J=7 Hz, 1H, OCH), 6.82

1H, ArH5 >, 7.08 , 7.55

Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity)

402 (M+, 85), 289 (3), 288 (15), 273 (4), 247 (100), 232

(1); exact mass calcd for C 1 3 H1 4 O3 F3 I m/e 401.9936, found m/e 401.9936.

1-<3-iodo-4-methoxyphenyl>-l-buten-3-ol (186). To a

solution of 302 mg (1.00 mmol) of

a , 0-unsaturated ketone 183 in 10 mL

of tetrahydrofuran was added 1 .2

mL (1.2 mmol) of 1 M lithium

triethylborohydride in OMe tetrahydrofuran at 0°C under 186 argon. The resulting solution was stirred for 10 min and then hydrolyzed with 0.5 mL of water followed by addition of 1 mL of 30 % of hydrogen peroxide with stirring at room temperature for 3 h. The aqueous layer was saturated with potassium carbonate, filtered, and the organic layer was concentrated in vacuo to give 302 mg (100 >s) of allylic alcohol 186 as a colorless oil. This material was used in subsequent reactions without purification: IR (CH2 Cl2 > 3600 (sharp),

3450 (broad), 1590, 970 cm"l; *H NMR (CDCI3 ) 5 1.32 (d. 188

J=7 Hz, 3H, CH3 ), 2.55 (broad s, 1H, OH), 3.81 (s, 3H,

OCH3 ), 4.40

1H, =CHC0H), 6.40

Hz, 1H, ArH5 ), 7.10

J=2 Hz, 1H, ArH2 ); 13C NMR 6 23.5 , 56.4

< OCH3 ) , 6 8 . 8 (CHOH), 86.3 , 110.9 (Ars), 127.5

, 132.9 (CH=CHCH0H),

137.4 ; mass spectrum, m/e (relative intensity) 304 (M+, 60), 289 (6 ), 286 (3), 261 (7), 247

(100), 134 (14); exact mass calcd for C1 1 H 1 3 O2 I m/e

303.9957, found m/e 303.9974.

1-(3-iodo-4-methoxyphenyl)-3-butanol (187).

Method A. To a solution of

310 mg (0.77 mmol) of

trifluoroacetate 185 in 5 mL of

methanol was added 0.5 mL of 3 N

OMe aqueous sodium hydroxide in a

single portion. The reaction mixture was stirred at room temperature for 5 min and concentrated in vacuo. The residual oil was diluted with

20 mL of dichloromethane, washed with 20 mL of 1 N aqueous hydrochloric acid, 20 mL of brine, and two 20-mL portions of water, dried (MgS0 4 ), and concentrated in vacuo to give 226 mg (96 *) of alcohol 187 as a pale 189 yellow oil.

Method B. To a solution of 220 mg (0.72 mmol) of allylic alcohol 1 8 6 and 1.34 g <7.2 mmol) of p- toluenesulfonyl hydrazide in 5 mL of ethanol warmed under reflux was added a solution of 1.63 g <12 mmol) of sodium acetate in 5 mL of water over a 5 h period. The mixture was cooled, poured into 30 mL of saturated aqueous ammonium chloride, and extracted with three 30-mL portions of dichloromethane. The combined organic layers were washed with two 20-mL portions of brine and 20 mL of water, dried

(eluted with ethyl acetate-hexane, 3:7) to give 193 mg

<87 fc) of saturated alcohol 1 8 7 as a pale yellow oil: IR

3600 (sharp), 3450 (broad) cm-*; lH NMR (CDCI3 )

6 1.20

(broad s, 1H, OH), 2.35-2.70 , 3.70-4.00 (m with s at 3.82, 4H, OCH3 and 0CH), 6.70

ArH5 ), 7.06

1H, ArH2 ); mass spectrum, m/e (relative intensity) 306

(30), 247 (82), 161 (18), 146 (69); exact mass calcd for

CHH 1 5O2 I 306.0113, found m/e 306.0108. 190

4- Crel - < 2S , 4R, 6 S , 9aS ) -2-Benzyloxy-4- <3-iodo-4-m«thoxyphenyl>octohydro-4H-quinolizin-6-yl]-1 -<3-iodo-4-*«thoxyphenyl)-1-butene-<3S)-ol (188) and 4-Crel-<2S,4R,6 S ,9a S)-

2-Benzyloxy-4-<3-iodo-4-methoxyphenyl>octahydro-4H- quinolizin-6 -yll-1-(3-iodo-4-methoxyphenyl)-1-butene-

<3R)-ol (189). To a solution of 198 mg <0.255 mmol) of a,/?

-unsaturated ketone 181

in a mixture of 5 mL of

OMe tetrahydrofuran and 2 mL of dichloromethane

OH was added 0.51 mL <0.510 mmol) of 1 M OMe 15 lithium

188 triethylborohydride in tetrahydrofuran with

H cooling in an ice bath under argon. The OMe mixture was stirred for

30 min during which the OH solution gradually OMe became homogeneous. 189 The solution was hydrolyzed with 0.2 mL of water and concentrated in vacuo. The residual white foam was chromatographed over

50 g of silica gel

3:7) to give 140 <71 k) of allylic alcohol 188 as a 191 white foam and 43 mg <22 H) of isomeric allylic alcohol

189 as a colorless oil.

Allylic alcohol 188: mp 100-102°C

3200 (broad), 1590, 960 cm"*; *H NMR (CDC1 3 ) 8

0.80-1.90 Cm, 10H, CH2 , CH2 CHOH), 1.90-2.30 , 2.90-3.10

3.60-3.78

3.90 (s , 3H, OCH3 ), 3.90-4.10

(m, 1H, CH0H), 4.52

J=12 Hz, 1H, ArCH2 0 ), 6.02

CH0HCH = CH) , 6.45 (broad d, J = 15 Hz, 1H, CH0HCH=CH>, 6.73

ArH5 ' (ArHs)>, 7.25-7.75

(ArH2 '>» and ArH), 7.80 (broad s, 1H, ArH2 ' (ArH2 >); 13C

NMR (CDCL3 ) 8 20.5, 22.8, 24.2, 37.1, 42.1 (C-2, C-4, C-6 ,

C-7, and C-8 ), 36.1 (C-10), 50.6 (C-5), 55.0 (C-9), 56.4

(C-14 and C-15), 57.6 , 70.0 (C-16), 71.2 (C-3),

73.0 (C-ll), 86.2 (Ar3 and Ar3 '>, 110.8 (Ars and Ar5 '),

126.8 (C-12), 127.5

(Ar&' (Arfc)), 128.4

132.2 (AriO, 137.2 and Ari), 138.8 ,

138.9 )» 157.5

(Ar4 >); mass spectrum (FAB on glycerol), m/e (relative intensity) 780

384 (3), 369 (6 ), 368 (16), 108 (24), 107 (13), 91 (100). 192

Isomeric allylic alcohol 169: IR (CH2 CI2 ) 3595

(sharp), 3200 (broad), 1590, 970 cm"*; NMR (CDCI3 ) 5

0.85-0.95 (m, 1H, CH2 ), 0.98 (d, J=12 Hz, 1H, CH2 )r 1.10

(d, J=14 Hz, 1H, CH2 >, 1.55-1.95 (m, 7H, CH2 and

CH2 CHOH), 2.05 (d, J =12 Hz, 1H, CH2 CHOH), 2.12 (d, J=12

Hz, 1H, CH2 CH(N)Ar), 2.70-2.82 (broad s, 1H, OH), 3.10

(broad d, J=12 Hz, 1H, NCHCH2 CHOH), 3.50-3.85 (m, 3H,

NCH, BzOCH, and CHOH), 3.90 (s, 6 H, two OCH3 ), 3.98 (d,

J=12 Hz, 1H, ArCHN), 4.50 (d, J=12 Hz, 1H, ArCH2 0 ), 4.52

(d, J=12 Hz, 1H, ArCH2 0 ), 5.85 (4-line dd , J=15, 3 Hz,

1H, CH0HCH=CH), 6.20-6.45 (m, 1H, CH0HCH=CH), 6.60 (d,

J=9 Hz, 1H, ArHs (ArHs')), 6.80 (d, J=9 Hz, 1H, ArHs'

(ArHs)), 7.10 (broad s, 1H, ArH& (ArHfeO), 7.20-7.30 (m,

6 H, ArHg' (ArHg)), 7.35-7.68 (m with a at 7.68, 2H, ArH2 and ArH2 '); 13c NMR (CDCI3 ) 8 19.6, 22.9, 24.1, 34.5,

40.9 (C-2, C-4, C-6 , C-7, and C-8 ), 36.4 (C-10), 51.6 (C-

5), 56.5 (C-9, C-14, and C-15), 57.9 (C-l), 69.8 (C-16),

70.8 (C-3), 73.4 (C-ll), 86.2 (Ar3 and Ar3 '), 110.9 (Ars and Ars'), 127.5 (C-12, Arfe (Ar6 '), Ar3 », and Ars**),

127.8 (Ar6 ' (Ar6 )), 128.4 (Ar2" and Ars"), 129.5 (Ar4 »),

131.5 (C-13), 132.1 (AriO, 137.3 (Ar2 (Ar2') and Ari),

138.4 (Ari"), 139.2 (Ar2 ' (Ar2 >), 157.4 (Ar4 (Ar4 >)),

158.2 (Ar4 ' (Ar4 >); mass spectrum (FAB on glycerol), m/e

(relative intensity) 780 (M^+H, 13), 654 (10), 476 (7),

369 (8 ), 368 (8 ), 108 (4), 107 (8 ), 91 (100). 193

4-Crgl-<2S,4R,6S,9aS)-2-Benzyloxy-4-<3-lodo-4-»«thoxyphenyl>octahydro-4H-quinolizin-6-yll-1-<3-iodo-4-*«thoxy- pheyl)-1-butan-<3R)-ol (190). To a solution o£ 140 mg

<0.180 mmol) of allylic

_ ^ alcohol 188 and 335 mg PhCHX), " ^ 16 .... <1.80 mmol) of p-

toluenesulfony1

hydrazide in 5 mL of

dimethoxyethane warmed

under reflux was added 190 , . , , a solution of 408 mg

<3.00 mmol) of sodium acetate in 5 mL of water over a 4 h period. The mixture was cooled to room temperature, poured into 20 mL of water, and extracted with three 30- mL portions of dichloromethane. The combined organic layers were washed with 50 mL of water, dried

, 1598 em“l; *H NMR

, 1.20-1.35

1 H, CH2 >, 1.40-1.90

2.03 (broad d, J=12 Hz, 1H, ArCH2 CH2 CH0 H), 2.20 (broad d,

J=12 Hz, 2H, CH2 CH(N)Ar), 2.64 , 2.88 (broad d, J=12 Hz, 1H, NCHCH2 CHOH) , 3.58-

3.75 (m, 2H, NCH and BzOCH), 3.82-4.10 (m with two e at

3.88 and 3.91, 8 H, two OCH3 , CHOH, and ArCHN), 4.48 (d,

J=12 Hz, 1H, ArCH2 0 >, 4.56 ,

6.70-6.95

ArHs'), 7.15 (broad d, J=9 Hz, 1H, ArHs (ArH6 ')>, 7.20-

7.52 (m, 7H, ArHs' (ArHs>, ArH, and ArH2 (ArH2 '>), 7.68

(broad s, 1H, ArH2 ' (ArH2 )); NMR (CDCI3 ) 6 20.7,

22.8, 24.2, 37.3, 42.4 (C-2, C-4, C-6 , C-7, and C-8 ),

30.3 (C-13), 35.8 (C-10), 39.4 (C-12), 50.4 (C-5), 55.0

(C-9), 56.4 (C-14 (C-15)), 56.5 (C-15 (C-14)), 57.5 (C-

1), 69.7 (C-ll and C-16), 71.4 (C-3), 85.8 (Ar3 and

Ar3 '), 110.0 (Ars and Ars'>, 127.5 (Ars# Ars', Ar3 », and

Ars**), 128.4 (Ar2 M and Ars*^# 129.5 (Ar4 “), 137.0 (Ari and Ari'), 138.7 (Ari«), 139.5 (Ar2 and Ar2 '># 156.3 (Ar4

(Ar4 ')), 157.7 (Ar4 ' ); mass spectrum, m/e (relative intensity) 781 (M+, 7), 655 (3), 534 (6 ), 520 (3), 476

(59), 384 (4), 369 (7), 368 (30), 108 (12), 107 (10), 91

(100).

Anal. Calcd for C3 4 H4 1 NO4 I2 : C, 52.25; H, 5.29.

Found: C, 53.00; H, 5.25.

4-Crel-<2S,4R,6R,9aS)-2-Benzyloxy-4-(3-iodo-4-methoxyphenyl)octahydro-4H-quinolizin-6-yl3-1-(3-iodo-4-aethoxy- phenyl)butyl (3R)-acetate (121). To a solution of 245 mg (0.314 mmol) of alcohol

190 in 5 mL of H PhCHjO dichloromethane was 16 OMe added 0.3 mL (3.18

mmol) of acetic OAc 17,18 anhydride, 0.3 mL (2.15 OMe mmol) of triethylamine, 15 and a catalytic amount 121 of 4-dimethylaminopyridine. The mixture was stirred at room temperature for

3 days and diluted with 10 mL of dichloromethane. The excess solvent and reagents were removed in vacuo and residual yellow oil was chromatographed over a Lobar size

B column (eluted with ethyl acetate-hexane, 3:7) to give

218 mg (85 H) of acetate 121 as a white foam: mp 61-64°C;

IR (CHCI3 ) 1720 cm-1; *H NMR (CDCI3 ) 8 0.70-2.30 (m with s at 1.83, 15H, CH2 and OCH3 ), 2.30-2.68 (m, 4H,

ArCH2CH2>, 3.30-3.65 (m, 2H, NCHCH2 CHOAC and NCH), 3.65-

4.00 (m with two s at 3.75 and 3.82, 8 H, BzOCH, two OCH3 , and ArCHN), 4.48 (s, 2H, ArCH2 0 ), 4.70-5.07

HCOAc) , 6.65 (d, J=9 Hz, 1H, ArHs (ArHsO ) , 6 . 6 8 (d, J = 9

Hz, 1H, ArHs' (ArHs)), 7.04 (dd, J = 9, 2 Hz, 1H, ArHg,

(ArH6 '>), 7.15-7.45 (m, 6 H, ArH^' (ArH6 > and ArH), 7.55

(d, J=2 Hz, 1H, ArH2 (ArH2 ')), 7.72 (broad s, 1H, ArH2 '

(ArH2 )>; 13C NMR (CDCI3 ) 5 20.4, 20.5, 24.1, 37.5, 42.5 196

35.4 (C-IO, C-12, and C-13), 49.9 (C-9), 50.1

72.1 >, 111.0

(Ars and Ars'), 127.5 (Ars, Ar£' , Ar3 **, and Ars"), 128.3

138.5 >»

156.5 (Ar4 (Ar4 ')), 157.3 (Ar4 ' (Ar4 )), 170.7 (C-17); mass spectrum, m/e (relative intensity) 823 (M+, 3), 764

(1), 490 (1), 476 (85), 247 (36), 108 (25), 107 (19), 91

(100).

<♦>-3-0-Benzyllythrancepine-II (192) and 4-[rel-

(2S,4R,6R,9aS)-2-Benzyloxy-4-(4-methoxyphenyl)octahydro-

4H-quinolizin-6-yl]-1-(4-methoxyphenyl)butyl (3R)-acetate

(193). To a suspension o£ 262 mg (0.237 mmol) of

4 H 6 PhCHjO H 3 0 PhCH ,0

192 193 197 tetrakis

<+)-3-0-benzyllythrancepine-II <192) as a white solid as well as acetate 193 as a colorless oil.

<♦)-3-0-Benzyllythrancepine-II <192): mp 169-170°C

(ether-hexane); IR 1725 cm"l; lH NMR

0.80-0.95, , 1.13

Hio>, 1.49 <4-line ddd, J=11.8, 11.8, 11.8 Hz, 1H, H2 >,

1.57-1.71

3H, H4 ', H6 , and Hi2 >, 1.92-2.30

C<0)CH3 and H 1 2 '), 2.21 <8 -line ddd, J=12.3, 6 .6 , 2.7 Hz,

1H, H2 '), 2.43 <7-line ddd, J=15.0, 11.5, 3.4 Hz, 1H,

Hio')» 2.56 <8 -line ddd, J=16.0, 10.1, 3.4 Hz, 1H, Hj.3 ) ,

2.72 <8 -1ine ddd, J=16.0, 6.4, 3.8 Hz, 1H, H1 3 O , 3.16

2.5, 2.5 Hz, 1H, Hs>, 3.70 <9-line dddd, J=11.5, 11.5,

4.5, 4.5 Hz, 1H, H3 >, 3.87 (s, 3H, OCH3 ), 3.88 (s, 3H,

OCH3 ), 3.99 , 4.45

Hz, 1H, ArCH2 0 >, 4.52 (d, J=11.9 Hz, 1H, ArCH2 0 ), 5.35

<8 -line dddd, J=9.9, 3.6, 3.6, 3.6 Hz, 1H, Hu), 6.62

J=2.3 Hz, 1H, ArH2 '>, 6.81

(ArHs'>), 6 . 8 8 Cd, J=8.4 Hz, 1H, ArHs' (ArHs)), 7.05

J=8 .1, 2.4 Hz, 1H, ArHs (ArHs')), 7.06

Hz, 1H, ArHs' (ArH6 >>, 7.21-7.33 (m, 5H, ArH), 7.42

J = 2.3 Hz, 1H, ArH2); 13C NMR

29.7, 34.5 (C-10, C-12, and C-13), 20.6, 23.4, 24.1, 38.0

(C-5), 56.0 (C-28 (C-29)), 56.2 (C-29 (C-28)), 57.0 (C-

1), 69.4 (C-30), 71.0

22)), 112.2 CC-22 , 127.3 (C-15 and C-23), 127.4

(Ar3 and Ars), 128.3

25), 130.1 (C-18 (C-20)), 130.7 (C-20 (C-18)), 136.5 (C-

14 (C-24)), 137.6 (C-24 (C-14)), 138.8 (Ari), 154.9 (C-17 and C-21); mass spectrum, m/e (relative intensity) 569

(M*, 34), 510 (67), 469 (11), 482 (5), 402 (47), 374 (6 ),

361 (5), 279 (12), 253 (14), 91 (100), 82 (85); exact mass calcd for C3 SH4 3 NO5 m/e 569.3142, found m/e

569.3111.

Acetate 193: IR (CH2 Cl2 > 1720 cm"l; lH NMR (CDCI3 ) <5

0.90-2.10 (m with s at 1.83, 15H, CH2 and OCH3 ), 2.40- 199

2.60 (m, 4H, ArCH2 CH2 >» 3.50-3.80 (m, 2H, NCHCH2 CHOAC and

NCH), 3.80-4.05 , 4.56

Hz, 1H, ArCH2 0 ), 4.85-4.95 (m, 1H, HCOAc), 6.83

Hz, 4H, ArH), 7.02

5H, ArH); mass spectrum, m/e (relative intensity) 571

(M+ , 7), 512 (3), 464 (6 ), 377 (3), 365 (3), 351 (3), 350

(62), 107 (54), 91 (100) exact mass calcd for C3 6 H4 5 NO5 m/e 571.3299, found m/e 571.3298.

rel-(2S>-Carbethoxymethyl-<6 R>- C<2R>-hydroxy-4-(4- methoxyphenyl)butyl] piperidine (195). A mixture of 29 mg

(0.0515 mmol) of benzyl

ether 162 and 1 mL H solution of W-4 Ra-Ni in

ethanol was stirred COzEt vigorously under hydrogen

balloon for 2 days. The OMe solution was filtered and

195 the collected solid was rinsed with 10 mL of dichloromethane and 10 mL of methanol in sequence. The combined filtrates were concentrated in vacuo and chromatographed over 5 g of silica gel (eluted with ethyl acetate-methanol, 1:19) to give 11 mg (61 *) of amino alcohol 195 as a pale yellow 200

Oil: IR 3100 (broad), 1712 cm"!; J-H NMR (CDC1 3 ) 6

1.25-2.10 (m with a at 2.00, 11H, CH2 , OH, and NH), 1.25

(t, J=7 Hz, 3H, CO2 CH2 CH3 ), 2.20-2.85 Cm, 4H, CH2 C0 2 Et and ArCH2 >, 3.05-3.60 (m, 2H, CHCH2 C0 2 Et and NCH), 3.55-

4.00 (m, 1H, HOCH), 4.17

(d, J = 9 Hz, 2H, ArH), 7.13

262 (10), 242 (4), 228 (5), 214 (5), 170 (100), 121 (63); exact mass calcd for C2 0 H3 1 NO4 m/e 349.2254, found m/e

349.2258.

rel-(2S,4R,9aS)-2-Benzyloxy-4-(4-methoxyphenyl)- octahydro-4H-quinolizin-6-one (196). To a solution of 1.26

g (4.58 mmol) of alcohols 53 PhCHjO and 54 in 15 mL of

dimethylformamide was added

540 mg (13.7 mmol) of sodium

hydride in a single OMe portion at room temperature.

^8® The mixture was stirred for i h followed by addition of 4.75 g (27.7 mmol) of benzyl bromide over a 5 min period. The resulting solution was stirred at room temperature for 6 h, concentrated in vacuo, diluted with 100 mL of dichloromethane, and washed with three 50-mL portions of water. The organic layer was 201 dried (MgS0 4 ), concentrated in vacuo, and chromatographed over a Lobar elze C column (eluted with ethyl acetate- hexane, 1:1) to give 800 mg (48 *) of benzyl ether 196 as a yellow foam: IR (CH2 CI2 ) 1625 (s) cm"l; lH NMR (CDCl3 > 8

1.30-2.80 (m, 10H, CH2 > > 3.55-4.10 (m with a at 3.75, 5H,

NCH, ArCH2 0 CH, and OCH3 ), 4.30 (a, 2H, ArCH2 0 ), 5.75 (dd,

J=9, 4 Hz, 1H, ArCHN), 6.70-7.40 (m, 9H, ArH); mass spectrum, m/e (relative intensity) 365 (M+, 85), 274

(27), 258 (16), 257 (16), 160 (25), 91 (100); exact mass calcd for C2 3 H2 7 NO3 m/e 365.1992, found m/e 365.1997.

rel-(2S,4R,9aS)-2-Benzyloxy-4-(4-methoxyphenyl)- octahydro-4H-quinolizine (197). To a solution of 402 mg

(1.10 mmol) of lactam 196

in 10 mL of tetrahydrofuran

was added 209 mg (5.50

mmol) of lithium aluminum

hydride in a single

OMe portion at room temperature. The mixture 197 was warmed under reflux for 1 h. The resulting suspension was cooled, poured into

5 mL of 3 N aqueous sodium hydroxide, and filtered. The filter cake was washed with 100 mL of dichloromethane and the combined filtrates were washed with 50 mL of brine and two 50-mL portions of water, dried (MgS0 4 >, and concentrated in vacuo to give 362 mg <94 X) of amine 197 as a yellow oil. This material was used in subsequent reactions without purification: IR 1610 (medium) cm-1; lH NMR 6 0.75-2.80 , 3.05-3.35

BzOCH), 3.90

ArCH2 0 ), 6.80

ArH); mass spectrum, m/e (relative intensity) 351 (M+,

4), 350 (11), 260 (9), 245 (100), 244 (34), 243 (4), 217

(2), 161 (48), 91 (99); exact mass calcd for C2 3 H2 9 NO2 m/e 351.2199, found m/e 351.2225.

rel-(2S,4R,9aS)-2-Hydroxy-4-(4-methoxyphenyl)-

198). Method A. To a solution of

56 mg <0.159 mmol) of benzyl

ether 197 in 2 mL of

dichloromethane was added

210 mL <0.210 mmol) of 1 M

boron tribromide in hexane

with cooling in an ice bath

under argon. The mixture was

stirred for 10 min, hydrolyzed with 10 mL of 5 N aqueous potassium hydroxide, warmed to room temperature and extracted with three 20-mL portions 203 of dichloromethane. The combined organic layers were washed with 20 mL of brine and 20 mL of water, dried

(MgS0 4 >, and concentrated in vacuo. The resulting yellow oil was chromatographed over 15 g of silica gel (eluted with 10 X ammonium hydroxide in methanol - chloroform,

1:14) to give 27 mg <65 X) of amino alcohol 198 as a yellow oil.

Method B. A mixture of 330 mg <0.77 mmol) of formate

127 in 1 mL of 3 N aqueous sodium hydroxide and 5 mL of methanol was stirred at room temperature for 1 h. The resulting solution was concentrated in vacuo, diluted with 50 mL of dichloromethane, washed with two 30-mL portions of brine, dried (MgS0 4 >, and concentrated in vacuo to give 280 mg <91 X) of alcohol 129 as a yellow oil. For practical purposes, this crude product can be used directly without purification.

To a solution of 280 mg <0.70 mmol) of hydroxy lactam 129 in 10 mL of tetrahydrofuran was added 265 mg

(6.98 mmol) of lithium aluminum hydride in a single portion at room temperature. The mixture was warmed under reflux for 1 h, cooled, poured into 5 mL of 3 N aqueous sodium hydroxide, and filtered. The filter cake was washed with 50 mL of methanol and 50 mL of dichloromethane in sequence. The combined filtrates were washed with two 50-mL portions of brine and 50 mL of 204 water, dried , and concentrated in vacuo. The residue was chromatographed over 50 g of silica gel

(eluted with 10 X ammonium hydroxide in methanol- chloroform, 1:7) to give 160 mg (88 X) of amino alcohol

198 as a yellow oil. This material was identical (NMR,

IR, MS, and TLC) to the product of method A: IR (CH2 CI2 )

3600 (sharp), 3400 (broad), 1610 (weak) cm-1; NMR

(CDCI3 ) 5 0.80-2.90 (m, 13H, CH2 and OH), 3.10-3.45 (m,

1H, NCH), 3.70-3.95

OCH3 ), 4.00 (dd, J=ll, 3 Hz, 1H, ArCHN), 6.89 (d, J=3

Hz, 2H, ArH), 7.30 (d, J=3 Hz, 2H, ArH); mass spectrum, m/e (relative intensity) 261 (M+, 46), 260 (23), 246 (2),

244 (5), 243 (3), 218 (16), 216 (26), 188 (4), 154 (58),

161 (33), 134 (100), 110 (32), 121 (27); exact mass calcd for C 3.6 H2 3 NO2 m/e 261.1729, found m/e 261.1722.

(+)-Lythrancepine-II (4) To a solution of 8.4 mg

(1.48 x lO-2 mmol) of

(+)-3-0-benzyl- HO 26,27 lythrancepine-II (192)

s>,oOAc in 1.5 mL of

dichloromethane was

Me< added 236 mL (5.92 x (e0 28 10"2 mmol) of 0.25 M

boron tribromide in dichloromethane dropwise with cooling in an ice bath under argon. The mixture waa stirred for 3 min and 1 mL of water and 4 drops of saturated aqueous sodium bicarbonate were added. The solution was partitioned between 10 mL of dichloromethane and 5 mL of water. The aqueous layer was extracted with five 10-mL portions of dichloromethane, dried , concentrated in vacuo.

The resulting pale yellow oil was chromatographed over 10 g of silica gel (eluted with 10 a ammonium hydroxide in methanol-ethyl acetate-hexane, 1:6:9) to give 3.8 mg (54 se) of (+)-lythrancepine-II (4) as a white solid after crystallization from hexane. This material was identical

(500 MHz 1H-NMR, IR, MS, and TLC) to an authentic sample of (-*•)-lythrancepine-II: mp 139-1420C; IR (CH2Cl2> 3685

(sharp), 3600 (sharp), 1729 cm"l; NMR (CDCI3 ) 5 0.82-

0.93 (m, 1H, H7 (Hq )), 1.13-1.22 (m, 1H, Hq (H7 )), 1.37-

1.48 (m with 4-line ddd at 1.42, J=11.6, 11.6, 11.6 Hz,

2H, H2 and Hio>, 1.55-1.73 (m, 5H, H4 , He, H7 ', Hq ', and

OH), 1.81-1.93 (m, 3H, H4 ', H6 ', and H1 2 ), 1.93-2.06 (m with s at 1.98, 4H, C(0 )CH3 and H 1 2 '), 2.10 (broad d,

J=12.7 Hz, 1H, H2 '), 2.44 (7-line ddd, J=14.2, 12.6, 3.0

Hz, 1 H, H 1 0 ), 2.56 (8 -line ddd, J=16.2, 11.1, 3.5 Hz, 1H,

H 1 3 ), 2.74 (broad d, J=16.3 Hz, 1H, H 1 3 ), 3.18 (broad d,

J=10.9 Hz, 1H, Hg), 3.50 (broad d, J=11.3 Hz, 1H, H5 ),

3.85-4.00 (m with two s at 3.87 and 3.89, 7H, two OCH3 and H3 ), 4.03 (broad d, J=10.0 Hz, 1H, Hi), 5.32 (m, 1H, 2 0 6

Hii), 6.64 (broad s, 1H, ArH2'>» 6.82 (d, J=8.3 Hz, 1H,

ArHs (ArHsO), 6 . 8 8

(6 -line ddd, J=8.3, 2.6, 2.6 Hz, 2H, ArHs and ArH&'),

7.40 (d, J=2.2 Hz, 1H, ArH2 ); 13C NMR (CDCI3 ) S 20.5,

23.7, 24.1, 38.3 (C-4, C-6 , C-7, and C-8 ), 21.3 (C-27),

27.5, 29.7, 34.5 (C-10, C-12, and C-13), 40.6 (C-2), 49.8

(C-9), 50.9 (C-5), 56.0 (C-28 (C-29)), 56.2 (C-29 (C-

28)), 57.0 (C-l), 65.1 (C-3), 71.1 (C-ll), 110.7 (C-16

(C-22)>, 112.1 (C-22 (C-16)), 127.2 (C-15 and C-23),

128.8 (C-19 and C-25), 130.0, (C-17 (C-20)), 130.7 (C-20

(C-17)), 136.1 (C-14 (C-24)), 137.3 (C-24 (C-14)), 155.1

(C-17 and C-21), 173.5 (C-26); mass spectrum, m/e

(relative intensity) 479 (M+, 62), 420 (100), 402 (61),

392 (9), 379 (20), 374 (5), 279 (6 ), 253 (9), 82 (94); exact mass calcd for C2 9 H3 7 NO5 m/e 479.2673, found m/e

479.2681.

<+)-Lythrancepine-III (14). To a solution of 2.0 mg

(4.17 x 10“3 mmol) of (+)-lythrancepine-II (4) in 0.5 mL of pyridine (6.18 mmol) was added 6 drops of acetic anhydride at room temperature. The mixture was stirred for 6 h followed by concentration in vacuo. The resulting yellow oil was first chromatographed over 5 g of silica gel (eluted with 10 * ammonium hydroxide in methanol- ethyl acetate-hexane, 1:7:11) and then further purified 207

by 0.5 mm thick

AcO. preparative thin-layer

chromatography over *OAc SiC>2 (eluted with 10 *£

ammonium hydroxide-

ethyl acetate-hexane, eO 5:18:24) to give 1.4 mg

14 <64 of < + >-

lythrancepine-III (14) as a white solid after crystallization from hexane. The material was identical (500 MHz *H-NMR, IR, MS, and TLC) to an authentic sample of ( + )-lythrancepine-III: mp 82-

84°C; IR 1728 cm“l; NMR (CDClg) S 0.87 (broad d, J=10.5 Hz, 1H, H7 (Hs>), 1.19 (broad d, J=12.8 Hz, 1H,

Hg ), 1.42 <8 -line ddd, J=15.2, 6.4, 3.0 Hz, 1H,

Hio>, 1.51 (4-line ddd, J=11.8, 11.8, 11.8 Hz, 1H, Hf),

1.62-1.74

J=ll.9, 11.9, 5.3 Hz, 1H, H4 ), 1.79 (6 -line ddd, J=12.0,

2.3, 2.3 Hz, 1H, H4 O, 1.84-1.93 * 1.93-2.06

(m with two s at 1.95 and 1.99, 8 H, COCH3 at C-ll and

COCH3 at C-3 respectively, H &', and Hi2 '>, 2.12 <8 -line ddd, J=ll.8 , 2.5, 4.5 Hz, 1H, H2 '>, 2.43 <7-line ddd,

J=14.9, 11.7, 3.0 Hz, 1H, Hi0 '>, 2.56 <8 -line ddd,

J = 16.0, 10.6, 3.2 Hz, 1H, H 3.3 ) , 2.74 <8 -line ddd, J = 16.3,

6.1, 3.7 Hz, 1H, Hi3 '>, 3.20 (broad d, J=11.3 Hz, 1H, 208

Hs>, 3.51 <6 -1ine ddd, J=12.9, 2.5, 2.5 Hz, 1H, H5 ), 3.87

Hz, 1H, Hi), 5.03 <9-line dddd, J=11.7, 11.7, 4.5, 4.5

Hz, 1H, H3 ), 5.34 (octet, J = 3.5 Hz, 1H, Hu ) , 6.63

J=2.0 Hz, 1H, ArH2 '>, 6.81

(ArHs')), 6 . 8 8

(d, J=2.3 Hz, 1H, ArH2 >; mass spectrum, m/e (relative intensity); 521 (M+, 67), 462 (100), 434 (7), 421 (15),

402 (83), 374 (5), 361 (5), 279 (7), 253 (5), 82 (37); exact mass calcd for C3 1 H3 9 NO9 521.2778, found m/e

521.2752. BIBLIOGRAPHY

1. Hanske, R. H. F. in "The Alkaloid"; Manske, R. H. F., Ed.; Academic Preaa: New York, 1968; Vol. X, p 566. 1970; Vol. XII, p 474, 488. 1973; Vol. XIV, p 539.

2. Fujita, E. Farumashia 1973, 9, 599.

3. Fujita, E.; Fuji, K. in "International Review o£ Science, Organic Chemistry Series Two"; Wiesner, K., Ed.; Butterworths: London, 1976, p 119.

4. Golebiewski, W. M.; Wrobel, J. T. in "The Alkaloids"; Rodrigo, R. G. A., Ed.; Academic Press: New York, 1981; Vol. XVIII, p 263-322.

5. In the review by Golebiewski and Wrobel (ref. 4), Lythraceae alkaloids are categorized as types A-C (type A: lactonic biphenyl alkaloids and lactonic ether alkaloids, type B: piperidine metacyclophane alkaloids, type C: quinolizidine metacyclophane alkaloids). We agree, however, that lactonic biphenyl alkaloids and lactonic ether alkaloids should be considered separately and simple phenylquinolizldine alkaloids should be categorized as fifth group of Lythraceae alkaloid, as classified by Fujita and his coworkers (ref. 3) .

6 . Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem^ Pharm^ Bull^, 1978, 26, 2515. Fuji, K.; Ichikawa, K.; Fuji, K. Tetrahedron Lett^, 1979, 361. Fuji, K.; Ichikawa, K.; Fuji, E. Chem^ SociJL Perkin I, 1980, 1066.

7. Ferris, J. P. JN Org^ Chenu, 1962, 27, 2985.

8 . Blomster, R. N.; Schwarting, A. E.; Bobbit, J. M. Lloydia, 1964, 27, 15. Appel, A.; Rother, A.;

209 210

Schwarting, A. E. Lloydia, 1965, 28, 84.

9. Douglas, B.; Kirkpatrick, J. L.; Ra££aut, R. F.; Ribeiro, 0.; Weisbach, J. A. Lloydia, 1964, 27, 25.

1 0 . Fujita, E. ; Fuji, K.; Beaaho, K.; Sumi, A.; Nakamura, S. Tetrahedron Lett^, 1967, 4595. Fujita, E.; Fuji, K.; Tanaka, K. Tetrahedron Lett^, 1968, 5905.

11. Fujita, E.; Beaaho, K.; Saeki, Y.; Ochiai, M.; Fuji, K. Llo^dia, 1971, 34, 306.

12. Wright, H.; Clardy, J.; Ferria, J. P. J.J. Am_j_ Chem^ Soc., 1973, 95, 6467.

13. Rother, A.; Schwarting, A. E. Experientia, 1974, 30, 222. Rother, A.; Schwarting, A. E.; lloydia, 1974, 38, 447.

14. Rother, A.; Schwarting, A. E. Phytochemistry, 1978, 1 7, 305.

15. For a preliminary study directed toward the total synthesis o£ lythrancine-V (10), see: Quick, J.; Khandelwal, Y.; Meltzer, P. C.; Weinberg, J. S. J.. OrChem^, 1983, 48, 5199.

16. Lythrumine (i) and monoacetyllythrumine

17. As mentioned before, lythrumine (i) and 211

monoacetyllythrumine (ii) were isolated from a different Lythraceoua plant, Lythrum lanceolatun.

18. The numbering system of Lythraceae alkaloids was first introduced by Spencer and his coworkers, in particular, for type A and B alkaloids and lythrumine-type alkaloids (1 and ii). See: Horsewood, P.; Golebiewski. W. M.; Wrobel, J. T.; Spencer, I. D.; Cohen, J. F.; Comer, F. Can,. Chem^, 1979, 57, 1615. The system closely corresponds to that introduced by Fujita and his coworkers for the lythrancine and lythrancepine groups (ref. 19).

19. Fujita, E.; Saeki, Y. J. Chenu SociX Chemx Commun.., 1971, 368. Fujita, E.; Saeki, Y. Cherny ScOii Perkin I, 1972, 2141. Fujita, E.; Saeki, Y. Jx Chemx SociX Perkin I, 1973, 297. Fujita, E.; Saeki, Y. Jjj. Chemx SociX. Perkin I, 1973, 301. Fujita, E.; Saeki, y7 J ± Chemi_SociX. Perkin I, 1973, 306.

20. Barrow, M. J.; Cradwick, P. D.; Sim, G. A.; J. Chenji SociX Perkin II, 1974, 1812.

21. Hanaoka, M.; Ogawa, N .; Arata, Y. Tetrahedron Lett^, 1973, 2355. Hanaoka, M.; Ogawa, N.; Arata, Y . Chenu Pharmx Bui1^ , 1975, 23, 2140. Hanaoka, M.; Kamei, M.; Arata, Y. Chemx Pharm^ Bui1 ^ , 1975, 23, 2191. Hanaoka, H.; Ogawa, N,; Arata, Y. Chemx Pharm^ Bull.., 1976, 24, 1045.

22. Loev, B.; Lantos, I.; Van Hoeven, H. 0. Tetrahedron Lett.., 1974, 1101. Lantos, I.; Loev, Tetrahedron Lettj., 1975, 2011. Seitz, D. E.; Miliua, R. A.; Quick, J. Tetrahedron LettA, 1982, 1439. Lantos, I.; Razgaitis, C.; Van Hoeven, H.; Loev, B. Ji 0rgx Chemx , 1977, 42, 228.

23. Wrobel, J. T.; Golebiewski, W. M. Tetrahedron Lett^, 1973, 4293.

24. Hart, D. J.; Kanai, K. J.. 0 rgx Chem^, 1982, 42, 1555.

25. For an overview of research in the area of acyliminium ion initiated olefin cyclizationa, see: Speckamp, W. N. “Stereoselective Synthesis of Natural Products-Workshop Conferences Hoechst"■ Bartmann and Winterfeldt, Eds; Excerpta Medics 212

(Elsevier); Amsterdam, 1979; Vol. 7, p 50. Speckamp, W. N. Reclj, Trav^ Chim^ Pays^Baa, 1961, 100, 345.

26. Hubert, J. C.; Steege, W.; Speckamp, W. M.; Huisman, H. 0. Synth^ Comm^, 1971, 1, 103.

27. Dijkink, J.; Schoemaker, H. E.; Speckamp, W. N. I§t£§hedron Lett, 1975, 4043. Dijkink, J.; Speckamp, W. N. Tetrahedron Lett.., 1975, 4047. Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron Lettj., 1975, 3943 and 4035. Schoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett.., 1976, 1515 and 4841.

28. Schoemaker, H. E.; Dijkink, J.; Speckamp, W. N. Tetrahedron, 1976, 34, 163. Dijkink, J.; Speckamp, W. N. Tetrahedron, 1976, 34, 173. Schoemaker, H. E.; Kruk, C.; Speckamp, W. N. Tetrahedron Lett.., 1979, 2437.

29. Hart, D. J. L Aru ChemA Soc^, 1960, 102, 397.

30. See ref. 29 and references cited therein.

31. For a review of Ad'3) strain, see Johnson, F. Chem^ Rev^, 1968, 6 8 , 375.

32. Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. 0rg^_ Chem^, 1983, 48, 289 and references cited therein.

33. It was found that sequential treatment of n- octanal (ill) with lithium hexamethyldisilazide and allylmagnesium bromide gave a 10 % yield of homoallylic amine lv.

1.LiHMDS n-C1Hl5CH 0 ------► «-C7H15CH(NH2)CH2CH=CH2 2.CH2=CHCH2MgBr

iii iV

Therefore in this case, addition of the amide to the carbonyl group competes with enolization.

34. Basha, A; Lipton, M; Weinreb, S. M. Tetrahedron Lett^, 1977, 4171. 213

35. Purchased from Texas Alkyls Inc.

36. Stevens, R. V.; Lee, A. W. M. Am,. Chem^ Soc^, 1979, 101, 7032.

37. This value compares favorably with coupling constants of 1.5 and 5.5 Hz obtained for H-l in 33 (see ref. 29).

38. Corey, E. J.; Suggs, J. W. Tetrahedron Lett., 1975, 2647.

39. (a) Brown, H. C.; Krishnamurthy, S. Am,j. Chem,. Soc^, 1973, 95, 1669. Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J_. 0rgA Chem^, 1980, 41, 1. Brown, H. C.; Krishnamurthy, S. J; Am^ Chem,. 1973, 95, 1669. Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J,. OrgA Chem^ 1980, 45, 1.

40. For a review of 4-dialkylaminopyridines as acylation catalysts, see: Hofle, G.; Steglich, W; Vorbruggen, H. Angew^ Chem^ IntA Ed^ Engl^, 1978, 17, 569.

41. The Mitsunobu reaction might also be a adaptable to inversion of the C-3 stereochemistry. For the use of this reaction to invert C-3 stereochemistry in Lythraceae alkaloids, see: Takano, S.; Shiahido, K. Chem,. Soc^^ Chem^ Comm,., 1981, 940 and references cited therein. For a review of the Mitsunobu reaction, see: Mitsunobu, 0. Synthesis, 1981, 1.

42. Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. HelVi Chim,. Acta, 1971, 54, 710.

43. Scheibye, S.; Pederson, B. S.; Lawesson, S.-0. Bui1A SgcA Chim,. Belg^, 1978, 87, 229.

44. Walter, W. ; Voss, J. in "The Chemistry of Amides"; Zabicky, J., Ed.; John Wiley & Sons: New York, 1970; 383.

45. Ireland, R. E.; Brown, Jr. F. R. J,. Org. Chenu, 1980, 45, 1868.

46. Raucher, S.; Klein, P. Tetrahedron Lett^, 1980, 4061.

47. DABC0 was used as the t-amine base in NMR studies because it has only single peak at 6 3.05. 214

48. Petersen, J. S.; Fels, G.; Rapoport, H. J.. Am^ Chem^ Soc., 1984, 106, 4539.

49. Borch, R. F.; Bernstein, M. D.; Durst, H. D. Chem^ Sgcir 1971, 93, 2897. For review; Lane, C. F. Synthesis, 1975, 135.

50. The H-l signal could not be analyzed in the spectrum of amino ester 62, because the acetate methylene protons are in the same region and caused complication.

51. We thank Dr. Ruth Hsu for performing this analysis at the Ohio State University Department of Chemistry X-Ray Crystallographic Facility.

52. Fujita, E.; Fuji, K.; Tanaka, K. Chem^ Soc^ ICii, 1971, 205.

53. U.S. Bronze H 44.

54. Purchased from Morton Thiokol, Inc., Alfa Products.

55. Lowry, T. H.; Richardson, K. S. in "Mechanism and Theory in Organic Chemistry"; Second Ed.; Harper & Row, Publishers; New York, 1981; 628. Carey, F. A.; Sundberg, R. J. in "Advanced Organic Chemistry"; Plenum Press; New York, 1977; 327. Alder, R. W.; Baker, R.; Brown, J. M. in "Mechanism in Organic Chemistry"; Wiley- Interscience; London, 1971; 65. and references cited therein.

56. Hart, D. J.; Tsai, Y. M. Org^ Chem^, 1982, 47, 4403.

57. Hart, D. J.; Tsai, Y. M. Tetrahedron Lett^, 1981, 1567.

58. For other reports of 2-aza-Cope rearrangements, see: Nossin, P. M. M.; Speckamp, W. M. Tetrahedron 1981, 3289. Ent, H.; Koning, H.; Speckamp, W. M.Tetrahedron LettA , 1983, 2109. For reports of 2-aza-Cope rearrangements in related systems, see: Oveman, L. E.; Mendelson, L. T. Am_. Chem^ Socj., 1981, 103, 5579.

59. Hart, D. J.; Yang, T. K. Tetrahedron Lett^, 1982, 2761. Hart, D. J.; Yang, T. K. Chem. Soc^ 215

Chem^ Comm., 1983, 3, 135.

60. Hart, D. J.; Yang, T. K. J,. Org^ Chemi# 1985, 50, 235.

61. Hancuao, A. J.; Brownfain, D. S.; Swern, D. Org^ Chem^, 1979, 44, 4148. Omura, K.; Swern, D. 1978, 34, 1651. For a review, Hancuao. A. J.; Swern, D. Synthesis, 1981, 165.

62. Newman, M. S.; Yu, Y. T. Am. Chem^ Soc.., 1952, 74, 507.

63. Runeberg, J. Acta Cheiru Scan., 1958, 12, 188.

64. It la known that If diazomethane la paeaed Into an acid chloride a chloromethylketone la formed, whereaa If the acid chloride la added dropwlae to exceaa diazomethane aolutlon a dlazoketone la formed. See: Arndt, F.; Amende, J. Chenu Berif 1928, 61, 1122.

65. Wolfrom, M. L.; Waiabrot, S. W.; Brown, R. L. J.. Am^ Chemi Soc., 1942, 64, 1701.

6 6 . It haa been reported that treatment of a dlazo ketone with hydrogen Iodide glvea a methyl ketone

67. Bromoacetone waa prepared by the alow addition of bromine to a aolutlon of potaaaium chlorate in aqueoua acetone, aee: Catch, J. R.; Elliott, D. F.; Hey, D. H.; Jonea, E. R. H. Chem,. Soc^, 1948, 272.

6 8 . Pederaen, B. S.; Scheibye, S.; Nilaaon, N. H.; Laweaaon, S. -0. Bul-K Soc^ Chim^ Belg^, 1978, 87, 223. Fritz, H.; Hug, P,; Laweaaon, S. -0.; Logemann, E.; Pederaen, B. S.; Sauter, H.; Scheibye, S.; Winkler, T. Bui 1^ Soc. Qh im.-. Belg^, 1978, 87, 525.

69. Bohlmann, F.; Winterfeldt, E.; Studt, P.; Laurent, H.; Boroachewaki, 6 .; Kleine, K. M. Chem^ Ber^, 1961, 94, 3151. Bohlmann, F.; Winterfeldt, E.; Boroachewaki, G.; Mayer-Mader, R.; Gatacheff, B. Chenji Ber^, 1963, 96, 1792.

70. Toromanoff, E. Bull^ Soc^ ChimA Frlf 1966, 3357. For a valuable diacuaaion of many aapecta of atereoeletronic control aee: Dealongchamp, P. in 216

"Organic Chemistry Series"; Baldwin, J. E., Ed.; Pergamon Press: Oxford, 19S3; Vol. 1, 211 and references cited therein. Ziegler, F. E.; Spitzner, E. B. Anu Chem^_ SoCj, , 1 9 7 3 ,95, 7146. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P. Am^ Chem^ Soc^, 19B 3, 105, 7154. Stevens, R. V. Acc^ Chem^ Res^, 1 9 8 4 , 17, 289. Stevens, R. V. in "Strategies and Tactics in Organic Synthesis"; Lindberg, T., Ed.; Academic Press: Orlando, 1984; 275.

71. A different explanation as to why paths b and d are favored over a and c was offered by Houk and his coworkers. See: Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. Anu Chenw Soc., 1 9 8 1 , 103, 2438. This theory predicts a strong preference for anti-periplanar attack of the hydride ion with respect to the vicinal ^c-H bond (eg. C- 8 pseudo-axial protons in 164aand 1 6 4 b). Thus, in the hydride reduction of conformation 1 6 4 a ,for example, underside approach of the hydride ion toward the iminium ir bond is preferred due to stablization of the o|-orbital (low-lying vacant orbital of the iminium ion) through electron delocalization from the o’C-H bond into the <7-|-orbital, producing the chair conformation in ring B of 1 6 2 a . For a valuable discussion of this aspect of stereoelectronic control, see: Haruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H. JN Anu ChemA Soc., 1 9 8 3 , 105, 2831.

72. (a) Envelope conformations are common in cyclopentane. If an envelope conformation is to exist in a cyclohexane, it has been calculated that this form is about 14 Kcal mol'l above the chair form which means less stable than half-chair form (10.8 Kcal mol~^). (b) Average bond length of C=C is 1.34 A and that of N=C is 1.28 A.

73. Trans-fused quinolizidines, because of the nature of the ring fusion, are incapable of ring inversion. Cis-fused quinolizidinea are conformationally mobile and can undergo ring inversion. Thus, there are one trans-fused and two cis-fused conformers available to both 162and 163 respectively.

74. Because the Bohlmann band region (2800-2700 cm'l) is quite close to the strong -CH3 stretching 217

vibration bands, it is difficult to support the existence or absence of Bohlmann band in the IR spectra of 162and 163and analogues thereof. See: ref 22 and Moynehan, T. M.; Schofield, K.; Jones, R. A. Y.; Katritzky, A. R. J± Chem.. Soc^, 1 9 6 2 , 2637. Generally, a signal due to a proton attached to a carbon atom between a nitrogen and a phenyl group was observed at about 5 4 in cia- quinolizidine derivatives and at about 5 3 in trans-quinolizidine derivatives. See: Ferris, J. P.; Boyce, C. B.; Briner, R. C.; Douglas, B.; Kirkpatrick, J. L.; Weisbach, J. A. Tetrahedron 1 9 6 6 , 3641. Bohlmann, F.p Shumann, D.; Arndt, C. Tetrahedron Lett^, 1 9 6 5 , 2705. The observed value of 63.85-4.30 for the H-l proton of 162agrees with this value. However, because other trans-fused quinolizidine derivatives contain different functional groups (eg. amides, thioamide etc.) and this value is that of an axial hydrogens, it is not possible to compare the chemical shifts of other trans-fused quinolizidines. Instead, it is preferably to compare the coupling constants of H-l and H-3 to figure out the conformations of this series.

75. For a review of sulfone chemistry, see: Magnus, P. D . Tetrahedron, 1 9 7 7 , 33, 2019.

76. Prepared from sodium benzenesulfinate and dimethyl sulfate. See: Field, L.; Clark, R. D. Organic Synthesis, Col. Vol. IV p 674.

77. Field, L. Synthesis, 1972, 123.

78. Benzyl chloride 1 7 3 was prepared by Mr. Duane Burnett from 3-hydroxy-2-anisaldehyde in three steps.

79. House, H. 0.; Larson, J. K. J.. Org,. Chem^, 1 9 6 8 , 33, 61.

80. Corey, E. J.; Chaykovsky, M. Am. ChemA Soci( 1 9 6 5 , 87, 1345.

81. Wuonola, M. A.; Woodward, R. B. Tetrahedron, 1 9 7 6 , 32, 1085.

82. Russell, G. A.; Mikol, G. J. J_. Aru Chem,. Soc^, 1 9 6 6 , 8 8 , 5498.

83. Trost, B. M.; Arndt, H. C.; Strege, P. E.; 218

Verhoeven, T. R. Tetrahedron Lett.^, 1976, 3477.

84. Grimm, R. A.; Bonner, W. A.; J_. Org^ Chem.., 1967, 32, 3470.

85. Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem BerA , 1959, 92, 2499. Wadsworth, W. S.; Emmons, W. D. Am^ ChemA Soc^, 1961, 83, 1733.

8 6 . Dauben, W. G.; Beasley, G. H.; Broadhurst, M. D.; Muller, B.; Peppard, D. J.; Pesnelle, P.; Suter, C . Am. Chenu Soc^, 1975, 97, 4973.

87. Compound 182 was prepared by Dr. Y.-M. Tsai. The sequential treatment of triphenylphosphine with bromoacetone in toluene under reflux (2 h> and 3 N aqueous sodium hydroxide in benzene gave 182 in 81 a yield. See: Ramirez, F.; Dershowitz, S. J.. QE2 i 1957, 22, 41. Shevchuk, M. I.; Volynskaya, E. M.; Kudla, N. I.; Dombrovski, A. V. Jj, Org. Qb§mi2. USSR, 1970, 6 , 341.

8 8 . Jackson, W. R.; Zurqiyah, A. Chem^ Soc^, 1965, 5280.

89. Semmelhack, M. F.; Stauffer, R. D. Org^ Chenu, 1975, 40, 3619.

90. Lithium and potassium tri-s-butylborohydride (L- and K-Selectride respectively) in THF give 1,4- reduction for some cyclic enones. See: Ganem, B. Ji Org^ Chenji, 1975, 40, 147. Fortunato, J. M.; Ganem, B. JA Org^ Chem^, 1976, 41, 2194.

91. Parnes, Z. N.; Loim, N. M.; Baranova, V. A.; Kursanov, D. N. J,. Org^ ChemiX USSR, 1971, 7, 2145. Kursanov, D. N.; Loim, N. M.; Baranova, V. A.; Moiseeva, L. V.;Zalukaev, L. P.; Parnes, Z. N. §XQ!=?2§§i§» 1973, 420. For review, see: Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis, 1974, 633.

92. Excess trifluoroacetic acid is critical for the conversion of 183 to trifluoroacetate 185. With 10 equivalents of trifluoroacetic acid under reflux, ketone 183 converted to several compounds such as saturated ketone 184, saturated alcohol 187, trifluoroacetate 185, as well as starting ketone 183 under reflux for 24 h. Addition of more trifluoroacetic acid completed the conversion to trifluoroacetate 185 in 2 h. 219

93. Sunagawa, M.; Kotsube, J. "Abstracts of Papers, 7th Symposium on Progress in Organic Reactions and Syntheses"; Gifu, Japan, 1980, p 52.

94. Hoffman, Jr. J. M.; Schlessinger, R. M. J_- ChemA Socir Chem_j_ Cgmm^, 1971, 1245.

95. Curry, D. C.; Uff, B. C.; Ward. N. D. J^ Chem. SociA j(C)., 1967, 1120.

96. Joesten, M. D.; Schaad, L. J. in "Hydrogen Bonging"; Marcel Dekker, Inc.: New York, 1974.

97. Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. JA Ami Chenji SoCi, 1971, 93, 5908. Coffen, D. L.;Schaer, B.; Bizzarro, F. T.; Cheung, J. B. ^ Orgi Chen»i, 1984, 49, 296.

98. Semmelhack, M. F.; Ryono, L. S. J. An^ Chenji Sgc^, 1975, 97, 3873. Semmelhack, M. F.; Helquist, P. M.; Jones, L. D.; Keller, L.; Mendelson, L.; Ryono, L. P.; Smith, J. G.; Stauffer, R. D. Jz Ami Chemi SoCi, 1981, 103, 6460 and references cited therein. For the mechanistic studies of nickel coupling, see: Tsou, T. T.; Kochi, J. K. J ± Ami Chemi Soc^, 1979, 101, 6319. Tsou, T. T.; Kochi, J. K. JA Ai^ Chemi SoCi, 1979, 101, 7547.

99. Brandt, S.; Marfat, A.; Helquist, P. Tetrahedron Letti, 1979, 2193.

100. Schunn, R. A. Inorgi Synthi, 1973, 13, 124. Brandt, S., Ph.D. Thesis, Department of Chemistry, State University of New York at Stony Brook, 1979, 152. For a generation of Ni(0> 191 in situ, see: Kende, A. S.; Liebeskind, L. S.; Braitsch, D. M* Tetrahedron Letti, 1975, 3375. Mori, M.; Hashimoto, Y.; Ban. Y. Tetrahedron Letti, 1980, 631.

101. Prepared from nickel-aluminum alloy and sodium hydroxide in water, see: Pavlic, A. A.; Adkins, H. J_. Anti Chemi Soc. , 1946, 6 8 , 1471.

102. Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, 0. Tetrahedron Letti, 1984, 5397.

103. This result suggests that the hydrogenolysis of benzyl ethers analogous to 192 with W-4 Ra-Ni 220

could provide a new approach to the synthesis of piperidine metacyclophane alkaloids (type C ) .

104. Debenzylation methods have been reviewed. See: Hartung, W. H.; Simonoff, R. Organic Reactions, 1953, 7, 263. McCloskey, G. M. Advan. Carbghydi Chem^, 1957, 12, 137. Greene, T.~w7“In "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York, 1981, p 29 and references cited therein.

105. Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.; Heienhofer, J. JA Org^ Chem^, 1978, 43, 4194.

106. Anantharamaiah, G. M.; Sivanandaiah, K. M. Qben>i Soc. Perkin I, 1977, 490.

107. Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. Org^ Chemj,, 1979, 44, 1661.

108. Morita, T.; Okamoto, Y.; Sakurai, H. J. Chem. Sgci-t Chemj, Comm. , 1978, 874.

109. Jung, M. E.; Lyster, M. A. J^ Qrg.. Chemi, 1977, 42, 3761.

110. Kutney, J. P.; Abdurahman, N.; Quesne, P. L.; Piers, E.; Vlattas, I. JA Anti Chemi SoCi, 1 9 6 6 , 8 8 , 3656. Kutney, J. P.; Abdurahman, N.; Gletsos, C.; Quesne, P. L.; Piers, E.; Vlattas. I. Ji An»i Chemi SoCi, 1970, 92, 1727.

111. Frazer, M. J.; Gerrard, W. Ji Chenji SgCi, 1955, 2959. Gerrard, W.; Wheelans, M. A. Ji Chenji Sgc^, 1956, 4296. Manchandm P. S. Ji Chemi SoCi^ Chemi Cgmnji, 1971, 667.

112. We thank Professor Eiichi Fujita for graciously supplying a samples of authentic <+)- lythrancepine-II and -III.

113. For reviews of two-dementional NMR, see: Benn, R.; Gunter, H. Angew^ Chenji Inti Edi Engli, 1983, 22, 350. Shoolery, J. N. Ji Natural Products, 1984, 47, 226.

114. Bowden, E.; Adkins, H. Ami Chemi Soc^, 1940, 62, 2422.

115. Gaux, B.; Henaff, P. L. Bui 1A SgCi Chinji Frif 2 2 1

1974, 505.

116. McCord, T. J.; Thornton, D. E.; Hulme, K. L.; Davis, A. L. Texi Sciif 1978, 30, 357. Chem Absti, 1979, 91, 117861bT