Approaches to 3,4,5-substituted piperidines via 1,2,5,6-tetrahydropyridines prepared by ring-closing metathesis

Accepted Manuscript

Approaches to 3,4,5-substituted piperidines via 1,2,5,6-tetrahydropyridines prepared

by ring-closing metathesis

Maxime G..P. Buffat, Eric.J. Thomas

PII:

S0040-4020(15)30225-8

10.1016/j.tet.2015.11.040

TET 27297

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 1 October 2015

Revised Date: 5 November 2015

Accepted Date: 17 November 2015

Please cite this article as: Buffat MGP, Thomas EJ, Approaches to 3,4,5-substituted piperidines via

1,2,5,6-tetrahydropyridines prepared by ring-closing metathesis, Tetrahedron (2015), doi: 10.1016/

j.tet.2015.11.040.

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Approaches to 3,4,5-substituted piperidines

via 1,2,5,6-tetrahydropyridines prepared by

ring-closing metathesis

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Maxime G. P. Buffat and Eric J. Thomas*

1

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Tetrahedron

journal homepage: www.elsevier.com

Approaches to 3,4,5-substituted piperidines via 1,2,5,6-tetrahydropyridines prepared

by ring-closing metathesis

Maxime G. P. Buffat and Eric J. Thomas*^*

The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

Synthetic

approaches

to

(1RS,2SR,6SR)-7-arylmethyl-2-alkoxymethyl-4,7-diaza-9-

oxabicyclo[4.3.0]nonan-8-ones, potentially selective muscarinic M₁receptor agonists, by

hydration of 1,2,5,6-tetrahydropyridines were investigated. 3-Substituted N-tosyl-1,2,5,6-

tetrahydropyridines were prepared by ring-closing metathesis (RCM). The direct hydration of

these by hydroboration-oxidation was not usefully selective, but cis-3-hydroxymethyl-4-tert-

butyldimethylsilyloxy-N-tosylpiperidine was prepared from 3-hydroxymethyl-N-tosyl-1,2,5,6-

tetrahydropyridine by epoxidation, mesylation, reductive elimination, silylation and

hydroboration-oxidation. Problems were encountered during attempts to prepare 3-

alkoxymethyl-1,2,5,6-tetrahydropyridines with protected amino and cyclobutyl substituents at

C5 by ring-closing metathesis, perhaps because of steric hindrance. Nevertheless interesting

chemistry was encountered during the synthesis of the RCM prcursors including a novel

coupling via a 2-ethenyl-N-nosylaziridine and the formation of an oxaazathiocin by an

intramolecular substitution of the nitro group of an N-nosyl protected amine by a proximate

hydroxyl substituent.

Available online

Keywords:

1,2,5,6-Tetrahydropyridines

Ring-closing metathesis

Nucleophilic aromatic substitution

Muscarinic receptor agonists

Aziridines

.

1. Introduction

2. Results and discussion

Agonists of M₁receptors can alleviate the symptoms of

Alzheimer’s disease although there still remains a need for more

compounds that show sufficient selectivity for M₁receptors over

other muscarinic receptors.¹Early computational studies²

identified the oxazolidinonyl-fused piperidines 1 as of interest in

this context but it was necessary to synthesise representative

examples to validate these predictions. The 1,2,5,6-

tetrahydropyridines 2, that could be accessed by ring-closing

metathesis of dienes 3,³were seen as useful precursors of

piperidines 1. The results of early studies into the synthesis and

hydration of 1,2,5,6-tetrahydropyridines, our first approach to the

oxazolidinonyl-piperidines 1, are reported herein.

2.1 Preliminary studies on the synthesis and hydration of 1,2,5,6-

tetrahydropyridines en route to piperidines 1 (R = H)

To check the viability of the overall strategy, preliminary studies

were concerned with the preparation and hydration of 3-

substituted tetrahydropyridines analogous to 2 that lacked the 5-

amino- and 5-alkyl substituents. N-Alkylation of N-but-3-enyl

toluene p-sulfonamide (7) using the 2-substituted propenyl

bromides 4 – 6⁴gave the bis-N-alkylated sulfonamides 8 – 10.^3a

Ring closing metathesis using the Grubbs 2 catalyst led to the 3-

substituted tetrahydropyridines 11 – 13³and O-alkylation of the

3-(hydroxymethyl)tetrahydropyridine 13 provided the benzyl

ether 14, see Scheme 1. However, in our hands, hydroboration of

these tetrahydropyridines using borane in THF gave mixtures of

products with only modest yields of the desired secondary

alcohols at C4 after oxidation of the intermediate alkylboranes.

Epoxidation of the 3-(hydroxymethyl)tetrahydropyridine 13

using either a Sharpless epoxidation⁵or meta-chloroperbenzoic

acid gave the epoxide 15. Both enantiomers of the epoxide were

prepared using the Sharpless epoxidations and were shown to

Figure 1 A ring-closing metathesis approach to the piperidines 1

———

*

Corresponding author. Tel.: +44 (0) 161 275 4613; e-mail address: e.j.thomas@manchester.ac.uk

2

Tetrahedron

ACCEPTED MANUSCRIPT

have e.e.s of 90% by chiral GC. As expected, reduction of the

hydroxypiperidines, it would appear that these compounds may

racemic epoxide using sodium cyanoborohydride in the presence

of boron trifluoride diethyl etherate⁶gave the vicinal diol 16. To

access 4-hydroxypiperidines, the allylic alcohol 18 was prepared

by reductive elimination⁷of the mesylate 17 derived from the

hydroxyepoxide 15. After protection of the alcohol 18 as its tert-

butyldimethylsilyl ether 19, hydroboration-oxidation of the

exocyclic double-bond using borane in THF gave a mixture of

the epimeric primary alcohols 20 and 21 together with the tertiary

alcohol 22, see Scheme 1.

be accessed, albeit more circuitously, by hydroboration of 3-

methylene-4-silyloxypiperidines, cf. 19. A synthesis of protected

3-hydroxymethyl-5-amino-1,2,5,6-tetrahydropyridines 23 by

ring-closing metathesis of dienes 24 (P = protecting groups), see

Figure 2, was therefore investigated with a view to studying the

hydration of these compounds.

Figure

2 An approach to protected 3-hydroxymethyl-5-

aminotetrahydropyridines by RCM

.

The first approach to a bis(alkenyl)amine 24 was based on the

alkylation of the 2-(tert-butyldimethylsilyloxymethyl)-

propylamine 25 using the 2-(nosylamino)but-3-enyl mesylate 30,

see Scheme 2. The primary amine 25 was prepared by careful

aminolysis of the bromide 4⁴using a large excess of ammonia.

The mesylate 30 was prepared from the Garner aldehyde 26 that

was prepared using Taylor’s procedure⁸except that DCC rather

than EDCI was used for the Weinreb amide formation. A Wittig

reaction of the Garner aldehyde 26 gave the alkene 27 and

hydrolysis followed by nosylation of the resulting hydroxyalkyl-

Scheme 1 Synthesis and hydration of 1,2,5,6-tetrahydropyridines

Reagents and conditions (i) 7, NaH, DMF, rt, 1 h, then add the

bromide, rt, 6-18 h (8, 88%; 9, 94%; 10, 73%); (ii) Grubbs 2 cat.,

DCM, heat under reflux, 15 h (11, 76%; 12, 83%; 13, 77%); (iii)

NaH, THF, rt, 1 h, then BnBr, KI (cat.), rt, 24 h (82%); (iv)

o

Ti(OⁱPr)₄, diethyl D-(−)- or L-(+)-tartrate, −23 C, 10 min, add

t

13, BuO₂H, tol., DCM, 6 h (45-59%); (v) mCPBA, DCM, rt, 20

o

h (69%): (vi) NaBH₃CN, THF, BF₃.Et₂O, 0 C then heat under

o

reflux, 2 h (77%); (vii) MsCl, Et₃N, DCM, DMAP (cat.), 0 C,

o

1.5 h (61%); (viii) KI, Zn powder, DMF, 110 C, 1.5 h (87%);

(ix) TBSOTf, 2,6-lut., DCM, −20 ^oC, 1.5 h (57%); (x) BH₃.THF,

o

0 C to rt, 4 h, then NaOH, 30% aq. H₂O₂, rt, 18 h (20/21, 57%,

20 : 21 = 3 : 1; 22, 14%).

Structures were assigned to the products in Scheme 1 on the basis

of spectroscopic data and literature precedent as the 3-

(hydroxymethyl)tetrahydropyridine 13 and the ester 12 were

known compounds.³The cis-configuration indicated for alcohol

20 was provisionally assigned to the major product of

hydroboration of the alkene 19 on the basis that the

hydroboration had taken place on the less hindered face of the

alkene; similarly for the tertiary alcohol 22.

Scheme 2 An approach to the bis(alkenyl)amine 35 by N-

alkylation Reagents and conditions (i) liq. NH₃under reflux,

Et₂O, 2 h (86%); (ii) CH₃PPh₃Br, KHMDS, THF, rt, 1 h, cool to

o

−78 C, add 26, −78 ^oC to rt, 2 h (90%); (iii) aq. HCl, rt, 30 min

(90%); (iv) Na₂CO₃, NosCl, acetone, H₂O, TBAI (cat.), 0 ^oC to rt,

i

18 h (90%); (v) Pr₂NEt, DCM, rt, add MsCl, rt, 10 min (97%);

(vi) 25, 30, K₂CO₃, rt, 18 h (72%); (vii) CbzCl, satd. aq. K₂CO₃,

rt, 1 h (80%); (viii) Grubbs 2 cat., DCM, heat under reflux 6 h

(81%); (ix) TBAF, THF, 0 ^oC to rt, 30 min (49%).

Although the direct hydroboration of the 3-substituted 1,2,5,6-

tetrahydropyridines 11 – 14 had not given the required 4-

3

ammonium salt 28 gave the protected amino-alcohol 29. The

conversion of this acohol into its rather sensitive mesylate 30 was

rather difficult but was eventually achieved using freshly distilled

mesyl chloride and Hünig’s base (not triethylamine). However,

alkylation of the primary amine 25 using the mesylate 30 did not

give the expected bis(alkenyl)amine 35. Instead the isomeric

amine 31 was the major product. Ring-closing metathesis of the

Cbz-protected diene 32 derived from the amine 31 was successful

but gave the dihydropyrrole derivative 33 that was deprotected to

give the alcohol 34 rather than the required tetrahydropyridine,

see Scheme 2.

The benzyl protected bis(alkenyl)amine 43 was therefore prepared

ACCEPTED MANUSCRIPT

from the Garner aldehyde 26 by reductive amination using the 2-

(benzyloxymethyl)propylamine 42 that had been prepared from the

bromide 41.¹⁰Nosylation of amine 43 gave the amide 44 and

treatment with toluene p-sulfonic acid in methanol and water

selectively removed the acetonide group and gave the protected

amino-alcohol 45. This was oxidised using the Dess-Martin

periodinane to the aldehyde 46 but attempts to convert this aldehyde

into

the

corresponding

terminal

alkene

using

methylene(triphenyl)phosphorane were complicated by elimination

and gave the N-propenylsulfonamide 47 as the major product.

Reactions with the Petasis¹¹or Tebbe¹²reagents either resulted in

decomposition or led to intractable mixtures. A modest yield of the

αβ-unsaturated ester 48 was obtained from the aldehyde 46 via a

Horner-Wadsworth-Emmons reaction and reduction gave the

corresponding alcohol 49, see Scheme 4. However, preliminary

attempts to carry out a ring-closing metathesis of this diene using the

Grubbs 2 catalyst to prepare a 1,2,5,6-tetrahydropyridine, cf. 23,

resulted in the formation of complex mixtures.

1

The unexpected amine 31 was identified on the basis of its H

NMR spectrum that showed the NH-nosyl group to be attached to

a primary CH₂group. Moreover, conversion of the secondary

amine into its Cbz-derivative 32 resulted in the additional

deshielding of three rather than four neighbouring protons. The

formation of this isomeric amine 31 is consistent with the

participation of the N-nosyl azididine 36 that reacts at its allylic

2-position with the primary amine 25, see Figure 3.

These studies into the synthesis of 1,2,5,6-tetrahydropyridines 23 had

been complicated by the use of nosyl protecting groups. The use of

another protecting group may have avoided these issues, but at this

stage the structures of the target oxazolidinonylpiperidines 1 were

refined to those with a cyclobutyl group at C6, see 50, since these

were thought likely to have improved selectivity for binding to the

M₁receptors. This required the synthesis of the 1,2,5,6-

tetrahydropyridines 51 (P = protecting groups), see Figure 4.

Figure 3 Formation of the dienylamine 31

The reductive amination of the racemic Garner aldehyde 26 using

amine 25 was therefore investigated. This gave the secondary

amine 37 that was protected its nosyl derivative 38. An attempted

removal of the acetonide group from this silyl ether resulted in

loss of the tert-butyldimethylsilyl group to give the alcohol 39.

When this was reacted with sodium hydride and benzyl bromide

in an attempt to convert the alcohol into its benzyl ether,

cyclisation by substitution of the nitro group of the nosyl group

took place and the cyclic ether 40 was isolated, see Scheme 3.

The displacement of the nitro group by methoxide is known for a

4-nitrophenylsulfonamide⁹but the intramolecular displacement

of the nitro group from a 2-nitrosulfonamide by an alkoxide is, to

our knowledge, unprecedented, although such SNAr reactions are

well known for softer nucleophiles and for heterocycles.

Scheme 4 Synthesis of metathesis precursors Reagents and

conditions (i) liq. NH₃, reflux, Et₂O, 2 h (77%); (ii) 26, MgSO₄,

DCM, rt, 24 h, NaBH₄, MeOH, rt, 2 h (63%); (iii) Na₂CO₃, NosCl,

o

acetone, H₂O, TBAI (cat.), 0 C to rt, 18 h (75%); (iv) PTSA.H₂O,

Scheme 3 Unexpected formation of an oxaazathiocin Reagents

and conditions (i) 25, MgSO₄, DCM, rt, 24 h, then NaBH₄, MeOH,

rt, 2 h (92%); (ii) Na₂CO₃, NosCl, acetone, H₂O, TBAI (cat.), 0 ^oC to

rt, 18 h (79%); (iii) PTSA.H₂O, MeOH, rt, 1.5 h (99%); (iv), BnBr,

NaH, THF, rt. 5 h (52%).

MeOH, rt, 5 d (98%); (v) Dess-Martin periodinane, DCM, rt, 45 min

(88%); (vi) CH₃PPh₃Br, ⁿBuLi, THF, rt, 30 min, cool to −78 ^oC, add

o

46, THF, −78 C to rt, 2 h (72%); (vii) (EtO)₂P(O)CH₂CO₂Et, NaH,

THF, 0 ^oC, 1 h, add 46, THF, rt, 1 h (48, 27%; 47, 24%); (viii)

DIBAL-H, hexanes, THF, −78 ^oC, 2 h (74%).

4

Tetrahedron

In our hands, the adddition of vinylmagnesium bromide to

ACCEPTED MANUSCRIPT

sulfinylimine 55 gave only modest yields (39 - 46%) of the

adducts 56 and 57, perhaps because of competing deprotonation

in this hindered system.¹⁴Nevertheless, the diastereoselectivity

was very good at −78 ^oC, 56 : 57 = 97.5 : 2.5, albeit lower, ca. 75

o

: 25, at 0 C. Structures were assigned to sulfinylamines 56 and

57 on the basis of precedent¹⁴and hydrolysis gave the racemic

but-3-en-2-ylamine 58, see Scheme 5

.

Figure 4 Revised synthetic targets

The major sulfinylamine 56 was deprotected to give the alcohol

59 that was oxidised to the aldehyde 60, see Scheme 6. Reductive

amination of aldehyde 60 with the prop-2-enylamine 25 gave the

secondary amine 61 that was protected as its benzyloxycarbonyl

derivative 62. However attempts to effect a ring-closing

metathesis of this diene using the Grubbs 2 catalyst were

unsuccessful, with the starting material being recovered

unchanged, see Scheme 6.

2.2. Attempts to prepare the 5,5-disubstituted 1,2,5,6-

tetrahydropyridines 51 by ring-closing metathesis

Following the metathesis strategy, the tetrahydropyridines 51

were to be prepared from dienes 52 by ring-closing metathesis.

Reductive amination of the aldehyde 53 using the amine 25 was

envisaged as a route to the dienes 52. The aldehyde 53 is the

synthetic equivalent of a reduced α-alkylated amino acid. It was

decided to study the synthesis of this aldehyde from the known¹³

ketone 54, see Figure 5.

Figure 5 Proposed synthesis of the metathesis precursors 52

In anticipation of an asymmetric synthesis of the chiral aldehyde

53 from the ketone 54, initial studies focussed on the addition of

vinylmagnesium bromide to the tert-butylsulfinylimine 55

prepared fom the ketone 54.¹⁴However, the racemic tert-

butanesulfinamide was more accessible at the time, see

experimental,¹⁵and so the ketone 54 was condensed with racemic

tert-butanesulfinamide to give the racemic sulfinylimine 55 for

preliminary studies. Just one geometrical isomer of the

sulfinylimine was isolated and this was assigned the (Z)-

configuration shown by analogy with other reactions of the

ketone 54 and similar systems in which the cyclobutyl substituent

provides more steric hindrance than the silyloxymethyl group,

see Scheme 5.¹³

Scheme 6 Synthesis of the metathesis precursor 62 Reagents and

conditions (i) TBAF, THF, 0 C to rt, 30 min (69%); (ii) Dess-

Martin periodinane, DCM, rt, 45 min (88%); (iii) 25, DCM,

MgSO₄or 4Å sieves, rt, 24 - 48 h, then NaBH₄, MeOH, rt, 2 h

(93%); (iv) CbzCl, K₂CO₃, THF, rt, 1 h (94%).

o

To check whether this difficulty was due to the protecting groups

in the diene 62, the racemic Cbz-protected amine 63 that had

already been prepared from the ketone 54,¹³was converted to the

secondary amine 66 by desilylation, oxidation of the resulting

alcohol 64 and reductive amination of the aldehyde 65 using the

amine 25. Nosylation of the amine 66 gave the fully protected

diene 67. This diene has the same protecting groups as were

present in the diene 32 that was successfully cyclised to the

dihydropyrrole 33. However, attempts to carry out ring-closing

metathesis with diene 67 using the Grubbs 2 catalyst were

unsuccessful with starting material recovered unchanged, see

Scheme 7.

At this stage of the programme, the dienylamines 62 and 67 had

been prepared but attempts to carry out a ring-closing metathesis

to access a 5,5-disubstituted 1,2,5,6-tetrahydropyridine, cf. 51,

had been unsuccessful. This difficulty may have been due to

steric hindrance as ring-closing metathesis had delivered the

1,2,5,6-tetrahydropyridines 11 – 13 that lacked the allylic

acylamino and cyclobutyl substituents, cf. also the cyclisation of

diene 32 that had the same protecting groups as the diene 67. The

allylic benzyloxycarbonyl group in diene 67 may have also

coordinated to metathesis intermediates so preventing progress of

the catalytic cycle.

Scheme 5 Diastereoselective addition to the sulfinylimine 55

Reagents and conditions (i) Ti(OEt)₄, THF, tert-

butanesulfinamide, heat under reflux until complete (TLC)

(52%); (ii) CH₂=CHMgBr, THF, tol., 78 C, 15 h (39%, 95%

de); (iii) aq. HCl, rt, 12 h (99%).

o

5

4. Experimental

ACCEPTED MANUSCRIPT

4.1. General experimental procedures

¹H and ¹³C NMR spectra were recorded on Varian Unity Inova

400 and Varian Unity Inova 300 spectrometers with residual non-

deuterated solvent as the internal standard. Only distinguishable

peaks are reported for minor isomers in isomeric mixtures. IR

spectra were recorded on an ATI Mattson Genesis FTIR as thin

films produced by evaporation of a dichloromethane solution on

sodium chloride plates unless otherwise stated. Mass spectra

were recorded on Fison VG Trio 2000 and Kratos Concept

spectrometers. Chemical ionisation (CI+) was performed using

ammonia.

Chromatography

refers

to

flash

column

Scheme 7 Synthesis of metathesis precursor 67 Reagents and

conditions (i) TBAF, THF, 0 C to rt, 30 min (86%); (ii) Dess-

Martin periodinane, DCM, rt, 45 min (95%); (iii) 25, DCM,

MgSO₄or 4Å sieves, rt, 24 - 48 h, then NaBH₄, MeOH, rt, 2 h

(86%); (iv) NosCl, Na₂CO₃, TBAI (cat.), acetone, H₂O, 0 ^oC to rt,

18 h (42%).

chromatography using Merck silica gel 60 H (230-300 mesh).

Tetrahydrofuran (THF) was dried and distilled from sodium

metal using benzophenone as an indicator under an atmosphere

of nitrogen. Dichloromethane was dried and distilled from

calcium hydride under an atmosphere of nitrogen. Ether refers to

diethyl ether, which was dried and distilled from sodium metal

using benzophenone as an indicator under an atmosphere of

nitrogen. Light petroleum refers to the fraction of petroleum ether

distilled between 40-60 °C. Benzene and hexane were dried over

sodium metal. Butyllithium (1.6 M in hexanes) was titrated

against a solution of propan-2-ol in xylene with 2,2′-bipyridine as

an indicator. Triethylamine and di-isopropylamine were dried

over potassium hydroxide pellets. Brine refers to saturated

aqueous sodium chloride.

o

Although further investigations of the ring closing metathesis of

dienyl precursors of the required 1,2,5,6-tetrahydropyridines 51

may have led to a successful conclusion, parallel studies into an

alternative approach to the required oxazolidinonylpiperidines 50

based on the cyclisation of preformed oxazolidinones 68, see

Figure 6, had given promising results,^13,16and the RCM approach

described herein, was not taken any further at this time.

4.2. Experimental procedures

4.2.1 N-But-3-enyl-N-[2-(tert-butyldimethylsilyloxymethyl)prop-

2-enyl] 4-methylbenzenesulfonamide (8)^3a

Sodium hydride (160 mg, 3.96 mmol, 1.05 eq., 60% in mineral

oil) was added to the sulfonamide 7 (796 mg, 3.77 mmol) in

DMF (10 mL). After 1 h, the bromopropene 4 (1 g, 3.77 mmol)

in DMF (5 mL) was added and the mixture stirred for 6 h. After

careful addition of water (15 mL), the aqueous phase was

extracted with ether (3 × 20 mL), and the organic extracts were

dried (Na₂SO₄) and concentrated under reduced pressure.

Chromatography (ethyl acetate : light petroleum = 1 : 4) of the

residue gave the title compound 8 (1.36 g, 88%), as a colourless

oil, R_f= 0.67 (ethyl acetate : light petroleum = 1 : 4) (Found: M⁺

+ H, 410.2191. C₂₁H₃₆NO₃SSi requires M, 410.2185); ν_max/cm^-1

2955, 2928, 2857, 1599, 1462, 1343, 1252, 1160, 1110, 1092,

917, 837, 815, 777 and 657; δ_H(300 MHz, CDCl₃) 0.06 (6 H, s, 2

× SiCH₃), 0.91 [9 H, s, SiC(CH₃)₃], 2.25 (2 H, td, J 6.8, 8.9 Hz,

2′-H₂), 2.44 (3 H, s, CH₃), 3.17 (2 H, m, 1′-H₂), 3.79 (2 H, s, 1-

H₂), 4.05 (2 H, s, 2-CH₂), 4.96-5.06 (3 H, m, 3-H, 4′-H₂), 5.24 (1

H, d J 0.8 Hz, 3-H′), 5.65 (1 H, tdd, J 6.8, 10.8, 16.5 Hz, 3′-H)

and 7.30 and 7.70 (each 2 H, d, J 8.0 Hz, ArH); δ_C(75 MHz,

CDCl₃) −5.4, 18.3, 21.5, 25.9, 32.7, 47.2, 50.7, 63.7, 113.2,

116.9, 127.2, 129.6, 134.7, 137.0, 143.2 and 143.5; m/z (CI+) 427

(M⁺+ 18, 5%) and 410 (M⁺+ 1, 100).

Figure 6 Alternative approach to piperidines 50

3. Summary and conclusions

This paper has described some preliminary investigations into the

synthesis of a series of novel oxazolidinonyl-fused piperidines of

interest as potential M₁receptor agonists. The approach used was

based on the synthesis of 1,2,5,6-tetrahydropyridines by RCM

followed by selective hydration and oxazolidinone ring

formation. During the course of the work, several interesting

reactions were encountered including the unexpected formation

of the rearranged amine 31 and the cyclisation of the alcohol 39

to the oxaazathiocin 40. The use of chiral sulfinylimines for the

synthesis of the RCM precursors was also promising and

although only racemic intermediates were used in our work, this

chemistry should provide for an asymmetric synthesis if so

desired.

4.2.2

N-But-3-enyl-N-(2-ethoxycarbonylprop-2-enyl)

4-

The approach was eventually discontinued in favour of an

alternative strategy based on the assembly of the piperidine onto

a preformed oxazolidinone, cf. 68, see Figure 6.^13,16However

further studies, especially into the use of different protecting

groups, could lead to a successful conclusion to the metathesis

approach and indeed to a more efficient synthesis overall.

methylbenzenesulfonamide (9)

Following the procedure for the preparation of sulfonamide 8, the

bromopropene 5 (1 g, 5.18 mmol) after stirring for 18 h and

chromatography (ethyl acetate : light petroleum = 1 : 4), gave

title compound 9 (1.58 g, 94%) as a colourless oil, R_f= 0.73

(ethyl acetate : light petroleum = 3 : 2) (Found: M⁺

+

6

Tetrahedron

H, 338.1421. C H NO S requires M, 338.1426); ν /cm^-1

2.44 (3 H, s, CH ), 3.18 (2 H, t, J 5.8 Hz, 6-H ), 3.81 (2 H, m, 1-

ACCEPTED MANUSCRIPT

17 24

4

max

3

2

2979, 2927, 2863, 1712, 1640, 1598, 1450, 1342, 1303, 1265,

1160, 1091, 1023, 955, 920, 815, 754 and 707; δ_H(300 MHz,

CDCl₃) 1.30 (3 H, t, J 7.0 Hz, CH₃), 2.22 (2 H, q, J 7.5 Hz, 2′-

H₂), 2.43 (3 H, s, CH₃), 3.22 (2 H, m, 1′-H₂), 4.03 (2 H, s, 1-H₂),

4.21 (2 H, q, J 7.0 Hz, OCH₂), 4.98-5.10 (2 H, m, 4′-H₂), 5.69 (1

H, m, 3′-H), 5.93 and 6.36 (each 1 H, d, J 1.0 Hz, 3-H) and 7.30

and 7.71 (each 2 H, d, J 8.5 Hz, ArH); δ_C(75 MHz, CDCl₃) 14.2,

21.5, 32.8, 48.5, 48.6, 60.9, 117.2, 127.2(2), 129.7, 134.4, 136.0,

136.9, 143.3 and 165.9; m/z (CI+) 338 (M⁺+ 1, 100%).

H₂), 4.21 (2 H, q, J 7.0 Hz, OCH₂), 6.99 (1 H, m, 4-H) and 7.34

and 7.71 (each 2 H, d, J 7.0 Hz, ArH); δ_C(75 MHz, CDCl₃) 14.2,

21.5, 25.8, 41.8, 44.0, 60.8, 127.3, 127.7, 129.7, 133.3, 136.9,

143.7, 164.8; m/z (CI+) 327 (M⁺+ 18, 58%) and 310 (M⁺+ 1,

100%).

4.2.6 3-Hydroxymethyl-1-(4-methylphenylsulfonyl)-1,2,5,6-

tetrahydropyridine (13)^3a

Following the procedure for the preparation of the

terahydropyridine 11, the diene 10 (1.3 g, 4.4 mmol) and Grubbs

2 catalyst, after stirring for 15 h and chromatography (ethyl

acetate : light petroleum = 1 : 2), gave the alcohol 13 (910 mg,

77%) that was rerystallised from diethyl ether to give the title

compound 13 as a white solid, m.p. 102-103 °C (lit.^3a102.8-

4.2.3 N-But-3-enyl-N-(2-hydroxymethylprop-2-enyl) 4-

methylbenzenesulfonamide (10)

Following the procedure for the preparation of sulfonamide 8,

bromopropene 6 (3.13 g, 20.7 mmol), after stirring for 15 h and

chromatography (ethyl acetate : light petroleum = 1 : 4), gave the

title compound 10 (4.26 g, 73%) as a colourless oil, R_f= 0.20

o

103.5 C), R_f= 0.11 (ethyl acetate : light petroleum = 1 : 2)

(Found: C, 58.03; H, 6.55; N, 5.41; S, 11.84%. C₁₃H₁₇NO₃S

requires C, 58.40; H, 6.41; N, 5.24; S, 11.99%; Found: M⁺+

H, 268.1008. C₁₃H₁₈NO₃S requires M, 268.1007); ν_max/cm^-13516,

2926, 2853, 1683, 1597, 1461, 1347, 1293, 1241, 1163, 1094,

1000, 965, 915, 817 and 738; δ_H(300 MHz, CDCl₃) 2.21-2.28 (2

H, m, 5-H₂), 2.44 (3 H, s, CH₃), 3.16 (2 H, t, J 5.8 Hz, 6-H₂), 3.60

(2 H, d, J 2.0 Hz, 1-H₂), 4.03 (2 H, s, 3-CH₂), 5.75 (1 H, m, 4-H)

and 7.33 and 7.69 (each 2 H, d, J 8.3 Hz, ArH); δ_C(75 MHz,

CDCl₃) 21.5, 25.0, 42.6, 45.3, 65.1, 121.6, 127.7, 129.6, 133.2,

134.0 and 143.6; m/z (CI+) 285 (M⁺+ 18, 35%) and 268 (M⁺+ 1,

100).

(ethyl acetate : light petroleum = 1 : 2) (Found: M⁺

+

H, 296.1316. C₁₅H₂₂NO₃S requires M, 296.1320); ν_max/cm^-13450,

2925, 2865, 1664, 1452, 1334, 1157, 1091, 917, 815 and 755; δ_H

(300 MHz, CDCl₃) 2.24 (2 H, td, J 7.0, 8.5 Hz, 2′-H₂), 2.45 (3 H,

s, CH₃), 3.21 (2 H, m, 1′-H₂), 3.81 (2 H, s, 1-H₂), 4.19 (2 H, s, 2-

CH₂), 4.98 and 5.03 (each 1 H, m, 4′-H), 5.05 and 5.19 (each 1

H, s, 3-H), 5.65 (1 H, tdd, J 6.8, 9.8, 17.5 Hz, 3′-H) and 7.32 and

7.71 (each 2 H, d, J 8.0 Hz, ArH); δ_C(75 MHz, CDCl₃) 21.5,

32.7, 47.9, 51.0, 63.3, 115.0, 117.1, 127.1, 129.8, 134.5, 136.5,

143.5 and 144.2; m/z (CI+) 313 (M⁺+ 18, 30%) and 296 (M⁺+ 1,

100).

4.2.7 3-Benzyloxymethyl-1-(4-methylphenylsulfonyl)-1,2,5,6-

tetrahydropyridine (14)

4.2.4 3-(tert-Butyldimethylsilyloxymethyl)-1-(4-

methylphenylsulfonyl)-1,2,5,6-tetrahydropyridine (11)

Sodium hydride (74 mg, 1.85 mmol, 1.1 eq., 60% in mineral oil)

was added to the alcohol 13 (450 mg, 1.68 mmol) in THF (4

mL). After 1 h, benzyl bromide (0.260 mL, 2.19 mmol, 3.0 eq.)

and KI (28 mg, 0.17 mmol, 0.1 eq.) were added. The suspension

was stirred at rt for 24 h and then poured into water (4 mL). The

mixture was extracted with ether (3 × 5 mL) and the organic

extracts were dried (Na₂SO₄) and concentrated under reduced

pressure. Chromatography (ethyl acetate : light petroleum = 1 :

20) gave the title compound 14 (478 mg, 92%, 87% conversion)

as a colourless oil, R_f= 0.38 (ethyl acetate : light petroleum = 1 :

The Grubbs 2 catalyst (70 mg, 0.08 mmol, 2.5 mol%) was added

to the diene 8 (1.36 g, 3.32 mmol) in DCM (73 mL) and the

mixture was stirred under reflux for 15 h. After concentration

under reduced pressure, the residue was immediately absorbed

onto silica. Chromatography (ethyl acetate : light petroleum = 1 :

10) gave title compound 11 (960 mg, 76%) as a colourless oil, R_f

= 0.31 (ethyl acetate : light petroleum = 1 : 10) (Found: M⁺+

H, 382.1877. C₁₉H₃₂NO₃SSi requires M, 382.1872); ν_max/cm^-1

2954, 2928, 2855, 1462, 1342, 1251, 1163, 1097, 837, 777 and

663; δ_H(300 MHz, CDCl₃) 0.05 (6 H, s, 2 × SiCH₃), 0.89 [9 H, s,

SiC(CH₃)₃], 2.21 (2 H, m, 5-H₂), 2.44 (3 H, s, CH₃), 3.15 (2 H, t,

J 5.8 Hz, 6-H₂), 3.54 (2 H, d, J 2.0 Hz, 1-H₂), 4.03 (2 H, s, 3-

CH₂), 5.68 (1 H, m, 4-H) and 7.32 and 7.68 (each 2 H, d, J 8.0

Hz, ArH); δ_C(75 MHz, CDCl₃) −5.4, 18.3, 21.5, 24.8, 25.8, 42.7,

45.2, 65.1, 119.7, 127.7, 129.6, 133.3, 133.9 and 143.4; m/z (CI+)

399 (M⁺+ 18, 40%) and 382 (M⁺+ 1, 100).

2) (Found: M⁺

+ H, 358.1472. C₂₀H₂₄NO₃S requires M,

358.1477); ν_max/cm^-12922, 2853, 1597, 1494, 1453, 1341,1244,

1207, 1162, 1095, 926, 815 and 741; δ_H(300 MHz, CDCl₃) 2.24-

2.26 (2 H, m, 5-H₂), 2.44 (3 H, s, CH₃), 3.17 (2 H, t, J 5.8 Hz, 6-

H₂), 3.61 (2 H, d, J 2.0 Hz, 1-H₂), 3.91 (2 H, s, 3-CH₂), 4.44 (2

H, s, PhCH₂), 5.76 (1 H, m, 4-H), 7.28-7.37 (7 H, m, ArH) and

7.69 (2 H, d, J 8.3 Hz, ArH); δ_C(75 MHz, CDCl₃) 21.5, 25.0,

42.6, 45.6, 71.9, 72.2, 123.2, 127.7, 127.8, 128.4, 129.6, 131.6,

133.3, 137.9 and 143.5; m/z (CI+) 375 (M⁺+ 18, 30%), 358 (M⁺

+ 1, 4) and 94 (100).

4.2.5 3-Ethoxycarbonyl-1-(4-methylphenylsulfonyl)-1,2,5,6-

tetrahydropyridine (12)^3a

Following the procedure for the preparation of the

tetrahydropyridine 11, the diene 9 (500 mg, 1.48 mmol) and

Grubbs 2 catalyst, after stirring for 2 h and chromatography

(ethyl acetate : light petroleum = 3 : 2), gave the title compound

12³(378 mg, 83%), R_f= 0.57 (ethyl acetate : light petroleum = 3

4.2.8 (1SR,6SR)-1-Hydroxymethyl-3-(4-methylphenylsulfonyl)-3-

aza-7-oxabicyclo[4.1.0]heptane (15)

m-Chloroperbenzoic acid (1.56 g, 6.35 mmol, 2 eq.) was added in

portions to the alkene 13 (849 mg, 3.18 mmol) in DCM (11.5

mL) and the mixture was stirred at rt for 20 h. Saturated aqueous

sodium sulfite (10 mL) was added and the aqueous phase was

basified with aqueous sodium hydroxide (3.75 M, 4 mL, 15

mmol). The mixture was extracted with ether (3 × 15 mL) and the

organic extracts were dried (Na₂SO₄) and concentrated under

o

: 2), as a white solid, m.p. 65-66 °C (lit.^3a63.1-63.8 C) (Found:

M⁺+ H, 310.1110. C₁₅H₂₀NO₄S requires M, 310.1113); ν_max/cm^-1

2981, 2925, 2897, 1709, 1657, 1597, 1461, 1344, 1304, 1265,

1202, 1165, 1104, 1051, 971, 918, 816 and 729; δ_H(300 MHz,

CDCl₃) 1.29 (3 H, t, J 7.0 Hz, CH₃), 2.37-2.42 (2 H, m, 5-H₂),

7

reduced pressure to give the racemic title compound 15 (621 mg,

ACCEPTED MANUSCRIPT

69%) as a white solid, m.p. 138-139 °C, R_f= 0.21 (ethyl acetate :

light petroleum = 3 : 2) (Found: C, 54.85; H, 6.49; N, 4.83; S,

11.15%. C₁₃H₁₇NO₄S requires C, 55.11; H, 6.05; N, 4.94; S,

11.32%; Found: M⁺, 283.0883. C₁₃H₁₇NO₄S requires M,

283.0878); ν_max/cm^-13457, 2924, 2868, 1598, 1459, 1339, 1163,

1094, 905, 816 and 744; δ_H(400 MHz, CDCl₃) 2.12 (2 H, m, 5-

H₂), 2.25 (1 H, br. s, OH), 2.45 (3 H, s, CH₃), 2.57 (1 H, ddd, J

6.5, 8.5, 12.0 Hz, 4-H), 3.00 (1 H, d, J 14.0 Hz, 2-H), 3.35 (1 H,

br. s, 6-H), 3.45 (1 H, m, 4-H′), 3.66 and 3.77 (each 1 H, d, J

12.3 Hz, 1-CH), 3.77 (1 H, d, J 14.0 Hz, 2-H′) and 7.33 and 7.64

(each 2 H, d, J 8.0 Hz, ArH); δ_C(100 MHz, CDCl₃) 21.5, 25.0,

39.4, 45.0, 54.2, 58.7, 63.6, 127.4, 129.6, 132.9 and 143.7; m/z

(CI+) 284 (M⁺+ 1, 100%).

4.2.10 (1SR,6RS)-1-Mesyloxymethyl-3-(4-methylphenylsulfonyl)-

3-aza-7-oxabicyclo[4.1.0]heptane (17)

Triethylamine (0.182 mL, 1.31 mmol, 2 eq.) and DMAP (cat.)

were added to the alcohol 15 (185 mg, 0.65 mmol) and

methanesulfonyl chloride (0.053 mL, 0.685 mmol, 1.05 eq.) in

DCM (2 mL) at 0 °C, and the reaction mixture was stirred at 0 °C

for 1.5 h. Water (2 mL) was added and the aqueous layer was

extracted with ether (3 × 5 mL). The organic extracts were dried

(Na₂SO₄) and concentrated under reduced pressure.

Chromatography (ethyl acetate : light petroleum = 1 : 2) of the

residue gave the title compound 17 (144 mg, 61%) as a yellow

oil, R_f= 0.30 (ethyl acetate : light petroleum = 1 : 2) (Found: M⁺

+ H, 362.0730. C₁₄H₂₀NO₆S₂requires M, 362.0732); ν_max/cm^-1

3028, 2935, 2852, 1597, 1459, 1354, 1341, 1255, 1166, 1094,

958, 910, 812 and 743; δ_H(300 MHz, CDCl₃) 2.11-2.16 (2 H, m,

5-H₂), 2.45 (3 H, s, CH₃), 2.61 (1 H, td, J 7.0, 12.0 Hz, 4-H), 3.08

(3 H, s, SCH₃), 3.12 (1 H, d, J 13.7 Hz, 2-H), 3.31 (1 H, br. s, 6-

H), 3.41 (1 H, dtd, J 1.0, 4.5, 12.0 Hz, 4-H′), 3.88 (1 H, dd, J 1.0,

13.8 Hz, 2-H′), 4.13 and 4.39 (each 1 H, d, J 11.8 Hz, 1-CH) and

7.34 and 7.64 (each 2 H, d, J 8.0 Hz, ArH); δ_C(75 MHz, CDCl₃)

21.5, 24.8, 37.9, 39.0, 44.7, 55.2, 55.8, 71.5, 127.5, 130.0, 133.2

and 144.0; m/z (CI+) 379 (M⁺+ 18, 20%), 362 (M⁺+ 1, 45) and

208 (100).

D-(−)-Diethyl tartrate (74 mg, 0.36 mmol, 1.1 eq.) in DCM

(0.3 mL) was added to a cold solution (−23 °C) of titanium tetra-

isopropoxide (102 mg, 0.36 mmol, 1.1 eq.) in DCM (3 mL).

After 10 min at −23 °C, the alkene 13 (87 mg, 0.33 mmol) in

DCM (0.4 mL) and tert-butyl hydroperoxide (4 M in toluene,

0.29 mL, 1.16 mmol, 3.6 eq.) were added dropwise. The mixture

was stirred for 6 h then aqueous sodium hydroxide (30% in brine,

3.25 mL, 0.98 mmol, 3 eq.) was added. The mixture was warmed

to 0 °C, stirred for 30 min, filtered through a short pad of celite,

dried (Na₂SO₄) and concentrated under reduced pressure.

Chromatography (ethyl acetate : light petroleum = 3 : 2) of the

residue gave the (1R,6R)-enantiomer of the title compound 15

(54 mg, 59%, 92% ee), R_f= 0.21 (ethyl acetate : light petroleum

4.2.11 3-Methylene-1-(4-methylphenylsulfonyl)piperidin-4-ol

(18)

20

= 3 : 2); m.p. 138-139 °C; [α]_D+2.3 (c 1.5, CHCl₃) (Found:

Potassium iodide (294 mg, 1.77 mmol, 5.0 eq.) then Zn powder

(46 mg, 0.71 mmol, 2.0 eq.) were added to the mesylate 17 in

DMF (2 mL). The mixture was heated at 110 °C for 1.5 h then

allowed to cool to rt and water (2 mL) was added. Following

extraction with ether (3 × 5 mL), the organic extracts were dried

(Na₂SO₄), and concentrated under reduced pressure to give the

title compound 18 (82 mg, 87%) used without further

purification, R_f= 0.30 (ethyl acetate : light petroleum = 3 : 2)

(Found: M⁺+ H, 268.1012. C₁₃H₁₈NO₃S requires M, 268.1007);

ν_max/cm^-13476, 2925, 2854, 1596, 1461, 1343, 1305, 1162, 1089,

1010, 921 and 815; δ_H(300 MHz, CDCl₃) 1.65 (1 H, br. s, OH),

1.70 (1 H, dtd, J 3.8, 7.5, 13.0 Hz, 5-H), 1.98 (1 H, dtd, J 4.0, 7.8,

13.0 Hz, 5-H′), 2.44 (3 H, s, CH₃), 3.06 (1 H, ddd, J 4.0, 7.5, 11.5

Hz, 6-H), 3.35 (1 H, ddd, J 3.8, 7.8, 11.5 Hz, 6-H′), 3.50 and 3.80

(each 1 H, d J 12.5 Hz, 2-H), 4.14 (1 H, m, 4-H), 5.07 and 5.11

(each 1 H, s, 3-CH) and 7.33 and 7.67 (each 2 H, d, J 8.1 Hz,

ArH); δ_C(75 MHz, CDCl₃) 21.5, 33.6, 42.9, 49.7, 69.4, 111.5,

127.7, 129.7, 133.1, 142.9 and 143.6; m/z (CI+) 285 (M⁺+ 18,

6%), 268 (M⁺+ 1, 100) and 250 (M⁺− 17, 27).

M⁺, 283.0883. C₁₃H₁₇NO₄S requires M, 283.0878) with

spectroscopic data identical to those of the racemate. Using L-

(+)-diethyl tartrate, the (1S,6S)-enantiomer was obtained (45%,

20

99% ee), [α]_D−2.4 (c 1.5, CHCl₃) (Found: M⁺, 283.0883.

C₁₃H₁₇NO₄S requires M, 283.0878).

4.2.9 3-Hydroxymethyl-1-(4-methylphenylsulfonyl)piperidin-3-ol

(16)

Sodium cyanoborohydride (1 M in THF, 2.3 mL, 2.3 mmol, 12

eq.) was added to the racemic epoxy alcohol 15 (54 mg, 0.19

mmol) in THF (4.5 mL) at 0 °C. Boron trifluoride diethyl

etherate (0.144 mL, 1.14 mmol, 6 eq.) was then added dropwise

and the reaction mixture was allowed to attain rt before being

heated under reflux for 2 h. After cooling, the reaction was

poured onto a mixture of ice and saturated aqueous sodium

bicarbonate (5 mL). Dichloromethane (5 mL) was added and the

aqueous layer extracted with dichloromethane (3 × 5 mL). The

organic extracts were dried (Na₂SO₄) and concentrated under

reduced pressure. Chromatography (ethyl acetate

: light

petroleum = 1 : 1) of the residue gave the title compound 16 (42

mg, 77%) as a pale yellow oil, R_f= 0.15 (ethyl acetate : light

petroleum = 3 : 2) (Found: M⁺+ H, 286.1118. C₁₃H₂₀NO₄S

requires M, 286.1113); ν_max/cm^-13458, 2936, 2853, 1597, 1494,

1464, 1450, 1400, 1337, 1307, 1291, 1161, 1107, 1091, 1062,

1008, 959, 919, 816, 770 and 741; δ_H(400 MHz, CDCl₃) 1.35

and 1.53 (each 1 H, m, 4-H), 1.66 and 1.89 (each 1 H, m, 5-H),

2.43 (3 H, s, CH₃), 2.66-2.71 (2 H, m, 1-H and 6-H), 2.90 (1 H,

m, OH), 3.20-3.32 (3 H, m, 1-H′, 6-H′, OH), 3.48-3.60 (2 H, m,

3-CH₂) and 7.33 and 7.64 (each 2 H, d, J 8.0 Hz, ArH); δ_C(100

MHz, CDCl₃) 21.0, 21.5, 31.5, 46.6, 52.8, 67.1, 70.1, 127.6,

129.7, 132.8 and 143.7; m/z (CI+) 303 (M⁺+ 18, 22%) and 286

(M⁺+ 1, 100).

4.2.12 4-tert-Butyldimethylsilyloxy-3-methylene-1-(4-

methylphenylsulfonyl)piperidine (19)

2,6-Lutidine (0.289 mL, 2.48 mmol,

2 eq.) then tert-

butyldimethylsilyl triflate (0.427 mL, 1.86 mmol, 1.5 eq.) were

added to the alcohol 18 (332 mg, 1.24 mmol) in DCM (3 mL) at

−20 °C and the reaction mixture was stirred for 1.5 h. Water (3

mL) was added and the aqueous layer was extracted with ether (3

× 5 mL). The organic extracts were dried (Na₂SO₄) and

concentrated under reduced pressure. Chromatography (ethyl

acetate : light petroleum = 1 : 2) of the residue gave the title

compound 19 (269 mg, 57%), R_f= 0.67 (ethyl acetate : light

petroleum = 1 : 2) (Found: M⁺+ H, 382.1878. C₁₉H₃₂NO₃SSi

requires M, 382.1872); ν_max/cm^-12954, 2928, 2886, 2856, 1598,

8

Tetrahedron

ACCEPTED MANUSCRIPT

1463, 1351, 1254, 1166, 1122, 1104, 1092, 1054, 1024, 926,

The bromide 4 (2.6 g, 9.8 mmol) in ether (2.5 mL) was added to

909, 858, 838, 815, 778 and 712; δ_H(300 MHz, CDCl₃) −0.03

and 0.00 (each 3 H, s, SiCH₃), 0.80 [9 H, s, SiC(CH₃)₃], 1.68 and

1.82 (each 1 H, m, 5-H), 2.44 (3 H, s, CH₃), 3.03 (1 H, ddd, J 3.8,

7.5, 11.5 Hz, 6-H), 3.32 (1 H, ddd, J 3.5, 7.5, 11.5 Hz, 6-H′),

3.45 and 3.74 (each 1 H, d, J 12.0 Hz, 2-H), 4.06 (1 H, dd, J 4.0,

7.3 Hz, 4-H), 4.98 and 5.04 (each 1 H, s, 3-CH) and 7.33 and

7.67 (each 2 H, d, J 8.3 Hz, ArH); δ_C(75 MHz, CDCl₃) −5.1,

−5.0, 18.0, 21.5, 25.6, 34.7, 42.8, 49.7, 70.0, 111.0, 127.8, 129.5,

133.1, 143.1 and 143.5; m/z (CI+) 382 (M⁺+ 1, 20%) and 88

(100).

liquid ammonia (125 mL) under reflux (cold finger) and the

reaction was stirred under reflux for 2 h. The ammonia was

allowed to evaporate overnight and the resulting salt was

dissolved in MeOH (50 mL). Solid Na₂CO₃(5 g, 47 mmol, 5 eq.)

was added and the mixture was stirred for 2 h then concentrated

under reduced pressure. The resulting oil was dissolved in DCM,

and the solution filtered through celite and concentrated under

reduced pressure to provide the title compound 25 (1.7 g, 86%),

as a yellow oil, not usually distilled because of loss of material

on distillation, R_f= 0.30 (MeOH); b.p. 58-60 °C at 0.5 mmHg

(Found: M⁺+ H, 202.1629. C₁₀H₂₄NOSi requires M, 202.1627);

ν_max/cm^-13300, 2954, 2929, 2887, 2857, 1580, 1471, 1361, 1254,

1084, 1006, 904, 839 and 776; δ_H(300 MHz, CDCl₃) 0.08 (6 H,

s, 2 × SiCH₃), 0.92 [9 H, s, SiC(CH₃)₃], 1.34 (2 H, br. s, NH₂),

3.30 (2 H, s, 1-H₂), 4.17 (2 H, s, 2-CH₂) and 4.99 and 5.06 (each

1 H, d, J 1.3 Hz, 3-H); δ_C(75 MHz, CDCl₃) −5.4, 18.3, 25.9,

44.4, 65.0, 108.3 and 150.2; m/z (CI+) 202 (M⁺+ 1, 100%).

4.2.13 Hydroboration-oxidation of the 3-methylenepiperidine

(19)

Borane (1 M in THF, 0.26 mL, 0.26 mmol, 1.5 eq.) was added to

the alkene 19 (66 mg, 0.17 mmol) in THF (1 mL) at 0 °C and the

solution was stirred at 0 °C for 1 h and at rt for 4 h. Aqueous

sodium hydroxide (3 M, 0.58 mL, 1.74 mmol, 10 eq.) was added

at 0 °C followed by hydrogen peroxide (30% in water, 0.089 mL,

0.87 mmol, 5 eq.). The solution was stirred at rt for 18 h, then

diluted with ether (5 mL) and washed with water (5 mL). The

aqueous phases were extracted with ether (3 × 5 mL) and the

organic extracts dried (Na₂SO₄) and concentrated under reduced

pressure. Chromatography (ethyl acetate : light petroleum = 1 :

10) of the residue gave (3SR,4SR)-(4-tert-butyldimethylsilyloxy-

4.2.15 (2R)-1-Hydroxybut-3-en-2-ylammonium chloride (28)

Methyltriphenylphosponium bromide (32.0 g, 89.5 mmol, 1.95

eq.) was azeotroped with benzene then suspended in THF (755

mL) at rt and potassium hexamethyldisilazide (0.5 M in toluene

172 mL, 86 mmol, 1.9 eq.) was added. The yellow suspension

was stirred at rt for 1 h, then cooled to −78 °C and the aldehyde

26 (10.5 g, 45.8 mmol) in THF (150 mL) was added. The cooling

bath was removed and the mixture was stirred for 2 h. Methanol

(75.5 mL) was added and the mixture was poured into saturated

aqueous potassium sodium tartrate and water (1:1, 1500 mL).

Following extraction with ether (2 × 1500 mL) and drying

(MgSO₄), the mixture was concentrated under reduced pressure.

Chromatography (ethyl acetate : light petroleum = 1 : 9) gave the

known alkene 27 (9.4 g, 90%). This alkene 27 was dissolved in

aqueous hydrogen chloride (6 M, 31 mL, 186 mmol, 4.5 eq.) and

the solution stirred at rt for 30 min. Concentration under reduced

pressure gave the title compound 28 (4.6 g, 90%) as a waxy

3-hydroxy-3-methyl-1-(4-methylphenylsulfonyl)piperidine

22

(10 mg, 14%), as a colourless oil, R_f= 0.73 (ethyl acetate : light

petroleum = 1 : 2) (Found: M⁺+ H, 400.1983. C₁₉H₃₄NO₄SSi

requires M, 400.1978); ν_max/cm^-13507, 2954, 2930, 2884, 2857,

1598, 1463, 1352, 1339, 1304, 1254, 1166, 1093, 997, 926, 837,

776 and 741; δ_H(400 MHz, CDCl₃) −0.01 and 0.01 (each 3 H, s,

SiCH₃), 0.77 [9 H, s, SiC(CH₃)₃], 1.18 (3 H, s, 3-CH₃), 1.56 (1 H,

qd, J 4.8, 13.5 Hz, 5-H), 1.63 (1 H, br. s, OH), 2.07 (1 H, m 5-

H′), 2.44 (3 H, s, CH₃), 2.76-2.82 (2 H, m, 2-H and 6-H), 3.03 (1

H, d, J 11.5 Hz, 2-H′), 3.25 (1 H, m, 6-H′), 3.48 (1 H, dd, J 2.8,

5.0 Hz, 4-H) and 7.34 and 7.65 (each 2 H, d, J 8.0 Hz, ArH); δ_C

(100 MHz, CDCl₃) −4.8, −4.3, 17.9, 21.6, 22.4, 25.7, 29.4, 41.6,

52.5, 70.4, 71.9, 127.6, 129.6, 132.8 and 143.6; m/z (CI+) 400

(M⁺+ 1, 100%). The second fraction was a mixture of (3SR,4SR)-

and (3RS,4SR)-4-tert-butyldimethylsilyloxy-3-hydroxymethyl-1-

(4-methylphenylsulfonyl)piperidines 20 and 21 (40 mg, 57%; 20

: 21 = 75 : 25), R_f= 0.64 (ethyl acetate : light petroleum = 1 : 2)

(Found: M⁺+ H, 400.1968. C₁₉H₃₄NO₄SSi requires M, 400.1978);

ν_max/cm^-13531, 2953, 2928, 2884, 2857, 1598, 1468, 1338, 1306,

1254, 1216, 1166, 1090, 1067, 1046, 980, 944, 905, 839, 814,

776 and 745; δ_H(400 MHz, CDCl₃) major epimer 20 −0.02 and

0.00 (each 3 H, s, SiCH₃), 0.73 [9 H, s, SiC(CH₃)₃], 1.71-1.76 (2

H, m, 5-H₂), 1.94 (1 H, m, 3-H), 2.42 (3 H, s, CH₃), 2.67 (1 H, t,

J 10.5 Hz, 2-H), 2.81 (1 H, ddd, J 5.5, 8.8, 11.3 Hz, 6-H), 3.29-

3.33 (2 H, m, 2-H′ and 6-H′), 3.55 (1 H, dd, J 6.5, 10.8 Hz, 3-

CH), 3.65 (1 H, dd, J 6.8, 10.8 Hz, 3-CH′), 3.98 (1 H, m, 4-H)

and 7.32 and 7.64 (each 2 H, d, J 8.0 Hz, ArH); minor epimer 21

0.01 (6 H, s, 2 × SiCH₃), 0.83 [9 H, s, SiC(CH₃)₃], 2.51 (1 H, dd,

J 9.0, 11.5 Hz, 2-H) and 2.60 (1 H, m, 6-H); δ_C(100 MHz,

CDCl₃) major epimer 20 −5.2, −4.5, 17.9, 21.5, 25.5, 32.1, 41.5,

42.9, 43.8, 62.4, 66.1, 127.6, 129.5, 132.8 and 143.5; minor

epimer 21 −5.0, −4.3, 17.8, 21.6, 25.6, 32.9, 43.9, 45.1, 46.0,

62.2, 69.1, 129.6 and 133.0; m/z (CI+) 400 (M⁺+ 1, 100%).

20

white solid, [α]_D−11.0 (c 1.97, MeOH), {lit.^{8 .}[α]_D+12.9

(2S)-enantiomer (c 0.54, MeOH)}; ν_max/cm^-13387, 3014, 2934,

2895, 1608, 1509, 1429, 1354, 1243, 1154, 1052, 993 and 950;

δ_H(300 MHz, CD₃OD) 3.59 (1 H, m, 2-H), 3.73-3.81 (2 H, m, 1-

H₂), 5.43 (1 H, d, J 10.8 Hz, 4-H), 5.47 (1 H, d, J 17.5 Hz, 4-H′)

and 5.89 (1 H, ddd, J 7.3, 10.8, 17.5 Hz, 3-H); δ_C(75 MHz,

CD₃OD) 56.7, 63.0, 121.5 and 132.4; m/z (ES⁺) 88 (M⁺- 35,

100%).

4.2.16 (2R)-1-Hydroxy-N-(2-nitrophenylsulfonyl)but-3-en-2-

ylamine (29)

Sodium carbonate (6.6 g, 74 mmol, 2 eq.) in water (24 mL) was

added to the ammmonium salt 28 (4.6 g, 37.2 mmol) in acetone

(18 mL) at 0 ^oC followed by 2-nitrobenzenesulfonyl chloride

(9.85 g, 44 6 mmol, 1.2 eq.) and TBAI (trace). The mixture was

allowed to warm to rt then stirred for 1.5 h before being filtered

through celite and concentrated under reduced presure. The

residue was dissolved in chloroform (50 mL) and water (50 mL)

was added. The aqueous layer was extracted with chloroform (3

× 50 mL) and the organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Recrystallisation of the

residue from DCM gave the title compound 29 (9.1 g, 90%), as a

white solid, m.p. 104-105 °C, R_f= 0.31 (ethyl acetate : light

20

4.2.14 2-(tert-Butyldimethylsilyloxymethyl)prop-2-enylamine (25)

petroleum = 3 : 2), [α]_D−63.3 (c 1.56, MeOH) (Found: C,

9

44.19; H, 4.13; N, 10.12; S, 11.97%, C H N O S requires C,

4.2.19 (S)-N-Benzyloxycarbonyl-N-[2-(tert-

butyldimethylsilyloxymethyl)prop-2-enyl]-N-[1-(2-

nitrophenylsulfonylamino)but-3-en-2-yl]amine (32)

₁₂ACCEPTED MANUSCRIPT

10

2

5

44.11; H, 4.44; N, 10.29; S, 11.78%; Found M⁺+ NH₄, 290.0816.

C₁₀H₁₆N₃O₅S requires M, 290.0811); ν_max/cm^-13540, 3338, 2934,

2883, 1540, 1441, 1413, 1360, 1343, 1304, 1167, 1125, 1061,

833, 854, 784 and 742; δ_H(300 MHz, CD₃OD) 3.51 (2 H, d J 6.0

Hz, 1-H₂), 3.97 (1 H, m, 2-H), 5.0 (1 H, dt, J 10.5, 1.3 Hz, 4-H),

5.12 (1 H, dt, J 17.3, 1.3 Hz, 4-H′), 5.71 (1 H, ddd, J 6.3, 10.5,

17.3 Hz, 3-H), 7.74-7.86 (3 H, m, ArH) and 8.08 (1 H, m, ArH);

δ_C(75 MHz, CD₃OD) 60.0, 65.6, 117.7, 125.9, 131.9, 133.5,

134.9, 135.7, 136.3 and 149.5; m/z (CI+) 290 (M⁺+ 18, 100%).

Benzyl chloroformate (0.272 mL, 1.33 mmol, 1.1 eq.) and

saturated aqueous potassium carbonate (3 mL) were added to the

amine 31 (552 mg, 1.21 mmol) in THF (3 mL) at rt and the

reaction mixture was stirred at rt for 1 h. Water (3.5 mL) was

added and the aqueous layer was extracted with ether (3 × 8 mL).

The organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography (ethyl acetate

: light

petroleum = 1 : 6) of the residue gave the title compound 32 (572

4.2.17 1-Mesyloxy-N-(2-nitrophenylsulfonyl)but-3-en-2-ylamine

(30)

mg, 80%), R_f= 0.40 (ethyl acetate : light petroleum = 1 : 2),

20

[α]_D−4.5 (c 1.47, CHCl₃) (Found: M⁺+ H, 590.2338.

Freshly distilled di-isopropylethylamine (0.64 mL, 3.67 mmol)

and mesyl chloride (0.284 mL, 3.67 mmol) were added to the

alcohol 29 (1 g, 3.67 mmol) in DCM (20 mL) at rt. And the

reaction mixture was stirred for 10 min before addition of water

(20 mL). The aqueous layer was extracted with DCM (3 × 10

mL), dried (MgSO₄) and concentrated under reduced pressure to

give the title compound 30 (1.25 g, 97%), used without further

purification, R_f= 0.40 (ethyl acetate : light petroleum = 3 : 2)

C₂₈H₄₀N₃O₇SSi requires M, 590.2356); ν_max/cm^-13374, 2953,

2928, 2886, 2855, 1700, 1542, 1463, 1411, 1361, 1252, 1230,

1171, 1110, 994, 838, 778 and 739; δ_H(300 MHz, DMSO-d₆, 120

°C) 0.03 (6 H, s, 2 × SiCH₃), 0.89 [9 H, s, SiC(CH₃)₃], 3.27 and

3.38 (each 1 H, dd, J 7.3, 13.5 Hz, 1′-H), 3.78 and 3.93 (each 1

H, d, J 16.5 Hz, 1-H), 4.05 (2 H, s, 2-CH₂), 4.21 (1 H, q, J 7.3

Hz, 2′-H), 4.90 (1 H, m, 3-H), 5.07-5.13 (5 H, m, 3-H′, 4′-H₂and

PhCH₂), 5.91 (1 H, m, 3′-H), 7.29-7.36 (5 H, m, ArH), 7.64 (1 H,

br. s, NH), 7.80-7.91 (3 H, m, ArH) and 7.99 (1 H, m, ArH); δ_C

(75 MHz, DMSO-d₆, 120 °C) −6.2, 17.2, 25.0, 44.0, 48.0, 59.4,

63.3, 65.8, 109.8, 117.1, 123.6, 126.7, 126.9, 127.5, 128.9, 130.0,

131.7, 133.1, 134.0, 136.1, 144.4, 147.5 (br) and 154.6; m/z (CI+)

590 (M⁺+ 1, 10%) and 102 (100).

(Found: M⁺

+ NH₄, 368.0581. C₁₁H₁₈N₃O₇S₂requires M,

368.0586); ν_max/cm^-13320, 3098, 3026, 2941, 2893, 1594, 1538,

1442, 1352, 1248, 1175, 1126, 1097, 1060, 990, 964, 915, 854,

824, 784 and 741; δ_H(300 MHz, CDCl₃) 3.01 (3 H, s, SO₂CH₃),

4.21 (1 H, dd, J 6.0, 10.5 Hz, 1-H), 4.26 (1 H, J 4.5, 10.5 Hz, 1-

H′), 4.36 (1 H, m, 2-H), 5.16 (1 H, dd, J 0.8, 10.5 Hz, 4-H), 5.24

(1 H, dd, J 0.8, 17.3 Hz, 4-H′), 5.69 (1 H, ddd, J 6.7, 10.5, 17.3

Hz, 3-H), 5.89 (1 H, d, J 8.5 Hz, NH), 7.73-7.78 (2 H, m, ArH),

7.88 (1 H, m, ArH) and 8.11 (1 H, m, ArH); δ_C(75 MHz, CDCl₃)

37.5, 55.8, 70.1, 119.5, 125.4, 130.8, 132.1, 133.0, 133.8, 134.1

and 147.6; m/z (CI+) 368 (M⁺+ 18, 20%), 272 (80) and 255

(100).

4.2.20 N-Benzyloxycarbonyl-4-(tert-

butyldimethylsilyloxymethyl)-2-(2-

nitrobenzenesulfonylaminomethyl)-2,5-dihydropyrrole (33)

The Grubbs 2 catalyst (44 mg, 0.051 mmol, 5 mol%) was added

to the diene 32 (603 mg, 1.02 mmol) in degassed DCM (40 mL)

and the mixture was stirred under reflux for 6 h. After

concentration under reduced pressure, the residue was absorbed

onto silica. Chromatography (ethyl acetate : light petroleum = 1 :

4) gave the title compound 33 (466 mg, 81%) as a brown oil, R_f=

0.31 (ethyl acetate : light petroleum = 1 : 4), [α]_D²⁰−15.2 (c 1.25,

CHCl₃) (Found: M⁺+ NH₄, 579.2301. C₂₆H₃₉N₄O₇SSi requires M,

579.2308); ν_max/cm^-13375, 2952, 2928, 2885, 2856, 1706, 1542,

1413, 1361, 1345, 1253, 1166, 1095, 838, 779 and 739; δ_H(300

MHz, DMSO-d₆, 120 °C) 0.08 (6 H, s, 2 × SiCH₃), 0.91 [9 H, s,

SiC(CH₃)₃], 3.26 (1 H, td, J 6.0, 13.0 Hz, 2-CH), 3.36 (1 H, ddd,

J 3.75, 5.5, 13.0 Hz, 2-CH′), 3.96 (1 H, m, 5-H), 4.14 (1 H, d, J

14.8 Hz, 5-H′), 4.20 and 4.24 (each 1 H, d, J 14.5 Hz, 4-CH),

4.60 (1 H, m, 2-H), 5.07 and 5.13 (each 1 H, d, J 12.8 Hz,

PhHCH), 5.61 (1 H, m, 3-H), 7.29-7.36 (4 H, m, ArH), 7.45 (1 H,

br. s, ArH), 7.76-7.90 (3 H, m, ArH) and 7.97-8.00 (1 H, m,

ArH); δ_C(75 MHz, DMSO-d₆, 120 °C) −6.2, 17.1, 25.0, 44.8,

52.9, 59.0, 63.4, 65.5, 120.4, 123.6, 126.7, 126.9, 127.5, 128.9,

130.0, 131.6, 133.0, 136.2, 140.2, 147.5 (br) and 153.3; m/z (CI+)

579 (M⁺+ 18, 20%), 562 (M⁺+ 1, 10%) and 99 (100).

4.2.18 (S)-N-[2-(tert-Butyldimethylsilyloxymethyl)prop-2-enyl]-

N-[1-(2-nitrophenylsulfonylamino)but-3-en-2-yl]amine (31)

Potassium carbonate (908 mg, 6.56 mmol, 2 eq.) was added to

the mesylate 30 (1.15 g, 3.28 mmol) and the amine 25 (661 mg,

3.28 mmol) in DCM (14 mL) and the reaction mixture was

stirred at rt for 18 h. Saturated aqueous ammonium chloride (15

mL) was added and the aqueous layer was extracted with ether (3

× 15 mL). The organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography (ethyl

acetate : light petroleum = 1 : 6) of the residue gave the title

compound 31 (1.07 g, 72%) as a pale yellow oil, R_f= 0.38 (ethyl

acetate : light petroleum = 3 : 2), [α]_D²¹−24.0 (c 3.04, CHCl₃)

(Found: M⁺

+ H, 456.1991. C₂₀H₃₄N₃O₅SSi requires M,

456.1988); ν_max/cm^-13336, 2953, 2928, 2884, 2855, 1542, 1463,

1359, 1253, 1169, 1099, 1078, 852, 838 and 778; δ_H(300 MHz,

CDCl₃) 0.07 (6 H, s, 2 x SiCH₃), 0.90 [9 H, s, SiC(CH₃)₃], 2.95 (1

H, dd, J 9.0, 13.5 Hz, 1′-H), 3.02 (1 H, d, J 13.8 Hz, 1-H), 3.15-

3.26 (3 H, m, 1-H′, 1′-H′ and 2′-H), 4.10-4.20 (2 H, m, 2-CH₂),

4.95 and 5.09 (each 1 H, d, J 1.5 Hz, 3-H), 5.15 (1 H, d, J 17.5

Hz, 4′-H), 5.18 (1 H, d, J 10.5 Hz, 4′-H′), 5.55 (1 H, ddd, J 7.3,

10.5, 17.5 Hz, 3′-H), 7.70-7.76 (2 H, m, ArH) and 7.85 and 8.12

(each 1 H, m, ArH); δ_C(75 MHz, CDCl₃) −5.4, 18.3, 25.9, 47.1,

48.9, 59.3, 64.9, 110.8, 118.2, 125.3, 131.1, 132.6, 133.5, 136.9,

146.4 and 148.1; m/z (CI+) 456 (M⁺+ 1, 100%).

4.2.21 N-Benzyloxycarbonyl-4-hydroxymethyl-2-(2-

nitrobenzenesulfonylaminomethyl)-2,5-dihydropyrrole (34)

Tetra-n-butylammonium fluoride (1 M in THF, 1 mL, 1 mmol,

1.2 eq.) was added to the silyl ether 33 (466 mg, 0.83 mmol) in

THF (3.5 mL) at 0 °C and the reaction mixture warmed to rt and

stirred for 30 min. Brine (5 mL) was added and the aqueous layer

was extracted with ether (3 × 10 mL). The organic extracts were

dried (MgSO₄) and concentrated under reduced pressure.

10

Tetrahedron

ACCEPTED MANUSCRIPT

Chromatography (ethyl acetate : light petroleum = 1 : 2 to 3 :

and 8.05 (1 H, d, J 7.8 Hz, ArH); δ (75 MHz, DMSO-d , 120

C

6

2 ) gave the title compound 34 (184 mg, 49%), R_f= 0.21 (ethyl

°C) −6.3, 17.2, 23.0, 25.0, 26.4, 27.4, 49.0, 49.9, 54.5, 61.5, 64.1,

79.1, 92.7, 112.0, 123.6, 129.7, 131.1, 131.5, 133.9, 142.5, 147.2,

150.6; m/z (CI+) 617 (M⁺+ 18, 1%), 600 (M⁺+ 1, 2) and 58

(100).

20

acetate : light petroleum = 3 : 2), [α]_D−41.2 (c 1.02, CHCl₃)

(Found: M⁺

+ NH₄, 465.1440. C₂₀H₂₅N₄O₇S requires M,

465.1444); ν_max/cm^-13361, 2903, 2870, 1694, 1662, 1540, 1416,

1361, 1341, 1164, 1121, 1027, 853 and 739; δ_H(300 MHz,

DMSO-d₆, 120 °C) 3.24-3.36 (2 H, m, 2-CH₂), 3.95 (1 H, m, 5-

H), 4.03 (2 H, s, 4-CH₂), 4.14 (1 H, d, J 14.7 Hz, 5-H′), 4.43 (1

H, br. s, OH), 4.58 (1 H, m, 2-H), 5.07 and 5.12 (each 1 H, d, J

12.8 Hz, PhHCH), 5.57 (1 H, q, J 1.7 Hz, 3-H), 7.30-7.37 (4 H,

m, ArH), 7.44 (1 H, m, ArH), 7.76-7.90 (3 H, m, ArH) and 7.98

(1 H, m, ArH); δ_C(75 MHz, DMSO-d₆, 120 °C) 44.8, 53.1, 57.3,

63.4, 65.5, 119.9, 123.6, 126.8, 127.0, 127.6, 129.0, 131.6, 132.8,

133.0, 136.3, 141.4, 147.5 (br) and 153.3; m/z (CI+) 465 (M⁺+

18, 60%), 448 (M⁺+ 1, 50%), 404 (65) and 94 (100).

4.2.24 N-tert-Butyloxycarbonyl-4-[2-hydroxymethylprop-2-enyl-

N-(2-nitrophenylsulfonyl)amino]methyl-2,2-dimethyl-1,3-

oxazolidine (39)

Toluene p-sulfonic acid hydrate (1 M in methanol, 1.1 mL, 1.1

mmol) was added to the silyl ether 38 (630 mg, 1.05 mmol) in

methanol (10.5 mL) and the reaction mixture was stirred for 1.5

h. Saturated aqeous sodium hydrogen carbonate (15 mL) was

added and the mixture was extracted with ether (3 × 20 mL). The

organic extracts were dried (MgSO₄) and the concentrated under

reduced pressure. Chromatography (ethyl acetate

: light

4.2.22 N-tert-Butyloxycarbonyl-4-[2-(tert-

butyldimethylsilyloxymethyl)prop-2-enylamino]methyl-2,2-

dimethyl-1,3-oxazolidine (37)

petroleum = 1 : 4 to 3 : 2) of the residue gave the title compound

39 (503 mg, 99%), R_f= 0.23 (ethyl acetate : light petroleum = 3 :

2) (Found: M⁺

+ H, 486.1908. C₂₁H₃₂N₃O₈S requires M,

The propenylamine 25 (475 mg, 2.35 mmol) in DCM (10 mL)

and an excess of MgSO₄(1.15 g, 9.43 mmol, 5 eq.) were added

to the racemic aldehyde 26 (540 mg, 2.35 mmol) in DCM (12

mL) and the reaction mixture was stirred for 24 h then filtered

through celite. Concentration under reduced pressure gave the

imine that was dissolved in MeOH (13.5 mL). Sodium

borohydride (108 mg, 2.83 mmol, 1.2 eq.) was added and the

reaction mixture stirred at rt for 2 h. Saturated aqueous sodium

carbonate was added and the aqueous layer was extracted with

ether (3 × 15 mL). The organic extracts were dried (MgSO₄) and

concentrated under reduced pressure to give the title compound

37 (900 mg, 92%), as an oil, R_f= 0.25 (ethyl acetate : light

petroleum = 1 : 4) (Found: M⁺, 414.2913. C₂₁H₄₂N₂O₄Si requires

M, 414.2914); ν_max/cm^-13349, 2978, 2955, 2934, 2883, 2857,

1694, 1472, 1391, 1366, 1258, 1175, 1086, 1073, 848 and 776;

δ_H(300 MHz, DMSO-d₆, 120 °C) 0.07 (6 H, s, 2 × SiCH₃), 0.91

[9 H, s, SiC(CH₃)₃], 1.44 (12 H, s, C(CH₃)₃and 2-CH₃], 1.48 (3

H, s, 2-CH₃′), 2.58 and 2.75 (each 1 H, d, J 10.5 Hz, 4-CH), 3.19

(2 H, s, 1′-H₂), 3.80-3.90 (3 H, m, 4-H, 5-H₂), 4.13 (2 H, s, 2′-

CH₂) and 4.98 and 5.04 (each 1 H, s, 3′-H); δ_C(75 MHz, DMSO-

d₆, 120 °C) −6.1, 17.2, 23.2, 25.1, 26.2, 27.5, 50.0, 50.6, 56.3,

63.8, 65.2, 78.3, 92.3, 108.7, 147.0 and 150.8; m/z (CI+) 415 (M⁺

+ 1, 100%).

486.1910); ν_max/cm^-13436, 2980, 2935, 2883, 1691, 1546, 1392,

1368, 1257, 1165, 852 and 771; δ_H(300 MHz, DMSO-d₆, 120

°C) 1.44 [12 H, s, 2-CH₃, C(CH₃)₃], 1.50 (3 H, s, 2-CH₃′), 3.33-

3.48 (2 H, m, 4-CH₂), 3.86 (4 H, s, 1′-H₂, 2′-CH₂), 3.94-4.23 (3

H, m, 5-H₂, 4-H), 4.44 (1 H, br. s, OH), 5.00 and 5.17 (each 1 H,

s, 3′-H), 7.81-7.89 (3 H, m, ArH) and 8.04 (1 H, d, J 7.7 Hz,

ArH); δ_C(75 MHz, DMSO-d₆, 120 °C) 23.0, 26.4, 27.4, 49.3,

50.3, 54.5, 61.5, 64.1, 79.1, 92.7, 111.5, 123.6, 129.6, 131.1,

131.5, 133.8, 143.8, 147.2 and 150.6; m/z (CI+) 503 (M⁺+ 18,

2%), 486 (M⁺+ 1, 5) and 386 (100).

4.2.25 3-tert-Butyloxycarbonyl-2,2-dimethyl-4-[(3-methylene-

6,6-dioxoperhydrobenzo[g]-1-oxa-5-aza-6-thiocin-5-yl)methyl]-

1,3-oxazolidine (40)

Benzyl bromide (0.123 mL, 1.02 mmol, 1.1 eq.) and sodium

hydride (60% in mineral oil, 56 mg, 1.40 mmol, 1.5 eq.) were

added to the alcohol 39 (454 mg, 0.93 mmol) in THF (2.5 mL).

After stirring for 5 h, saturated aqueous ammonium chloride (5

mL) was added and the aqueous phase was extracted with ether

(3 × 5 mL). The organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography (ethyl

acetate : light petroleum = 1 : 10 to 1 : 2) of the residue gave the

title compound 40 (235 mg, 52%), R_f= 0.14 (ethyl acetate : light

petroleum = 1 : 4) (Found: M⁺+ H, 439.1901. C₂₁H₃₁N₂O₆S

requires M, 439.1903); ν_max/cm^-12979, 2935, 2976, 1690, 1588,

1526, 1473, 1455, 1392, 1366, 1351, 1341, 1258, 1212, 1168,

1104, 1091, 1069, 1004, 915 and 771; δ_H(300 MHz, DMSO, 120

°C) 1.42 [9 H, s, C(CH₃)₃], 1.45 and 1.49 (each 3 H, s, 2-CH₃),

2.90-3.04 (2 H, m, 4-CH₂), 3.94 (1 H, dd, J 5.5, 9.0 Hz, 5-H),

4.06 (1 H, dd, J 1.5, 9.0 Hz, 5-H′), 4.14-4.20 (2 H, m 4-H, 4′-H),

4.35 (1 H, d, J 15.5 Hz, 4′-H′), 4.68 and 4.81 (each 1 H, d, J 14.0

Hz, 2′-H), 5.20 and 5.26 (each 1 H, s, 3′-CH), 7.29 (1 H, dt, J 1.0,

7.5 Hz, ArH), 7.37 (1 H, dd, J 1.0, 8.0 Hz, ArH), 7.63 (1 H, ddd,

J 1.75, 7.5, 8.0 Hz, ArH) and 7.78 (1 H, dd, J 1.75, 7.5 Hz, ArH);

δ_C(75 MHz, CDCl₃) 23.1, 26.4, 27.4, 45.8, 48.8, 54.7, 64.3, 78.3,

79.0, 92.6, 117.3, 123.0, 123.4, 128.3, 133.0, 133.8, 139.5, 150.8

and 156.0; m/z (CI+) 456 (M⁺+ 18, 5%), 439 (M⁺+ 1, 20), 400

(50), 339 (70) and 58 (100).

4.2.23 N-tert-Butyloxycarbonyl-4-[2-(tert-

butyldimethylsilyloxymethyl)prop-2-enyl-N-(2-

nitrophenylsulfonyl)amino]methyl-2,2-dimethyl-1,3-oxazolidine

(38)

Following the procedure for the preparation of compound 29, the

amine 37 (879 mg, 2.12 mmol), after stirring for 3 h and

chromatography (ethyl acetate : light petroleum = 1 : 20 to 1 : 4),

gave the title compound 38 (1.0 g, 79%), as an oil, R_f= 0.38

(ethyl acetate : light petroleum = 1 : 4) (Found: M⁺

+

H, 600.2771. C₂₇H₄₆N₃O₈SSi requires M, 600.2775); ν_max/cm^-1

2955, 2930, 2884, 2857, 1697, 1546, 1472, 1463, 1390, 1366,

1256, 1167, 1105, 1090, 918, 852 and 778; δ_H(300 MHz,

DMSO-d₆, 120 °C) 0.05 (6 H, s, 2 × SiCH₃), 0.90 [9 H, s,

SiC(CH₃)₃], 1.43 (3 H, s, 2-CH₃), 1.44 [9 H, s, C(CH₃)₃], 1.50 (3

H, s, 2-CH₃′), 3.34 (1 H, dd, J 4.2, 14.0 Hz, 4-CH), 3.43 (1 H, dd,

J 9.0, 14.0 Hz, 4-CH′), 3.84-4.13 (7 H, m, 4-H, 5-H₂, 1′-H₂, 2′-

CH₂), 5.04 and 5.19 (each 1 H, s, 3′-H), 7.81-7.92 (3 H, m, ArH)

4.2.26 2-(Benzyloxymethyl)prop-2-enylamine (42)

11

The bromide 41 (170 mg, 0.705 mmol) in ether (0.5 mL) was

4.2.29 3-[N-(2-Benzyloxymethylprop-2-enyl-N-2-

nitrophenylsulfonyl)]amino-2-(tert-

butyloxycarbonyl)aminopropan-1-ol (45)

ACCEPTED MANUSCRIPT

added to liquid ammonia (50 mL) under reflux (cold finger) and

the reaction was stirred under reflux for 2 h. The ammonia was

allowed to evaporate overnight and the resulting salt was

dissolved in MeOH (25 mL). Solid Na₂CO₃(500 mg, 4.7 mmol,

6.7 eq.) was added and the mixture was stirred for 2 then

concentrated under reduced pressure. The resulting oil was

dissolved in DCM, filtered through celite and concentrated under

reduced pressure to provide the title compound 42 (97 mg, 77%),

as a pale yellow oil, R_f= 0.11 (methanol : ethyl acetate = 1 : 20)

(Found: M⁺+ H, 178.1235. C₁₁H₁₆NO requires M, 178.1232);

ν_max/cm^-13371, 3086, 3064, 3031, 2855, 1654, 1585, 1494, 1453,

1363, 1315, 1206, 1096, 1075, 909 and 741; δ_H(300 MHz,

CDCl₃) 1.37 (2 H, br. s, NH₂), 3.37 (2 H, s, 1-H₂), 4.06 (2 H, s, 3-

CH₂), 4.51 (2 H, s, PhCH₂), 5.11-5.13 (2 H, m, 3-H₂) and 7.27-

7.39 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) 44.7, 72.0, 72.1, 111.4,

127.6, 127.7, 128.4, 138.2 and 147.4; m/z (CI+) 178 (M⁺+ 1,

100%).

Toluene p-sulfonic acid (17 mg, 0.091 mmol, 0.5 eq.) in

methanol (0.9 mL) was added to the oxazolidine 44 (105 mg,

0.182 mmol) in methanol (2 mL) and the reaction mixture stirred

at rt for 5 d. Saturated aqueous sodium hydrogen carbonate (5

mL) was added and the mixture concentrated under reduced

pressure. Ether (5 mL) was added and the aqueous layer was

extracted with more ether (3 × 5 mL). The organic extracts were

dried (MgSO₄) and concentrated under reduced pressure to give

the title compound 45 (96 mg, 98%), R_f= 0.39 (ethyl acetate :

light petroleum = 3 : 2) (Found: M⁺+ H, 536.2066. C₂₅H₃₄N₃O₈S

requires M, 536.2067); ν_max/cm^-13419, 3093, 3070, 3026, 2976,

2931, 2872, 1705, 1545, 1504, 1451, 1367, 1247, 1165, 1064,

926, 851, 784 and 739; δ_H(300 MHz, DMSO-d₆, 120 °C) 1.39 [9

H, s, C(CH₃)₃], 3.39-3.43 (4 H, m, 1-H₂, 3-H₂), 3.71 (1 H, m, 2-

H), 3.90 (2 H, s, 1′-H₂), 4.06 (2 H, s, 2′-CH₂), 4.34 (1 H, br. s,

OH), 4.43 (2 H, s, PhCH₂), 5.14 and 5.22 (each 1 H, s, 3′-H),

5.77 (1 H, br. d, J 7.5 Hz, NH), 7.27-7.38 (5 H, m, ArH), 7.77-

7.87 (3 H, m, ArH) and 8.04 (1 H, d, J 7.5 Hz, ArH); δ_C(75

MHz, DMSO-d₆) 28.1, 48.1, 49.3, 50.1, 61.4, 70.1, 71.2, 77.7,

114.7, 124.3, 127.3, 127.4, 128.1, 130.3, 132.1, 132.3, 134.3,

138.0, 140.1, 147.1 and 154.9; m/z (CI+) 536 (M⁺+ 1, 1%), 436

(20) and 91 (100).

4.2.27 N-tert-Butyloxycarbonyl-4-[2-(benzyloxymethyl)prop-2-

enylamino]methyl-2,2-dimethyl-1,3-oxazolidine (43)

Following the procedure for the preparation of oxazolidine 37,

the propenylamine 42 (345 mg, 1.95 mmol), after 48 h for imine

formation, 2 h for reduction and chromatography (ethyl acetate :

light petroleum = 1 : 2), gave the title compound 43 (476 mg,

63%), as an oil, R_f= 0.12 (ethyl acetate : light petroleum = 1 : 2)

(Found: M⁺+ H, 391.2598. C₂₂H₃₅N₂O₄requires M, 391.2597);

ν_max/cm^-13379, 3066, 2978, 2932, 2871, 1694, 1476, 1454, 1389,

1368, 1256, 1174, 1088, 909, 849 and 738; δ_H(300 MHz,

DMSO-d₆, 120 °C) 1.44 [12 H, s, 2-CH₃, C(CH₃)₃], 1.49 (3 H, s,

2-CH₃′), 2.58 (1 H, dd, J 8.5, 11.7 Hz, 4-CH), 2.76 (1 H, dd, J

3.5, 11.7 Hz, 4-CH′), 3.22 (2 H, s, 1′-H₂), 3.80-3.89 (3 H, m, 4-H

and 5-H₂), 4.02 (2 H, s, 2′-CH₂), 4.49 (2 H, s, PhCH₂), 5.09 (2 H,

s, 3′-H₂) and 7.24-7.37 (5 H, m, ArH); δ_C(75 MHz, DMSO-d₆,

120 °C) 23.2, 26.1, 27.4, 50.1, 51.0, 56.4, 65.2, 70.9, 71.0, 78.3,

92.3, 110.8, 126.5, 126.6, 127.4, 138.0, 144.8 and 150.8; m/z

(CI+) 391 (M⁺+ 1, 60%), 279 (40) and 58 (100).

4.2.30 N-(2-Benzyloxymethylprop-2-enyl) 2-

nitrobenzenesulfonamide (47)

Dess Martin periodinane (255 mg, 0.524 mmol, 2 eq.) was added

to the alcohol 45 (141 mg, 0.262 mmol) in DCM (2.5 mL) at rt

and the reaction mixture was stirred at rt for 45 min. Saturated

aqueous sodium bicarbonate (4 mL) and saturated aqueous

sodium bisulfite (1 mL) were added and the aqueous layer was

extracted with ether (3 × 5 mL). The organic extracts were

washed with saturated aqueous sodium bicarbonate (2 × 1 mL)

and brine (1 mL), then dried (MgSO₄) and concentrated under

reduced pressure to give aldehyde 46 (123 mg, 88%), R_f= 0.44

(ethyl acetate : light petroleum = 3 : 2); ν_max/cm^-13417, 2978,

2931, 2863, 1708, 1546, 1368, 1166, 924, 782 and 738; δ_C(75

MHz, CDCl₃) 28.2, 46.3, 50.7, 53.4, 58.0, 70.4, 72.2, 80.5, 117.8,

124.2, 127.6, 128.3, 131.3, 131.7. 132.6, 133.8, 137.7, 139.7,

147.7, 155.7 and 198.9.

4.2.28 N-tert-Butyloxycarbonyl-4-[2-(benzyloxymethyl)prop-2-

enyl-N-(2-nitrophenylsulfonyl)amino]methyl-2,2-dimethyl-1,3-

oxazolidine (44)

Following the procedure for the preparation of compound 38,

amine 43 (2.15 g, 5.5 mmol), after stirring for 18 h and

chromatography (ethyl acetate : light petroleum = 1 : 4 to 1 : 2),

gave the title compound 44 (2.37 g, 75%), as an oil, R_f= 0.11

(ethyl acetate : light petroleum = 1 : 4) (Found: M⁺, 575.2302.

C₂₈H₃₇N₃O₈S requires M, 575.2301); ν_max/cm^-13092, 2979, 2934,

2877, 1694, 1590, 1545, 1453, 1388, 1370, 1256, 1167, 1090,

923, 851, 774 and 738; δ_H(300 MHz, DMSO-d₆, 120 °C) 1.42 (3

H, s, 2-CH₃), 1.43 [9 H, s, C(CH₃)₃], 1.50 (3 H, s, 2-CH₃′), 3.34

(1 H, dd, J 4.2, 14.0 Hz, 4-CH), 3.45 (1 H, dd, J 9.0, 14.0 Hz, 4-

CH′), 3.79-4.13 (7 H, m, 4-H, 5-H₂, 1′-H₂, 2′-CH₂), 4.45 (2 H, s,

PhCH₂), 5.12 and 5.23 (each 1 H, s, 3′-H), 7.26-7.37 (5 H, m,

ArH), 7.78-7.90 (3 H, m, ArH) and 8.03 (1 H, m, ArH); δ_C(75

MHz, DMSO-d₆, 120 °C) 23.0, 26.4, 27.4, 49.3, 50.3, 54.5, 64.1,

70.0, 71.2, 79.1, 92.7, 114.2, 123.6, 126.6, 126.7, 127.4, 129.7,

131.0, 131.5, 133.9, 137.6, 140.3, 147.2, 150.6; m/z (EI) 575

(M⁺, 1%) and 49 (100).

Methyl(triphenyl)phosphonium bromide (19 mg, 0.052 mmol,

1.2 eq.) was azeotroped with benzene and suspended in THF (1

mL) at rt. n-Butyllithium (1.6 M in THF, 0.03 mL, 0.047 mmol,

1.1 eq.) was added and the suspension was stirred at rt for 30

min. After cooling to −78 °C, the aldehyde 46 (23 mg, 0.043

mmol) in THF (1 mL) was added. The cooling bath was removed

and the mixture was stirred for a further 2 h. The mixture was

added to saturated aqueous ammonium chloride (5 mL) and the

mixture was extracted with ether (3 × 5 mL). After drying

(MgSO₄) and concentration under reduced pressure,

chromatography (ethyl acetate : light petroleum = 1 : 10 to 1 : 2)

of the residue gave the title compound 47 (11 mg, 72%), R_f=

0.05 (ethyl acetate : light petroleum = 1 : 10) (Found: M⁺+

H, 363.1021. C₁₇H₁₉N₂O₅S requires M, 363.1015); ν_max/cm^-1

3338, 3093, 3029, 2921, 2859, 1540, 1350, 1168, 1069, 853 and

738; δ_H(300 MHz, CDCl₃) 3.86 (2 H, d, J 6.2 Hz, 1-H₂), 3.98 (2

H, s, 2-CH₂), 4.49 (2 H, s, PhCH₂), 5.15 and 5.19 (each 1 H, s, 3-

H), 5.72 (1 H, br. t, J 6.2 Hz, NH), 7.30-7.41 (5 H, m, ArH),

12

Tetrahedron

7.73-7.78 (2 H, m, ArH) and 7.89 and 8.14 (each 1 H, m,

Hz, ArH); δ (75 MHz, CDCl ) 28.3, 49.1, 50.2, 60.4, 62.8, 70.3,

ACCEPTED MANUSCRIPT

C

3

ArH); δ_C(75 MHz, CDCl₃) 46.4, 71.4, 72.4, 115.8, 125.3, 127.8,

128.4, 131.1, 132.7, 133.5, 133.9, 137.6, 140.6 and 148.0; m/z

(CI+) 380 (M⁺+ 18, 70%), 363 (M⁺+ 1, 15) and 70 (100).

72.2, 79.7, 117.5, 124.1, 127.6, 128.1, 128.4, 128.6, 131.5,

131.7(2) 133.4, 133.6, 137.8, 139.6, 147.6 and 155.3; m/z (TOF-

ES⁺) 600 (M⁺+ 39, 30%), 584 (M⁺+ 23, 80) and 462 (100).

4.2.31 Ethyl 5-[N-(2-Benzyloxymethylprop-2-enyl)-N-(2-

nitrophenylsulfonyl)]amino-4-(tert-butoxycarbonyl)aminopent-2-

enoate (48)

4.2.33 2-Methylpropane sulfinamide¹⁵

A solution of 2-methylpropanethiol (14.1 cm³, 125 mmol) in

DCM (50 mL) was cooled to −40 °C and at 30 min intervals, a

slurry (50 mL) of a suspension of m-chloroperbenzoic acid (63.2

Triethyl phosphonoacetate (0.29 mL, 1.46 mmol, 2 eq.) was

added to a suspension of sodium hydride (60% in mineral oil, 44

mg, 1.09 mmol, 1.5 eq.) in THF (2 mL) and the mixture was

stirred at 0 °C for 1 h. The aldehyde 46 (389 mg, 0.73 mmol) in

THF (5 mL) was added and the mixture was stirred at rt for 1 h.

Water (10 mL) as added and the aqueous layer was extracted

with ether (3 × 10 mL). The organic extracts were dried (MgSO₄)

and concentrated under reduced pressure. Chromatography (ethyl

acetate : light petroleum = 1 : 10) of the residue gave the title

compound 48 (119 mg, 27%) as a colourless oil, R_f= 0.22 (ethyl

acetate : light petroleum = 1 : 2) (Found: M⁺+ Na, 626.2133.

C₂₉H₃₇N₃O₉SNa requires M, 626.2148); ν_max/cm^-13366, 3092,

2979, 2930, 2866, 1712, 1659, 1544, 1513, 1451, 1368, 1272,

1248, 1164, 928, 853, 782 and 738; δ_H(300 MHz, CDCl₃) 1.28

(3 H, t, J 7.2 Hz, OCH₂CH₃), 1.43 [9 H, s, C(CH₃)₃], 3.27 (1 H,

dd, J 4.2, 15.2 Hz, 5-H), 3.60 (1 H, dd, J 11.3, 15.2 Hz, 5-H′),

3.72 and 3.76 (each 1 H, d, J 13.2 Hz, 1′-H), 4.00 and 4.13 (each

1 H, d, J 15.8 Hz, 2′-CH), 4.19 (2 H, q, J 7.2 Hz, OCH₂CH₃),

4.25 and 4.31 (each 1 H, d, J 11.7 Hz, PhHCH), 4.61 (1 H, m, 4-

H), 4.92 (1 H, br. d, J 9.0 Hz, NH), 5.23 and 5.26 (each 1 H, s,

3′-H), 5.96 (1 H, dd, J 1.75, 15.5 Hz, 2-H), 6.73 (1 H, dd, J 5.0,

15.5 Hz, 3-H), 7.20-7.36 (5 H, m, ArH), 7.50 (1 H, m, ArH),

7.57-7.63 (2 H, m, ArH) and 8.00 (1 H, d, J 7.7 Hz, ArH); δ_C(75

MHz, CDCl₃) 14.2, 28.3, 48.8, 49.2, 60.6, 65.8, 70.2, 72.2, 80.1,

117.9, 122.6, 124.2, 127.6, 127.7, 128.4, 131.5, 131.7, 133.4,

133.5, 137.8, 139.5, 144.6, 147.5, 155.3 and 165.7; m/z (TOF-

ES⁺) 642 (M⁺+ 39, 20%), 626 (M⁺+ 23, 50) and 504 (100). The

sulfonamide 47 (64 mg, 24%) was also isolated.

o

g, 256 mmol, 2.05 eq.) in DCM (500 mL) cooled to −78 C was

added in portions with vigorous stirring (exothermic reaction)

over 10 h. The resulting white suspension was stirred at −30 °C

overnight, then cooled to −78 °C and filtered. The filtrate was

concentrated under reduced pressure then dried under high

vacuum to provide crude tert-butanesulfinic acid (13.5 g, 88%).

Thionyl chloride (40.3 mL, 552.5 mmol, 5 eq.). was added to this

sulfinic acid at −40 °C under nitrogen and the yellow solution

was allowed to warm to rt and was stirred for 2 h. Concentration

under high vacuum gave tert-butylsulfinyl chloride (12.9 g, 83%)

as a brown oil. This sulfinyl chloride in DCM (582 mL) was

added to aqueous ammonia (38% in water 582 mL, 220 mmol,

2.4 eq.) and the mixture stirred at rt for 1 h. The aqueous layer

was then saturated with NaCl and extracted with DCM (4 × 600

cm³). The organic extracts were dried (MgSO₄) and concentrated

under reduced pressure to yield the title compound (9.2 g, 83%)

as a white solid crystallised from hexane. R_f= 0.23 (EtOAc);

m.p. 103-104 °C [lit.¹⁴for the (S)-enantiomer 106 C (TCI)];

o

ν_max/cm^-13231, 2979, 2959, 2928, 2869, 1677, 1570, 1475, 1461,

1364, 1309, 1193, 1132, 1030 and 893; δ_H(300 MHz, CDCl₃)

1.19 [9 H, s, C(CH₃)₃] and 3.96 (2 H, br. s, NH₂); δ_C(75 MHz,

CDCl₃) 22.1 and 55.2; m/z (CI+) 139 M⁺+ 18, 100%) and 122

(M⁺+ 1, 100).

4.2.34 N-tert-Butylsulfinyl-2-tert-butyldimethylsilyloxy-1-

cyclobutylethanimine (55)

tert-Butylsulfinamide (1.17 g, 9.63 mmol, 1.1 eq.) was added to

solution of Ti(OEt)₄(0.5 M, 5.5 mL, 26.3 mmol, 3 eq., technical

grade, ~20% Ti) and the ketone 54 (2 g, 0.876 mmol) in THF (36

mL) and the solution was heated under reflux until complete

(TLC). After cooling to rt, the mixture was added to brine (40

mL) and the resulting suspension was filtered through a plug of

Celite, the filter cake being washed with EtOAc (40 mL). The

organic extract was washed with brine (30 mL) and the brine

washings extracted with EtOAc (30 mL). The organic extracts

were dried (Na₂SO₄) and concentrated under reduced presure.

Chromatography (ethyl acetate : light petroleum = 1 : 20) of the

residue gave the title compound 55 (1.51 g, 52%), R_f= 0.47

(ethyl acetate : light petroleum = 1 : 4) (Found: M⁺+

H, 332.2075. C₁₆H₃₄NO₂SSi requires M, 332.2079); ν_max/cm^-1

2978, 2953, 2897, 2858, 1619, 1472, 1361, 1255, 1181, 1112,

1079, 852 and 779; δ_H(300 MHz, CDCl₃) 0.08 (6 H, s, 2 ×

SiCH₃), 0.91 [9 H, s, SiC(CH₃)₃], 1.28 [9 H, s, SC(CH₃)₃], 1.75-

2.30 (6 H, m, 3 × CH₂), 3.68 (1 H, pent, J 8.3 Hz, 1′-H) and 4.66

and 4.73 (each 1 H, d, J 16.7 Hz, 2-H; δ_C(75 MHz, CDCl₃) −5.8,

17.9, 18.0, 22.2, 25.6, 25.8, 26.2, 41.2, 56.8, 63.2 and 189.1; m/z

(CI+) 332 (M⁺+ 1, 100%).

4.2.32 5-[N-(2-Benzyloxymethylprop-2-enyl)-N-(2-

nitrophenylsulfonyl)]amino-4-(tert-butoxycarbonyl)aminopent-2-

en-1-ol (49)

Di-isobutylaluminium hydride (1 M in hexanes, 0.59 mL, 0.59

mmol, 3.3 eq.) was added to the ester 48 (108 mg, 0.18 mmol) at

o

−78 C and the mixture stirred at this temperature for 2 h before

o

being allowed to warm to 0 C. After 30 min, water (20 µL),

saturated aqueous potassium sodium tartrate (0.5 mL) and ether

(0.5 mL) were added and the mixture was allowed to warm to rt.

The aqueous phase was extracted with ether (3 × 2 mL), dried

(MgSO₄) and concentrated under reduced presure to give the title

compound 49 (74 mg, 74%), R_f= 0.27 (ethyl acetate : light

petroleum = 3 : 2) (Found: M⁺+ Na, 584.2034. C₂₇H₃₅N₃O₈SNa

requires M, 584.2043); ν_max/cm^-13420, 3095, 2976, 2927, 2892,

2867, 1706, 1544, 1515, 1451, 1367, 1246, 1164, 1093, 1069,

1020, 972, 926, 851, 780 and 737; δ_H(300 MHz, CDCl₃) 1.43 [9

H, s, C(CH₃)₃], 3.25 (1 H, dd, J 5.2, 15.0 Hz, 5-H), 3.55 (1 H, dd,

J 10.0, 15.0 Hz, 5-H′), 3.77 (2 H, s, 1′-H₂), 4.03 and 4.09 (each 1

H, d, J 15.0 Hz, 2′-CH), 4.10-4.16 (2 H, m, 1-H₂), 4.30 (2 H, s,

PhCH₂), 4.46 (1 H, m, 4-H), 4.82 (1 H, br. d, J 9.2 Hz, NH), 5.24

and 5.25 (each 1 H, s, 3′-H), 5.56 (1 H, dd, J 6.0, 15.5 Hz, 3-H),

5.83 (1 H, td, J 5.2, 15.5 Hz, 2-H), 7.21-7.38 (5 H, m, ArH), 7.51

(1 H, m, ArH), 7.58-7.62 (2 H, m, ArH) and 8.02 (1 H, d, J 7.5

4.2.35 (2RS)-[(RS)- and (2RS)-[(SR)- N-tert-Butylsulfinyl]-1-tert-

butyldimethylsilyloxy-2-cyclobutylbut-3-en-2-ylamine (56) and

(57)

13

Vinyl magnesium bromide (1 M in THF, 10 mL, 10 mmol, 1.1

eq.) was added slowly to the imine 55 (3.03 g, 9.14 mmol), in

toluene (44 mL) at −78 °C and the reaction mixture stirred at −78

°C for 15 h. Water (30 mL) was slowly added and the reaction

mixture was allowed to warm to rt. The aqueous phase was

extracted with ether (2 × 50 mL) and the organic extracts were

dried (Na₂SO₄) and concentrated under reduced pressure.

Chromatography (ethyl acetate : light petroleum = 1 : 4) of the

residue gave the title compound 56 (1.27 g, 39%, 95% de), R_f=

0.24 (ethyl acetate : light petroleum = 1 : 4) (Found: M⁺+

H, 360.2392. C₁₈H₃₈NO₂SSi requires M, 360.2392); ν_max/cm^-1

3292, 2954, 2859, 1471, 1408, 1388, 1363, 1254, 1181, 1162,

1102, 1074, 1005, 988, 939, 923, 838, 778 and 754; δ_H(300

MHz, CDCl₃) 0.03 and 0.05 (each 3 H, s, SiCH₃), 0.87 [9 H, s,

SiC(CH₃)₃], 1.20 [9 H, s, SC(CH₃)₃], 1.64-2.3 (6 H, m, 3 × CH₂),

2.94 (1 H, pent, J 8.2 Hz, 1′-H), 3.53 and 3.60 (each 1 H, d, J 9.5

Hz, 1-H), 3.82 (1 H, br. s, NH), 5.23 (1 H, dd, J 17.5, 1.2 Hz, 4-

H), 5.27 (1 H, dd, J 11.0, 1.2 Hz, 4-H′) and 5.89 (1 H, dd, J 11.0,

17.5 Hz, 3-H); δ_C(75 MHz, CDCl₃) −5.6(2), 18.1(2), 22.7, 23.4,

23.6, 25.8, 39.9, 55.9, 63.5, 68.1, 116.5 and 138.9; m/z (CI+) 360

(M⁺+ 1, 100%).

δ (300 MHz, CDCl ) 1.22 [9 H, s, C(CH ) ], 1.61-2.01 (6 H,

ACCEPTED MANUSCRIPT

H 3 3 3

m, 3 × CH₂), 3.04 (1 H, m, 2-CH), 3.39 (1 H, s, NH), 3.48 (1 H,

dd, J 3.5, 12.0 Hz, 1-H), 3.65 (1 H, dd, J 6.5, 12.0 Hz, 1-H′), 3.75

(1 H, br. s, OH), 5.25 (1 H, dd, J 17.5, 1.0 Hz, 4-H), 5.36 (1 H,

dd, J 11.0, 1.0 Hz, 4-H′) and 5.88 (1 H, dd, J 11.0, 17.5 Hz, 3-H);

δ_C(75 MHz, CDCl₃) 17.8, 22.3, 22.6, 23.1, 37.6, 55.9, 64.9, 66.7,

116.9 and 138.6; m/z (CI+) 279 (20%) and 246 (M⁺+ 1, 100).

4.2.38 (2RS)-2-[(RS)-N-tert-Butylsulfinylamino]-2-cyclobutylbut-

3-enal (60)

Following the procedure for the preparation of compound 46, the

alcohol 59 (467 mg, 1.79 mmol), after stirring for 45 min, gave

the title compound 60 (408 mg, 88%), R_f= 0.34 (ethyl acetate :

light petroleum = 3 : 2) (Found: M⁺+ H, 244.1367. C₁₂H₂₂NO₂S

requires M, 244.1371); ν_max/cm^-13215, 2978, 2950, 2867, 2824,

1728, 1636, 1474, 1365, 1257, 1179, 1060 and 928; δ_H(400

MHz, CDCl₃) 1.21 [9 H, s, C(CH₃)₃], 1.72-2.04 (6 H, m, 3 ×

CH₂), 2.98 (1 H, pent, J 8.5 Hz, 2-CH), 4.08 (1 H, s, NH), 5.35 (1

H, d, J 17.5 Hz, 4-H), 5.44 (1 H, d, J 11.0 Hz, 4-H′), 5.93 (1 H,

dd, J 11.0, 17.5 Hz, 3-H) and 9.46 (1 H, s, CHO); δ_C(100 MHz,

CDCl₃) 18.0, 22.6, 22.7, 23.2, 39.1, 56.7, 70.6, 119.8, 133.7 and

198.2; m/z (CI+) 244 (M⁺+ 1, 100%).

o

After reacting for 6 h at 0 C, the imine 55 (100 mg, 0.301

mmol) in toluene (1 mL) and vinylmagnesium bromide (1 M in

THF, 0.362 mL, 0.312 mmol, 1.2 eq.) gave a mixture of the

sulfinylamines 56 and 57 (50 mg, 46%) after chromatography,

ratio 56 : 57 = 75 : 25; δ_H(300 MHz, CDCl₃) minor isomer 57

0.07 (6 H, s, 2 × SiCH₃), 0.89 [9 H, s, SiC(CH₃)₃], 1.21 [9 H, s,

SC(CH₃)₃], 3.61 and 3.70 (each 1 H, d, J 9.5 Hz, 1-H), 3.89 (1 H,

br. s, NH) and 5.96 (1 H, dd, J 11.0, 17.5 Hz, 3-H); δ_C(75 MHz,

CDCl₃) minor isomer 57 17.8, 18.1, 23.2, 23.5, 41.7, 62.7, 67.0

and 137.4.

4.2.39 (2RS)-N-[2-(tert-Butyldimethylsilyloxymethyl)prop-2-

enyl]-2-[(RS)-N-tert-butylsulfinylamino]-2-cyclobutylbut-3-en-1-

ylamine (61)

Following the procedure for the preparation of compound 37, the

racemic aldehyde 60 (408 mg, 1.57 mmol), after stirring for 40 h

to form the imine and 2.5 h for the reduction, gave the title

compound 61 (625 mg, 93%) as a pale yellow oil, R_f= 0.19

(ethyl acetate : light petroleum = 3 : 2) (Found: M⁺

+

H, 429.2984. C₂₂H₄₅N₂O₂SSi requires M, 428.2971); ν_max/cm^-1

3312, 3223, 2954, 2931, 2900, 2858, 1657, 1638, 1471, 1362,

1255, 1106, 1068, 1005, 921, 838 and 777; δ_H(400 MHz, CDCl₃)

0.04 (6 H, s, 2 × SiCH₃), 0.88 [9 H, s, SiC(CH₃)₃], 1.19 [9 H, s,

SC(CH₃)₃], 1.67 (1 H, m, NH), 1.74-1.94 (6 H, m, 3 × CH₂), 2.60

and 2.67 (each 1 H, d, J 12.2 Hz, 1-H), 2.95 (1 H, pent, J 8.2 Hz,

2-CH), 3.20 (2 H, s, 1′-H₂), 4.07 (1 H, s, SNH), 4.09 and 4.14

(each 1 H, d, J 14.3 Hz, 2′-CH), 4.95 and 5.07 (each 1 H, s, 3′-

H), 5.21 (1 H, d, J 17.2 Hz, 4-H), 5.28 (1 H, d, J 11.0 Hz, 4-H′)

and 5.84 (1 H, dd, J 11.0, J 17.2 Hz, 3-H); δ_C(100 MHz, CDCl₃)

−5.4, 17.9, 18.3, 22.7, 23.1, 23.3, 25.8, 40.3, 52.2, 55.3, 55.8,

63.1, 64.7, 110.1, 116.3, 140.3 and 146.9; m/z (CI+) 429 (M⁺+ 1,

100%).

4.2.36 2-Amino-2-cyclobutylbut-3-en-1-ol (58)

Hydrogen chloride (4 M in dioxane, 2 mL, 8 mmol, 16 eq.) was

added to the sulfinylamine 56 (184 mg, 0.511 mmol, 1 eq.) in

methanol (1 mL) and the reaction mixture was stirred at rt for 12

h. After concentration under reduced pressure, the residue was

dissolved in methanol (3 mL) and an excess of Na₂CO₃(500 mg,

4.71 mmol, 9 eq.) was added. The mixture was stirred at rt for 2 h

then concentrated under reduced pressure. The residue was

dissolved in DCM (5 mL), and the solution filtered through celite

then concentrated under reduced pressure to give the title

compound 58 (72 mg, 99%), R_f= 0.37 (methanol : ethyl acetate =

1 : 4) (Found : M⁺+ H, 142.1236. C₈H₁₆NO requires M,

142.1232); ν_max/cm^-13351, 3289, 3081, 2974, 2938, 2864, 1586,

1414, 1249, 1059, 997 and 917; δ_H(300 MHz, CDCl₃) 1.63-1.87

(6 H, m, 3 × CH₂), 2.11 (3 H, br. s, OH, NH₂), 2.48 (1 H, m, 1′-

H), 3.32 (2 H, s, 1-H₂), 5.19 (1 H, d, J 17.2 Hz, 4-H), 5.21 (1 H,

d, J 11.0 Hz, 4-H′) and 5.82 (1 H, dd, J 11.0, J 17.5 Hz, 3-H); δ_C

(75 MHz, CDCl₃) 17.6, 22.2, 22.5, 41.4, 58.9, 66.9, 114.5 and

141.0; m/z (CI+) 142 (M⁺+ 1, 100%).

4.2.40 (2RS)-N-Benzyloxycarbonyl-N-[2-(tert-

butyldimethylsilyloxymethyl)prop-2-enyl]-2-[(RS)-N-tert-

butylsulfinylamino]-2-cyclobutylbut-3-en-1-ylamine (62)

Following the procedure for the preparation of compound 32, the

amine 61 (625 mg, 1.46 mmol), after stirring for 1 h and

chromatography (ethyl acetate : light petroleum = 1 : 5 to 1 : 1),

gave the title compound 62 (590 mg, 94%), as a pale yellow oil,

R_f= 0.70 (ethyl acetate : light petroleum = 3 : 2) (Found: M⁺+

H, 563.3348. C₃₀H₅₁N₂O₄SSi requires M, 563.3339); ν_max/cm^-1

3271, 2953, 2936, 2899, 2857, 1703, 1471, 1415, 1362, 1252,

1112, 1068, 1007, 921, 838 and 776; δ_H(400 MHz, CDCl₃) 0.02

(6 H, s, 2 × SiCH₃), 0.88 [9 H, s, SiC(CH₃)₃], 1.16 [9 H, s,

SC(CH₃)₃], 1.74-2.09 (6 H, m, 3 × CH₂), 2.94 (1 H, pent, J 8.7

Hz, 2-CH), 3.44 and 3.48 (each 1 H, br. d, J 16.0 Hz, 1-H), 3.86

(1 H, br. d, J 17.0 Hz, 1′-H), 4.00 (2 H, br. s, 2′-CH₂), 4.13 (1 H,

4.2.37 (2RS)-[(RS)-N-tert-Butylsulfinyl]-1-hydroxy-2-

cyclobutylbut-3-en-2-ylamine (59)

Following the procedure for the preparation of compound 34, the

silyl ether 56 (765 mg, 2.13 mmol), after stirring for 30 min and

chromatography (ethyl acetate : light petroleum = 3 : 2 to 3 : 1),

gave the title compound 59 (384 mg, 69%), R_f= 0.19 (ethyl

acetate : light petroleum = 3 : 2); ν_max/cm^-13386, 3304, 2977,

2945, 2865, 1638, 1474, 1414, 1364, 1254, 1176, 1044 and 925;

14

Tetrahedron

br. d, J 17.0 Hz, 1′-H′), 4.50 and 4.80 (each 1 H, br. s, 3′-H),

s, 2 × SiCH ), 0.92 [9 H, s, SiC(CH ) ], 1.61-1.95 (6 H, m, 3 ×

ACCEPTED MANUSCRIPT

3

5.05-5.32 (4 H, m, 4-H₂and PhCH₂), 6.03 (1 H, br. dd, J 11.0,

17.0 Hz, 3-H) and 7.30 (5 H, m, ArH); δ_C(100 MHz, CDCl₃)

−5.4, 17.5, 18.3, 22.9, 23.1, 23.3, 25.8, 40.9, 51.3, 55.2, 56.4,

64.1, 65.3, 67.4, 109.5, 116.4, 127.6, 127.8, 128.2, 136.3, 139.1,

144.5 and 157.9; m/z (CI+) 563 (M⁺+ 1, 100%).

CH₂), 2.65 and 2.80 (each 1 H, d, J 11.7 Hz, 1-H), 3.09 (1 H,

pent, J 8.7 Hz, 2-CH), 3.20 and 3.26 (each 1 H, d, J 14.0 Hz, 1′-

H), 4.14 (2 H, s, 2-CH₂), 4.97 (1 H, s, 3′-H), 5.07 (2 H, s,

PhCH₂), 5.08 (1 H, d, J 17.5 Hz, 4-H), 5.11 (1 H, s, 3′-H′), 5.22

(1 H, d, J 10.7 Hz, 4-H′), 5.48 (1 H, br. s, NH), 5.88 (1 H, dd, J

10.7, 17.5 Hz, 3-H) and 7.30-7.38 (5 H, m, ArH); δ_C(75 MHz,

CDCl₃) −5.4, 17.4, 18.3, 23.2, 23.3, 25.9, 41.0, 51.9, 52.0, 60.3,

64.8, 66.2, 110.5, 114.2, 127.9, 128.0, 128.4, 136.7, 138.0, 146.7

and 155.0; m/z (CI+) 459 (M⁺+ 1, 100%).

4.2.41 N-Benzyloxycarbonyl-1-hydroxy-2-cyclobutylbut-3-en-2-

ylamine (64)

Following the procedure for the preparation of compound 34, the

silyl ether 63 (509 mg, 1.31 mmol), after stirring for 30 min and

chromatography (ethyl acetate : light petroleum = 1 : 10 to 1 : 4)

gave the title compound 64 (308 mg, 86%), R_f= 0.15 (ethyl

acetate : light petroleum = 1 : 4) (Found: M⁺+ H, 276.1601.

C₁₆H₂₂NO₃requires M, 276.1599); ν_max/cm^-13411, 3345, 3086,

3065, 3034, 2975, 2944, 2895, 2866, 1703, 1505, 1455, 1257,

1096, 1070, 994, 919 and 741; δ_H(300 MHz, CDCl₃) 1.67-1.92

(6 H, m, 3 × CH₂), 2.66 (1 H, m, 2-CH), 3.68 and 3.76 (each 1 H,

d, J 17.5 Hz, 1-H), 4.25 (1 H, br. s, OH), 3.97 (1 H, br. s, NH),

5.10 (2 H, s, PhCH₂), 5.16 (1 H, d, J 17.3 Hz, 4-H), 5.32 (1 H, d,

J 10.7 Hz, 4-H′), 5.87 (1 H, dd, J 10.7, 17.2 Hz, 3-H) and 7.30-

7.39 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) 17.3, 22.3, 22.8, 40.7,

63.5, 66.5, 67.1, 115.5, 128.2, 128.3, 128.6, 136.1, 136.7 and

156.7; m/z (CI+) 276 (M⁺+ 1, 20%) and 185 (100).

4.2.44 2-(Benzyloxycarbonylamino]-N-[2-(tert-

butyldimethylsilyloxymethyl)prop-2-enyl]-N-(2-

nitrophenylsulfonyl)-2-cyclobutylbut-3-en-1-ylamine (67)

Following the procedure for the preparation of compound 30,

amine 66 (143 mg, 0.312 mmol), after stirring for 18 h and

chromatography (ethyl acetate : light petroleum = 1 : 10 to 1: 4),

gave the title compound 67 (84 mg, 42%) as a pale yellow oil, R_f

= 0.24 (ethyl acetate : light petroleum = 1 : 4) (Found: M⁺−

C₄H₉, 586.2050. C₂₈H₃₆N₃O₇SSi requires M, 586.2043); ν_max/cm^-1

3384, 3090, 2952, 2933, 2895, 2857, 1727, 1545, 1499, 1462,

1366, 1249, 1163, 1102, 997, 924, 842, 777 and 737; δ_H(300

MHz, CDCl₃) 0.00 (6 H, s, 2 × SiCH₃), 0.87 [9 H, s, SiC(CH₃)₃],

1.64-1.95 (6 H, m, 3 × CH₂), 3.09 (1 H, pent, J 8.5 Hz, 2-CH),

3.65 (1 H, d, J 15.3 Hz, 1-H), 3.83 (2 H, br. s, 1′-H₂), 3.85 (1 H,

d, J 15.2 Hz, 1-H′), 4.07 (2 H, s, 2′-CH₂), 4.88 (1 H, s, 3′-H),

5.02 (2 H, s, PhCH₂), 5.09 (1 H, s, 3′-H′), 5.12 (1 H, d, J 17.7 Hz,

4-H), 5.28 (1 H, d, J 11.2 Hz, 4-H′), 6.01 (1 H, dd, J 11.2, 17.7

Hz, 3-H), 7.28-7.37 (5 H, m, ArH), 7.54-7.65 (3 H, m, ArH) and

8.00 (1 H, m, ArH); δ_C(75 MHz, CDCl₃) −5.5, 17.1, 18.3, 22.5,

23.1, 25.8, 40.3, 50.8, 51.2, 61.4, 63.9, 66.4, 112.2, 114.8, 124.2,

128.1, 128.2, 128.5, 131.5(2), 133.5, 133.6, 136.5, 137.9, 142.2,

147.8 and 154.9; m/z (AP-) 678 (M⁺+ 35, 100) and 642 (M⁺− 1,

75).

4.2.42 2-Benzyloxycarbonylamino-2-cyclobutylbut-3-enal (65)

Following the procedure for the preparation of compound 46, the

alcohol 64 (211 mg, 0.766 mmol), after stirring for 45 min, gave

the title compound 65 (199 mg, 95%), R_f= 0.40 (ethyl acetate :

light petroleum = 1 : 4) (Found: M⁺+ H, 274.1446. C₁₆H₂₀NO₃

requires M, 274.1443); ν_max/cm^-13333, 3089, 3065, 3032, 2981,

2946, 2898, 2867, 1729, 1714, 1514, 1455, 1257, 1093, 1065,

988, 925 and 740; δ_H(300 MHz, CDCl₃) 1.65-1.99 (6 H, m, 3 ×

CH₂), 2.87 (1 H, m, 2-CH), 5.11 (2 H, s, PhCH₂), 5.23 (1 H, d, J

17.5 Hz, 4-H), 5.37 (1 H, br. d, J 10.7 Hz, 4-H′), 6.09 (1 H, dd, J

10.7, 17.5 Hz, 3-H), 7.37 (5 H, m, ArH) and 9.42 (1 H, s, CHO);

δ_C(75 MHz, CDCl₃) 17.9, 22.3, 22.9, 39.0, 67.2, 68.2, 116.8,

128.3(2), 128.6, 133.0, 135.9, 155.4 and 197.4; m/z (CI+) 291

(M⁺+ 18, 20%) and 274 (M⁺+ 1, 100).

5. Acknowledgments

We thank Muscagen for a studentship (to M. G. P. B.).

6. References and notes

4.2.43 2-(Benzyloxycarbonylamino]-N-[2-(tert-

butyldimethylsilyloxymethyl)prop-2-enyl]-2-cyclobutylbut-3-en-

1-ylamine (66)

1. (a) Broadley, K. J.; Kelly, D. R. Molecules 2001, 142; (b)

Caccamo, A.; Fisher, A.; LaFerla, F. M. Curr. Alzheimer

The amine 25 (155 mg, 0.765 mmol, 1.05 eq.) in DCM (1 mL)

was added to the aldehyde 65 (199 mg, 0.729 mmol) and 4Å

molecular sieves (500 mg) in DCM (2 mL). The mixture was

stirred for 48 h, filtered through celite and concentrated under

reduced pressure to give the imine that was dissolved in MeOH

(3 mL). Sodium borohydride (44 mg, 1.15 mmol, 1.6 eq.) was

added and the reaction mixture was stirred at rt for 2 h. Saturated

aqueous sodium bicarbonate (5 mL) was added, the mixture

concentrated under reduced pressure, and the aqueous layer was

extracted with ether (3 × 10 mL). The organic extracts were dried

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Chromatography (ethyl acetate : light petroleum = 3 : 2) of the

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ν_max/cm^-13356, 3082, 2953, 2932, 2894, 2857, 1730, 1496, 1466,

1251, 1091, 913, 840 and 776; δ_H(300 MHz, CDCl₃) 0.07 (6 H,

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7. Supplementary Material

1

Copies of H and ¹³C spectra of key compounds are available as

supplementary data.

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