Stereoselective synthesis of trans-threo-trans-oligopyrrolidines: Potential agents for RNA cleavage

FULL PAPER

Stereoselective Synthesis of trans-threo-trans-Oligopyrrolidines:

Potential Agents for RNA Cleavage

Hans-Dieter Arndt,^{[b, c]}R¸diger Welz,^[b]Sabine M¸ller,*^{[b, d]}Burkhart Ziemer,^[b]and

Ulrich Koert*^[a]

Abstract: The 2,5-trans-substituted oli-

gopyrrolidines constitute a promising

class of novel RNA-binding agents as

well as potential building blocks for ar-

tificial anion channels. A convergent

synthesis of terpyrrolidine 1 and pyrro-

lidino-THF-pyrrolidine 2 is reported,

relying upon convergent coupling of

2,5-trans-pyrrolidinecarboxaldehydes

through bridging alkyne units under

Felkin Anh control and subsequent

closure of the central ring. After com-

plete deprotection, the free polyamine

products were isolated in excellent

yield and purity. Crystal structure anal-

yses of a terpyrrolidine and a pyrrolidi-

no-THF-pyrrolidine documented their

helical privileged conformations. The

compounds were then screened for

RNA cleavage activity. Unlike the only

weakly active simple polyamines, p-ni-

trosulfonamide 33 was found to induce

cleavage at mm concentrations under

physiologically relevant conditions.

Keywords:

polyamines

helical structures

pyrrolidines

¥

RNA binding ¥ synthesis design

Introduction

tegrity. More specifically, the prominent aminoglycoside

class of antibiotics can be viewed as closely related poly-

cations, albeit conformationally restricted.^[11,13,14]These

agents are geared towards binding of folded RNA structures

and will interfere with bacterial protein synthesis, mainly

through their selective interaction with eubacterial 16S

rRNA.^[15]Inspired by this natural example of conformation-

al and spatial constraining to tailor specific molecular func-

tions within a specific class of compounds, our goal became

the investigation of novel structural motifs for selective

anion binding.

By this model, it was envisioned that prototypical trans-

threo-trans-oligopyrrolidines such as 1 might integrate the

potential of an anion-binding polyamine into a flexible

backbone with a helical conformational bias (Scheme 1).

Molecules of this type are the amine counterparts of the

cation-binding oligotetrahydrofurans,^[16]which have been

synthesized, conformationally characterized and successfully

Polyamines such as spermine play a multitude of roles in

3]

biomolecular recognition events.^[1

Their still emerging

functions range from membrane stabilization^[4]through the

modulation of receptors,^[5]enzymes,^[6,7]and protein aggrega-

tion^[8]to a very general interaction with folded oligonucleo-

tides and oligonucleotide protein complexes.^[2,6,9

The

12]

global association of polyamines with cellular RNA in eu-

karyotes^[1](50 60% of total content) further highlights the

particular affinity of polyamines for RNA and by extension

the importance of these polycations for RNA structure in-

[a] Prof. Dr. U. Koert

Fachbereich Chemie der Philipps-Universit‰t Marburg

Hans-Meerwein-Strasse 35032 Marburg/Lahn (Germany)

Fax : (+49)6421-28-25677

E-mail: koert@chemie.uni-marburg.de

[b] Dr. H.-D. Arndt, Dr. R. Welz, Prof. Dr. S. M¸ller, Dr. B. Ziemer

Institut f¸r Chemie der Humboldt-Universit‰t zu Berlin

Brook-Taylor-Strasse 2, 12489 Berlin (Germany)

E-mail: sabine.mueller@orch.ruhr-uni-bochum.de

burkhard.ziemer@chemie.hu-berlin.de

used as building blocks for artificial transmembrane cation

20]

channels.^[16

A privileged helical conformation had been

deduced for them from modelling studies, as well as from X-

ray structures of synthetic intermediates. In order to ad-

vance the corresponding application of oligopyrrolidine sub-

units in anion channels, as well as to evaluate their potential

for selective interaction with RNA, we embarked upon

opening up a reliable synthetic route to stereodefined ter-

pyrrolidines 1. Of additional interest was a synthetic route

to pyrrolidine tetrahydrofuran hybrids 2, which could link

the oligopyrrolidines to the oligotetrahydrofurans character-

ized previously.

[c] Dr. H.-D. Arndt

New Address: Max-Planck Institut fur Molekulare Physiologie

Abteilung IV–Chemische Biologie

Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)

[d] Prof. Dr. S. M¸ller

New Address: Fakult‰t f¸r Chemie, NC 3/171

Universit‰tsstrasse 150, 44780 Bochum (Germany)

Supporting information for this article is available on the WWW

under http://www.chemeurj.org/ or from the author.

Chem. Eur. J. 2004, 10, 3945 3962

DOI: 10.1002/chem.200400181

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3945

FULL PAPER

With the exception of spermine/spermidine derivatives,

stereochemically complex polyamines are scarcely docu-

mented in the literature, completely the opposite to the poly-

ether field. This is most probably due to the infrequent oc-

currence of polyamine substructures in natural products, es-

pecially with regard to oligopyrrolidines. 2,2’-Bispyrrolidine

has frequently been applied as a chiral auxiliary, and routes

towards its stereoselective synthesis have been devised.^[21,22]

Vinylogous Mannich reactions have been successfully em-

ployed for the synthesis of aza-annonines.^[23,24]Recently this

reaction has been implemented in an iterative process for

the stereodivergent synthesis of 2,5-linked oligotetrahydro-

furan-, -pyrrole and -thiophene libraries.^[25]However, no

fully deprotected oligopyrrolidine products have been re-

ported. Here we give a full account^[26]of the stereoselective

synthesis of the oligopyrrolidines 1 and 2 on gram scales,

their complete structural characterization, protecting groups

and deprotection, and further improvements in the synthetic

methods. Furthermore, preliminary experiments conducted

with RNA oligonucleotides indicate that derivatives of oli-

gopyrrolidines interact with RNA in a selective fashion, and

are promising candidates for designed RNA cleavage

agents.

Scheme 2. Synthesis of aldehyde 4: a) MeOH, dimethoxypropane, H⁺,

508C; b) NaBH₄, THF/MeOH; c) TBDPSCl, imidazole, DMF; d) Boc₂O,

pyridine, DMAP, CH₂Cl₂; e) NaBH₄, CH₂Cl₂/MeOH, ꢀ108C; f) dime-

thoxypropane, cat. CSA, 08C; g) TMSCN, cat. TMSOTf, CH₂Cl₂, ꢀ358C;

h) cat. KOtBu, tBuOH, toluene, 08C; i) DiBAH, toluene/PE, ꢀ708C!

ꢀ608C.

O-protected to give the TBDPS silylether 6 and further

transformed^[27]into the N-Boc-protected lactam 7. Known

procedures were adapted such as to minimize purification

efforts along the way. A carefully controlled NaBH₄reduc-

tion of 7 in CH₂Cl₂/MeOH at ꢀ108C then yielded the hemi-

aminal, which was found to be prone to self-condensation

and was therefore transformed into the stable aminal 8 by

acid-catalysed transacetalization. Treatment of the N-acyl-

iminum ion^[28]precursor 8 with TMSCN and catalytic

amounts of TMSOTf gave a 3:1 mixture of the trans nitrile

9 and the cis nitrile 10, independent of aminal stereochemis-

try. The minor cis isomer 10 could easily be separated by

column chromatography on 10 g scale, and was further epi-

merized to 9 under basic conditions. A DIBAH reduction of

the nitrile 9 led to the trans aldehyde 4. Neutral workup

conditions and a minimal excess of DIBAH were crucial to

maximize the yield.

Results and Discussion

Our plan for the synthesis of oligopyrrolidines was guided

by the necessity to provide the hitherto unknown target

molecules in sufficient quantity for structural studies and

further experimentation. Therefore, a retrosynthetic analysis

of 1 relying on the symmetry of the target structures

(Scheme 1) led us to disconnect the central ring into an

The stereocontrolled addition of carbon nucleophiles to

the carbonyl group of the aldehyde 4 was investigated next.

The two possible products 11 and 12 (Scheme 3) would be

expected, from a Felkin Anh-type attack in the case of 11

(1’R), whereas a chelation-controlled transition state should

lead to the 1’S alcohol 12. Felkin Anh control had been ach-

ieved even for acetylide nucleophiles in the case of closely

related aldehydes,^[29,30]setting the precedent for our plan-

ning.

Scheme 1. Retrosynthetic disconnection of 2,5-trans-threo-trans-oligopyr-

rolidines. R = TBDPS.

open-chain precursor, which would result from a diastereo-

selective addition of alkyne 3 to aldehyde 4 under Felkin

Anh control. Ring-closure should then be attainable through

suitable nucleophilic substitution reactions. The alkyne 3

and its precursor aldehyde 4 should be accessible from read-

ily available pyroglutamic acid (5) (Scheme 1), making alde-

hyde 4 a pivotal building block.

The synthesis of the pyrrolidine carboxaldehyde

4

(Scheme 2) began with the esterification of 5 in order to

ease its reduction to the corresponding alcohol, which was

Scheme 3. Addition of C-nucleophiles to aldehyde 4.

3946

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Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

In encouraging first experiments, primary alkyllithium re-

agents gave the Felkin Anh product exclusively (Table 1),

albeit in moderate yield (entries 1 2).¹In contrast, Li-acety-

zinc ion towards aldehyde 4: (+)-13 exhibited a mismatched

case of double stereodifferentiation (low reactivity, 40%

yield and 86:14 selectivity), while (ꢀ)-13 resulted in a per-

fectly matched case (90% isolated yield, 154:1 stereoselec-

tivity by HPLC).

Table 1. Reaction of aldehyde 4 with nucleophiles.

The cerium acetylide addition was therefore used routine-

ly in the subsequent course of the terpyrrolidine synthesis

(Scheme 4). The aldehyde 4 was converted into the alcohol

14 in 51% yield after chromatographic separation of the un-

desired epimer. Desilylation of the terminal alkyne (14!15)

and subsequent O-TMS protection delivered the alkyne 3 in

high yield. Lithiation of alkyne 3 and treatment with the al-

dehyde 4 gave the two epimeric alcohols 16 and 17 in 95%

yield with a 2:1 stereoselectivity in favour of the Felkin

Anh product 16. In this case the presence of HMPT was

beneficial: the addition was unselective otherwise (1:1).

After chromatographic separation of the two epimers, com-

pound 16 was deprotected to yield the C₂-symmetric diol 18,

which was saturated (H₂, Pt/C) to give diol 19.

R-M

conditions

(0.5mmol scale)

Yield

[%]^[a]

(1’R):(1’S)

[b]

1

2

3

4

MeLi

BuLi

Et₂O, ꢀ1008C!ꢀ788C

Et₂O, ꢀ908C!ꢀ788C

THF, ꢀ908C!ꢀ788C, 4 h

THF, ꢀ788C!ꢀ608C, 2 h

THF/HMPT, ꢀ908C!

ꢀ508C, 1 h

5

>895:5

>905:5

60:40

51:49

70:30

[b]

TMS-CꢁC-Li

80

77

TMS-CꢁC-Li

5TMS-C ꢁC-Li

84^[c]

6

7

TIPS-CꢁC-Li

THF, ꢀ788C, 1 h

49^[b]

62:38

55:45

TMS-CꢁC-CeCl₂THF, ꢀ788C, 10 min (0.5/ 95/93

15mmol)

THF, ꢀ408C!08C, 4 h

8

9

TMS-CꢁC-Ti-

Cl(OiPr)₂

88^[c]

40^[d]

90

75:25

TMS-CꢁC-

13, toluene, 208C, 24 h

14:86^[e]

1:154^[e]

Zn(OTf)

10 TMS-CꢁC-

(ent)-13, toluene, 208C,

24 h

Zn(OTf)

With diol 19 to hand, it was envisaged that substitution of

the two OH groups with nitrogen nucleophiles under S_N2

conditions should complete the synthesis of the central pyr-

rolidine ring. Several attempts treating the ditosylate, dime-

sylate, or ditriflate of 19 with primary amines or azide

proved futile, however, the N-Boc groups preferentially at-

tacking the activated positions in an intramolecular substitu-

tion reaction, leading to cyclic carbamates. More successful

was the conversion of the diol 19 via the cyclic 1,4-sulfite 20

into the cyclic 1,4-sulfate 21 (Scheme 4).^[34,35]Treatment of

cyclic 1,4-sulfate 21 with LiN₃under nonbasic conditions in

DMF/HMPT occurred without major side reactions of the

Boc groups and led to the desymmetrized azido alcohol 22

in good yield. Mesylation of the remaining OH group and

hydrogenolytic cleavage of the azide to the amine induced a

spontaneous closure of the central pyrrolidine ring to yield

the bis-N-Boc-protected terpyrrolidine 23. N-Boc-protection

of the hindered central pyrrolidine ring nitrogen then gave

the tris-N-Boc-protected terpyrrolidine 24.

[a] Isolated, (R)+(S). [b] Not optimized. [c] Side product formation.

[d] Incomplete conversion. [e] Determined by HPLC.

lides displayed only modest selectivity (entries 3 6), which

was also rather insensitive towards solvent composition

(hexanes/Et₂O, Et₂O, THF) or temperature. Only the addi-

tion of HMPT to the solvent mixture would slightly improve

the outcome (entry 5). Partial TMS-group scrambling was

difficult to suppress in this case, however, especially on

larger scales. Mg-acetylides gave somewhat similar results

(data not shown). Use of a less basic organocerium re-

agent^[31]did not improve the stereoselectivity, but did give a

much cleaner reaction, allowing essentially quantitative

yields (entry 7). A titanium acetylide^[32]gave the Felkin

Anh product preferentially, but the aldehyde 4 was found

to epimerize slightly under these reaction conditions

(entry 8).²To overcome these mixed results, we turned our

attention to reagent control. Carreira et al. have developed

an effective method for the stereocontrolled addition of zinc

acetylides to aldehydes by the use of N-methylephedrine

(13) as a chiral ligand.^[33]In the event, the chelation-control-

led compound 12 was obtained as the main product (en-

tries 9 10). Interestingly, in neither case was the chiral auxil-

iary 13 able to override the apparent chelating effect of the

An X-ray crystal structure analysis of compound 24

showed the correct stereochemical assignment of the threo-

trans-threo-trispyrrolidine and provided further conforma-

tional insights. As can be seen in Scheme 4, the pyrrolidine

rings adopt envelope-like conformations with the substitu-

ents in the 2- and 5-postions pointing in axial directions.

This illustrates the A^1,3strain exerted by the N-Boc

groups.^[36]One of the ring connections (C5 C6) is in a

ꢀ

gauche conformation, whereas the second one (C9 C10)

1

Stereochemical assignments were made after transformation of the N-

adopts an anti arrangement, presumably enforced by the

inward-pointing tBu substituent. Overall, the molecule still

displays a fairly helical arrangement of the five-membered

rings, despite being encumbered with bulky protecting

groups.

Boc amino alcohols into cyclic carbamates as reported previously

(ref. [26]) and were confirmed by X-ray crystallography of the final

products (see above). As a general guide, the -OH resonance of the

Felkin Ahn alcohol product was found to be significantly shifted down-

field in the CDCl₃¹H NMR spectrum in relation to its diastereomer

(ca. 1 ppm), indicating a strong hydrogen bond to the neighbouring

Boc group.

The synthesis of the tricyclic pyrrolidine tetrahydrofuran

hybrid 2 required the stereocontrolled elaboration of a cen-

tral 2,5-trans-disubstituted THF ring (Scheme 5). The prop-

argylic alcohol 17 was envisaged as a suitable synthetic pre-

cursor for compound 2. To this end, alcohol 17 was tempora-

rily protected as its acetate (!25). This was desilylated to

provide the propargylic alcohol 26, which was hydrogenated

2

It should be noted that the presence of sulfonamides (Ts, Ns) instead

of Boc protection on the ring nitrogen was found to result in considera-

ble Felkin Ahn control (6 11:1) for Li-acetylide additions. However,

the corresponding aldehydes were difficult to prepare and were also

found to be rather sensitive. Moreover, either downstream deprotection

was difficult (Ts) or the intermediates were prone to side reactions

(Ns). Therefore this route was abandoned.

Chem. Eur. J. 2004, 10, 3945 3962

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Scheme 4. Synthesis and X-ray crystal structure of Boc-protected terpyrrolidine 24: a) TMS-CꢁC-CeCl₂, THF, ꢀ808C; b) K₂CO₃, aq. MeOH; c) TMS-Im,

CH₂Cl₂, 08C; d) 1 equiv nBuLi, 2 equiv HMPT, THF, then 4; e) cat. CSA, THF/MeOH, 08C; f) H₂, cat. Pt/C, MeOH; g) 1 equiv SOCl₂, NEt₃, CH₂Cl₂,

ꢀ108C; h) cat. RuCl₃, NaIO₄, CCl₄/CH₃CN/H₂O, 0 8C; i) DMF/HMPT (0.2m), 8 equiv LiN₃, 40 h; k) THF, conc. H₂SO₄, 08C; l) MsCl, NEt₃, ꢀ208C;

m) H₂, cat. Pd/C, MeOH/THF; n) Boc₂O, NEt₃, DMF.

ture (ꢀ408C) in order to avoid migration of the acetoxy

group. The closure of the central THF ring was then initiat-

ed by cleavage of the acetate with 2 equivalents of methyl-

lithium. The resulting lithium alkoxide reacted sluggishly,

but addition of KOtBu to the mixture accelerated the reac-

tion, inducing ring-closure to the target tricycle 28 in 44%

yield. A biscarbamate was inevitably obtained as a by-prod-

uct in this case, resulting from the nucleophilic and electro-

philic properties of the two Boc groups in the molecular

neighbourhood. The two N-Boc groups of 28 were removed

in quantitative yield by use of TMSOTf,^[37]to give the bis-

pyrrolidine 29 with the O-TBDPS groups intact.^[38]HF-

mediated cleavage of the two silyl ethers in 29 finally pro-

vided the fully deprotected pyrrolidine-tetrahydrofuran-pyr-

rolidine hybrid 2 in an excellent 94% yield.

The symmetry of the final product was readily apparent

from its NMR spectra. To confirm the stereochemical as-

signments and to gain further insights into conformational

preferences, derivatives of diamine 29 were screened for

crystallinity. The bis-trifluoroacetamide 30 (Tfa₂O, 81 %)

proved to fulfil this requirement, and crystals of sufficient

quality for X-ray structure analysis were obtained. The crys-

Scheme 5. Synthesis of 2,5-trans-dipyrrolidino-THF 2: a) Ac₂O, NEt₃, cat.

tal structure of compound 30 confirmed the threo-trans-

DMAP, CH₂Cl₂, 08C; b) cat. CSA, CH₂Cl₂/MeOH; c) H₂, cat. Pt/C,

threo configuration of the two lateral pyrrolidines and the

EtOAc; d) 10 equiv MsCl, NEt₃, ꢀ408C; e) 2 equiv MeLi, THF,

central THF ring (Figure 1). Moreover, the compound

ꢀ788C!08C, then 2 equiv KOtBu; f) TMSOTf, 2,6-lutidine, PhSMe,

adopts an ideal C₂-symmetric conformation in the solid state

ꢀ788C!RT, 1 H; then aq. Na₃PO₄(pH 12); g) (CF₃CO)₂O, pyridine,

CH₂Cl₂, ꢀ208C; h) MeOH/conc. HF 10:1.

(coinciding with a crystallographic axis). In comparison with

the tris-pyrrolidine 24, the five-membered rings now do

adopt half-chair conformations, with the substituents point-

ing more in equatorial directions. This is especially apparent

at the central THF ring, where a close to ideal trans-substi-

tuted half chair with two adjacent gauche-configured ring

to the saturated alcohol 27 with Pt/C as the optimal catalyst.

Conversion of 27 into the corresponding mesylate required

a large excess of mesyl chloride (10 equiv) and low tempera-

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Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

amino aldehydes was investigated further.^[2]It has been re-

ported that the use of N-benzyl and N-tosyl groups can lead

to excellent Felkin Anh stereocontrol for additions to a-

amino aldehydes.^[41]The N-benzyl- and N-tosyl-protected

amino aldehyde 35 was accessed from N-tosyl-l-alanine 34

in three straightforward steps (perbenzylation, ester reduc-

tion, Swern oxidation) and was found to be stable and enan-

tiopure after crystallization (Scheme 7). Addition of lithiat-

Figure 1. X-ray crystal structure of 2,5-trans-bispyrrolidino-THF 30.

connections is observed, leading to a helical ladder of rings.

The documentation of this privileged conformation here val-

idates the design principles that had previously guided the

oligo-THF-based ion channels,^{[17,18,20,39]}and should probably

also extend to other oligo-THFs and oligopyrrolidines.

With regard to the terpyrrolidine system, the removal of

the N-Boc groups and the O-silylethers from the fully pro-

tected terpyrrolidine 24 was subsequently achieved as fol-

lows (Scheme 6). Treatment of tris-tBu-carbamate 24 with

Scheme 7. a) BnBr, K₂CO₃, DMF; b) LiAlH₄, THF; c) (COCl)₂, DMSO,

EtN(iPr)₂, CH₂Cl₂, ꢀ658C; d) LiCꢁCTMS, THF, ꢀ788C.

ed TMS acetylene to aldehyde 35 gave the secondary alco-

hol 36 as a single stereoisomer (>95%), which is exception-

ally noteworthy for an alanine derivative, as here methyl

and hydrogen substituents are discriminated by a small ace-

tylide nucleophile. The diastereochemical assignment of 36

was verified by X-ray crystallography (Figure 2). Notably,

Scheme 6. Deprotection of the terpyrrolidine core (!1): a) TMSOTf,

2,6-lutidine, PhSMe, ꢀ788C!RT, 1 h, then aq. Na₃PO₄(pH 12);

b) MeOH/conc. HF 10:1; c) pNSCl, NEt₃, DMAP, CH₂Cl₂; d) TBAF,

THF; e) TFA/CH₂Cl₂1:1; f) PhSH, K₂CO₃, DMF, 358C, 16 h.

Figure 2. Transition state model for additions to aldehyde 35 and X-ray

crystal structure of alcohol 36.

TMSOTf generated the corresponding tris-TMS-carbamate

through O-silylation. After hydrolysis at pH 12 the O-

TBDPS-protected triamine 31 could still be purified by

normal silica gel chromatography. Silyl ether 31 was con-

verted into the fully deprotected target compound 1 by desi-

lylation with methanolic HF. However, attempts to depro-

tect the bis-Boc-protected terpyrrolidine 23 to give the ter-

pyrrolidine 31 were less clean. The sluggish Boc protection

step was therefore circumvented by the introduction of a p-

Ns (p-nitrophenylsulfonyl) group^[40]onto the central pyrroli-

dine nitrogen. After subsequent TBAF-mediated cleavage

of the silyl ethers, the diol 32 was obtained. The two N-Boc

groups in 32 were cleaved with TFA to yield sulfonamide

33, with the UV-active p-Ns group serving as an easily trace-

able purification tag. This was finally removed with PhSH/

the ground-state (product) conformation found for 36 in the

crystal is in qualitative agreement with the transition state

model depicted in Figure 2 and illustrates the role of both

N-protecting groups. Firstly, the electron-withdrawing N-

tosyl group should lower the s_C_ꢀ_N-orbital and hyperconjuga-

tively affect the adjacent p_C=O-LUMO in the Felkin Anh-

type transition state.^[42,43]Secondly, the two N-protecting

groups together effectively block one face of the C=O bond,

favouring the approach of the nucleophile from the least

hindered direction.^[44]Furthermore, the asymmetrically sub-

stituted nitrogen atom with its bulky SO₂group enforces an

anti arrangement of the sulfonamide and methyl substituent,

which can in turn lock the carbonyl oxygen on the methyl

[40]

K₂CO₃to give the triamino-diol 1 in 91% yield. Notably,

ꢀ

deprotection by-products could easily be removed in this

last step by extraction. By this latter route the fully depro-

tected trispyrrolidine 1 was available from 23 in good yield

and excellent purity.

With the synthesis of asymmetrically substituted oligopyr-

rolidines in mind, the influence of the N-protecting groups

on the stereoselective addition of alkynyl nucleophiles to a-

group side, due to mutual repulsion of the C=O and the N

SO₂dipoles.^[41]Presumably all factors cooperatively contrib-

ute to the exceptionally high stereoselectivity observed here.

These findings were successfully integrated into the syn-

thesis of bispyrrolidine 45 (Scheme 8). To this end, the di-

protected aminoaldehyde 35 was allowed to react with the

lithiated alkyne 3, to provide the Felkin Anh product 37 in

Chem. Eur. J. 2004, 10, 3945 3962

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Scheme 8. Synthesis of bispyrrolidine 41: a) nBuLi, 3, THF, ꢀ788C, then 35; b) cat. CSA, THF/MeOH 1:1; c) H₂, cat. Pt/C, MeOH; d) 1 equiv SOCl₂,

NEt₃, CH₂Cl₂, ꢀ108C; e) cat. RuCl₃, NaIO₄, CCl₄/CH₃CN/H₂O, 0 8C; f) TBAN₃, THF, 358C, then pH 2; g) MsCl, NEt₃, CH₂Cl₂, ꢀ208C; h) PBu₃,

CH₃CN; i) Boc₂O, THF/H₂O, pH 10, 608C, 24 h.

high yield as a single stereoisomer. Removal of the TMS

group under acidic conditions gave the propargylic diol 38,

which was hydrogenated to deliver the saturated diol 39.

This was converted into the corresponding cyclic 1,4-sulfate

(39!40!41) to set up pyrrolidine ring formation. En route,

X-ray crystal structure analysis of the 1,4-sulfite confirmed

the stereochemical assignments (see Supporting Informa-

tion). In a search for a substitute for the LiN₃/HMPT ring-

Scheme 9. Ts/Bn removal: a) nBuLi, ꢀ788C; b) TMSCl, RT.

opening conditions used earlier, it was then found that treat-

ment of the cyclic 1,4-sulfate 41 with anhydrous tetrabutyl-

ammonium azide in THF would give clean results. Under

optimized conditions a mixture of the azido alcohol 42 to-

gether with its regioisomer was obtained in 78 90% com-

bined yield. The stereo- and regioconvergent ring-closure of

the second pyrrolidine ring was then initiated by conversion

of both regioisomers of 42 into the corresponding mesylates.

The azido mesylates were found to cyclize spontaneously to

the bispyrrolidine 43 under Staudinger conditions^[45]with

PBu₃in acetonitrile. In contrast with the reductive process

described earlier, no evidence of a free aminomesylate

could be found, which could indicate an alternative reaction

pathway. Finally, compound 43 was transformed into the bis-

N-Boc-protected bispyrrolidine 44, although forcing condi-

tions were again necessary to overcome steric hindrance.

The cleavage of the N-benzyl and N-tosyl groups from

bispyrrolidine 44 proved somewhat troublesome under stan-

dard conditions. First attempts to cleave the N-tosyl group

with Na/NH₃resulted in complex mixtures, whereas treat-

ment with Na/Hg^[46]left the substrate unaffected. Attempts

at reductive (Pd black, 10 atm H₂) or oxidative (KOtBu/O₂

or RuO₄) cleavage of the N-benzyl group failed. Finally,

benzylic metallation was found to be the method of choice.

Whereas use of LiNEt₂at ꢀ788C selectively metallated the

Ts-Me group (65% yield in a model system, see Supporting

Information) and that of LDA led to complex mixtures, the

concomitant removal of both protecting groups was cleanly

achieved by treatment of 44 with BuLi in THF followed by

TMSCl (Scheme 9). The moderate yield can probably be at-

tributed to product isolation problems. No TMS-containing

side products were found, indicating a fast fragmentation of

the metallated species. Presumably benzylic metallation by

BuLi triggers b-elimination of sulfinate^[47]from 44 to afford

the corresponding imine as intended,³and this is subse-

quently cleaved by hydrolysis to provide the target amine

45. This route has not only established optimized procedures

for oligopyrrolidine synthesis, but should also generally

allow the incorporation of amino acid side chains into asym-

metric oligopyrrolidines for artificial anion channels.

Beginning to study the potential of oligopyrrolidines for

interactions with oligonucleotides, we turned our attention

to RNA. RNA is fairly susceptible towards base-induced

fragmentation reactions, and this has been explored in the

51]

design of artificial nucleases.^[48

Interestingly, it had been

reported that simple diamines can induce ssRNA strand

breaks, which triggered our interest.^[52,53]However, the con-

ditions used in kinetics experiments (up to 1m compound)^[53]

proved impractical for a preliminary screening in our case.

Accordingly, assay conditions allowing comparison of the

ssRNA cleavage activities of the oligopyrrolidines 1, 2 and

33 with those of several simple di-, tri- and tetraamines were

found (see Supporting Information); some of these had also

been covered in work by Komiyama.^[53]Under dilute single-

turnover conditions (1 5m m compound, 200 nm ssRNA,

2 mm EDTA, 50 mm TRIS, pH 8.0, 508C), simple diamines

barely showed any detectable cleavage activity above back-

ground. Terpyrrolidine 1 was weakly active, comparable to

spermine. The latter compound had earlier been suspected

to induce RNA strand breaks nonspecifically under certain

conditions.^[54]Tetraazacrown 12C4 gave rise to more cleav-

age products, which is in qualitative agreement with experi-

3

Non-chelating imines are fairly inert towards alkyllithium reagents at

low temperature. This most likely course of events is also corroborated

by model experiments (see Supporting Information).

3950

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Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

ments reported by Kalesse.^[50]Most interestingly, the pyrroli-

dino-THF 2 and especially the terpyrrolidine sulfonamide

33 furnished even higher levels of cleavage products in com-

parison.

These findings were investigated in more detail by com-

parison of compound 33 with the hairpin ribozyme

(Figure 3). The hairpin ribozyme is a self-cleaving endonu-

when the single-stranded RNA substrate was treated with

terpyrrolidone 33 in the absence of the ribozyme strand.

The preference for cleavage by pyrrolidine 33 at the 3-

and 4-positions is not clear at this point. The previous obser-

vations of polyamines influencing the catalytic properties of

hairpin ribozymes^[54,59,60]might suggest synergistic interac-

tions between compound 33 and the ribozyme. However,

polyamine-supported hairpin ribozyme catalysis as described

in the literature proceeds with the same specificity as ob-

served for the hairpin ribozyme in the presence of magnesi-

um ions alone, with only the 5-mer cleavage product being

obtained.^[54,59]Even though it cannot be completely ruled

out at this point that 33 interacts with the ribozyme and as a

result changes the active conformation of the ribozyme as

well as its specificity, production of the tri- and tetramers is

more likely to result from direct degradation of the sub-

strate induced by 33 in a dose-dependent manner. This inter-

pretation gains strong support from the observation that

cleavage also occurred in the absence of ribozyme and that

the cleavage rate was dependent on the concentration of the

terpyrrolidine. This strongly suggests that the cleavage reac-

tion was specifically caused by 33.

clease/self-joining ligase derived from the tobacco ringspot

58]

virus satellite RNA.^[55

Its 50 bp minimal sequence will

catalyse the reversible selective cleavage of a suitable 14-

mer RNA substrate between the 5- and 6-positions (Fig-

ure 3). Ribozyme activity is dependent on the presence of

positively charged cofactors, typically magnesium ions, in mm

concentrations. However, aminoglycosides or polyamines

such as spermine have also been shown to support hair-

[54,59]

pin ribozyme cleavage, even in the absence of Mg²⁺

.

In the presence of both Mg²⁺(10 mm) and the terpyrroli-

dine 33 (2 mm), three major cleavage products were ob-

served (Figure 3a d). In particular, tri-, tetra- and 5-mers

were produced. While the 5-mers are expected results of the

hairpin ribozyme cleavage reaction, the tri- and tetramers

appeared as new additional products. In the absence of

Mg²⁺, only the tri- and tetramer cleavage products were ob-

served (Figure 3e h), implying that their formation is direct-

ly linked to compound 33. In this experiment the concentra-

tion of 33 was doubled, resulting in a higher rate of tri- and

tetramer formation. Strikingly, cleavage rates at 4 mm con-

centration of compound 33 or 10 mm MgCl₂are virtually the

same (ꢂ0.1 min^ꢀ1; for overall conditions refer to Experi-

mental Section). A similar cleavage pattern was observed

It had previously been shown that the chemical stability

of phosphodiester bonds of some oligoribonucleotides in the

presence of a cofactor such as polyvinylpyrolidine is se-

quence-dependent.^[67]Chemical stability of phosphodiester

bonds seems to be ™coded∫ in such a way that structural

properties such as the degree of base stacking may be re-

sponsible for the stability/instability of certain phosphodiest-

er bonds. The tri- and tetramers obtained in the presence of

Figure 3. Secondary structure of the hairpin ribozyme with its substrate (left). The solid line arrow denotes the site of cleavage by the ribozyme, dotted

line arrows mark the sites of cleavage induced by terpyrrolidine 33. The substrate RNA carries a fluorescein label at the 5’-end. ALF-recorded traces of

RNA cleavage reactions (right; for details see Experimental Section). a) d) Competition experiment: 10 nm ribozyme, 200 nm substrate, 2 mm 33, 10 mm

MgCl₂, 5 0 mm TRIS-HCl (pH 7.5), 378C; a) 5min, b) 10 min, c) 20 min, d) 35min; e) h) conditions as in a) d), except 0 m m MgCl₂(ribozyme deactivat-

ed), 2 mm EDTA and 4 mm 33; e) 5min, f) 10 min, g) 20 min, h) 35min. Peaks marked 3, 4, 5and 13 refer to 3-, 4-, 5-mer products, respectively. The

peak denoted ™X∫ is not a RNA-oligomer but a UV-active substance, most probably compound 33 or a product thereof. The apparent peak splitting for

the short oligomers is probably due to stereoisomers in the fluorescent label, as described earlier,^[60]or to degradation of the initially formed 2’,3’-cyclic

phosphoric acid diester to 2’- or 3’-phosphoric acid monoester.

Chem. Eur. J. 2004, 10, 3945 3962

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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3951

S. M¸ller, U. Koert et al.

FULL PAPER

procedures. PE: light petroleum, boiling range 40 608C; MTBE: methyl

tert-butyl ether. Thin-layer chromatography (TLC) was performed on

glass-supported Merck silica gel plates (60 F₂₅₄). Spots were viewed under

UV light and by heat staining with 2% molybdophosphoric acid in etha-

nol. Flash column chromatography (FCC) was performed on Merck silica

gel 60 (40 63 mm). Melting points were determined from pulverized ma-

terial in glass capillaries and are uncorrected. ¹H and ¹³C NMR spectra

were obtained on Bruker DPX 300 or AMX 600 spectrometers, respec-

tively. All resonances are referenced to residual solvent signals.^[65]IR:

Perkin Elmer FT-IR Spektrum 1600 or BioRad FT-IR 3000 MX. Optical

rotations: Perkin Elmer spectrophotopolarimeter 241, cuvette path

length 10 cm. CHCl₃for spectroscopy was filtered over basic aluminium

oxide before use. MS: Finnigan MAT 95(EI: 70 eV; FAB) or MSI Con-

cept 1H (ESI). Elemental analyses: Leco CHNS 932 Analysator (micro-

analytical facility, HU Berlin).

compound 33 might therefore reflect preferential hydrolysis

of phosphodiester bonds at particularly sensitive sites. Alter-

natively, inherent compound selectivity may account for the

observed cleavage products. In either case, compound 33 is

a promising lead structure for further functional design. It

has been demonstrated to induce RNA cleavage to a consid-

erable extent. CA-rich sequences seem to be most suscepti-

ble for terpyrrolidone-induced cleavage, suggesting that 33

may be capable of evolution into a tailored small molecular

tool for selective RNA hydrolysis.

Conclusion

(S)-2-(tert-Butyldiphenylsilyloxy)methyl-pyrrolidin-5-one (6): Pyroglu-

tamic acid 5 (33.6 g, 260 mmol) was suspended in anhydrous MeOH

(65mL), and 2,2-dimethoxypropane (65mL, 0.53 mol, 2 equiv) and conc.

HCl (0.54 mL, 6.5 mmol, 2.5 mol%) were added. The mixture was

warmed to 508C with stirring to give a clear solution. After 6 h the mix-

ture was cooled to 58C and neutralized with sat. NaHCO₃solution

(approx. 5mL). The volatiles were evaporated, and the residue was dis-

solved in EtOAc (200+50 mL) and filtered over a pad of Celite. The fil-

trate was concentrated, coevaporated with toluene (2î100 mL) and

dried to give crude pyroglutamic acid methyl ester 46 (35.5 g, 0.248 mol,

95%), which was used directly for the next step. R_f= 0.39 in EtOAc/

MeOH 8:1.

In summary, conformationally restricted polyamines are

promising candidates for RNA-targeting ™shaped∫ polycat-

ions and may become building blocks for artificial anion

channels as well. Here we have detailed the stereoselective

synthesis of 2,5’-threo-trans-configured bis- and terpyrroli-

dines, which have been stereochemically assigned and inves-

tigated by X-ray crystallography. Most importantly, a gener-

al preference for helical conformers was found in the solid

state, and for the pyrrolidino-THF-pyrrolidine 30 a perfectly

helical arrangement was discovered, confirming model cal-

culations made earlier for similar systems.^[17]The optimized

synthesis was based on diastereoselective additions of al-

kynes to pyrrolidinecarboxaldehydes, where Felkin Anh

control proved rather difficult to establish. Ligand-accelerat-

ed chelation control was found to be operative under Car-

reira×s Zn(OTf)₂/N-methylephedrine conditions,^[33]which in

turn allowed completely anti-Felkin Anh selective addition.

On the other hand, perfect Felkin Anh selectivity was ach-

ieved with Ts/Bn protection, which was then utilized for the

synthesis of an asymmetric bispyrrolidine. Various amino

acid side chains may thus be integrated into the skeleton,

paving the way for oligopyrrolidine amino acids in the

future.

In incubation experiments with RNA at physiologically

relevant temperature (378C) and pH (7.5 8), oligopyrroli-

dine sulfonamide 33 was found to induce RNA cleavage

with surprising potency in relation to simple di- and polya-

mines or terpyrrolidine 1. In comparison with the evolutio-

narily tailored hairpin ribozyme, its activity is still about 10⁵

times lower. However, in view of the small-molecule nature

and singularity of terpyrrolidine 33, a very promising lead

has been found and is likely to evolve in further studies. The

synthetic groundwork presented here should allow an ap-

proach to this goal.

A 1 L three-necked, round-bottomed flask fitted with a mechanical over-

head stirrer was charged with THF/MeOH 3:2 (200 mL), the system was

cooled to ꢀ108C (internal), and NaBH₄(8.2 g, 0.22 mol, 1.1 equiv) was

added. A solution of crude ester 46 (28.6 g, 200 mmol) in THF (75mL)

was added dropwise, while the flask temperature was kept below 58C.

After the addition was complete, the mixture was stirred for 1 h (TLC

monitoring, R_f= 0.12 in EtOAc/MeOH 8:1). Occasionally, more NaBH₄

(1 2 g) had to be added to complete conversion. Conc. HCl (30 mL) was

then added dropwise (Caution!) to the stirred, ice-cooled mixture, until

the gas evolution had ceased and the pH had reached 2. The mixture was

warmed to RT and stirred for 3 h, neutralized with solid NaHCO₃

(approx. 20 g), stirred for 30 min and diluted with MTBE (100 mL).

MgSO₄(15g) was added, and the solids were removed by filtration over

a pad of Celite. The filtrate was concentrated and coevaporated with tol-

uene (2î100 mL) to give crude pyroglutaminol 47 (23.0 g, 200 mmol,

quant.) as a colourless solid.

Crude alcohol 47 (23.0 g, 200 mmol) was dissolved in DMF (200 mL), the

mixture was cooled to 08C, and imidazole (15.3 g, 220 mmol, 1.1 equiv)

was added, followed by TBDPSCl (23 mL, 220 mmol, 1.1 equiv). The

mixture was stirred for 3 h at RT. The solvents were removed, and the

residue was partitioned between MTBE (200 mL) and water (100 mL).

The aqueous layer was extracted with MTBE (3î75mL), and the com-

bined extracts were washed with brine (100 mL), dried with MgSO₄and

concentrated. FCC (900 g, MTBE!MTBE/acetone 4:1!2:1) of the resi-

due gave TBDPS-ether 6 (66.0 g, 187 mmol, 93%) as a sticky gum, which

crystallized from PE/MTBE 10:1 in colourless blocks. R_f= 0.25(MTBE/

acetone 4:1); m.p. 77.5 788C; [a]²_D⁰= 15.4 (c = 0.825in CHCl ₃); ¹H

NMR (300 MHz, CDCl₃): d = 1.05(s, 9H; tBu), 1.69 1.80 (m, 1H; 3-

H_2A), 2.14 (dt, J = 12.9/7.8 Hz, 1H; 3-H_2B), 2.27 2.34 (m, 2H; 4-H₂), 3.52

(dd, J = 10.3, 7.2 Hz, 1H; 1’-H_2A), 3.62 (dd, J = 10.3, 4.2 Hz, 1H; 1’-

H_2B), 3.80 (m, 1H; 2-H), 6.22 (s, 1H; NH), 7.32 7.43 (m, 6H; arom.),

7.63 (d, J = 7.5Hz, 4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

19.1 (Si-C(CH₃)₃), 22.7 (C-3), 26.7 (Si-C(CH₃)₃), 29.7 (C-4), 55.6 (C-2),

67.3 (C-1’), 127.8, 129.8, 132.9, 135.5 (arom.), 178.0 (C-5) ppm; IR (KBr):

ꢀ

Experimental Section

n˜ = 3196 (N H), 3069, 2929, 2855, 1691 (C=O), 1586, 1472, 1460, 1426,

1391, 1336, 1298, 1238, 1162, 1109, 1034, 996, 951, 870, 824, 793, 745, 706,

639, 616 cm^ꢀ1; elemental analysis calcd (%) for C₂₁H₂₇NO₂Si (353.54): C

71.34, H 7.70, N 3.96; found: C 71.09, H 7.58, N 4.02.

General: All reactions sensitive to air or moisture were conducted in

flame-dried glassware under an atmosphere of dry Argon. THF and Et₂O

were distilled from purple sodium/benzophenone. CH₂Cl₂, toluene, hex-

anes, pyridine and Et₃N were distilled under Ar from CaH₂. MeOH was

distilled from Mg(OMe)₂. Organolithium and amide base solutions were

titrated against diphenylacetic acid.^[61]All starting materials and reagents

were used as received unless noted otherwise. Lithium azide,^[62]tetrabuty-

lammonium azide^[63]and N-tosylalanine^[64]were prepared by literature

(S)-N-tert-Butoxycarbonyl-2-(tert-butyldiphenylsilyloxy)methyl-pyrroli-

din-5-one (7): A solution of amide 6 (16.5g, 46.7 mmol) in CH ₂Cl₂

(80 mL) was cooled to 08C, and pyridine (5mL) and DMAP (1.12 g,

9.34 mmol, 0.2 equiv) were added, followed by Boc₂O (10.2 g, 46.8 mmol,

1.0 equiv). The mixture was stirred at 08C with continuous gas evolution.

After 3 h more Boc₂O (3.0 g, 13.7 mmol, 0.3 equiv) was introduced, and

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Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

the mixture was stirred overnight at RT. Sat. NH₄Cl solution was added

(75mL), and the well stirred mixture was acidified with 2 n HCl to pH 4

(Caution!). The layers were separated, and the aqueous layer was ex-

tracted with MTBE (3î75mL). The combined organic layers were

washed with H₃PO₄(0.1m), H₂O, and brine (100 mL each), dried with

MgSO₄, concentrated and coevaporated with toluene (100 mL). Crystalli-

zation from hot PE/MTBE 20:1 (5mLg ^ꢀ1) gave Boc-protected amide 7

10 min, TMSOTf (0.10 mL, 0.33 mmol, 1 mol%) was added dropwise and

the system was stirred for 3 min (TLC monitoring). Sat. NaHCO₃

(10 mL) and H₂O (60 mL) were added, and the biphasic mixture was vig-

orously stirred for 15min. The layers were separated and the aqueous

layer was extracted with MTBE (2î50 mL). The organic layers were

combined, washed with brine (50 mL), dried (MgSO₄) and concentrated.

FCC (200 g, PE/MTBE 5:1!3:1) provided trans-nitrile

9 (10.7 g,

23.0 mmol, 72%) as a colourless gum, followed by cis-nitrile 10 (3.41 g,

7.34 mmol, 23%) as a colourless solid, which was crystallized from PE at

ꢀ208C.

(19.7 g, 43.3 mmol, 93%) as colourless prisms. R_f

= 0.33 (MTBE/PE

1:1); m.p. 1108C; [a]²_D⁰1.30 in CHCl₃); ¹H NMR

=

ꢀ38.4 (c

=

(300 MHz, CDCl₃): d = 1.04 (s, 9H; Si-tBu), 1.42 (s, 9H; Boc), 2.05 2.12

(m, 2H; 3-H₂), 2.41 (ddd, J = 18/8/4 Hz, 1H; 4-H₂), 2.78 (dt, J = 18/

11 Hz, 1H; 4-H₂), 3.59 (dd, J = 10.4/2.4 Hz, 1H; 1’-H_2A), 3.88 (dd, J =

10.4/4.2 Hz, 1H; 1’-H_2B), 4.20 (m, 1H; 2-H), 7.35 7.45 (m, 6H; arom.),

7.57 7.65 (m, 4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.1

(Si-C(CH₃)₃), 21.1 (C-3), 26.8 (Si-C(CH₃)₃), 28.0 (O-C(CH₃)₃), 32.3 (C-4),

58.7 (C-2), 64.9 (C-1’), 82.6 (O-C(CH₃)₃), 127.8, 129.8, 132.6, 133.0, 135.5

(arom.), 149.8 (Boc-C=O), 174.9 (C-5) ppm; IR (KBr): n˜ = 3070, 3050,

3030, 2985, 2975, 2954, 2949, 2931, 1748 (-CO-NR₂), 1705(Boc-C =O),

1580, 1472, 1464, 1432, 1410, 1365, 1310, 1276, 1258, 1156, 1112, 1077,

1034, 999, 896, 860, 821, 742, 706, 620, 597 cm^ꢀ1; elemental analysis calcd

(%) for C₂₆H₃₅NO₄Si (453.66): C 68.84, H 7.78, N 3.09; found: C 69.03, H

7.63, N 3.17.

Compound 9: R_f= 0.37 (PE/MTBE 4:1); [a]²_D⁰= ꢀ39.4 (c = 0.900 in

1

CHCl₃); H NMR (300 MHz, CDCl₃, 9:11 mixture of rotamers): d = 1.05

(s, 9H; Si-tBu), 1.34/1.53 (each s, 44:56, 9H; Boc), 2.10 2.55 (m, 4H; 3-

H₂, 4-H₂), 3.58/3.87 (each dd, J = 10.3, 4.7 Hz, 0.88H; 1’-H_2A), 3.67 (dd,

J = 10.1, 2.7 Hz, 1.12H; 1’-H_2B), 3.91/4.05(each brm, 44:56, 1H; 2-H),

4.46/4.52 (each d, J = 8.1 Hz, 1H; 5-H), 7.30 7.45 (m, 6H; arom.), 7.55

7.65(m, 4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.0 (Si-

C(CH₃)₃), 26.9 (Si-C(CH₃)₃), 26.9 (C-3), 28.1 (O-C(CH₃)₃), 29.8 (C-4),

48.2 (C-5), 58.3 (C-2), 63.9/64.0 (C-1’), 81.1/81.3 (O-C(CH₃)₃), 119.1/119.4

(-CN), 127.6, 129.5, 133.8, 135.2 (arom.). 153.1/153.7 (Boc-C=O) ppm; IR

(film): n˜ = 3072, 3050, 2962, 2932, 2859, 2244 (CꢁN), 1706 (C=O), 1590,

1474, 1428, 1376, 1338, 1256, 1169, 1113, 1083, 1045, 983, 920, 846, 823,

775, 742, 703, 610 cm^ꢀ1; elemental analysis calcd (%) for C₂₇H₃₆N₂O₃Si

(464.68): C 69.79, H 7.81, N 6.03; found: C 69.90, H 7.78, N 6.07.

(2S,5S)- and (2S,5R)-N-tert-Butoxycarbonyl-2-(tert-butyldiphenylsilyloxy)-

methyl-5-methoxy-pyrrolidine (8a and 8b): A solution of amide 7 (25.7 g,

56.6 mmol) in CH₂Cl₂/MeOH 3:1 (650 mL) was cooled to ꢀ108C, and

NaBH₄(6.3 g, 170 mmol, 3 equiv) was added in one portion. The stirred

solution became clear within minutes, and was allowed to warm to 08C

over 2 h. After the starting material was consumed (product R_f= 0.43 in

MTBE/PE 1:1), sat. NaHCO₃(200 mL) and H₂O (100 mL) were added,

and the ice-cooled mixture was stirred until the gas evolution ceased

(2 h). The layers were separated, the aqueous layer was extracted with

CH₂Cl₂(2î150 mL), and the combined organic layers were washed with

brine (100 mL), dried with Na₂SO₄and carefully concentrated to approx.

70 mL.

Compound 10: R_f= 0.17 (PE/MTBE 4:1); m.p. 60.5 618C (PE); [a]_D²⁰

=

+22.3 (c = 1.33 in CHCl₃); ¹H NMR (300 MHz, CDCl₃, 2:3 mixture of

rotamers): d = 1.07 (s, 9H; Si-tBu), 1.34/1.51 (each s, 42:58, 9H; Boc),

1.97 2.37 (m, 4H; 3-H₂, 4-H₂), 3.60 4.02 (m, 3H; 1’-H₂, 2-H), 4.40/4.57

(each brm, 58:42, 1H; 5-H), 7.37 7.47 (m, 6H; arom.), 7.55 7.65 (m, 4H;

arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.2 (Si-C(CH₃)₃), 24.4/

24.6 (C-3), 26.9 (Si-C(CH₃)₃), 28.2 (O-C(CH₃)₃), 29.6/30.3 (C-4), 49.5(C-

5), 59.4 (C-2), 64.1/64.9 (C-1’), 81.4/81.6 (O-C(CH₃)₃), 119.5(-CN), 127.7,

129.7, 133.2/133.3, 135.6 (arom.) ppm, C=O of Boc not detected; IR

(film): n˜ = 3073, 2956, 2932, 2886, 2857, 2238 (CꢁN), 1702 (C=O), 1473,

1429, 1391, 1347, 1260, 1166, 1112, 1048, 988, 868, 823, 775, 742, 704,

2,2-Dimethoxypropane (25mL, 0.20 mol, 3.6 equiv) was now added at

08C, followed by CSA (130 mg, 0.56 mmol, 1 mol%). After conversion of

the starting material (15min) sat. NaHCO ₃solution was added (15mL),

and the mixture was washed with H₂O (50 mL). The aqueous layer was

extracted with MTBE (2î50 mL), and the organic layers were combined,

washed with brine (50 mL), dried (Na₂SO₄) and concentrated. FCC

(300 g, PE/MTBE 85:15) gave methyl aminals 8a and 8b (24.6 g,

52.6 mmol, 93%) as a 5:2 diastereomeric mixture, which was separated

for analytical purposes only. Elemental analysis calcd (%) for

C₂₇H₃₉NO₄Si (469.70): C 69.04, H 8.37, N 2.98; found: C 68.89, H 8.52, N

2.87.

616 cm^ꢀ1

.

Epimerization of the cis-nitrile (10): Compound 10 (4.89 g, 10.5mmol) in

toluene (40 mL) was stirred at 08C with tBuOH (1 mL) and KOtBu

(0.24 g, 2.1 mmol, 0.2 equiv) for 90 min. The mixture was washed with

sat. NH₄Cl (50 mL) containing HCl (2n, 1 mL), the aqueous layer was

extracted with MTBE (2î30 mL), and the combined organic layers were

washed with brine (50 mL), dried (MgSO₄) and evaporated. FCC (60 g)

gave 9 (2.65g, 54%) and 10 (2.05g, 43%), identical to the substances de-

scribed before.

(2S,5S)-N-tert-Butoxycarbonyl-2-(tert-butyldiphenylsilyloxy)methyl-pyr-

rolidine-5-carbaldehyde (4): Nitrile 9 (6.97 g, 15.0 mmol) was dissolved in

toluene/PE 3:1 (90 mL), and the mixture was cooled to ꢀ708C (internal).

DIBAH (1m in hexanes, 21 mL, 21 mmol, 1.4 equiv) was added dropwise

while the internal temperature was kept under ꢀ608C. The mixture was

stirred until the conversion was complete (1 h). Meanwhile, a mixture of

sat. NH₄Cl (200 mL) and Rochelle salt solution (1m, 60 mL) was adjusted

to pH 6.5with solid tartaric acid (approx. 1 g). MTBE (05 mL) was

added, and the stirred suspension was cooled to 08C, degassed and satu-

rated with Ar. The reaction mixture was then transferred slowly by can-

nula into the stirred buffer solution. This biphasic mixture was vigorously

stirred until all solids were dissolved (3 h, pH 7.0). The layers were sepa-

rated, and the aqueous layer was extracted with MTBE (2î100 mL). The

combined organic layers were washed with brine (100 mL), dried

(Na₂SO₄) and concentrated. FCC (100 g, PE/MTBE 3:1) and crystalliza-

tion (hexanes, ꢀ158C) provided aldehyde 4 (4.61 g, 9.86 mmol, 66%) as

colourless prisms. R_f= 0.18 (PE/MTBE 4:1); m.p. 708C; [a]²_D⁰= ꢀ60.1

Compound 8a: R_f= 0.36 (PE/MTBE 6:1); m.p. 57 598C; [a]²_D⁰= ꢀ35.8

1

(c = 0.702 in CHCl₃); H NMR (300 MHz, CDCl₃, 2:1 mixture of rotam-

ers): d = 1.05(s, 9H; Si- tBu), 1.35/1.45 (each s, 2:1, 9H; Boc), 1.70 1.85

(m, 1H; 3-H_2A), 1.87 1.95(m, 1H; 3-H _2B), 2.10 2.25(brm, 2H; 4-H ₂),

3.26 (s, 3H; -OMe), 3.45 3.75 (brm, 1H; 1’-H_2A), 3.80 4.00 (m, 2H; 1’-

H

_2B, 2-H), 5.18 (brm, 1H; 5-H), 7.34 7.43 (m, 6H; arom.), 7.65 7.70 (m,

4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.3 (Si-C(CH₃)₃),

26.9 (Si-C(CH₃)₃), 27.4 (C-3), 28.0 (O-C(CH₃)₃), 32.2 (C-4), 55.1 (-OMe),

59.2 (C-2), 67 (b, C-1’), 79.9 (O-C(CH₃)₃), 89.7 (C-5), 127.6, 129.5, 133.8,

135.5 (arom.); C=O of Boc not detected.

Compound 8b: R_f= 0.28 (PE/MTBE 6:1); ¹H NMR (300 MHz, CDCl₃,

11:9 mixture of rotamers): d = 1.06 (s, 9H; Si-tBu), 1.28/1.47 (each s,

56:44, 9H; Boc), 1.71 1.86 (m, 1H; 3-H_2A), 1.87 2.00 (m, 1H; 3-H_2B),

2.02 2.20 (brm, 2H; 4-H₂), 3.32/3.37 (each s, 55:45, 3H; -OMe), 3.48 (m,

2H; 1’-H_2A), 3.70 (m, 2H; 1’-H_2B), 3.82 4.03 (m, 1H; 2-H), 4.93/5.05

(each d, J = 4.1/4.4 Hz, 1H; 5-H), 7.34 7.43 (m, 6H; arom.), 7.58 7.65

1

(c = 1.14 in CHCl₃); H NMR (300 MHz, CDCl₃, 9:11 mixture of rotam-

(m, 4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃):

d = 19.2 (Si-

ers): d = 1.06 (s, 9H; Si-tBu), 1.34/1.43 (each s, 45:55, 9H; Boc), 1.88

2.18 (m, 3H; 3-H₂, 4-H_2A), 2.20 2.40 (m, 1H; 4-H_2B), 3.59 (dd, J = 16.8,

6.4 Hz, 0.55H; 1’-H_2A), 3.66 (m, 0.9H; 1’-H₂), 3.87 (dd, J = 16.8, 4.5Hz,

0.55H; 1’-H_2B), 4.04/4.15 (each m, 45:55, 1H; 2-H), 4.18/4.30 (each m,

1H; 5-H), 7.36 7.46 (m, 6H; arom.), 7.61 7.65 (m, 4H; arom.), 9.53/9.60

C(CH₃)₃), 24.6/24.4 (C-3), 26.9 (Si-C(CH₃)₃), 27.7/27.9 (O-C(CH₃)₃), 29.2/

30.5 (C-4), 55.7/56.5 (-OMe), 58.2 (C-2), 63.8/63.9 (C-1’), 79.6/79.8 (O-

C(CH₃)₃), 89.9/90.3 (C-5), 127.7, 129.7, 133.2, 135.5 (arom.), 153.5/153.9

(Boc-C=O).

(each d, 55:45,

J =

2.6 Hz, 1H; -CHO) ppm; ¹³C NMR (75MHz,

(2S,5S)- and (2S,5R)-N-tert-Butoxycarbonyl-2-(tert-butyldiphenylsilyloxy)-

methyl-5-cyano-pyrrolidine (9 and 10): Aminal 8 (5:2 diastereomeric mix-

ture, 15.0 g, 32.0 mmol) in CH₂Cl₂(100 mL) was cooled to ꢀ358C, and

TMSCN (5.0 mL, 40 mmol, 1.25 equiv) was added with stirring. After

CDCl₃): d = 19.2 (Si-C(CH₃)₃), 25.0 (C-3), 26.9 (Si-C(CH₃)₃), 27.1 (C-4),

28.3 (O-C(CH₃)₃), 59.2/59.4 (C-2), 63.9/64.3 (C-1’), 65.7/66.0 (C-5), 80.8/

80.9 (O-C(CH₃)₃), 127.7, 129.7/129.8, 132.4/133.5, 135.5 (arom.), 153.4/

Chem. Eur. J. 2004, 10, 3945 3962

www.chemeurj.org

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3953

S. M¸ller, U. Koert et al.

FULL PAPER

154.3 (Boc-C=O), 200.6 (-CHO) ppm; IR (KBr): n˜ = 3075, 3055, 2980,

2958, 2929, 2907, 2864, 2808, 1738 (-HC=O), 1697 (Boc-C=O), 1590,

1471, 1428, 1386, 1374, 1176, 1114, 1092, 1061, 1036, 1007, 998, 851, 823,

; elemental analysis calcd (%) for

C₂₇H₃₇NO₄Si (467.68): C 69.34, H 7.97, N 2.99; found C 69.09, H 7.78, N

3.09.

CDCl₃): d = 19.2 (Si-C(CH₃)₃), 26.5(C-4), 26.8 (Si-C( CH₃)₃), 27.9 (C-3),

28.3 (O-C(CH₃)₃, C-4), 60.9 (C-5), 64.3 (C-2, C-1’’), 68.0 (C-1’), 73.5(C-

3’), 80.8 (O-C(CH₃)₃), 83.0 (C-2’), 127.7, 129.7, 133.2, 133.3, 135.5

(arom.), 156.7 (Boc-C=O) ppm; HRMS (EI): m/z: calcd for

C₂₇H₃₈NO₄Si: 468.2570; found: 468.2568 [MꢀC₂H]⁺; elemental analysis

calcd (%) for C₂₉H₃₉NO₄Si (493.72): C 70.55, H 7.96, N 2.84; found C

70.12, H 8.00, N 2.82.

774, 744, 709, 704, 614 cm^ꢀ1

(2S,5S,1’R)- and (2S,5S,1’S)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenyl-

silyloxy)methyl-2-(1’-hydroxy-3’-trimethylsilyl)-prop-2’-ynyl-pyrrolidine

(14 and 48): CeCl₃¥7H₂O (8.8 g, 23.6 mmol, 1.5equiv) was cautiously de-

hydrated under high vacuum (0.01 mbar, 1 h at 808C, 1 h at 1008C, 3 h at

1508C). The resulting fine powder was covered with Ar, cooled to RT,

and suspended in THF (100 mL). The suspension was cooled to ꢀ608C,

and a precooled (ꢀ708C) solution of TMS-ethynyl-lithium (freshly pre-

pared, 23.6 mmol, 1.5equiv) in THF (40 mL) was added by cannula over

5min, giving a yellow suspension. The mixture was stirred for 30 min and

cooled to ꢀ808C, and a solution of aldehyde 4 (7.36 g, 15.7 mmol) in

THF (50 mL) was added dropwise over 10 min. After the addition was

complete, the mixture was stirred for 10 min and poured into an ice-

cooled mixture of MTBE (200 mL) and H₂O (200 mL). After stirring for

30 min, the mixture was filtered over a pad of Celite. The layers were

separated, and the aqueous layer was extracted with MTBE (3î50 mL).

The organic layers were combined, washed with brine (200 mL) and con-

centrated. FCC (800 g, PE/MTBE 5:1!7:2!3:1) provided (1’R)-alcohol

14 (4.56 g, 8.06 mmol, 51%) followed by (1’S)-alcohol 48 (3.72 g,

6.57 mmol, 42%), each as a colourless gum.

Compound 14: R_f= 0.35( n-hexane/MTBE 10:3); ¹H NMR (300 MHz,

CDCl₃): d = 0.16 (s, 9H; TMS), 1.03 (s, 9H; Si-tBu), 1.33 (s, 9H; Boc),

1.76 (m, 1H; 4-H_2A), 1.97 (m, 1H; 3-H_2A), 2.32 (m, 2H; 3-, 4-H_2B), 3.61

(dd, J = 9.8, 6.4 Hz, 1H; 1’’-H_2A), 3.69 (dd, J = 9.8, 3.1 Hz, 1H; 1’’-H_2B),

3.96 (m, 1H; 5-H), 4.14 (d, J = 8.5Hz, 1H; 2-H), 4.40 (dd, J = 9.5,

1.0 Hz, 1H; 1’-H), 5.97 (d, J = 9.5Hz, 1H; -OH), 7.32 7.45 (m, 6H;

arom.), 7.60 7.66 (m, 4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

ꢀ0.4 (Si-CH₃), 19.0 (Si-C(CH₃)₃), 26.2 (C-4), 26.6 (Si-C(CH₃)₃), 28.1 (O-

C(CH₃)₃, C-3), 60.7 (C-5), 64.1, 64.5 (C-1’’ and C-2), 68.8 (C-1’), 80.4 (O-

C(CH₃)₃), 89.9 (C-2’), 104.9 (C-3’), 127.6, 129.5, 133.2, 133.3, 135.3

(arom.), 156.6 (Boc-C=O) ppm; IR (film): n˜ = 3369 (-OH), 3072, 3051,

2961, 2932, 2898, 2859, 2172 (CꢁC), 1694, 1668, 1473, 1403, 1251, 1174,

1113, 1056, 1010, 978, 844, 760, 741, 702, 614 cm^ꢀ1; elemental analysis

calcd (%) for C₃₂H₄₇NO₄Si₂(565.90): C 67.92, H 8.37, N 2.48; found C

68.07, H 8.58, N 2.51.

(2S,5S,1’R)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsilyloxy)methyl-

2-[1’-(trimethylsilyl)oxy]-prop-2’-ynyl-pyrrolidine (3): Alcohol 15 (4.00 g,

8.3 mmol) was dissolved in CH₂Cl₂(50 mL), and the system was cooled

to 08C. 1-Trimethylsilyl-imidazole (3.92 mL, 26.8 mmol, 3.2 equiv) and

imidazole (68 mg, 1 mmol, 0.1 equiv) were added, and the mixture was

stirred for 30 min. Sat. NH₄HCO₃(100 mL) was added, the mixture was

stirred for 10 min, and the layers were separated. The aqueous layer was

extracted with MTBE (2î50 mL), and the combined organic layers were

washed with brine (50 mL), dried (Na₂SO₄) and concentrated. FCC

(100 g, PE/MTBE 15:1!9:1) gave TMS ether 3 (4.57 g, 8.08 mmol, 97%)

as a colourless gum. R_f= 0.28 (n-hexane/MTBE 15:1); [a]²_D¹= ꢀ69.7 (c

= 0.64 in CHCl₃); ¹H NMR (300 MHz, CDCl₃, 73:27 mixture of rotam-

ers): d = 0.11/0.13 (each s, 73:27, 9H; TMS), 1.04/1.05(each s, 27:73,

9H; Si-tBu), 1.29/1.47 (each s, 73:27, 9H; Boc), 1.95 2.35 (m, 4H; 3-, 4-

H₂), 2.34/2.38 (each d, J = 2.2 Hz, 73:27, 1H; 3’-H), 3.50 (dd, J = 9.6,

7.2 Hz, 1H; 1’’-H₂), 3.70 (dd, J = 9.6, 3.1 Hz, 1H; 1’’-H₂), 3.81 3.95(m,

2H; 2-H, 5-H), 4.84/5.08 (each t, J = 2.0 Hz, 27:73, 1H; 1’-H), 7.32 7.43

(m, 6H; arom.), 7.60 7.67 (m, 4H; arom.) ppm; ¹³C NMR (75MHz,

CDCl₃): d = ꢀ0.3/ꢀ0.2 (TMS), 19.2 (Si-C(CH₃)₃), 24.4 (C-3), 26.8 (Si-

C(CH₃)₃), 27.7 (C-4), 28.4/28.6 (O-C(CH₃)₃), 59.7/59.9 (C-2), 62.1 (C-1’),

63.1/63.3 (C-5), 63.8/64.2 (C-1’), 72.8/72.9 (C-3’), 79.4 (O-C(CH₃)₃), 83.9

(C-2’), 127.7, 129.6, 133.4/133.6, 135.5 (arom.), 153.3/153.8 (Boc-C=

O) ppm; IR (film): n˜ = 3310 (CꢁC-H), 3072, 3051, 2960, 2932, 2859,

2130 (CꢁC), 1693, 1474, 1428, 1392, 1367, 1334, 1253, 1176, 1114, 1043,

925, 883, 844, 742, 703, 615 cm^ꢀ1

; HRMS (EI): m/z: calcd for

C₃₂H₄₇NO₄Si₂565.3044; found: 565.3036 [M]⁺; elemental analysis calcd

(%) for C₃₂H₄₇NO₄Si₂(565.90): C 67.92, H 8.37, N 2.48; found C 68.03, H

8.49, N 2.40.

(2’S,5’S,2’’S,5’’S,1R,4R) and (2’S,5’S,2’’S,5’’S,1R,4S)-1,4-Bis-[N’-tert-butoxy-

carbonyl-5-(tert-butyldiphenylsilyloxy)methyl]-pyrrolidin-2’-yl-1-(trimeth-

ylsilyl)oxy-2-butyn-4-ol (16 and 17): Alkyne 3 (11.1 g, 19.5mmol) in THF

(400 mL) was cooled to ꢀ808C, nBuLi (8.92 mL, 2.18m in hexanes,

20.5mmol, 1.05equiv) was added dropwise, and the mixture was stirred

for 30 min. HMPT (9.0 mL, 50 mmol, 2.5 equiv) was added, and the mix-

ture was stirred for 15min. Then a precooled solution ( ꢀ808C) of alde-

hyde 4 (10.1 g, 21.5mmol, 1.1 equiv) in THF (30 +10 mL) was added by

cannula over 15min, and the system was stirred for 1 h. The mixture was

warmed over 30 min to ꢀ708C, and sat. NH₄Cl and H₂O were added

(200 mL each). The mixture was warmed to r.t. and the layers were sepa-

rated. The aqueous layer was extracted with MTBE (2î150 mL), and the

combined organic layers were washed with brine (2î100 mL), dried

(MgSO₄) and concentrated. Triple FCC (300 g, and 2î1000 g, PE/MTBE

7:2!3:1!5:2) gave unconverted alkyne 3 (1.73 g, 3.06 mmol, 16%), fol-

lowed by (4R)-alcohol 16 (10.9 g, 10.5mmol, 54%), and (4 S)-alcohol 17

(5.23 g, 5.06 mmol, 26%), each as colourless gums (95% yield based on

conversion).

Compound 48: R_f= 0.25( n-hexane/MTBE 10:3); ¹H NMR (300 MHz,

CDCl₃, 85:15 mixture of rotamers): d = 0.17 (s, 9H; TMS), 1.05(s, 9H;

Si-tBu), 1.28/1.47 (each s, 85:15, 9H; Boc), 1.80 2.35 (m, 4H; 3-, 4-H ₂),

3.54 (dd, J = 9.6, 7.2 Hz, 0.85H; 1’’-H₂), 3.58 3.66 (m, 0.3H; 1’’-H₂), 3.74

(dd, J = 9.6, 3.1 Hz, 0.85H; 1’’-H₂), 3.90 (m, 1H; 5-H), 4.05 (m, 1H; 2-

H), 4.54 (m, 2H; 1’-H, -OH), 7.30 7.45(m, 6H; arom.), 7.61 7.65(m,

4H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = ꢀ0.4 (Si-CH₃), 19.0

(Si-C(CH₃)₃), 25.7, 26.4 (C-3, C-4), 26.6 (Si-C(CH₃)₃), 28.0 (O-C(CH₃)₃,

C-4), 59.5 (C-5), 62.8 (C-2), 63.5 (C-1’’), 66.5(C-1 ’), 80.5(O- C(CH₃)₃),

89.8 (C-2’), 105.0 (C-3’), 127.5, 129.5, 133.2, 135.3 (arom.), 156.3 (Boc-C=

O) ppm; HRMS (EI): m/z: calcd for C₃₂H₄₇NO₄Si₂: 565.3044; found:

565.3049 [M]⁺.

(2S,5S,1’R)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsilyloxy)methyl-

2-(1’-hydroxy-prop-2’-ynyl)-pyrrolidine (15): TMS-protected alkyne 14

(13.6 g, 24.0 mmol) was dissolved in THF/MeOH (1:1, 200 mL), and the

system was cooled to 08C. H₂O (1.3 mL, 72 mmol, 3 equiv) and K₂CO₃

(5.0 g, 36 mmol, 1.5 equiv) were added, and the suspension was stirred

for 4 h. Acetic acid (4 mL) was added, and the mixture was concentrated

in vacuo to approx. 50 mL. The residue was partitioned between EtOAc

(150 mL) and brine (75 mL). The layers were separated, and the aqueous

layer was extracted with EtOAc (50 mL). The combined organic layers

were washed with brine (50 mL), dried (MgSO₄) and concentrated. FCC

(400 g, PE/MTBE 5:2 !2:1!1:1) provided alkyne 15 (11.5g, 23.2 mmol,

97%) as a clear, viscous oil. R_f= 0.19 (n-hexane/MTBE 3:1); ¹H NMR

(300 MHz, CDCl₃, 92:8 mixture of rotamers; data for major rotamer):

d = 1.05(s, 9H; Si- tBu), 1.33/1.48 (each s, 92:8, 9H; Boc), 1.75(m, 1H;

3-H_2A), 1.98 (m, 1H; 4-H_2A), 2.23 2.35(m, 2H; 3-, 4-H _2B), 2.39 (d, J =

2.1 Hz, 1H; 3’-H), 3.60 (dd, J = 9.8, 6.5Hz, 1H; 1 ’’-H₂), 3.69 (dd, J =

9.8, 3.0 Hz, 1H; 1’’-H₂), 4.01 (m, 1H; 5-H), 4.05 (d, J = 8.6 Hz, 1H; 2-

H), 4.47 (d, J = 9.1 Hz, 1H; 1’-H), 5.88 (d, J = 9.1 Hz, -OH), 7.33 7.43

(m, 6H; arom.), 7.60 7.66 (m, 4H; arom.) ppm; ¹³C NMR (75MHz,

Compound 16: R_f= 0.21 (n-hexane/MTBE 3:1); [a]²_D⁰= ꢀ53.5 (c =

1

1.53 in MeOH); H NMR (300 MHz, CDCl₃, 70:30 mixture of rotamers):

d = 0.09/0.11 (each s, 70:30, 9H; TMS), 1.04 (s, 18H; Si-tBu), 1.28 (s,

35% of 9H; N’-Boc), 1.31 (s, 47% of 9H; N’’-Boc), 1.46 (s, 18% of 9H;

Boc), 1.70 (m, 1H; 4’’-H₂), 1.90 2.05(m, 3H; 4 ’-H₂, 4’’-H₂), 2.05 2.25 (m,

3H; 3’-H₂, 3’’-H₂), 2.25 2.35 (m, 1H; 3’’-H₂), 3.47/3.52 (each m, 70:30,

1H; CH₂-OSi), 3.60 (m, 1H; CH₂-OSi), 3.64 3.73 (m, 2H; CH₂-OSi), 3.83

(m, 1H; 5’-H), 3.90 4.01 (m, 2H; 5’’-H, 2’-H), 4.11 (m, 1H; 2’’-H), 4.49

(d, J = 8.8 Hz, 1H; 4-H), 4.86, 5.08 (each s, 30:70, 1H; 1-H), 5.61/5.79

(each d, J = 8.8 Hz, 70:30, 1H; -OH), 7.34 7.40 (m, 12H; arom.), 7.60

7.65(m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = ꢀ0.03/ꢀ0.02

(TMS), 19.0 (Si-C(CH₃)₃), 24.4 (C-4’), 26.4 (C-4’’), 26.6 (Si-C(CH₃)₃),

27.4/27.5(C-3 ’/C-3’’), 28.1/28.5( N’-C(O)O-C(CH₃)₃), 28.2 (N’’-C(O)O-

C(CH₃)₃), 59.5/59.7 (C-2’), 60.6 (C-5’’), 62.1 (CH₂-OSi), 62.9 (C-5’), 63.8

(C-1), 64.0 (CH₂-OSi, C-2’’), 67.8/67.9 (C-4), 79.1/79.2 (N’-C(O)O-

C(CH₃)₃), 80.5( N’’-C(O)O-C(CH₃)₃), 83.6 (C-3), 85.1, 85.2 (C-2), 127.4,

127.5, 129.4, 129.5, 133.2, 133.3, 133.4, 135.5 (arom.), 153.1/153.3 (N’-C=

O), 156.3 (N’’-C=O) ppm; IR (film): n˜ = 3409 (-OH), 3072, 3051, 2960,

3954

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

2930, 2859, 2248 (CꢁC), 1694, 1590, 1473, 1428, 1392, 1334, 1253, 1174,

1114, 1036, 909, 883, 845, 824, 775, 739, 703, 614 cm^ꢀ1; elemental analysis

calcd (%) for C₅₉H₈₄N₂O₈Si₃(1033.56): C 68.56, H 8.19, N 2.71; found: C

68.49, H 8.39, N 2.74.

(2’S,5’S,2’’S,5’’S,4R,7R)-4,7-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldi-

phenylsilyloxy)methyl]-pyrrolidin-2’-yl-(2-oxo-1,3-dioxa)-thiepane (20):

Diol 19 (4.1 g, 4.25mmol) in CH ₂Cl₂(250 mL) was cooled to ꢀ208C, and

NEt₃(2.4 mL, 17 mmol, 4 equiv) was added. SOCl₂(340 mL, 4.68 mmol,

1.1 equiv) was added dropwise. After 20 min, sat. NaHCO₃solution

(100 mL) was added, and the mixture was stirred for 1 h. The layers were

separated, and the aqueous layer was extracted with Et₂O (3î100 mL).

The combined organic layers were washed with phosphate buffer (0.5m,

pH 2, 2î100 mL) and brine (100 mL), dried (MgSO₄) and concentrated.

Filtration over silica gel (10 g, Et₂O) gave cyclic sulfite 20 (4.26 g,

4.21 mmol, 99%) as a colourless gum. R_f= 0.30 (n-hexane/MTBE 2:1);

[a]²_D⁰= ꢀ23.0 (c = 1.29 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): d =

1.03 (s, 18H; Si-tBu), 1.30, 1.33, 1.47, 1.49 (each s, 45:40:8:7, 18H; Boc),

1.62 1.70 (m, 2H; 5-H₂), 1.85 2.30 (m, 10H; 5-H₂, 3’-H₂, 4’-H₂), 3.50 3.60

(m, 2H; CH₂-OSi), 3.65 3.71 (m, 2H; CH₂-OSi), 3.74/3.85(each m, 1:1,

2H; 2’-H), 3.88 4.02 (m, 2H; 5’-H), 4.60/4.94 (each d, 1:5, J = 10.1 Hz,

1:5, 1H; 4-H), 5.20/5.59 (each m, 1:5, 1H; 4-H), 7.34 7.43 (m, 12H;

arom.), 7.60 7.65(m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

19.2 (Si-C(CH₃)₃); 23.8/23.9 (C-4’), 26.8 (Si-C(CH₃)₃), 27.5(C-3 ’), 28.2/

28.3/28.5(O-C( CH₃)₃), 30.7 (C-5), 58.8/59.3 (C-5’), 61.2/61.6 (C-2’), 64.5

(CH₂-OSi), 73.2/74.2 (0.55:0.45, C-4), 79.7 (O-C(CH₃)₃), 127.7, 129.7,

133.5, 135.5, 154.2 (Boc-C=O); MS (ESI): m/z: calcd for C₅₆H₇₈N₂O₉Si₂S:

1033.5; found: 1033.5 [ M+Na]⁺.

Compound 17: R_f= 0.13 (n-hexane/MTBE 3:1); ¹H NMR (300 MHz,

CDCl₃, 73:27 mixture of rotamers): d = 0.10/0.12 (each s, 73:27, 9H;

TMS), 1.05(s, 18H; Si- tBu), 1.28/1.29/1.46 (each s, 33:47:20, 18H; Boc),

1.85 2.05, 2.05 2.25, 2.25 2.3 (each m, 8H; 3’-H₂, 3’’-H₂, 4’-H₂, 4’’-H₂),

3.37 3.60 (m, 2H; CH₂-OSi), 3.63 3.78 (m, 2H; CH₂-OSi), 3.83 4.10 (m,

4H; 2’-H, 5’-H, 2’’-H, 5’’-H), 4.17/4.35(each d, J = 5.0 Hz, 73:27, 1H;

-OH), 4.56 (m, 1H; 4-H), 4.87/5.10 (each s, 27:73, 1H; 1-H), 7.33 7.43

(m, 12H; arom.), 7.60 7.64 (m, 8H; arom.) ppm; ¹³C NMR (75MHz,

CDCl₃): d = ꢀ0.2/ꢀ0.1 (TMS), 19.2 (Si-C(CH₃)₃), 26.7 26.9 (4î, C-3’,

C-3’’, C-4’, C-4’’), 26.8 (Si-C(CH₃)₃), 28.2/28.6 (N’-C(O)O-C(CH₃)₃), 28.3

(N’’-C(O)O-C(CH₃)₃), 59.6/59.7/60.1 (C-5’, C-5’’), 62.3/64.1 (C-1), 62.8/

63.6 (C-2’), 63.0 (C-2’’), 63.7, 64.2 (CH₂-OSi), 66.1 (C-4), 79.3 (N’’-

C(O)O-C(CH₃)₃), 80.5/80.6 (N’-C(O)O-C(CH₃)₃), 84.6, 85.1 (C-2, C-3),

127.6, 127.7, 129.6, 133.2, 133.4, 133.6, 135.6 (arom.), 153.4/153.7 (N’-Boc-

C=O), 156.4 (N’’-Boc-C=O) ppm; HRMS (EI): m/z: calcd for

C₅₄H₇₆N₂O₆Si₃: 932.5011; found: 932.5013 [MꢀBoc+H]⁺.

(2’S,5’S,2’’S,5’’S,1R,4R)-1,4-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldi-

phenylsilyloxy)methyl]-pyrrolidin-2’-yl-2-butyne-1,4-diol (18): TMS ether

16 (5.17 g, 5.00 mmol) in THF/MeOH (3:1, 100 mL) was cooled to

ꢀ108C, and CSA (23 mg, 0.10 mmol, 2.5mol%) was added. After 15min

(TLC monitoring), the mixture was partitioned between EtOAc

(100 mL) and brine/H₂O (50 mL each). The layers were separated, the

aqueous layer was extracted with EtOAc (2î50 mL), and the combined

organic layers were washed with brine (50 mL), dried with MgSO₄and

concentrated. FCC (120 g, cyclohexane/EtOAc 5:2 !2:1) yielded diol 18

(2’S,5’S,2’’S,5’’S,4R,7R)-4,7-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldi-

phenylsilyloxy)methyl]-pyrrolidin-2’-yl-(2,2-dioxo-1,3-dioxa)-thiepane

(21): Cyclic sulfite 20 (4.26 g, 4.21 mmol) was dissolved in CCl₄/CH₃CN

(1:1, 140 mL), H₂O (50 mL) was added, and the well stirred emulsion

was cooled to 08C. NaIO₄(3.6 g, 17 mmol, 4 equiv) and RuCl₃¥H₂O

(15mg) were added, and the mixture was stirred for 30 min. After dilu-

tion with Et₂O (400 mL), the layers were separated, and the organic

layer was washed with H₂O (100 mL) and brine (3î75mL), dried

(MgSO₄) and concentrated at RT. Filtration over silica gel (10 g, Et₂O)

provided cyclic sulfate 21 (4.20 g, 4.09 mmol, 96%) as a colourless gum.

(4.54 g, 4.72 mmol, 94%) as a colourless gum. R_f

= 0.22 (n-hexane/

MTBE 1:1); [a]²_D⁰= ꢀ38.7 (c = 1.12 in MeOH); ¹H NMR (300 MHz,

CDCl₃): d = 1.03 (s, 18H; Si-tBu), 1.31, 1.47 (each s, 91:9, 18H; Boc),

1.77 (m, 2H; 3’-H₂), 1.96 (m, 2H; 4’-H₂), 2.18 2.35(m, 4H; 3 ’-, 4’-H₂),

3.58 (dd, J = 9.7, 6.5Hz, 2H; C H₂-OSi), 3.67 (dd, J = 9.7, 2.9 Hz, 2H;

CH₂-OSi), 4.01 (m, 2H; 5’-H), 4.09 (d, J = 8.2 Hz, 2H; 2’-H), 4.58 (d, J

= 8.2 Hz, 2H; 1-H), 5.48 (d, J = 8.2 Hz, 2H; -OH), 7.30 7.44 (m, 12H;

arom.), 7.60 7.65(m, 8H; arom) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

19.1 (Si-C(CH₃)₃), 26.6 (Si-C(CH₃)₃), 26.6/26.9 (C-4’, C-4’’), 27.4 (C-3’, C-

3’’), 28.3 (O-C(CH₃)₃), 60.7 (C-5’, C-5’’), 63.6 (C-2’, C-2’’), 64.1 (CH₂-

OSi), 67.5(C-1), 80.7 (O- C(CH₃)₃), 84.4 (C-2), 127.7, 129.7, 133.3, 133.5,

135.5 (arom.), 156.5 (Boc-C=O) ppm; IR (film): n˜ = 3400 (-OH), 3071,

2960, 2931, 2858, 1691, 1668, 1473, 1428, 1403, 1395, 1367, 1256, 1172,

1112, 855, 823, 774, 740, 702, 614 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₅₁H₆₈N₂O₆Si₂: 860.4616; found: 860.4600 [MꢀBoc+H]⁺; elemental anal-

ysis calcd (%) for C₅₉H₈₄N₂O₈Si₃(961.382): C 69.96, H 7.97, N 2.91;

found: C 70.02, H 8.03, N 2.95.

1

R_f= 0.38 (n-hexane/MTBE 1:1); [a]²_D⁰= ꢀ63.5(c = 1.30 in CHCl₃); H

NMR (300 MHz, CDCl₃): d = 1.05(s, 18H; Si- tBu), 1.32/1.49 (each s,

88:12, 18H; Boc), 1.60 1.71 (m, 2H; 5-H₂), 1.72 1.87 (m, 2H; 5-H₂),

1.88 2.05(m, 4H; 3 ’-H₂, 4’-H₂), 2.05 2.28 (m, 4H; 3’-H₂, 4’-H₂), 3.60 (dd,

J = 9.8, 6.0 Hz, 2H; CH₂-OSi), 3.66 (dd, J = 9.8 and 2.9 Hz, 2H; CH₂-

OSi), 3.89 (d, J = 8.1 Hz, 2H; 2’-H), 3.95(m, 2H; 5 ’-H), 5.40 (d, J =

8.9 Hz, 2H; 4-H), 7.33 7.44 (m, 12H; arom.), 7.59 7.65 (m, 8H;

arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.2 (Si-C(CH₃)₃), 26.8

(Si-C(CH₃)₃), 26.9 (C-4’), 27.6 (C-3’), 28.3/28.4 (O-C(CH₃)₃), 29.4 (C-5),

58.8 (C-5’), 61.0 (C-2’), 64.5( CH₂-OSi), 80.1 (O-C(CH₃)₃), 82.9 (C-4/C-7),

127.7, 129.6, 133.3, 135.5 (arom.), 154.0 (Boc-C=O) ppm; IR (film): n˜ =

3071, 2958, 2928, 2856, 1690, 1472, 1428, 1392, 1366, 1257, 1199, 1174,

1112, 896, 856, 823, 741, 702, 611 cm^ꢀ1; HRMS (ESI): m/z: calcd for

C₅₆H₇₉N₂O₁₀Si₂S: 1027.499; found: 1027.490 [M+H]⁺.

(2’S,5’S,2’’S,5’’S,1R,4R)-1,4-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldi-

phenylsilyloxy)methyl]-pyrrolidin-2’-yl-butane-1,4-diol (19): Alkyne 18

(4.52 g, 4.70 mmol) was dissolved in MeOH (100 mL), and Pt/C (5 wt%,

100 mg) was added. The flask was filled with H₂, and the mixture was hy-

drogenated for 16 h (1 atm). The flask was purged with Ar, and the mix-

ture was diluted with EtOAc (50 mL) to redissolve the precipitate, fil-

tered over a pad of Celite and concentrated. FCC (80 g, PE/EtOAc 2:1!

1:1) gave diol 19 (4.19 g, 4.34 mmol, 92%) as a colourless resin, which

crystallized from MeOH at ꢀ258C. R_f= 0.14 (n-hexane/EtOAc 3:2), R_f

(alkene) = 0.54; m.p. 128.5 1298C (MeOH); [a]²_D⁰= ꢀ40.2 (c = 0.560

(2’S,5’S,2’’S,5’’S,1R,4S)-1,4-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldi-

phenylsilyloxy)methyl]-pyrrolidin-2’-yl-4-azido-butan-1-ol (22): Cyclic

sulfate 21 (4.10 g, 4.00 mmol) was dissolved in DMF/HMPT (1:1, 20 mL),

LiN₃(1.6 g, 32 mmol, 8 equiv) was added, and the solution was stirred for

40 h at r.t. DMF was removed in vacuo, and the residue was partitioned

between CHCl₃(250 mL) and brine/H₂O (1:1, 200 mL). The layers were

separated, and the aqueous layer was extracted with CHCl₃(4î50 mL).

The extracts were concentrated and coevaporated with toluene (80 mL).

The crude sulfate (R_f= 0.23 in CDCl₃/MeOH 10:1) was dissolved in

THF (80 mL), H₂O (700 mL) was added, and the pH was adjusted to 2

with conc. H₂SO₄(ca. 300 mL). After complete cleavage of the sulfate

(12 h, TLC monitoring), the mixture was partitioned between Et₂O and

sat. NaHCO₃solution (100 mL each). The layers were separated, and the

aqueous layer was extracted with Et₂O (3î75mL). The combined organ-

ic extracts were washed with brine (2î50 mL), dried (MgSO₄) and con-

centrated. FCC (80 g, PE/EtOAc 3:1) gave azide 22 (2.89 g, 2.91 mmol,

1

in CHCl₃); H NMR (600 MHz, CDCl₃): d = 1.04 (s, 18H; Si-tBu), 1.28/

1.45(each s, 86:14, 18H; Boc), 1.46 (m, 2H; 2-H ₂), 1.51 (s, 2H; 2-H₂),

1.70 (m, 2H; 4’-H₂), 1.87 2.20 (m, 6H; 3’-H₂, 4’-H₂), 3.53 (m, 2H; CH₂-

OSi), 3.68 (m, 2H; CH₂-OSi), 3.82 (brs, 2H; 1-H), 3.90 4.05(m, 4H; 2 ’-

H, 5’-H), 4.41/4.62 (each s, 2H; -OH), 7.32 7.44 (m, 12H; arom.), 7.60

7.66 (m, 8H; arom) ppm; ¹³C NMR (150 MHz, CDCl₃): d = 19.2 (Si-

C(CH₃)₃), 25.9 (C-4’), 27.1 (C-3’), 28.3/28.6 (86:14, O-C(CH₃)₃), 30.0 (C-

2), 59.5/60.2 (14:86, C-2’), 63.7/63.8 (approx. 10:1, C-5’), 64.1 (CH₂-OSi),

73.2/74.4 (15:85, C-1), 80.0/80.2 (86:14, O- C(CH₃)₃), 127.7, 129.7, 133.3,

133.5, 135.5 (arom.), 153.8/155.6 (Boc-C=O) ppm; IR (film): n˜ = 3400

(-OH), 1691, 1668, 1403, 1395, 1112 cm^ꢀ1; HRMS (FAB): calcd for

C₅₆H₈₀N₂O₈Si₂: 964.5553; found: 964.5537 [M]⁺; elemental analysis calcd

(%) for C₅₆H₈₀N₂O₈Si₂(965.414): C 69.67, H 8.35, N 2.90; found C 69.31,

H 8.20, N 2.92.

73%) as a colourless gum. R_f= 0.36 (n-hexane/EtOAc 5:2); [a]_D²⁰

=

ꢀ32.9 (c = 0.917 in CHCl₃); ¹H NMR (600 MHz, CDCl₃): d = 1.04 (s,

18H; Si-tBu), 1.27/1.28/1.46 (each s, 52:30:18, 18H; Boc), 1.25 1.35 (m,

2H; 3-H₂), 1.50 1.60 (m, 2H; 2-H₂), 1.66 (m, 1H; 4-H), 1.81 (m, 2H),

1.92 (m, 1H), 1.97 (m, 1H; 4’-H₂, 4’’-H₂), 2.03 (m, 3H; 3’-H₂, 3’’-H₂), 2.22

(m, 1H; 3’-H₂), 3.46 3.60 (m, 2H; CH₂-OSi), 3.63 3.75(m, 2H; C H₂-

OSi), 3.68 (d, J = 8 Hz, 1H; -OH), 3.90 (m, 1H; 2’’-H), 3.96 (m, 1H; 2’-

H), 4.03 (m, 1H; 1-H), 4.08 (m, 2H; 5’-H, 5’’-H), 7.36 7.41 (m, 12H;

Chem. Eur. J. 2004, 10, 3945 3962

www.chemeurj.org

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3955

S. M¸ller, U. Koert et al.

FULL PAPER

arom.), 7.61 7.64 (m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

19.2 (Si-C(CH₃)₃), 24.5(C-4 ’), 27.1 (C-3’), 27.2 (Si-C(CH₃)₃), 27.4, 28.6

(O-C(CH₃)₃), 30.1 (C-2), 59.9/60.8 (C-2’), 60.4 (C-4), 63.3, 63.8 (C-5’),

64.3 (CH₂-OSi), 75.8 (C-1), 80.0, 80.2 (O-C(CH₃)₃), 128.1, 128.2, 130.0,

130.1, 133.3, 133.5, 135.9, 136.0, 153.8/155.6 (Boc-C=O) ppm; IR (film):

calcd (%) for C₆₁H₈₇N₃O₈Si₂(1046.55): C 70.00, H 8.37, N 4.02; found C

69.90, H 8.28, N 4.05.

General procedure for Boc group cleavage with TMSOTf (GP1): A solu-

tion of the compound in CH₂Cl₂(10 mm) with thioanisole (12 equiv per

Boc group) and 2,6-lutidine (6 equiv per Boc group) was cooled to

ꢀ788C, and TMSOTf (3 equiv per Boc group) was added dropwise. After

10 min the cooling bath was removed, and the mixture was allowed to

ꢀ

n˜ = 3441 (O H), 3400 (O H), 3071, 3050, 2960, 2930, 2858, 2096 (-N₃),

1692, 1676, 1473, 1428, 1392, 1367, 1255, 1174, 1112, 909, 857, 822, 738,

702, 614 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₅₆H₇₉N₅O₇Si₂: 990.560;

found: 990.544 [M+H]⁺; elemental analysis calcd (%) for C₅₆H₇₈N₅O₇Si₂

(989.442): C 67.98, H 7.95, N 7.08; found C 67.72, H 8.28, N 6.86.

warm to RT (1 2 h). Phosphate buffer (1m) was added (¹= v/v), and the

2

mixture was stirred for 10 min and partitioned between CH₂Cl₂(2:1 v/v)

and brine (¹= v/v). The layers were separated, the organic layer was ex-

2

tracted with CH₂Cl₂(3 î, 1:1 v/v), and the combined extracts were

(2S,5S,2’S,5’S,2’’S,5’’S)-N,N’’-Di-tert-butoxycarbonyl-2,5’’-bis-[(tert-butyl-

diphenylsilyloxy)methyl]-dodecahydro-terpyrrole (23): Azide 22 (1.95g,

1.98 mmol) in CH₂Cl₂(40 mL) was cooled to ꢀ258C, and NEt₃(2.3 mL,

16 mmol, 8 equiv) and MsCl (0.63 mL, 8.0 mmol, 4 equiv) were added.

The solution was allowed to warm to 08C over 2 h, sat. NH₄HCO₃solu-

tion and brine (20 mL each) were then added, and the layers were sepa-

rated. The organic layer was extracted with Et₂O (3î30 mL), and the

combined extracts were washed with citric acid (5%, 2î30 mL) and

brine (50 mL), dried (MgSO₄), concentrated at 108C and dried in vacuo.

R_f(mesylate) = 0.52 (n-hexane/EtOAc 2:1). The crude mesylate (2.05g,

1.92 mmol) was dissolved in MeOH/THF (3:2, 100 mL). Pd/C (10 wt%,

200 mg) was added, and the flask was filled with H₂(1 atm). After com-

plete cleavage of the azide (6 h, TLC monitoring) the flask was purged

with Ar, and the mixture was filtered over a pad of silica gel (5g,

MeOH). NaHCO₃(0.35g, 4.0 mmol, 2 equiv) was added, and the mixture

was stirred for 72 h at RT, after which it was concentrated. The residue

was partitioned between Et₂O and NaHCO₃(100 mL each). The aqueous

layer was extracted with Et₂O (50 mL), and the combined organic layers

were washed with brine (50 mL), dried (MgSO₄) and concentrated. Triple

FCC (2î50 g and 30 g, CH₂Cl₂/MeOH 93:7!90:10) gave terpyrrolidine

23 (1.02 g, 1.08 mmol, 54%) as an off-white resin. R_f= 0.18 (CH₂Cl₂/

washed with brine (¹= v/v), dried (Na₂SO₄) and concentrated to give the

4

crude amine.

(2S,5S,2’S,5’S,2’’S,5’’S)-2,5’’-Bis-[(tert-butyldiphenylsilyloxy)methyl]-do-

decahydro-terpyrrole (31): Tri-Boc-terpyrrolidine 24 (126 mg, 120 mmol)

was deprotected as described in GP1. FCC (10 g, CHCl₃/MeOH/

HCOOH 100:6:5!100:10:5) provided triamine 31 (88.1 mg, 118 mmol,

98%) as

100:10:5); [a]_D

a

colourless resin. R_f

=

0.15(CHCl ₃/MeOH/HCOOH

=

ꢀ9.3 (c

=

0.518 in CH₂Cl₂); ¹H NMR (300 MHz,

CDCl₃): d = 1.03 (s, 18H; Si-tBu), 1.39 1.65, 1.80 2.03 (2îm, 12H; 3-

H₂, 3’-H₂, 3’’-H₂, 4-H₂, 4’-H₂, 4’’-H₂), 3.23 3.45(m, 6H; 2-H, 2 ’-H, 2’’-H,

5-H, 5’-H, 5’’-H), 3.57 3.61 (m, 4H; CH₂-OSi), 7.34 7.43 (m, 12H;

arom.), 7.65 7.68 (m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

19.2 (Si-C(CH₃)₃), 26.9 (Si-C(CH₃)₃), 28.0, 29.1, 29.2 (C-3/C-4’’, C-3’/C-4’,

C-3’’/C-4), 59.6 (C-2’, C-5’), 60.6 (C-2, C-5’’), 62.8 (C-5, C-2’’), 65.4 (CH₂-

OSi), 127.7, 129.7, 133.3, 135.6 (arom.) ppm; IR (film): n˜ = 3414, 3269,

3048, 2958, 2931, 2893, 2858, 1472, 1428, 1112, 999, 824, 740, 703,

614 cm^ꢀ1; HRMS (FAB): m/z: calcd for C₄₆H₆₂N₃O₂Si₂: 746.4381; found:

744.4389 [MꢀH]⁺.

(2S,5S,2’S,5’S,2’’S,5’’S)-2,5’’-Bis-(hydroxymethyl)-dodecahydro-terpyrrol

(5): Terpyrrolidine 31 (60.0 mg, 80.4 mmol) was dissolved in MeOH

(6 mL, polypropylene flask), conc. HF (0.6 mL) was added (Caution!),

and the solution was stirred for 24 h at RT. The volatiles were removed

in vacuo, and the residue was redissolved in MeOH (5mL), and the solu-

tion was adjusted to pH>12 with NaOH (2m). Silica gel (500 mg) was

added, and the volatiles were removed in vacuo. FCC of the immobilised

material (5g, CH ₂Cl₂/MeOH/aq. NH₃60:30:5!60:30:8) provided the tri-

aminodiol 1, which was re-dissolved in CHCl₃and filtered over Celite to

1

MeOH 100:8); [a]²_D⁰= ꢀ32.9 (c = 0.917 in CHCl₃); H NMR (300 MHz,

CDCl₃/TFA 99:1): d = 1.04 (s, 18H; Si-tBu), 1.28 (s, 18H; Boc), 1.71

1.85(m, 4H; 4-H ₂, 3’’-H₂), 2.01 2.22 (m, 8H; 3-H₂, 3’-H₂, 4’-H₂, 4’’-H₂),

3.51 3.56 (m, 2H; CH₂-OSi), 3.71 3.75(m, 2H; C H₂-OSi), 3.89 4.01 (m,

2H; 2-H, 5’’-H), 4.08 4.24 (m, 4H; 5-H, 2’-H, 5’-H, 2’’-H), 7.33 7.45(m,

12H; arom.), 7.59 7.67 (m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃/

TFA 99:1): d = 19.1 (Si-C(CH₃)₃), 26.8 (Si-C(CH₃)₃), 25.8, 26.7, 28.0 (C-

3, C-3’, C-3’’, C-4, C-4’, C-4’’), 28.1 (O-C(CH₃)₃), 58.7 (C-2’, C-5’), 59.3

(C-2, C-5’’), 63.3, 63.4, 63.4 (C-5, C-2’’, CH₂-OSi), 81.3 (O-C(CH₃)₃),

127.7, 129.7, 133.1, 133.2, 135.4, 135.5 (arom.), 156.0 (Boc-C=O) ppm; IR

(film): n˜ = 3353, 3072, 3050, 2959, 2929, 2857, 1691, 1472, 1462, 1428,

yield a colourless oil (19.8 mg, 73.5 mmol, 91%). R_f

= 0.27 (CH₂Cl₂/

MeOH/aq. NH₃5:5:1); [ a]²_D⁴0.47 in MeOH); ¹H NMR

=

1.3 (c

=

(300 MHz, [D₄]MeOH/NaOD 99:1): d = 1.38 1.52, 1.86 1.99 (2 m, 12H;

3-H₂, 3’-H₂, 3’’-H₂, 4-H₂, 4’-H₂, 4’’-H₂), 2.96 3.02 (m, 4H; 2’-H, 2’’-H, 5-H,

5’-H), 3.24 (dt, J = 12.4, 6.0 Hz, 2H; 2-H, 5’’-H), 3.42 3.51 (m, 4H; CH₂-

OH) ppm; ¹³C NMR (75MHz, [D ₄]MeOH/NaOD 99:1): d = 28.8 (C-3/

C-4’’), 30.2, 30.3 (C-3’/C-4’, C-3’’/C-4), 60.6 (C-2, C-5’’), 63.4, 63.8 (C-5/C-

2’’, C-2’/C-5’), 65.5 (CH₂-OH) ppm; HRMS (FAB): m/z: calcd for

C₁₄H₂₈N₃O₂: 270.2181; found: 270.2179 [M+H]⁺.

1391, 1366, 1334, 1256, 1175, 1112, 940, 858, 823, 774, 740, 702, 614 cm^ꢀ1

;

HRMS (ESI): m/z: calcd for C₅₆H₈₀N₃O₆Si₂: 946.559; found: 946.555

[M+H]⁺; elemental analysis calcd (%) for C₁₁₂H₁₆₄N₆O₁₅Si₄(1946.874,

(23)₂¥3H₂O): C 69.10, H 8.49, N 4.32; found: C 68.92, H 8.48, N 4.25.

(2S,5S,2’S,5’S,2’’S,5’’S)-N,N’,N’’-Tri-tert-butoxycarbonyl-2,5’’-bis-[(tert-bu-

tyldiphenylsilyloxy)methyl]-dodecahydro-terpyrrole (24): Terpyrrolidine

23 (381 mg, 402 mmol) was dissolved in DMF (4 mL), NEt₃(0.16 mL,

1.2 mmol, 3 equiv) and Boc₂O (132 mg, 600 mmol, 1.5equiv) were added,

and the solution was stirred for 24 h at RT. The mixture was diluted with

Et₂O (75mL), washed with sat. NaHCO ₃, NaHSO₄(1m), H₂O and brine

(15mL each), dried (MgSO ₄) and concentrated. FCC (20 g, PE/MTBE

4:1) and recrystallisation from n-hexane gave tri-Boc terpyrrole 24

(241 mg, 230 mmol, 57%) as a colourless powder. Crystals suitable for X-

ray crystallography were grown from a saturated n-hexane solution over

(2S,5S,2’S,5’S,2’’S,5’’S)-N,N’’-Di-tert-butoxycarbonyl-N’-(4’’’-nitrophenyl)-

sulfonyl-2,5’’-bis-[hydroxymethyl]-dodecahydro-terpyrrole (32): Terpyrro-

lidine 23 (405mg, 427 mmol) in CH₂Cl₂(6 mL) was cooled to 08C, and

NEt₃(178 mL), pNsCl (142 mg, 640 mmol, 1.5equiv) and DMAP (50 mg,

0.45mmol, 1.1 equiv) were added. The cooling bath was removed, and

the mixture was stirred for 18 h at RT. The solution was diluted with

Et₂O (50 mL), washed with NaHSO₄(1m) and brine (10 mL each), dried

(MgSO₄) and concentrated. FCC (20 g, PE/EtOAc 5:1!4:1) gave the sul-

fonamide (421 mg, 312 mmol, 87%) as a yellow foam (R_f= 0.19 in n-

hexane/EtOAc 5:1). The sulfonamide (304 mg, 269 mmol) was dissolved

in THF (5mL), and TBAF (1.0 m in THF, 0.54 mL, 540 mmol, 2 equiv)

was added. After 2 h the mixture was partitioned between EtOAc

(50 mL) and NH₄Cl (25mL), and the aqueous layer was extracted with

EtOAc (2î10 mL). The combined organic extracts were washed with

NaHSO₄(1m) and brine (10 mL each), dried (Na₂SO₄) and concentrated.

FCC (4 g, EtOAc/PE 1:1!5:1) provided diol 98 (146 mg, 225 mmol,

12 weeks. R_f

=

0.30 (n-hexane/MTBE 3:1); m.p. 175.5 1768C (n-

hexane); [a]²_D⁵

=

ꢀ25.9 (c

=

0.830 in CH₂Cl₂); ¹H NMR (300 MHz,

CDCl₃): d = 1.02 (s, 18H; Si-tBu), 1.44 1.48 (m, 27H; Boc), 1.85 2.22

(m, 12H; 3-H₂, 3’-H₂, 3’’-H₂, 4-H₂, 4’-H₂, 4’’-H₂), 3.35 3.85 (m, 4H; CH₂-

OSi), 3.86 4.00 (m, 2H; 2-H, 5’’-H), 4.01 4.10, 4.11 4.18 (2îm, 2H; 5-H,

2’’-H), 4.20 4.32, 4.38 4.48 (2îm, 2H; 2’-H, 5’-H), 7.33 7.40 (m, 12H;

arom.), 7.61 7.64 (m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d =

19.2 (Si-C(CH₃)₃), 26.9 (Si-C(CH₃)₃), 25.2, 26.8, 27.5, 28.1, 28.2, 28.3, 28.5,

28.6 (C-3, C-3’, C-3’’, C-4, C-4’, C-4’’), 28.6/28.6 (O-C(CH₃)₃), 59.5, 60.1,

60.5, 61.0 (C-2, C-2’, C-5’, C-5’’), 63.5, 63.6, 63.8 (C-5, C-2’’, CH₂-OSi),

79.0, 79.2, 79.4 (O-C(CH₃)₃), 127.6, 127.7, 129.4, 129.5, 129.6, 129.7, 133.7,

135.5, 135.6 (arom.), 153.7, 153.8, 153.9 (Boc-C=O) ppm; IR (film): n˜ =

3072, 3051, 2963, 2932, 2887, 2859, 1690, 1474, 1456, 1428, 1393, 1366,

1347, 1175, 1113, 1056, 740, 703, 614 cm^ꢀ1; HRMS (FAB): m/z: calcd for

C₆₁H₈₈N₃O₈Si₂: 1046.6110; found: 1046.6118 [M+H]⁺; elemental analysis

84%) as a colourless solid. R_f= 0.32 (EtOAc/n-hexane 5:1); m.p. 156

1

1638C; [a]_D= ꢀ2.6 (c = 1.325in CH Cl₂); H NMR (300 MHz, CDCl₃):

2

d = 1.45/1.52 (each s, 18H; Boc), 1.23 1.99 (m, 12H; 3-H₂, 3’-H₂, 4’-H₂,

4’’-H₂, 4-H₂, 3’’-H₂), 3.47 3.61 (m, 2H; CH₂-OH), 3.61 3.74 (m, 2H; CH₂-

OH), 3.83 4.02 (m, 2H; 2-H, 5’’-H), 4.02 4.08, 4.40 4.57, 4.62 4.83 (3î

m, 4H; 5-H, 2’-H, 5’-H, 2’’-H), 8.01 8.22, 8.32 8.36 (2îm, 4H; ar-

om.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 21.0, 24.6, 25.5, 25.9, 26.9,

27.4 (C-3, C-3’, C-3’’, C-4, C-4’, C-4’’), 28.5(O-C( CH₃)₃), 59.1, 59.7, 60.4,

3956

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

60.8, 61.6, 62.0, 62.9, 63.3 (C-2, C-5, C-5’’, C-2’’, C-2’, C-5’), 63.9, 66.2

(CH₂-OH), 80.2/81.3 (O-C(CH₃)₃), 124.4, 128.0, 128.2 (arom.), 146.6/146.7

(SO₂-C_Ar), 149.5(NO ₂-C_arom), 154.0, 155.3/155.4 (Boc-C=O) ppm; IR

(KBr): n˜ = 3432, 2975, 1691, 1646, 1604, 1532, 1477, 1456, 1395, 1369,

1349, 1308, 1288, 1254, 1168, 1123, 1096, 1056, 1028, 1009, 993, 736, 690,

3072, 3052, 2961, 2932, 2859, 1749, 1694, 1668, 1473, 1428, 1393, 1368,

1231, 1172, 1112, 1023, 849, 823, 740, 703, 614 cm^ꢀ1; HRMS (ESI): m/z:

calcd for C₅₈H₇₉N₂O₉Si₂: 1003.532; found: 1003.531 [M+H]⁺; elemental

analysis calcd (%) for C₅₈H₇₈N₂O₉Si₂(1003.419): C 69.42, H 7.84, N 2.79;

found: C 69.54, H 8.07, N 2.88.

625cm ^ꢀ1

; HRMS (FAB): m/z: calcd for C₃₀H₄₆N₄O₁₀SNa: 677.2832;

(2’S,5’S,2’’S,5’’S,1R,4S)-1,4-Bis-[N’-tert-butoxycarbonyl-5-(tert-butyldiphe-

nylsilyloxy)methyl]-pyrrolidin-2’-yl-4-acetoxy-butan-1-ol (27): Alkyne 26

was hydrogenated in EtOAc (100 mL) by the procedure given for com-

pound 19. Double FCC (100 g + 30 g, n-hexane/MTBE/MeOH 66:33:1!

59:40:1) gave alcohol 27 (4.00 g, 3.97 mmol, 98%) as a colourless gum.

R_f= 0.21 (n-hexane/MTBE/MeOH 66:33:1); [a]²_D⁰= ꢀ53.5 (c = 1.446

in CHCl₃); ¹H NMR (300 MHz, CDCl₃): d = 1.03 (s, 18H; Si-tBu), 1.24,

1.28, 1.48, 1.50 (each s, 18H; Boc), 2.00/2.04 (s, 3H; Ac), 1.49 1.61, 1.80

2.21 (2îm, 12H; 2-H₂, 3-H₂, 3’-H₂, 3’’-H₂, 4’-H₂, 4’’-H₂), 3.43 3.55 (m,

2H; CH₂-OSi), 3.59 3.84 (m, 3H; CH₂-OSi, 1-H), 3.86 4.13 (m, 4H; 2’-

H, 5’-H, 2’’-H, 5’’-H), 4.49 (dd, J = 8.5, 1.5 Hz, 1H; 1-H), 5.39 5.50/5.68

5.88 (each m, 1H; 4-H), 7.33 7.45 (m, 12H; arom.), 7.59 7.66 (m, 8H;

arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.2 (Si-C(CH₃)₃), 21.2

(Ac), 26.1, 26.8, 26.9, 27.8, 29.0, 29.5(C-2, C-3, C-3 ’, C-3’’, C-4’, C-4’’),

26.8 (Si-C(CH₃)₃), 28.3/28.5(O-C( CH₃)₃), 59.0, 59.2, 59.3 (C-5’, C-5’’),

60.2, 60.3 (C-2’, C-2’’), 63.6, 63.8 (CH₂-OSi), 74.6, 75.0 (C-1, C-4), 79.4,

79.6, 80.2 (O-C(CH₃)₃), 127.6, 127.7, 129.5, 129.7, 133.4, 133.5, 133.7,

135.5 (arom.), 153.6, 155.6 (Boc-C=O), 170.5(Ac-C =O) ppm; IR (film):

n˜ = 3460, 3071, 3050, 2961, 2932, 2858, 1739, 1692, 1473, 1428, 1391,

1367, 1244, 1174, 1113, 702, 613 cm^ꢀ1; HRMS (FAB): m/z: calcd for

C₅₃H₇₃N₂O₇Si₂: 905.4956; found: 905.4963 [MꢀBoc]⁺; elemental analysis

calcd (%) for C₅₈H₈₂N₂O₉Si₂(1007.451): C 69.15, H 8.20, N 2.78; found:

C 68.91, H 8.10, N 2.95.

found: 677.2837 [M+Na]⁺.

(2S,5S,2’S,5’S,2’’S,5’’S)-N’-(4’’’-Nitrophenyl)sulfonyl-2,5’’-bis-(hydroxy-

methyl)-dodecahydro-terpyrrole (33): Di-Boc-terpyrrolidine 32 (110 mg,

169 mmol) was dissolved in CH₂Cl₂(2 mL), TFA (2 mL) was added, and

the mixture was stirred for 1 h. The volatiles were removed in vacuo, and

the residue was coevaporated with toluene/EtOH (2:1, 10 mL). FCC

(10 g, CHCl₃/MeOH/aq. NH₃80:10:1!50:10:1!30:10:1) gave diamine

33 (70.2 mg, 156 mmol, 92%) as a yellow gum. R_f= 0.12 (CHCl₃/MeOH/

aq. NH₃50:10:1); [a]_D²⁴

(300 MHz, [D₄]MeOH/NaOD 99:1): d

=

11.1 (c

=

0.88 in CH₂Cl₂); ¹H NMR

1.23 1.56, 1.72 1.98 (2îm,

=

12H; 3-H₂, 3’-H₂, 3’’-H₂, 4-H₂, 4’-H₂,4’’-H₂), 3.34 3.40 (m, 4H; 2’’-H, 5-

H), 3.44 3.54 (m, 6H; 2-H, 5’’-H, CH₂-OH), 3.82 (dt, J = 6.4, 8.3 Hz,

2H; 2’-H, 5’-H), 8.22 (d, J = 9.0 Hz, 2H; arom.), 8.43 (d, J = 9.0 Hz,

2H; arom.) ppm; ¹³C NMR (75MHz, [D ₄]MeOH/NaOD 99:1): d = 28.2,

28.4, 29.8 (C-3’/C-4’, C-3’’/C-4, C-3/C-4’’), 60.0, 60.1 (C-2/C-5’’, C-5/C-2’’),

65.9 (CH₂-OH), 68.1 (C-2’/C-5’), 125.8, 130.1, 148.8, 151.6 (arom.) ppm;

IR (film): n˜ = 3333, 2956, 2924, 2872, 1528, 1350, 1309, 1161, 1044, 736,

621 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₂₀H₃₁N₄O₆S: 455.1964, 455.1962

[M+H]⁺.

(2’S,5’S,2’’S,5’’S,1R,4S)-1,4-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldi-

phenylsilyloxy)methyl]-pyrrolidin-2’-yl-1-(trimethylsilyl)oxy-4-acetoxy-2-

butyne (25): Alcohol 17 (4.41 g, 4.56 mmol) in CH₂Cl₂(70 mL) was

cooled to 08C, NEt₃(2.5mL, 18 mmol, 4 equiv), Ac ₂O (0.86 mL,

9.1 mmol, 2 equiv) and DMAP (11 mg, 0.09 mmol, 2 mol%) were added,

and the mixture was stirred for 1 h at 08C and for 1 h at RT. The mixture

was diluted with Et₂O and sat. NH₄HCO₃(100 mL each) and stirred for

15min, and the layers were separated. The aqueous layer was extracted

with Et₂O (2î50 mL), and the combined organic layers were washed

with brine (2î30 mL), dried (Na₂SO₄) and concentrated. Double FCC

(100 g and 20 g, PE/MTBE 4:1) provided ester 25 (4.67 g, 4.34 mmol,

(2S,5S,2’S,5’S,2’’S,5’’S)-2,5-Bis-[N’-tert-butoxycarbonyl-5’-(tert-butyldiphe-

nylsilyloxy)methyl]-pyrrolidin-2’-yl-tetrahydrofuran (28): Alcohol 27

(2.48 g, 2.46 mmol) and NEt₃(8.4 mL, 60 mmol, 24 equiv) in CH₂Cl₂

(125mL) were cooled to ꢀ508C, and MsCl (2.3 mL, 30 mmol, 12 equiv)

was added dropwise. The mixture was slowly was allowed to warm to

ꢀ158C, until conversion was complete (TLC monitoring). The mixture

was poured into sat. oxalic acid and H₂O (5 +0 50 mL) and the layers

were separated. The aqueous layer was extracted with Et₂O (2î75mL),

and the combined organic layers were washed with phosphate buffer

(1m, pH 7) and brine (50 mL each), dried (MgSO₄) and concentrated at

r.t. Silica gel filtration (30 g, Et₂O) gave the mesylate (2.51 g, 2.31 mmol,

94%) as a colourless foam. The mesylate (321 mg, 296 mmol) in THF

(6 mL) was cooled to ꢀ788C, and MeLi (640 mL, 0.92m in cumene/THF,

0.59 mmol, 2 equiv) was added dropwise. The solution was stirred at

ꢀ788C for 30 min and at 08C for 30 min. KOtBu (34 mg, 0.30 mmol,

1 equiv) was added, and the mixture was allowed to warmed to r.t. over

30 min. The mixture was partitioned between Et₂O and sat. NH₄Cl

(30 mL each), the aqueous layer was extracted with Et₂O (2î15mL),

and the combined organic layers were washed with brine (20 mL), dried

(MgSO₄) and concentrated. FCC (10 g, PE/MTBE 4:1!1:1!0:1) provid-

ed tetrahydrofuran 28 (123 mg, 130 mmol, 44%) followed by a dicarba-

mate side product (86.3 mg, 106 mmol, 36%), each as a colourless gum.

95%) as a colourless foam. R_f= 0.30 (n-hexane/MTBE 4:1); [a]_D²⁵

=

1

ꢀ64.5( c = 1.014 in CHCl₃); H NMR (300 MHz, CDCl₃): d = 0.07 0.10

(m, 9H; TMS), 1.03 (s, 18H; Si-tBu), 1.27/1.48 (each s, 18H; Boc), 2.02/

2.05(each s, 3H; Ac), 1.78 2.28, 2.33 2.50 (2 m, 8H; 3 ’-H₂, 3’’-H₂, 4’-H₂,

4’’-H₂), 3.43 3.74 (m, 3H; CH₂-OSi), 3.78 4.07 (m, 5H; CH₂-OSi, 2’-H,

5’-H, 2’’-H, 5’’-H), 5.07 (m, 1H; 1-H), 5.97 6.08 (m, 1H; 4-H), 7.33 7.45

(m, 12H; arom.), 7.59 7.64 (m, 8H; arom.) ppm; ¹³C NMR (75MHz,

CDCl₃): d = ꢀ0.2/ꢀ0.1 (TMS), 19.2 (Si-C(CH₃)₃), 20.9 (Ac), 24.9, 26.4,

26.9, 27.7 (C-3’, C-3’’, C-4’, C-4’’), 26.8 (Si-C(CH₃)₃), 28.3, 28.4 (2î), 28.6

(O-C(CH₃)₃), 59.6, 59.7 (C-5’, C-5’’), 62.2, 62.4 (C-1, C-4), 62.9, 63.3 (C-2’,

C-2’’), 64.0, 64.2 (CH₂-OSi), 79.4, 79.7, 80.3, 80.6 (O-C(CH₃)₃), 86.0, 86.4

(C-2, C-3), 127.6, 127.7, 129.6, 129.7, 133.4, 135.5 (arom.), 153.0, 153.7

(Boc-C=O), 169.5(Ac-C =O) ppm; IR (film): n˜ = 3072, 3051, 2960, 2932,

2859, 1750, 1695, 1474, 1462, 1428, 1392, 1367, 1335, 1253, 1230, 1174,

1113, 1036, 927, 882, 845, 823, 740, 703, 613 cm^ꢀ1; HRMS (ESI): m/z:

calcd for C₆₁H₈₇N₂O₉Si₃: 1075.572; found: 1075.592 [M+H]⁺; elemental

analysis calcd for C₆₁H₈₆N₂O₉Si₃(1075.600): C 68.12, H 8.06, N 2.60;

found: C 68.17, H 8.10, N 2.66.

Compound 28: R_f= 0.28 (n-hexane/MTBE 4:1); [a]²_D⁴= ꢀ63.1 (c =

1

0.900 in CHCl₃); H NMR (300 MHz, CDCl₃): d = 1.03 (s, 18H; Si-tBu),

1.26/1.46 (s, 18H; Boc), 1.51 1.61 (m, 4H; 3-H₂, 4-H₂), 1.74 2.09 (m, 8H;

3’-H₂, 3’’-H₂, 4’-H₂, 4’’-H₂), 3.42 3.53 (m, 2H; CH₂-OSi), 3.61 3.76 (m,

2H; CH₂-OSi), 3.84 4.01 (m, 2H; 5’-H, 5’’-H), 4.01 4.10 (m, 2H; 2’-H,

2’’-H), 4.31 4.45 (m, 2H; 2-H, 5-H), 7.33 7.45 (m, 12H; arom.), 7.59 7.67

(2’S,5’S,2’’S,5’’S,1R,4S)-1,4-Bis-[N’-tert-butoxycarbonyl-5-(tert-butyldiphe-

nylsilyloxy)methyl]-pyrrolidin-2’-yl-4-acetoxy-2-butyn-1-ol (26): TMS-

ether 25 (4.39 g, 4.08 mmol) was deprotected by the procedure given for

compound 16. FCC (100 g, PE/MTBE 2:1) provided alcohol 26 (4.08 g,

(m, 8H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃):

d = 19.0 (Si-

C(CH₃)₃), 22.4, 24.3, 25.4, 26.8, 27.2, 27.6 (C-3, C-3’, C-3’’, C-4, C-4’, C-

4’’), 26.6 (Si-C(CH₃)₃), 28.1, 28.3 (O-C(CH₃)₃), 59.2, 59.6 (C-2’, C-2’’, C-5’,

C-5’’), 78.8, 78.9 (C-2, C-5), 79.5 (O-C(CH₃)₃), 127.4, 129.3, 129.4, 133.2,

133.4, 135.3, 135.4 (arom.); 154.0 (Boc-C=O) ppm; IR (film): n˜ = 3071,

3050, 2963, 2932, 2859, 1694, 1473, 1428, 1392, 1366, 1256, 1176, 1113,

739, 703, 614 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₅₆H₇₉N₂O₇Si₂: 947.543;

found: 947.547 [M+H]⁺; elemental analysis calcd (%) for C₅₆H₇₈N₂O₇Si₂

(947.399): C 70.99, H 8.30, N 2.96; found C 71.01, H 8.63, N 2.92.

4.07 mmol, 100%) as a colourless foam. R_f

= 0.20 (n-hexane/MTBE

2:1); [a]²_D⁴= ꢀ54.1 (c = 0.194 in CHCl₃); ¹H NMR (300 MHz, CDCl₃):

d = 1.03 (s, 18H; Si-tBu), 1.28/1.48 (each s, 18H; Boc), 2.03/2.06 (each s,

3H; Ac), 1.65 1.71, 1.88 2.17, 2.21 2.48 (3îm, 8H; 3’-H₂, 3’’-H₂, 4’-H₂,

4’’-H₂), 3.49 3.66 (m, 4H; CH₂-OSi), 3.86 4.08 (m, 3H; 5’-H, 2’’-H, 5’’-H),

4.10 4.21 (m, 1H; 2’-H), 4.49 (dd, J = 8.5, 1.5 Hz, 1H; 1-H), 5.95 6.03

(m, 1H; 4-H), 7.33 7.45(m, 12H; arom.), 7.59 7.64 (m, 8H; arom.) ppm;

¹³C NMR (75MHz, CDCl ₃): d = 19.2 (Si-C(CH₃)₃), 20.9 (Ac), 26.5, 26.9,

27.0, 27.6 (C-3’, C-3’’, C-4’, C-4’’), 26.8 (Si-C(CH₃)₃), 28.2, 28.3, 28.4 (O-

C(CH₃)₃), 59.3, 59.5, 59.6, 59.7, 60.8 (C-5’, C-5’’), 63.1 (C-4), 63.6, 63.7 (C-

2’, C-2’’), 63.9, 64.1 (CH₂-OSi), 68.4 (C-1), 79.4, 79.8, 80.0, 80.6, 81.0 (O-

C(CH₃)₃), 127.6, 127.7, 129.6, 133.1, 133.3, 133.6, 135.5 (arom.), 153.1,

Side product (1,2-bis-[8’-(tert-butyldiphenylsilyloxy)methyl]-1’-aza-3’-oxa-

bicyclo[3.3.0]octan-2’-on-4’-yl-ethane: R_f= 0.03 (n-hexane/MTBE 1:1);

¹H NMR (300 MHz, CDCl₃): d = 1.04 (s, 18H; Si-tBu), 1.85 2.28 (m,

12H; 1-H₂, 6’-H₂, 7’-H₂), 3.48 3.60 (m, 2H; CH₂-OSi), 3.64 3.73 (m, 2H;

CH₂-OSi), 3.93 4.02 (m, 4H; 5’-H, 8’-H), 4.30 4.39 (m, 2H; 4’-H), 7.31

7.44 (m, 12H; arom.), 7.59 7.67 (m, 8H; arom.) ppm; ¹³C NMR

153.7, 156.9 (Boc-C=O), 169.2 (Ac-C=O) ppm; IR (film): n˜

= 3423,

Chem. Eur. J. 2004, 10, 3945 3962 www.chemeurj.org

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3957

S. M¸ller, U. Koert et al.

FULL PAPER

(75MHz, CDCl ₃): d = 19.0 (Si-C(CH₃)₃), 26.6 (Si-C(CH₃)₃), 27.2 (C-7’),

30.8 (C-1), 31.5(C-6 ’), 59.5 (C-8’), 64.7 (C-5’), 65.8 (CH₂-OSi), 78.9 (C-

4’), 127.7, 129.6, 133.2, 135.5 (arom.), 160.6 (C-2’).

(2.0 g, 52 mmol, 1.3 equiv) in THF (60 mL). The mixture was stirred for

1 h. H₂O (2.1 mL, Caution!) and NaOH (2m, 5.8 mL) were then added

dropwise. The white suspension was heated at reflux for 10 min, cooled

to RT and filtered through a pad of Celite. The volatiles were removed in

vacuo, and recrystallization of the residue from hot MTBE provided al-

cohol 49 (7.88 g, 24.7 mmol, 60%) as colourless crystals. R_f= 0.14 (n-

hexane/MTBE 1:1); m.p. 1118C (MTBE); [a]²_D¹= ꢀ3.2 (c = 1.10 in

EtOH); ¹H NMR (300 MHz, CDCl₃): d = 0.90 (d, J = 6.6 Hz, 3H; 3-

H₃), 1.67 (m, 1H; -OH), 2.43 (s, 3H; Ts-CH₃), 3.26 (bt, J = 5.9 Hz, 2H;

1-H₂), 4.01 (hex, J = 6.9 Hz, 1H; 2-H), 4.15(d, J = 15.6 Hz, 1H; N-

(2S,5S,2’S,5’S,2’’S,5’’S)-2,5-Bis-[5’-(tert-butyldiphenylsilyloxy)methyl]-pyr-

rolidin-2’-yl-tetrahydrofuran (29): Di-Boc compound 28 (598 mg,

631 mmol) was deprotected as described in GP 1. FCC (15g, cyclohexane/

EtOAc 1:1!EtOAc!EtOAc/MeOH 85:15) gave diamine 29 (464 mg,

621 mmol, 98%) as a colourless oil. R_f= 0.26 (CHCl₃/MeOH/HCOOH

100:5:5); [ a]_D

=

ꢀ6.7 (c

=

0.867 in CH₂Cl₂); ¹H NMR (300 MHz,

CDCl₃): d = 1.02 (s, 18H; Si-tBu), 1.30 1.65/1.72 2.00 (m, 12H; 3-H₂, 4-

H₂, 3’-H₂, 3’’-H₂, 4’-H₂, 4’’-H₂), 2.99 3.17 (m, 4H; 2’-H, 2’’-H, 5’-H, 5’’-H),

3.36 3.47 (m, 2H; CH₂-OSi), 3.48 3.64 (m, 4H; CH₂-OSi, 2îNH), 3.74

3.85(m, 2H; 2-H, 5-H), 7.33 7.42 (m, 12H; arom.), 7.61 7.66 (m, 8H; ar-

om.) ppm; ¹³C NMR (300 MHz, CDCl₃): d = 19.2 (Si-C(CH₃)₃), 26.8 (Si-

C(CH₃)₃), 27.6, 27.7, 29.5(C-3/C-4, C-3 ’/C-3’’, C-4’/C-4’’), 59.0 (CH₂-OSi),

61.8, 66.9 (C-2’/C-2’’, C-5’/C-5’’), 82.4 (C-2, C-5), 127.6, 129.5, 133.7, 135.6

(arom.) ppm; IR (film): n˜ = 3070, 3048, 2959, 2931, 2858, 1472, 1428,

1390, 1112, 1087, 824, 740, 702, 613 cm^ꢀ1; HRMS (ESI): m/z: calcd for

C₄₆H₆₃N₂O₃Si₂: 747.438; found: 747.437 [M+H]⁺.

CH₂-Ph), 4.66 (d, J

arom.), 7.72 (d,

=

15.6 Hz, 1H; N-CH₂-Ph), 7.27 7.36 (m, 7H;

J

=

8.3 Hz, 2H; arom.) ppm; ¹³C NMR (75MHz,

CDCl₃): d = 14.1 (C-3), 21.5(Ts- CH₃), 47.5( CH₂-Ph), 55.9 (C-2), 64.8

(CH₂-OH), 127.8, 127.9, 128.7, 129.8, 128.5, 137.7, 138.1, 143.4 (ar-

om.) ppm; IR (KBr): n˜

= 3483 (-OH), 2975, 2931, 1320, 1304, 1150,

1090, 1015, 730, 658 cm^ꢀ1; elemental analysis calcd (%) for C₁₇H₂₁NO₃S

(319.42): C 63.92, H 6.63, N 4.39, S 10.04; found C 63.91, H 6.54, N 4.41,

S 9.97.

(S)-N-Benzyl-2-(p-tolylsulfonyl-amino)propanal (35): DMSO (3.1 mL,

43 mmol, 3.3 equiv) was added dropwise (Caution!) to a stirred solution

of oxalyl chloride (1.85mL, 21.6 mmol, 1.7 equiv) in CH ₂Cl₂(60 mL) at

ꢀ658C, and the system was allowed to warm to ꢀ558C over 20 min. The

solution was cooled to ꢀ808C, alcohol 49 (4.19 g, 13.1 mmol) in CH₂Cl₂

(15mL) was added dropwise, and the mixture was stirred for 30 min.

EtN(iPr)₂(17.5mL, 0.1 mol, 7.8 equiv) was then added dropwise, and the

mixture was allowed to warm to 08C and stirred for 20 min. The mixture

was extracted with H₃PO₄(2m, 100 mL), and the aqueous layer was ex-

tracted with Et₂O (2î50 mL). The organic layers were combined,

washed with phosphate buffer (1m, pH 7) and brine (30 mL each), dried

(Na₂SO₄), filtered over silica gel (20 g, 50 mL Et₂O rinse) and concentrat-

ed at RT. Recrystallization from hexanes/MTBE (1:4, 10 mLg^ꢀ1) at 48C

(2S,5S,2’S,5’S,2’’S,5’’S)-2,5-Bis-[N’-trifluoroacetyl-5’-(tert-butyldiphenylsi-

lyloxy)methyl]-pyrrolidin-2’-yl-tetrahydrofuran

(30):

Diamine

29

(73.8 mg, 98.8 mmol) and pyridine (25 mL, 0.3 mmol, 3 equiv) in anhy-

drous CHCl₃(2 mL) were cooled to ꢀ208C, and trifluoroacetic anhydride

(35 mL, 0.25mmol, 2.5equiv) in CHCl (0.5mL) was added dropwise.

3

The mixture was stirred for 1 h, reaching 08C, quenched by addition of

sat. NH₄HCO₃(3 mL) and partitioned between MTBE and H₂O (15mL

each). The aqueous layer was extracted with MTBE (3î5mL), and the

combined organic layers were washed with citric acid (5wt%) and brine

(10 mL each), dried (MgSO₄) and concentrated. FCC (5g, n-hexane/

MTBE 10:3) provided bis-trifluoroacetamide 30 (75.4 mg, 80.3 mmol,

81%) as a colourless solid. Single crystals for X-ray crystallography were

obtained from acetone/n-heptane (1:1, 100 mLg^ꢀ1) by slow evaporation

(8 weeks). R_f= 0.23 (n-hexane/MTBE 3:1); m.p. 137 139.58C (n-hep-

tane); [a]²_D⁵= ꢀ6.7 (c = 0.46 in CHCl₃); ¹H NMR (300 MHz, CDCl₃,

major rotamer): d = 1.03 (s, 18H; Si-tBu), 1.52 1.72 (m, 4H; 3-H₂, 4-H₂,

3’-H₂, 4’-H₂), 1.92 2.19 (m, 7H; 3-H₂, 4-H₂, 3’-H₂, 4’-H₂, 3’’-H₂, 4’’-H₂),

2.22 2.46 (m, 1H; 3’’-H₂), 3.61 (dd, J = 10.6, 2.6 Hz, 2H; CH₂OSi), 3.73

3.84 (m, 1H; 2-H), 3.89 3.97 (m, 1H; 5-H), 4.12 4.34 (m, 4H; 2’-H, 2’’-

H, 5’-H, 5’’-H), 7.31 7.43 (m, 12H; arom.), 7.53 7.63 (m, 8H; ar-

om.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 19.2 (Si-C(CH₃)₃), 24.6 (C-

4’, C-4’’), 26.8 (Si-C(CH₃)₃), 28.1 (C-3’, C-3’’), 30.1 (C-3, C-4), 60.0, 60.2,

61.0 (C-2’/C-2’’, C-5’/C-5’’), 62.6 (CH₂-OSi), 79.0, 79.3 (C-2, C-5), 127.7,

127.8, 129.7, 129.9, 133.2, 133.3, 135.5 (arom.) ppm; trifluoroacetyl not de-

tected; IR (film): n˜ = 3072, 3050, 2958, 2932, 2858, 1673 (C=O), 1472,

1429, 1229, 1183, 1143, 1112, 1064, 999, 823, 741, 702, 615cm ^ꢀ1; elemental

analysis calcd (%) for C₅₀H₆₀N₂O₅F₆Si₂(939.202): C 63.94, H 6.44, N

2.98; found C 63.98, H 6.44, N 3.15.

gave aldehyde 35 (3.18 g, 10.0 mmol, 77%) as colourless needles. R_f

=

0.37 (n-hexane/MTBE 1:1); m.p. 81.5 82.58C (MTBE); [a]²_D²= ꢀ69.2

(c = 1.01 in CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): d = 1.13 (d, J =

7.2 Hz, 3H; 3-H₃), 2.44 (s, 3H; Ts-CH₃), 4.17 (q, J = 7.2 Hz, 1H; 2-H),

4.17 (d, J = 14.8 Hz, 1H; N-CH₂-Ph), 4.53 (d, J = 14.8 Hz, 1H; N-CH₂-

Ph), 7.29 7.35(m, 7H; arom.), 7.75(d, J = 8.3 Hz, 2H; arom.), 9.28 (s,

1H; -CHO) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 11.1 (C-3), 21.5(Ts-

CH₃), 49.1 (CH₂-Ph), 61.4 (C-2), 127.2, 128.5, 128.8, 129.9, 135.4, 137.0,

143.9 (arom.), 198.9 (CHO) ppm; IR (KBr): n˜ = 3132, 2923, 1729, 1634,

1598, 1455, 1399, 1386, 1334, 1171, 1155, 832, 736, 659 cm^ꢀ1; HRMS (EI):

m/z: calcd for C₁₇H₂₀NO₃S: 318.1128; found: 318.1131 [M+H]⁺; elemen-

tal analysis calcd (%) for C₁₇H₁₉NO₃S (317.40): C 64.33, H 6.03, N 4.41, S

10.10; found C 64.29, H 6.09, N 4.56, S 10.06.

(3RS,4SR)-N-Benzyl-N-tosyl-4-amino-1-trimethylsilyl-1-pentyn-3-ol (36):

Trimethylsilylacetylene (0.86 mL, 12 mmol, 4 equiv) in THF (10 mL) was

treated at ꢀ788C with nBuLi (2.3m in hexanes, 1.9 mL, 4.4 mmol,

1.5equiv) for 15min, and the mixture was cooled to ꢀ908C. Racemic al-

dehyde 35 (934 mg, 2.94 mmol) in THF (10 mL) was added dropwise,

and the mixture was allowed to warm to ꢀ308C in 2 h. The mixture was

partitioned between MTBE (30 mL) and HCl (0.5m, 20 mL), and the

aqueous layer was extracted with MTBE (3î25mL). The combined or-

ganic layers were washed with brine (50 mL), dried (MgSO₄) and concen-

trated. FCC (50 g, PE/MTBE/MeOH 50:10:1!30:10:1) gave racemic

syn-alcohol 36 (1.03 g, 2.48 mmol, 84%) as a colourless solid. Single crys-

tals for X-ray crystallography were obtained from n-hexane/MTBE

(10:1). R_f= 0.46 (n-hexane/MTBE 1:1); m.p. 93.5 94.58C (n-hexane);

(2S,5S,2’S,5’S,2’’S,5’’S)-2,5-Bis-(5’-hydroxymethyl)-pyrrolidin-2’-yl-tetrahy-

drofuran (6): TBDPS-ether 29 (207 mg, 277 mmol) was dissolved in

MeOH (10 mL, polypropylene flask), conc. HF (1.0 mL) was added

(Caution!), and the mixture was stirred for 16 h at RT. The volatiles

were removed in vacuo, and FCC (15g, CHCl ₃/MeOH/aq. NH₃45:15:1

+0%!1%!2%!5 % HO) gave diamino diol 2, which was taken up

2

in CHCl₃and filtered over Celite to yield a colourless oil (70.1 mg,

259 mmol, 94%). R_f= 0.20 (CHCl₃/MeOH/aq. NH₃/H₂O 45:15:1:3); [ a]_D²⁴

= 14.7 (c = 0.68 in MeOH); ¹H NMR (300 MHz, [D₄]MeOH/NaOD

99:1): d = 1.37 1.62, 1.86 2.18 (2 m, 12H; 3-H₂, 3’-H₂, 3’’-H₂, 4-H₂, 4’-H₂,

4’’-H₂), 3.07 (dd, J = 15.8, 7.6 Hz, 2H; 2’-H, 2’’-H), 3.25 3.33 (m, 2H; 5’-

H, 5’’-H), 3.44 3.52 (m, 4H; CH₂-OH), 3.80 (dd, J = 14.0, 7.8 Hz, 2H; 2-

H, 5-H) ppm; ¹³C NMR (75MHz, [D ₄]MeOH/NaOD 99:1): d = 28.5,

28.6 (C-3’/C-3’’, C-4’/C-4’’), 30.6 (C-3, C-4), 60.2, 62.9 (C-2’/C-2’’, C-5’/C-

5’’), 65.8 (CH₂-OH), 83.5(C-2, C-5) ppm; HRMS (FAB): m/z: calcd for

C₁₄H₂₇N₂O₃: 271.2021; found: 271.2029 [M+H]⁺.

¹H NMR (300 MHz, CDCl₃): d

= 0.14 (s, 9H; TMS), 1.16 (d, J =

7.0 Hz, 3H; 5-H₃), 2.26 (d, J = 5.6 Hz, 1H; -OH), 2.42 (s, 3H; Ts-CH₃),

4.09 (m, 1H; 4-H), 4.33 (t, J = 5.6 Hz, 1H; 3-H), 4.36 (d, J = 16.0 Hz,

1H; N-CH₂-Ph), 4.52 (d, J = 16.0 Hz, 1H; N-CH₂-Ph), 7.25 7.41 (m,

7H; arom.), 7.70 (d,

J =

8.3 Hz, 2H; Ts-arom.) ppm; ¹³C NMR

(75MHz, CDCl ₃): d = 0.1 (TMS), 13.3 (C-5), 21.7 (Ts-CH₃), 48.9 (CH₂-

Ph), 58.5 (C-4), 66.2 (C-3), 91.6 (C-2), 104.3 (C-1), 127.3, 127.4, 128.6,

129.9, 137.9, 138.2, 143.6 (arom.) ppm; IR (film): 3492, 3062, 3030, 2959,

2173, 1496, 1455, 1362, 1338, 1249, 1204, 1154, 1117, 1090, 1069, 1010,

921, 844, 816, 762, 733, 698, 666, 602 cm^ꢀ1; elemental analysis calcd (%)

for C₂₂H₂₉NO₃SiS (415.622): C 63.58, H 7.03, N 3.37, S 7.72; found: C

63.42, H 7.17, N 3.32, S 7.68.

(S)-N-Benzyl-2-(p-tolylsulfonyl-amino)propanol (49): N-Tosylalanine

(10 g, 41 mmol) was dissolved in DMF (75mL), K ₂CO₃(28 g, 0.2 mol,

5equiv) and BnBr (17 mL, 0.14 mol, 3.5equiv) were added, and the mix-

ture was stirred at RT for 2 h. It was then partitioned between MTBE

(200 mL) and sat. NH₄Cl solution (75mL), washed with H ₂O and brine

(50 mL each), dried (MgSO₄), concentrated, coevaporated with toluene

(2î150 mL) and dried in vacuo. The crude benzyl ester (approx. 18 g) in

THF (30 mL) was added dropwise to an ice-cooled suspension of LiAlH₄

(2S,5S,1’R,4’R,5’S)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsilyloxy)-

methyl-2-[N’-benzyl-5’-(p-tolylsulfonyl)amino-4’-hydroxy-1’-(trimethylsi-

3958

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

lyl)oxy]-2’-hexynyl-pyrrolidine (37): Alkyne

2

(4.73 g, 8.36 mmol,

(s, 3H; Ts-Me), 3.13 3.18 (m, 1H; 4’-H), 3.52 3.69 (m, 3H; 1’-H, 1’’-H₂),

3.76 3.83 (m, 1H; 5’-H), 3.90 3.99 (m, 2H; 2-H, 5-H), 4.13/4.70 (each d,

J = 15.4 Hz, 2H; N-CH₂-Ph), 4.29/5.23 (each s, 2H; OH), 7.26 7.30 (m,

5H; Bn-arom.), 7.35 7.44 (m, 8H; arom.), 7.61 7.71 (m, 6H; ar-

1.2 equiv) in THF (40 mL) was cooled to ꢀ788C, and nBuLi (2.5m in

hexanes, 3.34 mL, 8.36 mmol, 1.2 equiv) was added slowly with stirring.

After 40 min, aldehyde 35 (2.21 g, 6.96 mmol) dissolved in THF (40 mL)

was added dropwise (10 min). The mixture was stirred at ꢀ788C for 2 h,

and was then allowed to warm to ꢀ258C over 1.5h. The mixture was ex-

tracted with NH₄HCO₃/H₂O (1:2, 150 mL), and the aqueous layer was ex-

tracted with MTBE (2î50 mL). The combined organic layers were

washed with brine (50 mL), dried (MgSO₄) and evaporated. FCC (2î

100 g, CH₂Cl₂/n-hexane 3:1!1:0!CH₂Cl₂/acetone 99:1!98:2) delivered

om.) ppm; ¹³C NMR (75MHz, CDCl ₃):

d = 12.9 (C-6’), 19.2 (Si-

C(CH₃)₃), 21.5(Ts-Me), 26.8 (2î, Si-C( CH₃)₃), 28.3 (2î, O-C(CH₃)₃),

26.8, 29.8, 32.6 (C-3, C-4, C-2’, C-3’), 47.9 (N-CH₂-Ph), 58.8 (C-5’), 60.4

(C-2), 63.4 (C-5), 64.0 (C-1’’), 74.7 (C-4’), 75.9 (C-1’), 80.5(O- C(CH₃)₃),

127.1, 127.4, 127.7, 127.8, 128.4, 128.5, 129.7, 133.2, 133.4, 135.5, 137.9,

ꢀ

138.3, 143.1 (arom.), 156.0 (Boc-C=O) ppm; IR (film): n˜ = 3384 (O H),

3070, 2960, 2932, 2859, 1687, 1668, 1456, 1428, 1393, 1367, 1338, 1266,

1166, 1113, 1092, 1007, 860, 821, 775, 736, 703, 659 cm^ꢀ1; HRMS (EI): m/

z: calcd for C₄₂H₅₃N₂O₇SiS: 757.3343; found: 757.3299 [MꢀC₄H₉]⁺; ele-

mental analysis calcd (%) for C₄₆H₆₂N₂O₇SiS (815.16): C 67.78, H 7.67, N

3.44, S 3.93; found C 67.59, H 7.64, N 3.37, S 3.65.

alcohol 37 (5.63 g, 6.37 mmol, 92%) as a colourless gum. R_f

= 0.24

(CH₂Cl₂/acetone 98:2); [a]²_D⁰= ꢀ38.0 (c = 1.00 in CHCl₃); ¹H NMR

(300 MHz, CDCl₃, 71:29 mixture of rotamers): d = 0.07/0.10 (each s, 9H;

TMS), 1.04/1.06 (each s, 9H; Si-tBu), 1.11 (m, 3H; 6’-H₃), 1.29/1.47

(each s, 71:29, 9H; Boc), 1.89 (d, J = 5.7 Hz, 1H, -OH), 1.95 2.23 (m,

4H; 3-, 4-H₂), 2.43 (s, 3H; Ts-Me), 3.48/3.72 (each dd, J = 9.4, 7.1 Hz,

2H; 1’’-H₂), 3.79 3.95(m, 2H; 2-H, 5-H), 4.02 4.14 (m, 1H; 5 ’-H), 4.37

4.44 (m, 1H; 4’-H), 4.40/4.64 (each d, J = 16 Hz, 2H; N-CH₂-Ph), 4.85/

5.05 (each t, J = 2 Hz, 29:71, 1H; 1’-H), 7.24 7.28 (m, 5H; Bn-arom.),

7.30 7.46 (m, 8H; arom.), 7.63 7.69 (m, 6H; arom.) ppm; ¹³C NMR

(75MHz, CDCl ₃): d = 0.0 (TMS), 12.6 (C-6’), 19.4 (2î, Si-C(CH₃)₃),

21.7 (Ts-Me), 24.6 (C-4), 27.0 (Si-C(CH₃)₃), 27.8 (2î, C-3), 28.5(2î, O-

C(CH₃)₃), 48.7 (CH₂-Ph), 58.3 (C-5’), 59.8 (2î, C-2), 62.3 (C-1’), 63.1 (2î

, C-5), 64.3 (C-1’’), 66.0 (2î, C-4’), 79.7 (2î, O-C(CH₃)₃), 83.5(2î, C-

2’), 86.5(2î, C-3 ’), 127.3, 127.8, 127.9, 128.1, 128.7, 129.7, 129.9, 133.5,

133.7, 135.7, 137.8, 138.4, 143.5 (arom.), 153.9 (Boc-C=O) ppm; IR (film):

(2S,4R,7R,2’S,5’S,1’’S)- and (2R,4R,7R,2’S,5’S,1’’S)-4-[N’-tert-Butoxycar-

bonyl-5’-(tert-butyldiphenylsilyloxy)methyl]-pyrrolidin-2’-yl-7-[1’’-N’’-

benzyl-(p-tolylsulfonyl)amino]-ethyl-2-oxo-1,3-dioxathiepane (40a and

40b): Diol 39 (2.74 g, 3.36 mmol) in CH₂Cl₂(150 mL) was cooled to

ꢀ108C, and NEt₃(1.9 mL, 13 mmol, 4 equiv) was added. A solution of

SOCl₂(0.27 mL, 3.7 mmol, 1.1 equiv) in CH₂Cl₂(15mL) was added drop-

wise over 20 min, until the mixture became yellow. After complete con-

version (5min, TLC monitoring), the mixture was partitioned between

Et₂O (250 mL) and sat. NaHCO₃solution (50 mL). The layers were sepa-

rated, and the organic layer was washed with H₂O, NaHSO₄(2m) and

brine (50 mL each), dried (Na₂SO₄) and concentrated. FCC (100 g, PE/

MTBE 4:1!3:1!2:1!1:1) gave the (2R)-sulfite 40a (1.28 g, 1.48 mmol,

44%) as a colourless solid, followed by the (2S)-sulfite 40b (1.45g,

1.68 mmol, 50%) as a colourless syrup. Compound 40a crystallized from

toluene/n-hexane in colourless needles, and X-ray crystallography con-

firmed the stereochemical assignments (see Supporting Information for

details).

ꢀ

n˜ = 3453 (O H), 3067, 2959, 2250w (CꢁC), 1686, 1395, 1337, 1254, 1164,

1112, 1034, 846, 734, 704 cm^ꢀ1

;

elemental analysis calcd (%) for

C₄₉H₆₆N₂O₇Si₂S (883.31): C 66.63, H 7.53, N 3.17, S 3.63; found C 66.54,

H 7.67, N 3.06, S 3.43.

(2S,5S,1’R,4’R,5’S)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsilyloxy)-

methyl-2-[N’-benzyl-5’-(p-tolylsulfonyl)amino-1’,4’-dihydroxy]-2’-hexynyl-

pyrrolidine (37): TMS-ether 37 (4.29 g, 4.86 mmol) in THF/MeOH (1:1,

80 mL) was cooled to 08C, and CSA (57 mg, 0.24 mmol, 5 mol%) was

added. After 30 min, sat. NaHCO₃solution (10 mL) was added, and the

organic solvents were removed in vacuo. The residue was partitioned be-

tween EtOAc and brine (50 mL each). The aqueous layer was extracted

with EtOAc (50 mL), and the combined organic layers were dried

(MgSO₄) and concentrated. FCC (100 g, PE/EtOAc 3:1!2:1!1:1) gave

diol 38 (3.73 g, 4.60 mmol, 95%) as a colourless gum; R_f= 0.23 (n-

Compound 40a: R_f= 0.33 (n-hexane/MTBE 3:1); m.p. 153 1548C (n-

hexane); [a]²_D⁴

=

+25.3 (c = 0.708 in CH₂Cl₂); ¹H NMR (300 MHz,

CDCl₃, 78:22 mixture of rotamers): d = 0.62 0.79 (m, 1H; 5-H₂), 0.91 (d,

J = 6.8 Hz, 3H; 2’’-H₃), 1.01 (s, 9H; Si-tBu), 1.24 (s, 78:22, 9H; Boc),

1.26 1.70 (m, 3H; 5-H₂, 6-H₂), 1.85 2.14 (m, 4H; 3’-H₂, 4’-H₂), 2.42 (s,

3H; Ts-Me), 3.50 (dd, J = 9.6, 6.4 Hz, 1H; CH₂-OSi), 3.55 3.66 (m, 2H;

CH₂-OSi, 2’-H), 3.82 3.96 (m, 3H; 5’-H, 1’’-H, N-CH₂-Ph), 4.26 (t, J =

10.2 Hz, 1H; 7-H), 4.74 4.84 (m, 2H; 4-H, N-CH₂-Ph), 7.21 7.62 (m,

17H; arom.), 7.70 (d, J = 8.3 Hz, 2H; arom.) ppm; ¹³C NMR (75MHz,

hexane/EtOAc 2:1); [a]_D²⁴

=

ꢀ15.2 (c

=

1.43 in CH₂Cl₂); ¹H NMR

CDCl₃): d

= 13.9 (C-2’’), 19.2 (Si-C(CH₃)₃), 21.5(Ts-Me), 26.8 (Si-

(300 MHz, CDCl₃, 93:7 mixture of rotamers): d = 1.06 (s, 9H; Si-tBu),

1.12 (d, J = 6.8 Hz, 3H; 6’-H₃), 1.31/1.48 (each s, 93:7, 9H; Boc), 1.97

2.29 (m, 4H; 3-H₂, 4-H₂), 2.42 (s, 3H; Ts-Me), 3.57 3.70 (m, 2H; 1’’-H₂),

3.86 3.96 (m, 1H; 2-H), 4.05 4.09 (m, 2H; 5-H, 5’-H), 4.42 4.44 (m, 1H;

C(CH₃)₃), 28.3 (O-C(CH₃)₃), 23.2, 27.4, 28.5, 29.8 (C-3’, C-4’, C-5, C-6),

47.4 (N-CH₂-Ph), 56.0 (C-1’’), 59.1(C-5’), 61.3 (C-2’), 64.4 (CH₂-OSi), 74.5

(C-4), 74.6 (C-7), 79.7 (O-C(CH₃)₃), 126.9, 127.0, 127.7, 127.8, 128.8,

129.2, 129.7, 129.9, 133.3, 133.5, 135.4, 137.5, 137.6, 143.5 (arom.), 153.8

(Boc-C=O) ppm; IR (film): n˜ = 3070, 2960, 2932, 2858, 1687, 1456, 1428,

1394, 1366, 1342, 1210, 1167, 1113, 1086, 1006, 948, 864, 740, 706, 657,

613 cm^ꢀ1; elemental analysis calcd (%) for C₄₆H₆₀N₂O₈SiS₂(861.20): C

64.16, H 7.02, N 3.25, S 7.45; found C 64.19, H 7.00, N 3.28, S 7.33.

4’-H), 4.38/4.65(each d,

J = 16.2 Hz, 2H; N-CH₂-Ph), 4.54 (d, J =

8.3 Hz, 1H; 1’-H), 5.41/5.75 (each d, J = 8.3 Hz, 93:7, 1H; -OH), 7.24

7.33 (m, 5H; Bn-arom.), 7.36 7.44 (m, 8H; arom.), 7.62 7.73 (m, 6H; ar-

om.) ppm; ¹³C NMR (75MHz, CDCl ₃):

d = 12.7 (C-6’), 19.2 (Si-

C(CH₃)₃), 21.5(Ts-Me), 26.7 (C-4), 26.9 (2î, Si-C( CH₃)₃), 27.4 (C-3),

28.3 (2î, O-C(CH₃)₃), 48.7 (N-CH₂-Ph), 58.4 (C-5’), 60.6 (C-2), 63.8 (C-

5), 64.2 (C-1’’), 65.8 (2î, C-4’), 67.1 (C-1’), 80.7 (O-C(CH₃)₃), 84.4 (C-3’),

85.4 (C-2’), 127.1, 127.4, 127.7, 127.8, 128.5, 129.7, 129.8, 133.2, 133.4,

135.5, 137.7, 138.1, 143.4 (arom.), 156.3 (Boc-C=O) ppm; IR (film): n˜ =

Compound 40b: R_f= 0.14 (n-hexane/MTBE 3:1); [a]_D²⁴

= +31.6 (c =

0.776 in CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃, major rotamer): d = 0.99

(d, J = 6.8 Hz, 3H; 2’’-H₃), 1.02 (s, 9H; Si-tBu), 1.29 (s, 9H; Boc), 0.85

1.10, 1.22 1.55, 1.60 1.75, 1.93 2.13 (each m, 8H; 5’-H₂, 6’-H₂, 3’-H₂, 4’-

H₂), 2.43 (s, 3H; Ts-Me), 3.45 3.56 (m, 1H; CH₂-OSi), 3.56 3.71 (m, 2H;

CH₂-OSi, 7-H), 3.72 3.76 (m, 1H; 2’-H), 3.78 3.95(m, 2H; 1 ’’-H, 5’-H),

4.00 (d, J = 15.1 Hz, 1H; N-CH₂-Ph), 4.63 (d, J = 15.1 Hz, 1H; N-CH₂-

Ph), 5.37 (d, J = 11.3 Hz, 1H; 4-H), 7.30 7.62 (m, 17H; arom.), 7.69 (d,

J = 8.3 Hz, 2H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 12.9 (C-

2’’), 19.2 (Si-C(CH₃)₃), 21.5(Ts-Me), 26.8 (Si-C( CH₃)₃), 28.2 (O-

C(CH₃)₃), 23.4, 27.5, 28.5, 30.9 (C-3’, C-4’, C-5, C-6), 48.0 (N-CH₂-Ph),

56.5 (C-1’’), 58.6 (C-5’), 61.0 (C-2’), 64.4 (CH₂-OSi), 73.6 (C-4), 78.0 (C-

7), 79.7 (O-C(CH₃)₃), 127.1, 127.7, 127.9, 128.7, 128.8, 129.6, 129.9, 133.5,

135.5, 143.6 (arom.), 153.7 (Boc-C=O) ppm; IR (film): n˜ = 3070, 2961,

2931, 2858, 1690, 1456, 1428, 1393, 1366, 1342, 1266, 1211, 1168, 1112,

1087, 1043, 1007, 960, 945, 863, 821, 739, 717, 703, 658, 607 cm^ꢀ1; elemen-

tal analysis calcd (%) for C₄₆H₆₀N₂O₈SiS₂(861.20): C 64.16, H 7.02, N

3.25, S 7.45; found: C 64.21, H 7.32, N 3.45, S 7.01.

ꢀ

3405(O H), 3068, 2961, 2935, 2862, 2251 (CꢁC), 1669, 1456, 1401, 1337,

1259, 1162, 1112, 1017, 913, 818, 734, 704, 658 cm^ꢀ1; HRMS (ESI): m/z:

calcd for C₄₆H₅₉N₂O₇SiS: 811.381; found: 811.380 [M+H]⁺; elemental

analysis calcd (%) for C₄₆H₅₈N₂O₇SiS (811.13): C 68.12, H 7.21, N 3.45, S

3.95; found C 67.85, H 7.37, N 3.37, S 3.73.

(2S,5S,1’R,4’R,5’S)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsilyloxy)-

methyl-2-[N’-benzyl-5’-(p-tolylsulfonyl)amino-1’,4’-dihydroxy]-hexyl-pyr-

rolidine (39): Alkyne 38 (1.05g, 1.29 mmol) was dissolved in MeOH

(20 mL), and Pt/C (5%, 50 mg) was added. The mixture was degassed

and hydrogenated (1 bar) for 6 h with vigorous stirring. The flask was

purged with Ar, the catalyst was filtered off over a pad of Celite, and the

solvents were removed in vacuo. FCC (100 g, PE/EtOAc 2:1!1:1) pro-

vided saturated diol 39 (936 mg, 1.15mmol, 89%) as a colourless foam;

1

R_f= 0.24 (n-hexane/EtOAc 1:1); [a]²_D⁴= ꢀ7.6 (c = 0.51 in CH₂Cl₂); H

NMR (300 MHz, CDCl₃, 83:17 mixture of rotamers): d = 0.96 (d, J =

7.1 Hz, 3H; 6’-H₃), 1.05(s, 9H; Si- tBu), 1.29/1.45(each s, 83:17, 9H;

Boc), 1.30 1.60 (m, 4H; 2’-H₂, 3’-H₂), 1.82 2.28 (m, 4H; 3-H₂, 4-H₂), 2.42

(2S,4R,7R,2’S,5’S,1’’S)- and (2R,4R,7R,2’S,5’S,1’’S)-4-[N’-tert-Butoxycar-

bonyl-5’-(tert-butyldiphenylsilyloxy)methyl]-pyrrolidin-2’-yl-7-[1’’-N’’-

benzyl-(p-tolylsulfonyl)amino]-ethyl-2,2-dioxo-1,3-dioxathiepane

(41):

Chem. Eur. J. 2004, 10, 3945 3962

www.chemeurj.org

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3959

S. M¸ller, U. Koert et al.

FULL PAPER

Cyclic sulfite 40 (3.46 g, 4.02 mmol, mixture of diastereomers) in CCl₄/

CH₃CN (1:1, 170 mL) and H₂O (50 mL) was cooled to 08C. NaIO₄(3.4 g,

16 mmol, 4 equiv) and RuCl₃¥H₂O (approx. 1 mg) were added to the vig-

orously stirred emulsion. The mixture turned brownish-green, and con-

version was complete after 20 min (TLC). The mixture was extracted

with Et₂O (500 mL), and the organic layer was washed with H₂O

(100 mL) and brine (3î100 mL). The organic layer was dried (MgSO₄)

and concentrated at RT to yield cyclic sulfate 41 (3.64 g, quant.) as a col-

ourless syrup, which was >95% pure (¹H NMR). FCC (4 g, n-hexane/

MTBE 2:1) of 68.0 mg crude material gave pure 41 (64.4 mg, 73.4 mmol,

98%). R_f= 0.25( n-hexane/MTBE 2:1); [a]²_D⁴= ꢀ26.0 (c = 1.268 in

15.5 Hz, 1H; N-CH₂-Ph), 4.47 (d, J = 15.7 Hz, 1H; N-CH₂-Ph), 7.26

7.65(m, 17H; arom.), 7.69 (d, J = 8.3 Hz, 2H; arom.) ppm; ¹³C NMR

(75MHz, CDCl ₃): d = 14.1 (C-6’), 19.2 (Si-C(CH₃)₃), 21.5(Ts-Me), 26.8

(2î, Si-C(CH₃)₃), 28.3 (O-C(CH₃)₃), 26.4, 26.9, 29.4, 31.6 (C-3, C-4, C-2’,

C-3’), 48.6 (CH₂-Ph), 57.6 (C-5’), 60.3 (C-5), 63.6 (C-2), 64.0 (C-1’’), 65.8

(C-1’), 74.8 (C-4’), 80.3 (O-C(CH₃)₃), 127.1, 127.3, 127.7, 127.8, 128.3,

128.5, 129.6, 129.7, 133.2, 133.4, 135.5, 137.2, 137.8, 143.2 (arom.), 155.8

(Boc-C=O) ppm; MS (ESI): m/z: calcd for C₄₆H₆₁N₅O₆SiSNa: 862.4;

found: 862.3 [M+Na]⁺.

(4S,5S,8S,3’S,4’R)-4-[N’-Benzyl-3’-hydroxy-4’-(p-tolylsulfonyl)amino]pen-

tyl-8-(tert-butyldiphenylsilyloxy)methyl-1-aza-3-oxa-bicyclo[3.3.0]octan-2-

one (50): R_f= 0.04 (n-hexane/acetone 5:1); ¹H NMR (300 MHz, CDCl₃):

d = 0.90 (d, J = 6.9 Hz, 3H; 5’-H₃), 0.99 (s, 9H; Si-tBu), 1.14 1.60, 1.83

2.18 (several m, 8H; 1’-H₂, 2’-H₂, 6-H₂, 7-H₂), 2.36 (s, 3H; Ts-Me), 3.30

3.45(m, 2H; 8-H, 3 ’-H), 3.55 3.70 (m, 3H; 4’-H, 1’’-H₂), 3.85 3.97 (m,

2H; 4-H, 5-H), 4.00/4.60 (2îd, J = 15.5 Hz, each 1H; N-CH₂-Ph), 7.19

7.35 (m, 13H; arom.), 7.55 7.65 (m, 6H; arom.) ppm; ¹³C NMR

(75MHz, CDCl ₃): d = 11.9 (C-5’), 19.3 (Si-C(CH₃)₃), 21.5(Ts-Me), 26.8

(Si-C(CH₃)₃), 28.5, 30.0, 31.5, 32.0 (C-6, C-7, C-1’, C-2’), 48.5( CH₂-Ph),

58.6 (C-4’), 59.4 (C-5), 65.1 (C-8), 65.9 (C-1’’), 74.2 (C-3’), 80.7 (C-4),

127.1, 127.7, 127.9, 128.4, 128.8, 129.7, 129.8, 133.3, 135.6, 137.6, 137.8,

143.5(arom.), 160.7 ( C=O)) ppm; HRMS (FAB, KI): m/z: calcd for

C₄₂H₅₂N₂O₆SiSK: 779.2952; found: 779.2959 [M+K]⁺.

1

CH₂Cl₂); H NMR (300 MHz, CDCl₃, mixture of conformers): d = 0.90

1.05(m, 12H; 2 ’’-H₃, Si-tBu), 1.28 (s, 9H; Boc), 1.40 1.88, 1.89 2.40

(each m, 8H; 5’-H₂, 6’-H₂, 3’-H₂, 4’-H₂), 2.42 (s, 3H; Ts-Me), 3.48 3.70

(m, 3H; CH₂-OSi, 2’-H), 3.83 4.07 (m, 3H; 1’’-H, 5’-H, N-CH₂-Ph), 4.62

4.81 (m, 2H; N-CH₂-Ph, 7-H), 5.21 (d, J = 11.7 Hz, 1H; 4-H), 7.31 7.66

(each m, 17H; arom.), 7.70 (d, J = 8.3 Hz, 2H; arom.) ppm; ¹³C NMR

(75MHz, CDCl ₃): d = 13.4 (C-2’’), 19.2 (Si-C(CH₃)₃), 21.6 (Ts-Me), 26.8

(Si-C(CH₃)₃), 28.3 (O-C(CH₃)₃), 23.3, 27.6, 28.7 (C-3’, C-4’, C-5, C-6),

48.0 (N-CH₂-Ph), 55.6 (C-1’’), 58.7 (C-5’), 60.8 (C-2’), 64.5( CH₂-OSi),

80.1 (O-C(CH₃)₃), 83.7, 85.1 (C-4, C-7), 127.0, 127.7, 128.2, 129.0, 129.2,

129.7, 130.0, 133.4, 135.5, 137.0, 137.2, 143.9 (arom.), 153.8 (Boc-C=

O) ppm; IR (film): n˜ = 3070, 2960, 2931, 2858, 1750, 1689, 1456, 1428,

1393, 1368, 1342, 1200, 1168, 1112, 1088, 1042, 1007, 961, 908, 893, 854,

(2S,5S,2’S,5’S,1’’S)-2-[N’-tert-Butoxycarbonyl-5’-(tert-butyldiphenylsilyloxy)-

methyl]-pyrrolidin-2’-yl-5-[1’’-(N’’-benzyl-N’’-tosyl)amino]-ethyl-pyrroli-

dine (43): Alcohols 40 (mixture of regioisomers, 590 mg, 702 mmol) and

NEt₃(1.2 mL, 8.4 mmol, 12 equiv) in CH₂Cl₂(30 mL) were cooled to

ꢀ408C, MsCl (0.34 mL, 4.2 mmol, 6 equiv) was added dropwise, and the

mixture was allowed to warm to ꢀ158C over 1 h. The mixture was parti-

tioned between PE (100 mL) and NaHSO₄(1m, 40 mL), and the aqueous

layer was extracted with Et₂O (50 mL). The combined organic layers

were washed with H₂O (2î20 mL) and brine (50 mL), dried (MgSO₄),

concentrated at 108C and dried in vacuo to give the corresponding mesy-

lates (650 mg, quant.) as a colourless gum (R_f= 0.14 in n-hexane/acetone

4:1). The mesylates (457 mg, 498 mmol) were dissolved in CH₃CN

(50 mL), treated with PBu₃(0.37 mL, 1.5mmol, 3 equiv), and stirred for

14 h at RT. H₂O (0.1 mL) was added, and the solvents were removed at

408C. FCC (50 g, CHCl₃/MeOH/HCOOH 100:3:0.3!100:5:0.3 !100:5:1;

fractions washed with sat. NaHCO₃before concentration) gave bispyrro-

lidine 43 (330 mg, 423 mmol, 85%) as a colourless oil. R_f= 0.20 (CHCl₃/

821, 766, 731, 704, 659, 614 cm^ꢀ1

; HRMS (ESI): m/z: calcd for

C₄₆H₆₀N₂O₉SiS₂: 877.359; found: 877.374 [M+H]⁺.

(2S,5S,1’S,4’R,5’S)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsilyloxy)-

methyl-2-[N’-benzyl-5’-(p-tolylsulfonyl)amino-1’-azido-4’-hydroxy]-hexyl-

pyrrolidine and (2S,5S,1’R,4’S,5’S)-N-tert-butoxycarbonyl-5-(tert-butyldi-

phenylsilyloxy)methyl-2-[N’-benzyl-5’-(p-tolylsulfonyl)amino-4’-azido-1’-

hydroxy]-hexyl-pyrrolidine (42a and 42b): TBAN₃(3.4 g, 0.013 mol,

3 equiv) was coevaporated with toluene (50 mL), dried in vacuo

(0.01 mbar, 2 h), and added to a solution of 3.57 g (3.88 mmol for 98%

purity) of the crude cyclic sulfate 41 in THF (150 mL). The flask was

sealed under Ar and stirred at 358C, until the conversion was complete

(36 h). The flask was cooled to 08C, and conc. H₂SO₄was added drop-

wise (Caution!), until the sulfo monoester began to cleave (approx.

1 mL, pH 1 2, TLC monitoring). After the polar monoester had been

consumed (8 h), CO₃^2ꢀbuffer (2m, pH 10, 100 mL) and PE (100 mL)

were added. The layers were separated, and the aqueous layer was ex-

tracted with MTBE (2î100 mL). The combined organic layers were

washed with H₂O (30 mL) and brine (100 mL), dried (MgSO₄) and con-

centrated. FCC (60 g, PE/acetone 5:1!4:1) provided the alcohols 42a

and 42b (2:3 mixture of regioisomers, 2.54 g, 3.02 mmol, 78%), followed

by the cyclic carbamate 50 (294 mg, 384 mmol, 10%), each as a colourless

foam. The regioisomers 42a and 42b could be separated by FCC

(CH₂Cl₂/PE/EtOAc 10:10:1!10:10:2!10:10:3), which was done on ana-

lytical scale only.

1

MeOH/HCOOH 100:5:1); [a]²_D⁰= ꢀ9.9 (c = 1.056 in CH₂Cl₂); H NMR

(300 MHz, CDCl₃/TFA 99:1): d = 0.89 (d, J = 6.9 Hz, 3H; 2’’-H₃), 1.00

(s, 9H; Si-tBu), 1.18/1.34 (each s, 9H; Boc-tBu), 1.40 1.60 (m, 2H; 3-H₂),

1.78 (m, 2H; 4-H₂), 1.95 2.20 (m, 4H; 3’-, 4’-H₂), 2.36 (d, 3H; Ts-Me),

3.00 (m, 1H; 5-H), 3.59 3.74 (m, 3H; 2’-H, 1’’’-H₂), 3.82 4.05(m, 2H; 2-

H, 5’-H), 4.33 (m, 1H; 1’’-H), 3.90 (d, J = 15.1 Hz, 1H; N-CH₂-Ph), 4.85

(d, J = 15.1 Hz, 1H; N-CH₂-Ph), 7.19 7.46 (m, 13H; arom.), 7.54 7.75

(m, 6H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃/TFA 99:1): d = 15.0

(C-2’’), 19.2 (Si-C(CH₃)₃), 21.5(Ts-Me), 26.9 (2î, Si-C( CH₃)₃), 28.3 (2î,

O-C(CH₃)₃), 26.4, 26.9, 29.4, 29.7 (C-3, C-4, C-3’, C-4’), 48.6 (CH₂-Ph),

54.6 (C-1’’), 59.5 (C-5’), 60.3 (C-2’), 63.6 (C-1’’’), 63.7 (C-5), 63.8 (C-2),

82.8 (O-C(CH₃)₃), 127.4, 127.8, 128.1, 128.8, 129.1, 129.9, 129.9, 133.1,

133.2, 135.5, 136.7, 137.0, 143.6 (arom.), 157.7 (Boc-C=O) ppm; IR (film):

n˜ = 3410, 3070, 2959, 2932, 2872, 2862, 1687, 1553, 1456, 1428, 1393,

1365, 1342, 1172, 1113, 910, 821, 774, 704, 658, 604 cm^ꢀ1; HRMS (EI):

m/z: calcd for C₄₆H₆₂N₃O₅SiS: 796.4179; found: 796.4171 [M+H]⁺.

Compound 42a: R_f

=

0.29 (CH₂Cl₂/PE/EtOAc 10:10:2); ¹H NMR

(300 MHz, CDCl₃, mixture of conformers): d = 0.96 (d, J = 6.8 Hz, 3H;

6’-H₃), 1.03 (s, 9H; Si-tBu), 1.23 (s, 9H; Boc), 1.23 1.31, 1.36 1.50, 1.57

1.75(m, 4H; 2 ’-H₂, 3’-H₂), 1.95 2.17 (m, 4H; 3-H₂, 4-H₂), 2.42 (s, 3H; Ts-

Me), 3.22 3.36 (m, 1H; 4’-H), 3.44 3.52 (m, 1H; 1’’-H₂), 3.62 3.78 (m,

3H; 1’’-H₂, 1’-H, 5’-H), 3.83 4.01 (m, 2H; 2-H, 5-H), 4.01/4.67 (each d, J

= 15.7 Hz, each 1H; N-CH₂-Ph), 7.26 7.65(m, 17H; arom.), 7.69 (d, J =

8.1 Hz, 2H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 12.1 (C-6’),

19.2 (Si-C(CH₃)₃), 21.5(Ts-Me), 26.8 (Si-C( CH₃)₃), 28.3 (O-C(CH₃)₃),

25.2, 26.3, 27.0, 31.5 (C-3, C-4, C-2’, C-3’), 48.2 (CH₂-Ph), 58.7 (C-5’),

59.3, 59.6 (C-2, C-5), 64.0 (C-1’), 64.0 (C-1’’), 74.5(C-4 ’), 79.9 (O-

C(CH₃)₃), 127.1, 127.7, 127.7, 127.8, 128.3, 128.7, 128.8, 129.6, 129.7,

133.2, 133.4, 135.5, 137.7, 137.9, 143.4 (arom.), 154.3 (Boc-C=O) ppm; IR

(film): n˜ = 3641, 3068, 2959, 2869, 2361, 2337, 2098 (N₃), 1688, 1435,

(2S,5S,2’S,5’S,1’’S)-4-[N’-tert-Butoxycarbonyl-5’-(tert-butyldiphenylsilyloxy)-

methyl]-pyrrolidin-2’-yl-5-[N-tert-butoxycarbonyl-1’’-(N’’-benzyl-N’’-tosyl)-

amino]-ethyl-pyrrolidine (44): Pyrrolidine 43 (24.0 mg, 30.1 mmol) was

dissolved in THF (3 mL), CO₃^2ꢀ-buffer (pH 10, 1 mL) and Boc₂O (26 mg,

0.12 mmol, 4 equiv) were added, and the solution was heated at 608C for

24 h. The mixture was partitioned between MTBE (30 mL) and brine

(10 mL), and the organic layer was dried with MgSO₄and concentrated.

FCC (3 g, n-hexane/MTBE 4:1!3:1) provided Boc-protected bispyrroli-

dine 44 (18.7 mg, 20.9 mmol, 69%) as a colourless gum. R_f= 0.26 (n-

1395, 1371, 1341, 1162, 1113, 705 cm^ꢀ1

; MS (ESI); m/z: calcd for

C₄₆H₆₁N₅O₆SiSNa: 862.4; found: 862.3 [M+Na]⁺; HRMS (EI); m/z: calcd

for C₄₂H₅₃N₅O₆SiS: 783.3486; found: 783.3497 [MꢀC₄H₉]⁺.

Compound 42b: R_f

=

0.20 (CH₂Cl₂/PE/EtOAc 10:10:2); ¹H NMR

hexane/MTBE 3:1); [a]_D²⁰

=

ꢀ11.0 (c

=

1.090 in CH₂Cl₂); ¹H NMR

(300 MHz, CDCl₃): d = 0.84 0.90 (m, 3H; 6’-H₃), 1.03 (s, 9H; Si-tBu),

1.28 (s, 9H; Boc), 1.25 1.31, 1.44 1.47, 1.55 1.67 (each m, 4H; 2’-H₂, 3’-

H₂), 1.95 2.22 (m, 4H; 3-H₂, 4-H₂), 2.42 (s, 3H; Ts-Me), 3.19 3.27 (m,

1H; 4’-H), 3.49 3.57 (m, 1H; 1’’-H₂), 3.60 3.73 (m, 2H; 1’’-H₂, 1’-H),

(300 MHz, CDCl₃): d = 0.98 (d, J = 7.1 Hz, 3H; 2’’-H₃), 1.06 (s, 9H; Si-

tBu), 1.24/1.28/1.48/1.53 (each s, 18H; 2îBoc), 1.27 1.81, 1.83 2.18 (m,

8H; 3-H₂, 4-H₂, 3’-H₂, 4’-H₂), 2.42 (d, 3H; Ts-Me), 3.42 3.51 (m, 1H; 1’’’-

H₂), 3.59 3.68 (m, 1H; 1’’’-H₂), 3.74 4.16 (m, 4H; 2-H, 5-H, 2’-H, 5’-H),

4.19 4.74 (m, 3H; 1’’-H, N-CH₂-Ph), 7.23 7.72 (m, 17H; arom.), 7.82 (d,

3.73 3.85(m, 1H; 5 ’-H), 3.88 3.99 (m, 2H; 2-H, 5-H), 4.23 (d, J

=

3960

¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Chem. Eur. J. 2004, 10, 3945 3962

Oligopyrrolidines

3945 3962

J = 8.1 Hz, 2H; arom.) ppm; ¹³C NMR (75MHz, CDCl ₃): d = 15.0 (C-

2’’), 19.2 (Si-C(CH₃)₃), 21.5(Ts-Me), 24.4, 25.8, 26.3, 26.8 (C-3, C-4, C-3 ’,

C-4’), 26.4 (Si-C(CH₃)₃), 28.3, 28.5(2îO-C( CH₃)₃), 50.0 (CH₂-Ph), 54.5

(C-1’’), 59.5, 60.4, 61.3 (C-2, C-2’, C-5, C-5’), 64.0 (C-1’’’), 79.1, 79.3 (O-

C(CH₃)₃), 127.1, 127.4, 127.7, 128.0, 128.8, 129.4, 129.7, 133.1, 135.5,

135.6, 138.2, 138.4, 142.5 (arom.), 153.3, 153.7 (Boc-C=O) ppm; IR (film):

n˜ = 3066, 2972, 2931, 2858, 1690, 1474, 1455, 1428, 1391, 1366, 1342,

1255, 1167, 1113, 821, 763, 738, 703, 659 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₅₁H₆₉N₃O₇SiS: 895.4626; found: 895.4652 [M]⁺.

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7.8 mmol, 39%) as a colourless wax. R_f= 0.26 (CHCl₃/MeOH/HCOOH

100:10:1); ¹H NMR (300 MHz, CDCl₃): d = 0.84 0.93 (m, 3H; 2’’-H₃),

1.02/1.03 (each s, 1:2, 9H; Si-tBu), 1.22/1.23/1.45/1.47 (each s, 2:2:1:1,

18H; Boc), 1.55 1.69 (m, 2H), 1.75 1.95 (m, 3H), 1.95 2.15 (m, 3H; pyr-

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(m, 6H; arom.), 7.58 7.65 (m, 4H; arom.); MS (ESI): m/z: calcd for

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Acknowledgement

This work was supported by the Deutsche Forschungsgemeinschaft, the

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Received: February 23, 2004

Published online: June 28, 2004

3962

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Chem. Eur. J. 2004, 10, 3945 3962

Article Doi

Stereoselective synthesis of trans-threo-trans-oligopyrrolidines: Potential agents for RNA cleavage

DOI: 10.1002/chem.200400181

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