One-step stereospecific strategy for the construction of the core structure of the 5, 11-methanomorphanthridine alkaloids in racemic as well as in optically pure form: Synthesis of (±)-pancracine and (±)- brunsvigine

FULL PAPER

DOI: 10.1002/ejoc.201100601

One-Step Stereospecific Strategy for the Construction of the Core Structure of

the 5,11-Methanomorphanthridine Alkaloids in Racemic as well as in Optically

Pure Form: Synthesis of (؎)-Pancracine and (؎)-Brunsvigine

Ganesh Pandey,*^[a]Ravindra Kumar,^[a]Prabal Banerjee,^[a]and Vedavati G. Puranik^[b]

Keywords: Alkaloids / Synthesis design / Cycloaddition / Azomethine ylides / Ring-closing metathesis

The unique core structure of the complex pentacyclic 5,11-

methanomorphanthridine has been constructed stereospecif-

ically in one step by an intramolecular [3+2] cycloaddition of

a non-stabilized azomethine ylide (AMY), generated by the

using a chiral dipolarophile was applied to construct the core

structure 68 with 63% ee. This strategy was successfully ap-

plied to the formal synthesis of (Ϯ)-pancracine and the total

synthesis of (Ϯ)-brunsvigine. An unprecedented and inter-

sequential double desilylation of 14 using Ag^IF as a one-elec- esting skeletal rearrangement product 49 was observed dur-

tron oxidant. The formation of the single diastereomer in the

key step is explained by the preferred transition state pro-

duced by endo attack of the AMY on the “Re” face of the

dipolarophile. An asymmetric version of the cycloaddition

ing the attempted assembly of the E ring from 46 through

Horner–Wadsworth–Emmons reactions. Mechanisms involv-

ing azetidinium salt formation or the Grob-type fragmenta-

tion are advanced to explain the observed rearrangement.

Introduction

The Amaryllidaceae alkaloids^[1]have long been a source

of structurally intriguing target molecules due to their ar-

chitectural diversity, limited supply and wide range of

promising biological activities that continue to challenge

the capabilities of contemporary organic synthesis. These

alkaloids encompass functionally and structurally diverse

pentacyclic 5,11-methanomorphanthridine frameworks and

were first isolated by Wildman and Brown^[2]in 1955 from

various plant species such as Pancratium, Narcissus and

Brunsvigia. In general, the alkaloids of this group, such as

(–)-pancracine (1),^[2](–)-brunsvigine (2),^[3](–)-montanine

(3),^[4](–)-coccinine (4),^[4](–)-manthine (5),^[4](–)-nangustine

(6)^[5]and (+)-montabuphine (7),^[6]possess identical struc-

tural features except for the oxygen substitutions in the E

ring (i.e., methoxy or hydroxy) and the stereochemistry at

C-2 and C-3, except for (–)-nangustine (6), as shown in Fig-

ure 1. These alkaloids have been shown to display anxi-

olytic, anti-depressive, anti-convulsive and weak hypoten-

sive activities.^[7]Owing to the unique structural features and

important biological activities associated with these alka-

loids, considerable synthetic efforts have been directed

Figure 1. Members of the montanine type of alkaloids.

towards their syntheses, but an efficient and conceptually

new route has remained elusive.

Scrutiny of the literature revealed that construction of

the core pentacyclic 5,11-methanomorphanthridine skel-

eton 8 has mainly been achieved through only three strate-

gies, such as the Pictet–Spengler reaction from 9, the intra-

molecular amination of 10 and the intramolecular radical

cyclization of 11 (Figure 2). Hoshino and co-workers^[8]ac-

complished the synthesis of 1–4 in racemic form from a

precursor of type 10, obtained by the Pictet–Spengler reac-

tion of the corresponding cyclohexane derivative. Jin and

Weinreb^[9]also used a similar cyclization protocol starting

from a compound of type 10 in their synthesis of (–)-

pancracine (1) and (–)-coccinine (4). In another approach,

Hoshino and co-workers^[10]used radical cyclization of a

[a] Division of Organic Chemistry, National Chemical Laboratory,

Homi bhabha Road, Pune 411008, India

Fax: +91-020-2590-2628

E-mail: gp.pandey@ncl.res.in

[b] Center for Material Characterization, National Chemical Labo-

ratory,

Homi bhabha Road, Pune 411008, India

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201100601.

Eur. J. Org. Chem. 2011, 4571–4587

4571

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

Figure 2. Main strategies adopted for the synthesis of the 5,11-methanomorphanthridine alkaloid skeleton.

precursor of type 11 to construct skeleton 8. Overman,^[11]14a on the “Re” face of the α,β-unsaturated carbonyl moi-

Pearson,^[12]Ikeda,^[13]Sha,^[14]Banwell,^[15]Chang,^[16]Hashi- ety would be energetically more favoured than exo attack

moto^[17]and Pansare^[18]and their co-workers all used pre- (B) due to steric repulsion (Figure 3). Such a cycloaddition

cursors of type 9 in their respective elaborations of these was also expected to fulfil all the stereochemical require-

alkaloids. However, in all these strategies, the syntheses ments of 8 in a single step without using a starting material

were elaborated from a precursor having the desired stereo- with fixed stereocentres.

chemistry at C-4a and C-11a and relative disposition of the

methylene bridge of 8, which involved its construction in a

stepwise manner.

We viewed the synthesis of 8 from an entirely different

angle (Scheme 1), employing the [3+2] cycloaddition of a

non-stabilized azomethine ylide (AMY, 8a) for the con-

struction of the core-substituted CD-ring system, which on

further elaboration by employing a suitable C–C bond-

forming reaction would provide the E ring.

Figure 3. Empirical view of transition state 14a (hydrogen atoms

have been omitted for simplicity).

Enthused by the above concept and design, we pursued

our initial retrosynthetic plan for (Ϯ)-pancracine (1), which

is shown in Scheme 2.

Scheme 1. Retrosynthetic analysis.

Model Studies

In this article we present the full details^[19]of our concept

To check the feasibility of our proposed strategy, we

and the development of a strategy that leads to the total

studied the intramolecular [3+2] cycloaddition of non-stabi-

synthesis of montanine-type Amaryllidaceae alkaloids.

lized azomethine ylide 22a, as shown in Scheme 3. Key pre-

cursor 22 was easily prepared in 72% yield by the Heck

coupling of 21 with ethyl acrylate (8 equiv.). Compound 21

was prepared in 78% yield by the deprotection of the

Results and Discussion

N-Boc moiety of 20 using TFA followed by N-alkylation

with (iodomethyl)trimethylsilane in the presence of excess

Background and Concept

Our continuing interest in exploring the application of K₂CO₃in dry CH₃CN under reflux. The crucial cycload-

non-stabilized azomethine ylides (AMYs), generated by se- dition step involved the dropwise addition of 22 to a stirred

quential double desilylation of α,αЈ-bis(trimethylsilyl)-sub- heterogeneous mixture of flame-dried Ag^IF (2.5 equiv.) in

stituted alkyl(methyl)amines using Ag^IF as a one-electron dry CH₃CN at room temperature. Chromatographic purifi-

oxidant,^[20]for the total synthesis of architecturally complex cation of the crude mass gave the expected tetracyclic core

alkaloids^[21]led us to envisage the intramolecular 1,3-di- 23 of 5,11-methanomorphanthridine in 65% yield, which

polar cycloaddition of AMYs of type 8a for the stereospec- was fully characterized by IR, ¹H and ¹³C NMR, and mass

ific construction of the critical CD ring of 5,11-meth- spectral analyses. The relative stereochemistry of 23 was

anomorphanthridine alkaloids in a single step. While confirmed by 2D NMR studies.

designing the synthetic route, it was very clear to us from

Inspired by the success of this strategy for the construc-

the beginning that intramolecular endo attack (A) of AMY tion of the ABCD-ring system of 5,11-methanomor-

4572

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

Scheme 2. Initial retrosynthetic plan for the synthesis of pancracine (1).

Scheme 3. Reagents and conditions: (a) (Boc)₂O, NaOH, H₂O, 0 °C to room temp., overnight, 90%; (b) I₂, CF₃COOAg, CHCl₃, 1 h,

70%; (c) TFA, CH₂Cl₂, 0 °C to room temp., 4 h, quant.; (d) ICH₂TMS, K₂CO₃, CH₃CN, reflux, 10 h, 78%; (e) ethyl acrylate,

Pd(OAc)₂, PPh₃, K₂CO₃, CH₃CN, reflux, 10 h, 72%; (f) Ag^IF, CH₃CN, room temp., 12 h, 65%.

phanthridine skeleton 23, we proceeded with the proposed

synthesis of montanine-type alkaloids by this strategy.

The cycloaddition reaction of the AMY 14a, generated

from 14 according to the standard cycloaddition protocol,

gave 13 (56% isolated yield) as a single diastereoisomer

(Scheme 5). The stereochemistry of 13 was assigned on the

basis of extensive COSY, NOESY and HETCOR NMR

Formal Total Synthesis of (؎)-Pancracine (1)

Initially, we focused our attention on synthesizing 12, an spectral studies.^[22]With fused tetracyclic intermediate 13 in

advanced intermediate used by Overman and Shim^[11]in the hand, the only task remaining to complete the formal syn-

total synthesis of (Ϯ)-pancracine (1), by the intramolecular thesis of 1 was the construction of the E ring, which we had

cycloalkylation of cycloadduct 13. The cycloaddition pre- envisaged by a cycloalkylation strategy. Whereas debenzo-

cursor 14 was prepared (60%) by Heck coupling of 15 with ylation of 13 by stirring with LiOH/MeOH at room tem-

methyl vinyl ketone (MVK, 8 equiv.). Compound 15 was perature resulted in unexpected epimerized alcohol 30 in

synthesized in 81% yield by N-alkylation of 17 with 16 in 98% yield (confirmed by X-ray crystallography),^[23]reaction

CH₃CN at reflux in the presence of activated K₂CO₃fol- at 0 °C gave 29 (Scheme 5). However, because the stereo-

lowed by simple benzoylation of the primary hydroxy chemistry at C-11a at this stage was irrelevant for accomp-

group. The bis(silylated) secondary amine 17 was synthe- lishing the synthesis of the final natural product, we contin-

sized (61% overall yield) easily by starting from 3-propan- ued with 30. Cycloalkylation of the corresponding mesylate

1-ol (24) as shown in Scheme 4.

derivative of 30 by using LDA/THF^[24]at –78 °C produced

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4573

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

Scheme 4. Reagents and conditions: (a) (Boc)₂O, Et₃N, CH₂Cl₂, 0 °C to room temp., 36 h; (b) CH₃CH(OEt)₂, PPTS, benzene, reflux,

10 h, 90% over two steps; (c) sBuLi, TMEDA, THF, –78 °C, 4 h then TMSCl, 2 h, 92%; (d) p-TsA, MeOH/H₂O, room temp., 4 h, quant.;

(e) 1 n HCl, dioxane, 45 min, reflux, 92%; (f) ICH₂TMS, K₂CO₃, CH₃CN, reflux, 10 h, 80%; (g) 16, K₂CO₃, CH₃CN, reflux, 10 h;

(h) BzCl, Et₃N, CH₂Cl₂, 0 °C to room temp., 6 h, 81%; (i) Pd(OAc)₂, PPh₃, K₂CO₃, MVK, CH₃CN, reflux, 12 h, 60%.

Scheme 5. Reagents and conditions: (a) Ag^IF, CH₃CN, room temp., 12 h, 56%; (b) LiOH/MeOH, at 0 °C; (c) LiOH/MeOH, room temp.,

3 h, 98%.

the rearranged product 34 in 65% yield. The formation of that would allow the synthesis of other alkaloids of this

34 indicated the possible involvement of the thermo- class. Because there are a variety of oxygen substituents at

dynamic enolate 32 in this rearrangement (Scheme 6).

C-2 and C-3 in the E ring, it was essential to consider build-

This unexpected setback led us to explore an alternative ing a regioselective double bond (masked oxygen function-

strategy of generating the kinetic enolate from 30 by using ality) in the E ring. In this context, we envisioned 36 as an

KHMDS/THF^[25]at –78 °C, which produced the expected ideal precursor, which in turn we visualized could be ob-

cyclized product 33 (11a-epi-12) in 58% yield. To complete tained from 37 by employing a suitable method (Scheme 7).

the formal total synthesis of 1, compound 33 was trans-

Towards this end, different approaches were attempted,

formed into 35 by reductive elimination of the correspond- and their failures and successes are presented in chronologi-

ing enol triflate by using [Pd(PPh₃)₄]/Et₃SiH in THF^[26]cal order of the development.

(71% yield). The required enol triflate was generated from

33 by the reaction of the corresponding lithium enolate of

33 with Comins reagent.^[27]

First-Generation Approach – Intramolecular Mukaiyama-

Type Aldol Reaction

After accomplishing the synthesis of 35,^[19]an advanced

intermediate used by Overman and Shim^[11]in the synthesis

of 1, we realized the limitation of this approach for the syn-

Initially, we planned to synthesize enone 36 from cy-

thesis of other members of this class of alkaloids. Therefore, cloadduct 38, which is appropriately equipped with a

we turned our attention towards designing a general route ketone as well as an acetal, by an intramolecular Mukai-

4574

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

Scheme 6. Reagents and conditions: (a) MsCl, Et₃N, CH₂Cl₂, 0 °C to room temp., 15 min, quant.; (b) LDA, THF, –78 °C to room temp.,

5 h, 65%; (c) KHMDS, THF, –78 °C to room temp., 5 h, 58%; (d) LDA, THF, Comins reagent, –78 °C to room temp., 6 h; (e) [Pd-

(PPh₃)₄], Et₃SiH, LiCl, THF, 60 °C, 24 h, 71% over two steps.

Scheme 7. General route for the synthesis of 1–5.

Scheme 8. Reagents and conditions: (a) Iodoxybenzoic acid, ethyl acetate, reflux, 10 h, quant.; (b) ethylene glycol, p-TsA, benzene, Dean–

Stark, overnight, 90%; (c) TFA, CH₂Cl₂, 0 °C to room temp., 4 h, quant.; (d) ICH₂TMS, K₂CO₃, CH₃CN, reflux, 10 h, 77%; (e) 16,

K₂CO₃, CH₃CN, reflux, 10 h, 85%; (f) Pd(OAC)₂, PPh₃, K₂CO₃, MVK, CH₃CN, reflux, 12 h, 65%; (g) Ag^IF, CH₃CN, room temp., 12 h,

53%; (h) TMSOTf, 2,6-lutidine, –20 °C, THF.

yama-type aldol reaction.^[28]Based upon the above premise,

We attempted first the aldol reaction of 38 by subjecting

38 was synthesized (53% isolated yield) as a single dia- it to TMSOTf (2 equiv.) and 2,6-lutidine (3 equiv.)^[30]at

stereomer from 42 according to the usual cycloaddition –20 °C in THF; however, 36 could not be obtained, and

procedure. The synthesis of 42 along with its cycloaddition instead we ended up with an unidentifiable product. This

reaction is depicted in Scheme 8. The structure and stereo- un-anticipated failure led us to try the classic acid/base-cat-

chemistry of 38 were confirmed by single-crystal X-ray alysed intramolecular aldol reaction^[31]with the unmasked

1

crystallography as well as detailed 2D H NMR spectral aldehyde. Towards this end, we initially attempted to depro-

analyses.^[29]

tect the dioxolane moiety of 38 under mild reaction condi-

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4575

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

Scheme 9. Reagents and conditions: (a) 3 n HCl, THF/H₂O, room temp., 8 h, 90%; (b) 3 n HCl, THF/H₂O, reflux. 10 h, 88%.

Table 1. Reaction conditions employed in the attempts to perform the aldol reaction.

Entry

Starting material

Conditions

Inference

1

2

3

4

5

6

7

8

9

38

43

45

2,6-lutidine, TMSOTf, –20 °C^[30]

3 n HCl, THF, room temp., overnight

3 n HCl, THF, reflux, 10 h

unidentified

43

45

KHMDS, TMSOTf, THF, –78 °C

KHMDS, Bu₂BOTf, DME, –78 °C

LiHMDS, TiCl₄, CH₂Cl₂, –78 °C

3 n HCl, THF/H₂O, reflux

starting material

complex mixture

Camphorsulfonic acid/xylene, reflux^[36]

NaOMe/MeOH, room temp.^[37]

KOH/MeOH, room temp.

10

11

DBU, toluene, reflux

tions, namely by using (a) p-TsA, acetone, (b) PPh₃, CBr₄, (12%). Therefore, we proceeded with compound 48, and its

THF, 0 °C,^[32](c) DDQ, CH₃CN/H₂O (9:1), room temp.^[33]reaction with the lithium salt of diethyl methylphosphonate

and (d) TMSI, CH₃CN,^[34]etc.; however, no reaction was gave 46 in 92% yield (Scheme 10). Compound 48 was easily

observed. Furthermore, stirring 38 with 3 n HCl in THF/ synthesized (39% yield) in two steps by starting from 41

H₂O (1:1) at room temperature produced only epimerized using an identical cycloaddition reaction. The structure of

product 43 instead of the expected aldehyde 44. The stereo- compound 48 was unambiguously confirmed by 1D and 2D

chemistry of 43 was confirmed by spectroscopic analysis NMR analyses as well as by single-crystal X-ray crystal-

and single-crystal X-ray crystallography (Scheme 9).^[35]

lography.^[39]

Finally, aldehyde 45 was obtained by heating 43 at reflux

Attempted deprotection of the acetal moiety of 46 under

with 3 n HCl for 10 h, which was then subjected to different a variety of acidic conditions (3 n HCl/THF/H₂O, oxalic

acid- as well as base-catalysed aldol reactions (Table 1, En- acid/THF/H₂O) prior to executing the HWE reaction re-

tries 7–11), but all attempts failed to deliver any identifiable sulted only in the rearranged product 49 in 68% yield along

product. Furthermore, we tried to obtain the aldol reaction with some unidentifiable product. The formation of 49 may

product from 38 as well as 43 (11a-epi-38) under various be rationalized by invoking the intermediacy of the thermo-

reaction conditions (Table 1), but again all our attempts dynamic enol ether followed by rearrangement by Grob-

failed to deliver the corresponding enone.

type fragmentation^[40]or by the azetidium salt intermediate

55, as shown in Scheme 11. This rearranged skeletal product

supports our earlier observation for the formation of 34.

After all these failures, we reached the conclusion that

both 38 and 46 during dioxolane deprotection under

thermodynamic reaction conditions either rearrange from a

Second-Generation Approach – Horner–Wadsworth–

Emmons (HWE) Reaction

After these frustrating and unanticipated hurdles in ob- five- to a seven-membered ring to relieve strain or it stops

taining 36 or 11a-epi-36 by the aldol reaction, we evaluated with the epimerization at the C-11a centre to reduce the

the intramolecular HWE reaction^[38]of substrate 46. We steric congestion between the ketone and the acetal, which

initially tried to synthesize 46 by treating 38 with diethyl in turn probably does not allow it to form the cyclic enone

chlorophosphonate in the presence of KHMDS at –78 °C; because it would lead to a conformationally strained system

however, this approach gave product 46 in very poor yield with three sp²-hybridized carbon atoms in the E ring.

4576

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

Scheme 10. Reagents and conditions: (a) KHMDS, ClPO(OEt)₂, THF, –78 °C to room temp., 2 h, 12%; (b) Pd(OAc)₂, PPh₃, K₂CO₃,

ethyl acrylate, CH₃CN, reflux, 12 h, 70%; (c) Ag^IF, CH₃CN, room temp., 12 h, 56%; (d) CH₃PO(OEt)₂, nBuLi, –78 °C, then 48, 2 h,

THF, 92%; (e) oxalic acid, THF/H₂O (1:1), reflux, 10 h, 68%.

Scheme 11. Plausible mechanism for the formation of 49 [R = CH₂P(O)(OEt)₂].

Third-Generation Approach – Ring-Closing Metathesis

(RCM) Approach

This observation was not very surprising as it is known

that a free/unprotected amine coordinates to the ruthenium

atom and reduces the catalytic activity of the catalyst. For-

tunately, it has also been established that ammonium salts

With the above disappointing results, we envisaged to install are tolerated very well by the ruthenium catalyst.^[42]There-

the C-2=C-3 double bond by ring-closing metathesis fore, the metathesis of 59 in the presence of different acids

(RCM) of a substrate of type 59, which can be synthesized such as p-TsA,^[43]Ti(OiPr)₄^[44]and HCl^[45]by using Grubbs’

by starting from 48. Because our initial attempt to synthe- second-generation catalyst in boiling benzene for 10–15 h

size 57a by one-carbon Wittig olefination of the corre- was examined. The best cyclization results were obtained

sponding aldehyde, obtained by hydrolysis of 48 using by using 59·HCl, which produced a mixture of 60 and 61

methylenetriphenylphosphorane, was found to be low-yield- in 93% yield (dr = 2.5:1). Both diastereomers 60 and 61

ing (45%), 57b was obtained in 68% yield by using benzyl- were isolated pure by column chromatography and were

1

idenetriphenylphosphorane. DIBAl-H reduction of 57b characterized by H and ¹³C NMR spectroscopy. The ste-

gave 58 in 96% yield, which on Swern oxidation followed reochemistry at C-1 was assigned on the basis of extensive

by reaction with vinylmagnesium bromide (1 m solution in COSY and NOESY studies.

THF) gave the corresponding alcohol, purified as the acet-

At this stage, we realized the potential of both 60 and 61

ate derivative 59 (95% yield, dr = 2.5:1). RCM of 59 by for the synthesis of natural products 1–5 by functional-

using either Grubbs’ catalysts (first or second generat- group interconversions, exploiting the stereochemistry of

ion)^[41]in CH₂Cl₂or benzene (room temperature to reflux) the allylic acetoxy functionality for directing the hydroxyla-

failed to give the expected cyclized product (Scheme 12).

tion of the double bond.

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4577

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

Scheme 12. Reagents and conditions: (a) (i) oxalic acid, THF/H₂O (1:1), reflux, 24 h; (ii) benzylidenediphenylphosphorane, nBuLi then

aldehyde, 0 °C to room temp., overnight, 68%; (b) DIBAl-H, CH₂Cl₂, –78 °C to room temp., 1 h, 96%; (c) (i) (COCl)₂, DMSO, CH₂Cl₂,

–78 °C, 2 h then TEA, quant.; (ii) vinylmagnesium bromide, THF, 0 °C to room temp., 6 h, quant.; (iii) Ac₂O, TEA, DMAP, CH₂Cl₂,

0 °C to room temp., 4 h, 94%; (d) 59·HCl, Grubbs’ 2nd generation catalyst (10 mol-%), benzene, reflux, 12 h, 93%.

Total Synthesis of (؎)-Brunsvigine (2)

failed to yield the desired compound 65. Therefore, we first

deprotected the acetate moiety to the corresponding alcohol

To achieve a total synthesis of 2, the major diastereomer 64 (NaOMe/MeOH, 91% yield) and then mesylated it. The

60 was subjected to dihydroxylation (OsO₄, trimethylamine corresponding mesyl derivative of 64 was heated at reflux

N-oxide, pyridine, tBuOH/H₂O) to afford 62 as a single dia- with DBU in toluene (2 d) to afford 65 in 89% yield. Aceto-

stereomer in quantitative yield. The stereochemical out- nide deprotection by passing HCl (gas) into a methanolic

come was confirmed by single-crystal X-ray analysis.^[46]In- solution of 65 afforded the (Ϯ)-brunsvigine·HCl (2·HCl)

stallation of the pivotal Δ^1,11adouble bond required to salt in quantitative yield (Scheme 13). For better purifica-

complete the total synthesis of 2 was initially attempted by tion and characterization, 2·HCl was transformed into the

deacetylation^[47]of the acetonide-protected dihydroxy com- corresponding diacetate derivative 2A by using Ac₂O in

pound 63 using DBU at an elevated temperature, but this pyridine. Note that compound 2A can be synthesized from

Scheme 13. Reagents and conditions: (a) OsO₄, trimethylamine N-oxide, pyridine, tert-butanol/H₂O, 18 h, quant.; (b) 2,2-dimethoxypro-

pane, p-TsA, acetone, room temp., 6 h, 95%; (c) NaOMe, MeOH, room temp., 4 h, 91%; (d) (i) MsCl, TEA, DMAP, CH₂Cl₂, 0 °C to

room temp., 5 h, quant.; (ii) DBU, toluene, 110 °C, 2 d, 89%; (e) HCl_(gas), MeOH, 30 min, quant.; (f) Ac₂O, DMAP, pyridine, 20 h, quant.

4578

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

Scheme 14. Reagents and conditions: (a) Pd(OAc)₂, PPh₃, K₂CO₃, 67, CH₃CN, reflux, 12 h, 65%; (b) (i) Ag^IF, CH₃CN, room temp., 18 h;

(ii) LAH, THF, 0 °C to room temp., 46% over two steps.

60 without purification of any intermediate in 80% overall obtain 66 in 65% yield (Scheme 14).^[50]Intramolecular

yield. The spectroscopic data for compounds 65 and 2A cycloaddition of 66 gave the corresponding cycloadduct,

were found to be in excellent agreement with those re- which was subjected to LAH reduction without purification

ported.^[14]

and characterization to give 68 (ee = 63% after crystalli-

zation)^[51]in 46% yield over two steps. Compound 68 can

easily be converted into RCM products 60 and 61 via 59 as

demonstrated earlier in Scheme 12.

Development of a Chiral Auxiliary Based Asymmetric 1,3-

Dipoar Cycloaddition Strategy for the Synthesis of the

Enantiomerically Enriched 5,11-Methanomorphanthridine

Skeleton

Conclusions

After succeeding in synthesizing 5,11-methanomor-

We have successfully developed a conceptually novel and

phanthridine alkaloids in racemic form, we turned our at- efficient protocol featuring a one-step stereospecific con-

tention towards developing a conceptually new and general struction of the core structure of the 5,11-methanomor-

protocol for the synthesis of these alkaloids in enantiomer- phanthridine alkaloid by the 1,3-dipolar cycloaddition of a

ically enriched form. Most of the asymmetric approaches non-stabilized AMY, and this strategy was elegantly applied

known for the synthesis of montanine alkaloids are mainly to the formal synthesis of (Ϯ)-pancracine. To develop a ge-

based on chiral-pool strategies except for two recent reports neral and versatile route to the synthesis of these types of

on the formal synthesis of pancracine^[17,18]based on alkaloids, different protocols, such as Mukaiyama-type al-

organocatalytic approaches. The asymmetric 1,3-dipolar cy- dol, Horner–Wadsworth–Emmons (HWE) and RCM reac-

cloaddition of azomethine ylides to a variety of alkenes has tions, were attempted for the efficient construction of the E

emerged as one of the most powerful strategies for the con- ring. An RCM protocol was found to be a robust strategy

struction of enantiopure pyrrolidine ring systems.^[48,49]for assembling the E ring with a double bond at the appro-

Therefore, developing an asymmetric [3+2] cycloaddition priate position. This strategy was successfully used for the

approach for assembling the 5,11-methanomorphanthridine total synthesis of (Ϯ)-brunsvigine. We have also envisaged

framework appeared to be worth exploring as this would extending the use of the RCM products 60/61 to the total

be an entirely new concept in this area.

synthesis of other members of this class by stereoselective

In this regard, we designed our strategy starting from the functionalization of the double bond and exploiting the ste-

same intermediate 41 and equipped it with Evans’ oxazolid- reochemistry of the acetoxy/hydroxy functionality at the al-

inone chiral auxiliary 67 by the Heck coupling reaction to lylic position, as shown in Scheme 15.

Scheme 15. Outlines of the synthesis of other montanine alkaloids.

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4579

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

(6-Iodo-1,3-benzodioxol-5-yl)-N,N-bis[(trimethylsilyl)methyl]-

methanamine (21): A 100 mL round-bottomed flask, equipped with

an argon gas balloon and a magnetic stirring bar was charged with

a solution of 20 (4 g, 10.61 mmol) in dry CH₂Cl₂(40 mL) and co-

oled to 0 °C. Trifluoroacetic acid (6.05 g, 53.05 mmol) was intro-

duced dropwise into the stirring solution through a syringe at 0 °C,

and then the mixture was warmed to room temp. and stirred for a

further 4 h. The reaction mixture was recooled to 0 °C and basified

with an aqueous NaOH solution (pH = 10). The organic layer was

separated, and the aqueous layer was extracted with CH₂Cl₂

(2ϫ30 mL). The combined extracts were washed with brine, dried

with Na₂SO₄, and concentrated to give the crude amine, which was

used without further purification in the next step. (Iodomethyl)tri-

methylsilane (3.15 mL, 21.22 mmol) was added to a stirred hetero-

geneous solution of the crude amine and K₂CO₃(3.75 g,

26.25 mmol) in CH₃CN (60 mL), and the mixture was heated at

reflux for 10 h. The reaction mixture was cooled to room temp.,

and K₂CO₃was filtered off by using suction. The filtrate was con-

centrated under reduced pressure to give a pasty mass, which was

dissolved in ethyl acetate and washed with water (2ϫ20 mL), brine

(20 mL), dried with Na₂SO₄, and concentrated again to afford a

yellow oil, which was purified by silica gel column chromatography

(petroleum ether/ethyl acetate, 95:5) to obtain 21 as a pale-yellow

oil (3.5 g, 78%). R_f= 0.4 (petroleum ether/ethyl acetate, 9:1). IR

We have also developed an asymmetric route to the con-

struction of the 5,11-methanomorphanthridine framework

through a chiral auxiliary based intramolecular asymmetric

1,3-dipolar cycloaddition of a non-stabilized azomethine

ylide. This methodology not only has potential to be ex-

tremely useful in the synthesis of natural-product targets,

but also provides a new entry to the field of intramolecular

asymmetric 1,3-dipolar cycloaddition reactions.

Experimental Section^[52]

General: All reactions requiring anhydrous conditions were per-

formed under a positive pressure of argon by using oven-dried

glassware (110 °C), which were cooled under argon. Solvents for

anhydrous reactions were dried according to Perrin and co-

workers.^[37]Benzene, CH₂Cl₂, and triethylamine were distilled from

CaH₂and stored over molecular sieves and KOH, respectively.

THF and diethyl ether were distilled from sodium benzophenone

ketyl. Solvents used for chromatography were distilled at their re-

spective boiling points according to known procedures. Petroleum

ether used in the experiments had a boiling range of 60–80 °C.

All commercial reagents were obtained from Sigma–Aldrich and

Lancaster Chemical Co. (U.K.). n-Butyllithium and s-butyllithium

were titrated by using diphenylacetic acid as indicator. TMSCl and

MsCl were distilled before use. The progress of reactions was moni-

tored by TLC, performed on aluminium sheets precoated with sil-

ica gel 60 (Merck, 230–400 mesh). Compounds were visualized by

heating after dipping in an alkaline solution of KMnO₄and

(NH₄)₆Mo₇O₂₄(6.25 g) in aqueous H₂SO₄(250 mL). Column

chromatography was performed on silica gel (60–120/100–200/230–

400 mesh). Typical syringe and cannula techniques were used to

transfer air- and moisture-sensitive reagents. All melting points

were recorded with Thermonik and Büchi melting-point instru-

ments. IR spectra were recorded with Perkin–Elmer 599-B IR and

1620 FT-IR spectrometers. ¹H NMR spectra were recorded with

Bruker ACF 200, AV 400 and DRX 500 instruments by using de-

uteriated solvents. Chemical shifts are reported in ppm, proton

coupling constants (J) are reported as absolute values in Hz, and

multiplicity is given as follows: br., broadened; s, singlet; d, doublet;

t, triplet; dt, doublet of triplets; td, triplet of doublets; ddd, doublet

of doublet of doublets; m, multiplet). ¹³C NMR spectra were re-

corded with Bruker ACF 200, AV 400 and DRX 500 instruments

operating at 50, 100 and 125 MHz, respectively. ¹³C NMR chemical

shifts are reported in ppm relative to the central line of CDCl₃(δ

= 77.0 ppm). Mass spectra were recorded with a PE SCIEX API

QSTAR pulsar spectrometer (LC-MS), automated GC–MS with

a solid-probe facility mass spectrometer and high-resolution mass

spectrometry (HRMS) were recorded with an MSI (U.K.) Auto-

concept instrument with ionization by electron impact, achieved at

an ionization potential of 70 eV. X-ray data for four compounds

were collected at T = 296 K with a SMART APEX CCD single-

crystal X-ray diffractometer by using Mo-K_αradiation (λ =

0.7107 Å) to a maximum θ range of 25.00°. The structures were

solved by direct methods using SHELXTL.^[53]All the data were

corrected for Lorentzian, polarisation and absorption effects.

SHELX-97 (SHELXTL) was used for structure solution and full-

matrix least-squares refinement on F². Hydrogen atoms were in-

cluded in the refinement as per the riding model. The refinements

were carried out by using SHELXL-97. Microanalysis data were

obtained by using a Carlo–Erba CHNS-O EA 1108 Elemental

Analyser at National Chemical Laboratory.

(neat): ν_max= 2954, 2925, 2358, 1502, 1475, 1247, 1103, 1041 cm^–1.

˜

¹H NMR (200 MHz, CDCl₃): δ = 7.22 (s, 1 H), 7.12 (s, 1 H), 5.97

(s, 2 H), 3.37 (s, 2 H), 1.97 (s, 4 H), 0.05 (s, 18 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 148.0 (C), 146.7 (C), 135.6 (C), 117.7 (CH),

109.7 (CH), 100.9 (CH₂), 86.4 (C), 69.4 (CH₂), 50.3 (CH₂), –1.5

[Si(CH₃)₃] ppm. MS: m/z = 450.34 [M + 1]⁺. C₁₆H₂₈INO₂Si₂

(449.48): calcd. C 42.75, H 6.28, N 3.12; found C 42.56, H 6.07, N

3.28.

Ethyl (E)-3-[6-({Bis[(trimethylsilyl)methyl]amino}methyl)-1,3-benzo-

dioxol-5-yl]acrylate (22): Ethyl acrylate (1.74 mL, 16.03 mmol) was

added to a mixture of K₂CO₃(0.55 g, 4.00 mmol), Pd(OAc)₂

(0.04 g, 0.16 mmol), PPh₃(0.09 g, 0.32 mmol) and 21 (1.00 g,

2.00 mmol) in dry CH₃CN (15 mL). The mixture was purged with

argon to degas it properly. The reaction mixture was stirred at room

temp. for 1 h and heated at reflux under argon for an additional

12 h. The volatile material was removed under reduced pressure,

the whole dark-brown mass was dissolved in CH₂Cl₂, and the or-

ganic layer was washed with 0.1 n HCl (3ϫ10 mL). The aqueous

layer was extracted with CH₂Cl₂(2ϫ10 mL), and the combined

organic extracts were washed with brine, dried with Na₂SO₄, con-

centrated under reduced pressure, and the residue was purified by

column chromatography (petroleum ether/ethyl acetate, 95:5) to

give 0.61 g (72%) of 22 as a yellow liquid. R_f= 0.3 (petroleum

ether/ethyl acetate, 9:1). IR (CHCl ): ν_max= 2954, 2898, 2360, 1712,

˜

3

1631, 1504, 1485, 1257, 1176, 1041 cm^–1. ¹H NMR (300 MHz,

CDCl₃): δ = 8.12 (d, J = 15.9 Hz, 1 H), 7.01 (s, 1 H), 6.97 (s, 1 H),

6.14 (d, J = 15.9 Hz, 1 H), 5.95 (s, 2 H), 4.20 (q, J = 7.1 Hz, 2 H),

3.46 (s, 2 H), 1.85 (s, 4 H), 1.54 (t, J = 7.1 Hz, 3 H), 0.27 (s, 18 H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 167.0 (CO), 149.2 (C), 146.9

(C), 141.8 (CH), 135.3 (C), 127.6 (C), 117.4 (CH), 110.4 (CH),

105.6 (CH), 101.2 (CH₂), 63.2 (CH₂), 60.2 (CH₂), 50.7 (CH₂), 14.3

(CH), –1.1 [Si(CH₃)₃] ppm. MS: m/z

= 422.12 [M +

1]⁺.

C₂₁H₃₅NO₄Si₂(421.68): calcd. C 59.81, H 8.37, N 3.32; found C

59.63, H 8.19, N 3.11.

Ethyl 4,5-Methylenedioxy-9-azatricyclo[7.2.1.0^2,7]dodeca-2,4,6-tri-

ene-11-carboxylate (23): A solution of 22 (0.50 g, 1.90 mmol) in dry

CH₃CN (30 mL) was added slowly to an argon-flushed 100 mL

two-necked flask containing vacuum-dried Ag^IF (0.590 g,

4.7 mmol) in dry CH₃CN (30 mL) at room temp. The colour of the

4580

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

reaction mixture gradually turned to dark brown with concomitant

deposition of silver on the surface of the flask in the form of a

mirror. The reaction was monitored periodically by TLC. After

stirring for 12 h, the reaction mixture was filtered through a small

plug of basic alumina, and the solvent was evaporated to give a

crude brown residue, which was purified by silica gel column

chromatography (petroleum ether/acetone, 55:45) to give 23 (0.21 g,

65%) as a white solid. R_f= 0.3 (petroleum ether/acetone, 6:4); m.p.

methylsilane (2.3 mL, 15.10 mmol) was added to this solution,

which was heated at reflux for 10 h. The reaction mixture was co-

oled to room temp., and K₂CO₃was filtered off under suction. The

filtrate was concentrated under vacuum to remove CH₃CN. The

resultant pasty mass was dissolved in ethyl acetate and washed with

water (2ϫ20 mL). The water extract was partitioned by ethyl acet-

ate again (2 ϫ 20 mL), and the combined organic layers were

washed with brine (20 mL), dried with Na₂SO₄, and concentrated

under vacuum to give 40 as a reddish yellow oil (3.7 g, 77% yield

over two steps). This material can be used in the next step without

further purification. An analytically pure sample was obtained by

passing the oil through a small silica gel column. R_f= 0.2 (petro-

260–262 °C. IR (CHCl ): ν_max= 2360, 1730, 1586, 1481, 1380 cm^–1.

˜

3

¹H NMR (500 MHz, CDCl₃): δ = 6.47 (s, 1 H), 6.36 (s, 1 H), 5.79

(br. s, 2 H), 4.24 and 3.83 (ABq, J = 17.0 Hz, 2 H), 4.06 (q, J =

7.3 Hz, 2 H), 3.37 (dd, J = 12.8, 4.1 Hz, 1 H), 3.20 (br. d, J =

1.8 Hz, 1 H), 3.12 (br. dd, J = 11.4, 1.8 Hz, 1 H), 3.04 (dd, J = leum ether/ethyl acetate, 9:1). IR (CHCl ): ν_max= 3346, 3166, 2954,

˜

3

11.5, 2.3 Hz, 1 H), 2.98 (d, J = 11.5 Hz, 1 H), 2.96 (dd, J = 10.0,

2896, 1679, 1612, 1415, 1253, 1192, 1132, 1041 cm^{–1 1}H NMR

.

4.3 Hz, 1 H), 1.17 (t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (50 MHz, (200 MHz, CDCl₃): δ = 4.95 (dd, J = 4.7, 3.5 Hz, 1 H), 3.99 (m, 2

CDCl₃): δ = 172.9 (CO), 146.5 (C), 145.8 (C), 133.9 (C), 124.1 (C),

106.7 (CH), 106.3 (CH), 100.6 (CH₂), 60.7 (CH₂), 59.0 (CH₂), 57.4

(CH₂), 55.3 (CH₂), 53.7 (CH), 42.0 (CH), 13.3 (CH₃) ppm. MS:

m/z = 276.32 [M + 1]⁺. C₁₅H₁₇NO₄(275.30): calcd. C 65.44, H

6.22, N 5.09; found C 65.34, H 6.18, N 5.19.

H), 3.78 (m, 2 H), 2.66 (br. d, J = 9.5 Hz, 1 H), 2.26 (d, J = 13.7 Hz,

1 H), 2.04–1.96 (m, 2 H), 1.81 (m, 1 H), 1.43 (m, 1 H), 0.08 (s, 9

H), 0.06 (s, 9 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 104.3

(CH), 65.1 (CH₂), 64.9 (CH₂), 48.3 (CH), 37.9 (CH₂), 30.9 (CH₂),

–2.4 [Si(CH₃)₃], –2.7 [Si(CH₃)₃] ppm. LC–MS: m/z = 276

[M + H]⁺. C₁₂H₂₉NO₂Si₂(275.54): calcd. C 52.31, H 10.61, N 5.08;

found C 52.56, H 10.48, N 4.94.

tert-Butyl

N-[2-(1,3-Dioxolan-2-yl)-1-(trimethylsilyl)ethyl]carba-

mate (39): A mixture of 27 (5 g, 20.2 mmol) and iodoxybenzoic

acid (8.5 g, 30 mmol) in ethyl acetate (70 mL) was heated at reflux

under argon overnight. After cooling to room temp., the reaction

mixture was passed through a pad of Celite and concentrated under

vacuum to produce the corresponding aldehyde, which was pure

enough to be used in the next step. For characterization, it was

passed through a small column of silica gel. R_f= 0.3 (petroleum

2-(1,3-Dioxolan-2-yl)-N-[(6-iodo-1,3-benzodioxol-5-yl)methyl]-1-(tri-

methylsilyl)-N-[(trimethylsilyl)methyl]ethanamine (41): K₂CO₃

(3.58 g, 25.87 mmol) and 16 (6.7 g, 17.5 mmol) were added to a

solution of 40 (5 g, 17.5 mmol) in dry CH₃CN (50 mL). The pro-

gress of the reaction was monitored by TLC (completed in approxi-

mately 10 h). On completion of the reaction, the mixture was co-

oled, filtered, and the solvent evaporated under vacuum. The re-

sultant pasty mass was taken up in ethyl acetate and washed with

water (2ϫ25 mL). The aqueous layer was extracted with ethyl acet-

ether/ethyl acetate, 9:1). IR (CHCl ): ν_max= 3389, 1720, 1643, 1465,

˜

3

1313, 1176 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 9.81 (br. s, 1

H), 4.53 (br. s, 1 H), 3.51 (m, 1 H), 2.52 (m, 2 H), 1.41 (s, 9 H),

0.01 (s, 9 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 202.0 (CO), ate (2 ϫ20 mL), and the combined organic layers were washed with

156.2 (CO), 80.3 (C), 45.1 (CH₂), 37.1 (CH), 28.3 (CH₃), –4.3 brine (40 mL), dried with Na₂SO₄, and concentrated under vacuum

[Si(CH₃)₃] ppm. MS (MALDI-TOF): m/z = 246 [M + H]⁺. A mix-

ture of aldehyde (5 g, 20 mmol), ethylene glycol (1.5 g, 25 mmol)

and p-TsA (0.25 g) was heated at reflux in benzene (80 mL) under

Dean–Stark conditions for 8–10 h. The solvent was evaporated un-

der reduced pressure, and the whole residue was dissolved in ethyl

acetate (50 mL). The organic layer was washed with water

(2ϫ25 mL), brine, and dried with Na₂SO₄. Column chromatog-

raphy (petroleum ether/ethyl acetate, 95:5) of the crude reaction

mixture afforded 39 (4.5 g, 90% yield over two steps) as a white

crystalline solid. R_f= 0.3 (petroleum ether/ethyl acetate, 9:1); m.p.

to give a brown mass, which was purified by column chromatog-

raphy (petroleum ether/ethyl acetate, 98:2) to give 41 as a pale-

yellow oil (8 g, 85 %). R_f= 0.4 (petroleum ether/ethyl acetate,

9.2:0.8). IR (CHCl ): ν

= 2950, 2891, 1502, 1469, 1245, 1130,

˜

3

max

1103 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 7.20 (s, 1 H), 7.10 (s,

1 H), 5.95 (s, 2 H), 5.05 (dd, J = 6.3, 3.9 Hz, 1 H), 3.94 (m, 2 H),

3.84 (m, 2 H), 3.60 and 3.48 (ABq, J = 15.3 Hz, 2 H), 2.45 (dd, J

= 8.6, 5.7 Hz, 1 H), 2.18 (d, J = 14.5 Hz, 1 H), 2.05 (d, J = 14.5 Hz,

1 H), 2.01 (m, 1 H), 1.65 (m, 1 H), 0.13 (s, 9 H), 0.05 (s, 9 H) ppm.

¹³C NMR (50 MHz, CDCl₃): δ = 148.7 (C), 147.3 (C), 136.1 (C),

57–59 °C. IR (CHCl ): ν

= 3440, 3357, 1693, 1500, 1390, 1365, 118.3 (CH), 110.2 (CH), 104.1 (CH), 101.6 (CH₂), 87.0 (C), 64.4

˜

3

max

1249, 1170, 1043, 1027 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ =

(CH₂), 64.9 (CH₂), 64.8 (CH₂), 50.8 (CH), 45.1 (CH₂), 31.5 (CH₂),

4.86 (t, J = 4.7 Hz, 1 H), 4.46 (br. d, J = 9.0 Hz, 1 H), 3.83 (m, 2

–0.7 [Si(CH₃)₃], –0.9 [Si(CH₃)₃] ppm. MS (MALDI-TOF): m/z =

H), 3.77 (m, 2 H), 3.23 (m, 1 H), 1.68 (dd, J = 9.4, 4.3 Hz, 2 H), 536.1190 [M + H]⁺. C₂₀H₃₄INO₄Si₂(535.57): calcd. C 44.85, H

1.37 (s, 9 H), –0.02 (s, 9 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 156.3 (CO), 103.9 (CH), 79.1 (C), 65.1 (CH₂), 64.6 (CH₂), 37.6

(CH), 35.8 (CH₂), 28.6 (CH₃), –3.2 [Si(CH₃)₃] ppm. LC–MS: m/z

= 290 [M + H]⁺. C₁₃H₂₇NO₄Si (289.45): calcd. C 53.94, H 9.40, N

4.84; found C 53.96, H 9.38, N 4.70.

6.40, N 2.62; found C 44.63, H 6.31, N 2.81.

(E)-4-[6-({[2-(1,3-Dioxolan-2-yl)-1-(trimethylsilyl)ethyl][(trimethyl-

silyl)methyl]amino}methyl)-1,3-benzodioxol-5-yl]but-3-en-2-one (42):

The experimental procedure was the same as that used for 15, and

the product mixture was purified by column chromatography (pe-

troleum ether/ethyl acetate, 96:4) to give pure 42 in 65% yield as a

yellow solid. R_f= 0.3 (petroleum ether/ethyl acetate, 9.2:0.8); m.p.

2-(1,3-Dioxolan-2-yl)-1-(trimethylsilyl)-N-[(trimethylsilyl)methyl]-

ethanamine (40): A 100 mL round-bottomed flask equipped with

an argon gas balloon and a magnetic stirring bar was charged with

a solution of 39 (5 g, 16.77 mmol) in dry CH₂Cl₂(50 mL) and co-

oled to 0 °C. TFA (7.7 mL, 100.62 mmol) was introduced dropwise

to the stirred mixture through a syringe. The mixture was stirred

further until the disappearance of the starting material (approx.

completed in 4 h). The volatile material was evaporated under re-

duced pressure, and the reduced mass was dissolved in dry CH₃CN.

The reaction mixture was then cooled to 0 °C and basified by slow

addition of excess activated K₂CO₃(pH = 10). (Iodomethyl)tri-

105–107 °C. IR (CHCl ): ν

= 2850, 2593, 2360, 2341, 1666,

˜

3

max

1593, 1479, 1251, 1039 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ =

7.80 (d, J = 15.6 Hz, 1 H), 7.02 (s, 1 H), 6.92 (s, 1 H), 6.38 (d, J =

15.6 Hz, 1 H), 5.89 (s, 1 H), 5.88 (s, 1 H), 4.86 (dd, J = 5.5, 4.1 Hz,

1 H), 3.83–3.80 (m, 2 H), 3.72–3.65 (m, 3 H), 3.47 (d, J = 14.2 Hz,

1 H), 2.27 (dd, J = 7.8, 5.5 Hz, 1 H), 2.26 (s, 3 H), 2.10–1.90 (m,

3 H), 1.60–1.50 (m, 1 H), 0.00 (s, 9 H), –0.04 (s, 9 H) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 197.7 (CO), 149.4 (C), 146.5 (C),

140.0 (CH), 135.7 (C), 126.8 (CH), 126.2 (C), 109.8 (CH), 105.3

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4581

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

(CH), 103.6 (CH), 101.0 (CH₂), 64.4 (CH₂), 64.3 (CH₂), 55.9 as described for 42 but by using ethyl acrylate instead of methyl

FULL PAPER

(CH₂), 49.5 (CH), 44.5 (CH₂), 30.3 (CH₂), 27.5 (CH₃), –0.8

[Si(CH₃)₃], –1.4 [Si(CH₃)₃] ppm. MS (MALDI-TOF): m/z =

478.2465 [M + H]⁺. C₂₄H₃₉NO₅Si₂(477.75): calcd. C 60.34, H 8.23,

N 2.93; found C 60.26, H 8.20, N 2.73.

vinyl ketone (MVK) to give 47 in 70% yield as a yellow amorphous

solid after silica gel column chromatography (petroleum ether/ethyl

acetate, 95:5). R_f= 0.3 (petroleum ether/ethyl acetate, 9:1); m.p.

101–103 °C. IR (CHCl ): ν

= 3054, 2954, 1706, 1618, 1504,

˜

3

max

1479, 1402, 1265, 1178, 1041 cm^–1. ¹H NMR (200 MHz, CDCl₃):

δ = 8.04 (d, J = 15.8 Hz, 1 H), 7.08 (s, 1 H), 7.00 (s, 1 H), 6.16 (d,

J = 15.8 Hz, 1 H), 5.96 (br. s, 2 H), 4.94 (dd, J = 5.8, 4.3 Hz, 1 H),

4.24 (q, J = 7.1 Hz, 2 H), 3.95–3.77 (m, 5 H), 3.56 (d, J = 14.1 Hz,

1 H), 2.33 (dd, J = 8.2, 5.3 Hz, 1 H), 2.17 (d, J = 14.5 Hz, 1 H),

2.01 (d, J = 14.5 Hz, 1 H), 2.11–2.00 (m, 1 H), 1.65–1.53 (m, 1 H),

1.31 (t, J = 7.1 Hz, 3 H), 0.08 (s, 9 H), 0.05 (s, 9 H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 167.1 (CO), 149.4 (C), 146.8 (C),

141.7 (CH), 135.4 (C), 127.2 (C), 117.4 (CH), 110.0 (CH), 105.6

(CH), 103.8 (CH), 101.3 (CH₂), 64.7 (CH₂), 64.6 (CH₂), 60.3

(CH₂), 56.3 (CH₂), 49.5 (CH), 44.7 (CH₂), 30.6 (CH₂), 14.4 (CH₃),

0.5 (CH₃), –1.1 (CH₃) ppm. HRMS (EI): calcd. for C₂₅H₄₁NSi₂O₆

[M]⁺507.24753; found 507.24753.

1-[10-(1,3-Dioxolan-2-ylmethyl)-4,5-methylenedioxy-9-azatricyclo-

[7.2.1.0^2,7]dodeca-2,4,6-trien-11α-yl]ethanone (38): The experimen-

tal procedure applied for 38 was identical to that for 13, and the

product was purified by silica gel column chromatography (petro-

leum ether/acetone, 80:20) followed by crystallization from ethanol

to give 38 in 53% isolated yield as a white crystalline solid. R_f=

0.3 (petroleum ether/acetone, 8:2); m.p. 154–156 °C. IR (CHCl₃):

ν

˜

= 2958, 1708, 1483, 1359, 1139, 1039 cm^{–1 1}H NMR

.

max

(500 MHz, CDCl₃): δ = 6.37 (s, 1 H), 6.34 (s, 1 H), 5.78 (br. s, 2 H),

4.97 (dd, J = 6.9, 2.3 Hz, 1 H), 4.18 and 3.63 (ABq, J = 17.0 Hz, 2

H), 3.87–3.82 (m, 2 H), 3.77–3.73 (m, 2 H), 3.53 (td, J = 8.7,

3.7 Hz, 1 H), 3.33 (d, J = 8.7 Hz, 1 H), 3.26 (dd, J = 11.2, 2.5 Hz,

1 H), 2.97 (d, J = 2.5 Hz, 1 H), 2.87 (d, J = 11.5 Hz, 1 H), 2.06 (s,

3 H), 1.81–1.79 (m, 1 H), 1.40 (m, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 207.6 (CO), 146.3 (C), 145.5 (C), 134.9 (C), 125.3 (C),

106.6 (CH), 106.3 (CH), 103.5 (CH), 100.4 (CH₂), 64.6 (CH), 64.5

(CH), 64.3 (CH₂), 64.3 (CH₂), 59.9 (CH₂), 53.9 (CH₂), 43.4 (CH),

35.7 (CH₂), 32.2 (CH₃) ppm. MS (MALDI-TOF): m/z = 332.1489

[M + H]⁺. C₁₈H₂₁NO₅(331.37): calcd. C 65.24, H 6.39, N 4.23;

found C 65.14, H 6.47, N 4.11.

Ethyl (6R,7S,8S,9R)-7-[(1,3-Dioxolan-2-yl)methyl]-5,7,8,9-tetra-

hydro-6,9-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]azepine-8-

carboxylate (48): The experiment was performed by using the same

procedure as described for 23 to give 48 in 56% yield as a white

crystalline solid after silica gel column chromatography (petroleum

ether/acetone, 8:2). R_f= 0.3 (petroleum ether/acetone, 7.5:2.5); m.p.

129–131 °C. IR (CHCl ): ν

= 2972, 2892, 1727, 1670, 1610,

˜

3

max

1507, 1484, 1399, 1373, 1233, 1155, 1038 cm^{–1 1}H NMR

.

1-[10-(1,3-Dioxolan-2-ylmethyl)-4,5-methylenedioxy-9-azatricyclo-

[7.2.1.0^2,7]dodeca-2,4,6-trien-11β-yl]ethanone (43): A mixture of 38

(0.1 g, 0.3 mmol) and 3 n HCl (1 mL) in THF (3 mL) was stirred at

room temp. for 8–10 h. The solvent was evaporated under reduced

pressure, and the whole residue was dissolved in CH₂Cl₂(8 mL).

The organic layer was washed with saturated NaHCO₃solution

(2ϫ3 mL) and water (3 mL), and the aqueous layer was extracted

with CH₂Cl₂(2ϫ5 mL). The combined organic layers were washed

with brine, dried with Na₂SO₄, and column chromatography (chlo-

roform/methanol, 9:1) afforded 0.09 g of 43 (90%) as a white solid.

R_f= 0.25 (CHCl₃/MeOH, 9:1); m.p. 165–167 °C. ¹H NMR

(200 MHz, CDCl₃): δ = 6.38 (s, 1 H), 6.28 (s, 1 H), 5.81 (s, 2 H),

4.85 (dd, J = 5.4, 3.3 Hz, 1 H), 4.26 (d, J = 16.8 Hz, 1 H), 3.87–

3.77 (m, 3 H), 3.75–3.63 (m, 3 H), 3.24 (br. d, J = 9.0 Hz, 3 H),

3.06 (d, J = 2 Hz, 1 H), 2.20–2.11 (m, 1 H), 2.05 (s, 3 H), 1.74–

1.60 (m, 1 H) ppm. MS (MALDI-TOF): m/z = 332.1489 [M +

H]⁺. C₁₈H₂₁NO₅(331.37): calcd. C 65.24, H 6.39, N 4.23; found C

65.12, H 6.42, N 4.14.

(200 MHz, CDCl₃): δ = 6.48 (s, 1 H), 6.41 (s, 1 H), 5.86 (br. s, 2 H),

5.08 (dd, J = 7.3, 2.7 Hz, 1 H), 4.24 and 3.68 (ABq, J = 17.0 Hz, 2

H), 4.15 (q, J = 7.1 Hz, 2 H), 3.99–3.80 (m, 4 H), 3.55 (ddd, J =

11.9, 8.4, 3.0 Hz, 1 H), 3.38 (dd, J = 11.5, 2.8 Hz, 1 H), 3.17 (dd,

J = 8.8, 1.2 Hz, 1 H), 3.15 (br. d, J = 2.6 Hz, 1 H), 2.98 (td, J =

11.5, 1.2 Hz, 1 H), 1.80 (br. s, 1 H), 1.52 (br. s, 1 H), 1.25 (t, J =

7.1 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 172.2 (CO),

146.5 (C), 145.6 (C), 134.7 (C), 125.6 (C), 107.0 (CH), 106.4 (CH),

103.8 (CH), 100.6 (CH₂), 64.8 (CH₂), 64.6 (CH₂), 64.5 (CH), 60.3

(CH₂), 60.2 (CH₂), 57.9 (CH), 54.29 (CH₂), 43.6 (CH), 36.0 (CH₂),

14.1 (CH₃) ppm. HRMS (EI): calcd. for C₁₉H₂₃NO₆[M]⁺

361.15254; found 361.15344.

Diethyl (2-{(6R,7S,8S,9R)-7-[(1,3-Dioxolan-2-yl)methyl]-5,7,8,9-

tetrahydro-6,9-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]azepin-8-

yl}-2-oxoethyl)phosphonate (46): nBuLi in hexane (0.85 mL,

1.6 mmol) was added dropwise to a stirred solution of diethyl meth-

ylphosphonate (0.27 mL, 1.8 mmol) in dry THF (2 mL) at –78 °C

under argon over a period of 15 min. The resulting reaction mix-

ture was stirred at the same temperature for an additional 1 h.

Compound 48 (0.13 g, 0.36 mmol) in dry THF (2 mL) was added

dropwise to the resulting reaction mixture and allowed to react at

–78 °C for 1 h. After 1 h, the mixture was warmed to room tem-

perature over a period of 2 h. A saturated solution of NH₄Cl was

added to the reaction mixture, which was then extracted with ethyl

acetate (3 ϫ 10 mL). The combined organic layers were washed

with brine, dried with Na₂SO₄, and concentrated under vacuum to

obtain a viscous brown residue, which was purified by silica gel

chromatography (petroleum ether/acetone, 6:4) to afford 46

(0.156 g, 92%) as a brown viscous paste. R_f= 0.2 (petroleum ether/

(11β-Acetyl-4,5-methylenedioxy-9-azatricyclo[7.2.1.0^2,7]dodeca-

2,4,6-trien-10-yl)acetaldehyde (45): A mixture of 38 or 43 (0.2 g,

0.6 mmol) and 3 n HCl (1 mL) in THF (4 mL) was heated at reflux

for 10 h. The solvent was evaporated under reduced pressure, and

the whole residue was taken up in CH₂Cl₂(8 mL). The organic

layer was washed with saturated NaHCO₃solution (2ϫ3 mL) and

water (2ϫ3 mL). The aqueous layer was extracted with CH₂Cl₂

(2ϫ5 mL), and the combined organic extracts were washed with

brine, dried with Na₂SO₄, and concentrated under reduced pressure

to give 45 (0.18 g, 88% yield) as a brown paste. IR (CHCl ): ν

˜

3

max

= 2921, 1721, 1342, 1041 cm^–1. H NMR (500 MHz, CDCl₃): δ =

9.76 (dd, J = 2.0, 1.6 Hz, 1 H), 6.45 (s, 1 H), 6.37 (s, 1 H), 5.87

(br. s, 2 H), 4.26 and 3.91 (ABq, J = 17.2 Hz, 1 H), 4.00 (m, 1 H),

3.72–3.59 (m, 1 H), 3.34 (m, 1 H), 3.24–3.04 (m, 2 H), 2.77–2.63

(m, 1 H), 2.49–2.38 (m, 1 H), 2.15 (s, 3 H) ppm. MS (ESI): m/z =

320.23 [M + CH₃OH + 1]⁺.

1

acetone, 6:4). IR (CHCl ): ν

= 2925, 2851, 1701, 1607, 1505,

˜

3

max

1485, 1435, 1399, 1247, 1182, 1038 cm^{–1 1}H NMR (200 MHz,

.

CDCl₃): δ = 6.51 (s, 1 H), 6.41 (s, 1 H), 5.85 (br. s, 2 H), 5.01 (dd,

J = 7.1, 2.3 Hz, 1 H), 4.26 and 3.71 (ABq, J = 17.2 Hz, 2 H), 4.20–

4.06 (m, 4 H), 3.95–3.78 (m, 4 H), 3.69–3.53 (m, 2 H), 3.38 (dd, J

= 11.5, 2.9 Hz, 1 H), 3.23 (d, J = 13.4 Hz, 0.5 H), 3.12 (d, J =

Ethyl (E)-3-[6-({[2-(1,3-Dioxolan-2-yl)-1-(trimethylsilyl)ethyl][(tri-

methylsilyl)methyl]amino}methyl)-1,3-benzodioxol-5-yl]acrylate 13.4 Hz, 0.5 H), 3.11 (d, J = 2.9 Hz, 1 H), 3.26–3.02 (m, 2 H),

(47): The experiment was performed by using the same procedure 2.99–2.94 (m, 1 H), 2.88 (d, J = 11.6 Hz, 1 H), 1.82–1.99 (m, 1 H),

4582

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

1

1.38–1.49 (m, 1 H), 1.32 (t, J = 7.0 Hz, 6 H) ppm. ¹³C NMR 1038 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.34–7.09 (m, 5 H),

(100 MHz, CDCl₃): δ = 201.4 (CO), 146.9 (C), 134.5 (C), 124.8 (C), 6.45 (dd, J = 14.5, 3.3 Hz, 1 H), 6.43 (s, 1 H), 6.4 (s, 1 H), 6.25–

107.2 (CH), 106.5 (CH), 103.3 (CH), 100.8 (CH₂), 64.9 (CH), 64.9

6.10 (m, 1 H), 5.85 (br. s, 2 H), 4.25 and 3.76 (ABq, J = 17.1 Hz,

(CH₂), 64.6 (CH₂), 60.1 (CH₂), 54.0 (CH₂), 53.2 (CH), 53.2 (CH), 2 H), 3.89 (q, J = 7.1 Hz, 2 H), 3.48 (dd, J = 6.8, 6.7, Hz, 1 H),

53.0 (CH), 52.9 (CH), 44.6 (CH), 44.2 (CH₂), 43.2 (CH₂), 36.0 3.19 (dd, J = 5.2, 2.4 Hz, 1 H), 3.15 (dd, J = 11.5, 2.3 Hz, 1 H),

(CH), 31.9 (CH), 29.1 (CH), 22.7 (CH), 14.1 (CH₃) ppm. MS (ESI): 3.06 (d, J = 11.5 Hz, 1 H), 2.91 (dd, J = 6.0, 5.4 Hz, 1 H), 2.53–

m/z = 468.24 [M + H]⁺. C₂₂H₃₀NO₈P (467.45): calcd. C 56.53, H

6.47, N 3.00; found C 56.37, H 6.58, N 2.86.

2.47 (m, 1 H), 2.50–2.22 (m, 2 H), 1.13 (t, J = 7.0 Hz, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 171.6 (CO), 146.9 (C), 145.4

(C), 137.54 (C), 132.2 (CH), 131.0 (C), 132.1 (CH), 128.6 (CH),

128.5 (CH), 127.4 (CH), 127.1 (CH), 126.1 (CH), 108.3 (CH), 106.4

(CH), 100.6 (CH₂), 66.3 (CH), 60.9 (CH₂), 60.9 (CH₂), 55.7 (CH₂),

43.8 (CH), 39.7 (CH₂), 14.2 (CH₃) ppm. HRMS (EI): calcd. for

C₂₄H₂₅NO₄[M]⁺391.17836; found 391.17956.

Diethyl {2-[(6S,11S)-5,11-Dihydro-6,11-methano[1,3]dioxolo[4Ј,5Ј:4,5]-

benzo[1,2-c]azonin-10-yl]-2-oxoethyl}phosphonate (49): Oxalic acid

(0.4 g, 3.2 mmol) was added to a stirred solution of 46 (0.150 g,

0.32 mmol) in THF/H₂O (1:1; 6 mL), and the mixture was heated

at 80 °C for 10 h. After completion of the reaction, the mixture was

cooled to room temp. The volatile material was evaporated under

reduced pressure, the residue diluted with ethyl acetate and basified

by slow addition of saturated NaHCO₃(pH = 8). The aqueous

layer was separated in a separating funnel and washed with ethyl

acetate (2ϫ10 mL); the combined organic layers were dried with

Na₂SO₄, concentrated under reduced pressure and purified by col-

umn chromatography (petroleum ether/acetone, 4:6) to give 49 as

a yellow paste (0.088 g, 68%). R_f= 0.3 (petroleum ether/acetone,

[(6R,7S,8R,9R)-7-Cinnamyl-5,7,8,9-tetrahydro-6,9-methano[1,3]-

dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]azepin-8-yl]methanol (58): DIBAl-H

(1.46 n in toluene, 2.1 mL, 3.2 mmol) was added slowly over a

period of 10 min to a stirred solution of 57b (0.5 g, 1.2 mmol) in

dry CH₂Cl₂at –78 °C. After completion of the addition, the reac-

tion mixture was warmed to room temp. over 1 h. The reaction

mixture was diluted with CH₂Cl₂, a few drops of Na,K tartarate

were added, and the mixture was stirred for an additional 1 h, dried

with Na₂SO₄, passed through a small pad of Celite and concen-

2:3). IR (CHCl ): ν_max= 2983, 1607, 1504, 1486, 1439, 1265, 1243,

˜

3

1

1191, 1038 cm^–1. H NMR (200 MHz, CDCl₃): δ = 7.35 (m, 1 H), trated under reduced pressure to obtain the reduced product 58 as

7.10 (br. d, J = 7.5 Hz, 1 H), 6.78 (td, J = 7.5, 3.8 Hz, 1 H), 6.49

(s, 1 H), 6.38 (s, 1 H), 5.85 and 5.84 (ABq, J = 1.3 Hz, 2 H), 4.27–

4.15 (m, 9 H), 3.31 (br. s, 2 H), 1.26 (t, J = 7.1 Hz, 6 H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 160.1 (C), 160.1 (C), 146.5 (C), 146.4

a white paste (0.431 g, 96%), which was pure enough to be used in

the next step. R_f= 0.25 (petroleum ether/acetone, 3:2). IR (CHCl₃):

ν

= 3421, 3053, 2926, 2893, 2307, 1481, 1265, 1236, 1039 cm^–1.

˜

max

¹H NMR (200 MHz, CDCl₃): δ = 7.37–7.14 (m, 5 H), 6.55 (s, 1

(C), 135.6 (CH), 131.9 (CH), 131.4 (CH), 131.3 (CH), 128.6 (CH), H), 6.46 (d, J = 15.9 Hz, 1 H), 6.44 (s, 1 H), 6.33–6.19 (m, 1 H),

118.6 (CH), 118.4 (CH), 109.3, 105.8 (CH), 100.7 (CH₂), 62.5 6.84 (br. s, 2 H), 4.26 and 3.64 (ABq, J = 17.0 Hz, 2 H), 3.47 (dd,

(CH₂), 62.4 (CH₂), 47.9 (CH₂), 47.5 (CH₂), 29.7 (CH₂), 16.2 (CH₃), J = 10.4, 5.3 Hz, 1 H), 3.18 (d, J = 9.1 Hz, 1 H), 3.12 (dd, J = 9.1,

16.2 (CH₃) ppm. MS (ESI): m/z = 406.34 [M + H]⁺. C₂₀H₂₄NO₆P

(405.39): calcd. C 59.26, H 5.97, N 3.46; found C 59.37, H 6.08, N

3.58.

2.4 Hz, 1 H), 3.05 (br. s, 1 H), 3.04–2.90 (m, 1 H), 2.61–2.29 (m, 4

H), 2.0 (br. s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 146.5

(C), 145.4 (C), 137.5 (C), 131.8 (CH), 131.7 (CH), 128.4 (CH),

127.9 (CH), 127.0 (CH), 126.0 (CH), 125.9 (CH), 108.6 (CH), 106.4

(CH), 100.6 (CH₂), 67.7 (CH), 62.8 (CH₂), 60.9 (CH₂), 58.2 (CH),

55.1 (CH₂), 42.1 (CH), 39.8 (CH₂) ppm. HRMS (EI): calcd. for

C₂₂H₂₃NO₃[M]⁺349.16776; found 349.16859.

Ethyl (6R,7S,8R,9R)-7-Cinnamyl-5,7,8,9-tetrahydro-6,9-methano-

[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]azepine-8-carboxylate (57b): Oxalic

acid (3.5 g, 27.7 mmol) was added to a stirred solution of the pure

cycloadduct 48 (1 g, 2.7 mmol) in THF/H₂O (1:1; 50 mL), and the

reaction mixture was heated at reflux for 24 h. The reaction mixture

was cooled to room temp., and THF was evaporated under reduced

pressure at 45 °C, the residue diluted with ethyl acetate and basified

by slow addition of a saturated NaHCO₃solution (pH = 10) at

0 °C. The organic layer was separated in a separating funnel, and

the aqueous layer was again washed with ethyl acetate (3ϫ20 mL).

The combined organic layers were washed with brine, dried with

Na₂SO₄, and concentrated under reduced pressure to give the alde-

hyde as a brown residue, which was used in the Wittig olefination

reaction without further purification. The Wittig ylide was gener-

ated by slow addition of nBuLi (1.6 n in hexane, 1.87 mL, 3 mmol)

to a suspension of the corresponding salt (benzylidenetri-

1-[(6R,7S,8R,9R)-7-Cinnamyl-5,7,8,9-tetrahydro-6,9-methano[1,3]-

dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]azepin-8-yl)allyl Acetate (59): Dry

DMSO (0.09 mL, 1.29 mmol) was added under argon to a stirred

solution of oxalyl chloride (0.1 mL, 1.29 mmol) in CH₂Cl₂(2 mL)

at –78 °C. After 15 min, a solution of alcohol 58 (0.3 g, 0.86 mmol)

in dry CH₂Cl₂(2 mL) was added dropwise to the reaction mixture,

which was stirred at the same temperature for another 2 h. Excess

TEA (0.6 mL, 4.3 mmol) was added to the reaction mixture, which

was gradually warmed to room temp. over 30 min. The resulting

reaction mixture was diluted with CH₂Cl₂and extracted with water.

The aqueous layer was washed with CH₂Cl₂(3ϫ10 mL), and the

combined organic layers were washed with brine, dried with

phenylphosphorane; 1.6 g, 3.78 mmol) in dry THF (12 mL) under Na₂SO₄, and concentrated under vacuum to obtain the crude alde-

a positive pressure of argon at 0 °C. The appearance of an orange

colour indicated the generation of the ylide, which was stirred at

the same temperature for another 30 min and then slowly intro-

duced into the solution of the aldehyde (0.8 g, 2.5 mmol) in dry

THF (3 mL) over a period of 10 min. The reaction mixture was

warmed to room temp. and stirred overnight before the addition

of a saturated NH₄Cl solution. The aqueous layer was separated

and extracted with ethyl acetate (3ϫ20 mL). The combined or-

ganic layers were washed with brine, dried with Na₂SO₄, and con-

centrated to obtain a viscous brown mass, which was purified by

column chromatography (petroleum ether/acetone, 8:2) to yield 57b

as a pale-yellow paste (0.66 g, 68%). R_f= 0.3 (petroleum ether/

hyde quantitatively, which was pure enough to be used in the Grig-

nard reaction with vinylmagnesium bromide. For characterization,

it was purified by flash chromatography (petroleum ether/acetone,

4:1). R = 0.3 (petroleum ether/acetone, 3:2). IR (CHCl ): ν = 2953,

˜

f

3

2887, 1714, 1481, 1340, 1230, 1140, 1037 cm^–1

.

¹H NMR

(200 MHz, CDCl₃): δ = 9.33 (d, J = 2.7 Hz, 1 H), 7.29–7.16 (m, 5

H), 6.40 (d, J = 15.8 Hz, 1 H), 6.39 (s, 1 H), 6.38 (s, 1 H), 6.14

(app. ddd, J = 15.8, 7.3, 6.4 Hz, 1 H), 5.82 and 5.81 (ABq, J =

1.4 Hz, 2 H), 4.27 and 3.74 (ABq, J = 17.2 Hz, 2 H), 3.36 (app. q,

J = 7.0 Hz, 1 H), 3.29 (br. d, J = 5.0 Hz, 1 H), 3.07 (br. s, 2 H),

2.8 (app. td, J = 6.3, 2.7 Hz, 1 H), 2.4 (m, 1 H), 2.2 (m, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 201.8 (CO), 147.2 (C), 145.9

(C), 137.3 (C), 137.0 (C), 132.5 (CH), 132.0 (CH), 128.6 (CH),

acetone, 7:3). IR (CHCl ): ν

= 2929, 1731, 1502, 1482, 1232,

˜

3

max

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4583

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

128.5 (CH), 127.2 (CH), 126.8 (CH), 126.1 (C), 108.0 (CH), 106.9

4.6 Hz, 1 H), 3.00 (d, J = 11.0 Hz, 1 H), 2.95 (br. s, 1 H), 2.63 (dt,

(CH), 100.8 (CH₂), 67.6 (CH), 65.0 (CH), 60.7 (CH₂), 55.9 (CH₂), J = 17.0, 4.9 Hz, 1 H), 2.2–2.1 (m, 2 H), 1.54 (s, 3 H) ppm. ¹³C

43.1 (CH), 39.5 (CH₂) ppm. MS (ESI): m/z = 348 [M + 1]⁺, 380.40

[M + CH₃OH + 1]⁺. Vinylmagnesium bromide (VMB, 1 m in THF,

2.6 mL, 2.6 mmol) was added slowly to a stirred solution of the

aldehyde (0.3 g, 0.86 mmol) in dry THF (3 mL) at –78 °C under a

positive pressure of argon over a period of 10 min. The resulting

reaction mixture was stirred at room temp. overnight before

quenching with water. The aqueous layer was separated and ex-

tracted with ethyl acetate (3ϫ10 mL). The combined organic layers

were washed with brine and concentrated under reduced pressure

to give the allylic alcohol as a brown paste in quantitative yield,

which was isolated after acetate protection of the alcohol. Ac₂O

(0.1 mL, 1 mmol) was added dropwise to a stirred solution of the

NMR (125 MHz, CDCl₃): δ = 170.4 (CO), 146.4 (C), 145.5 (C),

132.4 (CH), 131.3 (CH), 127.0 (CH), 108.9 (CH), 106.9 (CH), 100.7

(CH₂), 67.5 (CH), 62.0 (CH₂), 60.0 (CH), 58.6 (CH₂), 56.6 (CH),

40.1 (CH), 33.3 (CH₂), 20.7 (CH₃) ppm. ¹H NMR (400 MHz,

C₆D₆): δ = 6.50 (s, 1 H), 6.32 (s, 1 H), 5.82–5.76 (m, 2 H), 5.70–

5.66 (m, 1 H), 5.38 (br. s, 2 H), 4.02 and 3.49 (ABq, J = 16.3 Hz,

2 H), 3.04 (td, J = 11.0, 4.8 Hz, 1 H), 3.17 (dd, J = 11.0, 1.3 Hz, 1

H), 3.00 (d, J = 11.0 Hz, 1 H), 2.49 (dt, J = 17.0, 4.8 Hz, 1 H),

2.43 (br. s, 1 H), 2.07–1.97 (m, 1 H), 1.71 (dt, J = 11.0, 3.5 Hz, 1

H), 1.55 (s, 3 H) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = 169.6 (CO),

146.6 (C), 145.7 (C), 132.5 (CH), 132.3 (CH), 127.2 (CH), 109.0

(CH), 106.9 (CH), 100.3 (CH₂), 67.5 (CH), 62.2 (CH₂), 60.0 (CH),

above alcohol (0.3 g, 0.86 mmol), DMAP (10 mg), and TEA 58.6 (CH₂), 56.9 (CH), 40.1 (CH), 33.7 (CH₂), 20.4 (CH₃) ppm.

(0.18 mL, 1.29 mmol) in dry CH₂Cl₂(3 mL) at 0 °C, and the mix-

ture was stirred at room temp. for 6 h. After completion of the

reaction, water (3 mL) was added, and the reaction mixture was

extracted with ethyl acetate. The combined organic layers were

washed with brine and concentrated under reduced pressure to give

a brown mass, which was purified by column chromatography (pe-

troleum ether/acetone, 4:1) to yield 59 (94% combined yield of two

diastereomers). R_f= 0.4 (petroleum ether/acetone, 7:3). For charac-

terization, the major isomer was isolated by slowly passing 20%

HRMS (EI): calcd. for C₁₈H₁₉NO₄[M]⁺313.13141; found

313.13631.

Minor Diastereomer (61): R_f= 0.3 (CH₂Cl₂/MeOH, 8:2; eluted with

2–3%). IR (CHCl ): ν

= 3381, 2949, 2924, 2554, 1737, 1732,

˜

3

max

1485, 1371, 1240, 1037 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ =

6.46 (br. s, 2 H), 5.90 (ABq, J = 1.4 Hz, 2 H), 5.80–5.70 (m, 1 H),

5.55 (dt, J = 10.1, 1.7 Hz, 1 H), 5.03 (m, 1 H), 4.22 and 3.73 (ABq,

J = 16.2 Hz, 2 H), 3.21 (br. d, J = 11.2 Hz, 1 H), 3.07 (d, J =

11.2 Hz, 1 H), 2.98 (br. s, 1 H), 2.67 (td, J = 11.0, 4.4 Hz, 1 H),

2.51 (dt, J = 15.7, 5.0 Hz, 1 H), 2.30–2.20 (m, 2 H), 2.12 (s, 3

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 170.4 (CO), 147.1 (C),

146.1 (C), 129.9 (CH), 129.1 (CH), 109.2 (CH), 107.0 (CH), 100.9

(CH₂), 72.0 (CH), 63.7 (CH), 61.6 (CH₂), 57.8 (CH₂), 57.7 (CH),

39.2 (CH), 31.9 (CH₂), 21.2 (CH₃) ppm. ¹H NMR (500 MHz,

C₆D₆): δ = 6.70 (s, 1 H), 6.29 (s, 1 H), 5.67 (app. dt, J = 10.1,

1.7 Hz, 1 H), 5.56–5.53 (m, 1 H), 5.40 and 5.32 (ABq, J = 1.4 Hz,

2 H), 5.36–5.33 (m, 1 H), 4.02 and 3.40 (ABq, J = 16.2 Hz, 2 H),

2.94 (br. d, J = 11.0 Hz, 1 H), 2.78 (d, J = 11.2 Hz, 1 H), 2.66 (br.

s, 1 H), 2.52 (m, 1 H), 2.30 (app. dt, J = 15.7, 5.0 Hz, 1 H), 1.93

(m, 1 H), 1.85 (m, 1 H), 1.81 (s, 3 H) ppm. HRMS (EI): calcd. for

C₁₈H₁₉NO₄[M]⁺313.13141; found 313.13631.

acetone/petroleum ether through the column. IR (CHCl ): ν

=

˜

3

max

3024, 2977, 1738, 1503, 1482, 1372, 1234, 1038 cm^{–1 1}H NMR

.

(500 MHz, CDCl₃): δ = 7.38 (d, J = 7.4 Hz, 2 H), 7.29 (dd, J =

7.7, 7.4 Hz, 2 H), 7.20 (dd, J = 7.4, 7.2 Hz, 1 H), 6.52–6.36 (m, 4

H), 5.90 (ABq, J = 1.5 Hz, 2 H), 5.82 (ddd, J = 17.4, 10.5, 6.9 Hz,

1 H), 5.27 (dd, J = 16.0, 8.2 Hz, 2 H), 4.80 (dd, J = 10.4, 6.8 Hz,

1 H), 4.32 and 3.75 (ABq, J = 16.9 Hz, 2 H), 3.16 (dd, J = 11.3,

2.0 Hz, 1 H), 3.01 (d, J = 11.3 Hz, 1 H), 2.87–2.80 (m, 2 H), 2.52

(m, 1 H), 2.41–2.33 (m, 2 H), 1.98 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 169.7 (CO), 147.1 (C), 145.5 (C), 137.6 (C),

135.7 (C), 135.5 (CH), 131.6 (CH), 130.8 (CH), 128.5 (CH), 128.3

(CH), 127.1 (CH), 126.1 (CH), 118.8 (CH₂), 108.7 (CH), 106.6

(CH), 100.8 (CH₂), 76.4 (CH), 69.6 (CH), 61.0 (CH₂), 59.1 (CH),

55.4 (CH₂), 42.0 (CH), 40.2 (CH₂), 21.2 (CH₃) ppm. HRMS (EI):

calcd. for C₂₆H₂₇NO₄[M]⁺417.19401; found 417.19417.

(6R,6aS,8R,9R,10R,10aR,11R)-8,9-Dihydroxy-5,6a,7,8,9,

10,10a,11-octahydro-6,11-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-

e]benzo[b]azepin-10-yl Acetate (62): Trimethylamine N-oxide dihy-

drate (27 mg, 0.24 mmol) was added to a solution of 60 (50 mg,

0.16 mmol) in a mixture of tBuOH (0.5 mL), pyridine (30 μL) and

water (30 μL). The solution was stirred until all solids had dis-

solved, and a crystal of OsO₄was added at room temp. The re-

sulting solution was stirred for 18 h. A pinch of Na₂SO₃was added

to the reaction mixture, which was stirred for an additional 30 min.

The solvent was removed by rotary evaporation, and the residue

was dissolved in CH₂Cl₂(5 mL) and partitioned with brine (2 mL).

The aqueous layer was extracted with CH₂Cl₂(2ϫ5 mL), and the

organic layers were dried with Na₂SO₄, concentrated and recrys-

tallized from ethanol to obtain 62 as a white crystalline solid as a

single diastereomer. R_f= 0.25 (CH₂Cl₂/MeOH, 9:1); m.p. 293–

(6R,6aS,10aR,11R)-5,6a,7,10,10a,11-Hexahydro-6,11-methano[1,3]-

dioxolo[4Ј,5Ј:4,5]benzo[1,2-e]benzo[b]azepin-10-yl Acetate (60 and

61): The mixture of isomers of 59 (0.2 g, 0.48 mmol) was dissolved

in dry CH₂Cl₂(3 mL) under argon and saturated with dry HCl_(gas)

at 0 °C to give the hydrochloride salt. After 30 min at 0 °C, CH₂Cl₂

was removed under argon, freshly distilled benzene was added to

59·HCl, and the mixture degassed thoroughly for 10 min. Grubbs

second-generation catalyst (80 mg, 10 mol-%) was added in two

portions, and the mixture was again degassed for 10–15 min. The

reaction mixture was then heated at reflux for 6 h. After completion

of the reaction, the mixture was diluted with ethyl acetate and

washed with a saturated K₂CO₃solution. The aqueous layer was

washed with ethyl acetate (3ϫ10 mL), and the combined organic

layers were washed with brine, dried with Na₂SO₄, and concen-

trated under reduced pressure to give cyclized products 60 and 61

as a yellowish oil (mixture of diastereomers), which were separated

by flash column chromatography in 93% combined yield [eluent: 2

and 4–5 % MeOH/CH₂Cl₂for the minor (40 mg) and major

(100 mg) isomers, respectively].

295 °C. IR (CHCl ): ν

= 3385, 3081, 2976, 2928, 1734, 1375,

˜

3

max

1

1246, 1217, 1047 cm^–1. H NMR (400 MHz, CD₃OD): δ = 6.62 (s,

1 H), 6.49 (s, 1 H), 5.90 (br. s, 2 H), 5.43 (br. s, 1 H), 4.33 and 4.03

(ABq, J = 15.6 Hz, 2 H), 3.70–3.64 (m, 1 H), 3.62 (br. s, 1 H), 3.41

(d, J = 10.5 Hz, 1 H), 3.25–3.18 (m, 1 H), 3.09 (br. s, 1 H), 2.65

(d, J = 11.4 Hz, 1 H), 2.35–2.26 (m, 1 H), 2.08–2.00 (m, 1 H), 1.88

(app. q, J = 11.5 Hz, 1 H), 1.51 (s, 3 H) ppm. ¹³C NMR (100 MHz,

Major Diastereomer (60): R_f= 0.25 (CH₂Cl₂/MeOH, 4:1; eluted CD₃OD): δ = 172.0 (CO), 149.2 (C), 148.5 (C), 132.2 (C), 125.8

with 4–5%). IR (CHCl ): ν

= 2926, 2360, 1726, 1483, 1240,

(C), 110.4 (CH), 109.0 (CH), 103.3 (CH₂), 72.6 (CH), 72.4 (CH),

71.2 (CH), 62.6 (CH₂), 61.5 (CH), 60.7 (CH₂), 54.1 (CH), 42.0

(CH), 36.2 (CH₂), 21.5 (CH₃) ppm. HRMS (EI): calcd. for

C₁₈H₂₁NO₆[M]⁺347.13689; found 347.13667.

˜

3

max

1040 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.46 (br. s, 2 H), 5.92

(m, 1 H), 5.84 (br. s, 1 H), 5.73–5.60 (m, 2 H), 4.22 and 3.80 (ABq,

J = 16.4 Hz, 2 H), 3.17 (br. d, J = 10.8 Hz, 1 H), 3.07 (td, J = 11.0,

4584

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

(3aR,4aS,5R,12R,12aR,13R,13aR)-2,2-Dimethyl-3a,4,4a,6, layer was washed with brine, dried with Na₂SO₄, and concentrated

12,12a,13,13a-octahydro-5,12-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo-

under reduced pressure. The residue was used in the next step with-

[1,2-b][1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-e]azepin-13-yl Acetate (63): out purification. The residue (12 mg) was heated at reflux with

2,2-Dimethoxypropane (0.1 mL, 0.8 mmol) was added to a solution

of 62 (50 mg, 0.15 mmol), p-TsA (43 mg, 0.22 mmol) and molecular

sieves in dry acetone (0.5 mL) at room temperature, and the pro-

gress of the reaction was monitored by TLC. After completion of

the reaction (6 h), the volatile material was evaporated under re-

duced pressure, and the residue was diluted with CH₂Cl₂and

washed with water. The aqueous layer was extracted with CH₂Cl₂

(3ϫ5 mL), and the combined organic layers were washed with

brine, dried with Na₂SO₄, and concentrated by rotary evaporation.

The crude product was pure enough to be used in the next step.

freshly distilled DBU (0.04 mL) in dry toluene (0.5 mL) at 110 °C

for 2 d. After completion of the reaction, monitored by analytical

HPLC, the volatile material was evaporated, and the residue was

purified by flash chromatography (CH₂Cl₂/MeOH, 97:3) to give 65

(8 mg, 89% yield). R_f= 0.4 (CH₂Cl₂/MeOH, 95:5). IR (CHCl₃):

ν

= 2975, 2925, 2853, 1735, 1628, 1480, 1376, 1260, 1041 cm^–1.

˜

max

¹H NMR (500 MHz, CDCl₃): δ = 6.55 (s, 1 H), 6.46 (s, 1 H), 5.87

(ABq, J = 1.5 Hz, 2 H), 5.70 (dd, J = 2.2 Hz, 1 H), 4.48–4.45 (m,

1 H), 4.34 and 3.78 (d, J = 17.0 Hz, 2 H), 4.27 (ddd, J = 11.6, 5.6,

5.6 Hz, 1 H), 3.33–3.30 (m, 1 H), 3.12 (dd, J = 10.8, 2.2 Hz, 1 H),

For analytical data, the product was purified by column 3.08 (m, 1 H), 3.04 (d, J = 10.8 Hz, 1 H), 2.28 (m, 1 H), 1.46 (s, 3

chromatography (CH₂Cl₂/MeOH, 9:1) to give 63 as a yellow paste

(50 mg, 95%). R = 0.3 (CH Cl /MeOH, 95:5). IR (CHCl ): ν

˜

max

H), 1.35 (s, 3 H),1.32 (m, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 155.6 (C), 146.8 (C), 146.1 (C), 132.4 (C), 124.5 (C), 112.3

f

2

3

= 2928_,2857, 1745, 1481, 1374, 1239, 1070 cm^{–1 1}H NMR (CH), 109.5 (C), 107.2 (CH), 106.8 (CH), 100.8 (CH₂), 73.9 (CH),

.

(500 MHz, CDCl₃): δ = 6.47 (s, 1 H), 6.43 (s, 1 H), 5.86 and 5.85

(ABq, J = 1.2 Hz, 2 H), 5.77 (app. t, J = 1.8 Hz, 1 H), 4.29–4.14

(m, 1 H), 4.19 and 3.75 (ABq, J = 16.5 Hz, 2 H), 3.81 (ddd, J =

2.7, 2.1, 2.0 Hz, 1 H), 3.22 (br. d, J = 10.8 Hz, 1 H), 2.99 (d, J =

11.1 Hz, 1 H), 2.93 (app. t, J = 10.7 Hz, 1 H), 2.87 (br. s, 1 H),

2.48 (m, 1 H), 2.40 (app. dt, J = 10.7, 2.7 Hz, 1 H), 1.51 (s, 3 H),

1.50 (s, 3 H), 1.29 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ

= 169.5 (CO), 146.5 (C), 145.7 (C), 108.6 (CH), 107.0 (CH), 100.8

(CH₂), 76.5 (CH), 74.5 (CH), 67.9 (CH), 61.9 (CH₂), 59.1 (CH),

59.0 (CH₂), 54.6 (CH), 40.1 (CH), 37.0 (CH₂), 28.3 (CH₃), 26.3

(CH₃), 20.4 (CH₃) ppm. MS (ESI): m/z = 388.0495 [M + 1]⁺.

C₂₁H₂₆NO₆(388.44): calcd. C 65.10, H 6.50, N 3.62; found C

65.23, H 6.38, N 3.49.

71.8 (CH), 62.2 (CH), 61.0 (CH₂), 55.2 (CH₂), 45.4 (CH), 33.2

(CH₂), 27.9 (CH₃), 25.3 (CH₃) ppm. HRMS (EI): calcd. for

C₁₉H₂₁NO₄[M]⁺327.14726; found 327.14706.

(6R,6aS,8R,9S,11S)-5,6a,7,8,9,11-Hexahydro-6,11-methano[1,3]-

dioxolo[4Ј,5Ј:4,5]benzo[1,2-e]benzo[b]azepine-8,9-diol·HCl

(Brunsvigine·HCl, 2·HCl): HCl gas was passed through a solution

of 65 (10 mg, 0.03 mmol) in dry methanol at 0 °C for 15 min. The

reaction mixture was stirred at the same temperature for an ad-

ditional 30 min. The volatile material was evaporated under re-

duced pressure to give the HCl salt of brunsvigine (2) in quantita-

1

tive yield. H NMR (500 MHz, D₂O): δ = 6.82 (s, 1 H), 6.71 (s, 1

H), 5.95 and 5.94 (ABq, J = 1.0 Hz, 2 H), 5.95 (m, 1 H), 4.75

merged with the D₂O peak, 4.45 (d, J = 15.6 Hz, 1 H), 4.17 (t, J

= 3.9 Hz, 1 H), 4.12–4.09 (m, 1 H), 3.97 (d, J = 2.8 Hz, 1 H), 3.76–

3.71 (m, 1 H), 3.69 (d, J = 11.0 Hz, 1 H), 3.56 (dd, J = 11.0, 2.0 Hz,

1 H), 3.33 (br. s, 1 H), 2.37 (ddd, J = 8.5, 5.2, 3.3 Hz, 1 H), 1.76

(ddd, J = 11.9, 11.9, 11.9 Hz, 1 H) ppm. HRMS (EI): calcd. for

C₁₆H₁₇NO₄287.1158; found 287.11472.

(3aR,4aS,5R,12R,12aR,13R,13aS)-2,2-Dimethyl-3a,4,4a,6,

12,12a,13,13a-octahydro-5,12-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo-

[1,2-b][1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-e]azepin-13-ol (64): NaOMe

(20 mg, 0.77 mmol) was added to a stirred solution of 63 (30 mg,

0.08 mmol) in distilled MeOH (0.5 mL), and the mixture was

stirred at room temp. for 4 h. After completion of the reaction, the

methanol was evaporated, and the residue was redissolved in

CH₂Cl₂and washed with water. The aqueous layer was extracted

with CH₂Cl₂(3ϫ5 mL), and the combined organic layers were

washed with brine, dried with Na₂SO₄, and concentrated to give a

white paste, which was purified by silica gel column chromatog-

raphy (CH₂Cl₂/MeOH, 85:15) to yield pure alcohol 64 as a white

viscous material in 91% yield. R_f= 0.2 (CH₂Cl₂/MeOH, 9:1). IR

(6R,6aS,8R,9S,11S)-5,6a,7,8,9,11-Hexahydro-6,11-methano[1,3]-

dioxolo[4Ј,5Ј:4,5]benzo[1,2-e]benzo[b]azepine-8,9-diyl Diacetate

(2A): Acetic anhydride (250 μL, 0.210 mmol) was added to a stirred

solution of the HCl salt of brunsvigine (10 mg, 0.028 mmol) and

DMAP (2 mg, 0.016 mmol) in dry pyridine (2 mL) at room temp.,

and the resulting reaction mixture was stirred for 20 h. Pyridine

was evaporated under reduced pressure, and the residue was puri-

fied by chromatography through a silica gel column (CH₂Cl₂/

MeOH, 97:3) to give 2A in 95% yield as a white crystalline solid.

R_f= 0.4 (CH₂Cl₂/MeOH, 98:2); m.p. 183–185 °C (ref.^[14]184 °C).

(CHCl ): ν

= 3337_,3018, 2926, 2399, 2360, 2333, 1506, 1485,

˜

3

max

1387, 1240, 1215, 1068 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ =

6.61 (s, 1 H), 6.52 (s, 1 H), 5.92 (ABq, J = 1.4 Hz, 2 H), 4.59 (br.

s, 1 H), 4.30 (m, 1 H), 4.23 and 3.77 (ABq, J = 16.3 Hz, 2 H), 3.95

(d, J = 3.3 Hz, 1 H), 3.30 (d, J = 10.5 Hz, 1 H), 3.04 (d, J =

10.5 Hz, 1 H), 3.05 (br. s, 1 H), 2.52–2.48 (m, 1 H), 2.41–2.38 (m,

1 H), 1.67 (ddd, J = 11.8, 10.5, 10.4 Hz, 1 H), 1.49 (s, 3 H), 1.31

(s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 147.4 (C), 146.8

(C), 130.4 (C), 108.9 (C), 108.0 (CH), 107.0 (CH), 101.2 (CH₂),

78.1 (CH), 74.5 (CH), 68.5 (CH), 61.6 (CH₂), 58.8 (CH₂), 58.1

(CH), 57.0 (CH), 40.4 (CH), 37.2 (CH₂), 28.3 (CH₃), 26.3 (CH₃)

ppm. HRMS (EI): calcd. for C₁₉H₂₃NO₅[M]⁺345.15762; found

345.15728.

IR (neat): ν

= 2932, 2875, 1735, 1528, 1482, 1241, 1048 cm^–1.

˜

max

¹H NMR (500 MHz, CDCl₃): δ = 6.54 (s, 1 H), 6.48 (s, 1 H), 5.89

and 5.86 (ABq, J = 1.2 Hz, 2 H), 5.55 (br. s, 1 H), 5.47 (dd, J =

4.0, 4.0 Hz, 1 H), 4.94 (ddd, J = 12.2, 4.0, 4.0 Hz, 1 H), 4.36 and

3.87 (ABq, J = 16.5 Hz, 1 H), 3.36–3.34 (m, 2 H), 3.09 (ABq, J =

11.0 Hz, 2 H), 3.06 (d, J = 11.0 Hz, 2 H), 2.22–2.20 (m, 1 H), 2.08

(s, 3 H), 2.00 (s, 3 H),1.80 (ddd, J = 11.6, 11.6, 11.6 Hz, 1 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 170.5 (CO), 170.0 (CO), 156.6

(C), 147.0 (C), 146.1 (C), 131.5 (C), 124.5 (C), 112.1 (CH), 107.5

(CH), 106.9 (CH), 100.8 (CH₂), 68.8 (CH), 66.1 (CH), 63.0 (CH),

61.2 (CH₂), 56.0 (CH₂), 45.4 (CH), 30.2 (CH₂), 21.0 (CH₃), 20.9

(CH₃) ppm. HRMS (EI): calcd. for C₂₀H₂₁NO₆[M]⁺371.1369;

found 371.13504.

(3aR,4aS,5R,12S,13aS)-2,2-Dimethyl-3a,4,4a,6,12,13a-hexahydro-

5,12-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-b][1,3]dioxolo[4Ј,5Ј:

4,5]benzo[1,2-e]azepine (65): Mesyl chloride (8 μL, 0.09 mmol) was

added to a stirred solution of 64 (10 mg, 0.03 mmol), DMAP

(2 mg) and TEA (12 μL, 0.09 mmol) in dry CH₂Cl₂(1 mL) at 0 °C.

The reaction mixture was stirred at room temp. for 10 h and then

diluted with water (1 mL) and extracted with CH₂Cl₂. The organic

(4S)-3-{(E)-3-[6-({[2-(1,3-Dioxolan-2-yl)-1-(trimethylsilyl)ethyl][(tri-

methylsilyl)methyl]amino}methyl)-1,3-benzodioxol-5-yl]acryloyl}-

4-benzyloxazolidin-2-one (66): Evans’ acryloyloxazolidinone 67

(2.13 gm, 9.18 mmol) was added to a mixture of K₂CO₃(2.53 g,

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4585

G. Pandey, R. Kumar, P. Banerjee, V. G. Puranik

FULL PAPER

18.36 mmol), Pd(OAc)₂(0.164 g, 0.73 mmol), PPh₃(0.385 g,

1.46 mmol) and 41 (5 g, 9.18 mmol) in dry CH₃CN (40 mL). The

mixture was degassed several times with argon, stirred for 1 h, and

then heated at reflux under argon for 12 h. The reaction mixture

was cooled to room temperature, diluted with CH₂Cl₂, and washed

with 0.1 n HCl (3ϫ20 mL) followed by brine. The combined or-

ganic layers were concentrated under reduced pressure, and the res-

idue was purified by column chromatography (petroleum ether/

ethyl acetate, 85:15) to give 3.8 g (65%) of 66 as a viscous pale-

yellow liquid. R_f= 0.25 (petroleum ether/ethyl acetate, 9:1). IR

and P. B. thank the Council of Scientific and Industrial Research

(CSIR), New Delhi, for research fellowships.

[1] For recent reviews, see: a) Z. Jin, Nat. Prod. Rep. 2003, 20,

606–614; b) Z. Jin, Nat. Prod. Rep. 2007, 24, 886–905.

[2] a) W. C. Wildman, C. J. Kaufman, J. Am. Chem. Soc. 1955, 77,

1248–1252; b) W. C. Wildman, C. L. Brown, J. Am. Chem. Soc.

1968, 90,6439–6146.

[3] a) L. J. Dry, M. E. Poynton, M. E. Thompson, F. L. Warren,

J. Chem. Soc. 1958, 4701–4704; b) M. Laing, R. C. Clark, Tet-

rahedron Lett. 1974, 15, 583–584; c) R. C. Clark, F. L. Warren,

K. G. R. Pachler, Tetrahedron 1975, 31, 1855–1859.

[4] Y. Inubushi, H. M. Fales, E. W. Warnhoff, W. C. Wildman, J.

Org. Chem. 1960, 25, 2153–2164.

[5] J. Labraña, A. K. Machocho, V. Kricsfalusy, R. Brun, C. Co-

dina, F. Viladomat, J. Bastida, Phytochemistry 2002, 60, 847–

852.

[6] F. Viladomat, J. Bastida, C. Codina, W. E. Campbell, S.

Mathee, Phytochemistry 1995, 40, 307–311.

[7] a) I. W. Southon, J. Buckinghham, Dictionary of the Alkaloids,

Chapman & Hall, New York, 1989, pp. 229, 735; b) A. F.

Schürmann da Silva, J. P. de Andrade, L. R. M. Bevilaqua,

M. M. de Souza, I. Izquierdo, A. T. Henriques, J. A. S. Zuan-

azzi, Pharmacol. Biochem. Behav. 2006, 85, 148–154.

[8] a) M. Ishizaki, O. Hoshino, Y. Iitaka, Tetrahedron Lett. 1991,

32, 7079–7082; b) M. Ishizaki, O. Hoshino, J. Org. Chem. 1992,

57, 7285–7295.

(CHCl ): ν

= 2925, 1778, 1703, 1600, 1041 cm^{–1 1}H NMR

.

˜

3

max

(500 MHz, CDCl₃): δ = 8.22 (d, J = 15.4 Hz, 1 H), 7.59 (d, J =

15.4 Hz, 1 H), 7.27–7.05 (m, 7 H), 5.92 (s, 2 H), 4.92 (m, 1 H), 4.71

(m, 1 H), 4.13 (m, 2 H), 3.84 (m, 2 H), 3.74 (m, 3 H), 3.53 (d, J =

14.0 Hz, 1 H), 3.28 (dd, J = 13.4, 3.0 Hz, 1 H), 2.77 (dd, J = 13.4,

9.6 Hz, 1 H), 2.32 (br. t, J = 5.9 Hz, 1 H), 2.13 (d, J = 13.9 Hz, 1

H), 1.96 (m, 1 H), 1.93 (d, J = 13.9 Hz, 1 H), 1.59 (m, 1 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 172.5 (CO), 165.2 (CO), 153.6

(C), 149.9 (C), 146.9 (C), 143.4 (CH), 136.4 (C), 135.5 (C), 129.5

(CH), 128.9 (CH), 127.4 (CH), 115.9 (CH), 109.9 (CH), 106.1

(CH), 103.9 (CH), 101.4 (CH₂), 66.1 (CH₂), 64.7 (CH₂), 64.6

(CH₂), 56.4 (CH₂), 55.4 (CH), 49.7 (CH), 44.7 (CH₂), 38.0 (CH₂),

30.5 (CH₂), 0.5 [Si(CH₃)₃], –1.0 [Si(CH₃)₃] ppm. MS (MALDI-

TOF): m/z = 639 [M + H]⁺. C₃₃H₄₆N₂O₇Si₂(638.91): calcd. C

62.04, H 7.26, N 4.38; found C 62.18, H 7.33, N 4.52.

{(6R,7S,8S,9R)-7-[(1,3-Dioxolan-2-yl)methyl]-5,7,8,9-tetrahydro-

6,9-methano[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]azepin-8-yl}methanol

(68): A cycloaddition reaction was performed as described for com-

pound 23. After the disappearance of the starting material, the re-

action mixture was filtered through a small plug of basic alumina

and eluted with methanol. The solvent was evaporated completely

to give a crude brown residue, which was redissolved in dry THF,

and the resulting solution was added to a suspension of LiAlH₄in

dry THF at 0 °C and the reaction mixture stirred at room temp.

for 4 h. After completion of the starting material, as monitored by

TLC, the reaction mixture was quenched with a saturated aqueous

Na₂SO₄solution and stirred for a further 1 h. The reaction mixture

was filtered through small pad of Celite, the solvent was evapo-

rated, and the crude mass was purified by column chromatography

(CH₂Cl₂/MeOH, 9:1) to give chiral alcohol 68 (46% yield over two

steps) as a white solid. R_f= 0.25 (CH₂Cl₂/MeOH, 9:1); m.p. 168–

[9] a) J. Jin, S. M. Weinreb, J. Am. Chem. Soc. 1997, 119, 2050–

2051; b) J. Jin, S. M. Weinreb, J. Am. Chem. Soc. 1997, 119,

5773–5784.

[10] M. Ishizaki, K.-I. Kurihara, E. Tanazawa, O. Hoshino, J.

Chem. Soc. Perkin Trans. 1 1993, 101–110.

[11] a) L. E. Overman, J. Shim, J. Org. Chem. 1991, 56, 5005–5007;

b) L. E. Overman, J. Shim, J. Org. Chem. 1993, 58, 4662–4672.

[12] W. H. Pearson, B. W. Lian, Angew. Chem. Int. Ed. 1998, 37,

1724–1725.

[13] M. Ikeda, M. Hamada, T. Yamashita, F. Ikegami, T. Sato, H.

Ishibashi, Synlett 1998, 1246–1248.

[14] a) C.-K. Sha, S.-J. Huang, C.-M. Huang, A.-W. Hong, T.-H.

Jeng, Pure Appl. Chem. 2000, 72, 1773–1776; b) C.-K. Sha, A.-

W. Hong, C.-M. Huang, Org. Lett. 2001, 3, 2177–2179; c) A.-

W. Hong, T.-H. Cheng, V. Raghukumar, C.-K. Sha, J. Org.

Chem. 2008, 73, 7580–7585.

[15] a) M. G. Banwell, A. J. Edwards, K. A. Jolliffe, M. Kemmler,

J. Chem. Soc. Perkin Trans. 1 2001, 1345–1348; b) M. G.

Banwell, O. J. Kokas, A. C. Willis, Org. Lett. 2007, 9, 3503–

3506; c) M. Matveenko, M. G. Banwell, A. C. Willis, Org. Lett.

2008, 10, 4693–4696; d) O. J. Kokas, M. G. Banwell, A. C. Wil-

lis, Tetrahedron 2008, 64, 6444–6451.

[16] M.-Y. Chang, H.-P. Chen, C.-Y. Lin, C.-L. Pai, Heterocycles

2005, 65, 1999–2004.

[17] M. Anada, M. Tanaka, N. Shimada, H. Nambu, M. Yama-

waki, S. Hashimoto, Tetrahedron 2009, 65, 3069–3077.

[18] S. V. Pansare, R. Lingampally, R. L. Kirby, Org. Lett. 2010, 12,

556–559.

170 °C. [α]²_D⁷= +10.5 (c = 0.45, MeOH). IR (CHCl ): ν_max= 3431,

˜

.

3

3053, 2985, 1635, 1404, 1265, 1236, 1040 cm^–1

¹H NMR

(200 MHz, CDCl₃): δ = 6.51 (s, 1 H), 6.42 (s, 1 H), 5.85 (br. s, 2 H),

5.08 (dd, J = 6.9, 2.6, Hz, 1 H), 4.22 and 3.70 (ABq, J = 16.7 Hz, 2

H), 3.99–3.80 (m, 4 H), 3.77–3.62 (m, 1 H), 3.50 (dd, J = 9.0,

10.6 Hz, 1 H), 3.29 (dd, J = 11.4, 8.1, 3.6 Hz, 1 H), 3.01 (dd, J =

2.7 Hz, 1 H), 2.95 (d, J = 2.7 Hz, 1 H), 2.85 (d, J = 11.4 Hz, 1 H),

2.55–2.44 (m, 1 H), 2.08 (br. s, 1 H), 1.85–1.58 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 146.2 (C), 145.7 (C), 135.9 (C), 125.2

(C), 107.1 (CH), 106.5 (CH), 104.0 (CH), 100.6 (CH₂), 64.9 (CH₂),

64.6 (CH₂), 62.9 (CH), 61.4 (CH₂), 60.5 (CH₂), 55.9 (CH), 52.5

(CH₂), 42.5 (CH), 34.7 (CH₂) ppm. MS (ESI): m/z = 320 [M +

H]⁺. HRMS (EI): calcd. for C₁₇H₂₁NO₅319.1419; found 319.1473.

[19] G. Pandey, P. Banerjee, R. Kumar, V. G. Puranik, Org. Lett.

2005, 7, 3713–3716.

[20] a) G. Pandey, G. Lakhsmaiah, G. Kumaraswamy, J. Chem.

Soc., Chem. Commun. 1992, 1313–1314; b) G. Pandey, G.

Lakhsmaiah, Tetrahedron Lett. 1993, 34, 4861–4864.

[21] a) G. Pandey, G. Lakshmaiah, A. Ghatak, Tetrahedron Lett.

1993, 34, 7301–7304; b) G. Pandey, T. D. Bagul, A. K. Sahoo,

J. Org. Chem. 1998, 63, 760–768; c) G. Pandey, A. K. Sahoo,

S. R. Gadre, T. D. Bagul, U. D. Phalgune, J. Org. Chem. 1999,

64, 4990–4994; d) G. Pandey, J. K. Laha, A. K. Mohankrish-

nan, Tetrahedron Lett. 1999, 40, 6065–6068; e) G. Pandey,

A. K. Sahoo, T. D. Bagul, Org. Lett. 2000, 2, 2299–2301; f) G.

Pandey, J. K. Laha, G. Lakhshmaiah, Tetrahedron 2002, 58,

3525–3534; g) G. Pandey, N. R. Gupta, T. M. Pimpalpalle, Org.

Supporting Information (see footnote on the first page of this arti-

cle): ¹H and ¹³C NMR spectra for all synthetic compounds, HPLC

spectrum for 68.

Acknowledgments

The authors are thankful to the Department of Science and Tech-

nology (DST), New Delhi, for funding this research program. R. K.

4586

www.eurjoc.org

Eur. J. Org. Chem. 2011, 4571–4587

5,11-Methanomorphanthridine Alkaloids

Lett. 2009, 11, 2547–2550; h) G. Pandey, N. R. Gupta, S. R.

Gadre, Eur. J. Org. Chem. 2011, 740–750.

[22] The absence of NOESY cross-peaks for 4a-H–12-H and 11a-

H–12-H clearly confirm the endo orientation of C-12 in 13 and

J(C-11a,C-4a) = 8.74 Hz for the cis configuration of C-11a and

C-4a.

[23] X-ray analysis of 30 (C₁₆H₁₉NO₄): CCDC-271169 contains the

supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

[24] a) H. O. House, W. V. Phillips, T. S. V. Sayer, C. C. Yau, J. Org.

Chem. 1978, 43, 700–710; b) G. Petrovic, Z. Cekovic, Org. Lett.

2000, 2, 3769–3772.

[38]

[39]

For reviews of the HWE reaction, see: a) J. Boutagy, R.

Thomas, Chem. Rev. 1974, 74, 87–99; b) B. E. Maryanoff, A. B.

Reitz, Chem. Rev. 1989, 89, 863–927; c) S. E. Kelly, Comp. Org.

Syn. 1991, 1, 729–817.

X-ray analysis of 48 (C₁₉H₂₃NO₆): CCDC-817476 contains the

supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

K. Prantz, J. Mulzer, Chem. Rev. 2010, 110, 3741–3766, and

references cited therein.

a) R. H. Grubbs, Handbook of Metathesis, Wiley-VCH,

Weinheim, Germany, 2003; b) R. H. Grubbs, T. M. Trnka, Ru-

thenium-Catalysed Olefin Metathesis, in: Ruthenium in Organic

Chemistry (Ed.: S.-I. Murahasi), Wiley-VCH, Weinheim, Ger-

many, 2004.

G. C. Fu, S. T. Nguyen, R. H. Grubbs, J. Am. Chem. Soc. 1993,

115, 9856–9857.

[40]

[41]

[25] M. H. Howard, F. J. Sardina, H. Rapoport, J. Org. Chem. 1990,

55, 2829–2838.

[26] W. J. Scott, J. K. Stille, J. Am. Chem. Soc. 1986, 108, 3033–

[42]

[43]

3040.

[27] D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299–

6302.

[28] a) T. Mukaiyama, M. Hayashi, Chem. Lett. 1974, 15; b) for the

intramolecular version, see: T. Mukaiama, Org. React. 1982,

28, 238–248; c) T. Mukaiyama, M. Murakami, Synthesis 1987,

1043–1054.

D. L. Wright, J. P. Schulte II, M. A. Page, Org. Lett. 2000, 2,

1847–1850.

Q. Yang, W.-J. Xiao, Z. Yu, Org. Lett. 2005, 7, 871–874.

K. Shimizu, M. Takimoto, Y. Sato, M. Mori, J. Organomet.

Chem. 2006, 691, 5466–5475.

[44]

[45]

[29] X-ray analysis of 38 (C₁₈H₂₁NO₅): CCDC-817477 contains the

supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

[30] a) Y. Yokozawa, T. Nakai, N. Ishikawa, Tetrahedron Lett. 1984,

25, 3987–3991; b) S. Murata, M. Suzuki, R. Noyori, Tetrahe-

dron 1988, 44, 4259–4275.

[46] X-ray analysis of 62 (C₁₈H₂₁NO₆): CCDC-817478 contains the

supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

[47] a) S. Elango, T.-H. Yan, J. Org. Chem. 2002, 67, 6954–6959; b)

S. Elango, T.-H. Yan, Tetrahedron 2002, 58, 7335–7338.

[48] a) K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863–

909; b) S. Karlsson, H.-E. Högsberg, Org. Prep. Proced. Int.

2001, 33, 103–172; c) G. Pandey, P. Banerjee, S. R. Gadre,

Chem. Rev. 2006, 106, 4484–4517, and references cited therein.

[49] I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765–2809, and

references cited therein.

[31] For recent reviews on aldol reactions, see: a) B. Alcaide, P.

Amendros, Eur. J. Org. Chem. 2002, 1595–1601, and references

cited therein; b) C. Palomo, M. Oiarbide, J. M. Garcia, Chem.

Eur. J. 2002, 8, 36–44.

[32] C. Johnstone, J. W. Kerr, J. S. Scott, Chem. Commun. 1996,

341–342.

[50] A. I. Meyers, M. J. McKennon, J. Org. Chem. 1993, 58, 3568–

[33] K. Tanemura, T. Suzuki, T. Horaguchi, J. Chem. Soc., Chem.

Commun. 1992, 2997–2998.

[34] M. E. Jung, W. A. Andrus, P. L. Ornstein, Tetrahedron Lett.

1977, 18, 4175–4178.

[35] X-ray analysis of 43 (C₁₈H₂₁NO₅): CCDC-817475 contains the

supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

[36] T. J. Donohoe, A. Raoof, G. C. Freestone, I. D. Linney, A.

Cowley, M. Helliwell, Org. Lett. 2002, 4, 3059–3062.

[37] M. Ousmer, N. A. Bruan, C. Bavoux, M. Perrin, M. A. Ciufol-

ini, J. Am. Chem. Soc. 2001, 123, 7534–7538, and references

cited therein.

3571.

[51] HPLC conditions: Chiralcel column: OD-H (250ϫ4.6 mm),

ethanol/petroleum ether (10:90), flow rate 0.5 mL/min

(280 psi), retention times of 27 and 30 min, ee (obsd.) ≈ 63%.

[52] For the experimental procedure and spectroscopic data for

compounds 13–15, 17, 26, 28–30, 33 and 34, see the Supporting

Information of ref.^[19]

[53] a) G. M. Sheldrick, SHELX-97, program for crystal structure

solution and refinement, University of Göttingen, Germany,

1997; b) G. M. Sheldrick, Acta Crystallogr., Sect. A: Found.

Crystallogr., 2008, 64, 112–122.

Received: April 29, 2011

Published Online: July 4, 2011

Eur. J. Org. Chem. 2011, 4571–4587

www.eurjoc.org

4587

Article Doi

One-step stereospecific strategy for the construction of the core structure of the 5, 11-methanomorphanthridine alkaloids in racemic as well as in optically pure form: Synthesis of (±)-pancracine and (±)- brunsvigine

DOI: 10.1002/ejoc.201100601

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201100601

Full text of DOI:10.1002/ejoc.201100601

Products guided by the article

R&D Labs maybe for 1333384-05-6

Relevant to this article

Hot Product