Further uses of pyrrole-based dienoxysilane synthons: A full aldol approach to azabicyclo[x.2.1]alkane systems

FULL PAPER

DOI: 10.1002/ejoc.200800040

Further Uses of Pyrrole-Based Dienoxysilane Synthons: A Full Aldol Approach

to Azabicyclo[x.2.1]alkane Systems

Franca Zanardi,*^[a]Claudio Curti,^[a]Andrea Sartori,^[a]Gloria Rassu,^[b]

Annamaria Roggio,^[b]Lucia Battistini,^[a]Paola Burreddu,^[b]Luigi Pinna,^[c]Giorgio Pelosi,^[d]

and Giovanni Casiraghi*^[a]

Keywords: Asymmetric synthesis / Aldol reactions / Diastereoselectivity / N-heterocycles / Ketones

Two racemic 2-azabicyclo[2.2.1]heptane structures, 15 and

21, and two chiral non-racemic 6-azabicyclo[3.2.1]octane

representatives, 28 and 36, have been synthesized starting

from 1-(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyloxy)-

pyrrole (TBSOP, 5) and suitable ketones, 9, 16, 22 and 29. 2-

Azabicycle 15 was then elaborated to racemic cyclopentane

amino acid 38, while 6-azabicycle 36 served to access the

enantiomerically pure normorphan-type structure 40. For all

substrates, a uniform synthetic scheme was implemented

based on the combination of two diastereoselective aldol-

type carbon–carbon bond-forming reactions, the efficiencies

of which were secured by appropriate aldol-stabilizing steps.

A mechanistic rationale accounting for the markedly dia-

stereoselective character of the key Mukaiyama aldol reac-

tions between TBSOP and the ketone acceptors has been

postulated that involves hetero-Diels–Alder transition-state

structures in which the preference for endo versus exo ad-

dition is governed by the electronic nature of the substituents

in the ketone substrates.

Germany, 2008)

Introduction

The vinylogous Mukaiyama aldol addition of pyrrole-

based dienoxysilane compounds to carbonyl substrates,

typically aldehydes, has now evolved into an established

methodology^[1]with a wide range of densely functionalized

heterocyclic and carbocyclic molecules and other useful

fragments in the portfolio.^[1,2]Recent notable achievements

in this area include, for example, the enantioselective syn-

thesis of the (20S) proteasome inhibitor (+)-lactacystin (1)

developed by Baldwin and co-workers,^[2a]the discovery of

the potent influenza virus neuraminidase inhibitor A-

315675 (2) by researchers at the Abbott group,^[2b,2e]

the stereoselective access to the pentacyclic alkaloid (–)-

cephalotaxine (3) by Royer and co-workers^[2c]and the Figure 1. Notable targets whose synthesis capitalized on the pyr-

role-based dienoxysilane chemistry.

stereocontrolled entry to a collection of hydroxylated

carbocyclic amines and amino acids, as exemplified by

structure 4, developed by us (Figure 1).^[2d,2f–2i]

In keeping with our longstanding interest in the develop-

ment of reliable procedures for the synthesis of highly sub-

stituted alicyclic and heterocyclic structures using furan-,

Viale G. P. Usberti 27A, 43100 Parma, Italy

[a] Dipartimento Farmaceutico, Università di Parma,

Fax: +39-0521-905006

pyrrole- and thiophene-based dienoxysilane synthons,^[1]we

now report a flexible approach to decorated azabicyclo-

[x.2.1]alkane systems^[3]from 1-(tert-butoxycarbonyl)-2-

(tert-butyldimethylsilyloxy)pyrrole (TBSOP, 5)^[4]and suit-

able ketones using a combination of two highly diastereo-

selective, aldol-based carbon–carbon bond-forming strate-

gies: a crossed vinylogous Mukaiyama aldol reaction

(VMAR)^[5]followed by an intramolecular silylative Mukai-

yama aldol reaction (ISMAR).

E-mail: giovanni.casiraghi@unipr.it

franca.zanardi@unipr.it

[b] Istituto di Chimica Biomolecolare del CNR,

Traversa La Crucca 3, 07040 Li Punti, Sassari, Italy

[c] Dipartimento di Chimica, Università di Sassari,

Via Vienna 2, 07100 Sassari, Italy

[d] Dipartimento di Chimica Generale ed Inorganica, Chimica

Analitica, Chimica Fisica, Università di Parma,

Viale G. P. Usberti 17A, 43100 Parma, Italy

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

Eur. J. Org. Chem. 2008, 2273–2287

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FULL PAPER

Unlike aldehydes, the use of ketone acceptors in simple isomers 7. Two reaction modes were especially productive:

and vinylogous Mukaiyama aldol-type addition reactions^[6]the use of SnCl₄in diethyl ether (Entry 2, 85% yield, 85:15

is still hampered by the intrinsically sluggish nature of the dr) and BF₃·OEt₂in CH₂Cl₂(Entry 3, 91% yield, 94:6 dr).

ketone component and the competing retrograde fragmen- Remarkably, when non-silicon Lewis acid promoters were

tation of the tertiary aldolate adducts formed. Notably, this employed, the reactions proceeded in a fully silylative man-

obstacle was pleasingly surmounted here by adopting pro- ner, with the TBS group from the donor installed on the

cedures that stabilize the emerging α,β-unsaturated ketols aldol hydroxy group. However, with silicon promoters (e.g.,

by in situ silylation or reduction.

TMSOTf or TESOTf), O-trimethylsilyl- or O-triethylsilyl-

carbinols emerged with only traces of the O-TBS congeners

(Entries 8 and 9). This suggests that minimal silicon scram-

bling occurred between the donor and promoter silicon

atoms during the silylative Mukaiyama aldol coupling reac-

tion. The relative stereochemistry of the major racemic ad-

duct 7a (and hence 7b and 7c by analogy) was firmly estab-

lished as (5R*,1ЈS*) (N,O-syn) by single-crystal X-ray

analysis, as shown in Figure 2.

Results and Discussion

Scheme 1 depicts the general concept for the construc-

tion of the targeted bicyclic entities formulated on the basis

of our own precedents.^[1,2d,2h,2i]Thus, a given aldol adduct

of generic formula C is first assembled by connecting pyr-

role A and ketone B through a crossed vinylogous Mukai-

yama aldol reaction (VMAR). Then, in preparation of the

second carbon–carbon bond juncture, C is elaborated to

aldehydes D/DЈ by double-bond saturation followed by ma-

nipulation of either the R¹or R²ketone end groups. Finally,

intermediates D/DЈ are subjected to an intramolecular si-

lylative Mukaiyama aldol reaction (ISMAR), a step that

completes the construction of the targeted bicyclic systems

E/EЈ.

Table 1. Optimization of the addition reaction between silyloxypyr-

role 5 and acetophenone 6, giving unsaturated lactams 7 and 8.^[a]

Entry Lewis acid

Solvent

Products Yield [%]^[b]syn/anti ratio^[c]

1

2

3

4

5

6

7

8

9

SnCl₄

BF₃·OEt₂

BF₃·OEt₂Hex/THF

TiCl₄

CH₂Cl₂

Et₂O

CH₂Cl₂

THF

7a, 8a

70

85

91

52

46

75:25

85:15

94:6

81:19

82:18

–

7a, 8a

[d]

CH₂Cl₂

–

ScOTf₃

7a, 8a

7b, 8b

7c, 8c

7a, 8a

trace

50

56

–

TMSOTf

TESOTf

TBSOTf

70:30

65:35

60:40

10

60

[a] Unless otherwise noted, all reactions were carried out at –80 °C

with 5 (200 mg, 0.67 mmol), 6 (0.87 mmol), Lewis acid promoter

(0.87 mmol), and solvent (3 mL). [b] Isolated combined yield. [c]

1

Determined by H NMR analysis of the unpurified reaction mix-

tures. [d] A complex reaction mixture was observed.

Scheme 1. Synthetic route to the azabicyclo[x.2.1]alkanes (X, Y =

0–n carbon atoms; PG = protecting group; VMAR = vinylogous

Mukaiyama aldol reaction; ISMAR = intramolecular silylative

Mukaiyama aldol reaction).

In principle, the scope of the proposed strategy was ex-

pected to be quite large because by utilizing various types

of ketones B (X, Y = 0–n carbon atoms) one would be

able to assemble the azabicycloalkane scaffolds with a high

degree of skeletal and stereochemical variation.

Preparative Work

We set about investigating this project by identifying use-

ful conditions for the vinylogous Mukaiyama aldol addition

between TBSOP (5) and acetophenone (6). Several Lewis

acid/solvent systems (Table 1) promoted the reaction effec-

tively, giving the expected silylated adducts 7 and 8 in high

isolated yields and with good margins of diastereoselectiv-

Figure 2. X-ray structure of the adduct 7a showing the N,O-syn

ity, invariably favouring the N,O-syn-configured (5R*,1ЈS*) stereodisposition (50% thermal ellipsoids).

2274 Eur. J. Org. Chem. 2008, 2273–2287

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A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

The conditions employed for pyrrole 5 and acetophenone

Having surmounted this initial obstacle, the synthesis of

(6) were also applicable to a variety of other simple ketone 15 then proceeded by manipulation of the ethyl carboxylate

substrates.^[7]However, as our targets were the azabicyclo- portion within 11 to a carbaldehyde. Thus, protection of

[x.2.1]alkane scaffolds, we explored the reactions of two the tertiary hydroxy group as a TBS ether and swapping the

achiral (9 and 16) and two chiral non-racemic substrates (22 N-Boc protecting group for the acid-tolerant benzyl moiety

and 29) which embodied at least one manipulatable ketone afforded ethyl ester 12 in a 71% isolated yield (three steps).

substituent.

Reduction of the ester functionality within 12 in the pres-

ence of a lactam carbonyl group was quite problematic.

However, after exploring several possibilities, we found that

the chemoselective reduction of the ester group to a pri-

mary alcohol could be carried out by employing LiN-

Me₂BH₃in THF, conditions that caused the simultaneous

transmigration of the tertiary carbinol TBS protecting

group to the newly formed primary hydroxy group to give

rise to carbinol 13 in a 70% isolated yield. Pleasingly, this

silyl transfer, albeit unexpected, proved inconsequential for

the synthesis overall.

After desilylation, oxidation of the primary hydroxy

group by a conventional Swern protocol (oxalyl chloride,

DMSO, Et₃N) was clean and productive, and returned the

aldehyde 14 in 81% yield. The way was now clear for the

second intramolecular aldol reaction which led to the five-

membered carbocycle of the 2-azabicycle skeleton. Accord-

ing to our precedent that smooth carbocyclization occurs

in a silylative and irreversible manner by exposing similar

aldehydo-lactams to the TBSOTf/DIPEA couple,^[2d,2h,2i]we

treated aldehyde 14 with this Lewis acid/Lewis base system.

As we had hoped, azacycle 15 was formed as a single dia-

stereoisomer with a cis relationship between the C-5 and C-

6 hydroxy substituents (60% isolated yield). The 2,2Ј-anti

relative stereochemistry of the first aldol construct 10, and

of all the intermediates, was not proved directly, but

emerged from a correlation with azabicycle 15, the product

of the second diastereoselective aldol construction. Strong

NOE contacts were observed between the axially disposed

7-H_axand the C-6 methyl protons, between 5-H and the

methyl protons themselves, as well as between 7-H_axand 5-

H, all consistent with their cis relationship. In addition,

the presence of a medium NOE contact between the C-6

hydroxy group and the benzyl CH₂group validated the as-

signment.

Synthesis of 2-Azabicyclo[2.2.1]heptanes 15 and 21

Pyruvic ester 9 and oxo(phenyl)acetate 16, the ketone

components of these syntheses, both possess a carboxylate

functional unit that can be easily manipulated to give an

aldehyde group, as demanded by the planned aldol carbo-

cyclization.

Targeting bicycle 15 (Scheme 2), the opening move was

the crossed aldol coupling between pyrrole 5 and pyruvate

9, which was examined with BF₃·OEt₂in CH₂Cl₂at –80 °C,

one of the best protocols found with acetophenone in the

preparatory work described above. Unfortunately, the con-

version was unacceptable, with only marginal amounts of

unsaturated and non-silylated^[8]tertiary carbinol 10 isolated

by column chromatography (25% yield). Realizing that a

retro-aldolization process was responsible for this sterile at-

tempt,^[6a]we opted not to isolate the unstable unsaturated

adduct 10, but to prepare the corresponding saturated ad-

duct 11 by directly exposing the crude reaction product to

catalytic hydrogen. Indeed, this dual addition–reduction

protocol proved successful, allowing the expedient synthesis

of the saturated 2,2Ј-anti compound 11, which was isolated

in a preparatively useful yield (75%, two steps) and with a

good margin of diastereoselectivity (90:10 dr) (Scheme 2).

The synthesis of azabicycle 21 commenced with oxo-

(phenyl)acetate 16 (Scheme 3), paralleling almost exactly

the chemistry exploited with pyruvate 9. The initial aldol

addition, promoted by BF₃·OEt₂, produced an unstable un-

saturated and non-silylated^[8]adduct (not isolated) which

was promptly hydrogenated and deprotected to give satu-

1

rated lactam 17 in Ͼ99:1 dr (by H NMR) and 60% yield

over two steps. Remarkably, the stereochemistry of 17,

which was conclusively confirmed at a later stage in the

synthesis, indicated a syn relationship of the N,O substitu-

ents at the two newly generated stereocentres C-2 and C-2Ј,

opposite to that observed in the pyruvate-derived congener

11. This point will be addressed later.

Prior to the decisive aldol carbocyclization, 17 was next

converted into aldehyde 20 by a clean five-step sequence

that involved the protection of certain functionalities to give

18, ester reduction to 19, desilylation and Swern oxidation

Scheme 2. Synthesis of 2-azabicyclo[2.2.1]heptane 15 (relative con-

figuration of racemic compounds). Double-headed arrows indicate

diagnostic NOE contacts.

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Figure 3. Proposed mechanism for the diastereo-divergent vinylog-

ous Mukaiyama aldol addition reaction between silyloxypyrrole 5

and ketones 9 and 16 (only one enantiomer shown).

Synthesis of 6-Azabicyclo[3.2.1]octane Systems 28 and 36

Scheme 3. Synthesis of 2-azabicyclo[2.2.1]heptane 21 (relative con-

figuration of racemic compounds). Double-headed arrows indicate

diagnostic NOE contacts.

Here, the task was to translate in a chiral environment

the concepts and results of the reactions with achiral

ketones 9 and 16. To this end, attention was focused on

(58% overall yield). Finally, exposure of aldehyde 20 to readily available (S)-configured oxo ester 22 (ex -ascorbic

TBSOTf/DIPEA (1:1, 3.0 equiv.) revealed bicycle 21 as a acid)^[10]and (R)-configured phenyl ketone 29 (ex -glyceral-

single diastereoisomer with the C-5 and C-6 hydroxy groups dehyde),^[11]both of which bear a stereocentre α to the re-

in a cis disposition (61% yield). Thus, the basic structure acting carbonyl group.

of the planned 2-azabicyclo[2.2.1]heptane system was as-

sembled.

To access azabicyclooctane 28, we first realized the aldol

reaction between 5 and 22 by employing BF₃·OEt₂as the

As for the pyruvate-derived bicycle 15, the stereochemis- promoter (Scheme 4). Pleasingly, by a sequential addition–

1

try of racemic 21 was certified by two-dimensional H–¹H reduction protocol, the saturated, non-silylated^[8]syn–syn

NOESY analysis which highlighted diagnostic correlations aldol adduct 23 was obtained in a virtually pure state (63%

between 7-H_axand the C-6 hydroxy proton, between 7-H_axyield over two steps) with high levels (Ͼ98:2 dr) of simple

(as well as the C-6 OH proton) and the C-5 silyloxy protect- and facial stereoselectivities, presumably via transition-state

ing group, and finally between the ortho protons of the C- TS3. The stereochemistry of 23 was not discernible at this

6 phenyl group and the benzyl CH₂group. Furthermore, point, so the adduct was advanced through the synthetic

the presence of long-range W coupling constants 7-H_eq–5- sequence. At a later stage (see below) it was determined that

H and 1-H–4-H corroborated the given structure. With this 23 was 2,2Ј-syn;2,4ЈЈ-syn-configured, as shown.

assignment, the stereochemistries of the initial syn-config-

ured adduct 17 and the intermediary compounds in this into an aldehyde, a multi-step manipulation was required.

synthesis were also confirmed as shown. This included nitrogen deprotection to 24 (CAN, MeCN),

To convert the C-5ЈЈ hydroxymethyl terminus within 23

Perhaps the most intriguing result in this section is the reprotection to 25 (NaH, PMBBr), acidic fission of the ace-

substrate-dependent stereodifferentiation of the first inter- tonide moiety (80% aq. AcOH, 80 °C), double silylation to

molecular aldol coupling reactions of ketones 9 and 16 26 (TESOTf, pyridine) and Swern oxidation^[12]to aldehydo-

which give rise to anti-configured 11 and syn-configured 17, lactam 27 (32% yield over five steps). Irrespective of the

respectively. Figure 3 delineates a rationale that accounts redundant functionalization of the aldehyde substrate, with

for this divergence based on hetero-Diels–Alder-like mech- a free tertiary alcohol and a methoxycarbonyl functionality,

anistic models.^[1b,9]

the silylative Mukaiyama-type cycloaldolization of 27 was

For 9, the best orbital alignment in the approach via TS1 productive (TBSOTf, DIPEA), predominantly affording the

requires the electron-withdrawing ethoxycarbonyl compo- azabicycle 28 (85:15 dr) in a good yield of 75% after silica

nent of the ketone to be oriented endo (methyl exo) with gel chromatography. This suggested that enolate silylation

respect to the diene, generating the anti-disposed adduct 11. occurred completely and retro-aldolization was totally sup-

However, for 16, one envisions the phenyl ring prevailing in pressed. The rigid nature of azabicycle 28 strongly facili-

1

the endo disposition, as in the approach via TS2, which tated its structural assignment by H and ¹³C NMR analy-

1

dictates a strong preference for the syn-disposed aldol prod- sis. In particular, the high-field H–¹H NOESY spectrum

uct 17.

of 28 revealed medium/strong correlations between 2-H and

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Eur. J. Org. Chem. 2008, 2273–2287

A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

Scheme 5. Synthesis of 6-azabicyclo[3.2.1]octane 36. Double-

headed arrows indicate diagnostic NOE contacts.

Scheme 4. Synthesis of 6-azabicyclo[3.2.1]octane 28. Double-

headed arrows indicate diagnostic NOE contacts.

8-H_ax, and between cis-disposed 2-H and 3-H, as well as

After exchanging Boc for PMB to give 33, dismantling

between 8-H_axand the C-4 hydroxy proton. In addition, of the acid-sensitive protecting groups (aq. AcOH) afforded

long-range W coupling constants between equatorially dis- a triol intermediate which was directly converted into si-

posed 1-H and 3-H and between 3-H and 5-H corroborated lylated lactam 34 in 71% yield over four steps. Aldehyde 35

this assignment. From this analysis, the structures of all the was then obtained in a further step by a modified Swern

intermediates shown in Scheme 4, which correlate with 28 oxidative protocol^[12]in 85% isolated yield. The second de-

by synthesis, were also ascertained with confidence.

cisive aldol reaction also proceeded uneventfully using our

Next, bicycle 36 was targeted starting from isopropylid- proven silylative methodology (TBSOTf/DIPEA) to give

ene-protected phenyl ketone 29 (Scheme 5). Quite unexpec- the six-membered carbocyclic frame of the azabicyclo-

tedly, however, neither BF₃·OEt₂nor any of the other con- octane 36 (72% yield, Ͼ98:2 dr). The stereochemistry of

1

ditions tested during the preparative work with acetophe- bicycle 36 was analyzed by extensive H NMR measure-

none (see above) promoted the aldol addition of silyloxydi- ments and provided the structure shown in Scheme 5.

ene 5 to this chiral ketone. To overcome this problem, a

Elaboration of Azabicycles 15 and 36

With a clean entry to azabicyclo[x.2.1]alkane structures

in hand, we finally addressed their elaboration to densely

revised, amine-buffered silylative strategy was adopted in

which the retrograde addition was hampered by in situ al-

dolate silylation.^[6a,13]

After considerable experimentation, effective coupling functionalized carbo- and heterocyclic entities. 2-Aza- and

was best achieved by employing TMSOTf as the Lewis acid 6-azabicycles 15 and 36 were selected to access racemic cy-

(3.0 equiv.) combined with 2,6-lutidine (2.0 equiv.). In this clopentane amino acid 38 and enantiopure normorphan 40,

case, the silylative addition proceeded via TS4, which pro- respectively (Scheme 6). For 38, bicycle 15 was first deben-

vided the O-trimethylsilyl-protected aldol product 30 after zylated by exposure to sodium in liquid ammonia and re-

aqueous workup (brine, pyridine). As partial desilylation protected to give the N-Boc derivative 37 in order to facili-

and fragmentation occurred during chromatographic purifi- tate the hydrolytic lactam fission (84% yield, two steps).

cation on silica, it was best to sequestrate the unsaturated The desired opening proceeded cleanly by exposure to

intermediate 30 promptly by catalytic H₂, arriving at the LiOH in wet THF to afford a protected amino acid which

more robust saturated lactam 31 (H₂, Pd/C; 70% yield over was fully deprotected (3  HCl) to furnish racemic amino

two steps, Ͼ98:2 dr).

acid 38 (hydrochloride salt, 58% yield over two steps).^[14]

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All moisture-sensitive reactions were carried out under a positive

pressure of nitrogen or argon. TLC analysis was performed on sil-

ica gel 60 F₂₅₄plates with visualization under short-wavelength UV

light or by dipping the plates into molybdate reagent (aqueous

H₂SO₄solution of cerium sulfate/ammonium molybdate) followed

by heating. Flash chromatography was performed on 40–63 µm sil-

ica gel using the indicated solvent mixtures. Melting points were

determined with an optical thermo-microscope and are uncor-

rected. Optical rotations were measured at ambient temperature

using a 100-mm cell with a 1-mL capacity and are given in units

of 10^–1degcm²g^–1. ¹H and ¹³C NMR spectra were recorded at 300/

75 MHz (Bruker Avance 300), 400/100 MHz (Varian Mercury Plus

MP400), or 600/150 MHz (Varian Inova SB-600). Chemical shifts

(δ) are given in parts per million (ppm) using [D]chloroform

(CHCl₃: δ_H= 7.26 ppm; CDCl₃: δ_C= 77.0 ppm), [D₄]methanol

(CD₂HOD: δ_H= 3.31 ppm; CD₃OD: δ_C= 49.0 ppm), or deuterium

oxide (DOH: δ_H= 4.75 ppm) as the internal reference. High-resolu-

tion mass spectrometry (HRMS) measurements were performed

with a mass spectrometer equipped with an external electrospray

ion source.

Scheme 6. Elaboration of azabicycles 15 and 36.

For the conversion of the 6-azabicycle 36 into the nor-

morphan structure 40, the stereochemistry and substituents

of the target molecule were already in place, and elabora-

tion of the lactam carbonyl group plus global deprotection

were solely required. Thus, after protection of the tertiary

carbinol within 36 as the O-TES ether, the carbonyl group

was reduced with in situ generated AlH₃(LiAlH₄/AlCl₃) to

provide amine 39 (89%, two steps) which was subjected to

Materials: 1-(tert-Butoxycarbonyl)-2-(tert-butyldimethylsilyloxy)-

pyrrole (5) was prepared from pyrrole according to a previously

hydrogenolytic removal of PMB and subsequent acidic desi- described protocol.^[15]Acetophenone (6), ethyl pyruvate (9) and

methyl oxo(phenyl)acetate (16) were purchased from Sigma Aldrich

and used without further purification.

lylation. This led to normorphan triol 40 in 89% yield over

two steps. The relative/absolute stereochemistries of both 38

and 40 were confirmed, as indicated, by chemical corre-

lation with the corresponding parent compounds 15 and 36,

and by the usual NMR techniques.

Methyl 2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoacetate (22)

was prepared from 5,6-isopropylidene--ascorbic acid (Aldrich) ac-

cording to the following three-step procedure.^[10]5,6-Isopropyl-

idene--ascorbic acid (5.0 g, 23.13 mmol) was added to a stirred

solution of K₂CO₃(6.8 g, 49.20 mmol) in H₂O (26 mL) at room

temperature. H₂O₂(30% v/v, 5.5 mL, 53.85 mmol) was slowly

added to the resulting yellowish solution, cooled to 0 °C. The

colourless reaction mixture was stirred at room temperature for

24 h, and then it was concentrated under vacuum to give a white

solid which was treated with EtOH (125 mL) and heated at reflux

for 30 min. The reaction mixture was filtered, while the solid resi-

due was treated again with EtOH (125 mL) and heated at reflux

for 30 min (twice). The collected filtrates were concentrated under

vacuum to furnish (R)-2-hydroxy-2-[(R)-2,2-dimethyl-1,3-dioxolan-

4-yl]acetic acid as a white solid (3.9 g, 96% yield). MeI (1.8 mL,

28.78 mmol) was slowly added to a solution of the above acid

(3.9 g, 22.14 mmol) in MeCN (24.4 mL) at room temperature. The

resulting mixture was heated at reflux at 80 °C for 3 h, filtered

through a Büchner funnel and concentrated under vacuum to give

a yellow oily residue which was purified by silica gel flash

chromatography (EtOAc/hexane, 80:20) to furnish methyl (R)-2-

[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyacetate (4.0 g, 95%

yield) as a colourless oil. [α]²_D⁰= +16.8 (c = 1.92, CHCl₃) {ref.^[10b]

[α]²_D⁰= +16.2 (c = 3.7, CH₂Cl₂)}. Freshly activated molecular

sieves (4 Å, 38.45 g) and pyridinium chlorochromate (18.24 g,

84.56 mmol) were sequentially added to a solution of the above

methyl ester (4.0 g, 21.14 mmol) in dry CH₂Cl₂(250 mL) at room

temperature. The resulting reaction mixture was vigorously stirred

for 16 h, filtered through a short pad of silica gel and purified by

silica gel flash chromatography (EtOAc/hexane, 40:60) to give

ketone 22 (2.59 g, 65% yield) as a colourless oil. [α]²_D⁰= –8.0 (c =

Conclusions

The stereocontrolled synthesis of four azabicycloalkane

systems, 15 and 21 (chiral racemic), and 28 and 36 (chiral

non-racemic), all of which embodied one quaternary ste-

reocentre, has been realized. 2-Aza- and 6-azabicycles 15

and 36 were then elaborated into densely functionalized cy-

clopentane amino acid 38 (racemic) and normorphan alka-

loid 40 (enantiopure), respectively. The constructions

shared a common synthetic route that featured two highly

diastereoselective, yet problematic aldol-based carbon–car-

bon bond formations. The problem of retro-addition that

plagues these processes was surmounted here by im-

plementing dual addition–reduction techniques or, better,

silylative aldol-stabilizing protocols.

The substrate-driven diastereoselectivity of the vinylog-

ous Mukaiyama aldol addition between pyrrolic diene 5

and ketones 9, 16, 22 and 29 was rationalized based on the

participation of hetero-Diels–Alder transition-state struc-

tures in which the endo versus exo paradigm is influenced,

as expected, by the electronic character of the substituents

in the ketone dienophile.

With these achievements emerging as a firm testament to

the vitality of the heterocyclic dienoxysilane scaffolds, we

anticipate their utility in organic synthesis to be enhanced

even more.

1

0.12, CHCl₃). H NMR (400 MHz, CDCl₃, 25 °C): δ = 5.07 (dd, J

= 7.6, 4.8 Hz, 1 H), 4.36 (dd, J = 8.8, 7.6 Hz, 1 H), 4.18 (dd, J =

8.8, 4.8 Hz, 1 H), 3.91 (s, 3 H), 1.48 (s, 3 H), 1.44 (s, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 191.3 (C_q), 161.5 (C_q),

111.7 (C_q), 78.2 (CH), 65.7 (CH₂), 53.1 (CH₃), 25.8 (CH₃), 25.2

(CH₃) ppm.

Experimental Section

General Experimental Procedures: All organic solvents were dried

and freshly distilled before use according to literature procedures.

2278

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Eur. J. Org. Chem. 2008, 2273–2287

A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]phenylmethanone (29) was

prepared from 2,3-O-isopropylidene--glyceraldehyde (ex -manni-

tol)^[16]according to the following procedure. tert-Butyllithium

(1.7  solution in pentane, 13.5 mL, 23.05 mmol) was added to a

stirred solution of bromobenzene (2.32 mL, 23.05 mmol) in anhy-

drous Et₂O (50 mL) under argon at –80 °C over a period of 20 min.

After 40 min, a diethyl ether solution of 2,3-O-isopropylidene--

glyceraldehyde (1.0 g, 7.68 mmol dissolved in 10 mL of Et₂O) was

slowly added at –80 °C. After 4 h, the reaction mixture was

quenched with saturated aqueous NH₄Cl (50 mL) and brine

(30 mL) while the temperature was allowed to reach an ambient

value (20 °C). The organic fraction was extracted with EtOAc

(three times), and the combined organic layers were dried (MgSO₄),

filtered and concentrated under vacuum. The resulting oily residue

was purified by silica gel flash chromatography (hexane/EtOAc,

80:20) to furnish [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]phenylmeth-

anol (1.36 g, 85% yield) as a 4:1 mixture of diastereoisomers. Dess–

Martin periodinane (3.04 g, 7.18 mmol) was added to a stirred

solution of the above carbinol mixture (1.36 g, 6.53 mmol) in dry

CH₂Cl₂(30 mL) under argon at room temperature, and the re-

sulting white slurry was stirred for 1 h. Saturated aqueous

NaHCO₃(about 20 mL) was then added until neutralization, and

saturated aqueous Na₂S₂O₃(10 mL) was added. The resulting mix-

ture was extracted with hexane (three times), and the combined

organic layers were dried (MgSO₄), filtered and concentrated under

vacuum. The resulting residue was purified by silica gel flash

chromatography (hexane/EtOAc, 60:40) to furnish ketone 29

(1.32 g, 98%) as white crystals. M.p. 50–52 °C. [α]²_D⁰= +11.82 (c =

0.99, CHCl₃) {ref.^[11]m.p. 61–62 °C, [α]²_D³= +15.3 (c = 3.6,

8.45, N 3.35; found C 65.98, H 8.56, N 3.23. Crystal data: see

below. ORTEP plot: see Figure 2.

Compound 8a: Colourless resin. ¹H NMR (300 MHz, CDCl₃,

25 °C): δ = 7.29 (m, 5 H), 7.09 (dd, J = 6.1, 2.1 Hz, 1 H), 5.74 (dd,

J = 6.0, 1.2 Hz, 1 H), 5.0 (t, J = 1.6 Hz, 1 H), 1.70 (s, 3 H), 1.63

(s, 9 H), 0.99 (s, 9 H), 0.12 (s, 3 H), –0.02 (s, 3 H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃, 25 °C): δ = 169.9 (C_q), 150.5 (C_q), 150.3 (CH),

143.2 (C_q), 127.7 (2 C, CH), 127.3 (CH), 126.4 (CH), 125.4 (2 C,

CH), 83.1 (C_q), 79.8 (C_q), 70.1 (CH), 28.1 (3 C, CH₃), 27.7 (CH₃),

26.1 (3 C, CH₃), 18.6 (C_q), –1.6 (CH₃), –2.2 (CH₃) ppm.

C₂₃H₃₅NO₄Si (417.61): calcd. C 66.15, H 8.45, N 3.35; found C

66.00, H 8.59, N 3.29.

Ethyl (R*)-2-[(R*)-1-(tert-Butoxycarbonyl)-5-oxopyrrolidin-2-yl]-2-

hydroxypropanoate (11): BF₃·OEt₂(0.55 mL, 4.37 mmol) was

added to a solution of ethyl pyruvate (9) (0.48 mL, 4.37 mmol) in

dry CH₂Cl₂(10 mL) under argon at –80 °C. After 5 min, a solution

of silyloxypyrrole 5 (1.0 g, 3.36 mmol, dissolved in 3 mL of dry

CH₂Cl₂) was added. After stirring at –80 °C for 4 h, pyridine

(0.53 mL, 6.55 mmol) was added, and the reaction mixture was

stirred for an additional 15 min. Water (10 mL) was added, and the

temperature was allowed to reach an ambient value. The reaction

mixture was extracted with CH₂Cl₂(three times), and the combined

organic layers were dried (MgSO₄), filtered and concentrated under

vacuum to give an oily residue which was almost entirely used as

such in the subsequent reductive reaction. A small portion of this

crude residue, however, was purified by silica gel flash chromatog-

raphy (hexane/EtOAc, 50:50) to furnish unsaturated lactam 10 as

a colourless resin. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.21

(dd, J = 6.1, 2.2 Hz, 1 H), 6.18 (dd, J = 6.1, 1.6 Hz, 1 H), 5.02 (t,

J = 2.1 Hz, 1 H), 4.2–4.4 (m, 2 H), 3.83 (s, 1 H), 1.55 (s, 9 H), 1.47

(s, 3 H), 1.30–1.40 (m, 3 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃,

25 °C): δ = 173.8 (C_q), 168.3 (C_q), 150.6 (C_q), 146.3 (CH), 128.2

(CH), 83.5 (C_q), 74.2 (C_q), 66.6 (CH), 62.3 (CH₂), 27.8 (3 C, CH₃),

22.2 (CH₃), 13.7 (CH₃) ppm.

1

MeOH)}. H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.99 (m, 2 H),

7.56 (tt, J = 7.4, 1.4 Hz, 1 H), 7.45 (m, 2 H), 5.27 (dd, J = 7.2,

5.9 Hz, 1 H), 4.31 (dd, J = 8.5, 7.3 Hz, 1 H), 4.24 (dd, J = 8.5,

5.9 Hz, 1 H), 1.46 (s, 3 H), 1.41 (s, 3 H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃, 25 °C): δ = 196.5 (C_q), 135.0 (C_q), 133.6 (CH), 128.7 (2 C,

CH), 128.6 (2 C, CH), 111.0 (C_q), 77.8 (CH), 66.2 (CH₂), 25.9

(CH₃), 25.6 (CH₃) ppm.

Palladium on carbon (60 mg) was added to a solution of the above

crude residue in anhydrous EtOAc (50 mL) at room temperature.

The reaction vessel was degassed under vacuum and thoroughly

purged with hydrogen (three times). The resulting heterogeneous

mixture was stirred under hydrogen for 12 h, after which time the

hydrogen was evacuated, the catalyst filtered off and the filtrate

concentrated under vacuum to give a crude residue which was puri-

fied by silica gel flash chromatography (hexane/EtOAc, 1:1) to fur-

nish pure lactam 11 (987 mg, 75% for two steps) as a white solid.

M.p. 101–102 °C. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 4.59 (d,

J = 8.8 Hz, 1 H), 4.22 (br. q, J = 7.1 Hz, 2 H), 3.50 (br. s, 1 H),

2.76 (ddd, J = 17.7, 10.9, 9.5 Hz, 1 H), 2.27 (ddd, J = 17.6, 10.0,

1.0 Hz, 1 H), 2.03 (m, 1 H), 1.72 (br. dd, J = 12.9, 9.4 Hz, 1 H),

1.49 (s, 9 H), 1.35 (s, 3 H), 1.20 (t, J = 7.2 Hz, 3 H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃, 25 °C): δ = 174.8 (2 C, 2Cq), 150.5 (C_q),

82.8 (C_q), 78.0 (C_q), 62.1 (CH₂), 61.3 (CH), 32.2 (CH₂), 27.6 (3 C,

CH₃), 23.5 (CH₃), 21.0 (CH₂), 13.8 (CH₃) ppm. C₁₄H₂₃NO₆

(301.34): calcd. C 55.80, H 7.69, N 4.65; found C 55.98, H 7.75, N

4.59.

(R*)-1-(tert-Butoxycarbonyl)-5-[(S*)-1-(tert-butyldimethylsilyloxy)-

1-phenylethyl]-1H-pyrrol-2(5H)-one (7a) and (R*)-5-[(R*)-1-(tert-

Butyldimethylsilyloxy)-1-phenylethyl]-1-(tert-butoxycarbonyl)-1H-

pyrrol-2(5H)-one (8a): See Table 1, Entry 3. To a solution of si-

lyloxypyrrole 5 (200 mg, 0.67 mmol) in anhydrous CH₂Cl₂(3.0 mL)

under argon at –80 °C was added acetophenone (6) (105 mg,

0.87 mmol). After 10 min, BF₃·OEt₂(110 µL, 0.87 mmol) was

slowly added, and the resulting mixture was stirred at –80 °C for

3 h. The reaction mixture was quenched at –80 °C with saturated

aqueous NaHCO₃(5 mL) and solid NaHCO₃(150 mg) while the

temperature was allowed to reach an ambient value. Further por-

tions of NaHCO₃were added until a neutral pH was achieved. The

mixture was extracted with CH₂Cl₂(three times). The combined

organic layers were dried (MgSO₄), filtered and concentrated under

vacuum to give an oily residue which was purified by silica gel flash

chromatography (hexane/Et₂O, 85:15) to furnish pure lactams 7a

(241 mg) and 8a (14 mg) in 86 and 5% yields, respectively.

Compound 7a: Colourless crystals. M.p. 89–91 °C. ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 7.48 (m, 2 H), 7.34 (m, 3 H), 6.81

(dd, J = 6.1, 2.2 Hz, 1 H), 6.01 (dd, J = 6.1, 1.6 Hz, 1 H), 5.0 (t, J

Ethyl

(R*)-2-[(R*)-1-Benzyl-5-oxopyrrolidin-2-yl]-2-(tert-butyldi-

methylsilyloxy)propanoate (12): Trifluoroacetic acid (TFA, 3.0 mL)

was added dropwise to a stirred solution of lactam 11 (0.98 g,

= 1.9 Hz, 1 H), 1.70 (s, 3 H), 1.50 (s, 9 H), 0.94 (s, 9 H), 0.12 (s, 3 3.27 mmol) in dry CH₂Cl₂(20 mL) at room temperature. After 2 h,

H), –0.03 (s, 3 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = the solvent was evaporated under vacuum, and the resulting oily

170.3 (C_q), 150.4 (C_q), 150.1 (CH), 146.0 (C_q), 128.2 (2 C, CH), residue was purified by silica gel flash chromatography (hexane/

127.3 (CH), 126.8 (CH), 125.2 (2 C, CH), 82.8 (C_q), 78.8 (C_q), 70.9 EtOAc, 90:10) to furnish an N-deprotected lactam intermediate

(CH), 27.9 (3 C, CH₃), 27.0 (CH₃), 26.2 (3 C, CH₃), 18.7 (C_q), –1.8 (0.65 g, 99%) as a white solid. M.p. 120–123 °C. ¹H NMR

(CH₃), –2.2 (CH₃) ppm. C₂₃H₃₅NO₄Si (417.61): calcd. C 66.15, H

(300 MHz, CDCl₃, 25 °C): δ = 7.45 (br. s, 1 H), 4.26 (q, J = 7.1 Hz,

Eur. J. Org. Chem. 2008, 2273–2287

www.eurjoc.org

2279

F. Zanardi, G. Casiraghi et al.

FULL PAPER

2 H), 4.00 (br. s, 1 H), 3.89 (dd, J = 8.5, 4.3 Hz, 1 H), 2.43 (ddd,

vacuum to give a residue which was purified by silica gel flash

J = 17.1, 10.1, 7.4 Hz, 1 H), 2.29 (m, 1 H), 2.14 (m, 1 H), 2.06 (m, chromatography (CH₂Cl₂/hexane, 65:35, to hexane/EtOAc, 60:40)

1 H), 1.45 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃, 25 °C): δ = 179.8 (C_q), 174.8 (C_q), 76.3 (C_q),

to furnish lactam 13 (0.59 g, 70% yield) as a white solid. M.p. 87–

89 °C. H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.2–7.4 (m, 5 H),

1

62.3 (CH₂), 60.7 (CH), 30.0 (CH₂), 22.4 (CH₃), 21.8 (CH₂), 14.1 5.11 (1/2 ABq, J = 14.7 Hz, 1 H), 4.34 (1/2 ABq, J = 14.7 Hz, 1

(CH₃) ppm.

H), 3.61 (dd, J = 8.7, 3.4 Hz, 1 H), 3.49 (ABq, ∆ν = 11.5 Hz, 2 H),

2.6 (br. s, 1 H), 2.49 (dt, J = 17.5, 9.4 Hz, 1 H), 2.35 (ddd, J =

17.2, 9.5, 4.6 Hz, 1 H), 1.9–2.1 (m, 2 H), 1.16 (s, 3 H), 0.91 (s, 9

H), 0.07 (s, 6 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ =

176.7 (C_q), 137.2 (C_q), 128.5 (2 C, CH), 128.2 (2 C, CH), 127.2

(CH), 75.9 (C_q), 66.6 (CH₂), 61.2 (CH), 46.6 (CH₂), 30.3 (CH₂),

25.8 (3 C, CH₃), 22.2 (CH₃), 20.8 (CH₂), 18.2 (C_q), –5.5 (CH₃),

–5.6 (CH₃) ppm. C₂₀H₃₃NO₃Si (363.57): calcd. C 66.07, H 9.15, N

3.85; found C 66.20, H 9.21, N 3.80.

The above lactam intermediate (0.65 g, 3.23 mmol) was dissolved

in anhydrous CH₂Cl₂(20 mL) at room temperature under argon,

and 2,6-lutidine (0.73 mL, 6.26 mmol) and tert-butyldimethylsilyl

trifluoromethanesulfonate (TBSOTf, 1.44 mL, 6.26 mmol) were se-

quentially added whilst stirring. After 2 h, additional portions of

TBSOTf (2ϫ1.44 mL, 2ϫ6.26 mmol) were added to the reaction

mixture. The reaction mixture was quenched with brine (50 mL)

and extracted with CH₂Cl₂(three times) 2 h after the last addition.

The combined organic layers were dried (MgSO₄), filtered and con-

centrated under vacuum to give a crude residue which was purified

by silica gel flash chromatography (hexane/EtOAc, 70:30 to 0:100).

This protected lactam intermediate was obtained (0.86 g, 85%) as

a white solid. M.p. 97–99 °C. ¹H NMR (300 MHz, CDCl₃): δ =

7.18 (br. s, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3.85 (dd, J = 8.0, 4.7 Hz,

(R*)-2-[(R*)-1-Benzyl-5-oxopyrrolidin-2-yl]-2-hydroxypropanal (14):

Tetrabutylammonium fluoride (TBAF, 635 mg, 2.43 mmol) was

slowly added to a stirred solution of lactam 13 (590 mg, 1.62 mmol)

in anhydrous THF (25 mL) under argon at room temperature. Af-

ter 1 h, the reaction mixture was quenched with H₂O (50 mL) and

saturated aqueous NH₄Cl (20 mL) at room temperature until neu-

1 H), 2.38 (ddd, J = 17.3, 10.3, 7.2 Hz, 1 H), 2.25 (ddd, J = 17.2, tralization. The mixture was extracted with EtOAc (three times)

9.8, 6.0 Hz, 1 H), 1.90–2.15 (m, 2 H), 1.45 (s, 3 H), 1.30 (t, J = and the combined organic layers were dried (MgSO₄), filtered and

7.1 Hz, 3 H), 1.90 (s, 9 H), 0.15 (s, 3 H), 0.10 (s, 3 H) ppm. ¹³C

concentrated under vacuum. The resulting residue was purified by

NMR (75.4 MHz, CDCl₃, 25 °C): δ = 179.0 (C_q), 173.8 (C_q), 79.0 silica gel flash chromatography (EtOAc/MeOH, 95:5) to furnish an

(C_q), 61.6 (CH), 61.3 (CH₂), 30.0 (CH₂), 25.6 (3 C, CH₃), 22.8 O-deprotected diol intermediate (0.38 g, 95% yield) as a colourless

1

(CH₃), 21.6 (CH₂), 18.3 (C_q), 14.1 (CH₃), –2.9 (CH₃), –3.2 (CH₃) resin. H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.30 (m, 5 H), 5.14

ppm.

(1/2 ABq, J = 14.7 Hz, 1 H), 4.33 (1/2 ABq, J = 14.7 Hz, 1 H),

3.61 (dd, J = 8.5, 3.5 Hz, 1 H), 3.54 (ABq, ∆ν = 27.6 Hz, 2 H),

2.85 (br. s, 2 H), 2.52 (dt, J = 17.3, 9.6 Hz, 1 H), 2.35 (ddd, J =

17.3, 9.5, 4.2 Hz, 1 H), 1.9–2.1 (m, 2 H), 1.19 (s, 3 H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃, 25 °C): δ = 177.0 (C_q), 137.0 (C_q), 128.6

(2 C, CH), 128.2 (2 C, CH), 127.4 (CH), 76.1 (C_q), 66.1 (CH₂),

62.3 (CH), 46.6 (CH₂), 30.3 (CH₂), 21.9 (CH₃), 20.9 (CH₂) ppm.

NaH (60% dispersion in mineral oil, 164 mg, 4.09 mmol) and ben-

zyl bromide (486 µL, 4.09 mmol) were sequentially added to a solu-

tion of the above lactam (860 mg, 2.73 mmol) in anhydrous THF

(50 mL) at room temperature. After being heated at reflux whilst

stirring for 4 h, the reaction mixture was quenched with saturated

aqueous NH₄Cl (50 mL) at room temperature until neutralization.

The mixture was extracted with EtOAc (three times) and the com-

bined organic layers were dried (MgSO₄), filtered and concentrated

under vacuum. The resulting residue was purified by silica gel flash

chromatography (hexane/EtOAc, 70:30) to furnish N-benzyllactam

12 (0.941 g, 85%, corresponding to a 71% yield over three steps)

Dimethyl sulfoxide (DMSO, 382 µL, 5.39 mmol) was added drop-

wise to a stirred solution of oxalyl chloride (2.0  in CH₂Cl₂,

1.54 mL, 3.08 mmol) in dry CH₂Cl₂(15 mL) at –80 °C under ar-

gon,. After 10 min, a solution of the previous diol intermediate

(0.38 g, 1.54 mmol) in dry CH₂Cl₂(15 mL) was added dropwise

over a period of 15 min. After 1 h, Et₃N (1.30 mL, 9.24 mmol) was

added and the reaction mixture was stirred at –80 °C for 10 min

and then warmed to 25 °C over a period of 2 h. Distilled water

(50 mL) was added, and the aqueous phase was extracted with

1

as a glassy solid. H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.2–7.4

(m, 5 H), 5.24 (1/2 ABq, J = 15.4 Hz, 1 H), 4.18 (m, 2 H), 4.15 (1/

2 ABq, J = 15.2 Hz, 1 H), 3.79 (dd, J = 6.7, 3.8 Hz, 1 H), 2.54 (dt,

J = 17.1, 9.6 Hz, 1 H), 2.31 (m, 1 H), 2.00 (m, 2 H), 1.49 (s, 3 H),

1.25 (t, J = 7.2 Hz, 3 H), 0.89 (s, 9 H), 0.18 (s, 3 H), 0.11 (s, 3 H) CH₂Cl₂(3ϫ). The collected organic layers were dried (MgSO₄),

ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 176.7 (C_q), 173.9 filtered and concentrated under reduced pressure to give a crude

(C_q), 136.7 (C_q), 128.7 (2 C, CH), 127.6 (2 C, CH), 127.3 (CH),

residue which was purified by silica gel flash chromatography

80.6 (C_q), 64.1 (CH), 61.5 (CH₂), 46.1 (CH₂), 30.0 (CH₂), 25.8 (3 (EtOAc/hexane, 75:25) to furnish aldehyde 14 (0.32 g, 85% yield)

C, CH₃), 23.9 (CH₃), 21.5 (CH₂), 18.3 (C_q), 14.0 (CH₃), –3.0 (CH₃),

–3.2 (CH₃) ppm. C₂₂H₃₅NO₄Si (405.60): calcd. C 65.15, H 8.70, N

3.45; found C 64.98, H 8.77, N 3.38.

as a colourless resin. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 9.65

(s, 1 H), 7.1–7.4 (m, 5 H), 5.16 (1/2 ABq, J = 15.1 Hz, 1 H), 4.21

(1/2 ABq, J = 15.0 Hz, 1 H), 4.69 (dd, J = 8.5, 3.6 Hz, 1 H), 2.3–

2.7 (m, 3 H), 2.10 (m, 1 H), 1.35 (s, 3 H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃, 25 °C): δ = 202.4 (CH), 176.3 (C_q), 136.0 (C_q),

128.4 (2 C, CH), 127.8 (2 C, CH), 127.3 (CH), 80.7 (C_q), 62.0 (CH),

46.5 (CH₂), 29.9 (CH₂), 20.9 (CH₂), 20.6 (CH₃) ppm. C₁₄H₁₇NO₃

(247.29): calcd. C 68.00, H 6.93, N 5.66; found C 67.87, H 7.01, N

5.59.

(R*)-1-Benzyl-5-[(R*)-1-(tert-butyldimethylsilyloxy)-2-hydroxypro-

pan-2-yl]pyrrolidin-2-one (13): n-BuLi (1.6  solution in hexane,

14.5 mL, 23.20 mmol) was added dropwise to a solution of

Me₂NH·BH₃(1.37 g, 23.20 mmol) in dry THF (25 mL) at 0 °C.

After stirring at 0 °C for 1 h, a portion of this reaction mixture

(5 mL, 4.64 mmol) was added dropwise to a solution of lactam 12

(941 mg, 2.32 mmol) in dry THF (150 mL) precooled to –15 °C.

Further portions of the reducing solution (4ϫ5 mL,

4ϫ4.64 mmol) were sequentially added to the reaction mixture

over a period of 4 h. After 15 h, the reaction mixture was quenched

with H₂O (130 mL) and 1  citric acid solution until the pH was 3–

4 and then was extracted with EtOAc (three times). The combined

organic layers were dried (MgSO₄), filtered and concentrated under

(1R*,4S*,5S*,6R*)-2-Benzyl-5-(tert-butyldimethylsilyloxy)-6-hy-

droxy-6-methyl-2-azabicyclo[2.2.1]heptan-3-one

(15):

TBSOTf

(0.90 mL, 3.93 mmol) was added dropwise to a solution of diiso-

propyl(ethyl)amine (DIPEA, 0.68 mL, 3.93 mmol) in dry CH₂Cl₂

(150 mL) at room temperature. After stirring for 5 min, a pre-

formed solution of aldehyde 14 (323 mg, 1.31 mmol) in dry CH₂Cl₂

(25 mL) was slowly added over a period of 15 min. After 2 h, a

2280

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Eur. J. Org. Chem. 2008, 2273–2287

A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

further portion of the DIPEA/TBSOTf solution (15 mL,

3.93 mmol) was added to the reaction mixture. After 5 h from the

beginning of the reaction, the mixture was quenched with brine

(m, 5 H), 6.12 (br. s, 1 H), 4.36 (t, J = 7.2 Hz, 1 H), 3.76 (s, 3 H),

2.15–2.30 (m, 2 H), 1.95 (m, 1 H), 1.59 (m, 1 H), 1.00 (s, 9 H), 0.15

(s, 3 H), 0.10 (s, 3 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C):

(150 mL) and extracted with CH₂Cl₂(three times). The combined δ = 178.3 (C_q), 172.6 (C_q), 138.9 (C_q), 128.1 (2 C, CH), 127.8 (CH),

organic layers were dried (MgSO₄), filtered and concentrated under

vacuum to give a residue which was purified by silica gel flash

chromatography (hexane/EtOAc, 80:20) to furnish lactam 15

124.5 (2 C, CH), 82.1 (C_q), 61.0 (CH), 52.1 (CH₃), 29.3 (CH₂), 25.8

(3 C, CH₃), 19.7 (CH₂), 18.8 (C_q), –3.7 (2 C, CH₃) ppm.

1

NaH (60% dispersion in mineral oil, 117 mg, 2.92 mmol) and ben-

zyl bromide (0.35 mL, 2.98 mmol) were sequentially added to a

solution of the previous lactam (710 mg, 1.95 mmol) in anhydrous

THF (50 mL) at room temperature. After being heated at reflux

whilst stirring for 4 h, the reaction mixture was quenched with satu-

rated aqueous NH₄Cl (40 mL) at room temperature until neutral-

ization. The mixture was extracted with EtOAc (three times), and

the combined organic layers were dried (MgSO₄), filtered and con-

centrated under vacuum. The resulting residue was purified by sil-

ica gel flash chromatography (hexane/EtOAc, 70:30) to furnish N-

benzyllactam 18 (0.81 g, 92%, corresponding to a 89% yield over

two steps) as a white solid. M.p. 128.5–129.0 °C. ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 7.47 (m, 2 H), 7.34 (m, 6 H), 7.12

(d, J = 6.9 Hz, 2 H), 5.30 (1/2 ABq, J = 15.9 Hz, 1 H), 4.53 (t, J

= 6.4 Hz, 1 H), 3.69 (s, 3 H), 3.67 (1/2 ABq, J = 15.9 Hz, 1 H),

2.25 (m, 2 H), 1.76 (m, 2 H), 1.00 (s, 9 H), 0.18 (s, 6 H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃, 25 °C): δ = 176.9 (C_q), 172.6 (C_q), 139.6

(C_q), 136.7 (C_q), 128.5 (2 C, CH), 128.2 (2 C, CH), 128.1 (CH),

127.1 (CH), 126.9 (2 C, CH), 126.1 (2 C, CH), 82.7 (C_q), 63.6 (CH),

52.5 (CH₃), 44.7 (CH₂), 29.8 (CH₂), 26.5 (3 C, CH₃), 20.5 (CH₂),

19.4 (C_q), –2.3 (CH₃), –2.5 (CH₃) ppm. C₂₆H₃₅NO₄Si (453.65):

calcd. C 68.84, H 7.78, N 3.09; found C 69.01, H 7.91, N 3.01.

(0.28 g, 60% yield) as a glassy solid. H NMR (600 MHz, CDCl₃,

25 °C): δ = 7.29 (m, 2 H, Ph), 7.23 (m, 3 H, Ph), 5.04 (1/2 ABq, J

= 15.0 Hz, 1 H, CH₂Ph), 4.01 (1/2 ABq, J = 15.6 Hz, 1 H, CH₂Ph),

3.89 (d, J = 4.2 Hz, 1 H, 5-H), 3.48 (s, 1 H, OH), 3.30 (m, 1 H, 1-

H), 2.81 (dd, J = 4.2, 1.8 Hz, 1 H, 4-H), 1.81 (dt, J = 10.8, 1.8 Hz,

1 H, 7-H_eq), 1.46 (br. d, J = 10.8 Hz, 1 H, 7-H_ax), 1.31 (s, 3 H, Me

on C-6), 0.92 (s, 9 H, tBu), 0.18 (s, 3 H, Me), 0.14 (s, 3 H, Me)

ppm. ¹³C NMR (150 MHz, CDCl₃, 25 °C): δ = 173.1 (C_q, C-3),

138.0 (C_q, Ph), 128.8 (2 C, CH, Ph), 128.3 (2 C, CH, Ph), 127.4

(CH, Ph), 76.4 (CH, C-5), 75.5 (C_q, C-6), 65.4 (CH, C-1), 52.1

(CH, C-4), 46.9 (CH₂, CH₂Ph), 35.2 (CH₂, C-7), 26.6 (CH₃, Me

on C-6), 26.0 (3 C, CH₃, tBu), 18.4 (C_q, tBu), –4.5 (CH₃, Me), –4.9

(CH₃, Me) ppm. C₂₀H₃₁NO₃Si (361.55): calcd. C 66.44, H 8.64, N

3.87; found C 66.31, H 8.70, N 3.79.

Methyl (S*)-2-Hydroxy-2-[(R*)-5-oxopyrrolidin-2-yl]-2-phenylace-

tate (17): BF₃·OEt₂(0.55 mL, 4.36 mmol) was added to a solution

of methyl oxo(phenyl)acetate (16) (0.62 mL, 4.36 mmol) in dry

CH₂Cl₂(8.0 mL) under argon at –80 °C. After 5 min, a solution

of silyloxypyrrole 5 (1.0 g, 3.36 mmol, dissolved in 3.0 mL of dry

CH₂Cl₂) was added. After stirring at –80 °C for 4 h, anhydrous

EtOAc (8.0 mL) and palladium on carbon (70 mg) were added to

the reaction mixture. The reaction vessel was degassed under vac-

uum and thoroughly purged with hydrogen (three times). The re-

sulting heterogeneous mixture was stirred under hydrogen while the

temperature was allowed to rise to room temperature over a period

of 2 h. After 12 h, the hydrogen was evacuated, pyridine (0.35 mL,

4.36 mmol) was added and the catalyst filtered off. The mixture

was quenched with H₂O (30 mL) and extracted with EtOAc (four

times). The combined organic layers were dried (MgSO₄), filtered

and concentrated under vacuum to give a residue which was puri-

fied by silica gel flash chromatography (pure EtOAc to EtOAc/

MeOH, 95:5) to furnish the N-deprotected lactam 17 (0.5 g, 60%

yield) as white crystals. M.p. 145–147 °C. ¹H NMR (300 MHz,

CDCl₃, 25 °C): δ = 7.80 (s, 1 H), 7.68 (m, 2 H), 7.36 (m, 3 H), 4.56

(s, 1 H), 4.51 (dd, J = 8.5, 2.0 Hz, 1 H), 3.86 (s, 3 H), 2.53 (dt, J

= 16.9, 9.3 Hz, 1 H), 2.18 (ddd, J = 17.1, 9.8, 3.9 Hz, 1 H), 1.8–

2.0 (m, 2 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 180.7

(C_q), 173.9 (C_q), 137.6 (C_q), 128.2 (2 C, CH), 127.9 (CH), 125.6 (2

C, CH), 80.7 (C_q), 60.7 (CH), 53.5 (CH₃), 30.0 (CH₂), 21.0 (CH₂)

ppm. C₁₃H₁₅NO₄(249.26): calcd. C 62.64, H 6.07, N 5.62; found

C 62.51, H 6.15, N 55.

(R*)-1-Benzyl-5-[(S*)-2-(tert-butyldimethylsilyloxy)-1-hydroxy-1-

phenylethyl]pyrrolidin-2-one (19): The title compound was prepared

from lactam 18 (810 mg, 1.79 mmol) according to the procedure

described for the synthesis of compound 13. Purification by silica

gel flash chromatography (CH₂Cl₂/hexane, 70:30, to hexane/

EtOAc, 60:40) furnished lactam 19 (0.65 g, 85% yield) as a white

1

solid. M.p. 123.8–124.8 °C. H NMR (300 MHz, CDCl₃, 25 °C): δ

= 7.33 (m, 10 H), 5.35 (1/2 ABq, J = 14.6 Hz, 1 H), 4.51 (1/2 ABq,

J = 14.6 Hz, 1 H), 4.01 (1/2 ABq, J = 9.8 Hz, 1 H), 3.88 (1/2 ABq,

J = 9.8 Hz, 1 H), 3.82 (dd, J = 8.6, 1.4 Hz, 1 H), 3.23 (s, 1 H), 1.98

(m, 1 H), 1.7–1.9 (m, 2 H), 1.42 (m, 1 H), 0.80 (s, 9 H), 0.02 (s, 3

H), 0.01 (s, 3 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ =

176.5 (C_q), 139.6 (C_q), 137.2 (C_q), 128.5 (2 C, CH), 128.2 (2 C,

CH), 128.1 (2 C, CH), 127.7 (CH), 127.2 (CH), 125.8 (2 C, CH),

79.0 (C_q), 66.5 (CH₂), 60.9 (CH), 46.8 (CH₂), 29.5 (CH₂), 25.5 (3

C, CH₃), 21.4 (CH₂), 17.9 (C_q), –5.6 (CH₃), –5.8 (CH₃) ppm.

C₂₅H₃₅NO₃Si (425.64): calcd. C 70.55, H 8.29, N 3.29; found C

70.43, H 8.34, N 3.35.

Methyl

(S*)-2-[(R*)-1-Benzyl-5-oxopyrrolidin-2-yl]-2-(tert-butyl-

(S*)-2-[(R*)-1-Benzyl-5-oxopyrrolidin-2-yl]-2-hydroxy-2-phenyl-

acetaldehyde (20): The title compound was prepared from lactam

19 (650 mg, 1.52 mmol) according to the two-step procedure de-

scribed for the synthesis of compound 14. After the first desilylative

reaction, purification by silica gel flash chromatography (EtOAc/

hexane, 70:30) furnished a diol intermediate (0.44 g, 94% yield) as

a white solid. M.p. 190.0–191.5 °C. ¹H NMR (300 MHz, CDCl₃,

25 °C): δ = 7.2–7.5 (m, 10 H), 5.30 (1/2 ABq, J = 14.6 Hz, 1 H),

4.46 (1/2 ABq, J = 14.6 Hz, 1 H), 4.08 (br. d, J = 11.9 Hz, 1 H),

3.89 (dd, J = 11.1, 7.3 Hz, 1 H), 3.80 (dd, J = 8.7, 1.5 Hz, 1 H),

3.15 (br. s, 1 H), 2.21 (br. s, 1 H), 1.95 (m, 1 H), 1.5–1.9 (m, 3 H)

ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 176.7 (C_q), 139.6

(C_q), 137.0 (C_q), 128.6 (2 C, CH), 128.5 (2 C, CH), 128.2 (2 C,

CH), 128.1 (CH), 127.3 (CH), 126.1 (2 C, CH), 80.2 (C_q), 66.6

(CH₂), 61.2 (CH), 46.8 (CH₂), 29.5 (CH₂), 21.4 (CH₂) ppm.

dimethylsilyloxy)-2-phenylacetate (18): 2,6-Lutidine (0.47 mL,

4.02 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate

(TBSOTf, 0.92 mL, 4.02 mmol) were sequentially added to a stirred

solution of lactam 17 (0.5 g, 2.01 mmol) dissolved in anhydrous

CH₂Cl₂(15 mL) at room temperature under argon. After 2 h, ad-

ditional portions of TBSOTf (2ϫ0.92 mL, 2ϫ4.02 mmol) were

added to the reaction mixture. After 12 h from the beginning of

the reaction, the mixture was quenched with brine (50 mL) and

extracted with CH₂Cl₂(three times). The combined organic layers

were dried (MgSO₄), filtered and concentrated under vacuum to

give a crude residue which was purified by silica gel flash

chromatography (hexane/EtOAc, 70:30 to 0:100). An O-protected

lactam intermediate was obtained (0.71 g, 97%) as a white solid.

M.p. 94.0–94.5 °C. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.35

Eur. J. Org. Chem. 2008, 2273–2287

www.eurjoc.org

2281

F. Zanardi, G. Casiraghi et al.

FULL PAPER

After the second oxidative step, purification by silica gel flash

chromatography (EtOAc/hexane, 50:50) furnished aldehyde 20

(0.36 g, 81 % yield) as a colourless resin. ¹H NMR (300 MHz,

solved in dry methanol (70 mL) at 0 °C whilst stirring. After

15 min, NaBH₄(130 mg, 3.43 mmol) was added at the same tem-

perature. After 30 min, two additional portions of NaBH₄

CDCl₃, 25 °C): δ = 9.62 (d, J = 1.1 Hz, 1 H), 7.3–7.5 (m, 8 H), (2ϫ65 mg, 2ϫ1.72 mmol) were sequentially added to the reaction

7.23 (d, J = 6.8 Hz, 2 H), 5.22 (1/2 ABq, J = 15.8 Hz, 1 H), 4.32

(t, J = 6.0 Hz, 1 H), 4.05 (d, J = 0.6 Hz, 1 H), 3.73 (1/2 ABq, J =

15.6 Hz, 1 H), 2.71 (dt, J = 16.9, 9.6 Hz, 1 H), 2.31 (dt, J = 16.9,

mixture over a period of 1 h. After 1 h, the mixture was quenched

with saturated aqueous NH₄Cl (50 mL) and extracted with CH₂Cl₂

(three times). The combined organic layers were dried (MgSO₄),

6.8 Hz, 1 H), 2.2–2.4 (m, 2 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, filtered and concentrated under vacuum to give a crude residue

25 °C): δ = 201.0 (CH), 177.0 (C_q), 135.5 (C_q), 135.4 (C_q), 129.1 (2 which was purified by silica gel flash chromatography (hexane/

C, CH), 129.0 (2 C, CH), 128.4 (CH), 127.9 (CH), 127.8 (2 C, CH),

EtOAc, 60:40). Pure lactam 23 was obtained (3.23 g, 63% over two

125.6 (2 C, CH), 84.3 (C_q), 60.8 (CH), 45.2 (CH₂), 29.7 (CH₂), 20.4 steps) as a colourless oil. [α]²_D⁰= +32.6 (c = 3.21, CHCl₃). ¹H NMR

(CH₂) ppm. C₁₉H₁₉NO₃(309.36): calcd. C 73.77, H 6.19, N 4.53;

found C 73.90, H 6.25, N 4.48.

(400 MHz, CDCl₃, 25 °C): δ = 4.52 (dd, J = 8.0, 1.2 Hz, 1 H), 4.37

(dd, J = 6.4, 5.2 Hz, 1 H), 4.15 (dd, J = 8.4, 7.2 Hz, 1 H), 4.00 (dd,

J = 8.8, 5.2 Hz, 1 H), 3.82 (s, 3 H), 3.61 (s, 1 H), 2.47 (ddd, J =

18.4, 12.4, 8.8 Hz, 1 H), 2.35 (ddd, J = 17.6, 9.2, 2.0 Hz, 1 H), 2.13

(m, 2 H), 1.53 (s, 9 H), 1.41 (s, 3 H), 1.31 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 25 °C): δ = 174.0 (C_q), 173.9 (C_q), 151.1 (C_q),

109.5 (C_q), 83.6 (C_q), 78.7 (C_q), 77.5 (CH), 65.2 (CH₂), 59.7 (CH),

53.6 (CH₃), 31.8 (CH₂), 27.9 (3 C, CH₃), 25.9 (CH₃), 24.4 (CH₃),

20.1 (CH₂) ppm. C₁₇H₂₇NO₈(373.40): calcd. C 54.68, H 7.29, N

3.75; found C 54.78, H 7.33, N 3.67.

(1R*,4S*,5R*,6S*)-2-Benzyl-5-(tert-butyldimethylsilyloxy)-6-hy-

droxy-6-phenyl-2-azabicyclo[2.2.1]heptan-3-one (21): The title com-

pound was prepared from aldehyde 20 (360 mg, 1.16 mmol) accord-

ing to the procedure described for the synthesis of compound 15.

Purification by silica gel flash chromatography (hexane/EtOAc,

85:15) furnished bicycle 21 (300 mg, 61 % yield) as a colourless

1

resin. H NMR (600 MHz, CDCl₃, 25 °C): δ = 7.40 (dd, J = 7.8,

6.0 Hz, 2 H, Ph), 7.38 (dd, J = 7.8, 7.2 Hz, 2 H, Ph), 7.32 (t, J =

7.2 Hz, 1 H, Ph), 7.20 (m, 3 H, CH₂-Ph), 6.87 (d, J = 7.2 Hz, 2 H,

CH₂-Ph), 4.59 (1/2 ABq, J = 15.0 Hz, 1 H, CH₂-Ph), 4.58 (m, 1 H,

5-H), 4.20 (s, 1 H, OH), 3.36 (q, J = 1.7 Hz, 1 H, 1-H), 2.76 (q, J

= 1.3 Hz, 1 H, 4-H), 2.36 (br. d, J = 10.2 Hz, 1 H, 7-H_ax), 2.35 (1/

2 ABq, J = 15.0 Hz, 1 H, CH₂-Ph), 1.96 (dq, J = 10.1, 1.7 Hz, 1

H, 7-H_eq), 0.87 (s, 9 H, tBu), 0.15 (s, 3 H, Me), 0.04 (s, 3 H, Me)

ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 173.8 (C_q, C-3),

142.2 (C_q, Ph), 136.3 (C_q, Ph), 128.6 (2 C, CH, Ph), 128.5 (2 C,

CH, Ph), 128.0 (2 C, CH, Ph), 127.8 (CH, Ph), 127.5 (CH, Ph),

126.2 (2 C, CH, Ph), 79.2 (C_q, C-6), 74.6 (CH, C-5), 67.7 (CH, C-

1), 53.7 (CH, C-4), 45.5 (CH₂, CH₂Ph), 38.6 (CH₂, C-7), 25.7 (3

C, CH₃, tBu), 18.0 (C_q, tBu), –4.6 (CH₃, Me), –5.0 (CH₃, Me) ppm.

C₂₅H₃₃NO₃Si (423.62): calcd. C 70.88, H 7.85, N 3.31; found C

70.71, H 7.91, N 3.24.

Methyl (S)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-2-[(R)-

5-oxopyrrolidin-2-yl]acetate (24): Cerium(IV) ammonium nitrate

(CAN) (525 mg, 0.96 mmol) was added in small portions to a

stirred solution of lactam 23 (1.79 g, 4.79 mmol) in CH₃CN

(200 mL) warmed to 80 °C. After stirring at 80 °C for 4 h, the reac-

tion mixture was quenched with saturated aqueous NaHCO₃until

complete neutralization and extracted with EtOAc (three times).

The combined organic layers were dried (MgSO₄), filtered and con-

centrated under vacuum to give a crude residue which was purified

by silica gel flash chromatography (EtOAc/MeOH, 95:5) to furnish

N-deprotected lactam 24 (1.45 g, 90 %) as a white glassy solid.

[α]²_D⁰= +22.1 (c = 2.22, CHCl₃). ¹H NMR (400 MHz, CDCl₃,

25 °C): δ = 6.94 (br. s, 1 H), 4.24 (t, J = 6.0 Hz, 1 H), 4.14 (br. dd,

J = 7.2, 4.8 Hz, 1 H), 4.07 (dd, J = 8.8, 6.8 Hz, 1 H), 3.96 (dd, J

= 8.8, 6.0 Hz, 1 H), 3.86 (s, 3 H), 3.85 (s, 1 H), 2.43 (m, 1 H), 2.3–

2.1 (m, 3 H), 1.38 (s, 3 H), 1.32 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 180.0 (C_q), 173.5 (C_q), 109.8 (C_q), 79.8 (C_q),

77.2 (CH), 65.0 (CH₂), 57.6 (CH), 53.4 (CH₃), 30.0 (CH₂), 25.8

(CH₃), 24.8 (CH₃), 21.0 (CH₂) ppm. C₁₂H₁₉NO₆(273.28): calcd. C

52.74, H 7.01, N 5.13; found C 52.85, H 7.13, N 5.09.

Methyl (S)-2-[(R)-1-tert-Butoxycarbonyl-5-oxopyrrolidin-2-yl]-2-

[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyacetate (23):

BF₃·OEt₂(2.6 mL, 20.64 mmol) was added to a solution of ketone

22 (2.59 g, 13.76 mmol) in dry CH₂Cl₂(58 mL) under argon at

–80 °C. After 15 min, a solution of silyloxypyrrole 5 (4.07 g,

13.76 mmol, dissolved in 5 mL of dry CH₂Cl₂) was added. After

stirring at –80 °C for 24 h, pyridine (3.3 mL, 41.28 mmol) was

added, and the reaction mixture was stirred for an additional

15 min. Water (50 mL) was added, and the temperature was al-

lowed to reach an ambient value. The reaction mixture was ex-

tracted with CH₂Cl₂(three times), and the combined organic layers

were dried (MgSO₄), filtered and concentrated under vacuum to

give an oily residue which was almost entirely used as such in the

subsequent reductive reaction. A small portion of this crude resi-

due, however, was purified by silica gel flash chromatography (hex-

ane/EtOAc, 60:40) to furnish an unsaturated lactam intermediate

as a colourless oil. [α]²_D⁰= +67.5 (c = 4.43, CHCl₃). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 7.33 (dd, J = 6.4, 2.4 Hz, 1 H), 6.13

(dd, J = 6.0, 2.0 Hz, 1 H), 4.97 (t, J = 2.0 Hz, 1 H), 4.34 (dd, J =

6.8, 5.2 Hz, 1 H), 4.15 (dd, J = 8.4, 6.8 Hz, 1 H), 4.06 (dd, J = 9.2,

5.2 Hz, 1 H), 3.80 (s, 3 H), 3.64 (s, 1 H), 1.55 (s, 9 H), 1.43 (s, 3

H), 1.31 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ =

172.2 (C_q), 168.3 (C_q), 150.9 (C_q), 147.7 (CH), 128.0 (CH), 109.8

(C_q), 83.8 (C_q), 78.5 (C_q), 78.1 (CH), 65.2 (CH₂), 64.1 (CH), 53.4

(CH₃), 27.9 (3 C, CH₃), 25.9 (CH₃), 24.4 (CH₃) ppm.

Methyl (S)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-2-[(R)-

1-(4-methoxybenzyl)-5-oxopyrrolidin-2-yl]acetate (25): NaH (60%

dispersion in mineral oil, 318 mg, 7.96 mmol) was added to a

stirred solution of the N-deprotected lactam 24 (1.45 g, 5.30 mmol)

in anhydrous THF (150 mL) under argon at room temperature. Af-

ter 30 min, p-methoxybenzyl bromide (PMBBr, 0.92 mL,

6.36 mmol) was added. After being warmed at 45 °C for 3 h, the

reaction mixture was quenched with saturated aqueous NH₄Cl at

room temperature until neutralization. The mixture was diluted

with H₂O and extracted with EtOAc (three times). The combined

organic layers were dried (MgSO₄), filtered and concentrated under

vacuum to leave a residue which was purified by silica gel flash

chromatography (EtOAc/MeOH, 90:10) to furnish lactam 25

(1.42 g, 68%) as a colourless oil. [α]²_D⁰= –20.0 (c = 7.2, CHCl₃). ¹H

NMR (400 MHz, CDCl₃, 25 °C): δ = 7.06 (d, J = 8.8 Hz, 2 H),

6.85 (d, J = 8.8 Hz, 2 H), 5.12 (1/2 ABq, J = 15.6 Hz, 1 H), 4.31

(t, J = 6.4 Hz, 1 H), 4.00 (dd, J = 8.8, 7.2 Hz, 1 H), 3.94 (dd, J =

8.4, 2.0 Hz, 1 H), 3.89 (dd, J = 8.8, 6.4 Hz, 1 H), 3.80 (s, 3 H), 3.77

(s, 3 H), 3.67 (1/2 ABq, J = 15.6 Hz, 1 H), 3.48 (s, 1 H), 2.58 (dt,

J = 16.8, 9.6 Hz, 1 H), 2.30 (ddd, J = 16.8, 9.6, 2.4 Hz, 1 H), 2.13

(m, 1 H), 1.99 (dq, J = 13.6, 10.8 Hz, 1 H), 1.36 (s, 3 H), 1.30 (s,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 176.8 (C_q),

NiCl₂·6H₂O (408 mg, 1.72 mmol) was added to a stirred solution

of the previous unsaturated intermediate (3.27 g, 8.80 mmol) dis-

2282

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2273–2287

A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

173.6 (C_q), 158.9 (C_q), 129.0 (C_q), 128.5 (2 C, CH), 113.9 (2 C,

CH), 109.4 (C_q), 78.9 (C_q), 77.5 (CH), 64.8 (CH₂), 59.7 (CH), 55.2 –5.8 (c = 1.85, CHCl₃). H NMR (400 MHz, CDCl₃, 25 °C): δ =

(CH₃), 53.2 (CH₃), 44.6 (CH₂), 29.9 (CH₂), 25.8 (CH₃), 24.8 (CH₃), 9.55 (d, J = 2.4 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.84 (d, J =

to furnish aldehyde 27 (0.77 g, 78% yield) as a glassy solid. [α]²_D⁰

=

1

21.2 (CH₂) ppm. C₂₀H₂₇NO₇(393.43): calcd. C 61.06, H 6.92, N

3.56; found C 60.90, H 7.00, N 3.49.

8.8 Hz, 2 H), 4.97 (1/2 ABq, J = 15.2 Hz, 1 H), 4.20 (d, J = 2.0 Hz,

1 H), 3.96 (1/2 ABq, J = 14.8 Hz, 1 H), 3.94 (d, J = 4.8 Hz, 1 H),

3.79 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 1 H), 2.45 (dt, J = 17.2, 10.4 Hz,

1 H), 2.54 (ddd, J = 16.8, 10.0, 1.2 Hz, 1 H), 2.17 (m, 1 H), 2.00

(m, 1 H), 0.88 (t, J = 8.0 Hz, 9 H), 0.53 (m, 6 H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 25 °C): δ = 201.0 (C_q), 177.4 (C_q), 172.5 (C_q),

158.9 (C_q), 130.0 (C_q), 129.0 (2 C, CH), 113.9 (2 C, CH), 81.5 (C_q),

78.3 (CH), 60.0 (CH), 55.2 (CH₃), 53.3 (CH₃), 45.6 (CH₂), 29.6

(CH₂), 21.5 (CH₂), 6.5 (3 C, CH₃), 4.6 (3 C, CH₂) ppm.

C₂₃H₃₅NO₇Si (465.61): calcd. C 59.33, H 7.58, N 3.01; found C

59.45, H 7.62, N 2.93.

Methyl (2S,3S)-2-Hydroxy-2-[(R)-1-(4-methoxybenzyl)-5-oxopyrrol-

idin-2-yl]-3,4-bis(triethylsilyloxy)butanoate (26): Lactam 25 (1.25 g,

3.18 mmol) was dissolved in 80% aqueous acetic acid (13.6 mL),

and the resulting mixture was warmed to 80 °C whilst stirring. Af-

ter 3 h, the reaction mixture was concentrated under vacuum to

leave a crude residue which was purified by silica gel flash

chromatography (EtOAc/MeOH, 90:10) to furnish a triol interme-

diate (876 mg, 78%) as a glassy solid. [α]²_D⁰= –43.3 (c = 4.15,

CHCl₃). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.05 (d, J =

8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 5.11 (1/2 ABq, J = 15.6 Hz,

1 H), 4.19 (dd, J = 8.4, 2.0 Hz, 1 H), 3.90–3.84 (m, 2 H), 3.79 (s,

6 H), 3.74 (t, J = 3.2 Hz, 1 H), 3.48 (1/2 ABq, J = 15.6 Hz, 1 H),

3.18 (br. s, 1 H), 2.63 (dt, J = 16.4, 10.0 Hz, 1 H), 2.42 (br. s, 1 H),

2.29 (ddd, J = 16.8, 10.0, 2.4 Hz, 1 H), 2.22 (m, 1 H), 2.06 (m, 1

H), 1.78 (br. s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ

= 177.6 (C_q), 175.06 (C_q), 159.0 (C_q), 128.5 (2 C, CH), 128.3 (C_q),

114.0 (2 C, CH), 79.3 (C_q), 73.8 (CH), 61.9 (CH₂), 60.3 (CH), 55.2

(CH₃), 53.3 (CH₃), 44.4 (CH₂), 30.1 (CH₂), 21.1 (CH₂) ppm.

Methyl (1S,2S,3S,4S,5R)-2-(tert-Butyldimethylsilyloxy)-4-hydroxy-

6-(4-methoxybenzyl)-7-oxo-3-(triethylsilyloxy)-6-azabicyclo[3.2.1]-

octane-4-carboxylate (28): The title compound was prepared from

aldehyde 27 (704 mg, 1.51 mmol) according to the procedure de-

scribed for the synthesis of compound 15. Purification by silica gel

flash chromatography (hexane/EtOAc, 70:30) furnished bicycle 28

(613 mg, 75% yield) as a white solid. M.p. 57–60 °C. [α]²_D⁰= –26.3

(c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃, 25 °C): δ = 7.18 (d,

J = 8.4 Hz, 2 H, Ar), 6.81 (d, J = 8.4 Hz, 2 H, Ar), 5.01 (1/2 ABq,

J = 15.0 Hz, 1 H, CH₂Ar), 4.43 (m, 1 H, 3-H), 4.15 (t, J = 2.4 Hz,

1 H, 2-H), 3.88 (1/2 ABq, J = 14.4 Hz, 1 H, CH₂Ar), 3.77 (s, 3 H,

OMe), 3.76 (s, 3 H, CO₂Me), 3.67 (s, 1 H, OH), 3.59 (dd, J =

5.4 Hz, 1 H, 5-H), 2.44 (m, 1 H, 1-H), 1.97 (dt, J = 12.0, 5.4 Hz,

1 H, 8-H_eq), 1.40 (d, J = 12.0 Hz, 1 H, 8-H_ax), 0.97 (m, 9 H,

SiCH₂CH₃), 0.96 (s, 9 H, tBu), 0.70 (m, 6 H, SiCH₂CH₃), 0.15 (s,

6 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 173.5

(C_q, C-7), 170.9 (C_q, CO₂Me), 158.6 (C_q, Ar), 129.4 (2 C, CH, Ar),

129.1 (C_q, Ar), 113.6 (2 C, CH, Ar), 77.4 (C_q, C-4), 74.8 (CH, C-

3), 71.1 (CH, C-2), 58.9 (CH, C-5), 54.9 (CH₃, OMe), 52.4 (CH₃,

CO₂Me), 45.8 (CH₂, CH₂Ar), 44.6 (CH, C-1), 31.9 (CH₂, C8), 26.0

(3 C, CH₃, tBu), 18.3 (C_q, tBu), 6.5 (3 C, CH₃, SiCH₂CH₃), 4.6

(3 C, CH₂, SiCH₂CH₃), –4.2 (CH₃, Me), –4.0 (CH₃, Me) ppm.

C₂₉H₄₉NO₇Si₂(579.87): calcd. C 60.07, H 8.52, N 2.42; found C

59.91, H 8.59, N 2.37.

The above triol intermediate (876 mg, 2.48 mmol) was dissolved in

anhydrous pyridine (8.1 mL) at room temperature under argon,

and triethylsilyl trifluoromethanesulfonate (TESOTf, 1.68 mL,

7.44 mmol) and 4-(dimethylamino)pyridine (DMAP, 46 mg,

0.37 mmol) were sequentially added whilst stirring. After 2 h, the

reaction mixture was quenched with saturated aqueous NH₄Cl un-

til neutralization and extracted with CH₂Cl₂(twice) and EtOAc

(twice). The combined organic layers were dried (MgSO₄), filtered

and concentrated under vacuum to give a crude residue which was

purified by silica gel flash chromatography (hexane/EtOAc, 70:30).

Pure lactam 26 was obtained (1.24 g, 86% yield) as a colourless oil.

[α]²_D⁰= –19.8 (c = 6.9, CHCl₃). ¹H NMR (400 MHz, CDCl₃, 25 °C):

δ = 7.08 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.07 (1/2

ABq, J = 15.2 Hz, 1 H), 4.20 (br. d, J = 8.8 Hz, 1 H), 3.97 (dd, J

= 5.6, 5.2 Hz, 1 H), 3.79 (s, 3 H), 3.73 (s, 3 H), 3.72 (s, 1 H), 3.61

(dd, J = 10.4, 4.4 Hz, 1 H), 3.56 (1/2 ABq, J = 15.2 Hz, 1 H), 3.43

(dd, J = 10.0, 6.0 Hz, 1 H), 2.65 (dt, J = 17.2, 9.2 Hz, 1 H), 2.26

(m, 2 H), 1.93 (m, 1 H), 1.0–0.8 (m, 18 H), 0.56 (m, 12 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 177.4 (C_q), 174.5 (C_q),

158.8 (C_q), 129.0 (C_q), 128.5 (2 C, CH), 113.8 (2 C, CH), 80.1 (C_q),

75.7 (CH), 64.0 (CH₂), 59.8 (CH), 55.2 (CH₃), 52.5 (CH₃), 44.5

(CH₂), 30.2 (CH₂), 21.6 (CH₂), 6.7 (3 C, CH₃), 6.6 (3 C, CH₃), 5.2

(3 C, CH₂), 4.1 (3 C, CH₂) ppm. C₂₉H₅₁NO₇Si₂(581.89): calcd. C

59.86, H 8.83, N 2.41; found C 59.78, H 8.90, N 2.43.

(S)-1-(tert-Butoxycarbonyl)-5-{(R)-[(R)-2,2-dimethyl-1,3-dioxolan-

4-yl](phenyl)(trimethylsilyloxy)methyl}pyrrolidin-2-one (31):

Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 2.63 mL,

14.55 mmol) was added to a solution of ketone 29 (1.0 g,

4.85 mmol) in dry CH₂Cl₂(30 mL) under argon at –80 °C. After

5 min, a solution of silyloxypyrrole 5 (2.88 g, 9.70 mmol, dissolved

in 10 mL of dry CH₂Cl₂) and 2,6-lutidine (1.13 mL, 9.70 mmol)

were sequentially added. After stirring at –80 °C for 4 h, pyridine

(9.70 mL, 0.78 mmol) was added, and the reaction mixture was

stirred for an additional 15 min. Brine (100 mL) was added, and the

temperature was allowed to reach an ambient value. The reaction

mixture was extracted with CH₂Cl₂(three times), and the combined

organic layers were dried (MgSO₄), filtered and concentrated under

vacuum to give an oily residue which was almost entirely used as

such in the subsequent reductive reaction. A small portion of this

Methyl (2S,3R)-3-Formyl-2-hydroxy-2-[(R)-1-(4-methoxybenzyl)-5-

oxopyrrolidin-2-yl]-3-(triethylsilyloxy)propanoate (27): Dimethyl

sulfoxide (DMSO, 1.51 mL, 21.30 mmol) was added dropwise to a

stirred solution of oxalyl chloride (2.0  in CH₂Cl₂, 5.3 mL,

10.65 mmol) in dry CH₂Cl₂(45 mL) at –80 °C under argon. After

1 h, a solution of the lactam 26 (1.24 g, 2.13 mmol) in dry CH₂Cl₂crude residue, however, was purified by silica gel flash chromatog-

(45 mL) was added dropwise at the same temperature. After 2.5 h, raphy (hexane/EtOAc, 80:20) to furnish unsaturated lactam 30 as

the reaction mixture was warmed to –35 °C and stirred for an ad-

ditional 1.5 h. The reaction mixture was cooled again to –80 °C,

and Et₃N (4.45 mL, 31.95 mmol) was slowly added. After 40 min

at –80 °C, the reaction mixture was warmed to 25 °C, quenched

with brine (100 mL) and extracted with EtOAc (three times). The

collected organic layers were dried (MgSO₄), filtered and concen-

trated under reduced pressure to give a crude residue which was

purified by silica gel flash chromatography (hexane/EtOAc, 70:30)

white crystals. M.p. 118–122 °C. [α]²_D⁰= –132.8 (c = 1.0, CHCl₃).

¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.49 (m, 2 H), 7.30 (m, 3

H), 6.77 (dd, J = 6.1, 2.1 Hz, 1 H), 5.68 (dd, J = 6.1, 1.2 Hz, 1 H),

5.32 (t, J = 1.8 Hz, 1 H), 4.72 (dd, J = 7.4, 5.9 Hz, 1 H), 4.33 (dd,

J = 9.0, 5.9 Hz, 1 H), 4.10 (dd, J = 9.0, 7.6 Hz, 1 H), 1.63 (s, 9 H),

1.42 (s, 3 H), 1.36 (s, 3 H), 0.04 (s, 9 H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃, 25 °C): δ = 170.0 (C_q), 150.7 (C_q), 150.2 (CH), 141.2 (C_q),

128.6 (CH), 127.8 (2 C, CH), 127.7 (2 C, CH), 125.6 (2 C, CH),

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www.eurjoc.org

2283

F. Zanardi, G. Casiraghi et al.

110.0 (C_q), 82.5 (C_q), 80.6 (C_q), 79.4 (CH), 65.9 (CH₂), 65.6 (CH), the first acidic deprotection, purification by silica gel flash

FULL PAPER

27.9 (3 C, CH₃), 25.4 (CH₃), 23.7 (CH₃), 1.83 (3 C, CH₃) ppm.

chromatography (EtOAc/MeOH, 98:2) furnished a triol intermedi-

ate (0.73 g, 80% yield) as a white foam. [α]²_D⁰= +42.0 (c = 1.0,

CHCl₃). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.30 (m, 5 H),

7.17 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 5.05 (1/2 ABq,

J = 14.5 Hz, 1 H), 4.50 (1/2 ABq, J = 14.5 Hz, 1 H), 4.23 (m, 1

H), 4.08 (dd, J = 5.9, 2.1 Hz, 1 H), 4.07–3.90 (br. s, 3 H), 3.78 (s,

3 H), 3.54 (m, 2 H), 1.84 (m, 3 H), 1.44 (m, 1 H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃, 25 °C): δ = 176.9 (C_q), 158.5 (C_q), 138.8 (C_q),

129.2 (2 C, CH), 128.8 (C_q), 127.9 (2 C, CH), 127.5 (CH), 125.7 (2

C, CH), 113.7 (2 C, CH), 81.6 (C_q), 71.9 (CH), 63.0 (CH₂), 62.3

(CH), 54.9 (CH₃), 45.9 (CH₂), 29.4 (CH₂), 20.7 (CH₂) ppm.

Palladium on carbon (30 mg) was added to a solution of the above

crude residue in anhydrous EtOAc (30 mL) at room temperature.

The reaction vessel was degassed under vacuum and thoroughly

purged with hydrogen (three times). The resulting heterogeneous

mixture was stirred under hydrogen for 12 h, after which time the

hydrogen was evacuated, the catalyst filtered off and the filtrate

concentrated under vacuum to give a crude residue which was puri-

fied by silica gel flash chromatography (hexane/EtOAc, 70:30) to

furnish pure lactam 31 (1.57 g, 70% for two steps) as a colourless

oil. [α]²_D⁰= –64.5 (c = 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃,

25 °C): δ = 7.52 (m, 2 H), 7.33 (m, 3 H), 4.80 (br. d, J = 8.5 Hz, 1

H), 4.49 (dd, J = 7.0, 5.7 Hz, 1 H), 4.19 (dd, J = 9.3, 5.7 Hz, 1 H),

4.12 (dd, J = 9.2, 7.5 Hz, 1 H), 1.7–2.1 (m, 4 H), 1.61 (s, 9 H), 1.34

(s, 3 H), 1.17 (s, 3 H), 0.12 (s, 9 H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃, 25 °C): δ = 175.0 (C_q), 151.1 (C_q), 141.0 (C_q), 127.5 (2 C,

CH), 127.4 (CH), 127.1 (2 C, CH), 109.4 (C_q), 82.9 (C_q), 82.4 (C_q),

79.2 (CH), 65.9 (CH₂), 60.3 (CH), 31.6 (CH₂), 27.8 (3 C, CH₃), 25.3

(CH₃), 23.8 (CH₃), 21.3 (CH₂), 2.14 (3 C, CH₃) ppm. C₂₄H₃₇NO₆Si

(463.64): calcd. C 62.17, H 8.04, N 3.02; found C 62.09, H 8.11, N

2.95.

After the second silylative step, purification by silica gel flash

chromatography (hexane/EtOAc, 60:40) furnished lactam 34

(1.07 g, 90% yield) as a colourless oil. [α]²_D⁰= +21.8 (c = 1.0,

CHCl₃). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.37 (m, 5 H),

7.20 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.23 (1/2 ABq,

J = 14.2 Hz, 1 H), 4.48 (1/2 ABq, J = 14.1 Hz, 1 H), 4.39 (dd, J =

6.0, 1.7 Hz, 1 H), 4.00 (m, 1 H), 3.80 (s, 3 H), 3.67 (dd, J = 11.0,

1.7 Hz, 1 H), 3.53 (dd, J = 11.0, 6.0 Hz, 1 H), 3.33 (s, 1 H), 2.00–

1.75 (m, 3 H), 1.24 (m, 1 H), 0.85 (m, 18 H), 0.7–0.4 (m, 12 H)

ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 175.7 (C_q), 158.6

(C_q), 137.9 (C_q), 129.2 (2 C, CH), 129.1 (C_q), 127.7 (2 C, CH),

127.5 (CH), 126.1 (2 C, CH), 113.7 (2 C, CH), 82.0 (C_q), 75.9 (CH),

65.0 (CH₂), 60.8 (CH), 54.8 (CH₃), 46.1 (CH₂), 28.9 (CH₂), 20.6

(CH₂), 6.4 (3 C, CH₃), 6.2 (3 C, CH₃), 5.5 (3 C, CH₂), 3.6 (3 C,

CH₂) ppm. C₃₃H₅₃NO₅Si₂(599.95): calcd. C 66.06, H 8.90, N 2.33;

found C 66.00, H 8.96, N 2.37.

(S)-5-{(R)-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl](phenyl)(trimethyl-

silyloxy)methyl}pyrrolidin-2-one (32): The title compound was pre-

pared from lactam 31 (1.50 g, 3.23 mmol) according to the pro-

cedure described for the synthesis of compound 24. Purification by

silica gel flash chromatography (hexane/EtOAc, 20:80) furnished

lactam 32 (1.17 g, quantitative) as a colourless oil. [α]²_D⁰= –23.9 (c

1

= 1.0, CHCl₃). H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.33 (m,

(2S,3R)-3-Hydroxy-3-[(S)-1-(4-methoxybenzyl)-5-oxopyrrolidin-2-

yl]-3-phenyl-2-(triethylsilyloxy)propanal (35): The title compound

was prepared from lactam 34 (1.0 g, 1.66 mmol) according to the

procedure described for the synthesis of compound 27. Purification

by silica gel flash chromatography (hexane/EtOAc, 60:40) furnished

aldehyde 35 (0.68 g, 85% yield) as a colourless oil. [α]²_D⁰= +2.2 (c

5 H), 6.45 (br. s, 1 H), 4.57 (t, J = 7.8 Hz, 1 H), 4.24 (t, J = 7.5 Hz,

1 H), 3.68 (t, J = 8.1 Hz, 1 H), 3.54 (dd, J = 8.1, 7.0 Hz, 1 H), 2.18

(dt, J = 17.2, 9.3 Hz, 1 H), 2.00 (ddd, J = 17.2, 8.0, 5.8 Hz, 1 H),

1.67 (m, 2 H), 1.52 (s, 3 H), 1.38 (s, 3 H), 0.25 (s, 9 H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃, 25 °C): δ = 177.6 (C_q), 140.5 (C_q), 128.1

(2 C, CH), 127.5 (CH), 125.3 (2 C, CH), 110.0 (C_q), 81.6 (CH),

79.5 (C_q), 65.0 (CH₂), 61.3 (CH), 29.2 (CH₂), 26.0 (CH₃), 24.6

(CH₃), 22.1 (CH₂), 2.69 (3 C, CH₃) ppm. C₁₉H₂₉NO₄Si (363.52):

calcd. C 62.78, H 8.04, N 3.85; found C 62.85, H 7.99, N 3.77.

1

= 1.0, CHCl₃). H NMR (300 MHz, CDCl₃, 25 °C): δ = 9.38 (d, J

= 2.6 Hz, 1 H), 7.45 (m, 5 H), 7.19 (d, J = 8.5 Hz, 2 H), 6.90 (d, J

= 8.5 Hz, 2 H), 5.30 (1/2 ABq, J = 14.2 Hz, 1 H), 4.61 (d, J =

2.6 Hz, 1 H), 4.43 (1/2 ABq, J = 14.3 Hz, 1 H), 3.92 (dd, J = 5.6,

1.6 Hz, 1 H), 3.82 (s, 3 H), 3.21 (s, 1 H), 1.93 (m, 2 H), 1.42 (m, 2

H), 0.84 (m, 9 H), 0.7–0.3 (m, 6 H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃, 25 °C): δ = 198.7 (CH), 175.9 (C_q), 158.7 (C_q), 135.1 (C_q),

129.1 (2 C, CH), 128.6 (CH), 128.3 (C_q), 128.1 (2 C, CH), 126.3 (2

C, CH), 113.9 (2 C, CH), 80.8 (C_q), 78.1 (CH), 60.2 (CH), 54.9

(CH₃), 46.3 (CH₂), 28.8 (CH₂), 20.9 (CH₂), 6.1 (3 C, CH₃), 4.3 (3

C, CH₂) ppm. C₂₇H₃₇NO₅Si (483.67): calcd. C 67.05, H 7.71, N

2.90; found C 67.19, H 7.79, N 2.83.

(S)-5-{(R)-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl](phenyl)(trimethyl-

silyloxy)methyl}-1-(4-methoxybenzyl)pyrrolidin-2-one (33): The title

compound was prepared from lactam 32 (1.00 g, 2.75 mmol) ac-

cording to the procedure described for the synthesis of compound

25. Purification by silica gel flash chromatography (hexane/EtOAc,

80:20) furnished lactam 33 (1.31 g, 99% yield) as white crystals.

M.p. 85–87 °C. [α]²_D⁰= +34.0 (c = 1.0, CHCl₃). ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 7.61 (m, 2 H), 7.35 (m, 3 H), 7.21

(d, J = 8.4 Hz, 2 H), 6.89 (d, J = 8.4 Hz, 2 H), 5.35 (1/2 ABq, J =

14.4 Hz, 1 H), 4.66 (t, J = 6.6 Hz, 1 H), 4.50 (1/2 ABq, J = 14.4 Hz,

1 H), 4.07 (dd, J = 9.0, 7.2 Hz, 1 H), 3.99 (dd, J = 9.0, 6.3 Hz, 1

H), 3.88 (br. d, J = 8.7 Hz, 1 H), 3.84 (s, 3 H), 1.97 (m, 1 H), 1.73

(m, 2 H), 1.41 (s, 3 H), 1.37 (s, 3 H), 0.92 (m, 1 H), 0.27 (s, 9 H)

ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 177.2 (C_q), 158.6

(C_q), 141.0 (C_q), 129.3 (2 C, CH), 129.2 (C_q), 127.8 (CH), 127.6 (2

C, CH), 127.0 (2 C, CH), 113.7 (2 C, CH), 109.9 (C_q), 82.6 (C_q),

79.8 (CH), 66.1 (CH₂), 59.3 (CH), 54.9 (CH₃), 46.1 (CH₂), 29.0

(CH₂), 25.5 (CH₃), 23.7 (CH₃), 22.6 (CH₂), 2.13 (3 C, CH₃) ppm.

C₂₇H₃₇NO₅Si (483.67): calcd. C 67.05, H 7.71, N 2.90; found C

66.89, H 7.80, N 2.85.

(1R,2S,3R,4R,5S)-2-(tert-Butyldimethylsilyloxy)-4-hydroxy-6-(4-

methoxybenzyl)-4-phenyl-3-(triethylsilyloxy)-6-azabicyclo[3.2.1]-

octan-7-one (36): The title compound was prepared from aldehyde

35 (650 mg, 1.34 mmol) according to the procedure described for

the synthesis of compound 15. Purification by silica gel flash

chromatography (hexane/EtOAc, 90:10 to 60:40) furnished bicycle

36 (570 mg, 72% yield) as white crystals. M.p. 140–142 °C. [α]²_D⁰

=

1

+35.2 (c = 1.0, MeOH). H NMR (600 MHz, CDCl₃, 25 °C): δ =

7.49 (m, 2 H, Ph), 7.37 (m, 2 H, Ph), 7.34 (m, 1 H, Ph), 7.01 (d, J

= 8.4 Hz, 2 H, Ar), 6.88 (d, J = 8.4 Hz, 2 H, Ar), 4.97 (1/2 ABq,

J = 15.6 Hz, 1 H, CH₂Ar), 4.36 (m, 1 H, 3-H), 4.22 (m, 1 H, 2-H),

4.10 (m, 2 H, 5-H, OH), 3.83 (s, 3 H, OMe), 3.32 (1/2 ABq, J =

15.6 Hz, 1 H, CH₂Ar), 2.80 (d, J = 12.0 Hz, 1 H, 8-H_ax), 2.76 (t, J

= 4.2 Hz, 1 H, 1-H), 2.09 (dt, J = 12.0, 4.8 Hz, 1 H, 8-H_eq), 0.96

(s, 9 H, tBu), 0.85 (m, 9 H, SiCH₂CH₃), 0.57 (m, 6 H, SiCH₂CH₃),

0.24 (s, 3 H, CH₃), 0.21 (s, 3 H, CH₃) ppm. ¹³C NMR (75.4 MHz,

(S)-5-[(1R,2R)-1-Hydroxy-1-phenyl-2,3-bis(triethylsilyloxy)propyl]-

1-(4-methoxybenzyl)pyrrolidin-2-one (34): The title compound was

prepared from lactam 33 (1.20 g, 2.48 mmol) according to the two-

step procedure described for the synthesis of compound 26. After

2284

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Eur. J. Org. Chem. 2008, 2273–2287

A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

CDCl₃, 25 °C): δ = 173.8 (C_q, C-7), 158.5 (C_q, Ar), 141.9 (C_q, Ph),

room temperature. After stirring at this temperature for 2 h, the

128.9 (C_q, Ar), 128.4 (2 C, CH, Ph), 127.6 (2 C, CH, Ar), 127.5 reaction mixture was concentrated under reduced pressure to give

(CH, Ph), 126.8 (2 C, CH, Ph), 113.7 (2 C, CH, Ar), 77.7 (CH, C- a mixture (67 mg, glassy solid) of amino acid 38 (64%, correspond-

3), 73.4 (C_q, C-4), 71.5 (CH, C-2), 59.3 (CH, C-5), 54.9 (CH₃, ing to a 58% yield for two steps, as the hydrochloride salt) and its

1

OMe), 45.9 (CH, C-1), 44.0 (CH₂, CH₂Ar), 28.5 (CH₂, C-8), 25.3 γ-lactone form (38-γ-lactone) (32%, as the hydrochloride salt). H

(3 C, CH₃, tBu), 17.5 (C_q, tBu), 6.43 (3 C, CH₃, SiCH₂CH₃), 4.70

NMR (300 MHz, D₂O, 25 °C): δ = 4.07 (d, J = 5.7 Hz, 1 H, 2-H-

(3 C, CH₂, SiCH₂CH₃), –4.6 (CH₃, Me), –4.8 (CH₃, Me) ppm. γ-lactone), 4.01 (d, J = 6.2 Hz, 1 H, 2-H), 3.2–3.4 (m, 2 H, 4-H, 4-

C₃₃H₅₁NO₅Si₂(597.93): calcd. C 66.29, H 8.60, N 2.34; found C

66.15, H 8.68, N 2.30.

H-γ-lactone), 3.11 (td, J = 8.9, 6.2 Hz, 1 H, 1-H), 2.70 (td, J = 8.8,

5.6 Hz, 1 H, 1-H-γ-lactone), 2.34 (dt, J = 14.0, 8.6 Hz, 1 H, 5a-H-

γ-lactone), 2.27 (dt, J = 14.6, 8.3 Hz, 1 H, 5a-H), 2.10 (ddd, J =

14.4, 8.7, 6.4 Hz, 1 H, 5b-H), 1.92 (dt, J = 13.8, 8.6 Hz, 1 H, 5b-

H-γ-lactone), 1.21 (s, 3 H, Me), 1.20 (s, 3 H, Me-γ-lactone) ppm.

¹³C NMR (75.4 MHz, D₂O, 25 °C): δ = 180.2 (C_q, COOH), 178.1

(C_q, CO-γ-lactone), 83.9 (CH, C-2-γ-lactone), 80.5 (CH, C-2), 79.3

(C_q, C-3-γ-lactone), 77.2 (C_q, C-3), 59.5 (CH, C-4), 59.0 (CH, C-

4-γ-lactone), 50.9 (CH, C-1-γ-lactone), 48.4 (CH, C-1), 31.5 (CH₂,

C-5), 31.3 (CH₂, C-5-γ-lactone), 25.9 (CH₃, Me), 22.5 (CH₃, Me-

γ-lactone) ppm. HRMS (positive ESI): calcd. for C₇H₁₄NO₄[M +

H]⁺176.0923; found 176.0907 (158.0815 for the γ-lactone form).

(1R*,4S*,5S*,6R*)-2-(tert-Butoxycarbonyl)-5-(tert-butyldimethyl-

silyloxy)-6-hydroxy-6-methyl-2-azabicyclo[2.2.1]heptan-3-one (37):

Anhydrous ammonia (10 mL) was condensed into a two-necked

flask containing a solution of bicycle 15 (250 mg, 0.69 mmol) in

anhydrous THF (20 mL) maintained at –78 °C. Sodium metal was

added to the mixture until a blue colour persisted. The reaction

mixture was stirred at –78 °C for 1 h and quenched by addition of

solid NH₄Cl (300 mg). The ammonia was evaporated, the mixture

was warmed to room temperature and the residue treated with

MeOH and a saturated aqueous NH₄Cl solution (until complete

neutralization), and extracted with EtOAc (three times). The or-

ganic extracts were dried (MgSO₄), filtered and concentrated under

vacuum to give an N-deprotected bicyclic intermediate (180 mg,

(1S,2S,3R,4R,5S)-2-(tert-Butyldimethylsilyloxy)-3-hydroxy-6-(4-

methoxybenzyl)-4-phenyl-4-(triethylsilyloxy)-6-azabicyclo[3.2.1]-

octane (39): Bicyclic lactam 36 (500 mg, 0.83 mmol) was dissolved

in anhydrous pyridine (20 mL) at room temperature under argon,

and triethylsilyl trifluoromethanesulfonate (TESOTf, 0.94 mL,

4.15 mmol) and 4-(dimethylamino)pyridine (DMAP, 20.3 mg,

0.16 mmol) were sequentially added whilst stirring. After 24 h, the

reaction mixture was concentrated under vacuum, and toluene

(50 mL) was added. The solution was concentrated, and the re-

sulting crude residue was purified by silica gel flash chromatog-

raphy (hexane/EtOAc, 95:5). A fully protected bicyclic lactam was

obtained (530 mg, 90 % yield) as a colourless oil. ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 7.30 (m, 5 H), 7.12 (d, J = 8.3 Hz,

2 H), 6.95 (d, J = 8.6 Hz, 2 H), 5.00 (1/2 ABq, J = 16.4 Hz, 1 H),

4.43 (m, 1 H), 4.18 (br. d, J = 4.7 Hz, 1 H), 4.12 (m, 1 H), 3.84 (s,

3 H), 3.35 (1/2 ABq, J = 16.1 Hz, 1 H), 3.10 (d, J = 11.0 Hz, 1 H),

2.66 (m, 1 H), 2.01 (dt, J = 9.9, 4.3 Hz, 1 H), 1.01 (s, 9 H), 0.77

(m, 18 H), 0.56 (m, 6 H), 0.21 (s, 3 H), 0.19 (s, 3 H), 0.11 (m, 6 H)

ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 174.8 (C_q), 158.3

(C_q), 142.0 (C_q), 129.4 (C_q), 127.9 (2 C, CH), 127.6 (2 C, CH),

127.5 (CH), 127.2 (2 C, CH), 113.7 (2 C, CH), 78.8 (CH), 75.0

(C_q), 71.9 (CH), 57.8 (CH), 54.9 (CH₃), 46.4 (CH), 43.4 (CH₂),

27.5 (CH₂), 25.5 (3 C, CH₃), 17.7 (C_q), 6.7 (3 C, CH₃), 6.4 (3 C,

CH₃), 5.5 (3 C, CH₂), 4.9 (3 C, CH₂), –4.7 (CH₃), –4.8 (CH₃) ppm.

1

98%) as a colourless resin. H NMR (300 MHz, CDCl₃, 25 °C): δ

= 5.69 (br. s, 1 H), 3.96 (d, J = 4.2 Hz, 1 H), 3.61 (br. s, 1 H), 3.49

(m, 1 H), 2.75 (m, 1 H), 2.0 (dt, J = 10.8, 1.9 Hz, 1 H), 1.61 (dq,

J = 10.8, 0.9 Hz, 1 H), 1.27 (s, 3 H), 0.95 (s, 9 H), 0.20 (s, 3 H),

0.17 (s, 3 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 176.7

(C_q), 84.8 (C_q), 73.6 (CH), 62.4 (CH), 51.8 (CH), 34.5 (CH₂), 26.0

(CH₃), 25.7 (3 C, CH₃), 18.1 (C_q), –4.7 (CH₃), –5.1 (CH₃) ppm.

Di-tert-butyl dicarbonate (240 mg, 1.10 mmol) and 4-(dimeth-

ylamino)pyridine (DMAP, 13.4 mg, 0.11 mmol) were sequentially

added to a solution of the previous N-deprotected bicyclic interme-

diate (150 mg, 0.55 mmol) in dry MeCN (20 mL) at room tempera-

ture under argon. After stirring at room temperature for 12 h, the

solvent was evaporated under reduced pressure, and the crude resi-

due was purified by silica gel flash chromatography (hexanes/

EtOAc, 70:30) to furnish bicyclic compound 37 (170 mg, 86%) as

1

a glassy solid. H NMR (300 MHz, CDCl₃, 25 °C): δ = 4.24 (m, 1

H), 3.89 (d, J = 4.0 Hz, 1 H), 3.54 (s, 1 H), 2.84 (m, 1 H), 1.96 (dt,

J = 11.1, 2.1 Hz, 1 H), 1.59 (s, 3 H), 1.52 (dt, J = 11.0, 0.6 Hz, 1

H), 1.50 (s, 9 H), 0.92 (s, 9 H), 0.18 (s, 3 H), 0.14 (s, 3 H) ppm.

¹³C NMR (75.4 MHz, CDCl₃, 25 °C): δ = 173.0 (C_q), 153.8 (C_q),

82.2 (C_q), 75.6 (C_q), 73.3 (CH), 65.3 (CH), 53.5 (CH), 31.9 (CH₂),

28.0 (3 C, CH₃), 26.1 (CH₃), 25.7 (3 C, CH₃), 17.8 (C_q), –4.7 (CH₃),

–5.1 (CH₃) ppm. C₁₈H₃₃NO₅Si (371.54): calcd. C 58.19, H 8.95, N

3.77; found C 58.03, H 9.01, N 3.70.

Dry THF (30 mL) was added to a reaction vessel containing anhy-

drous AlCl₃(0.93 g, 7.0 mmol) cooled to 0 °C under argon, and the

resulting colourless solution was stirred at the same temperature for

10 min. Lithium aluminium hydride (LiAlH₄, 21.0 mL of a 1.0 

solution in THF, 21.0 mmol) was added, and vigorous bubbling

was observed. The colourless AlH₃solution so obtained was

warmed to room temperature and stirred for 30 min, after which

time it was cooled again to –80 °C. The alane solution (10 mL,

1.4 mmol) was added by syringe to a precooled (–80 °C) solution

of the above bicyclic lactam intermediate (500 mg, 0.70 mmol) in

dry THF (30 mL), and the resulting colourless mixture was stirred

at –80 °C for 1 h, warmed to 20 °C and stirred for an additional

1 h. The reaction mixture was quenched with MeOH (10 mL), a

5% aqueous citric acid solution (5 mL) and water (50 mL), and the

resulting slurry was thoroughly extracted with EtOAc (five times).

The combined organic layers were dried (MgSO₄), filtered and con-

centrated under vacuum to give a crude residue which was purified

by silica gel flash chromatography (hexane/EtOAc, 95:5 to 80:20)

to provide amine 39 (480 mg, 99% yield, corresponding to 89%

yield for two steps) as a white resin. [α]²_D⁰= +1.8 (c = 1.0, CHCl₃).

(1S*,2S*,3R*,4R*)-4-Amino-2,3-dihydroxy-3-methylcyclopentane-

carboxylic Acid (38): Bicyclic lactam 37 (150 mg, 0.40 mmol) was

dissolved in THF (8 mL) and H₂O (4 mL), and the resulting mix-

ture was treated with LiOH (57.6 mg, 2.40 mmol). After 3 h, the

reaction mixture was quenched with a 1  aqueous HCl solution

(until pH = 2) and extracted with EtOAc (five times). The com-

bined organic layers were dried (MgSO₄), filtered and concentrated

under vacuum to give an oily residue which was purified by silica

gel flash chromatography (EtOAc/MeOH/AcOH, 8:2:1) to furnish

a protected cyclopentanecarboxylic acid intermediate (99 mg, 90%

1

yield) as a colourless resin. H NMR (300 MHz, D₂O, 25 °C): δ =

4.01 (d, J = 8.3 Hz, 1 H), 3.60 (m, 1 H), 3.06 (q, J = 8.5 Hz, 1 H),

2.13 (m, 1 H), 1.85 (dt, J = 13.4, 8.9 Hz, 1 H), 1.33 (s, 9 H), 1.13

(s, 3 H) ppm.

The above cyclopentanecarboxylic acid intermediate (95 mg,

0.34 mmol) was treated with a 3  aqueous HCl solution (5 mL) at

Eur. J. Org. Chem. 2008, 2273–2287

www.eurjoc.org

2285

F. Zanardi, G. Casiraghi et al.

FULL PAPER

¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.64 (m, 2 H), 7.36 (m, 3

on all F²performed using SHELXL97,^[18]as implemented in the

H), 6.98 (m, 2 H), 6.76 (m, 2 H), 4.82 (br. s, 1 H), 4.25 (d, J = WINGX program.^[19]Anisotropic displacement parameters were

12.8 Hz, 1 H), 4.00 (m, 3 H), 3.77 (s, 3 H), 3.57 (br. d, J = 11.7 Hz,

1 H), 2.92 (br. d, J = 11.7 Hz, 1 H), 2.86 (m, 1 H), 2.40 (m, 2 H),

1.62 (m, 1 H), 0.95 (s, 9 H), 0.81 (t, J = 8.4 Hz, 9 H), 0.22 (m, 6

refined for all non-hydrogen atoms, whereas hydrogen atoms were

located from Fourier maps and refined isotropically. Nine hydrogen

atoms, more exactly those on the terminal methyl groups, were in-

H), 0.13 (s, 3 H), 0.11 (s, 3 H) ppm. ¹³C NMR (75.4 MHz, CDCl₃, troduced into calculated positions. Analytical expressions of

25 °C): δ = 158.9 (C_q), 129.8 (2 C, Cq), 128.4 (2 C, CH), 127.9 (4

neutral atom scattering factors were employed according to the In-

C, CH), 127.5 (CH), 113.8 (2 C, CH), 77.4 (2 C, CH), 76.9 (C_q),

ternational Tables for X-ray Crystallography.^[20]Structure drawing

66.8 (CH), 61.3 (CH₂), 56.8 (CH₂), 55.2 (CH₃), 42.7 (CH), 26.0 (3 was carried out by using ORTEPIII.^[21]CCDC-673479 contains the

C, CH₃), 25.4 (CH₂), 18.3 (C_q), 7.1 (3 C, CH₃), 5.9 (3 C, CH₂), –4.6 supplementary crystallographic data for this paper. These data can

(CH₃), –4.9 (CH₃) ppm. C₃₃H₅₃NO₄Si₂(583.95): calcd. C 67.87, H

9.15, N 2.40; found C 67.98, H 9.29, N 2.37.

be obtained free of charge from the Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Crystal Data for 7a: M.p. 89–91 °C. C₂₃H₃₅NO₄Si, M_r= 417.62,

orthorhombic, space group Pcab, a = 10.774(1), b = 11.646(1), c =

38.777(4) Å, V = 4865.5(8) Å³, Z = 8, ρ_calcd.= 1.140 Mgm^–3, T =

298.15 K, F(000) = 1808, crystal size = 0.40ϫ0.30ϫ0.30 mm, θ

(1S,2S,3R,4R,5S)-4-Phenyl-6-azabicyclo[3.2.1]octane-2,3,4-triol

(40): Palladium on carbon (30 mg) was added to a solution of

amine 39 (450 mg, 0.64 mmol) in absolute EtOH (20 mL) at room

temperature. The reaction vessel was degassed under vacuum and

thoroughly purged with hydrogen (three times). The resulting

heterogeneous mixture was stirred under hydrogen for 3 h, after

which time the hydrogen was evacuated, the catalyst filtered off and

the filtrate concentrated under vacuum to give a crude residue

which was purified by silica gel flash chromatography (EtOAc/

MeOH/NH₃, 98:1:1) to furnish an N-deprotected amine intermedi-

ate (270 mg, 91%) as a white solid. M.p. 120–122 °C. [α]²_D⁰= +11.6

(c = 0.5, EtOH). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.51 (br.

d, J = 7.4 Hz, 2 H), 7.39 (br. t, J = 7.0 Hz, 2 H), 7.31 (br. d, J =

7.2 Hz, 1 H), 4.25 (br. d, J = 5.4 Hz, 1 H), 4.03 (m, 1 H), 3.94 (m,

1 H), 3.79 (br. s, 2 H), 3.08 (m, 2 H), 2.99 (d, J = 11.8 Hz, 1 H),

2.40 (m, 1 H), 1.62 (m, 1 H), 0.96 (s, 9 H), 0.79 (t, J = 8.0 Hz, 9

H), 0.22 (m, 6 H), 0.15 (s, 3 H), 0.13 (s, 3 H) ppm. ¹³C NMR

(75.4 MHz, CD₃OD, 25 °C): δ = 143.7 (C_q), 129.4 (2 C, CH), 128.9

(CH), 128.5 (2 C, CH), 78.7 (CH), 78.3 (CH), 77.6 (C_q), 61.2 (CH),

48.5 (CH₂), 42.9 (CH), 27.7 (CH₂), 26.5 (3 C, CH₃), 19.1 (C_q), 7.4

(3 C, CH₃), 7.0 (3 C, CH₂), –4.5 (CH₃), –4.7 (CH₃) ppm.

range for data collection

= 1.05–26.52°, index ranges =

–12ՅhՅ12, –14ՅkՅ14, –48ՅlՅ32, reflections collected =

25981, independent reflections = 4857, completeness to θ (26.52°)

= 96.0%, refinement method = full-matrix least squares on F², pa-

rameters = 342, goodness-of-fit on F²= 1.035, final R indices

[IϾ2σ(I)] = R₁= 0.0564, wR₂= 0.1485, largest difference peak and

hole = 0.26 and –0.37 eÅ^–3.

Supporting Information (see footnote on the first page of this arti-

cle): ¹H and ¹³C NMR spectra of compounds 7a, 8a, 10–15, 17–

21, 23–28 and 31–40.

Acknowledgments

This work was supported by the University of Parma. We thank

the Centro Interdipartimentale Misure “G. Casnati” (Università di

Parma) for the use of their instrumental facilities. A post-doctoral

fellowship to P. B. from the Centro Interdisciplinare di Studi Bio-

Molecolari e Applicazioni Industriali (CISI, Milano, Italy) is grate-

fully acknowledged.

The above N-deprotected amine intermediate (270 mg, 0.58 mmol)

was dissolved in THF (10 mL) and treated with a 1  aqueous HCl

solution (3.0 mL) at room temperature. After stirring at this tem-

perature for 3 h, the reaction mixture was concentrated under re-

duced pressure to give azabicycle 40 (134 mg, 98%, corresponding

to 89% yield for two steps) as a glassy solid as the hydrochloride

salt. [α]²_D⁰= +10.43 (c = 0.23, MeOH). ¹H NMR (600 MHz,

CD₃OD, 25 °C): δ = 7.49 (dd, J = 8.4, 1.2 Hz, 2 H, Ph), 7.44 (t, J

= 7.2 Hz, 2 H, Ph), 7.35 (tt, J = 7.2, 1.2 Hz, 1 H, Ph), 4.48 (dd, J

= 5.4, 1.2 Hz, 1 H, 5-H), 4.11 (br. d, J = 1.2 Hz, 1 H, 3-H), 3.98

(dt, J = 4.2, 1.8 Hz, 1 H, 2-H), 3.71 (dd, J = 11.4, 1.8 Hz, 1 H, 7-

H_endo), 3.32 (dd, J = 11.4, 5.4 Hz, 1 H, 7-H_exo), 3.16 (br. d, J =

12.6 Hz, 1 H, 8-H_ax), 2.72 (dt, J = 4.8, 4.0 Hz, 1 H, 1-H), 1.83

(dtd, J = 12.6, 4.8, 1.2 Hz, 1 H, 8-H_eq) ppm. ¹³C NMR (75.4 MHz,

CD₃OD, 25 °C): δ = 145.8 (C_q, Ph), 129.4 (2 C, CH, Ph), 128.4

(CH, Ph), 128.1 (2 C, CH, Ph), 78.2 (CH, C-3), 76.4 (CH, C-2),

74.7 (C_q, C-4), 61.8 (CH, C-5), 49.7 (CH₂, C-7), 42.6 (CH, C-1),

28.3 (CH₂, C8) ppm. C₁₃H₁₈ClNO₃(271.74): calcd. C 57.46, H

6.68, N 5.15; found C 57.29, H 6.74, N 5.10.

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2286

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Eur. J. Org. Chem. 2008, 2273–2287

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[8]

[9]

[10]

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Published Online: March 13, 2008

Eur. J. Org. Chem. 2008, 2273–2287

www.eurjoc.org

2287

Article Doi

Further uses of pyrrole-based dienoxysilane synthons: A full aldol approach to azabicyclo[x.2.1]alkane systems

DOI: 10.1002/ejoc.200800040

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