Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction

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PAPER

Diversity oriented and chemoenzymatic synthesis of densely functionalized

pyrrolidines through a highly diastereoselective Ugi multicomponent reaction†

Valentina Cerulli, Luca Banﬁ, Andrea Basso, Valeria Rocca and Renata Riva*

Received 24th September 2011, Accepted 27th October 2011

DOI: 10.1039/c1ob06632c

A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure

isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized

pyrrolidines. Both chiral substrates have been efﬁciently prepared by chemoenzymatic methodologies

from readily available achiral substrates. This highly convergent approach can ﬁnd an application in the

fragment-based drug discovery process.

In recent years our group has been involved in several projects

aimed at the development of diversity oriented syntheses of

pyrrolidine based scaffolds through multicomponent Ugi reaction,

Introduction

Fragment-based drug discovery (FBDD)^1,2represents a fast

either in the classical version^4,5or in the intramolecular variant.^6,7

The Ugi reaction is well known as a very useful method for the

highly convergent synthesis of peptide moieties with an acyclic

backbone:^8–10these structures are, however, not so interesting as

drug candidates because they are not conformationally restricted

enough for a potent interaction with biological targets. On the

contrary, cyclic scaffolds, such as for example pyrrolidines, display

more interesting pharmacophoric properties. These structures can

also be regarded as possible scaffolds in FBDD. Linking this cyclic

structure, preferably through a one-pot procedure, with two other

fragments, decorated with appropriate functional groups, would

then offer the chance to join fragments displaying weak activity,

gaining rapid access to interesting drug candidates.

A possibility to reach this goal is represented by the in-

tramolecular Ugi reaction¹¹in which a cyclic imine is reacted

with an isocyanide and a carboxylic acid (Ugi–Joullie´ reaction),

affording, for example, compounds 1, as depicted in retrosynthetic

Scheme 1.

The isocyanide and the carboxylic acid represent the two

fragments that carry the pharmacophoric groups, and thus they

should be relatively complex, being endowed with functional

groups and/or stereogenic centres.

A huge variety of carboxylic acids 5, provided with complex

structures and stereogenic centres, is readily accessible from com-

mercial sources, often in both enantiomeric forms. The availability

of functionalised and/or chiral isocyanides is, on the contrary,

much more limited. The commonly used commercially available

isocyanides are unfunctionalised, making these structures not

pharmacophoric at all. For this reason, we decided to develop

an enantioselective synthesis of both enantiomers of isocyanides

2 and 3, endowed with 2 important characteristics: 1) a protected

OH to be used as H bond acceptor or donor (in the deprotected

form); this group can moreover be regarded as a synthetic

equivalent of a carboxylic acid, which can be exploited for

growing screening methodology in medicinal chemistry, whose

concept was proposed in 1981.³This approach was conceived

as an efﬁcient alternative to the hit-to-lead process based on

high throughput screening (HTS). In HTS the activity of very

large collections of quite complex molecules is assayed on

a speciﬁc target, usually a protein. However, this method is

hampered by the need for large libraries, because the number

of different structures grows exponentially as the number of

heavy (non-hydrogen) atoms increases. On the contrary, in FBDD

small libraries (1000–2000 molecules) of low-weight molecules

(MW < 250 Da) may be sufﬁcient for disclosing fragments able

to give single-site interactions. This weak binding activity towards

the protein is studied employing several biophysical techniques,

such as NMR or X-ray crystallography. In this way it is possible

to evaluate the key weak interactions and to modulate them by

an appropriate choice of the decorations on single fragments.

Moreover, after ﬁnding different fragments able to interact with

neighbouring portions of the target, they can be combined (linked

or merged) in order to check if a match of activity occurs.

Indeed, the fragment can be used as a seed for growing, through

rationally designed chemical transformations, a larger molecule,

to give additional and more efﬁcient interactions. With respect to

HTS, FBDD therefore allows a more thorough exploration of the

chemical space.

However, after ﬁnding active fragments, an efﬁcient and conver-

gent methodology for joining them, possibly to a rigid scaffold, is

needed. We would like to present here a general strategy designed

towards this goal.

Department of Chemistry and Industrial Chemistry, University of Genova,

via Dodecaneso 31, 16146, Genova, (Italy). E-mail: riva@chimica.unige.it;

Fax: +39 010 3536118; Tel: +39 010 3536106

† Electronic supplementary information (ESI) available. See DOI:

10.1039/c1ob06632c

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envisioned desymmetrized diols 8 and 9 as possible precursors

of enantiomerically pure 4 and ent-4.

One of the milestones of this project is the possibility to also

explore the stereochemical diversity, because the two inputs of the

MCR are chiral, while the third one (5) can be either chiral or

achiral. For this reason we focussed our attention on the devel-

opment of methods able to produce both enantiomers of either

the isocyanides or the imines. Our results can therefore be seen

as an efﬁcient exploration of the chemical space because four out

of eight stereoisomers can readily be assembled through the same

methodology by an appropriate combination of stereoisomeric

isocyanides and imines, in a Diversity Oriented approach.

Results and Discussion

An attractive approach for obtaining these new compounds is

represented by chemoenzymatic syntheses, in particular those

exploiting the desymmetrization of prochiral (to give 6 and 7)

or meso compounds (to give 8 and 9).

The synthesis of monoacetates 6 and 7 was already optimized

in our group and they have been used as chiral building blocks

for several applications;^20–23however, none of them involved an

MCR. They have both been obtained through a very efﬁcient

monoacetylation of the corresponding diols promoted by vinyl

acetate in the presence of lipase from Porcine pancreas (PPL,

6, e.e. ≥ 98%) or from Pseudomonas cepacia (PCL, 7, e.e. >

95%) supported on celite, according to our previously reported

protocol.^22,23

The enantiodivergency of these monoacetates should allow the

independent conversion of them into both enantiomers of the

desired isocyanides through an appropriate choice of the order of

introduction of the needed functionalities.

Scheme 1 The retrosynthetic plan.

electrostatic interactions; 2) an aryl group, bonded to a C or an O

atom, to be used for p interactions.

The absolute conﬁguration is clearly crucial for a correct

interaction with the biological target. We envisaged that both

enantiomers of 2 or 3 could be obtained from a common chiral

building block, that is monoacetates 6 or 7, respectively.

For the synthesis of 2, the route depicted in Scheme 2 was

followed. Compound 6, a synthetic equivalent of desymmetrized

trishydroxymethylmethane (THYM*),²⁰was converted, under

Mitsunobu conditions, into the key aryl ether 11. Three branch

routes depart from this intermediate, two of them leading to (S)-2

(Route B and C) and one to (R)-2 (Route A). A stereoconservative

ozonolysis–reduction procedure afforded 12 (Routes A and B).

This intermediate was converted into both enantiomers of azide

15 by two complementary pathways of equal length: in Route A

the free OH of 12 was directly converted into the azide, whereas in

Route B it was protected and the azide was later installed on the

other arm. The Staudinger reduction gave amine 18, which was

in turn acylated with formic acid by means of DCC, a method

that was shown to be superior to others (i.e. treatment with 2,4,5-

trichlorophenyl formate). Finally, dehydration of formamides 19

furnished the desired isocyanides in excellent overall yield (67%

(R)-2, 52% (S)-2) after 9 synthetic steps from 6.

A slightly more efﬁcient synthesis of (S)-2 from the common

intermediate 11 (Route C) was attained just postponing the

ozonolysis and introducing ﬁrst the nitrogen atom precursor of

the isocyanide moiety. In this case the overall yield (8 steps from

6) was 64%. In order to explore the possibility to obtain 2 or its

enantiomer by a shorter sequence, we also tried to transform both

6 and 20 into bisformamides 25 (R = Ac or Ar), by treatment with

sodium diformylimide of the corresponding mesylates,²⁴having

in mind to selectively hydrolyze one formyl group. While the

nucleophilic substitution gave about 62% overall yield in both

The main problem when using this approach is, however, the

poor stereoselectivity usually encountered during the formation

of the new stereogenic carbon induced by the pre-existing one(s)

on the chiral imine.^7,12–15Only very few high inducing chiral imines

have been reported so far.^12,16For our purposes we selected imines

4 and ent-4, on the basis of two considerations: a) the already

demonstrated possibility to attain a complete diastereoselection

during the MCR, thanks to the conformational rigidity of this

bicyclic system;¹⁷b) the presence of the acetonide moiety, which

can be regarded as an additional source of diversity in the ﬁnal

compounds. As far as it concerns the ﬁrst point, it is worth noting

that the obtainment of complete stereoselection in the Ugi reaction

of chiral pyrrolines is not general: in more ﬂexible systems, even

with a stereogenic centre a to the imine carbon, diastereoselectivity

is poor or incomplete.^{7,13,15,17,18}

With regard to the second point, deblocking of the acetal

would leave a highly polar, sugar-like scaffold. It has been recently

stressed that often Ugi-based libraries have the drawback of being

too unpolar.¹⁹The presence in 1 of three blocked alcoholic moieties

allows us to modulate the polarity of the ﬁnal products. Imine

4 has been already prepared, but only in racemic form.¹⁷We

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Scheme 2 Reagents and conditions: a) di-t-butylazodicarboxylate, PPh₃, CH₂Cl₂, r.t.; b) i. O₃; CH₂Cl₂/MeOH 2 : 3, -78 ^◦C; ii. NaBH₄, -78 ^◦C; c) i.

MsCl, Et₃N, CH₂Cl₂, -30 ^◦C; ii. NaN₃, DMF, 50 ^◦C; d) 0.2 M KOH (MeOH), 0 ^◦C; e) tBuMe₂SiCl, imidazole, DMF, r.t.; f) PPh₃, THF/H₂O, r.t. then

50 ^◦C; g) HCO₂H, DCC, CH₂Cl₂, r.t.; h) POCl₃, Et₃N, CH₂Cl₂, -30 ^◦C; i) i. Jones reagent, Me₂CO, 0 ^◦C; ii. CH₂N₂, THF, 0 ^◦C.

cases, removal of the formyl group worked well only when R = Ar,

while when R = Ac only the diol precursor of 6 was identiﬁed in

the crude. On the other hand the formation of formamide via the

corresponding azide always gave excellent overall yields and thus

this slightly longer approach was deﬁnitely more efﬁcient.

In order to enhance the diversity of the chiral isocyanides

available by our strategy we also studied the oxidation of 23

into 24, which was isolated in moderate (62%) yield. Also

because of a not trivial isolation procedure, we preferred in this

work to delay the oxidation until after the MCR, as described

later.

Following a similar synthetic sequence we were able to trans-

form monoacetate 7 into both enantiomers of 3, again in excellent

yield (72% (R)-3, 68% (S)-3) after 7 synthetic steps from 7

(Scheme 3).

The absence of racemization in all the routes described in

Schemes 2 and 3 has been demonstrated by analysis of the Ugi

products (see later). Moreover, stereointegrity was demonstrated,

1

at the level of formamides 30, by H NMR of the Mosher esters

obtained after silyl protection removal.

We then turned to the enantioselective preparation of both

enantiomers of cyclic imines 4 and ent-4 (Scheme 4). For this

purpose we planned to exploit the enzymatic desymmetrization of

Scheme 3 Reagents and conditions: a) tBuMe₂SiCl, imidazole, DMF, r.t.;

b) 0.2 M KOH (MeOH), 0 ^◦C; c) i. MsCl, Et₃N, CH₂Cl₂, -30 ^◦C; ii. NaN₃,

DMF, 50 ^◦C; d) i. PPh₃, THF/H₂O, 50 ^◦C; ii. HCO₂H, DCC, CH₂Cl₂, r.t.;

meso diol 31, which can be obtained in three straightforward steps

e) POCl₃, Et₃N, CH₂Cl₂, -30 ^◦C.

from meso-erythritol.²⁵

The enzymatic monoacetylation of diol 31 and the enzymatic

hydrolysis of its diesters have been previously reported. However,

under the reported conditions,^25,26the e.e.s, although good, were

not as high as desired by us. Thus we screened other enzymes

and conditions. We found that Amano PS lipase was the best

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Scheme 4 Reagents and conditions: a) vinyl acetate, Amano PS lipase, 20 ^◦C; b) i. MsCl, Et₃N, CH₂Cl₂, -18 ^◦C; ii. NaN₃, DMF, 100 ^◦C; c) 1 M KOH

(MeOH), 0 ^◦C; d) i. (COCl)₂, DMSO, Et₃N, CH₂Cl₂-78 ^◦C; ii. PPh₃, THF, 50 ^◦C; e) 1 M phosphate buffer (pH 7)/H₂O 2 : 1, Amano PS lipase, 0 ^◦C; f)

vinyl butyrate, Amano PS lipase, r.t.

Table 1 Monohydrolysis of dibutyrate 33

Entry

Enzyme

Quantity (g enzyme/g 33)

Temp.

Time (min)

Yield

e.e.

1

2

3

4

5

6

7

8

Amano AK

Amano AY

PPL

Lipozyme RM

Lipozyme TM

Amano AS

Amano PS

0.20

0.16

0.25

0.40

0.12

0 ^◦

C

45

70

40

1440

240

40

66%

82%

not det.

31%

not det.

—

<35%^a

51%

<20%^b

no reaction

85%

25 ^◦

C

91%

97%

0 ^◦

60

94%

^aThis reaction showed a poor substrate selectivity, leading to nearly equal mixtures of dibutyrate, monobutyrate and diol at 50% conversion. ^bThis

reaction showed a very poor substrate selectivity, leading mainly dibutyrate, monobutyrate and diol at 50% conversion.

performing one in the acetylation of 31 using vinyl acetate as

solvent (e.e. 97%).

crude alcohols 35 were subjected to Swern oxidation to the

corresponding aldehydes, followed by Staudinger/aza-Wittig with

PPh₃to give the imines 4 and ent-4. They were used as such

(without the need to remove Ph₃PO) in the Ugi reaction with

commercial or chiral isocyanides and a variety of carboxylic acids.

First we performed an Ugi reaction with two commercially

available isocyanides to give Ugi adducts 36a,b and 37a (Scheme 5).

The yields reported in Scheme 5 are determined from the starting

azidoacetate 32 or azidobutyrate 34 (the isocyanide and carboxylic

acid were used in slight excess) and thus must be considered quite

For the synthesis of the opposite enantiomer, monohydrolysis

of the diacetate of 31 was not fully satisfactory. Thus we studied

the monohydrolysis of dibutyrate 33. Table 1 reports the results

obtained with various enzymes and various conditions. Once

again, the best enzyme was Amano PS lipase, and we found an

improvement in e.e. by performing the reaction at 0 ^◦C with a

lower amount of catalyst. The enantiomeric (+) monobutyrate

could be obtained as well by monobutyrylation of diol 31 with

vinyl butyrate. The reaction was, however, much slower than that

in vinyl acetate, and the e.e. slightly lower as well.

Having in hand the two chiral building blocks 8 and 9, we

converted them, by an identical sequence, into azido esters 32

and 34, by mesylation and S_N2 with sodium azide. Saponiﬁca-

tion afforded the moderately volatile enantiomeric azidoalcohols

(4R,5S)-35 and (4S,5R)-35. For this reason the sequence of

transformations from 32 and 34 to the Ugi adducts was carried

out without isolation or puriﬁcation of the intermediates. The

1

good (4 steps). At room temperature, H and ¹³C showed the

presence of two distinct sets of signals, in 95 : 5 (36) or 90 : 10

(37) ratio (in CDCl₃). In d₆-DMSO the ratios changed, becoming

about 2 : 1.

Moreover, at 120 ^◦C, complete coalescence of the two sets

of signals occurred. This clearly demonstrated that the two sets

are due to rotamers around the tertiary amide bond. In both

~

conformers the vicinal coupling constants J_3a–4( 0) demonstrate

=

unambiguously the trans relative conﬁguration. Actually, in 36a

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Scheme 5 Reagents and conditions: a) R¹NC, R²CO₂H, MeOH, r.t.; b) HF, CH₃CN–H₂O, -10 ^◦C; c) 2 or 3, R³CO₂H, MeOH, r.t.

◦

~

the dihedral angle is expected_◦to be 100 , whereas in the cis

cases, the d.r. was around 95% or higher (see the experimental

part). This analysis also allowed us to indirectly prove the

enantiomeric purity of starting isocyanides 2 or 3 and to rule out

any possible racemization during the Ugi reaction. From the d.r.s

listed in the experimental part we could ﬁgure out an e.e of at least

95% for both 2 and ent-2. Accordingly, also the stereoisomeric

purity of the imines was preserved, as in the reaction with achiral

isocyanides. A similar analysis was carried out for compounds 42a

and 42c too, with an analogous outcome. For 44a and 44b the ¹H

and ¹³C spectra indicated a d.r ≥ 95%.

As for 36 and 37, also compounds 39–46 showed, in CDCl₃, a

strong preference for one of the two rotamers, the ratios ranging

from 86 : 14 to >97 : 3 (42a–42c and 46c seem to be present as a

single rotamer).

Further exploration of chemical diversity can be carried out

by manipulation of the additional functional groups present in

these adducts (Scheme 6). For example, removal of the silyl

protection leads to alcohols 47–50. We prepared, in high yields,

some of these compounds (Table 1). Moreover, both silyl and

acetal protections can be simultaneously removed, by treatment

with a strong acid. This deprotection was ﬁrst demonstrated on 36a

to give 38a (Scheme 5). Under the same conditions, triols 51–54

have been obtained in good to excellent yields. These compounds

=

epimer it should be around 20 .¹⁷No signals attributable to the

cis diastereoisomers could be detected. Thus, under the detections

limits, the diastereoselectivity of the Ugi reaction turned out to be

complete (>98%). In the case of 36 the reaction was carried out

on both enantiomeric imines and chiral HPLC analysis showed in

both cases an e.e. comparable to that of the starting monoacetate

8 or monobutyrate 9.

Then we coupled the two enantiomeric imines 4 with both

enantiomers of chiral isocyanides 2 and 3 and six different

carboxylic acids. In principle it is possible to independently prepare

4 stereoisomers for each combination of 6 acids and 2 isocyanides:

this means 48 different products.

However, we prepared only a selection of them in order to

demonstrate the feasibility of the method. The results are reported

in Table 2. The yields are this time calculated from the isocyanide,

that was used as the limiting agent. Once again, no cis isomer

was detected. In the case of compounds 39 all four possible

stereoisomers were prepared, by appropriate combination of

1

isocyanides and imines. Interestingly, the H and ¹³C NMR of

diastereoisomeric pairs were nearly superimposable, not allowing

the measurement of a precise diastereomeric ratio. However, in

chiral HPLC analysis, they give four well separated peaks. In all

Table 2 Yields for the synthesis of compounds 39–54

Starting isocyanide R³

Yield of Ugi reaction

Yield of silyl removal

Yield of silyl and acetal removal

2

3

MeOCH₂

cy-Hex

3-BrC₆H₄

5-Cl-2-thienyl

ZNHCH₂CH₂

MeOCH₂

H₂C CH(CH₂)₂

5-Cl-2-thienyl

39a: 56% 39b: 54% 39c: 57% 39d: 80% 47a: 56%

51a: 59%

52a: 88%

53a: 93%

51c: 61%

40a: 73%

40c: 73%

41c: 73%

42c: 58%

43c: 80%

48a: 94%

49a: 91%

48c: 94%

49c: 95%

41a: 69%

42a: 56%

43a: 74%

44a: 68% 44b: 55%

50a: 100% 50c: 100% 54a: 100%

45c: 56%

46c: 67%

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Scheme 6 Reagents and conditions: a) HF, CH₃CN–H₂O, -10 ^◦C; b) CF₃CO₂H, H₂O, THF; c) i) Jones reagent; ii) CH₂N₂.

are, as expected, rather polar. Moreover, the conformation of the

pyrrolidine ring is no longer ﬁxed by the fused acetal, and thus

the tridimensional structure is modiﬁed, as demonstrated by the

different coupling constants, compared to 39–50.

Thus, the small library of compounds listed in Table 2 (29

molecules) represents a real diversity-oriented collection, where

not only the substituents (decorations) have been varied, but also

the scaffold itself and the stereochemistry.

(469 mL) and warming or, when speciﬁed, with ninhydrin (900

mg of ninhydrin in 300 mL nBuOH and 9 mL AcOH) or 2%

aqueous KMnO₄, followed by warming. R_fwere measured after

an elution of 7–9 cm. Column chromatographies were done with

the “ﬂash” methodology using 220–400 mesh silica. Petroleum

ether (40–60 ^◦C) is abbreviated as PE. In the extractive work-

up, aqueous solutions were always reextracted three times with

the appropriate organic solvent. Organic extracts were always

dried over Na₂SO₄and ﬁltered, before evaporation of the solvent

under reduced pressure. All reactions employing dry solvents were

carried out under a nitrogen atmosphere. Amano enzymes used

were a kind gift of Amano-Mitsubishi Italia.

The free alcohol in 47–50 can also be converted into a carboxylic

acid. This was demonstrated for 47a, that gave, after oxidation and

esteriﬁcation with diazomethane, ester 55a.

Conclusions

(R,E)-2-[(3-Bromophenoxy)methyl-5-methylhex-3-enyl acetate 11

The present work demonstrates the possibility to use the Ugi

reaction for the convergent synthesis of conformationally biased

peptidomimetics where all the inputs (including the isocyanide)

carry pharmacologically relevant appendages. Moreover, a full

control of relative and absolute conﬁguration has been achieved by

appropriately combining chiral, enantiomerically pure isocyanides

and imines obtained by a chemoenzymatic route, also thanks to

the high diastereoselectivity of Ugi reactions of rigid cyclic imines

4. Application of this strategy for the fragment-based assembly of

biologically active substances is in progress.

A

solution of 6²²(1.32 g, 3.87 mmol) in dry CH₂Cl₂

(9 mL) was cooled to 0 ^◦C and treated with 3-bromophenol

(1.00 g, 5.80 mmol), PPh₃(1.52 g, 5.80 mmol) and di-t-

butylazodicarboxylate (1.35 g, 5.86 mmol), stirred for 25 min

at the same temperature and then 1.7 h at room temperature.

After solvent removal the mixture was chromatographed with

PE/Et₂O 95 : 1 to 9 : 1 to give 11 (1.96 g, 81%) as a colourless

oil. R_f0.60 (PE/AcOEt 90 : 10). [a]_D-14.1 (c 1.4, CHCl₃). IR:

n

_max(CHCl₃)/cm^-12951, 2864, 1727, 1586, 1460, 1378, 1254,

1017, 972. d_H(300 MHz; CDCl₃, 25 ^◦C): 0.98 (6 H, d, J 6.9,

(CH₃)₂CH), 2.05 (3 H, s, COCH₃), 2.28 (1 H, centre of m,

(CH₃)₂CH), 2.80 (1 H, centre of m, CH(CH₂O–)₂), 3.94 (2 H,

d, J 6.0, CH₂OAr), 4.17 and 4.21 (2 H, AB part of an ABX

syst., J_AB9.9, J_AX5.1, J_BX5.1, CH₂OAc), 5.33 (1 H, ddd, J 1.2,

7.8, 15.3, (CH₃)₂CHCH CH), 5.60 (1 H, ddd, J 0.6, 6.6, 15.3,

(CH₃)₂CHCH = CH), 6.83 (1 H, ddd, J 1.2, 2.1, 7.8, H-6¢), 7.05–

7.16 (3 H, m, other aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C): 20.9

(COCH₃), 22.4 ((CH₃)₂CH), 31.2 ((CH₃)₂CH), 41.5 (CH(CH₂O–

)₂), 64.4 (CH₂OAc), 68.4 (CH₂OAr), 113.7 (C-6¢), 117.7 (C-2¢),

122.8 (C-3¢), 122.9 ((CH₃)₂CHCH = CH), 123.9 (C-4¢), 130.5 (C-

5¢), 141.6 ((CH₃)₂CHCH CH), 159.6 (C-1¢), 171.0 (C _◦O). GC-

MS (usual method but with initial temp. 70 ^◦C, rate 10 C min^-1,

ﬁnal temp. 280 ^◦C): R_t: 15.14 min; m/z (EI): 342 (M⁺(⁸¹Br), 0.19),

340 (M⁺(⁷⁹Br), 0.20), 169 (7.3), 109 (44), 95 (6.0), 93 (9.6), 81 (16),

79 (5.7), 67 (40), 55 (12), 43 (100), 41 (14). m/z (ESI+) 363.0572

(M + Na⁺). C₁₆H₂₁BrO₃Na requires 363.0572.

Experimental section

NMR spectra were taken at r.t. in CDCl₃or d₆-DMSO at 300 MHz

(¹H), and 75 MHz (¹³C), using as internal standards: for ¹H NMR

1

in CDCl₃: TMS; for H NMR in DMSO: the central peak of

DMSO (2.506); for ¹³C in CDCl₃the central peak of CDCl₃(at

77.02 ppm); for ¹³C NMR in DMSO: the central peak of DMSO

(39.43). Chemical shifts are reported in ppm (d scale), coupling

constants are reported in Hertz. Peak assignments were also made

with the aid of gCOSY and gHSQC experiments. In ABX systems,

the proton A is considered upﬁeld and B downﬁeld. GC-MS were

carried out using an HP-1 column (12 m long, 0.2 mm wide),

electron impact at 70 eV, and a mass temperature of about 170 ^◦C.

Only m/z > 33 were detected. All analyses were performed (unless

otherwise stated) with a constant He ﬂow of 1.0_◦mL min^-1with

initial temp. 100 ^◦C, init. time 2 min, rate 20 C min^-1, ﬁnal

temp. 290 ^◦C, inj. temp. 250 ^◦C, det. temp. 280 ^◦C. HR-MS

were recorded employing ESI+ or ESI- ionization method. IR

spectra were recorded as CHCl₃solutions. TLC analyses were

carried out on silica gel plates and viewed at UV (254 nm) or

developed by dipping into a solution of (NH₄)₄MoO₄·4 H₂O

(21 g) and Ce(SO₄)₂·4 H₂O (1 g) in H₂SO₄(31 mL) and H₂O

(R)-3-Acetoxy-2-((3-bromophenoxy)methyl)propanol 12

A solution of 11 (3.11 g, 9.11 mmol) in dry CH₂Cl₂/MeOH (1 : 1.5,

83 mL) was cooled to -78 ^◦C and submitted to ozonolysis (120 L

h^-1ozone ﬂow) until a pearl grey colour appeared (about 40 min).

Me₂S (3.75 mL, 51.04 mmol) was added, followed after 1 min,

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by NaBH₄(1.38 g, 36.48 mmol). The temperature was allowed to

increase up to -3 ^◦C in 2.5 h. The reaction was quenched with

saturated NH₄Cl solution. After extraction with Et₂O, the organic

layers were washed with brine and concentrated. Chromatography

with PE/AcOEt 7 : 3 + MeOH (0.5 to 1%) afforded 12 as a pale

yellow oil (2.76 g, 100%). R_f0.24 (PE/AcOEt 80 : 20 + 1% MeOH).

[a]_D-2.55 (c 1.4, CHCl₃). IR: n_max(CHCl₃)/cm^-13609, 3024, 2962,

2881, 1726, 1587, 1465, 1197, 1019. d_H(300 MHz; CDCl₃, 25 ^◦C):

2.04 (1 H, centre of m, OH), 2.09 (3 H, s, COCH₃), 2.36 (1 H,

septet, J 5.7, CH(CH₂O–)₃), 3.78 (2 H, centre of m, CH₂OH), 4.04

(2 H, d, J 6.0, CH₂OAr), 4.30 (2 H, d, J 6.0, CH₂OAc), 6.84 (1

H, ddd, J 1.2, 2.4, 7.8, H-6¢), 7.07–7.17 (3 H, m, other aromatics).

d_C(75 MHz; CDCl₃, 25 ^◦C): 20.8 (COCH₃), 40.7 (CH(CH₂O–)₃),

60.5 (CH₂OH), 62.2 (CH₂OAc), 66.1 (CH₂OAr), 113.5 (C-6¢),

117.6 (C-2¢), 122.7 (C-3¢), 124.0 (C-4¢), 130.5 (C-5¢), 159.3 (C-1¢),

171.4 (C O). GC-MS: R_t: 7.91 min; m/z (EI): 304 (M⁺(⁸¹Br),

1.1), 302 (M⁺(⁷⁹Br), 1.1), 174 (24), 172 (25), 132 (8.5), 131 (100),

71 (19), 65 (5.5), 61 (6.1), 43 (96). m/z (ESI+) 325.0047 (M + Na⁺).

C₁₂H₁₅BrO₄Na requires 325.0051.

phases were extracted with Et₂O and washed with brine. The crude

was puriﬁed by chromatography (PE/AcOEt 45 : 35 to 6 : 4) to give

14 as a pale yellow oil (562 mg, 100%). R_f0.25 (PE/Et₂O 80 : 20).

[a]_Dª 0 (c 2.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13604, 3038, 2959,

2881, 2101, 1587, 1464, 1188, 1020. d_H(300 MHz; CDCl₃, 25 ^◦C):

1.83 (1 H, t, J 4.8, OH), 2.26 (1 H, septet, J 5.8, CH(CH₂-)₃), 3.59

(2 H, d, J 6.0, CH₂N₃), 3.82 (2 H, broad t, J 5.0, CH₂OH), 4.02

and 4.04 (2 H, AB part of an ABX syst., J_AB9.4, J_AX6.0, J_BX5.3,

CH₂OAr), 6.84 (1 H, ddd, J 1.5, 2.4, 7.8, H-6¢), 7.07–7.18 (3 H, m,

other aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C): 40.9 (CH(CH₂–)),

50.0 (CH₂N₃), 61.3 (CH₂OH), 66.4 (CH₂OAr), 113.4 (C-6¢), 117.7

(C-2¢), 122.8 (C-3¢), 124.2 (C-4¢), 130.6 (C-5¢), 159.2 (C-1¢). GC-

MS: R_t: 7.89 min; m/z (EI): 287 (M⁺(⁸¹Br), 1.6), 285 (M⁺(⁷⁹Br),

1.6), 201 (14), 200 (8.7), 199 (13), 198 (7.3), 178 (12), 175 (7.5), 174

(94), 173 (11), 172 (100), 157 (14), 155 (13), 145 (9.8), 143 (9.2),

120 (20), 119 (5.2), 94 (7.4), 93 (27), 92 (6.6), 86 (14), 76 (8.8), 75

(9.3), 68 (6.6), 65 (29), 64 (11), 63 (17), 57 (9.8), 56 (9.1), 55 (8.9),

54 (7.5), 50 (5.8), 44 (6.0), 42 (12), 41 (27), 39 (16), 38 (5.9). m/z

(ESI-) 284.0028 (M - H⁺). C₁₀H₁₁BrN₃O₂requires 284.0035.

(R)-1-Acetoxy-3-azido-2-((3-bromophenoxy)methyl)propane 13

(R)- and (S)-1-Azido-3-(tert-butyl)dimethylsilyloxy-2-((3-

bromophenoxy)methyl)propane 15

a) Mesylate formation: alcohol 12 (825 mg, 2.72 mmol) was

dissolved in dry CH₂Cl₂(9 mL), cooled to -30 ^◦C, and treated

with Et₃N (493 mL, 3.54 mmol) and methanesulphonyl chloride

(253 mL, 3.26 mmol) and stirred for 1.8 h until the reaction was

complete (as determined by TLC with PE/AcOEt 60 : 40 + 1%

MeOH). Quenching with saturated NH₄Cl was followed by an

extraction with Et₂O. After treatment with brine the organic

phases were evaporated to dryness. b) Azide formation: crude

mesylate [R_f0.38 (PE/Et₂O 60 : 40 + 1% MeOH)] was taken up

in dry DMF (9 mL), treated with NaN₃(354 mg, 5.44 mmol) and

heated at 50 ^◦C for 20.5 h. After cooling, the mixture was treated

with H₂O and Et₂O and extracted. The organic phase was washed

with water (twice) and then with brine. After solvent removal

the crude was puriﬁed by chromatography (PE/AcOEt 90 : 10 to

85 : 15) to give pure 13 as a pale yellow oil (866 mg, 97%). R_f0.49

(PE/Et₂O 70 : 30). [a]_Dª 0 (c 2.0, CHCl₃). IR: n_max(CHCl₃)/cm^-1

3004, 2886, 2102, 1731, 1587, 1464, 1192. d_H(300 MHz; CDCl₃,

25 ^◦C): 2.09 (3 H, s, COCH₃), 2.41 (1 H, septet, J 6.0, CH(CH₂–)₃),

3.57 (2 H, d, J 6.3, CH₂N₃), 3.97 and 4.00 (2 H, AB part of an ABX

syst., J_AB7.6, J_AX4.1, J_BX3.7, CH₂OAr), 4.21 and 4.21 (2 H, AB

part of an ABX syst., J_AB11.5, J_AX6.2, J_BX6.2, CH₂OAc), 6.84 (1

H, ddd, J 1.5, 2.7, 7.8, H-6¢), 7.06–7.18 (3 H, m, other aromatics).

d_C(75 MHz; CDCl₃, 25 ^◦C): 20.8 (COCH₃), 38.4 (CH(CH₂–)),

49.7 (CH₂N₃), 62.3 (CH₂OAc), 65.6 (CH₂OAr), 113.4 (C-6¢),

117.6 (C-2¢), 122.8 (C-3¢), 124.2 (C-4¢), 130.6 (C-5¢), 159.1 (C-

1¢), 170.7 (C O). GC-MS: R_t: 8.13 min; m/z (EI): 329 (M⁺(⁸¹Br),

0.086), 327 (M⁺(⁷⁹Br), 0.080), 174 (6.0), 172 (6.5), 156 (14), 68

(24), 65 (5.4), 63 (5.1), 56 (5.3), 44 (11), 43 (100), 42 (7.1), 41

(31). m/z (ESI+) 350.0133 (M + Na⁺). C₁₂H₁₄BrN₃O₃Na requires

350.0116.

a) From 14: a solution of 14 (462 mg, 1.61 mmol) in dry DMF

(6.5 mL) was treated, at r.t., with imidazole (189 mg, mmol) and

t-butyldimethylsilyl chloride (316 mg, 2.10 mmol). After 4 h the

crude was diluted with water and Et₂O and extracted. The collected

organic layers were washed with water and ﬁnally with brine. After

solvent removal, chromatography with PE + Et₂O from 0.5% to

3% afforded (R)-15 as a colourless oil (621 mg, 96%). b) From 17:

compound 17 was transformed into the corresponding mesylate

[R_f0.41 (PE/Et₂O 60 : 40)] and then into azide (S)-15, following

the procedure reported for compound 13 in 89% yield. R_f0.51

(PE/Et₂O 98 : 2). (R)-15: [a]_D-1.49 (c 1.1, CHCl₃). (S)-15: [a]_D

+0.03 (c 1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13047, 2925, 2854,

2100, 1586, 1461, 1251, 1191, 1092, 1027. d_H(300 MHz; CDCl₃,

25 ^◦C): 0.050, 0.054 (2 ¥ 3 H, 2 s, CH₃Si), 0.89 (9 H, s, (CH₃)₃CSi),

2.22 (1 H, septet, J 5.9, CH(CH₂-)₃), 3.51 (2 H, d, J 6.3, CH₂N₃),

3.73 and 3.73 (2 H, AB part of an ABX syst., J_AB10.3, J_AX5.5, J_BX

5.5, CH₂OSi), 3.94 and 3.98 (2 H, AB part of an ABX syst., J_AB9.4,

J_AX6.2, J_BX6.2, CH₂OAr), 6.83 (1 H, ddd, J 1.5, 2.7, 8.1, H-6¢),

7.05–7.18 (3 H, m, other aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C):

-5.6 (CH₃Si), 18.2 (C(CH₃)₃), 25.8 ((CH₃)₃C), 41.4 (CH(CH₂–)),

49.8 (CH₂N₃), 60.7 (CH₂OSi), 66.0 (CH₂OAr), 113.4 (C-6¢), 117.8

(C-2¢), 122.8 (C-3¢), 124.0 (C-4¢), 130.5 (C-5¢), 159.5 (C-1¢). GC-

MS: R_t: 9.10 min; m/z (EI): 344 (M⁺(⁸¹Br) - 56, 3.1), 342 (M⁺

(⁷⁹Br) - 56, 3.2), 231 (22), 229 (22), 174 (7.2), 172 (7.5), 143 (5.7),

142 (29), 115 (7.1), 112 (8.5), 99 (5.7), 89 (5.1), 86 (5.1), 76 (6.1),

75 (28), 73 (27), 68 (9.0), 65 (6.3), 59 (20), 57 (7.7), 45 (8.7), 43

(7.3), 42 (100), 41 (20), 39 (8.1). m/z (ESI+) 422.0889 (M + Na⁺).

C₁₆H₂₆BrN₃O₂SiNa requires 422.0875.

(R)-1-Acetoxy-3-(tert-butyl)dimethylsilyloxy-2-((3-

(S)-3-Azido-2-((3-bromophenoxy)methyl)propanol 14

bromophenoxy)methyl)propane 16

A pre-cooled solution of KOH (0.2 M in MeOH, 17 mL) was added

at 0 ^◦C to 13 (645 mg, 1.97 mmol) and the mixture was stirred at the

same temperature for 1 h. After quenching with saturated NH₄Cl,

MeOH was removed under reduced pressure and the aqueous

Compound 16 was prepared from 12, following the procedure

reported for compound 15. Chromatography with PE/Et₂O 95 : 5

gave 16 as a pale yellow oil in 93% yield. R_f0.53 (PE/Et₂O 90 : 10).

[a]_D+3.22 (c 0.99, CHCl₃). IR: n_max(CHCl₃)/cm^-13000, 2886,

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1730, 1587, 1519, 1466, 1415, 1188, 1028. d_H(300 MHz; CDCl₃,

25 ^◦C): 0.04 (6 H, s, CH₃Si), 0.88 (9 H, s, (CH₃)₃CSi), 2.07 (3

H, s, COCH₃), 2.33 (1 H, septet, J 5.9, CH(CH₂–)₃), 3.75 and

3.75 (2 H, AB part of an ABX syst., J_AB10.4, J_AX5.7, J_BX5.7,

CH₂OSi), 3.98 and 4.01 (2 H, AB part of an ABX syst., J_AB

9.3, J_AX5.6, J_BX6.1 CH₂OAr), 4.20 and 4.20 (2 H, AB part of

an ABX syst., J_AB11.5, J_AX6.2, J_BX6.2 CH₂OAc), 6.83 (1 H,

ddd, J 1.2, 2.4, 7.8, H-6¢), 7.05–7.17 (3 H, m, other aromatics).

chromatographed with CH₂Cl₂/MeOH 95 : 5 + 3% Et₃N to give

18 as a yellow oil (546 mg, 96%). The preparation of formamide 19

can be performed also without the puriﬁcation of intermediate 18,

without affecting the overall yield. R_f0.48 [CH₂Cl₂/MeOH 90 : 10

+ 2% Et₃N, ninhydrin]. (R)-18: [a]_D-2.85 (c 1.0, CHCl₃). (S)-

18: [a]_D+3.06 (c 1.1, CHCl₃). IR: n_max(CHCl₃)/cm^-13674, 3614,

3018, 2923, 2853, 1587, 1462, 1189, 1089, 1039. d_H(300 MHz;

◦

CDCl₃, 25 C): 0.039, 0.045 (2 ¥ 3 H, 2 s, CH₃Si), 0.88 (9 H, s,

◦

d_C(75 MHz; CDCl₃, 25 C): -5.6 (CH₃Si), 18.2 (C(CH₃)₃), 20.9

(CH₃)₃CSi), 2.06 (1 H, septet, J 5.8, CH(CH₂–)₃), 2.89 (2 H, d,

J 6.3, CH₂NH₂), 3.76 (2 H, d, J 5.4, CH₂OSi), 3.98 and 4.02 (2

H, AB part of an ABX syst., J_AB9.3, J_AX5.8, J_BX6.2, CH₂OAr),

6.84 (1 H, ddd, J 1.2, 2.4, 8.1, H-6¢), 7.05–7.16 (3 H, m, other

aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C): –5.2, –5.6 (CH₃Si), 18.2

(C(CH₃)₃), 25.8 ((CH₃)₃C), 40.9 (CH₂NH₂), 43.3 (CH(CH₂–)),

61.7 (CH₂OSi), 66.8 (CH₂OAr), 113.3 (C-6¢), 117.7 (C-2¢), 122.7

(C-3¢), 123.7 (C-4¢), 130.4 (C-5¢), 159.7 (C-1¢). GC-MS: R_t: 8.65

min; m/z (EI): 360 (M⁺(⁸¹Br) - 15, 1.8), 358 (M⁺(⁷⁹Br) - 15, 1.7),

320 (5.1), 319 (18), 318 (100), 316 (100), 271 (5.1), 259 (7.3), 243

(6.4), 232 (5.7), 231 (38), 230 (5.9), 229 (36), 174 (5.9), 172 (6.4),

159 (8.4), 158 (8.9), 157 (7.8), 155 (7.3), 151 (5.5), 150 (5.5), 146

(5.9), 145 (12), 144 (65), 139 (6.8), 137 (7.1), 135 (8.7), 131 (6.5),

130 (5.7), 116 (5.2), 115 (19), 114 (12), 104 (18), 99 (12), 93 (5.1), 89

(15), 88 (13), 85 (13), 77 (9.1), 76 (21), 75 (84), 74 (45), 73 (78), 71

(5.1), 70 (75), 68 (5.0), 65 (5.8), 64 (5.1), 63 (7.0), 61 (9.0), 60 (8.2),

59 (44), 58 (12), 57 (15), 56 (34.8), 47 (11), 45 (17), 43 (21), 42 (5.5),

41 (53), 39 (11). m/z (ESI+) 374.1148 (M + H⁺). C₁₆H₂₉BrNO₂Si

requires 374.1151.

(COCH₃), 25.8 ((CH₃)₃C), 40.8 (CH(CH₂–)), 60.4 (CH₂OSi), 62.4

(CH₂OAc), 65.6 (CH₂OAr), 113.5 (C-6¢), 117.7 (C-2¢), 122.8 (C-

3¢), 123.8 (C-4¢), 130.5 (C-5¢), 159.6 (C-1¢), 171.0 (C O). GC-MS:

R_t: 9.18 min; m/z (EI): 361 (M⁺(⁸¹Br) - 57, 24), 359 (M⁺(⁷⁹Br) -

57, 23), 302 (8.2), 301 (47), 300 (8.1), 299 (45), 271 (16), 269 (14),

259 (13), 257 (12), 245 (5.4), 243 (6.1), 232 (7.4), 231 (54), 230

(7.5), 229 (52), 227 (5.6), 225 (6.0), 220 (20), 219 (5.4), 192 (5.5),

187 (5.7), 185 (5.9), 157 (7.9), 155 (7.3), 146 (22), 145 (19), 135

(5.7), 131 (7.5), 119 (5.5), 117 (100), 115 (16), 105 (6.1), 99 (9.1),

89 (12), 85 (6.9), 77 (10), 76 (13), 75 (80), 74 (5.9), 73 (38), 71 (6.4),

59 (16), 57 (6.0), 45 (6.3), 43 (90), 41 (15). m/z (ESI+) 439.0925

(M + Na⁺). C₁₈H₂₉BrO₄SiNa requires 439.0916.

(S)-3-(tert-Butyl)dimethylsilyloxy-2-((3-bromophenoxy)methyl)-

propanol 17

Compound 17 was prepared from 16, following the procedure

reported for compound 14. Chromatography with PE/Et₂O 60 : 40

gave 16 as a yellow oil in 88% yield. R_f0.24 (PE/Et₂O 80 : 20). [a]_D

+3.29 (c 1.1, CHCl₃). IR: n_max(CHCl₃)/cm^-13605, 3020, 2887,

1580, 1525, 1476, 1415, 1164, 1025. d_H(300 MHz; CDCl₃, 25 ^◦C):

0.06 and 0.08 (2 ¥ 3 H, 2 s, CH₃Si), 0.89 (9 H, s, (CH₃)₃CSi), 2.18

(1 H, centre of m, CH(CH₂–)₃), 2.47 (1 H, dd, J 5.4, 6.0, OH)

3.81–3.94 (2 H, m, CH₂OH), 3.89 (2 H, d, J 5.1, CH₂OSi), 4.04

and 4.07 (2 H, AB part of an ABX syst., J_AB9.4, J_AX5.8, J_BX6.7

CH₂OAr), 6.84 (1 H, ddd, J 1.2, 2.4, 7.8, H-6¢), 7.04–7.17 (3 H,

m, other aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.60, -5.58

(CH₃Si), 18.2 (C(CH₃)₃), 25.8 ((CH₃)₃C), 42.5 (CH(CH₂–)), 63.0,

63.3 (CH₂OSi and CH₂OH), 66.4 (CH₂OAr), 113.4 (C-6¢), 117.8

(C-2¢), 122.8 (C-3¢), 123.9 (C-4¢), 130.5 (C-5¢), 159.6 (C-1¢), 171.0

(C O). GC-MS: R_t: 8.75 min; m/z (EI): 361 (M⁺(⁸¹Br) - 57, 3.8),

359 (M⁺(⁷⁹Br) - 57, 4.0), 301 (18), 299 (17), 271 (6.8), 269 (6.2), 259

(5.8), 257 (5.3), 231 (22), 229 (22), 220 (5.8), 187 (5.2), 185 (5.4),

157 (5.9), 155 (5.4), 147 (5.2), 146 (39), 145 (29), 131 (9.5), 115

(15), 105 (17), 89 (11), 77 (12), 76 (15), 75 (100), 74 (5.3), 73 (27),

71 (6.3), 61 (5.6), 59 (13), 57 (7.1), 47 (6.5), 45 (9.2), 43 (9.9), 41

(35), 39 (6.2). m/z (ESI+) 397.0798 (M + Na⁺). C₁₆H₂₇BrO₃SiNa

requires 397.0811.

(R)- or (S)-1-(tert-Butyl)dimethylsilyloxy-2-((3-bromophenoxy)-

methyl)-3-formylaminopropane 19

a) From (R)- or (S)-18: a solution of 18 (512 mg, 1.37 mmol) in

◦

dry CH₂Cl₂(12 mL) was cooled to 0 C and treated with N,N¢-

dicyclohexylcarbodiimide (460 mg, 2.23 mmol) and formic acid

(85 mL, 2.25 mmol). After 10 min the reaction was stirred at r.t.

until complete (3 h). The crude was concentrated and taken up with

Et₂O/AcOEt 7 : 3 to remove most of the 1,3-dicyclohexylurea by

ﬁltration. After solvent removal chromatography with PE/Me₂CO

8 : 2 gave 19 (534 mg, 97%) as a pale yellow oil. b) From 23:

compound (S)-19 was prepared from 23, following the procedure

reported for compound 15 in 100% yield. R_f0.35 (PE/Et₂O

80 : 20). (R)-19: [a]_D-10.9 (c 1.0, CHCl₃). (S)-19: [a]_D+14.1 (c

1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13431, 2997, 2926, 2854, 1680,

1588, 1463, 1386, 1217, 1086. d_H(300 MHz; CDCl₃, 25 ^◦C) (2

amide rotamers a and b are visible, in a 81 : 19 a : b ratio): 0.04,

0.05 (2 ¥ 3 H, 2 s, CH₃Si, a + b), 0.88 (9 H, s, (CH₃)₃CSi, a + b),

2.14 (1 H, septet, J 5.7, CH(CH₂–)₃, b), 2.23 (1 H, septet, J 5.8,

CH(CH₂–)₃, a), 3.43–3.59 (2 H, m, CH₂NH, a + b), 3.73 and 3.75

(2 H, AB part of an ABX syst., J_AB10.3, J_AX5.9, J_BX4.8, CH₂OSi,

b), 3.79 (2 H, d, J 5.1, CH₂OSi, a), 3.91 and 3.94 (2 H, AB part of

an ABX syst., J_AB9.3, J_AX6.5, J_BX5.5, CH₂OAr, b), 3.95 and 3.99

(2 H, AB part of an ABX syst., J_AB9.3, J_AX5.6, J_BX6.4, CH₂OAr,

b), 5.88 (1 H, broad s, NH, b), 6.23 (1 H, broad s, NH, a) 6.82

(1 H, ddd, J 1.5, 2.4, 7.8, H-6¢, a, which is partially overlapped

with b), 7.04–7.17 (3 H, m, other aromatics, a + b), 8.02 (1 H,

d, J 12.0, CHO, b), 8.18 (1 H, d, J 1.5, CHO, a). d_C(75 MHz;

(R)- or (S)-1-Amino-3-(tert-butyl)dimethylsilyloxy-2-((3-

bromophenoxy)methyl)propane 18

A solution of (R)- or (S)-15 (610 mg, 1.52 mmol) in dry THF

(10 mL) was treated at 0 ^◦C with PPh₃(599 mg, 2.28 mmol)

and water (55 mL, 3.04 mmol). After evolution of N₂ﬁnished, the

reaction was allowed to stir at r.t. for 22 h. In order to complete the

hydrolysis of the intermediate phosphazene an equivalent amount

of water was added and the mixture was heated at 50 ^◦C for 5 h. The

mixture was partitioned between water and Et₂O and extracted.

The organic layers were washed with brine, concentrated and

◦

CDCl₃, 25 C): -5.58, -5.56 (CH₃Si, a + b), 18.2 (C(CH₃)₃, a +

b), 25.8 ((CH₃)₃C, a + b), 38.4 (a), 40.7 (b) (CH₂NH), 40.4 (a),

41.7 (b) (CH(CH₂–)), 61.1 (b), 62.6 (a) (CH₂OSi), 66.3 (b), 67.0 (a)

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(CH₂OAr), 113.28 (b), 113.33 (a) (C-6¢), 117.78 (b), 117.83 (a) (C-

2¢), 122.80 (a), 122.85 (b) (C-3¢), 124.1 (a), 124.3 (b) (C-4¢), 130.57

(a), 130.63 (b) (C-5¢), 159.2 (b), 159.4 (a) (C-1¢), 161.2 (a), 164.8

(b) (C O). GC-MS: R_t: 10.09 min; m/z (EI): 388 (M⁺(⁸¹Br) -

15, 0.50), 386 (M⁺(⁷⁹Br) - 15, 0.50), 347 (8.9), 346 (45), 345 (9.3),

344 (45), 271 (5.5), 269 (5.0), 232 (5.1), 231 (39), 230 (6.2), 229

(38), 173 (5.1), 172 (15), 157 (6.0), 155 (6.2), 151 (5.5), 150 (6.2),

159 (5.3), 145 (7.6), 139 (7.3), 137 (7.9), 135 (10), 131 (6.1), 117

(7.8), 116 (27), 115 (19), 102 (26), 99 (13), 98 (19), 91 (5.4), 89 (19),

88 (6.5), 86 (6.6), 85 (13), 77 (14), 76 (17), 75 (100), 74 (10), 73

(71), 71 (7.2), 70 (21), 65 (5.6), 63 (6.3), 61 (9.1), 60 (5.7), 59 (39),

58 (80), 57 (15), 56 (11), 55 (6.6), 47 (9.3), 45 (15), 44 (5.1), 43

(16), 42 (7.3), 41 (42), 39 (11). m/z (ESI+) 424.0925 (M + Na⁺).

C₁₇H₂₈BrNO₃SiNa requires 424.0920.

an ABX syst., J_AB9.2, J_AX7.6, J_BX5.0, CH₂OAr), 5.33 (1 H, ddd,

J 1.2, 8.1, 15.3, (CH₃)₂CHCH CH), 5.65 (1 H, ddd, J 0.9, 6.6,

15.6, (CH₃)₂CHCH = CH), 6.84 (1 H, ddd, J 1.5, 2.4, 7.8, H-6¢),

7.06–7.16 (3 H, m, other aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C):

22.4, 22.5 ((CH₃)₂CH), 31.3 ((CH₃)₂CH), 44.6 (CH(CH₂O–)₂),

63.8 (CH₂OAc), 69.3 (CH₂OAr), 113.6 (C-6¢), 117.8 (C-2¢), 122.8

(C-3¢), 123.3 ((CH₃)₂CHCH = CH), 124.0 (C-4¢), 130.5 (C-5¢),

142.2 ((CH₃)₂CHCH CH), 159.6 (C-1¢). GC-MS (usual met_◦hod

but with initial temp. 70 ^◦C, rate 10 ^◦C min^-1, ﬁnal temp. 280 C):

R_t: 14.36 min; m/z (EI): 300 (M⁺(⁸¹Br), 2.5), 298 (M⁺(⁷⁹Br), 2.1),

174 (37), 172 (40), 157 (8.4), 155 (7.3), 126 (22), 110 (8.4), 109

(96), 108 (9.5), 96 (12), 95 (30), 93 (18), 83 (34), 82 (23), 81 (61),

80 (5.3), 79 (18), 77 (11), 76 (9.4), 75 (6.5), 71 (16), 70 (9.3), 69

(37), 68 (8.6), 67 (100), 65 (12), 64 (5.6), 63 (7.9), 59 (11), 57 (37),

56 (8.5), 55 (85), 54 (5.4), 53 (18), 43 (69), 41 (75), 39 (23). m/z

(ESI+) 321.0472 (M + Na⁺). C₁₄H₁₉BrO₂Na requires 321.0466.

(R)- or (S)-1-(tert-Butyl)dimethylsilyloxy-2-((3-bromophenoxy)-

methyl)-3-isocyanopropane 2

(S,E)-1-Azido-2-((3-bromophenoxy)methyl)-5-methylhex-3-ene 21

A solution of (R)- or (S)-19 (123 mg, 306 mmol) in dry CH₂Cl₂

(2.5 mL) was cooled to -30 ^◦C and treated with Et₃N (196 mL,

1.41 mmol) and POCl₃(43 mL, 459 mmol). The colourless solution

became brick red in about 1 h. After 5.5 h, quenching with

5% NaHCO₃was followed by extraction with Et₂O/AcOEt 1 : 1.

The organic phases were washed with brine, concentrated and

chromatographed with PE/Me₂CO 98 : 2 to 8 : 2 to give 2 as a

colourless oil (112 mg, 95%). R_f0.40 (PE/Et₂O 95 : 5). (R)-2: [a]_D

+0.23 (c 1.0, CHCl₃). (S)-2: [a]_D-0.30 (c 1.0, CHCl₃). IR: n_max

(CHCl₃)/cm^-13020, 2999, 2152, 1584, 1466, 1423, 1189, 1026. d_H

(300 MHz; CDCl₃, 25 ^◦C): 0.07 (2 ¥ 3 H, 2 s, CH₃Si), 0.89 (9 H,

s, (CH₃)₃CSi), 2.36 (1 H, septet, J 5.8, CH(CH₂–)₃), 3.64 (2 H,

d, J 6.0, CH₂NC), 3.75 and 3.80 (2 H, AB part of an ABX syst.,

J_AB10.4, J_AX6.0, J_BX5.2, CH₂OSi), 3.96 and 4.03 (2 H, AB part

of an ABX syst., J_AB9.4, J_AX6.7, J_BX5.5, CH₂OAr), 6.83 (1 H,

ddd, J 1.8, 2.4, 7.8, H-6¢), 7.05–7.18 (3 H, m, other aromatics).

Compound 20 was transformed into the corresponding mesylate

[R_f0.89 (CH₂Cl₂/Et₂O 90 : 10); 0.12 (PE/Me₂CO 90 : 10] and then

into azide 21, following the procedure reported for compound

13. Chromatography with PE/CH₂Cl₂95 : 5 to 75 : 25 gave 21 as

a colourless oil in 95% yield. R_f0.46 (PE/CH₂Cl₂90 : 10). [a]_D

-20.3 (c 1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13020, 2953, 2868,

2099, 1590, 1463, 1194, 1021. d_H(300 MHz; CDCl₃, 25 ^◦C):

1.002, 0.999 (6 H, 2 d, J 6.6 and 6.6, (CH₃)₂CH), 2.30 (1 H,

centre of m, (CH₃)₂CH), 2.72 (1 H, centre of m, CH(CH₂O–)₂),

3.44 and 3.49 (2 H, AB part of an ABX syst., J_AB11.5, J_AX

5.7, J_BX5.2, CH₂N₃), 3.90 and 3.94 (2 H, AB part of an ABX

syst., J_AB9.4, J_AX7.2, J_BX5.3, CH₂OAr), 5.35 (1 H, ddd, J 1.2,

8.1, 15.3, (CH₃)₂CHCH CH), 5.66 (1 H, ddd, J 1.2, 6.6, 15.9,

(CH₃)₂CHCH = CH), 6.83 (1 H, ddd, J 1.2, 2.7, 7.8, H-6¢), 7.05–

7.17 (3 H, m, other aromatics). d_C(75 MHz; CDCl₃, 25 ^◦C): 22.21,

22.23 ((CH₃)₂CH), 31.2 ((CH₃)₂CH), 42.5 (CH(CH₂O–)₂), 52.7

(CH₂N₃), 68.6 (CH₂OAr), 113.5 (C-6¢), 117.8 (C-2¢), 122.8 (C-

3¢), 123.3 ((CH₃)₂CHCH = CH), 124.0 (C-4¢), 130.6 (C-5¢), 142.0

((CH₃)₂CHCH CH), 159.4 (C_◦-1¢). GC-MS (usual method but

with initial temp. 70 ^◦C, rate 10 C min^-1, ﬁnal temp. 280 ^◦C): R_t:

14.94 min; m/z (EI): 325 (M⁺(⁸¹Br), 0.30), 323 (M⁺(⁷⁹Br), 0.32),

174 (15), 172 (16), 157 (8.4), 155 (7.2), 110 (10), 109 (19), 108 (9.8),

96 (12), 95 (35), 94 (7.1), 93 (10), 82 (19), 81 (48), 80 (18), 79 (18),

77 (9.9), 76 (8.3), 75 (6.3), 70 (10), 69 (16), 68 (23), 67 (51), 65 (12),

64 (6.4), 63 (9.4), 56 (15), 55 (100), 54 (9.9), 53 (20), 50 (5.5), 43

(32), 42 (11), 41 (72), 39 (25). m/z (ESI+) 346.0543 (M + Na⁺).

C₁₄H₁₈BrN₃ONa requires 346.0531.

◦

d_C(75 MHz; CDCl₃, 25 C): -5.6 (CH₃Si), 18.2 (C(CH₃)₃), 25.8

((CH₃)₃C), 40.0 (CH₂NC), 40.9 (CH(CH₂–)), 60.1 (CH₂OSi), 65.4

(CH₂OAr), 113.3 (C-6¢), 117.8 (C-2¢), 122.8 (C-3¢), 124.3 (C-4¢),

130.6 (C-5¢), 157.3 (NC), 159.1 (C-1¢). GC-MS: R_t: 8.82 min; m/z

(EI): 370 (M⁺(⁸¹Br) - 15, 0.26), 368 (M⁺(⁷⁹Br) - 15, 0.23), 329 (8.5),

328 (44), 327 (8.5), 326 (43), 301 (6.5), 299 (6.7), 271 (12), 269 (11),

259 (11), 257 (10), 233 (5.0), 232 (14), 231 (100), 230 (15), 229 (96),

220 (7.7), 187 (23), 185 (24), 180 (6.0), 179 (5.5), 157 (14), 155 (14),

151 (5.1), 150 (9.4), 149 (7.9), 146 (6.5), 139 (9.7), 137 (9.6), 135

(12), 131 (6.0), 127 (9.9), 115 (13), 114 (24), 99 (9.4), 89 (6.7), 86

(5.0), 85 (11), 84 (39), 78 (5.4), 77 (7.3), 76 (20), 75 (34), 74 (6.0),

73 (46), 71 (11), 64 (5.2), 63 (6.7), 59 (25), 58 (10), 57 (12), 55 (5.7),

53 (5.1), 47 (6.6), 45 (12), 43 (14), 41 (37), 39 (10). m/z (ESI+)

406.0795 (M + Na⁺). C₁₇H₂₆BrNO₂SiNa requires 406.0814.

N-((S,E)-2-((3-Bromophenoxy)methyl)-5-methylhex-3-enyl)-

formamide 22

(S,E)-2-((3-Bromophenoxy)methyl)-5-methylhex-3-en-1-ol 20

Compound 21 was transformed into the corresponding primary

amine following the procedure reported for compound 18. R_f0.45

(CH₂Cl₂/MeOH 90 : 10 + 2% Et₃N, ninhydrin). The crude was

directly transformed into 22 following the procedure reported for

compound 19. Chromatography with CH₂Cl₂+ 1.5% MeOH gave

22 as an ivory foam. R_f0.39 (CH₂Cl₂+ 2% MeOH). [a]_D-33.1 (c

1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13437, 3029, 2954, 2869, 1683,

1590, 1573, 1464, 1190. d_H(300 MHz; CDCl₃, 25 ^◦C) (2 amide

rotamers a and b are visible, in a 79 : 21 a : b ratio): 0.998, 0.995

Compound 20 was prepared from 11, following the procedure

reported for compound 14. Chromatography with PE/Et₂O 75 : 25

gave 20 as a colourless oil in 100% yield. R_f0.23 (PE/Et₂O 80 : 20).

[a]_D-32.1 (c 2.1, CHCl₃). IR: n_max(CHCl₃)/cm^-13606, 3002, 2955,

2870, 1589, 1463, 1193, 1020. d_H(300 MHz; CDCl₃, 25 ^◦C): 1.00

(6 H, d, J 6.9, (CH₃)₂CH), 1.70 (1 H, t, J 6.2, OH), 2.31 (1 H,

centre of m, (CH₃)₂CH), 2.70 (1 H, centre of m, CH(CH₂O–)₂),

3.74 (2 H, centre of m, CH₂OH), 3.97 and 4.00 (2 H, AB part of

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(6 H, 2 d, J 6.9 and 6.6, (CH₃)₂CH, a + b), 2.28 (1 H, centre

of m, (CH₃)₂CH, a + b), 2.57–2.74 (1 H, m, CH(CH₂-)₂, a + b),

3.28–3.65 (2 H, m, CH₂NH, a + b), 3.83 and 3.86 (2 H, AB part of

an ABX syst., J_AB9.4, J_AX8.3, J_BX1.4, CH₂OAr, b), 3.87 and 4.00

(2 H, AB part of an ABX syst., J_AB9.3, J_AX7.3, J_BX5.0, CH₂OAr,

a), 5.25 (1 H, ddd, J 1.2, 8.4, 15.6, (CH₃)₂CHCH CH, b), 5.29 (1

H, ddd, J 0.9, 8.1, 15.3, (CH₃)₂CHCH CH, a), 5.64 (1 H, ddd, J

0.6, 6.6, 15.9, (CH₃)₂CHCH = CH, a), 5.65 (1 H, ddd, J 0.6, 6.3,

15.6, (CH₃)₂CHCH = CH, b), 5.76 (1 H, broad s, NH, a + b), 6.83

(1 H, ddd, J 1.2, 2.4, 7.8, H-6¢, a + b), 7.05–7.18 (3 H, m, other

aromatics, a+b), 8.02 (1 H, d, J 11.7, CHO, b), 8.20 (1 H, d, J 1.2,

CHO, a). d_C(75 MHz; CDCl₃, 25 ^◦C): 22.2, 22.3, 22.4 ((CH₃)₂CH,

a + b), 31.1 (a), 31.2 (b) ((CH₃)₂CH), 39.8 (a), 43.2 (b) (CH₂NH),

42.1 (a), 43.3 (b) (CH(CH₂–)₂), 68.6 (b), 70.0 (a) (CH₂OAr), 113.4

(b), 113.5 (a) (C-6¢), 117.68 (b), 117.72 (a) (C-2¢), 122.6 (b), 123.6

(a) ((CH₃)₂CHCH CH), 122.76 (a), 122.83 (b) (C-3¢), 124.1 (a),

124.2 (b) (C-4¢), 130.57 (a), 130.62 (b) (C-5¢), 142.1 (a), 142.9 (b)

((CH₃)₂CHCH CH), 159.1 (b), 159.3 (a) (C-1¢), 161.2 (a), 164.8

10 g CrO₃, 8.6 mL 96% H₂SO₄, 14 mL H₂O, and brought up

to 40 mL with H₂O) until the yellow-brown colour persisted.

After 2 h 5% NH₄H₂PO₄solution saturated with NaCl was

added. The pH of the aqueous phase was adjusted to 2 by

careful addition of HCl. The extraction was performed with

AcOEt/MeOH 90 : 10. The organic layers were washed with 5%

Na₂SO₃solution saturated with NaCl and concentrated. R_f0.31

(PE/Me₂CO 50 : 50, developed with KMnO₄). b) Methyl ester

formation: crude acid was dissolved in dry THF (5 mL) to give a

yellowish solution. After cooling to 0 ^◦C, diazomethane solution

was added dropwise until the peculiar yellow colour persisted.

The excess of CH₂N₂was eliminated by addition of few drops

of AcOH. The solvent was evaporated and AcOH was removed

azeotropically by addition of n-heptane. Chromatography with

PE/Me₂CO 70 : 30 to 50 : 50 afforded 24 as a yellow oil (75 mg,

62%). R_f0.38 (PE/Me₂CO 50 : 50, developed with KMnO₄). [a]_D

+4.12 (c 2.1, CHCl₃). IR: n_max(CHCl₃)/cm^-13436, 3035, 2989,

2974, 1730, 1686, 1587, 1501, 1466, 1192. d_H(300 MHz; CDCl₃,

25 ^◦C) (2 amide rotamers a and b are visible, in a 85 : 15 a : b ratio):

3.02 (1 H, centre of m, CHCH₂NH, b), 3.10 (1 H, ddt, J_t4.8, J_d

5.2, J_d8.2 CHCH₂NH, a), 3.62–3.84 (2 H, m, CH₂NH, a + b),

3.76 (3 H, s, OCH₃, a), 3.78 (3 H, s, OCH₃, b), 4.19 and 4.23 (2

H, AB part of an ABX syst., J_AB9.3, J_AX4.4, J_BX5.5, CH₂OAr, a,

which is partially overlapped with b), 6.01 (1 H, broad s, NH, b),

6.18 (1 H, broad s, NH, a), 6.83 (1 H, ddd, J 1.8, 2.4, 7.2, H-6¢,

a, which is partially overlapped with b), 7.05–7.18 (3 H, m, other

aromatics, a + b), 8.05 (1 H, d, J 11.7, CHO, b), 8.19 (1 H, d, J 1.2,

CHO, a). d_C(75 MHz; CDCl₃, 25 ^◦C): 36.6 (a), 39.7 (b) (CH₂NH),

44.8 (a), 45.9 (b) (CHCH₂NH), 52.4 (a), 52.6 (b) (OCH₃), 66.2 (b),

66.7 (a) (CH₂OAr), 113.4 (b), 113.5 (a) (C-6¢), 117.9 (b), 118.0 (a)

(C-2¢), 122.8 (a), 123.2 (b) (C-3¢), 124.5 (a), 124.8 (b) (C-4¢), 130.6

(a), 130.7 (b) (C-5¢), 158.6 (b), 158.9 (a) (C-1¢), 161.3 (a), 164.7

(b) (HC O), 171.2 (b), 172.3 (a) (CO₂Me). GC-MS: R_t: 8.89 min;

m/z (EI): 317 (M⁺(⁸¹Br), 0.26), 315 (M⁺(⁷⁹Br), 0.26), 145 (10), 144

(100), 112 (44), 87 (9.7), 84 (7.7), 63 (6.2), 59 (9.9), 58 (28), 56 (11),

55 (19), 41 (6.0), 58 (2.3), 56 (0.3), 46 (0.4), 43 (0.3), 41 (0.9). m/z

(ESI+) 337.9996 (M + Na⁺). C₁₂H₁₄BrNO₄Na requires 338.0004.

◦

(b) (C _◦O). GC-MS (usual method but with initial temp. 70 C,

rate 10 C min^-1, ﬁnal temp. 280 ^◦C): R_t: 9.17 min; m/z (EI): 327

(M⁺(⁸¹Br), 0.51), 325 (M⁺(⁷⁹Br), 0.58), 174 (10), 172 (11), 155

(7.4), 154 (34), 153 (16), 110 (12), 109 (100), 108 (32), 98 (9.0), 96

(17), 95 (24), 93 (20), 84 (6.2), 82 (5.6), 81 (46), 79 (13), 77 (7.7),

76 (5.0), 69 (7.6), 68 (5.0), 67 (42), 65 (6.9), 59 (13), 58 (45), 56

(5.7), 55 (25), 53 (10), 46 (8.3), 43 (15), 41 (31), 39 (12). m/z (ESI+)

348.0576 (M + Na⁺). C₁₅H₂₀BrNO₂Na requires 310.0055.

(R)-2-((3-Bromophenoxy)methyl)-3-formylamino-1-propanol 23

Compound 23 was prepared from 22, following the procedure

reported for compound 12. Chromatography with PE/Et₂O 75 : 25

gave 23 as a colourless oil in 100% yield. R_f0.40 (PE/Me₂CO

50 : 50 + 1% EtOH). [a]_D-17.5 (c 1.1, CHCl₃). IR: n_max

(CHCl₃)/cm^-13433, 3000, 2878, 1676, 1588, 1496, 1465, 1190,

1023. d_H(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers a and b are

visible, in a 91 : 9 a : b ratio): 2.20 (1 H, centre of m, CH(CH₂-)₃, a

+ b), 3.31 (1 H, t, J 6.6, OH, a + b), 3.51 (2 H, t, J 6.3, CH₂NH,

b), 3.58 (2 H, t, J 6.3, CH₂NH, a), 3.62–3.83 (2 H, m, CH₂OH, a +

b), 3.93 and 4.01 (2 H, AB part of an ABX syst., J_AB9.4, J_AX7.5,

J_BX5.7, CH₂OAr, a, which is partially overlapped with b), 6.12

(1 H, broad s, NH, a + b), 6.83 (1 H, ddd, J 1.5, 2.7, 7.8, H-6¢,

a, which is partially overlapped with b), 7.05–7.18 (3 H, m, other

aromatics, a + b), 8.03 (1 H, d, J 12.3, CHO, b), 8.25 (1 H, d, J

1.8, CHO, a). d_C(75 MHz; CDCl₃, 25 ^◦C): 36.8 (CH₂NH, a + b),

40.9 (a), 41.4 (b) (CH(CH₂–)), 60.4 (a), 60.8 (b) (CH₂OH), 66.5

(b), 67.2 (a) (CH₂OAr), 113.3 (C-6¢, a + b), 117.7 (C-2¢, a + b),

122.8 (C-3¢, a + b), 124.1 (a), 124.3 (b) (C-4¢), 130.6 (C-5¢, a + b),

159.1 (b), 159.3 (a) (C-1¢), 162.7 (a), 165.3 (b) (C O). GC-MS:

R_t: 9.11 min; m/z (EI): 174 (M⁺(⁸¹Br) - 101, 7.2), 172 (M⁺(⁷⁹Br) -

101, 7.1), 117 (6.6), 116 (100), 98 (5.6), 86 (6.2), 71 (6.8), 70 (6.1),

65 (5.4), 59 (6.2), 58 (47), 56 (5.6), 46 (8.7), 43 (6.7), 41 (18), 39

(6.1). m/z (ESI+) 310.0042 (M + Na⁺). C₁₁H₁₄BrO₃Na requires

310.0055.

(S)-1-Acetoxy-2-benzyl-3-(tert-butyl)dimethylsilyloxypropane 27

Compound 27 was prepared from known monoacetate 7,²³follow-

ing the procedure reported for compound 15. Chromatography

with PE/Et₂O 95 : 5 gave 27 as a colourless oil in 99% yield.

R_f0.50 (PE/Et₂O 90 : 10). [a]_D+6.07 (c 1.8, CHCl₃). IR: n_max

(CHCl₃)/cm^-13670, 3627, 3028, 2990, 2946, 2920, 2852, 1725,

1432, 1382, 1363, 1188, 1085, 1020. d_H(300 MHz; CDCl₃, 25 ^◦C):

0.023, 0.019 (6 H, s, CH₃Si), 0.90 (9 H, s, (CH₃)₃CSi), 2.04 (3 H,

s, COCH₃), 2.10 (1 H, centre of m, CH(CH₂–)₃), 2.60 and 2.71 (2

H, AB part of an ABX syst., J_AB13.5, J_AX7.2, J_BX7.8, CH₂Ph),

3.52 and 3.57 (2 H, AB part of an ABX syst., J_AB10.0, J_AX5.5,

J_BX4.7, CH₂OSi), 4.05 and 4.05 (2 H, AB part of an ABX syst.,

J_AB11.1, J_AX5.8, J_BX5.8, CH₂OAc), 7.16–7.22 (5 H, m, Ph). d_C

(75 MHz; CDCl₃, 25 ^◦C): -5.6, -5.5 (CH₃Si), 18.3 (C(CH₃)₃), 20.9

(COCH₃), 25.9 ((CH₃)₃C), 34.2 (CH₂Ph), 42.2 (CH(CH₂–)), 61.8

(CH₂OSi), 64.3 (CH₂OAc), 126.0 (CH para of Ph), 128.3 (CH

meta of Ph), 129.1 (CH ortho of Ph), 139.8 (C ipso of Ph), 171.1

(C O). GC-MS: R_t: 7.46 min; m/z (EI): 265 (M⁺- 57, 2.0), 131

(5.1), 131 (47), 118 (10), 117 (100), 105 (5.1), 91 (31), 75 (40), 73

(S)-Methyl 2-((3-bromophenoxy)methyl)-3-

formylaminopropanoate 24

a) Oxidation to carboxylic acid: a solution of 23 (110 mg,

382 mmol) in dry acetone (stored on dry CuSO₄) was cooled to

0

^◦C and treated dropwise with Jones reagent (prepared from

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(11), 43 (18). m/z (ESI+) 323.2048 (M + H⁺). C₁₈H₃₁O₃Si requires

323.2042.

for compound 18. R_f0.46 (CH₂Cl₂/MeOH 95 : 5 + 2% Et₃N,

ninhydrin). The crude were directly transformed into (R)- and (S)-

30, respectively, following the procedure reported for compound

19. Chromatography with PE/Et₂O gave 30 as a pale yellow foam.

R_f0.48 (PE/Et₂O 40 : 60). (R)-30: [a]_D+0.90 (c 2.1, CHCl₃). (S)-

30: [a]_D-0.24 (c 1.8, CHCl₃). IR: n_max(CHCl₃)/cm^-13393, 3006,

2924, 2856, 1680, 1493, 1463, 1386, 1187, 1069. d_H(300 MHz;

CDCl₃, 25 ^◦C) (2 amide rotamers a and b are visible, in a 78 : 22

a : b ratio): 0.032, 0.038 (6 H, s, CH₃Si, a), 0.043, 0.049 (6 H, s,

CH₃Si, b), 0.91 (9 H, s, (CH₃)₃CSi, a), 0.92 (9 H, s, (CH₃)₃CSi, b),

1.88–2.08 (1 H, centre of m, CH(CH₂-)₃, a + b), 2.59 and 2.64 (2

H, AB part of an ABX syst., J_AB13.3, J_AX6.7, J_BX7.8, CH₂Ph, a,

which is partially overlapped with b), 3.23–3.66 (3 H, m, CH₂NH,

a + b and CH₂OSi, b), 3.53 and 3.66 (2 H, AB part of an ABX

syst., J_AB10.2, J_AX6.0, J_BX3.9, CH₂OSi, a), 5.89 (1 H, broad s,

NH, b), 6.36 (1 H, broad s, NH, a), 7.14–7.33 (5 H, m, Ph, a +

b), 7.94 (1 H, d, J 12.0, CHO, b), 8.14 (1 H, d, J 1.5, CHO, a).

d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6 (CH₃Si, a + b), 18.1 (C(CH₃)₃,

a + b), 25.9 ((CH₃)₃C, a + b), 34.8 (b), 35.5 (a) (CH₂Ph), 41.3 (a),

42.7 (b) (CH₂NH), 41.6 (a), 43.0 (b) (CH(CH₂–)), 63.0 (b), 65.2

(a) (CH₂OSi), 126.2 (a), 126.4 (b) (CH para of Ph), 128.4 (a), 128.6

(b) (CH meta of Ph), 128.9 (b), 129.0 (a) (CH ortho of Ph), 139.2

(b), 139.5 (a) (C ipso of Ph), 161.0 (a), 164.9 (b) (C O). GC-MS:

R_t: 8.52 min; m/z (EI): 292 (M⁺- 15, 1.6), 252 (5.1), 251 (21), 250

(100), 175 (8.2), 135 (5.1), 131 (16), 130 (21), 129 (15), 117 (22),

116 (25), 115 (14), 105 (7.0), 104 (6.1), 103 (8.5), 102 (67), 92 (8.9),

91 (99), 89 (19), 77 (8.2), 76 (5.8), 75 (78), 74 (6.2), 73 (30), 65 (7.3),

61 (5.5), 59 (13), 58 (7.1), 57 (6.2), 47 (5.7), 45 (6.8), 41 (6.9). m/z

(ESI+) 308.2036 (M + H⁺). C₁₇H₃₀NO₂Si requires 308.2046.

(S)-2-Benzyl-3-(tert-butyl)dimethylsilyloxypropanol 28

Compound 28 was prepared from 27, following the procedure

reported for compound 14. Chromatography with PE/Et₂O 95 : 5

to 80 : 20 gave 28 as a yellow oil in 90% yield. R_f0.47 (PE/Et₂O

80 : 20). [a]_D-26.3 (c 1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13610,

3480, 2997, 2945, 2925, 2889, 1496, 1418, 1189, 1105, 1041. d_H

(300 MHz; CDCl₃, 25 ^◦C): 0.053, 0.047 (6 H, s, CH₃Si), 0.90 (9 H,

s, (CH₃)₃CSi), 2.01 (1 H, centre of m, CH(CH₂-)₃), 2.62 and 2.62

(2 H, AB part of an ABX syst., J_AB13.9, J_AX7.6, J_BX7.6, CH₂Ph),

2.77 (1 H, broad t, J 4.6, OH), 3.62 and 3.77 (2 H, AB part of an

ABX syst., J_AB9.8, J_AX6.6, J_BX4.0, CH₂OSi), 3.70 (2 H, centre of

m, CH₂OH), 7.13–7.31 (5 H, m, Ph). d_C(75 MHz; CDCl₃, 25 ^◦C):

-5.6 (CH₃Si), 18.1 (C(CH₃)₃), 25.8 ((CH₃)₃C), 34.1 (CH₂Ph), 43.8

(CH(CH₂-)), 65.8 (CH₂OSi), 66.2 (CH₂OH), 126.0 (CH para of

Ph), 128.3 (CH meta of Ph), 129.0 (CH ortho of Ph), 140.0 (C ipso

of Ph). GC-MS: R_t: 7.00 min; m/z (EI): 265 (M⁺- 15, 0.037), 132

(11), 131 (100), 129 (7.1), 117 (6.3), 105 (30), 92 (5.5), 91 (54), 75

(56), 73 (8.1). m/z (ESI+) 281.1936 (M + H⁺). C₁₆H₂₉O₂Si requires

281.1937.

(R)- or (S)-1-Azido-2-benzyl-3-(tert-

butyl)dimethylsilyloxypropane 29

a) From 26: compound (R)-29 was prepared from known com-

pound 26,²³following the procedure reported for compound

15. Chromatography with PE to PE/Et₂O 95 : 5 gave (R)-

29 as a colourless oil in 92% yield. b) From 28: compound

28 was transformed into the corresponding mesylate [R_f0.82

(CH₂Cl₂/Et₂O/PE 1 : 0.5 : 1); 0.12 (PE/Me₂CO 90 : 10] and then

into azide (S)-29, following the procedure reported for compound

13 to give (S)-29 in 93% yield. R_f0.29 (PE). (R)-29: [a]_D-9.53

(c 2.6, CHCl₃). (S)-29: [a]_D+9.99 (c 2.1, CHCl₃). IR: n_max

(CHCl₃)/cm^-12999, 2929, 2852, 2099, 1463, 1191, 1107. d_H

(300 MHz; CDCl₃, 25 ^◦C): 0.04 (6 H, s, CH₃Si), 0.91 (9 H, s,

(CH₃)₃CSi), 1.98 (1 H, septet, J 6.2, CH(CH₂–)₃), 2.59 and 2.67 (2

H, AB part of an ABX syst., J_AB13.6, J_AX7.4, J_BX7.5, CH₂Ph),

3.28 and 3.30 (2 H, AB part of an ABX syst., J_AB12.1, J_AX6.6,

J_BX4.8, CH₂N₃), 3.46 and 3.54 (2 H, AB part of an ABX syst.,

J_AB10.0, J_AX5.8, J_BX4.4, CH₂OSi), 7.16–7.32 (5 H, m, Ph). d_C

Mosher¢s ester obtained from 30

a) Silyl ether removal: a solution of 30 (30 mg, 97.6 mmol) in

dry CH₃CN (1 mL) was cooled to -10 ^◦C and treated with

40% aqueous HF (50 mL). After stirring for 20 min at the same

temperature, the reaction was quenched with NaHCO₃(5% solu-

tion saturated with NaCl) and extracted with Et₂O. After solvent

removal, the crude was used as such for the following acylation.

R_f0.21 (AcOEt, ninhydrin); b) Mosher¢s ester formation: 25% of

the above prepared crude (24.4 mmol, _◦based on 30) was dissolved

in dry CH₂Cl₂(500 mL), cooled to 0 C, and treated with N,N-

dimethylamino pyridine (9.0 mg, 73.2 mmol) and either (R)- or (S)-

Mosher chloride (6.0 mL, 32.1 mmol). The solution was allowed

to stir at r.t. for 30 min. Then the crude was directly puriﬁed by

preparative TLC, to give the desired ester in 70% overall yield.

R_f0.34 (PE/AcOEt 4 : 6). The comparison between the proton

spectra of the diastereomeric esters, in particular signals due to

CH₂OCOC(OMe)(CF₃)Ph, demonstrate that the initial e.e. of 7

was maintained.

◦

(75 MHz; CDCl₃, 25 C): -5.52, -5.50 (CH₃Si), 18.3 (C(CH₃)₃),

25.9 ((CH₃)₃C), 34.7 (CH₂Ph), 43.0 (CH(CH₂–)), 51.7 (CH₂N₃),

62.1 (CH₂OSi), 126.1 (CH para of Ph), 128.4 (CH meta of Ph),

129.1 (CH ortho of Ph), 139.6 (C ipso of Ph). GC-MS: R_t: 7.29

min; m/z (EI): 277 (M⁺- 28, 0.38), 249 (5.7), 248 (30), 220 (14),

218 (12), 193 (5.5), 191 (19), 190 (13), 159 (5.2), 144 (8.1), 136

(6.0), 135 (39), 132 (5.4), 130 (5.8), 129 (10), 128 (17), 118 (7.1),

117 (48), 116 (32), 115 (20), 105 (8.5), 104 (5.3), 102 (6.4), 101 (6.3),

100 (6.3), 92 (8.3), 91 (100), 90 (6.1), 89 (58), 86 (36), 77 (8.0), 76

(7.7), 75 (100), 74 (9.0), 73 (36), 65 (7.8), 61 (7.3), 59 (32), 57 (8.0),

47 (7.6), 45 (11), 41 (9.0). m/z (ESI+) 278.1936 (M + H⁺- N₂).

C₁₆H₂₈NOSi requires 278.1940.

(R)- or (S)-2-Benzyl-1-(tert-butyl)dimethylsilyloxy-3-

isocyanopropane 3

Compounds (R)- and (S)-3 were prepared from (R)- and (S)-30,

respectively, following the procedure reported for compound 2.

Chromatography with PE to PE/Et₂O 97 : 3 gave 30 as a pale

yellow oil. R_f0.44 (PE/AcOEt 97 : 3). (R)-3: [a]_D-19.3 (c 2.2,

CHCl₃). (S)-3: [a]_D+19.2 (c 2.2, CHCl₃). IR: n_max(CHCl₃)/cm^-1

3001, 2945, 2923, 2884, 2852, 2151, 1506, 1468, 1413, 1189, 1122,

(R)- or (S)-2-Benzyl-3-(tert-butyl)dimethylsilyloxy-1-

formylaminopropane 30

Compounds (R)- and (S)-29 were transformed into the cor-

responding primary amines following the procedure reported

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1029. d_H(300 MHz; CDCl₃, 25 ^◦C): 0.06, 0.07 (6 H, s, CH₃Si),

0.91 (9 H, s, (CH₃)₃CSi), 2.08 (1 H, centre of m, CH(CH₂–)₃), 2.62

and 2.71 (2 H, AB part of an ABX syst., J_AB13.7, J_AX8.1, J_BX7.0,

CH₂Ph), 3.41 (2 H, centre of m, CH₂NC), 3.56 and 3.67 (2 H, AB

part of an ABX syst., J_AB10.3, J_AX6.8, J_BX4.1, CH₂OSi), 7.18–

7.34 (5 H, m, Ph). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.5 (CH₃Si),

18.2 (C(CH₃)₃), 25.8 ((CH₃)₃C), 34.1 (CH₂Ph), 41.7 (CH₂NC),

42.4 (CH(CH₂-)), 61.7 (CH₂OSi), 126.5 (CH para of Ph), 128.6

(CH meta of Ph), 129.0 (CH ortho of Ph), 138.6 (C ipso of Ph),

156.5 (NC) (signal very difﬁcult to detect). GC-MS: R_t: 7.12 min;

m/z (EI): 273 (M⁺- 15, 0.33), 233 (5.5), 232 (28), 205 (11), 132

(3.3), 131 (29), 129 (14), 117 (7.1), 115 (9.4), 114 (8.2), 92 (9.7), 91

(100), 89 (9.1), 84 (14), 77 (5.5), 76 (5.5), 75 (69), 73 (12), 65 (6.2),

59 (6.5), 41 (5.3). m/z (ESI+) 290.1933 (M + H⁺). C₁₇H₂₈NOSi

requires 290.1940.

GC-MS: R_t: 6.08 min; m/z (EI): 214 (M⁺- 15, 1.8%); 173 (2.0);

115 (41); 113 (3.8); 84 (22); 59 (8.2); 43 (100); 42 (6.4); 41 (6.7).

(4S,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-

yl)methyl butanoate 9

A suspension of known dibutyrate 33²⁵(2.50 g, 8.27 mmol) in

H₂O (30 mL) was treated with 1 M pH 7 phosphate buffer

(K₂HPO₄/KH₂PO₄) (60 mL), cooled to 0 ^◦C, and treated with

Amano PS lipase (375 mg). The suspension was stirred at 0 ^◦C

for 1 h. The mixture was saturated with NaCl, diluted with

AcOEt and ﬁltered through a celite cake, washing thoroughly

with AcOEt. The phases were separated and the organic phase

dried, evaporated to dryness, and chromatographed (PE/AcOEt

6 : 4) to give pure 9 as a colourless liquid (1.81 g, 94%). [a]_D-14.3

(c 2.5, CHCl₃). Lit:²⁵-11.1. The e.e. (97%) was determined by

GC of the corresponding Mosher¢s ester, after standardization

on a racemic sample. The monobutyrate was esteriﬁed with (R)-

Mosher¢s chloride, and analyzed on a HP-1 column. (0.33 m,

0.201 mm i.d., 12 m). Flow: 1 mL min^-1; isothermal at 170 ^◦C.

R_t19.58 min. R_tof the other diastereomer: 19.03 min. All other

analytical spectroscopic data were in accord with those already

reported.²⁵

(4R,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-

yl)methyl acetate 8

Diol 31 (2.01 g, 12.4 mmol) was dissolved in vinyl acetate (30 mL)

◦

and treated with Amano PS lipase (1.05 g), and stirred at 20 C

under nitrogen for 20 h. Then it was ﬁltered, washing the ﬁlter with

CH₂Cl₂, evaporated to dryness and chromatographed (PE/AcOEt

50 : 50 to 30 : 70), to give pure 42 as a colourless liquid (2.02 g,

80%). [a]_D+19.9 (c 2, CHCl₃). Lit.²⁵+16.6. The e.e. (97%) was

determined by benzoylation and by HPLC analysis on Daicel

Chiralpak AD 250 ¥ 4.6 column, after standardization with a

racemic sample. Flow: 0.8 mL min^-1.; isocratic elution with n-

hexane/i-PrOH 97 : 3; temp.: 35 ^◦C. R_t13.19 min (4R,5S) and

14.20 min (4S,5R). All other analytical-spectroscopic data were in

accord with those already reported.²⁵

(4R,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-

yl)methyl butanoate 9

A solution of diol 31 (100 mg, 616 mmol) in dry THF (1.5 mL)

was treated with vinyl butyrate (390 ml, 3.08 mmol) and Amano

PS lipase (50 mg). The mixture was stirred for 14 days and then

ﬁltered, washing the ﬁlter with CH₂Cl₂, evaporated to dryness

and chromatographed (PE/AcOEt 60 : 40), to give pure 9 as a

colourless liquid (100 mg, 71%). [a]_D+13.9 (c 2, CHCl₃). The e.e.,

determined as above, was 95%.

(4R,5S)-5-(Azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl

acetate 32

(4S,5R)-5-(Azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl

butanoate 34

a) Mesylate formation: monoacetate (4R,5S)-8 (1.90 g, 9.30 mmol)

was dissolved in dry CH₂Cl₂(30 mL), cooled to -18 ^◦C, and treated

with Et₃N (3.90 mL, 27.9 mmol) and methanesulphonyl chloride

(1.08 mL, 13.95 mmol). After 15 min the reaction was complete

(as determined by TLC with PE/Et₂O/CH₂Cl₂1 : 1 : 1). It was

poured into saturated NaHCO₃(40 mL) and extracted 4 times

with Et₂O. b) Azide formation: the organic phases were evaporated

to dryness, taken up in dry DMF (8 mL), treated with NaN₃(1.515

It was prepared from (4S,5R)-9 following the same procedure

used for (4R,5S)-32. The isolated yield after chromatography was

80%. R_f0.51 (PE/Et₂O 70 : 30). Found: C, 51.4; H, 7.5; N, 16.2%.

C₁₁H₁₉N₃O₄requires C, 51.35; H, 7.44; N, 16.33%. [a]_D+23.1 (c

2, CHCl₃). IR: n_max(CHCl₃)/cm^-12964, 2106, 1729, 1373, 1255,

1165, 1080. d_H(300 MHz; CDCl₃): 0.95 (3 H, t, CH₃CH₂), 1.39

(3 H, s, CH₃CCH₃), 1.51 (3 H, s, CH₃CCH₃), 1.67 (2 H, sextet,

J 7.4, CH₂CH₃), 2.34 (2 H, t, J 7.4, CH₂C O), 3.30–3.48 (2 H,

m, CH₂N₃), 4.10–4.28 (2 H, m, CH₂OC O), 4.30–4.40 (2 H, m,

CH–O). d_C(75 MHz; CDCl₃): 13.6 (CH₃CH₂), 18.3 (CH₂CH₃),

25.2, 27.7 (CH₃–C–CH₃), 35.9 (CH₂C O), 50.4 (CH₂N₃), 62.0

(CH₂OC O), 74.5, 75.7 (CHO), 109.5 ((CH₃)₂)C, 173.2 (C O).

GC-MS: R_t: 5.80 min; m/z (EI): 242 (M⁺- 15, 6.9%); 201 (5.0);

143 (100); 113 (11); 102 (4.8); 101 (4.8); 84 (56); 71 (58); 59 (11);

58 (6.3); 55 (6.9); 43 (79); 42 (9.8); 41 (16).

◦

g, 23.3 mmol) and heated at 100 C for 42 h. After cooling, the

mixture was treated with H₂O (60 mL), saturated aqueous NH₄Cl

(40 mL), and Et₂O (50 mL). The phases were separated, and

the organic phase evaporated to dryness and chromatographed

(PE/Et₂O 75 : 25 to 50 : 50) to give pure 32 as a colourless liquid

(1.75 g, 82%). R_f0.47 (PE/Et₂O 50 : 50). Found: C, 47.35; H, 6.7;

N, 18.0%. C₉H₁₅N₃O₄requires C, 47.16; H, 6.60; N, 18.33%. [a]_D

-22.4 (c 2, CHCl₃). IR: n_max(CHCl₃)/cm^-12968, 2103, 1737, 1372,

1186, 1039. d_H(300 MHz; CDCl₃): 1.39 (3 H, s, CH₃CCH₃), 1.51

(3 H, s, CH₃CCH₃), 2.11 (3 H, s, CH₃C O), 3.37 and 3.42 (2 H,

AB part of an ABX syst., J_AB12.9, J_AX4.2, J_BX6.6, CH₂N₃), 4.12

and 4.23 (2 H, AB part of an ABX syst., J_AB11.7, J_AX6.7, J_BX

4.6, CH₂OAc), 4.30–4.41 (2 H, m, CH–O). d_C(75 MHz; CDCl₃):

20.9 (CH₃C O), 25.2, 27.7 (CH₃–C–CH₃), 50.4 (CH₂N₃), 62.4

(CH₂OAc), 74.4, 75.6 (CHO), 109.6 ((CH₃)₂)C, 170.6 (C O).

(3aR,4S,6aS)-N-Benzyl-2,2-dimethyl-5-propionyltetrahydro-3aH-

[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide 36a

a) Hydrolysis of acetate: a solution of azidoacetate (4R,5S)-32

(1.75 g, 7.63 mmol) in absolute MeOH (35 mL) was cooled to

0 ^◦C and treated with 1 M KOH in MeOH (13.0 mL, 13.0 mmol).

After 20 min the mixture was quenched with saturated aqueous

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NH₄Cl (60 mL) and extracted four times with Et₂O (80 + 40 +

30 + 20 mL). The organic extracts were dried over Na₂SO₄, and

concentrated to dryness. The residue was taken up with Et₂O and

dried again on Na₂SO₄, ﬁltered, evaporated and brieﬂy (30 min)

stripped at 1 mbar to give crude azidoalcohol (4R,5S)-35 (1.344 g,

94%), that was used as such for the next reaction. b) Oxidation to

aldehyde: dimethyl sulfoxide (183 mL, 2.58 _◦mmol) was dissolved

in dry CH₂Cl₂(10 mL) and cooled to -70 C. The solution was

treated with a 1.63 M solution of (COCl)₂in CH₂Cl₂(1.33 mL,

2.17 mmol. After 10 min, a solution of crude alcohol (4R,5S)-35

(193 mg, 1.03 mmol) in CH₂Cl₂(5 mL) was added. After 10 min,

Et₃N (677 mL, 4.86 mmol) was ﬁnally added. The temperature

was allowed to rise to -60 ^◦C in 1 h. The oxidation to the

azidoaldehyde was complete by TLC (PE/AcOEt 1 : 1; R_f35: 0.35;

R_fazidoaldehyde: 0.52). Thus the mixture was poured into 5%

aqueous (NH₄)H₂PO₄(35 mL) + 2 M HCl (2 mL). Extraction with

Et₂O, washings with saturated NaCl, and evaporation gave the

rather volatile azidoaldehyde as an oil. c) Imine formation: it was

taken up at once in dry THF (5 mL), treated with freshly activated

HPLC Analysis of 36a and 36b

The two enantiomers were analyzed at chiral HPLC (Daicel

Chiralpak AD 250 ¥ 4.6 mm, 0.8 mL min^-1, Vinj = 20 ml, T =

◦

35 C, eluent: n-hexane/i-PrOH 85 : 15; ﬂow: 0.8 mL min^-1). R_t:

36a: 20.19, 36b: 12.32 min. Analysis indicated for 36a an e.e. of

97% and for 36b an e.e. of 96%.

(3aR,4S,6aS)-5-Benzoyl-N-(tert-butyl)-2,2-dimethyltetrahydro-

3aH-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide 37a

It was prepared in 49% overall yield (from 32) following the same

procedure used for 36a, but employing benzoic acid and tert-butyl

isocyanide. Thick oil. R_f0.49 (PE/AcOEt 50 : 50). [a]_D+144.9 (c

2, CHCl₃). IR: n_max(CHCl₃)/cm^-13419, 2962, 2926, 1670, 1614,

1520, 1415, 1367, 1293, 1195, 1150, 1045. d_H(300 MHz; CDCl₃,

◦

25 C) (2 amide rotamers are visible, in a 90 : 10 ratio. Only the

signals of major rotamer are reported): 1.32 (3 H, s, (CH₃)₂C),

1.36 (9 H, s, C(CH₃)₃), 1.46 (3 H, s, (CH₃)₂C), 3.63 and 3.81 (2 H,

AB part of an ABX syst., J_AB13.4, J_AX4.2, J_BX0, H-6), 4.78 (1

H, dd, J 4.2, 6.0, H-6a), 4.90 (1 H, s, H-4), 5.19 (1 H, d, J 6.0, H-

3a), 5.30 (1 H, s, NH), 7.37–7.52 (5 H, m, aromatics). d_C(75 MHz;

CDCl₃, 25 ^◦C): 24.7, 26.7 (CH₃CCH₃), 51.4 (C(CH₃)₃), 54.6 (C-6),

66.2 (C-4), 79.6 (C-6a), 80.6 (C-3a), 111.8 (O–C–O), 127.2 (¥2),

128.5 (¥2), 130.4 (aromatic CH), 135.1 (aromatic quat.), 168.1,

170.5 (C O). m/z (ESI+) 355.1645 (M + Na⁺). C₁₈H₂₄N₂O₄Na

requires 355.1634.

˚

powdered 3 A mol. sieves (50 mg) and triphenylphosphine (325

mg, 1.241 mmol) and immediately heated at 50 ^◦C for 24 h.

After cooling, the mixture was diluted with CH₂Cl₂, ﬁltered and

cautiously evaporated (the imine 4 is rather volatile) to dryness.

d) Ugi reaction: the residue was taken up in dry MeOH (6 mL),

and treated with propionic acid (93 mL, 1.24 mmol) and benzyl

isocyanide (151 mL, 1.24 mmol). The solution was stirred at r.t.

for 48 h, and then evaporated to dryness. The crude product was

taken up in AcOEt, washed with saturated aqueous NaHCO₃,

evaporated again, and chromatographed (PE/AcOEt 45 : 55 to

30 : 70) to give pure compound 36a as a foam (201 mg, 55% from

32). R_f0.31 (PE/AcOEt 30 : 70). [a]_D-83.8 (c 2, CHCl₃). IR: n_max

(CHCl₃)/cm^-13673, 3615, 2977, 1670, 1629, 1521, 1420, 1375,

1205, 1156, 1036. d_H(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers

are visible, in a 95 : 5 ratio. Only the signals of major rotamer are

reported): 1.13 (3 H, t, J 7.5, CH₃CH₂), 1.33 (3 H, s, (CH₃)₂C),

1.42 (3 H, s, (CH₃)₂C), 2.26 (1 H, dq, J_d15.9, J_q7.5, CHHCH₃),

2.40 (1 H, dq, J_d15.9, J_q7.5, CHHCH₃), 3.62 (1 H, dd, J 4.8,

12.0, H-6), 3.76 (1 H, d, J 12.0, H-6), 4.30–4.48 (2 H, m, CH₂Ph),

4.82 (1 H, s, H-4), 4.89 (1 H, t, J 5.1, H-6a), 5.13 (1 H, d, J 5.7,

H-3a), 7.15 (1 H, broad s, NH), 7.20–7.35 (5 H, m, aromatics). d_C

(75 MHz; CDCl₃, 25 ^◦C): 9.0 (CH₃CH₂), 24.8, 26.8 (CH₃CCH₃),

27.6 (CH₂CH₃), 43.3 (CH₂Ph), 53.0 (C-6), 65.4 (C-4), 79.7 (C-6a),

80.7 (C-3a), 111.9 (O–C–O), 127.36, 127.43 (¥2), 128.6 (aromatic

CH), 138.0 (aromatic quat.), 169.3, 173.7 (C O). GC-MS: R_t:

9.80 min; m/z (EI): 332 (M⁺, 8.2), 274, (9.7), 199 (6.2), 198 (9.5),

142 (100), 124 (6.5), 106 (8.2), 91 (26), 85 (5.8), 84 (11), 68 (16),

57 (22), 43 (6.3). m/z (ESI+) 355.1645 (M + Na⁺). C₁₈H₂₄N₂O₄Na

requires 355.1634.

General procedure for the synthesis of Ugi adducts 39–46

Imine 4 or ent-4 were prepared from azidoacetate 32 or azidobu-

tyrate 34, as described for the synthesis of 36a and 36b. Then

the crude imine (500 mmol, estimated on the amount of starting

azidoalcohol 35) was dissolved in dry MeOH (2.5 mL) and treated

˚

with powdered 4 A mol. sieves (50 mg), the appropriate carboxylic

acid (400 mmol), and ﬁnally with a solution of isocyanides 2 or

3 (330 mmol) in MeOH (1 mL). The solution was stirred at r.t.

for 48 h, and then evaporated to dryness. The crude product was

taken up in AcOEt, washed with saturated aqueous NaHCO₃,

evaporated again, and chromatographed (PE/AcOEt). The yields

reported are based on the isocyanide (limiting agent).

Compound 39a

Thick oil. Yield: 56%. R_f0.48 (PE/AcOEt 30 : 70). [a]_D-46.0 (c

2.4, CHCl₃). IR: n_max(CHCl₃)/cm^-13000, 2875, 1669, 1588, 1521,

1463, 1375, 1191, 1027, 921. d_H(300 MHz; CDCl₃, 25 ^◦C) (2 amide

rotamers are visible, in a 87 : 13 ratio. Only the signals of major

rotamer are reported): 0.036, 0.043 (2 ¥ 3 H, 2 s, CH₃Si), 0.89 (9 H,

s, (CH₃)₃CSi), 1.32 (3 H, s, (CH₃)₂C), 1.42 (3 H, s, (CH₃)₂C), 2.17

(1 H, septet, J 5.9, H-2¢), 3.35–3.44 (2 H, m, H-1¢), 3.40 (3 H, s,

OCH₃), 3.57 (1 H, dd, J 4.7, 12.4, H-6), 3.71 (2 H, d, J 5.4, H-3¢),

3.84 (1 H, d, J 12.4, H-6), 3.88–3.98 (2 H, m, CH₂OAr), 4.09 and

4.01 (2 H, AB syst., J 14.3, CH₂OCH₃), 4.74 (1 H, s, H-4), 4.86 (1

H, t, J 5.2, H-6a), 5.04 (1 H, d, J 6.0, H-3a), 6.85 (1 H, ddd, J 0.9,

1.8, 7.8, H-6¢¢), 6.90 (1 H, broad t, NH), 7.04–7.09 (2 H, m, H-2¢¢,

H-4¢¢), 7.13 (1 H, t, J 8.0, H-5¢¢). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.5

(CH₃Si), 18.2 (C(CH₃)₃), 24.7, 26.8 (CH₃CCH₃), 25.9 ((CH₃)₃C),

38.8 (C-1¢), 41.1 (C-2¢), 51.9 (C-6), 59.0 (OCH₃), 61.6 (C-3¢), 65.8

(C-4), 66.7 (CH₂OAr), 71.6 (CH₂OCH₃), 79.7 (C-6a), 80.2 (C-3a),

(3aS,4R,6aR)-N-Benzyl-2,2-dimethyl-5-propionyltetrahydro-

3aH-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide 36b

A solution of azidobutyrate 34 (1.47 g, 5.73 mmol) in MeOH

(20 mL) was cooled at 0 ^◦C and treated with 4 M NaOH (2.50 mL,

10 mmol). The mixture was stirred at 0 ^◦C for 4 h. The work-

up was made as above to afford crude azidoalcohol (4S,5R)-35.

From 1/10 of this alcohol, the same procedure described for the

enantiomer gave pure 36b as a foam (103 mg, 54% from 34). [a]_D

+84.8 (c 2, CHCl₃).

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111.9 (O–C–O), 113.5 (C-6¢¢), 117.8 (C-2¢¢), 122.7 (C-3¢¢), 123.9 (C-

4¢¢), 130.5 (C-5¢¢), 159.6 (C-1¢¢), 168.9, 169.1 (C O). m/z (ESI+)

637.2010 (M + Na⁺). C₂₇H₄₃BrN₂O₇SiNa requires 637.1921.

(2 H, m), 1.57–1.88 (6 H, m), 2.14 (1 H, septet, J 5.9, H-2¢), 2.31

(1 H, tt, J 3.3, 11.4, CHC O), 3.25–3.49 (2 H, m, H-1¢), 3.54

(1 H, dd, J 4.8, 12.6, H-6), 3.67 and 3.69 (2 H, AB part of an

ABX syst., J_AB10.2, J_AX5.9, J_BX4.9, H-3¢), 3.83 (1 H, d, J 12.6,

H-6), 3.88 and 3.93 (2 H, AB part of an ABX syst., J_AB9.2, J_AX

5.1, J_BX6.4, CH₂OAr), 4.75 (1 H, s, H-4), 4.85 (1 H, t, J 5.1,

H-6a), 5.10 (1 H, d, J 6.0, H-3a), 6.84 (1 H, ddd, J 1.3, 2.4, 8.0,

H-6¢¢), 6.98 (1 H, t, J 5.8, NH), 7.04–7.09 (2 H, m, H-2¢¢, H-

4¢¢), 7.13 (1 H, t, J 8.1, H-5¢¢). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6

(CH₃Si), 18.1 (C(CH₃)₃), 24.7, 26.6 (CH₃CCH₃), 25.7 ((CH₃)₃C),

25.4, 25.56, 25.61, 28.5, 28.8 (cyclohexyl CH₂), 38.2 (C-1¢), 41.2

(C-2¢), 41.9 (cyclohexyl CH), 52.4 (C-6), 61.3 (C-3¢), 65.1 (C-4),

66.4 (CH₂OAr), 79.5 (C-6a), 80.2 (C-3a), 111.6 (O-C-O), 113.4

(C-6¢¢), 117.7 (C-2¢¢), 122.6 (C-3¢¢), 123.7 (C-4¢¢), 130.3 (C-5¢¢),

159.5 (C-1¢¢), 169.4, 175.8 (C O). m/z (ESI+) 653.2634 (M +

H⁺). C₃₁H₅₀BrN₂O₆Si requires 653.2622.

Compound 39b

Thick oil. Yield: 54%. R_f0.48 (PE/AcOEt 30 : 70). [a]_D-28.3 (c

2.4, CHCl₃). IR: n_max(CHCl₃)/cm^-13000, 2875, 1669, 1588, 1521,

1463, 1375, 1191, 1027, 921. d_H(300 MHz; CDCl₃, 25 ^◦C) (2

amide rotamers are visible, in a 86 : 14 ratio. Only the signals of

major rotamer are reported): 0.04 (6 H, s, CH₃Si), 0.89 (9 H, s,

(CH₃)₃CSi), 1.32 (3 H, s, (CH₃)₂C), 1.42 (3 H, s, (CH₃)₂C), 2.18

(1 H, septet, J 5.9, H-2¢), 3.35–3.44 (2 H, m, H-1¢), 3.40 (3 H, s,

OCH₃), 3.60 (1 H, dd, J 4.8, 12.6, H-6), 3.66–3.78 (2 H, m, H-3¢),

3.84 (1 H, d, J 12.4, H-6), 3.88–3.98 (2 H, m, CH₂OAr), 4.09 and

4.01 (2 H, AB syst., J 14.3, CH₂OCH₃), 4.73 (1 H, s, H-4), 4.86

(1 H, t, J 5.2, H-6a), 5.04 (1 H, d, J 6.0, H-3a), 6.85 (1 H, ddd,

J 0.9, 1.8, 7.8, H-6¢¢), 6.92 (1 H, broad t, NH), 7.04–7.09 (2 H,

m, H-2¢¢, H-4¢¢), 7.12 (1 H, t, J 8.0, H-5¢¢). d_C(75 MHz; CDCl₃,

25 ^◦C): -5.5 (CH₃Si), 18.2 (C(CH₃)₃), 24.7, 26.8 (CH₃CCH₃), 25.9

((CH₃)₃C), 38.8 (C-1¢), 40.9 (C-2¢), 51.9 (C-6), 59.0 (OCH₃), 61.7

(C-3¢), 65.9 (C-4), 66.7 (CH₂OAr), 71.6 (CH₂OCH₃), 79.8 (C-6a),

80.2 (C-3a), 111.9 (O-C-O), 113.4 (C-6¢¢), 117.8 (C-2¢¢), 122.7 (C-

3¢¢), 123.9 (C-4¢¢), 130.5 (C-5¢¢), 159.6 (C-1¢¢), 169.0 (2 C O). m/z

(ESI+) 615.2110 (M + H⁺). C₂₇H₄₄BrN₂O₇Si requires 615.2101.

Compound 40c

Thick oil. Yield: 73%. R_f0.38 (PE/AcOEt 70 : 30). [a]_D+32.8 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13685, 3430, 3090, 2990, 2925,

2854, 1667, 1588, 1516, 1436, 1375, 1192, 1152, 1128, 1095. d_H

(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers are visible, in a

94 : 6 ratio. Only the signals of major rotamer are reported): 0.030,

0.032 (2 ¥ 3 H, 2 s, CH₃Si), 0.87 (9 H, s, (CH₃)₃CSi), 1.32 (3 H,

s, (CH₃)₂C), 1.40 (3 H, s, (CH₃)₂C), 1.13–1.30 (2 H, m), 1.43–1.56

(2 H, m), 1.57–1.88 (6 H, m), 2.16 (1 H, septet, J 6.0, H-2¢), 2.32

(1 H, tt, J 3.3, 11.4, CHC O), 3.24–3.50 (2 H, m, H-1¢), 3.56

(1 H, dd, J 4.7, 12.2, H-6), 3.68 and 3.70 (2 H, AB part of an

ABX syst., J_AB10.2, J_AX5.4, J_BX5.4, H-3¢), 3.84 (1 H, d, J 12.2,

H-6), 3.88 and 3.93 (2 H, AB part of an ABX syst., J_AB9.2, J_AX

5.3, J_BX6.3, CH₂OAr), 4.75 (1 H, s, H-4), 4.85 (1 H, t, J 5.1,

H-6a), 5.11 (1 H, d, J 6.0, H-3a), 6.84 (1 H, ddd, J 1.2, 2.4, 8.0,

H-6¢¢), 7.01 (1 H, t, J 6.0, NH), 7.04–7.09 (2 H, m, H-2¢¢, H-

4¢¢), 7.13 (1 H, t, J 8.1, H-5¢¢). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6

(CH₃Si), 18.2 (C(CH₃)₃), 24.7, 26.7 (CH₃CCH₃), 25.8 ((CH₃)₃C),

25.4, 25.6, 25.7, 28.5, 28.9 (cyclohexyl CH₂), 38.3 (C-1¢), 41.1

(C-2¢), 41.9 (cyclohexyl CH), 52.4 (C-6), 61.3 (C-3¢), 65.1 (C-4),

66.4 (CH₂OAr), 79.5 (C-6a), 80.2 (C-3a), 111.7 (O-C-O), 113.4

(C-6¢¢), 117.7 (C-2¢¢), 122.6 (C-3¢¢), 123.7 (C-4¢¢), 130.4 (C-5¢¢),

159.6 (C-1¢¢), 169.4, 175.8 (C O). m/z (ESI+) 653.2630 (M +

H⁺). C₃₁H₅₀BrN₂O₆Si requires 653.2622.

Compound 39c

Thick oil. Yield: 57%. R_f0.48 (PE/AcOEt 30 : 70). [a]_D+27.5

(c 2, CHCl₃). m/z (ESI+) 615.2110 (M + H⁺). C₂₇H₄₄BrN₂O₇Si

requires 615.2101. All the other spectroscopic data were identical

with those of its enantiomer 39b.

Compound 39d

Thick oil. Yield: 80%. R_f0.48 (PE/AcOEt 30 : 70). [a]_D+45.4

(c 2, CHCl₃). m/z (ESI+) 615.2107 (M + H⁺). C₂₇H₄₄BrN₂O₇Si

requires 615.2101. All the other spectroscopic data were identical

with those of its enantiomer 39a.

HPLC analysis of stereoisomers 39a–d

HPLC was performed on Daicel Chiralpak AD 250 ¥ 4.6 mm,

1.0 mL min^-1, V_inj= 10 mL, T = 35 ^◦C, ﬂow: 0.8 mL min^-1; eluent:

0–15 min n-hexane/i-PrOH 9 : 1 → 30 min n-hexane/i-PrOH 8 : 2.

R_t: 39a: 13.27 min, 39b: 17.81 min, 39c 7.94 min, 39d 7.46 min.

From these chromatograms we deduced the following d.r.s:

39a: a:b:c:d = 96.6 : 2.5 : 0.9 : 0

39b: a:b:c:d = 2.7 : 95.9 : 0 : 1.4

39c: a:b:c:d = 1.7 : 0 : 96.2 : 2.1

39d: a:b:c:d = 0 : 1.9 : 2.7 : 95.4.

Compound 41a

Thick oil. Yield: 69%. R_f0.35 (PE/AcOEt 70 : 30). [a]_D-57.3 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13655, 3426, 2927, 2850, 1673,

1620, 1589, 1432, 1280, 1194, 1150, 1048. d_H(300 MHz; CDCl₃,

25 ^◦C) (2 amide rotamers are visible, in a 92 : 8 ratio. Only the

signals of major rotamer are reported): 0.038, 0.043 (2 ¥ 3 H, 2

s, CH₃Si), 0.88 (9 H, s, (CH₃)₃CSi), 1.32 (3 H, s, (CH₃)₂C), 1.46

(3 H, s, (CH₃)₂C), 2.21 (1 H, septet, J 5.8, H-2¢), 3.46 (2 H, t, J

6.2, H-1¢), 3.61 (1 H, dd, J 4.1, 12.6, H-6), 3.72 and 3.74 (2 H,

AB part of an ABX syst., J_AB10.3, J_AX5.7, J_BX5.1, H-3¢), 3.80

(1 H, d, J 12.6, H-6), 3.94 and 3.99 (2 H, AB part of an ABX

syst., J_AB9.3, J_AX5.7, J_BX5.7, CH₂OAr), 4.78 (1 H, dd, J 4.1,

5.9, H-6a), 4.91 (1 H, s, H-4), 5.16 (1 H, d, J 5.9, H-3a), 6.85 (1

H, ddd, J 1.2, 2.4, 8.0, H-6¢¢), 6.99 (1 H, t, J 5.9, NH), 7.03–7.17

(3 H, m, H-2¢¢, H-4¢¢, H-5¢¢), 7.27 (1 H, t, J 7.6, H meta to Br),

Compound 40a

Thick oil. Yield: 73%. R_f0.38 (PE/AcOEt 70 : 30). [a]_D-52.7 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13685, 3430, 3090, 2990, 2925,

2854, 1667, 1588, 1516, 1436, 1375, 1192, 1152, 1128, 1095. d_H

(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers are visible, in a

94 : 6 ratio. Only the signals of major rotamer are reported): 0.029,

0.034 (2 ¥ 3 H, 2 s, CH₃Si), 0.87 (9 H, s, (CH₃)₃CSi), 1.32 (3 H,

s, (CH₃)₂C), 1.40 (3 H, s, (CH₃)₂C), 1.13–1.30 (2 H, m), 1.43–1.56

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7.37 (1 H, dt, J_t1.3, J_d7.7, H para to Br), 7.58 (1 H, ddd, J 1.2,

2.1, 7.8, H para to C O), 7.63 (1 H, t, J 1.6, H ortho to Br and

C

Compound 42c

Thick oil. Yield: 58%. R_f0.35 (PE/AcOEt 70 : 30). [a]_D+51.7 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13002, 2928, 2854, 1674, 1589,

1505, 1424, 1190, 1151, 1126, 1058. d_H(300 MHz; CDCl₃, 25 ^◦C)

(only one amide rotamer is visible): 0.03 (6 H, s, CH₃Si), 0.87 (9 H,

s, (CH₃)₃CSi), 1.33 (3 H, s, (CH₃)₂C), 1.42 (3 H, s, (CH₃)₂C), 2.19

(1 H, septet, J 6.0, H-2¢), 3.30–3.57 (2 H, m, H-1¢), 3.70 and 3.73

(2 H, AB part of an ABX syst., J_AB10.2, J_AX5.4, J_BX5.4, H-3¢),

3.80–4.00 (2 H, m, CH₂OAr), 4.16 (1 H, d, J 12.0, H-6), 4.89–4.98

(2 H, m, H-6a, H-4), 5.07 (1 H, d, J 6.0, H-3a), 6.82 (1 H, dt, J_t

2.1, J_d7.2, H-6¢¢), 6.88 (1 H, d, J 3.9, H ortho to Cl), 6.95 (1 H,

t, J 5.7, NH), 7.02–7.15 (3 H, m, H-2¢¢, H-4¢¢, H-5¢¢), 7.22 (1 H,

d, J 3.9, H meta to Cl). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.57, -5.54

(CH₃Si), 18.2 (C(CH₃)₃), 24.8, 26.8 (CH₃CCH₃), 25.9 ((CH₃)₃C),

38.9 (C-1¢), 40.8 (C-2¢), 54.6 (C-6), 61.7 (C-3¢), 66.6, 66.8 (C-4

and CH₂OAr), 80.0 (C-6a and C-3a), 112.1 (O-C-O), 113.4 (C-

6¢¢), 117.8 (C-2¢¢), 122.7 (C-3¢¢), 123.9 (C-4¢¢), 126.6 (CH ortho

to Cl), 130.0 (CH meta to Cl), 130.5 (C-5¢¢), 136.0, 136.1 (quat.

thienyl group), 159.5 (C-1¢¢), 161.6, 168.9 (C O). m/z (ESI+)

687.1320 (M + H⁺). C₂₉H₄₁ClN₂O₆SSi requires 687.1327.

O). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6 (CH₃Si), 18.1 (C(CH₃)₃),

24.6, 26.7 (CH₃CCH₃), 25.7 ((CH₃)₃C), 38.7 (C-1¢), 41.0 (C-2¢),

54.6 (C-6), 61.4 (C-3¢), 65.9 (C-4), 66.7 (CH₂OAr), 79.4 (C-6a),

80.6 (C-3a), 111.9 (O–C–O), 113.3 (C-6¢¢), 117.8 (C-2¢¢), 122.5,

122.6 (C-3¢¢ and quat. bromobenzoic group), 123.8 (C-4¢¢), 125.7

(C para to Br), 129.9 (CH meta to Br), 130.4 (C-5¢¢ and C meta to

Br and C O), 133.4 (C para to C O), 136.7 (quat. bromobenzoic

group), 159.4 (C-1¢¢), 168.7, 168.9 (C O). m/z (ESI+) 725.1252

(M + H⁺). C₃₁H₄₃Br₂N₂O₆Si requires 725.1257.

Compound 41c

Thick oil. Yield: 73%. R_f0.35 (PE/AcOEt 70 : 30). [a]_D+43.4 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13773, 3675, 3610, 3424, 3200,

3104, 2947, 2853, 1671, 1625, 1590, 1525, 1463, 1420, 1246, 1157,

1044, 921. d_H(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers are

visible, in a 92 : 8 ratio. Only the signals of major rotamer are

reported): 0.04 (6 H, s, CH₃Si), 0.88 (9 H, s, (CH₃)₃CSi), 1.32 (3

H, s, (CH₃)₂C), 1.46 (3 H, s, (CH₃)₂C), 2.22 (1 H, septet, J 5.8,

H-2¢), 3.37–3.56 (2 H, m, H-1¢), 3.64 (1 H, dd, J 4.2, 12.6, H-6),

3.72 and 3.74 (2 H, AB part of an ABX syst., J_AB10.3, J_AX5.7, J_BX

5.1, H-3¢), 3.80 (1 H, d, J 12.6, H-6), 3.93 and 3.99 (2 H, AB part

of an ABX syst., J_AB9.3, J_AX5.7, J_BX6.0, CH₂OAr), 4.79 (1 H, dd,

J 4.1, 5.9, H-6a), 4.90 (1 H, s, H-4), 5.15 (1 H, d, J 5.9, H-3a), 6.85

(1 H, ddd, J 1.2, 2.4, 8.0, H-6¢¢), 7.02 (1 H, t, J 5.9, NH), 7.03–7.17

(3 H, m, H-2¢¢, H-4¢¢, H-5¢¢), 7.27 (1 H, t, J 7.6, H meta to Br), 7.37

(1 H, dt, J_t1.3, J_d7.7, H para to Br), 7.58 (1 H, ddd, J 1.2, 2.1, 7.8,

H para to C O), 7.63 (1 H, t, J 1.6, H ortho to Br and C O). d_C

(75 MHz; CDCl₃, 25 ^◦C): -5.6 (CH₃Si), 18.2 (C(CH₃)₃), 24.7, 26.7

(CH₃CCH₃), 25.8 ((CH₃)₃C), 38.9 (C-1¢), 40.9 (C-2¢), 54.6 (C-6),

61.6 (C-3¢), 65.9 (C-4), 66.7 (CH₂OAr), 79.5 (C-6a), 80.8 (C-3a),

112.0 (O-C-O), 113.3 (C-6¢¢), 117.8 (C-2¢¢), 122.6, 122.7 (C-3¢¢ and

quat. bromobenzoic group), 123.9 (C-4¢¢), 125.8 (C para to Br),

130.0 (CH meta to Br), 130.4 (C-5¢¢ and C meta to Br and C O),

133.5 (C para to C O), 136.7 (quat. bromobenzoic group), 159.5

(C-1¢¢), 168.8, 168.9 (C O). m/z (ESI+) 725.1275 (M + H⁺).

C₃₁H₄₃Br₂N₂O₆Si requires 725.1257.

HPLC analysis of stereoisomers 42a–42c

HPLC was performed on Daicel Chiralpak AD 250 ¥ 4.6 mm,

◦

1.0 mL min^-1, V_inj= 20 mL, T = 25 C, ﬂow: 0–15 min: 0.8 mL

min^-1; 15–30 min: 1.0 mL min^-1; eluent: 0–15 min n-hexane/i-

PrOH 9 : 1 → 30 min n-hexane/i-PrOH 85 : 15). R_t: 42a: 24.38

min, 42c: 13.25 min, From these chromatograms we deduced the

following d.r.s: 42a: 95.3%; 42c: 93.8%.

Compound 43a

Thick oil. Yield: 74%. R_f0.37 (PE/AcOEt 50 : 50). [a]_D-34.3 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13683, 3434, 3006, 2855, 1711,

1670, 1588, 1506, 1435, 1249, 1091. d_H(300 MHz; CDCl₃, 25 ^◦C)

(2 amide rotamers are visible, in a 91 : 9 ratio. Only the signals of

major rotamer are reported): 0.039, 0.045 (2 ¥ 3 H, 2 s, CH₃Si),

0.88 (9 H, s, (CH₃)₃CSi), 1.31 (3 H, s, (CH₃)₂C), 1.40 (3 H, s,

(CH₃)₂C), 2.16 (1 H, septet, J 5.8, H-2¢), 2.41 (1 H, broad dt, J_t

5.4, J_d16.5, CHHCH₂NHZ), 2.59 (1 H, broad dt, J_t6.0, J_d16.5,

CHHCH₂NHZ), 3.31–3.53 (4 H, m, H-1¢ and CH₂NHZ), 3.57

(1 H, dd, J 4.6, 12.2, H-6), 3.65–3.77 (3 H, m, H-3¢ and H-6),

3.85–4.03 (2 H, m, CH₂OAr), 4.66 (1 H, s, H-4), 4.83 (1 H, dd, J

4.6, 5.7, H-6a), 4.96 (1 H, d, J 5.7, H-3a), 5.07 (2 H, s, CH₂Ph),

5.49 (1 H, broad t, ZNH), 6.80–6.91 (2 H, m, H-6¢¢ and NH),

7.02–7.15 (3 H, m, H-2¢¢, H-4¢¢, H-5¢¢), 7.30–7.40 (5 H, m, CH of

Compound 42a

Thick oil. Yield: 56%. R_f0.35 (PE/AcOEt 70 : 30). [a]_D-70.6 (c 1,

CHCl₃). IR: n_max(CHCl₃)/cm^-12926, 2854, 1730, 1673, 1589, 1521,

1424, 1241, 1152, 1127, 1047. d_H(300 MHz; CDCl₃, 25 ^◦C) (only

one amide rotamer is visible): 0.02, 0.03 (2 ¥ 3 H, 2 s, CH₃Si), 0.87

(9 H, s, (CH₃)₃CSi), 1.32 (3 H, s, (CH₃)₂C), 1.42 (3 H, s, (CH₃)₂C),

2.18 (1 H, septet, J 5.8, H-2¢), 3.43 (2 H, t, J 6.3, H-1¢), 3.70 (2 H,

d, J 6.4, H-3¢), 3.80–4.00 (2 H, m, CH₂OAr), 4.15 (1 H, d, J 12.0,

H-6), 4.82–5.00 (2 H, m, H-6a, H-4), 5.07 (1 H, d, J 5.9, H-3a),

6.82 (1 H, dt, J_t2.1, J_d7.5, H-6¢¢), 6.88 (1 H, d, J 3.9, H ortho to

Cl), 6.94 (1 H, t, J 5.7, NH), 7.02–7.15 (3 H, m, H-2¢¢, H-4¢¢, H-5¢¢),

7.21 (1 H, d, J 3.9, H meta to Cl). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6

(CH₃Si), 18.2 (C(CH₃)₃), 24.8, 26.9 (CH₃CCH₃), 25.8 ((CH₃)₃C),

38.9 (C-1¢), 41.0 (C-2¢), 54.6 (C-6), 61.6 (C-3¢), 66.75, 66.84 (C-4

and CH₂OAr), 80.0 (C-6a and C-3a), 112.2 (O–C–O), 113.5 (C-

6¢¢), 117.8 (C-2¢¢), 122.7 (C-3¢¢), 123.9 (C-4¢¢), 126.6 (CH ortho

to Cl), 130.0 (CH meta to Cl), 130.5 (C-5¢¢), 136.0, 136.1 (quat.

thienyl group), 159.5 (C-1¢¢), 161.7, 168.9 (C O). m/z (ESI+)

687.1300 (M + H⁺). C₂₉H₄₁ClN₂O₆SSi requires 687.1327.

◦

Ph). d_C(75 MHz; CDCl₃, 25 C): -5.6 (CH₃Si), 18.1 (C(CH₃)₃),

24.6, 26.7 (CH₃CCH₃), 25.7 ((CH₃)₃C), 34.1 (CH₂CH₂NHZ), 36.5

(CH₂NHZ), 38.7 (C-1¢), 40.9 (C-2¢), 52.8 (C-6), 61.6 (C-3¢), 65.8

(C-4), 66.5 (CH₂Ph), 66.7 (CH₂OAr), 79.4 (C-6a), 81.0 (C-3a),

111.9 (O-C-O), 113.3 (C-6¢¢), 117.7 (C-2¢¢), 122.6 (C-3¢¢), 123.8 (C-

4¢¢), 127.9 (¥3), 128.3 (¥2) (CH benzyl), 130.4 (C-5¢¢), 136.4 (quat.

benzyl), 159.4 (C-1¢¢), 156.3, 169.2, 171.2 (C O). m/z (ESI+)

748.2626 (M + H⁺). C₃₅H₅₁BrN₃O₈Si requires 748.2629.

Compound 43c

Thick oil. Yield: 80%. R_f0.37 (PE/AcOEt 50 : 50). [a]_D+20.6 (c 1,

CHCl₃). IR: n_max(CHCl₃)/cm^-13670, 3603, 3439, 3042, 2948, 2742,

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2394, 1711, 1669, 1589, 1501, 1434, 1190, 1033. d_H(300 MHz;

CDCl₃, 25 ^◦C) (2 amide rotamers are visible, in a 91 : 9 ratio. Only

the signals of major rotamer are reported): 0.04 (6 H, s, CH₃Si),

0.88 (9 H, s, (CH₃)₃CSi), 1.30 (3 H, s, (CH₃)₂C), 1.41 (3 H, s,

(CH₃)₂C), 2.16 (1 H, septet, J 5.8, H-2¢), 2.41 (1 H, broad dt, J_t

5.6, J_d16.6, CHHCH₂NHZ), 2.60 (1 H, broad dt, J_t5.8, J_d16.6,

CHHCH₂NHZ), 3.31–3.53 (4 H, m, H-1¢ and CH₂NHZ), 3.59

(1 H, dd, J 4.8, 12.0, H-6), 3.66–3.78 (3 H, m, H-3¢ and H-6),

3.84–4.03 (2 H, m, CH₂OAr), 4.65 (1 H, s, H-4), 4.83 (1 H, t,

J 5.5, H-6a), 4.97 (1 H, d, J 6.0, H-3a), 5.07 (2 H, s, CH₂Ph),

5.50 (1 H, broad t, ZNH), 6.85 (1 H, ddd, J 1.2, 2.4, 7.8, H-6¢¢),

6.92 (1 H, t, J 5.7, NH), 7.02–7.15 (3 H, m, H-2¢¢, H-4¢¢, H-5¢¢),

7.30–7.40 (5 H, m, CH of Ph). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6

(CH₃Si), 18.1 (C(CH₃)₃), 24.6, 26.7 (CH₃CCH₃), 25.8 ((CH₃)₃C),

34.1 (CH₂CH₂NHZ), 36.5 (CH₂NHZ), 38.8 (C-1¢), 40.8 (C-2¢),

52.8 (C-6), 61.8 (C-3¢), 65.8 (C-4), 66.5 (CH₂Ph), 66.7 (CH₂OAr),

79.4 (C-6a), 80.9 (C-3a), 111.9 (O-C-O), 113.3 (C-6¢¢), 117.8 (C-

2¢¢), 122.6 (C-3¢¢), 123.8 (C-4¢¢), 128.0 (¥3), 128.4 (¥2) (CH benzyl),

130.4 (C-5¢¢), 136.4 (quat. benzyl), 159.5 (C-1¢¢), 156.3, 169.2, 171.2

(C O). m/z (ESI+) 748.2610 (M + H⁺). C₃₅H₅₁BrN₃O₈Si requires

748.2629.

syst., J 14.1, CH₂OCH₃), 4.69 (1 H, s, H-4), 4.86 (1 H, t, J 5.2,

H-6a), 5.01 (1 H, d, J 6.0, H-3a), 6.83 (1 H, broad t, J 5.4, NH),

7.13–7.28 (5 H, m, Ph). d_C(75 MHz; CDCl₃, 25 C): -5.6, -5.5

◦

(CH₃Si), 18.2 (C(CH₃)₃), 24.7, 26.8 (CH₃CCH₃), 25.9 ((CH₃)₃C),

35.1 (CH₂Ph), 41.1 (C-1¢), 42.3 (C-2¢), 52.0 (C-6), 59.0 (OCH₃),

63.3 (C-3¢), 65.8 (C-4), 71.7 (CH₂OCH₃), 79.8 (C-6a), 80.3 (C-3a),

111.9 (O–C–O), 126.0 (CH para of Ph), 128.3 (CH meta of Ph),

129.1 (CH ortho of Ph), 139.8 (C ipso of Ph), 168.8, 168.9 (C O).

GC-MS (usual method but ﬁnal temp. 290 ^◦C for 4 min): R_t: 12.50

min; m/z (EI): 464 (M⁺-56, 14), 463 (48), 215 (12), 214 (73), 186

(39), 156 (11), 142 (12), 140 (6.0), 131 (18), 130 (8.3), 129 (5.9), 128

(5.0), 117 (8.5), 115 (7.3), 105 (5.5), 100 (6.4), 91 (38), 89 (5.3), 80

(7.6), 75 (36), 74 (5.5), 73 (23), 59 (9.1), 57 (5.7), 56 (6.9), 55 (6.0),

45 (100), 44 (22), 43 (14), 41 (9.8), 40 (9.1), 39 (5.3), 45 (21), 41 (21).

m/z (ESI+) 521.3038. (M + H⁺). C₂₇H₄₅N₂O₆Si requires 521.3047.

Comparison of ¹H and ¹³C NMR of 44a and 44b showed that d.r.

must be ≥95% in both cases (diagnostic are the signals of H-4 and

H-1¢ at ¹H NMR and of C-2¢ at ¹³C NMR).

Compound 45c

Colourless oil. Yield: 56%. R_f0.62 (PE/AcOEt 65 : 35). [a]_D

+50.6 (c 1.1, CHCl₃). IR: n_max(CHCl₃)/cm^-13671, 3610, 3428,

2973, 2926, 2853, 1664, 1638, 1511, 1416, 1174, 1157, 1044. d_H

(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers are visible, in a 93 : 7

ratio. Only the signals of major rotamer are reported): 0.026, 0.032

(6 H, s, CH₃Si), 0.90 (9 H, s, (CH₃)₃CSi), 1.29 (3 H, s, (CH₃)₂C),

1.42 (3 H, s, (CH₃)₂C), 1.96 (1 H, centre of m, H-2¢), 2.29–2.51

(4 H, m, (CH₂)₂CO), 2.54 and 2.64 (2 H, AB part of an ABX

syst., J_AB13.7, J_AX6.4, J_BX8.2, CH₂Ph), 3.26 (2 H, centre of m,

H-1¢), 3.46 and 3.52 (2 H, AB part of an ABX syst., J_AB10.2,

J_AX5.1, J_BX4.5, H-3¢), 3.65 (1 H, dd, J 4.8, 12.0, H-6), 3.78 (1

H, d, J 12.0, H-6), 4.71 (1 H, s, H-4), 4.87 (1 H, t, J 5.2, H-

6a), 4.98–5.08 (3 H, m, H-3a and CH₂= CH), 5.84 (1 H, centre

of m, CH₂CH), 6.88 (1 H, broad t, J 5.4, NH), 7.13–7.30 (5

H, m, Ph). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.54, -5.49 (CH₃Si),

18.2 (C(CH₃)₃), 24.8, 26.8 (CH₃CCH₃), 25.9 ((CH₃)₃C), 28.8, 33.3

((CH₂)₂CO), 35.1 (CH₂Ph), 40.9 (C-1¢), 42.4 (C-2¢), 53.0 (C-6),

63.1 (C-3¢), 65.5 (C-4), 79.6 (C-6a), 80.6 (C-3a), 111.8 (O–C–O),

115.5 (CH₂CH), 126.0 (CH para of Ph), 128.3 (CH meta of

Ph), 129.1 (CH ortho of Ph), 136.9 (CH₂CH), 139.9 (C ipso

of Ph), 169.2, 172.1 (C O). m/z (ESI+) 531.3246. (M + H⁺).

C₂₉H₄₇N₂O₅Si requires 531.3254.

Compound 44a

Yellow oil. Yield: 68%. R_f0.32 (PE/AcOEt 50 : 50). [a]_D-40.7 (c

1.7, CHCl₃). IR: n_max(CHCl₃)/cm^-13671, 3607, 3427, 2927, 2888,

2851, 1667, 1515, 1433, 1188, 1086, 1046. d_H(300 MHz; CDCl₃,

◦

25 C) (2 amide rotamers are visible, in a 85 : 15 ratio. Only the

signals of major rotamer are reported): 0.02, 0.04 (6 H, s, CH₃Si),

0.91 (9 H, s, (CH₃)₃CSi), 1.33 (3 H, s, (CH₃)₂C), 1.42 (3 H, s,

(CH₃)₂C), 1.96 (1 H, centre of m, H-2¢), 2.54 and 2.65 (2 H, AB

part of an ABX syst., J_AB13.5, J_AX6.5, J_BX8.2, CH₂Ph), 3.28 (2

H, centre of m, H-1¢), 3.41 (3 H, s, OCH₃), 3.53 and 3.66 (2 H, AB

part of an ABX syst., J_AB10.2, J_AX6.0, J_BX3.9, H-3¢), 3.61 (1 H,

dd, J 4.8, 12.3, H-6), 3.84 (1 H, d, J 12.3, H-6), 4.03 and 4.11 (2 H,

AB syst., J 14.1, CH₂OCH₃), 4.72 (1 H, s, H-4), 4.87 (1 H, t, J 5.1,

H-6a), 5.03 (1 H, d, J 5.7, H-3a), 6.80 (1 H, broad t, J 6.0, NH),

7.15–7.31 (5 H, m, Ph). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.54, -5.51

(CH₃Si), 18.2 (C(CH₃)₃), 24.8, 26.8 (CH₃CCH₃), 25.9 ((CH₃)₃C),

35.2 (CH₂Ph), 41.2 (C-1¢), 42.5 (C-2¢), 51.9 (C-6), 59.0 (OCH₃),

63.2 (C-3¢), 65.9 (C-4), 71.6 (CH₂OCH₃), 79.8 (C-6a), 80.3 (C-3a),

111.9 (O-C-O), 126.1 (CH para of Ph), 128.4 (CH meta of Ph),

129.1 (CH ortho of Ph), 139.9 (C ipso of Ph), 168.9, 169.0 (C O).

m/z (ESI+) 521.3038. (M + H⁺). C₂₇H₄₅N₂O₆Si requires 521.3047.

Compound 46c

Compound 44b

Colourless oil. Yield: 67%. R_f0.76 (PE/AcOEt 50 : 50). [a]_D+76.7

(c 1.9, CHCl₃). IR: n_max(CHCl₃)/cm^-13670, 3612, 3419, 2989,

2967, 2929, 1668, 1420, 1194, 1125, 1057, 1027. d_H(300 MHz;

White solid. M.p. 96.8–97.8 ^oC (PE/AcOEt/CH₂Cl₂). Yield: 55%.

R_f0.50 (PE/AcOEt 30 : 70). [a]_D-46.2 (c 2.0, CHCl₃). IR: n_max

(CHCl₃)/cm^-13673, 3609, 3439, 3005, 2971, 2929, 2888, 1664,

◦

CDCl₃, 50 C) (only one amide rotamer is visible either at 25 or

◦

1505, 1473, 1417, 1191, 1031, 923. d_H(300 MHz; CDCl₃, 25 C)

50 ^◦C): 0.01, 0.03 (6 H, s, CH₃Si), 0.89 (9 H, s, (CH₃)₃CSi), 1.32

(3 H, s, (CH₃)₂C), 1.42 (3 H, s, (CH₃)₂C), 1.96 (1 H, centre of m,

H-2¢), 2.54 and 2.63 (2 H, AB part of an ABX syst., J_AB13.7, J_AX

6.5, J_BX8.0, CH₂Ph), 3.30 (2 H, t, J 5.8, H-1¢), 3.48 and 3.54 (2

H, AB part of an ABX syst., J_AB9.4, J_AX5.2, J_BX3.2, H-3¢), 3.85

(1 H, broad s, H-6; at 25 ^◦C: 3.90 (1 H, dd, J 4.5, 12.0)), 4.18 (1

H, broad d, J 9.0, H-6; at 25 ^◦C: 4.17 (1 H, d, J 12.0)), 4.88–4.91

(2 H, m, H-4 and H-6a; at 25 ^◦C: 4.90 (1 H, s, H-4), 4.94 (1 H, t,

J 5.2, H-6a)), 5.05 (1 H, d, J 5.7, H-3a), 6.74 (1 H, broad s, NH),

(2 amide rotamers are visible, in a 87 : 13 ratio. Only the signals

of major rotamer are reported): 0.01, 0.02 (6 H, s, CH₃Si), 0.89 (9

H, s, (CH₃)₃CSi), 1.31 (3 H, s, (CH₃)₂C), 1.41 (3 H, s, (CH₃)₂C),

1.96 (1 H, centre of m, H-2¢), 2.54 and 2.62 (2 H, AB part of an

ABX syst., J_AB13.7, J_AX6.6, J_BX8.2, CH₂Ph), 3.27 (2 H, centre

of m, H-1¢), 3.40 (3 H, s, OCH₃), 3.45 and 3.52 (2 H, AB part of

an ABX syst., J_AB10.2, J_AX5.5, J_BX4.4, H-3¢), 3.61 (1 H, dd, J

4.5, 12.3, H-6), 3.84 (1 H, d, J 12.3, H-6), 4.03 and 4.11 (2 H, AB

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6.89 (1 H, d, J 3.9, H ortho to Cl), 7.10–7.26 (6 H, m, Ph and H

meta to Cl). d_C(75 MHz; CDCl₃, 25 ^◦C): -5.6, -5.5 (CH₃Si), 18.3

(C(CH₃)₃), 24.9, 26.9 (CH₃CCH₃), 25.9 ((CH₃)₃C), 35.1 (CH₂Ph),

41.1 (C-1¢), 42.3 (C-2¢), 54.7 (C-6), 63.4 (C-3¢), 66.8 (C-4), 80.1

(C-6a and C-3a), 112.1 (O-C-O), 126.1 (CH para of Ph), 126.6

(CH ortho to Cl), 128.3 (CH meta of Ph), 129.0 (CH ortho of Ph),

130.0 (CH meta to Cl), 136.0, 136.2 (quat. thienyl group), 139.8

(C ipso of Ph), 161.7, 168.7 (C O). m/z (ESI+) 593.2285. (M +

Na⁺). C₂₉H₄₂ClN₂O₅SSi requires 593.2272.

52.6 (C-6), 60.2 (C-3¢), 65.3 (C-4), 67.2 (CH₂OAr), 79.6 (C-6a),

80.4 (C-3a), 111.9 (O-C-O), 113.5 (C-6¢¢), 117.7 (C-2¢¢), 122.7 (C-

3¢¢), 124.0 (C-4¢¢), 130.5 (C-5¢¢), 159.4 (C-1¢¢), 171.0, 176.2 (C O).

m/z (ESI+) 539.1765 (M + H⁺). C₂₅H₃₆BrN₂O₆requires 539.1757.

Compound 48c

Thick oil. Yield: 94%. R_f0.36 (PE/AcOEt 70 : 30). [a]_D+50.3 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13672, 3601, 3430, 2966, 2927,

2853, 1660, 1622, 1589, 1513, 1428, 1374, 1191, 1043, 991. d_H

(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers are visible, in a 90 : 10

ratio. Only the signals of major rotamer are reported): 1.13–1.30

(2 H, m), 1.33 (3 H, s, (CH₃)₂C), 1.42 (3 H, s, (CH₃)₂C), 1.43–1.56

(2 H, m), 1.57–1.88 (6 H, m), 2.09 (1 H, broad signal, H-2¢), 2.36

(1 H, tt, J 3.0, 11.4, CHC O), 3.38 (1 H, dt, J_t5.1, J_d13.8, H-

1¢), 3.47–3.71 (4 H, m, H-1¢, H-3¢, H-6), 3.82–3.97 (3 H, m, H-6,

CH₂OAr), 4.77 (1 H, s, H-4), 4.88 (1 H, t, J 5.3, H-6a), 5.04 (1 H,

d, J 6.3, H-3a), 6.83 (1 H, ddd, J 1.5, 2.4, 7.8, H-6¢¢), 7.04–7.09

(2 H, m, H-2¢¢, H-4¢¢), 7.13 (1 H, t, J 8.1, H-5¢¢), 7.30 (1 H, t, J

6.0, NH). d_C(75 MHz; CDCl₃, 25 ^◦C): 24.7, 26.7 (CH₃CCH₃),

25.5, 25.59, 25.62, 28.5, 28.9 (cyclohexyl CH₂), 37.6 (C-1¢), 41.3

(C-2¢), 42.0 (cyclohexyl CH), 52.7 (C-6), 60.1 (C-3¢), 65.4 (C-4),

67.3 (CH₂OAr), 79.6 (C-6a), 80.5 (C-3a), 111.9 (O-C-O), 113.4

(C-6¢¢), 117.7 (C-2¢¢), 122.7 (C-3¢¢), 123.9 (C-4¢¢), 130.5 (C-5¢¢),

159.4 (C-1¢¢), 170.9, 176.2 (C O). m/z (ESI+) 539.1769 (M +

H⁺). C₂₅H₃₆BrN₂O₆requires 539.1757.

General procedure for the deblocking of TBDMS protection to give

compounds 47–50

A solution of Ugi a_◦dducts 39, 40, 41 or 43 in CH₃CN (18–28 mM)

was cooled at -10 C and treated with 40% aqueous HF (50 mL

per mL of acetonitrile). The reactions were stirred at -10 ^◦C until

complete (1.5–2.5 h) and then quenched with 5% aq NaHCO₃

solution saturated with NaCl(s), and diluted with AcOEt. The

phases were separated and the organic phase dried, evaporated to

dryness and chromatographed (PE/AcOEt 8 : 2 to AcOEt/MeOH

95 : 5 depending on the speciﬁc compound) to give pure 47–50.

Compound 47a

Thick oil. Yield: 56%. R_f0.57 (AcOEt/MeOH 95 : 5). [a]_D-31.2 (c

1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13673, 3604, 3422, 2984, 1663,

◦

1589, 1506, 1420, 1190, 1049, 919. d_H(300 MHz; CDCl₃, 25 C)

(2 amide rotamers are visible, in a 91 : 9 ratio. Only the signals

of major rotamer are reported): 1.32 (3 H, s, (CH₃)₂C), 1.43 (3

H, s, (CH₃)₂C), 2.17 (1 H, septet, J 5.3, H-2¢), 3.35–3.47 (1 H,

m, H-1¢), 3.41 (3 H, s, OCH₃), 3.47–3.75 (4 H, m, H-1¢, H-6 and

H-3¢), 3.84 (1 H, d, J 12.3, H-6), 3.89 and 3.94 (2 H, AB part

of an ABX syst., J_AB9.3, J_AX7.2, J_BX5.9, CH₂OAr), 4.03 and

4.10 (2 H, AB syst., J 14.3, CH₂OCH₃), 4.78 (1 H, s, H-4), 4.89

(1 H, t, J 5.1, H-6a), 5.01 (1 H, d, J 6.0, H-3a), 6.83 (1 H, ddd,

J 1.2, 2.4, 7.9, H-6¢¢), 7.04–7.09 (2 H, m, H-2¢¢, H-4¢¢), 7.13 (1

H, t, J 7.9, H-5¢¢), 7.24 (1 H, broad t, J 6.3, NH). d_C(75 MHz;

CDCl₃, 25 ^◦C): 24.7, 26.8 (CH₃CCH₃), 37.8 (C-1¢), 41.2 (C-2¢),

52.0 (C-6), 59.1 (OCH₃), 60.3 (C-3¢), 65.9 (C-4), 67.2 (CH₂OAr),

71.4 (CH₂OCH₃), 79.7 (C-6a), 80.3 (C-3a), 112.1 (O-C-O), 113.4

(C-6¢¢), 117.7 (C-2¢¢), 122.8 (C-3¢¢), 124.0 (C-4¢¢), 130.6 (C-5¢¢),

159.4 (C-1¢¢), 169.3, 170.5 (C O). m/z (ESI+) 523.1076 (M +

Na⁺). C₂₁H₂₉BrN₂O₇Na requires 523.1056.

Compound 49a

Thick oil. Yield: 91%. R_f0.61 (AcOEt). [a]_D-51.8 (c 1, CHCl₃). IR:

n

_max(CHCl₃)/cm^-13672, 3599, 3424, 2971, 1663, 1621, 1589, 1562,

1516, 1465, 1413, 1222, 1041. d_H(300 MHz; d₆-DMSO, 25 ^◦C) (2

amide rotamers a and b are visible, in a 63 : 37 a : b ratio): 1.66 (a

+ b) (3 H, s, (CH₃)₂C), 1.79 (a), 1.81 (b) (3 H, s, (CH₃)₂C), 2.41

(b) (1 H, septet, J 5.8, H-2¢), 2.51 (a) (1 H, septet, J 5.9, H-2¢),

3.52–4.00 (5 H, m, 2 H-1¢, 2 H-3¢, H-6), 3.75–4.00 (3 H, m, 1 H-6,

CH₂OAr), 4.60–4.85 (3 H, m, H-4, H-6a, H-3a), 6.88–7.00 (1 H,

m, H-6¢¢), 7.07–7.30 (3 H, m), 7.35–7.52 (2 H, m), 7.60–7.75 (2

◦

H, m). d_C(75 MHz; d₆-DMSO, 25 C): 24.5 (b), 24.6 (a), 26.57

(b), 26.61 (a) (CH₃CCH₃), 37.6 (b), 37.7 (a) (C-1¢), 41.0 (b), 41.3

(a) (C-2¢), 51.6 (b), 54.8 (a) (C-6), 61.4 (C-3¢), 65.9 (a), 68.7 (b)

(C-4), 66.7 (a+b) (CH₂OAr), 78.0 (b), 79.9 (a) (C-6a), 82.2 (a),

83.8 (b) (C-3a), 111.0 (b), 111.1 (a) (O–C–O), 113.91 (a), 113.95

(b) (C-6¢¢), 117.2 (b), 117.3 (a) (C-2¢¢), 121.6 (a), 121.7 (b), 122.1

(a + b) (C-3¢¢ and C-Br), 123.3 (a + b) (CH ortho to Br), 125.3 (b),

126.2 (a) (C-4¢¢), 128.9 (b), 129.8 (a) (C-5¢¢), 130.7 (a), 130.8 (b),

131.1 (a + b), (CH para to Br, CH meta to Br, and CH meta to Br

and C O), 132.7 (b), 133.0 (a) (C para to C O), 137.6 (a), 138.2

(b) (C-C O), 159.7 (a + b) (C-1¢¢), 167.7 (a), 168.2 (b), 168.5 (b),

168.6 (C O). m/z (ESI+) 611.0377 (M + H⁺). C₂₅H₂₉Br₂N₂O₆

requires 611.0392.

Compound 48a

Thick oil. Yield: 94%. R_f0.36 (PE/AcOEt 70 : 30). [a]_D-30.1 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13652, 3430, 3005, 2933, 2854,

1658, 1624, 1589, 1430, 1372, 1278, 1239, 1192, 1155, 1045, 992,

975. d_H(300 MHz; CDCl₃, 25 ^◦C) (2 amide rotamers are visible,

in a 90 : 10 ratio. Only the signals of major rotamer are reported):

1.13–1.30 (2 H, m), 1.33 (3 H, s, (CH₃)₂C), 1.41 (3 H, s, (CH₃)₂C),

1.43–1.56 (2 H, m), 1.57–1.88 (6 H, m), 2.17 (1 H, broad septet,

H-2¢), 2.35 (1 H, tt, J 3.3, 11.4, CHC O), 3.30–3.73 (5 H, m,

H-1¢, H-3¢, H-6), 3.82–3.95 (3 H, m, H-6, CH₂OAr), 4.77 (1 H, s,

H-4), 4.87 (1 H, t, J 5.1, H-6a), 5.09 (1 H, d, J 6.0, H-3a), 6.84

(1 H, ddd, J 1.5, 2.4, 7.8, H-6¢¢), 7.04–7.09 (2 H, m, H-2¢¢, H-4¢¢),

7.13 (1 H, t, J 8.1, H-5¢¢), 7.22 (1 H, t, J 6.0, NH). d_C(75 MHz;

CDCl₃, 25 ^◦C): 24.8, 26.7 (CH₃CCH₃), 25.5, 25.6, 25.7, 28.6, 29.0

(cyclohexyl CH₂), 37.5 (C-1¢), 41.2 (C-2¢), 42.0 (cyclohexyl CH),

Compound 49c

Thick oil. Yield: 95%. R_f0.61 (AcOEt). [a]_D+53.2 (c 1, CHCl₃).

-1

IR: n_max(CHCl₃)_/cm3672, 3601, 3430, 2966, 2927, 1660, 1622,

1589, 1513, 1428, 1374, 1191, 1043. d_H(300 MHz; CDCl₃, 25 ^◦C)

(2 amide rotamers are visible, in a 91 : 9 ratio. Only the signals of

major rotamer are reported): 1.33 (3 H, s, (CH₃)₂C), 1.47 (3 H, s,

(CH₃)₂C), 2.17 (1 H, broad septet, J 5.8, H-2¢), 3.32–3.74 (5 H, m,

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2 H-1¢, 1 H-6, H-3¢), 3.82 (1 H, d, J 12.6, H-6), 3.90 and 3.97 (2

H, AB part of an ABX syst., J_AB9.3, J_AX6.9, J_BX6.0, CH₂OAr),

4.80 (1 H, dd, J 4.1, 5.9, H-6a), 4.96 (1 H, s, H-4), 5.13 (1 H,

d, J 5.9, H-3a), 6.82 (1 H, ddd, J 1.5, 2.4, 7.7, H-6¢¢), 7.03–7.16

(3 H, m, H-2¢¢, H-4¢¢, H-5¢¢), 7.29 (1 H, t, J 7.6, H meta to Br),

7.22 (1 H, broad t, NH), 7.37 (1 H, dt, J_t1.3, J_d7.8, H para to

Br), 7.60 (1 H, ddd, J 1.2, 1.8, 7.8, H para to C O), 7.64 (1 H,

(C O). m/z (ESI+) 634.1751 (M + H⁺). C₂₉H₃₇BrN₃O₈requires

634.1764.

General procedure for the deblocking of cyclic acetal to give

compounds 38a and 51–54

The Ugi adducts 36a or 39–41 or 43 (150 mmol) were dis-

solved in THF (1.5 mL) and water (750 mL) and treated with

CF₃COOH (750 mL). The reactions were stirred at r.t. until

complete by TLC (21–144 h). Then the crudes were diluted with

benzene/EtOH/CH₂Cl₂, evaporated in order to remove H₂O and

ﬁnally chromatographed (typically with AcOEt/MeOH 95 : 5 to

8 : 2) to give pure products 38a or 51–54.

◦

t, J 1.5, H ortho to Br and C O). d_C(75 MHz; CDCl₃, 25 C):

24.7, 26.7 (CH₃CCH₃), 38.1 (C-1¢), 41.1 (C-2¢), 54.8 (C-6), 60.5

(C-3¢), 66.0 (C-4), 67.3 (CH₂OAr), 79.5 (C-6a), 81.1 (C-3a), 112.1

(O-C-O), 113.3 (C-6¢¢), 117.7 (C-2¢¢), 122.6, 122.7 (C-3¢¢ and quat.

bromobenzoic group), 124.0 (C-4¢¢), 125.8 (C para to Br), 130.1

(CH meta to Br), 130.3, 130.5 (C-5¢¢ and C meta to Br and C O),

133.7 (C para to C O), 136.6 (quat. bromobenzoic group), 159.3

(C-1¢¢), 169.1, 170.1 (C O). m/z (ESI+) 611.0384 (M + H⁺).

C₂₅H₂₉Br₂N₂O₆requires 611.0392.

Compound 38a

White foam. Yield: 99%. R_f0.37 (AcOEt/MeOH 90 : 10). [a]_D

+13.3 (c 0.84, CHCl₃). d_H(300 MHz; d₆-DMSO, 30 ^◦C) (2 amide

rotamers a and b are visible, in a 71 : 29 ratio): 0.88 (b) (0.87 H, t,

J 7.4, CH₃CH₂) 0.98 (a) (2.13 H, t, J 7.5, CH₃CH₂), 1.85 (b) (0.29

H, dq, J_d16.2, J_q7.5, CHHCH₃), 2.10 (b) (0.29 H, dq, J_d16.2, J_q

7.5, CHHCH₃), 2.26 (a) (1.42 H, q, J 7.5, CHHCH₃), 3.25–3.37

(a + b) (1 H, m, H-6), 3.47 (b) (0.29 H, dd, J 5.9, 11.6, H-6), 3.69

(a) (0.71 H, dd, J 6.6, 9.6, H-6), 3.91 (a) (0.71 H, q, J 2.7, H-3a),

3.99 (b) (0.29 H, q, J 4.4, H-3a), 4.04 (b) (0.29 H, t, J 5.4, H-6a),

4.07–4.17 (1.71 H, m, H-4 (a + b), H-6a (a)), 4.21–4.37 (a + b) (2

H, m, CH₂Ph), 4.99 (b) (0.29 H, d, J 4.8, OH), 5.07 (a) (0.71 H,

d, J 5.7, OH), 5.20 (a) (0.71 H, d, J 4.8, OH), 5.32 (b) (0.29 H, d,

J 4.8, OH), 7.17–7.37 (5 H, m, aromatics), 8.41 (a) (0.71 H, t, J

6.0, NH), 8.78 (b) (0.29 H, t, J 6.0, NH). d_C(75 MHz; d₆-DMSO,

30 ^◦C): 8.6 (a), 8.7 (b) (CH₃CH₂), 25.8 (b), 26.4 (a) (CH₂CH₃),

41.7 (a), 42.2 (b) (CH₂Ph), 50.10 (a), 50.14 (b) (C-6), 66.1 (b), 66.2

(a), 68.6 (b), 69.8 (a) (C-4, C-6a), 73.8 (a), 75.9 (b) (C-3a), 126.4

(a + b), 126.7 (a) (¥2), 127.2 (b) (¥2), 128.0 (a) (¥2), 128.1 (b) (¥2)

(aromatic CH), 139.1 (b), 139.4 (a) (aromatic quat.), 169.8 (a),

170.1 (b), 171.9 (a+b) (C O). m/z (ESI+) 315.1313 (M + Na⁺).

C₁₅H₂₀N₂O₄Na requires 315.1321.

Compound 50a

Thick oil. Yield: 100%. R_f0.23 (PE/AcOEt 50 : 50). [a]_D-16.2 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13683, 3424, 2995, 2935, 2868,

1721, 1660, 1590, 1506, 1429, 1372, 1243, 1148, 1126, 1055. d_H

(300 MHz; CDCl₃, 50 ^◦C) (2 amide rotamers are visible, in a 94 : 6

ratio. Only the signals of major rotamer are reported): 1.31 (3 H,

s, (CH₃)₂C), 1.41 (3 H, s, (CH₃)₂C), 2.15 (1 H, broad septet, H-

2¢), 2.40–2.68 (2 H, m, CH₂CH₂NHZ), 3.30–3.70 (4 H, m, H-1¢,

CH₂NHZ, 1 H-6, H-3¢), 3.75 (1 H, d, J 12.3, H-6), 3.79–3.95 (2

H, m, CH₂OAr), 4.73 (1 H, s, H-4), 4.84 (1 H, t, J 4.8, H-6a),

4.96 (1 H, d, J 6.0, H-3a), 5.07 (2 H, s, CH₂Ph), 5.54 (1 H, broad

peak, ZNH), 6.78–6.90 (2 H, m, H-6¢¢), 7.00–7.20 (4 H, m, H-2¢¢,

H-4¢¢, H-5¢¢, NH), 7.30–7.40 (5 H, m, CH of Ph). d_C(75 MHz;

CDCl₃, 25 ^◦C): 24.6, 26.7 (CH₃CCH₃), 34.3 (CH₂CH₂NHZ), 36.6

(CH₂NHZ), 38.1 (C-1¢), 40.9 (C-2¢), 52.9 (C-6), 60.7 (C-3¢), 65.8

(C-4), 66.7 (CH₂Ph), 67.2 (CH₂OAr), 79.4 (C-6a), 81.0 (C-3a),

112.1 (O-C-O), 113.4 (C-6¢¢), 117.8 (C-2¢¢), 122.7 (C-3¢¢), 124.1 (C-

4¢¢), 127.9 (¥3), 128.5 (¥2) (CH benzyl), 130.5 (C-5¢¢), 136.3 (quat.

benzyl), 159.3 (C-1¢¢), 156.4, 170.4, 171.5 (C O). m/z (ESI+)

634.1746 (M + H⁺). C₂₉H₃₇BrN₃O₈requires 634.1764.

Compound 51a

Compound 50c

Thick oil. Yield: 59%. R_f0.34 (CH₂Cl₂/EtOH 80 : 20). [a]_D-15.9

(c 1.0, CHCl₃). d_H(300 MHz; d₆-DMSO, 25 ^◦C) (2 amide rotamers

a and b are visible, in a 77 : 23 ratio): 2.05 (a + b) (1 H, septet, J

5.7, H-2¢), 3.15–3.30 (a + b) (3 H, m, 2 H-1¢ + H-6), 3.19 (b) (0.69

H, s, OCH₃), 3.27 (a) (2.31 H, s, OCH₃), 3.48 (a + b) (2 H, q, J

5.1, H-3¢), 3.56–3.66 (a + b) (1 H, m, H-6), 3.83–4.15 (a + b) (7

H, m, CH₂Ar, CH₂OMe, H-4, H-3a, H-6a), 4.59 (a) (0.77 H, t,

J 5.4, OH), 4.66 (b) (0.23 H, t, J 5.3, OH), 5.04 (b) (0.23 H, d,

J 5.1, OH), 5.10 (a) (0.77 H, d, J 5.4, OH), 5.24 (a) (0.77 H, d,

J 5.1, OH), 5.34 (b) (0.23 H, d, J 5.4, OH), 6.92–6.98 (a + b) (1

H, m, H-4¢¢), 7.07–7.15 (a + b) (2 H, m, H-2¢¢ and H-6¢), 7.20–

7.28 (a + b) (1 H, m, H-5¢), 8.08 (a) (0.77 H, t, J 6.0, N_◦H), 8.24

(b) (0.23 H, t, J 5.7, NH). d_C(75 MHz; d₆-DMSO, 25 C; only

the signals of major rotamer are shown): 37.3 (C-1¢), 41.1 (C-2¢),

49.3 (C-6), 58.2 (OCH₃), 59.1 (C-3¢), 66.4 (C-4), 66.4 (CH₂OAr),

70.0 (C-6a), 71.4 (CH₂OCH₃), 73.5 (C-3a), 114.0 (C-6¢¢), 117.2 (C-

2¢¢), 122.0 (C-3¢¢), 123.2 (C-4¢¢), 131.1 (C-5¢¢), 159.7 (C-1¢¢), 168.0,

169.9 (C O). m/z (ESI+) 483.0745 (M + Na⁺). C₁₈H₂₅BrN₂O₇Na

requires 483.0743.

Thick oil. Yield: 100%. R_f0.23 (PE/AcOEt 50 : 50). [a]_D+34.1 (c

1, CHCl₃). IR: n_max(CHCl₃)/cm^-13670, 3599, 3434, 2968, 1711,

1658, 1589, 1502, 1436, 1375, 1190, 1042. d_H(300 MHz; CDCl₃,

◦

25 C) (2 amide rotamers are visible, in a 89 : 11 ratio. Only the

signals of major rotamer are reported): 1.30 (3 H, s, (CH₃)₂C), 1.40

(3 H, s, (CH₃)₂C), 2.12 (1 H, broad septet, J 5.4, H-2¢), 2.38–2.66 (2

H, m, CH₂CH₂NHZ), 3.30–3.70 (4 H, m, H-1¢, CH₂NHZ, 1 H-6,

H-3¢), 3.75 (1 H, d, J 12.0, H-6), 3.79–3.95 (2 H, m, CH₂OAr),

4.72 (1 H, s, H-4), 4.82 (1 H, t, J 5.1, H-6a), 4.95 (1 H, d, J 5.7,

H-3a), 5.07 (2 H, s, CH₂Ph), 5.61 (1 H, t, J 6.0, ZNH), 6.78–

6.90 (2 H, m, H-6¢¢), 7.00–7.09 (2 H, m, H-2¢¢, H-4¢¢), 7.12 (1

H, t, J 7.8, H-5¢¢), 7.21 (1 H, t, J 5.8, NH), 7.30–7.40 (5 H, m,

CH of Ph). d_C(75 MHz; CDCl₃, 25 ^◦C): 24.6, 26.7 (CH₃CCH₃),

34.3 (CH₂CH₂NHZ), 36.6 (CH₂NHZ), 38.0 (C-1¢), 41.0 (C-2¢),

53.0 (C-6), 60.5 (C-3¢), 65.9 (C-4), 66.6 (CH₂Ph), 67.2 (CH₂OAr),

79.3 (C-6a), 81.1 (C-3a), 112.1 (O–C–O), 113.3 (C-6¢¢), 117.6 (C-

2¢¢), 122.7 (C-3¢¢), 123.9 (C-4¢¢), 128.1 (¥3), 128.4 (¥2) (CH benzyl),

130.5 (C-5¢¢), 136.3 (quat. benzyl), 159.3 (C-1¢¢), 156.4, 170.4, 171.5

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Compound 51c

H-4¢¢), 7.03–7.32 (a + b) (4 H, m, H-2¢¢, H-6¢¢, H-5¢¢, H meta to

Br), 7.37–7.47 (a + b) (1 H, m, H para to Br), 7.49–7.57 (a + b) (1

H, m, H para to C O), 7.69 (a) (0.75 H, t, J 1.5, H ortho to Br and

Thick oil. Yield: 61%. R_f0.34 (CH₂Cl₂/EtOH 80 : 20). [a]_D-9.35

(c 2.0, CHCl₃). d_H(300 MHz; d₆-DMSO, 25 ^◦C) (2 amide rotamers

a and b are visible, in a 77 : 23 ratio): 2.03 (a + b) (1 H, septet,

J 6.0, H-2¢), 3.15–3.30 (a + b) (3 H, m, 2 H-1¢ + H-6), 3.20 (b)

(0.69 H, s, OCH₃), 3.28 (a) (2.31 H, s, OCH₃), 3.35–3.43 (a + b)

(2 H, m, H-3¢), 3.56–3.66 (a + b) (1 H, m, H-6), 3.83–4.17 (a +

b) (7 H, m, CH₂Ar, CH₂OMe, H-4, H-3a, H-6a), 4.35–4.80 (1 H,

broad peak, OH), 4.90–5.50 (2 H, broad peak, OH), 6.92–6.98 (a

+ b) (1 H, m, H-4¢¢), 7.07–7.15 (a + b) (2 H, m, H-2¢¢ and H-6¢),

7.23 (b) (0.23 H, t, J 8.6, H-5¢), 7.24 (a) (0.77 H, t, J 8.9, H-5¢),

8.07 (a) (0.77 H, t, J 5.8, NH), 8.26 (b) (0.23 H, t, J 5.7, NH).

d_C(75 MHz; d₆-DMSO, 25 ^◦C; only the signals of major rotamer

are shown): 37.2 (C-1¢), 41.1 (C-2¢), 49.3 (C-6), 58.2 (OCH₃), 59.0

(C-3¢), 66.0 (C-4), 66.6 (CH₂OAr), 70.0 (C-6a), 70.2 (CH₂OCH₃),

73.5 (C-3a), 113.9 (C-6¢¢), 117.3 (C-2¢¢), 122.0 (C-3¢¢), 123.2 (C-

4¢¢), 131.1 (C-5¢¢), 159.7 (C-1¢¢), 168.0, 169.9 (C O). m/z (ESI+)

461.0917 (M + H⁺). C₁₈H₂₆BrN₂O₇requires 461.0923.

C

O), 7.71 (b) (0.25 H, t, J 1.5, H ortho to Br and C O), 8.06 (b)

(0.25 H, t, J 5.8, NH), 8.16 (a) (0.75 H, t, J 5.6, NH). d_C(75 MHz;

d₆-DMSO, 25 ^◦C; only the signals of major rotamer are shown):

37.3 (C-1¢), 41.2 (C-2¢), 54.0 (C-6), 59.2 (C-3¢), 65.6 (C-4), 66.4

(CH₂OAr), 70.1 (C-6a), 74.5 (C-3a), 114.0 (C-6¢¢), 117.2 (C-2¢¢),

121.5, 122.0 (C-3¢¢ and C-Br), 123.2 (C-4¢¢), 126.3 (CH ortho to

Br), 129.9, 130.5, 131.0, 131.1 (C-5¢¢, CH para to Br, CH meta

to Br, and CH meta to Br and C O), 132.9 (C para to C O),

137.9 (C-C O), 159.7 (C-1¢¢), 167.3, 170.2 (C O). m/z (ESI+)

571.0074 (M + H⁺). C₂₂H₂₅Br₂N₂O₆requires 571.0079.

Compound 54a

Thick oil. Yield: 100%. R_f0.46 (AcOEt/MeOH 80 : 20). [a]_D

-12.9 (c 1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13673, 3598, 3400

(broad), 2999, 2881, 1671, 1589, 1511, 1435, 1191, 1135, 1028.

◦

d_H(300 MHz; d₆-DMSO, 25 C) (2 amide rotamers a and b are

Compound 52a

visible, in a 77 : 23 ratio): 1.95–2.15 (a + b) (1 H, m, H-2¢), 2.24–

2.48 (a + b) (2 H, m, CH₂CH₂NH), 3.10–3.33 (a + b) (5.23 H, m,

2 H-1¢, 1 H-6 (a), 2 H-6 (b), CH₂NHZ), 3.47 (a + b) (2 H, t, J

5.3, H-3¢), 3.65 (a) (1 H, dd, J 6.3, 9.6, H-6), 3.83–4.15 (5 H, m,

H-6 (b), CH₂OAr (a + b), H-3a (a + b), H-6a (a + b), H-4), 4.61

(a) (0.77 H, t, J 5.3, OH), 4.65 (b) (0.23 H, t, J 5.3, OH), 4.98

(b) (0.46 H, s, CH₂Ph), 5.01 (a) (1.54 H, s, CH₂Ph), 5.05 (b) (0.23

H, d, J 5.1, OH), 5.11 (a) (0.77 H, d, J 5.7, OH), 5.26 (a) (0.77

H, d, J 5.1, OH), 5.36 (b) (0.23 H, d, J 5.1, OH), 6.81 (b) (0.23

H, broad s, NH), 6.92–6.98 (a + b) (1 H, m, H-4¢¢), 7.05–7.18 (a

+ b) (2 H, m, H-2¢¢, H-6¢¢), 7.19 (b) (0.23 H, t, J 8.3, H-5¢), 7.24

(a) (0.77 H, t, J 8.3, H-5¢), 7.28–7.41 (5.77 H, m, H of benzyl (a

+ b), NH (a)), 8.05 (a) (0.77 H, t, J 6.0, NH), 8.32 (b) (0.23 H,

t, J 5.8, NH). d_C(75 MHz; d₆-DMSO, 25 ^◦C; only the signals of

major rotamer are shown): 33.6 (CH₂CO), 36.4 (CH₂NHZ), 37.4

(C-1¢), 41.1 (C-2¢), 50.4 (C-6), 59.2 (C-3¢), 65.2 (PhCH₂), 66.0 (C-

4), 66.5 (CH₂OAr), 69.9 (C-6a), 70.4 (C-3a), 113.9 (C-6¢¢), 117.3

(C-2¢¢), 122.0 (C-3¢¢), 123.2 (C-4¢¢), 127.7 (¥3), 128.3 (CH benzyl),

131.1 (C-5¢¢), 137.1 (quat. benzyl), 156.0 (C O urethane), 159.7

(C-1¢¢), 169.6, 170.1 (C O). m/z (ESI+) 616.1251 (M + Na⁺).

C₂₆H₃₂BrN₃O₈Na requires 616.1270.

Thick oil. Yield: 88%. R_f0.37 (AcOEt/MeOH 90 : 10). [a]_D-158.8

(c 1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13669, 3597, 3418, 3003,

2928, 1667, 1590, 1516, 1418, 1180, 1139, 1026. d_H(300 MHz;

d₆-DMSO, 25 ^◦C) (2 amide rotamers a and b are visible, in a

70 : 30 ratio): 1.13–1.30 (2 H, m), 1.43–1.56 (2 H, m), 1.57–1.88

(6 H, m), 2.03 (1 H, broad signal, H-2¢), 2.35 (1 H, broad signal,

CHC O), 3.10–3.35 (a + b) (3 H, m, 2 H-1¢ + H-6), 3.35–3.43 (3

H, m, H-3¢ (a + b), H-6 (b)), 3.72 (a) (0.7 H, dd, J 6.0, 9.9, H-6),

3.83–4.15 (a + b) (4 H, m, CH₂Ar, H-3a, H-6a), 3.98 (a) (0.7 H,

d, J 3.3, H-4), 4.16 (b) (0.3 H, d, J 3.3, H-4), 4.60 (a) (0.70 H, t,

J 5.3, OH), 4.68 (b) (0.3 H, t, J 5.3, OH), 5.01 (b) (0.3 H, d, J

5.1, OH), 5.07 (a) (0.7 H, d, J 5.4, OH), 5.22 (a) (0.7 H, d, J 5.1,

OH), 5.34 (b) (0.3 H, d, J 5.1, OH), 6.92–6.98 (a + b) (1 H, m,

H-4¢¢), 7.06–7.15 (a + b) (2 H, m, H-2¢¢ and H-6¢), 7.19–7.28 (a+b)

(1 H, m, H-5¢), 7.93 (a) (0.7 H, t, J 5.8, NH), 8.41 (b) (0.3 H, t,

◦

J 5.6, NH). d_C(75 MHz; d6-DMSO, 25 C; only the signals of

major rotamer are shown): 25.1 (¥2), 25.5, 28.4, 28.5 (cyclohexyl

CH₂), 37.3 (C-1¢), 41.1 (C-2¢), 41.2 (CH cyclohexyl), 50.5 (C-6),

59.3 (C-3¢), 65.9 (C-4), 66.3 (CH₂OAr), 70.0 (C-6a), 73.9 (C-3a),

114.1 (C-6¢¢), 117.2 (C-2¢¢), 122.0 (C-3¢¢), 123.2 (C-4¢¢), 131.1 (C-

5¢¢), 159.8 (C-1¢¢), 170.4, 174.1 (C O). m/z (ESI+) 521.1245 (M

+ Na⁺). C₂₂H₃₁BrN₂O₆Na requires 521.1263.

Ester 55a

A solution of alcohol 47a (29.5 mg, 59.8 mmol) in acetone (1.5 mL),

cooled to 0 ^◦C, was treated slowly with Jones reagent (80 ml). After

1.2 h the reaction was quenched with 1 M KH₂PO₄, diluted with

CH₂Cl₂/MeOH 9 : 1 and extracted. The organic layer was then

washed with brine containing some 10% Na₂SO₃. The residue was

taken up in THF (1 mL), cooled to 0 ^◦C, and treated dropwise with

a freshly prepared ethereal CH₂N₂solution until the yellow colour

persisted. The mixture was treated with AcOH (50 mL) and then

evaporated to dryness. The crude was ﬁnally puriﬁed through a

preparative TLC eluted with AcOEt to obtain a colourless oil

(17.4 mg, 57%). R_f0.49 (AcOEt). [a]_D-81.4 (c 0.5, CHCl₃).

IR: n_max(CHCl₃)/cm^-13671, 3604, 3447, 2962, 2886, 1735, 1672,

1588, 1505, 1420, 1188, 1028. d_H(300 MHz; CDCl₃, 25 ^◦C) (2

amide rotamers are visible, in a 89 : 11 ratio. Only the signals of

major rotamer are reported): 1.32 (3 H, s, (CH₃)₂C), 1.42 (3 H, s,

Compound 53a

Thick oil. Yield: 93%. R_f0.37 (AcOEt/MeOH 90 : 10). [a]_D-32.3

(c 1.0, CHCl₃). IR: n_max(CHCl₃)/cm^-13671, 3598, 3402, 2998,

1663, 1589, 1527, 1466, 1416, 1207, 1168, 1024. d_H(300 MHz;

d₆-DMSO, 25 ^◦C)(2 amide rotamers a and b are visible, in a 75 : 25

ratio): 1.79 (b) (0.25 H, septet, J 5.8, H-2¢), 2.07 (a) (0.75 H, septet,

J 6.0, H-2¢), 2.88–3.09 (b) (0.5 H, m, H-1¢), 3.15–3.35 (2.5 H, m,

2 H-1¢ (a) + 1 H-6 (a + b)), 3.38–3.55 (2 H, m, H-3¢), 3.58–3.85

(a + b) (1.5 H, m, H-6 (a + b), CH₂OAr (b)), 3.85–4.20 (3.5 H,

m, CH₂OAr (a), H-3a (a + b), H-6a (a + b)), 4.16 (a) (0.75 H, d,

J 5.1, H-4), 4.49 (b) (0.25 H, d, J 5.7, H-4), 4.55 (b) (0.25 H, t, J

5.3, OH), 4.62 (a) (0.75 H, t, J 5.3, OH), 5.09 (a) (0.75 H, d, J 4.8,

OH), 5.15 (b) (0.25 H, d, J 5.4, OH), 5.35 (a) (0.75 H, d, J 5.1,

OH), 5.38 (b) (0.25 H, d, J 5.1, OH), 6.92–6.98 (a + b) (1 H, m,

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(CH₃)₂C), 2.17 (1 H, dq, J_q5.7, J_d6.8, H-2¢), 3.42 (3 H, s, OCH₃),

3.50–3.62 (1 H, m, 1 H-1¢ + 1 H-6), 3.65–3.78 (1 H, m, H-1¢), 3.73

(3 H, s, OCH₃), 3.85 (1 H, d, J 12.3, H-6), 4.05 and 4.12 (2 H, AB

syst., J 14.3, CH₂OCH₃), 4.11 and 4.15 (2 H, AB part of an ABX

syst., J_AB9.5, J_AX2.7, J_BX2.6, CH₂OAr), 4.77 (1 H, s, H-4), 4.85

(1 H, t, J 5.3, H-6a), 5.05 (1 H, d, J 6.0, H-3a), 6.84 (1 H, ddd, J

1.5, 2.4, 7.5, H-6¢¢), 6.97–7.17 (4 H, m, H-2¢¢, H-4¢¢, H-5¢, NH).

d_C(75 MHz; CDCl₃, 25 ^◦C) (only the signals of major rotamer are

reported): 24.7, 26.7 (CH₃CCH₃), 37.8 (C-1¢), 44.9 (C-2¢), 51.2,

(C-6), 52.4 (OCH₃), 59.1 (OCH₃), 65.5 (C-4), 66.3 (CH₂OAr),

71.6 (CH₂OCH₃), 79.7 (C-6a), 79.9 (C-3a), 111.9 (O-C-O), 113.6

(C-6¢¢), 118.0 (C-2¢¢), 122.8 (C-3¢¢), 124.4 (C-4¢¢), 130.6 (C-5¢¢),

159.0 (C-1¢¢), 169.0, 169.4, 171.8 (C O). m/z (ESI+) 551.1019

(M + Na⁺). C₂₂H₂₉BrN₂O₈Na requires 551.1005.

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Acknowledgements

The authors thank Mr.s Luca Soattin, Alessio Pasqualino and

Francesco Maugeri for their contribution to this work, MIUR

(PRIN 2006, PRIN 2009) for ﬁnancial assistance, Fondazione S.

Paolo for a contribution to the purchase of NMR instrument, and

Amano-Mitsubishi for the kind gift of enzymes.

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1274 | Org. Biomol. Chem., 2012, 10, 1255–1274

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Article Doi

Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction

DOI: 10.1039/c1ob06632c

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