O-Protecting groups as long-range stereocontrolling elements in the addition of acetylides to 4-substituted quinolines

TETRAHEDRON:

ASYMMETRY

Pergamon

Tetrahedron: Asymmetry 13 (2002) 2703–2706

O-Protecting groups as long-range stereocontrolling elements in

the addition of acetylides to 4-substituted quinolines

Giuseppe Guanti,* Sara Perrozzi and Renata Riva*

Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, I-16146 Genova, Italy

Received 17 October 2002; accepted 25 October 2002

Abstract—Addition of magnesium acetylides in the presence of chloroformate esters to racemic differently O-protected 2-(4-

quinolyl)propanols and to enantiopure 2-(4-quinolyl)-1,3-dialkoxypropanes, prepared by a chemoenzymatic route, gives almost

exclusive regioselective attack at C-2, with stereoselectivities from moderate to good, depending mainly on the bulkiness of the

1. Introduction

both triple bonds. Because we envisaged the employ-

ment of the appropriate 4-substituted quinolines as the

ﬁrst stage of the synthesis, we had to study the regio-

and diastereoselective functionalization of the parent

heterocycle, starting from compounds of general for-

mula 5 and 6, as summarized in Scheme 1. Preliminary

results in this ﬁeld have already been reported on

racemic compounds 5.¹⁷Herein, we report more details

on diastereoselective additions to 5 and extend our

study to optically active 6.

The quinoline nucleus, and also its hydrogenated form

are fragments frequently found in many natural prod-

ucts.^1–3Moreover, many quinoline derivatives are

known for their interesting biological properties, such

as antimalarial activity,^4,5antagonist activity with

respect to neurokinin-3,⁶glucagon⁷or cannabinoid⁵

receptors, antiprotozoal⁸and antitumor^9,10activity.

Dynemicin A, a recently discovered¹¹enediyne, con-

taining a quinoline derivative, has attracted the atten-

tion of many research groups for its notable

cytotoxicity and novel mode of action. Some syntheses

of this compound have also been reported.^12–14How-

ever, its complex structure and low stability has

prompted many research groups to design simpliﬁed

analogues, which still have their biological activity pro-

moted by the presence of the enediyne moiety.¹⁵In the

last years our group has been involved in the prepara-

tion of new artiﬁcial enediynes.¹⁶Among them, we

aimed to synthesize a new family of analogues of

natural Dynemicin A, namely compounds 1a,b, and the

corresponding hydroxymethyl derivatives 2a,b.

In our strategy we planned to assemble the 10-mem-

bered enediyne ring, starting from highly functionalized

quinoline-derived intermediates 3 and 4, provided with

* Corresponding authors. Tel./fax: +390103536105 (G.G.); tel.:

+390103536126; fax: +390103536118 (R.R.); e-mail: guanti@

chimica.unige.it; riva@chimica.unige.it

Scheme 1.

PII: S0957-4166(02)00711-5

2704

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2. Results and discussion

ously reported.²¹This compound was then protected

varying the groups at the two oxygenated functionali-

ties. For this purpose we planned to introduce two

O-protecting groups with orthogonal properties, having

in mind to manipulate them at different times after the

addition reaction. As previously experienced with ( )-

5a, we succeeded with the introduction of only a limited

number of protecting groups: triphenylmethyl ether and

their analogues, silyl ethers, anisyl ether, esters (Scheme

3). Protecting groups requiring the formation of the

alcoholate of 6a could not be introduced. Acetal pro-

tecting groups were the most troublesome: while the

methoxymethyl ether could be prepared in moderate

yield (40%) but with poorly reproducible results; we did

not succeed, for example, in the introduction of the

very versatile tetrahydropyranyl ether.

2.1. Preparation of quinolines ( )-5 and 6 and addition

of acetylides to the heterocyclic ring

For the preparation of ( )-5a, 4-ethylquinoline,

obtained through a Skraup-like reaction (Scheme

2),^18,19was heated under reﬂux in aqueous formalde-

hyde, following the same procedure employed for the

preparation of 1,3-propanediols with 2- or 4-pyridyl²⁰

or quinolyl²¹substituents at C-2. In this case, however,

a complex mixture of hemiacetal compounds of formal-

dehyde was formed. The mixture is best hydrolyzed

under basic conditions, which afford the desired ( )-5a

in high yield.

Several O-protected derivatives of ( )-5a, with different

properties, have been prepared in satisfactory to excel-

lent yields, following standard procedures, as reported

in Scheme 2.²²We also tried to introduce other protect-

ing groups into ( )-5a, with the groups differing not

only in their steric hindrance properties, but also in

their ability to give chelation in reactions involving

organometallic intermediates. Actually, in some cases

this is a great opportunity for controlling diastereose-

lectivity.²³However, all attempts to transform ( )-5a

into a series of common ethers characterized by chelat-

This was quite puzzling, since it prevented the study of

the addition reaction on a system bearing at the same

time a chelating and a ‘non-chelating’ group,²³a condi-

tion that should inﬂuence the diastereoselectivity during

the nucleophilic attack.

Having in hand a certain number of O-protected quino-

lines 5 and 6, we started our studies on the regio- and

diastereoselective addition of C-nucleophiles. The

propensity of quinolines, pyridines and isoquinolines to

undergo nucleophilic addition at C-2 and/or C-4 is well

known, and has received increased attention after the

discovery of Dynemicin A. For the synthesis of sim-

pliﬁed analogues of Dynemicin A, the functionalization

of the quinoline nucleus by means of C-nucleophiles is

ing

properties,

like

benzyl,

4-methoxybenzyl,

methoxymethyl (MOM), methoxyethoxyethyl (MEM)

or 2,4-dinitrophenyl ether, employing different condi-

tions,²²failed. We observed unexpectedly low reactivity

of ( )-5a and, in every case, the desired products could

not be isolated since the starting alcohol usually did not

react, while forcing reaction conditions only led to

decomposition of the substrate.

a

milestone either when performed on achiral

derivatives^24–28or partially rigid quinolines fused with

other rings and bearing at least two stereocenters.^29–31

The asymmetric synthesis of 1,2- and 1,4-dihydroquino-

lines by nucleophilic addition to a chiral aminal (with

C₂-symmetry) of quinoline-3-carbaldehyde is also

known.³²To the best of our knowledge only one exam-

ple is known in which the reaction is performed on a

quinoline with just one stereocenter.³³In order to pre-

pare the precursors of 1a,b and 2a,b it is important to

fully understand the regio- and stereochemical course of

the addition on such a conformationally ﬂexible

The optically active quinolines 6b–g were synthesized

starting from monoacetate 6a, which could be prepared

in very high chemical yield, with enantiomeric excess up

to 97.5% by asymmetrization of the corresponding diol

catalyzed by lipase from Candida antarctica, as previ-

Scheme 2.

Scheme 3.

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2705

nucleophilic attack occurring only on C-2 (with the

exception of entry 6 in which cerous acetylide also gave

a small additional amount of attack on C-4). Changing

the order of addition of the reagents, the reaction

temperature, or the counterion of the acetylide affected

only the yields, while the observed d.r. were not inﬂu-

enced in an appreciable manner. One exception was

seen with lithium acetylide, which gave a complex

reaction mixture, the addition products being present

only in negligible amounts. The screening was per-

formed on 100 mg of ( )-5b using 3 molar equiv. of a

0.5 M solution of acetylide in THF and 3 molar equiv.

of chloroformate. When the reaction was scaled up to

10–14 mmol, the amount of reagents was reduced to

not more than 1.5–2 molar equiv., without observing

appreciable changes. In all cases, however, the d.r. was

moderate, with 8 always predominating. This fact

prompted us to study the inﬂuence of the protecting

group of the primary alcohol function on the

diastereoselectivity.

quinolyl derivative with a pre-existing stereogenic cen-

ter remote from the one generated during the reaction.

Thus, every factor that can affect the regio- and

diastereoselectivity as well as the yield, leading to com-

pounds

8

and

9

(Scheme 4), was carefully

investigated.¹⁷

Compound ( )-5b was ﬁrst chosen as the starting sub-

strate and some meaningful data are presented in Table

1.^†The low electrophilicity of the heterocycle was

enhanced by performing the addition of the nucleophile

in the presence of a suitable alkyl or aryl chlorofor-

mate.³⁴In this case, the best results were obtained using

phenyl chloroformate, which allowed the addition to be

complete in most cases at −78°C. In contrast, the

reaction was very slow when benzyl or methyl chloro-

formate were used (entries 1 and 2) and, with the ﬁrst

reagent, we observed a decrease in the diastereomeric

ratio. The reaction was always very regioselective, with

The same reaction was performed on the complete

series of racemic quinolines 5, reproducing the condi-

tions of entry 3 (Table 1). The results are shown in

Table 2.

Apart from acetyl as a protecting group, for which a

diminished d.r. with respect to SiMe₂t-Bu was observed

(entry 5), in all other cases (entries 1–4, 6–11) higher

d.r. was noticed. In particular, the best results were

obtained using the triphenylmethyl group; in this case

d.r. up to 87:13 was observed (entry 8). This ratio can

be viewed as excellent considering the distance between

the newly formed and pre-existing stereogenic centers.

Moreover, simple fractional crystallization allowed us

to increase the d.r. up to 99:1 in a very simple manner.

Scheme 4.

Table 1. Addition of acetylides to (9)-5b using different experimental conditions (R⁶=SiMe₂t-Bu; R¹=Me; R²=SiMe₃)

Entry

R³

Nucleophile

Temperature (°C)

Isolated yield (%)^a

(9)-8a–c:(9)-9a–c^b

1

2

3

4

5

6

7

Bn

Me

Ph

SiMe₃CꢀCMgBr

SiMe₃CꢀCCeCl₂

SiMe₃CꢀCMgCl

−78 to −2^c

0^c

72 (69)

78 (76)

77 (64)

87 (84)

66 (63)^e

30 (24)^f

35 (34)

59:41^d(a)

66:34 (b)

68:32^d(c)

68:32 (c)

67:33 (c)

68:32 (c)

−78 to −2^c

−78 to 0^c

−78^c

0^c

−78 to 0^c

^aSince by-products derived from chloroformate are always present and not easy to separate from 8/9, the yield after purity determination by GLC

analysis is reported in brackets.

^bDetermined by GLC, if not otherwise speciﬁed.

^cReaction conditions: [for each entry order of addition of reagents was reported (quinoline=a, nucleophile=b, chloroformate=c, temperature

and reaction times were reported only if necessary); reactions were performed on 100 mg of ( )-5b, using 3 molar equiv. of nucleophile (0.5 M

sol. in THF) and 3 molar equiv. of chloroformate]. E1, E3, E7: a+b+c, E2: b+a+c (after 10 min), E4: b+c (−780°C, 1.5 h)+a (−78°C), E5:

b+a (3 h)+c, E6: b+a+c.

^dDetermined by GC–MS (HP-1 column).

^eThis reaction was performed on a preparative scale (10 mmol) under these conditions, but using 2–3 molar equiv. of nucleophile and 1.5 molar

equiv. of chloroformate to give, after 15 h, the mixture ( )-8,9 in 96% yield.

^fTogether with 4–5% products derived from addition of nucleophile on C-4.

^†Complete data have already been reported (Ref. 17).

2706

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

Table 2. Addition of acetylides to quinolines (9)-5 and 6 (R³=Ph; Met=MgBr)

Entry

Compound

R⁶

R¹

R²

Temperature (°C)

Isolated

8d–o:9d–o^b

yield (%)^a

1

2

3

4

5

6

7

8

(9)-5a

(9)-5c

(9)-5d

(9)-5e

(9)-5f

(9)-5g

(9)-5h

6b

H

Me

SiMe₃

−78−45^c

−780^c

−78−21^c

−78−14^c

−78^c

61 (41)

56 (41)

95 (86)

76 (73)

80 (69)

75 (73)

88 (82)

77 (76)

98 (85)

77^h

73:27^d(d)

70:30^d(e)

69:31^d(e)

67:33^e(f)

61:39^d(g)

70:30^e(h)

75:25^d(i)

87:13^d,f(j)

84:16^d,f(j)

84:16ⁱ(k)

84:16^j(l)

70:30ⁱ(m)

70:30ⁱ(n)

–

SiPh₂t-Bu

Me

Ac

p-OMe-C₆H₄

p-NO₂-C₆H₄

−78−30^c

−78−35^c

−78^c

Tr

9

Tr^g

Tr

Me

SiMe₃

−78^c

10

11

12

13

14

15

16

17

CH₂OCH₂Ph

CH₂OCH₂(p-OMe)C₆H₄

SiMe₃

−78^c

Tr

−78^c

75^h

CH₂OAc

CH₂OH

CH₂OSiEt₃

CH₂O(p-OMe)C₆H₄

−78^c

94

44

See text

87

6c

6d

6e

6f

MMTr^k

DMTr^l

Tr

−78^c

–

Tr

−78^c

60:40ⁱ(o)

–

6g

−78^c

See text

^aSee note (a), Table 1 (in this case GLC or HPLC).

^bIn all cases 8 prevailed.

^csee note (c), Table 1: E1, E3–E17: a+b+c, E2: a+c (0°C, 30 min)+b (−78°C).

^dDetermined by HPLC.

^eDetermined by GLC.

^fD.r. determined more precisely after Tr removal to give the corresponding alcohols ( )-8,9d.

^gThis reaction was performed on a preparative scale (14 mmol) under these conditions, but using 2–3 molar equiv. of nucleophile and 1.5 molar

equiv. of chloroformate to give, after 18 h, the mixture ( )-8,9j in 99% yield.

^hAfter removal of Tr.

ⁱDetermined by ¹H NMR.

^jDetermined by ¹³C NMR after Tr removal.

^kp-Methoxyphenyldiphenylmethyl.

^lDi(p-methoxyphenyl)phenylmethyl.

Using different acetylides—compounds having an

alkoxymethyl group instead of SiMe₃—we did not

observe appreciable effects on the results (entries 10

and 11), since these groups are probably too far away

from the zone responsible for asymmetric induction. In

this case, the addition products could not be separated

from the excess of alkyne employed, which meant that

accurate characterization and precise determination of

the d.r. could not be performed until after removal of

the trityl group. For analytical purposes, the mixture of

products could always be separated into pure ( )-8 and

( )-9, with the exception of compounds ( )-8–9h,k,l.

Anyway, the best separation in view of further synthetic

elaborations was obtained after O-protecting group

removal.

obtained 8,9 with the same d.r. as the trityl protected

derivative, but the yield was only moderate (entry 13),

while the DMTr group in 6c proved to be unstable

under the conditions utilized and, the disappearance of

starting material was accompanied by the formation of

many other products. Unexpected behavior was also

observed with 6e: the presence of a free hydroxyl

function was actually responsible for extensive decom-

position, which is in contrast with the results obtained

with alcohol ( )-5a (entry 1). Triethylsilyl protected 6f

was a good substrate for the addition reaction (entry

16), giving indeed an inseparable mixture of

diastereoisomers but in excellent overall yield, albeit

with a diminished diastereoisomeric ratio. Curious

behavior was seen with 6g, since the reaction evolved in

the usual manner, with the complete disappearance of

the quinoline and the formation of the expected

adducts. However, during puriﬁcation of the crude

mixture by chromatography, only the starting material

6g was recovered in near-quantitative yield, demon-

strating that in some cases this reaction can be

reversible.

The additions to 6b–g were performed using

trimethylsilylmagnesium acetylide (entries 12–17, Table

2). With 6b the chemical yield was excellent (entry 12),

while the d.r. was considerably lower than with com-

pound ( )-5h. Planning the forthcoming elaboration of

8,9, we also tested the addition reaction with substi-

tuted trityl derivatives, that can, in principle, be

removed under milder conditions.²²For this reason we

A rational interpretation of the factors affecting the

stereoselectivity in the racemic series is not easy. It is

clear from the experimental data that the attack of the

nucleophile always takes place on the same face of the

employed

(MMTr)

both

and

p-methoxyphenyldiphenylmethyl

di(p-methoxyphenyl)phenylmethyl

(DMTr) ethers: with the ﬁrst protecting group we

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2707

heterocycle, since diastereoisomer 8 always prevailed.

Use of force ﬁeld calculations performed with CSC

Chem 3D Plus for the simple trimethylsilyl ether

derived from ( )-5a suggested that the C-4-substituent

should preferentially adopt the conformation shown

in Scheme 5. In it the benzylic hydrogen—the smaller

substituent on the carbon bonded to the hetero-

cycle—is directed toward the peri hydrogen, slightly

tilted away from the aromatic plane.

The inﬂuence of the protecting groups on the

stereoselectivity of nucleophilic additions to hetero-

cycles is well known. Isobe’s group observed good

diastereoselectivity (up to 93:7) during the addition of

acetylides to 4-substituted quinolines bearing an O-

protecting group in a 1,6-relationship with the newly

created stereocenter.³⁶Moreover, we obtained excel-

lent results performing the same reaction on 3-substi-

tuted isoquinolines (with d.r. up to 95:5), bearing an

O-protecting group in the same relationship with the

newly formed stereogenic carbon at C-2.³⁷

Of the other two substituents, one is therefore nearly

perpendicular to the aromatic ring. In this hypothesis

it is reasonable that the bulkier –CH₂OR group

prefers to occupy this perpendicular position, and

that the nucleophile will attack preferentially from the

opposite side, as shown in transition state 10. How-

ever, the extent of the d.r. cannot depend on steric

effects alone. Actually, while the highest induction

observed with bulky groups (SiPh₂t-Bu and the best

of all, triphenylmethyl) can be reasonably explained

on steric grounds, it is not easy to understand the

behavior of ( )-5a and ( )-5g. In the ﬁrst case (entry

1) the reaction must occur on the alcoholate of ( )-

5a, and this fact should be responsible for a different

electronic environment in the transition state. On the

other hand, either anisyl or p-nitrophenyl groups

(entries 6 and 7) induced higher diastereoselectivities

and this can probably not be attributed to steric fac-

tors, but only to stereoelectronic effects, that have

not been clearly understood.

2.2. Relative conﬁguration of compounds 8 and 9

After our screening was complete we had to establish

the relative conﬁguration of compounds 8,9 and to

correlate the addition products to demonstrate

which epimer prevails during the addition of the

acetylide.

To solve the ﬁrst problem, we decided to transform

both ( )-8j and ( )-9j into tricyclic derivatives, hope-

fully suitable for NOE studies. As a ﬁrst goal we

planned to synthesize a cyclic acetonide. For this pur-

pose we exploited the epoxidation of ( )-8,9j, a reac-

tion that is known to be highly stereoselective on this

family of compounds, with the epoxide forming on

the opposite side of the triple bond on C-2.³⁸Both

compounds ( )-11,12 were obtained as

a single

diastereoisomer when ( )-8j and ( )-9j were separately

treated with m-chloroperbenzoic acid (Scheme 6).

Both derivatives were then reacted with p-toluenesul-

fonic acid in dry methanol. Under these conditions,

the trityl group was removed and the oxirane under-

went an acid catalyzed ring opening, with methanol

acting as nucleophile. The structure of compounds

( )-13,14 was established on the basis of the follow-

ing considerations: (1) the methoxy group must be

bonded on benzylic carbon; actually, acetylating ( )-

13, diacetate ( )-17 was isolated in which H₃was

shifted downﬁeld as expected, passing from an alco-

holic function to an acetoxy group (from 4.02 ppm as

broad doublet to 5.30 ppm as doublet); (2) the trans

relationship between OMe and OH was supposed on

the basis of the opening mechanism of epoxides and

conﬁrmed later on acetonide ( )-16 and on lactones

( )-18,19; (3) the trans relationship between H₂and

H₃was established by the coupling constants in the

proton spectrum.

The diminished stereoselectivity observed in the addi-

tions to derivatives 6 is most likely a consequence of

the fact that the two differently protected hydroxy-

methyl groups are more similar than the methyl and

the –CH₂OR of quinolines ( )-5, thus making the dif-

ferentiation between the two faces of the heterocycle,

based on steric hindrance, less pronounced. Also in

this case stereoisomer 8 prevailed, with the bulkier

–CH₂OCAr₃group lying nearly perpendicular to the

aromatic ring.

Generally, although the stereoselectivity of these reac-

tions is not impressive, it should be noted that they

involve the formation of a new stereocenter that has

a 1,4-relationship with the pre-existing one. Moreover,

the ﬁrst point of difference in the two oxygenated

substituents of the stereogenic centers, that is the O-

protecting group, has a 1,7-relationship with the

newly created center. This reaction therefore repre-

sents an example of long-range stereocontrol.³⁵

For the transformation of ( )-8j into a cyclic acetonide

we ﬁrst treated ( )-13 with NaHCO₃in methanol to

cleave the CꢁSiMe₃bond. We were surprised to isolate

as the major product, methyl carbamate ( )-15, which

was transformed into acetonide ( )-16 under standard

conditions. Since we demonstrated that the transforma-

tion of phenyl carbamate into methyl carbamate does

not occur during the treatment with acid, the only step

responsible for the observed reaction must be the sec-

ond, although this reaction is peculiar just for this

Scheme 5.

2708

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

Scheme 6.

substrate.^‡However, ( )-16 was found to be unsuitable

for the determination of the relative conﬁguration of all

the four stereocenters using spectroscopic methods and

this is most likely due to the fact that several conforma-

tions with comparable energy are present. NOEDIFF

experiments on ( )-16 conﬁrmed only that the junction

between the two saturated rings must be cis. Finally,

more useful information on the relative conﬁguration

of the stereocenters could be obtained from lactones

( )-18,19, obtained by selective oxidation of the pri-

mary alcoholic function of ( )-13 and ( )-14 with tetra-

propylammonium perruthenate (TPAPP), to give a

one-pot conversion into the tricyclic derivatives ( )-18

and ( )-19.³⁹Force ﬁeld calculations on slightly sim-

pliﬁed analogues, with H instead of SiMe₃and OMe

instead of OPh (Scheme 7), helped us make some

hypotheses on the three-dimensional structure of ( )-

18,19, which were conﬁrmed by H NMR spectra (both

1

chemical shift and coupling constants data) and

NOEDIFF experiments. In particular, the information

collected for both lactones, allowed us to make certain

conclusions: (1) the C_3aꢁO bond is axial with respect to

the nitrogen containing ring.

A

dihedral angle

(C_3aꢁH_3aꢁC₄ꢁH₄) of 54–56° was predicted by calcula-

tions for both stereoisomers, which is in good agree-

ment with the spectroscopic data obtained. Actually,

H₄and H_3agave two singlets at 5.10 and 5.73 ppm,

respectively, in 18 and two doublets at 5.12 and 5.73

ppm, respectively, in 19 with a constant of 1.5 Hz; (2)

the lactone ring is nearly planar; (3) one of the two

substituents (H for 18 and Me for 19) is directed

toward the aromatic ring, causing a strong upﬁeld shift

Scheme 7.

^‡The same reaction performed on an advanced intermediate in the synthesis of 1a,b gave indeed the expected product (Ref. 45).

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2709

in proton spectrum with respect to the opposite situa-

tion [H (18): 2.52 ppm; H (19): 3.15 ppm; Me (18): 1.21

ppm; H (19): 0.77 ppm]; (4) a strong NOE is observed

between H_3aand OMe as a consequence of the cis

junction between the ﬁve- and the six-membered ring;

(5) a moderate NOE effect is present between H_3aand

Me a to CꢂO in 18 and between H_3aand H a to CꢂO

in 19.

alternative hydrolysis in the presence of a lipase (from

Candida antarctica or porcine pancreas) was unsuccess-

ful: while the latter enzyme did not accept this substrate

at all, the former required the reaction to be carried out

at 60°C or above^§before a very sluggish reaction began.

For this reason we preferred to acetylate ( )-8d under

standard conditions, thus obtaining ( )-8g.

Removal of the p-anisyl group under oxidative condi-

tions (cerium ammonium nitrate) gave a faster compet-

itive 1,2-oxidation, with the formation of a quinoline

bearing the acetylenic moiety at C-2, followed by

slower protecting group cleavage. In this case we corre-

lated ( )-8h by transforming ( )-8d into the O-pro-

tected derivative under Mitsunobu conditions.

However, the same reaction performed in order to

prepare ( )-8i did not succeed and so the relative

stereochemistry of that compound is assumed just by

analogy with the very similar p-anisyl derivative. For

compounds ( )-8–9a,b we did not demonstrate the rela-

tive conﬁguration, although, on the basis of spectro-

scopic and chromatographic analogies, also in this case

the relative stereochemistry of the prevailing

diastereoisomer is most likely the same as the very

similar ( )-8c derivative.

In conclusion, all the data obtained agree with the

attribution of structure ( )-18 to the lactone derived

from ( )-8j and ( )-19 to the lactone obtained from

( )-9j. The most striking evidence for the assignment of

the relative stereochemistry to the carbon a to CꢂO

with respect to the other stereogenic centers is shown

by the chemical shifts of the substituents attached to it.

Since, during the transformation of ( )-8j and ( )-9j

into ( )-18,19, the initial present stereogenic centers

were not subjected to manipulations, the determination

of the relative conﬁguration of the two lactones allows

us to attribute structure ( )-8j to the prevailing

stereoisomer obtained by the addition of acetylides to

( )-5h and ( )-9j to the minor stereoisomer.

At this point we had only to correlate all major

obtained diastereoisomers reported in Table 2 with

( )-8j and the minor diastereoisomers with ( )-9j. The

correlation between ( )-8,9c,d,e and ( )-8,9j was quite

simple and was based on the interconversion of protect-

ing groups (Scheme 8). We established that ( )-8d can

be obtained after trityl removal from ( )-8j, and ( )-

8c,e were transformed into ( )-8d, by simple removal of

the silyl protecting group.

We chose to transform compounds ( )-8–9k,l into a

common intermediate that can also be obtained from

( )-8,9j after homologation at the acetylenic carbon.

Diastereomerically pure ( )-8j was transformed into

alkyne ( )-20, which was treated with t-butylmagne-

sium chloride and paraformaldehyde (Scheme 9). The

reaction was sluggish and very slow, affording, after

trityl removal, diol ( )-26 in modest yield. On the other

hand we tried to transform both diastereoisomeric mix-

tures ( )-8–9k,l into chromatographically separable

diols ( )-26,27. Both epimeric mixtures were separately

treated with boron triﬂuoride etherate in the presence

of ethanethiol, a method known to give cleavage of

benzyl-, p-methoxybenzyl- and trityl ethers.⁴³While the

mixture composed by ( )-8,9l was transformed, albeit

in moderate yield into ( )-26,27, under the same condi-

tions ( )-8,9k underwent only trityl cleavage in excel-

lent yield. The benzyl group could be removed only

forcing the conditions, that is working at reﬂux, but in

this case the reaction was not clean. For ( )-8,9l a

two-step sequence as summarized in Scheme 9 gave

better results. Since ( )-26 and ( )-27 are readily sepa-

rated, we ascertained that also in this series ( )-26,

which has been also obtained from ( )-8j, prevailed.

Since a methyl ether requires drastic conditions for its

removal, we preferred the methylation of ( )-8d, a

reaction that was found to be unexpectedly trouble-

some. Many methods were tested (NaH, MeI; MeOTf,

2,6-lutidine; CH₂N₂, SiO₂;⁴⁰MeI, Ag₂O⁴¹) but ( )-8f

was isolated in negligible amounts or did not form at

all and, in the last case, only decomposition of the

starting material was observed. Finally, using methyl

triﬂate and 2,6-di-t-butyl-4-methylpyridine instead of

2,6-lutidine and working at 60°C, allowed the desired

( )-8f to be obtained in reasonable yield.⁴²

Hydrolysis of the acetyl group in ( )-8g was not trivial,

since basic conditions also cleaved the CꢁSi bond. The

As the ﬁnal step we had to correlate compounds

obtained by nucleophilic addition to 6b,c,f with 8,9. We

easily demonstrated that the same diastereoisomer pre-

dominated, by cleaving the triethylsilyl ether of the

mixture 8,9o and acetylating the prevailing diastereoiso-

^§This enzyme can usually work at this temperature without losing its

activity (Ref. 37).

Scheme 8.

2710

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

Scheme 9.

mer of the free alcohol, that is 28 to give 8m (Scheme

10).^¶

Scheme 11.

3. Conclusions

Scheme 10.

In this paper we have reported a new example of

diastereoselective functionalization of quinoline deriva-

tives, in which the d.r. is mostly inﬂuenced by the

nature of a O-protecting group. The reaction has been

performed on racemic substrates like 5 and enantiomer-

ically pure compounds like 6 to give polyfunctionalized

derivatives, useful intermediates for more complex

molecules of potential biological activity. Part of this

project has already been realized in our group,⁴⁵while

other studies are currently under investigation and will

be presented in due course.

On the other hand, the reductive cleavage of one of the

two CꢁO bonds permitted conversion of 29 into (−)-9j

(Scheme 11). This reaction was quite difﬁcult and many

usually employed conditions (NaBH₄/DMSO, Red-Al^®,

Super-Hydride^®) failed. Finally, the reaction succeeded

under radical conditions with tri-n-butyltin hydride in

the presence of sodium iodide. The choice of solvent

was crucial: when commonly employed 1,2-

dimethoxyethane was used⁴⁴9j was not obtained, while

using THF and working in a sealed tube at 85°C,

compound 9j could be isolated, albeit in moderate

yield.

4. Experimental

4.1. General

NMR spectra were taken in CDCl₃, at 200 MHz (¹H),

and 50 MHz (¹³C), using TMS as internal standard.

Chemical shifts are reported in ppm (l scale), coupling

^¶The spectroscopic analogies between 8,9m and 8,9n allowed us to

suggest 8n as the most likely structure for the prevailing

diastereoisomer obtained by acetylide addition to 6c.

1

constants are reported in hertz. Peak assignment in H

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2711

NMR spectra was also made with the aid of double

resonance experiments. In ABX systems, the proton A

is considered downﬁeld and B upﬁeld. Peak assignment

in ¹³C spectra was made with the aid of DEPT experi-

ments. GC–MS were carried out on a HP-5971A instru-

ment, 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. Unless otherwise indicated analyses were

performed with a constant He ﬂow of 0.9 ml/min, init.

temp. 100°C, init. time 2 min, rate 20°C/min, ﬁnal

temp. 260°C, ﬁnal time 4 min, inj. temp. 250°C, det.

temp. 280°C. Diastereomeric ratios were determined by

GLC using a Carlo Erba FRACTOVAP gas chro-

matograph equipped with a RSL-150 or SE-54 (both 25

m long, 0.25 mm wide) column or by HPLC using a

Waters mod. 6000 instrument with an absorbance

detector mod. 440 (at 245 nm) and equipped with an

Erbasil column (10 mm, 250 mm×4.6 mm). R_tare in

min. IR spectra were measured with a Perkin–Elmer

881 instrument as CHCl₃solutions. Values of [h]_Dwere

determined on a Jasco DIP 181 polarimeter, in CHCl₃

(containing 0.75–1% EtOH) solution. Melting points

were measured on a Bu¨chi 535 apparatus and are

uncorrected. TLC analyses were carried out on silica

gel plates, which were developed by these detection

methods: (A) UV; (B) dipping into a solution of

(NH₄)₄MoO₄·4H₂O (21 g) and Ce(SO₄)₂·4H₂O (1 g) in

H₂SO₄(31 ml) and H₂O (469 ml) and warming. R_fwere

measured after an elution of 7–9 cm. Chromatographies

were carried out on 220–400 mesh silica gel (if not

otherwise speciﬁed) using the ‘ﬂash’ methodology.

Petroleum ether (40–60°C) is abbreviated as PE. In

extractive work-up, aqueous solutions were always re-

extracted thrice with the appropriate organic solvent.

Organic extracts were washed with brine, dried over

Na₂SO₄and ﬁltered, before evaporation of the solvent

under reduced pressure. All reactions employing dry

solvents were carried out under a nitrogen atmosphere.

The purity of all compounds was established by TLC,

¹H NMR, GC–MS. Lipase from recombinant C.

antarctica was a kind gift from Novo Nordisk, while

PLE was purchased from Fluka.

7.26 [1H, d, H₃, J=4.7]; 7.56 [1H, ddd, H₆, J=1.4, 6.8,

8.3]; 7.70 [1H, ddd, H₇, J=1.5, 6.9, 8.3]; 8.05 [1H, dd,

H₅, J=1.1, 8.4]; 8.12 [1H, dd, H₈, J=1.1, 8.4]; 8.82

[1H, d, H₂, J=4.5].

4.3. 2-Quinolin-4-yl-propan-1-ol, 5a

Ethylquinoline 7 (10.0 g, 63.61 mmol) was reﬂuxed with

aqueous formaldehyde (37%, 19 ml, 254.4 mmol) for

15.5 h. Excess formaldehyde was removed under

reduced pressure and the residue was taken up with

methanol and concentrated again. The residue was

dissolved in MeOH and stirred under nitrogen at rt in

the presence of anhydrous K₂CO₃(2.5 g) for 20 h. After

ﬁltration of the carbonate, the solution was concen-

trated under reduced pressure, diluted with water and

extracted as usual with Et₂O. After solvent removal,

crude product was chromatographed with PE/AcOEt,

2:8AcOEt and then AcOEt/EtOH, 97:3, to give pure

5a as a pale yellow oil (10.59 g, 89%). R_f0.16 (Et₂O, A).

IR: w_max3612, 2964, 1591, 1255, 1021. GC–MS (usual

conditions, but with init. temp. 80°C): R_t8.21; m/z 188

(5.6), 187 (M⁺, 42), 157 (42), 156 (100), 155 (11), 154

(30), 130 (7.5), 129 (8.6), 128 (14), 127 (7.8), 101 (5.2),

77 (6.4). ¹H NMR: 1.45 [3H, d, >CHCH₃, J=6.5];

3.82–4.04 [3H, m, >CHCH₂OH]; 7.32 [1H, d, H₃, J=

4.5]; 7.57 [1H, ddd, H₆, J=1.1, 6.9, 8.2]; 7.70 [1H, ddd,

H₇, J=1.4, 6.9, 8.5]; 8.11 [1H, dd, H₅, J=1.1, 7.9]; 8.13

[1H, dd, H₈, J=1.1, 8.1]; 8.84 [1H, d, H₂, J=4.6]. ¹³C

NMR: 17.33 [>CHCH₃]; 36.44 [>CHCH₃]; 67.20

[–CH₂O–]; 118.12 [C₃]; 123.06 [C₅]; 126.30 [C₆]; 127.40

[C_4a]; 128.92 and 129.53 [2C, C₇and C₈]; 147.67 [C₄];

149.44 [C₂]; 150.9 [C_8a].

4.4. Silylation of 5a

A solution of 5a (1.00 g, 5.34 mmol) in dry DMF (12

ml) was treated with imidazole (618 mg, 9.08 mmol)

and R₂tBuSiCl and stirred at rt for 1.5–2.5 h. The

solution was diluted with water/NaHCO₃sat. solution

(1:1) and extracted with Et₂O. The crude product was

puriﬁed by chromatography using PE/AcOEt 7:31:1

to give the corresponding products 5b (87% yield) and

5c (84% yield) as colorless oils.

4.2. 4-Ethylquinoline, 7

A solution of 1-chloro-3-pentanone (5.00 g, 85%, 35.25

mmol) in nitrobenzene (10 ml) was treated with freshly

distilled aniline (6.42 ml, 70.50 mmol) and concentrated

hydrochloric acid (2.94 ml, 35.25 mmol) and then

stirred at 100°C for 18 h. The solution was diluted with

Et₂O and extracted trice with 1N HCl. The aqueous

extract was treated with 6N NaOH until pH 10 was

reached. After ﬁltration over a Celite pad, an usual

extraction with Et₂O was performed. A rapid ﬁltration

over silica gel with PEPE/Et₂O, 8:2, then Et₂O, fol-

lowed by distillation under reduced pressure, gave com-

pound 7 in 41–49% overall yield as a colorless oil. Bp:

83°C, 0.9 mbar. R_f0.31 (PE/Et₂O 1:1, A). GC–MS

(usual conditions, but with init. temp. 70°C): R_t6.75;

m/z 158 (12), 157 (M⁺, 100), 154 (11), 143 (5.5), 142

(52), 130 (5.9), 129 (7.3), 128 (8.4), 116 (5.5), 115 (22),

4.4.1. 4-{[2-(tert-Butyldimethylsilyloxy)-1-methyl]ethyl}-

quinoline, 5b. R_f0.45 (PE/Et₂O 1:1, A). IR: w_max2829,

2883, 1244, 1092. GC–MS: R_t8.57; m/z 301 (M⁺, 0.12),

246 (5.6), 245 (21), 244 (100), 214 (6.6), 170 (6.8), 154

(7.3), 89 (5.4), 75 (16), 73 (19), 59 (5.6). ¹H NMR: −0.07

and −0.08 [6H, 2 s, >Si(CH₃)₂]; 0.81 [9H, s, –C(CH)₃];

1.43 [3H, d, >CHCH₃, J=6.6]; 3.72–3.94 [3H, m,

>CHCH₂O–]; 7.31 [1H, d, H₃, J=4.7]; 7.56 [1H, ddd,

H₆, J=1.4, 6.8, 8.4]; 7.70 [1H, ddd, H₇, J=1.4, 6.9,

8.2]; 8.12 [1H, dd, H₅or H₈, J=1.1, 8.1]; 8.14 [1H, dd,

H₅or H₈, J=1.1, 8.1]; 8.85 [1H, d, H₂, J=4.6]. ¹³C

NMR: −5.51 and −5.48 [2C, >Si(CH₃)₂]; 17.24

[>CHCH₃]; 18.24 [–C(CH₃)₃]; 25.82 [3C, –C(CH₃)₃];

36.25 [>CHCH₃]; 68.04 [–CH₂O–]; 118.36 [C₃]; 123.20

[C₅]; 126.18 [C₆]; 127.48 [C_4a]; 128.80 and 130.23 [2C,

C₇and C₈]; 148.25 [C₄]; 150.00 [C₂]; 150.58 [C_8a].

1

89 (5.1), 77 (7.8), 51 (5.4), 40 (6.3). H NMR: 1.40 [3H,

t, >CHCH₃, J=7.6]; 3.13 [2H, q, –CH₂CH₃, J=7.6];

2712

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

4.4.2. 4-{[2-(tert-Butyldiphenylsilyloxy)-1-methyl]ethyl}-

quinoline, 5c. R_f0.54 (PE/Et₂O 2:8, A). IR: w_max2930,

2859, 1729, 1590, 1462, 1374, 1240, 1105. GC–MS: R_t

12.67; m/z 425 (M⁺, 0.059), 370 (8.1), 369 (31), 368

(100), 290 (19), 199 (20), 184 (6.4), 181 (8.6), 154 (5.6),

and J_BX=6.6, 7.1]; 7.32 [1H, d, H₃, J=4.7]; 7.60 [1H,

ddd, H₆, J=1.3, 6.9, 8.5]; 7.73 [1H, ddd, H₇, J=1.4,

6.8, 8.1]; 8.15 [2H, dd, H₅and H₈, J=1.6, 8.5]; 8.89

[1H, d, H₂, J=4.6]. ¹³C NMR: 17.52 [>CHCH₃]; 20.77

[–COCH₃]; 32.90 [>CHCH₃]; 68.18 [–CH₂O–]; 117.95

[C₃]; 122.62 [C₅]; 126.59 [C₆]; 127.14 [C_4a]; 129.08 and

130.41 [2C, C₇and C₈]; 148.41 and 148.95 [2C, C₄and

C_8a]; 150.12 [C₂]; 170.90 [CO].

1

135 (5.0). H NMR: 0.95 [9H, s, –C(CH)₃], 1.47 [3H, d,

>CHCH₃, J=6.4]; 3.75–3.91 [3H, m, >CHCH₂O–];

7.20–7.57 [12H, m, H₃, H₆, aromatics of TBDPS], 7.67

[1H, ddd, H₇, J=1.3, 6.9, 8.3]; 7.85 [1H, d, H₅, J=8.4];

8.10 [1H, d, H₈, J=8.0]; 8.82 [1H, d, H₂, J=4.6]. ¹³C

NMR: 17.08 [>CHCH₃]; 19.18 [–C(CH₃)₃]; 26.75 [3C,

–C(CH₃)₃]; 36.17 [>CHCH₃]; 68.60 [–CH₂O–]; 118.54

[C₃]; 123.17 [C₅]; 126.23 [C₆]; 127.50 [C_4a]; 127.61 and

127.67 [4C, C meta of TBDPS]; 128.80 and 130.24 [2C,

C₇and C₈]; 129.61 and 129.71 [2C, C para of TBDPS];

133.31 and 133.44 [2C, C ipso of TBDPS]; 135.50 and

135.61 [4C, C ortho of TBDPS]; 148.31 [C₄]; 150.03

[C₂]; 150.27 [C_8a].

4.7. Preparation of O-Ar derivatives of 5a under Mit-

sunobu’s conditions

A solution of 5a (350 mg, 1.87 mmol) in dry CH₂Cl₂

(15 ml) was treated at rt with PPh₃(637 mg, 2.43

mmol), the appropriate phenol (p-methoxyphenol for 5f

and p-nitrophenol for 5g, 5.60 mmol) and diethyl azo-

dicarboxylate (382 ml, 2.43 mmol). The solution was

stirred for 1 h (5f) and 24 h (5g) with the addition of an

equivalent amount of the reagents after 7 h. After

quenching with NH₄Cl sat. sol. the mixture was

extracted with AcOEt. The organic layers were rapidly

washed with 1N aqueous NaOH and brine until pH:8

was reached. After solvent removal, chromatography

with the appropriate PE/Et₂O mixture gave 5f (77%

yield, colorless oil) and 5g (76% yield, pale yellow oil).

4.5. 4-[(2-Methoxy-1-methyl)ethyl]quinoline, 5d

A solution of 5a (520 mg, 2.78 mmol) in dry THF was

cooled to 0°C and treated with methyl iodide (346 ml,

5.55 mmol) and NaH (60% in mineral oil, 167 mg, 4.17

mmol). After 10 min the reaction was allowed to stir at

rt for 24 h (after 3 h an equivalent amount of both

reagents was added). The mixture was partitioned

between NH₄Cl sat. sol. and AcOEt and extracted as

usual. Chromatography with PE/Et₂O, 8:2Et₂O gave

5d as a pale yellow oil (324 mg, 58%). R_f0.48 (Et₂O, A).

IR: w_max2928, 2876, 1590, 1570, 1450, 1214, 1108.

GC–MS: R_t6.68; m/z 202 (6.5), 201 (M⁺, 46), 200 (27),

170 (18), 157 (8.0), 156 (25), 155 (5.4), 154 (15), 128

(8.1), 127 (5.2), 45 (100). ¹H NMR: 1.44 [3H, d,

>CHCH₃, J=6.8]; 3.36 [3H, s, –OCH₃]; 3.57 and 3.72

[2H, AB part of ABX system, >CHCH₂O–, J_AB=9.2,

4.7.1. 4-{[2-(p-Methoxyphenoxy)-1-methyl]ethyl}quino-

line, 5f. R_f0.49 (PE/AcOEt 1:1, A). IR: w_max2960, 1733,

1590, 1496, 1464, 1191, 1028. GC–MS: R_t10.52; m/z

294 (12), 293 (M⁺, 60), 171 (14), 170 (100), 168 (5.8),

155 (15), 154 (25), 124 (61), 123 (5.4, 109 (18). ¹H

NMR: 1.55 [3H, d, >CHCH₃, J=6.6]; 3.75 [3H, s,

–OCH₃]; 4.08 [1H, center of m, >CHCH₂O–]; 4.17 and

4.23 [2H, AB part of ABX system, >CHCH₂O–, J_AB

=

6.8, J_AXand J_BX=2.0, 4.1]; 6.80 [4H, s, p-anisyl]; 7.36

[1H, d, H₃, J=4.4]; 7.58 [1H, ddd, H₆, J=1.6, 7.0, 8.4];

7.72 [1H, ddd, H₇, J=1.2, 6.6, 8.4]; 8.15 [2H, d, H₅and

H₈, J=8.8]; 8.88 [1H, d, H₂, J=4.8]. ¹³C NMR: 17.75

[>CHCH₃]; 33.75 [>CHCH₃]; 55.60 [–OCH₃]; 72.62

[–CH₂O–]; 114.58 [2C, C ortho to –OMe]; 115.50 [2C, C

meta to –OMe]; 118.13 [C₃]; 122.87 [C₅]; 126.44 [C₆];

127.12 [C_4a]; 128.95 and 130.33 [2C, C₇and C₈]; 148.35

and 149.55 [2C, C₄and C_8a]; 150.10 [C₂]; 152.77 and

153.95 [2C, C quat. of p-anisyl].

J_AXand

J_BX=5.8, 7.2]; 3.91 [1H, sextuplet,

>CHCH₂O–, J=6.7]; 7.31 [1H, d, H₃, J=4.7]; 7.58

[1H, ddd, H₆, J=1.5, 6.9, 8.3]; 7.71 [1H, ddd, H₇,

J=1.3, 6.9, 8.5]; 8.13 [2H, dd, H₅and H₈, J=1.1, 8.4];

8.87 [1H, d, H₂, J=4.7]. ¹³C NMR: 18.01 [>CHCH₃];

34.04 [>CHCH₃]; 59.00 [–OCH₃]; 77.28 [–CH₂O–];

118.08 [C₃]; 122.93 [C₅]; 126.40 [C₆]; 127.26 [C_4a]; 128.94

and 130.40 [2C, C₇and C₈]; 148.43 [C₄]; 150.19 [C₂];

150.25 [C_8a].

4.6. Acetic acid 2-quinolin-4-yl-propyl ester, 5e

4.7.2. 4-[1-Methyl-2-(p-nitrophenoxy)ethyl]quinoline, 5g.

R_f0.67 (AcOEt 1:1, A). IR: w_max2966, 1592, 1497,

1342, 1193, 1111, 1016. GC–MS: R_t12.37; m/z 309

(6.1), 308 (M⁺, 30), 171 (13), 170 (100), 169 (6.7), 168

(7.5), 156 (19), 155 (25), 154 (35), 143 (7.4), 142 (6.5),

A solution of 5a (537 mg, 2.87 mmol) in dry pyridine (3

ml) was stirred at rt in the presence of acetic anhydride

(541 ml, 5.74 mmol) for 2.5 h. The solution was parti-

tioned between water/Et₂O and extracted as usual.

After solvent removal, residue pyridine was azeotropi-

cally removed with heptane. Chromatography with PE/

AcOEt 1:14:6 gave 5e as a pale yellow oil (631 mg,

96%). R_f0.55 (PE/AcOEt 1:1, A). IR: w_max3005, 3962,

1728, 1591, 1374, 1191. GC–MS: R_t7.44; m/z 229 (M⁺,

14), 170 (11), 169 (66), 168 (15), 157 (35), 156 (91), 155

(15), 154 (79), 130 (6.6), 129 (7.7), 128 (11), 127 (8.8),

1

128 (8.4), 127 (5.0). H NMR: 1.60 [3H, d, >CHCH₃,

J=6.5]; 4.07–4.41 [3H, m, >CHCH₂O–]; 6.91 [2H, dt,

H meta to NO₂, J=2.8, 9.3]; 7.37 [1H, d, H₃, J=4.5];

7.62 [1H, ddd, H₆, J=1.4, 6.9, 8.3]; 7.75 [1H, ddd, H₇,

J=1.3, 6.8, 8.3]; 8.14 [2H, dd, H₅and H₈, J=1.1, 8.2];

8.18 [2H, dt, H ortho to NO₂, J=2.8, 9.2]; 8.90 [1H, d,

H₂, J=4.6]. ¹³C NMR: 17.66 [>CHCH₃]; 33.54

[>CHCH₃]; 72.77 [–CH₂O–]; 114.44 [2C, C meta to

–NO₂]; 118.15 [C₃]; 122.63 [C₅]; 125.89 [2C, C ortho to

–NO₂]; 126.77 [C₆]; 128.91 [C_4a]; 129.24 and 130.60 [2C,

C₇and C₈]; 141.75 [CNO₂]; 148.49 and 148.61 [2C, C₄

and C_8a]; 150.18 [C₂]; 163.58 [C para to –NO₂].

1

101 (6.5), 77 (7.3), 51 (5.6), 43 (100). H NMR: 1.46

[3H, d, >CHCH₃, J=6.9]; 2.00 [3H, s, –COCH₃]; 4.02

[1H, sextuplet, >CHCH₂O–, J=6.9]; 4.25 and 4.43 [2H,

AB part of ABX system, >CHCH₂O–, J_AB=10.9, J_AX

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2713

4.8. 4-[1-Methyl-2-(trityloxy)ethyl]quinoline, 5h

4.9.2.

(S)-Acetic

acid

3-{[(p-methoxyphenyl)-

diphenyl]methoxy}-2-(quinolin-4-yl)propyl ester, 6c. R_f

0.30 (PE/Et₂O 2:8, A, B). [h]_D=+30.4 (c 1.08, CHCl₃).

IR: w_max2953, 1732, 1591, 1075, 1030. GC–MS: (usual

conditions, but with ﬁn. temp. 290°C) R_t18.73; m/z 517

(M⁺, 2.9), 273 (100), 228 (11), 195 (5.2), 186 (5.3), 168

A solution of 5a (493 mg, 2.63 mmol) in dry CH₂Cl₂

(20 ml) was treated with dry pyridine (317 ml, 3.94

mmol) and trityl chloride (807 mg, 2.89 mmol) and

stirred at rt for 22 h. The reaction was partitioned

between NH₄Cl sat. sol. and AcOEt and then extracted.

Residue pyridine was removed azeotropically with hep-

tane and the crude mixture was puriﬁed by chromatog-

raphy with PE/AcOEt 7:36:4 to give a white foam

(1.131 g, 96%), which crystallized from Et₂O to give a

white solid. Mp 124.3–125.9°C (Et₂O). R_f0.68 (PE/

AcOEt 1:1, A, B). IR: w_max2969, 1591, 1487, 1449,

1189, 1070. GC–MS: (usual conditions, but with ﬁn.

temp. 290°C) R_t14.21; m/z 429 (M⁺, 0.20), 244 (22),

243 (100), 170 (8.1), 165 (24), 154 (6.2), 105 (7.9), 77

1

(10), 165 (8.9), 154 (6.2), 105 (12), 77 (5.4), 43 (18). H

NMR: 1.92 [3H, s, –COCH₃]; 3.52 [2H, d,

–CH₂OMMTr, J=5.8]; 3.77 [3H, s, –OCH₃]; 4.11 [1H,

quintuplet, –CH(CH₂O–)₂, J=6.2]; 4.59 [2H, d,

–CH₂OAc, J=6.6]; 6.76 [2H, dt, H ortho to –OMe,

J=3.0, 9.2]; 7.14–7.36 [13H, m, H₃and aromatics of

MMTr]; 7.55 [1H, ddd, H₆, J=1.6, 7.0, 8.4]; 7.72 [1H,

ddd, H₇, J=1.4, 7.0, 8.4]; 7.98 [1H, broad d, H₅,

J=8.0]; 8.13 [1H, dd, H₈, J=1.2, 8.6]; 8.82 [1H, d,

H₂, J=4.8]. ¹³C NMR: 20.73 [–COCH₃]; 39.17

[–CH(CH₂O–)₂]; 55.11 [–OCH₃]; 63.42 and 64.29 [2C,

–CH(CH₂O–)₂]; 86.60 [–CPh₂Ar]; 112.99 [2C, C ortho

to OMe]; 119.16 [C₃]; 122.88 [C₅]; 126.56 [C₆]; 126.86

[2C, C para of Ph]; 127.35 [C_4a]; 127.73 and 128.19 [8C,

C ortho and meta of Ph]; 129.05 and 130.33 [2C, C₇and

C₈]; 130.24 [2C, C meta to OMe]; 135.11 [C para to

OMe]; 144.04 [2C, C ipso of Ph]; 145.49 [C₄]; 148.36

[C_8a]; 149.80 [C₂]; 158.49 [COMe of MMTra]; 170.82

[CO].

1

(5.1). H NMR: 1.45 [3H, d, >CHCH₃, J=6.9]; 3.34

and 3.41 [2H, AB part of ABX system, >CHCH₂O–,

J_AB=9.1, J_AXand J_BX=6.2, 7.2]; 3.91 [1H, sextuplet,

>CHCH₂O–, J=6.7]; 7.17–7.34 [16H, m, H₃and aro-

matics of Tr]; 7.52 [1H, ddd, H₆, J=1.2, 6.9, 8.3]; 7.70

[1H, ddd, H₇, J=1.4, 6.7, 8.3]; 8.02 [1H, d, H₅or H₈,

J=8.4]; 8.12 [1H, d, H₅or H₈, J=8.0]; 8.80 [1H, d, H₂,

J=4.7]. ¹³C NMR: 17.81 [>CHCH₃]; 34.36 [>CHCH₃];

68.21 [–CH₂O–]; 86.59 [–CPh₃]; 118.32 [C₃]; 123.26 [C₅];

126.16 [C₆]; 126.90 [3C, C para of Tr]; 127.42 [C_4a];

127.66 and 128.59 [12C, C ortho and meta of Tr];

128.81 and 130.26 [2C, C₇and C₈]; 143.90 [3C, C ipso

of Tr]; 148.32 [C₄]; 150.06 [C₂]; 150.58 [C_8a].

4.9.3. (S)-Acetic acid 3-{[bis-(p-methoxyphenyl)phenyl]-

methoxy}-2-(quinolin-4-yl)propyl ester, 6d. R_f0.42 (PE/

Et₂O 2:8, A, B). [h]_D=+33.0 (c 1.31, CHCl₃). IR: w_max

2953, 1730, 1604, 1299, 1196, 1029. GC–MS: (usual

conditions, but with ﬁnal temp. 290°C) R_t23.16; m/z

547 (M⁺, 0.79), 303 (100), 228 (9.2), 186 (5.6), 168 (10),

155 (7.3), 154 (9.6), 135 (12), 105 (13), 77 (6.2), 43 (24).

¹H NMR: 1.92 [3H, s, –COCH₃]; 3.51 [2H, d,

–CH₂ODMTr, J=5.4]; 3.77 [6H, s, –OCH₃]; 4.10 [1H,

quintuplet, –CH(CH₂O–)₂, J=6.2]; 4.58 [2H, d,

–CH₂OAc, J=6.6]; 6.75 [4H, apparent dd, H ortho to

–OMe, J=1.4, 8.8]; 7.12–7.34 [10H, m, H₃and aromat-

ics of DMTr]; 7.54 [1H, ddd, H₆, J=1.4, 7.0, 8.4]; 7.72

[1H, ddd, H₇, J=1.4, 7.0, 8.0]; 7.98 [1H, broad d, H₅,

J=8.4]; 8.13 [1H, dd, H₈, J=1.2, 8.4]; 8.82 [1H, d, H₂,

J=4.4]. ¹³C NMR: 20.74 [–COCH₃]; 39.20

[–CH(CH₂O–)₂]; 55.12 [2C, –OCH₃]; 63.36 and 64.34

[2C, –CH(CH₂O–)₂]; 86.33 [–CPhAr₂]; 113.00 [4C, C

ortho to OMe]; 119.18 [C₃]; 122.92 [C₅]; 126.55 [C₆];

126.73 [C para of Ph]; 127.37 [C_4a]; 127.73 and 127.95

[4C, C ortho and meta of Ph]; 129.05 and 130.35 [2C, C₇

and C₈]; 129.91 [4C, C meta to OMe]; 135.67 [2C, C

para to OMe]; 144.56 [C ipso of Ph]; 145.55 [C₄]; 148.38

[C_8a]; 149.82 [C₂]; 158.40 [2C, COMe of DMTr]; 170.84

[CO].

4.9. Triarylmethyl derivatives of 6a

The same procedure described above for the prepara-

tion of 5h was followed, starting from 6a and using

TrCl at reﬂux, to give 6b (100% yield) as a white foam

and MMTrCl at rt to give 6c (95% yield) as a white

foam or DMTrCl at rt to give 6d (85% yield) as a

yellow foam.

4.9.1. (S)-Acetic acid 2-(quinolin-4-yl)-3-(trityloxy)-

propyl ester, 6b. R_f0.35 (PE/Et₂O 2:8, A, B). [h]_D=

+31.4 (c 2.06, CHCl₃). IR: w_max2961, 1736, 1449, 1194,

1070, 1033. GC–MS: (usual conditions, but with ﬁn.

temp. 290°C) R_t16.52; m/z 410 (M⁺−77, 0.095), 244

(24), 243 (100), 228 (9.5), 186 (5.2), 168 (9.9), 167 (5.0),

166 (5.6), 165 (32), 154 (9.2), 105 (14), 77 (7.9), 43 (27).

¹H NMR: 1.91 [3H, s, –COCH₃]; 3.52 [2H, d,

–CH₂OTr, J=5.8]; 4.16 [1H, quintuplet, –CH(CH₂O–)₂,

J=6.2]; 4.58 [2H, d, –CH₂OAc, J=6.8]; 7.16–7.35

[16H, m, H₃and aromatics of Tr]; 7.54 [1H, ddd, H₆,

J=1.3, 6.3, 8.3]; 7.72 [1H, ddd, H₇, J=1.3, 6.9, 8.3];

7.98 [1H, broad d, H₅, J=8.4]; 8.13 [1H, broad d, H₈,

J=8.4]; 8.82 [1H, d, H₂, J=4.6]. ¹³C NMR: 20.73

[–COCH₃]; 39.18 [–CH(CH₂O–)₂]; 63.53 and 64.27 [2C,

–CH(CH₂O–)₂]; 86.92 [–CPh₃]; 119.16 [C₃]; 122.88 [C₅];

126.59 [C₆]; 127.04 [3C, C para of Tr]; 127.36 [C_4a];

127.76 and 128.51 [12C, C ortho and meta of Tr];

129.07 and 130.39 [2C, C₇and C₈]; 143.53 [3C, C ipso

of Tr]; 145.43 [C₄]; 148.40 [C_8a]; 149.82 [C₂]; 170.81

[CO].

4.10. (R)-2-(Quinolin-4-yl)-3-(trityloxy)propan-1-ol, 6e

A solution of 6b (1.90 g, mmol) was dissolved in dry

methanol (13 ml) and cooled to 0°C. A solution of 1 M

solution of KOH in MeOH (5 ml) was added and the

resulting mixture was stirred at the same temperature

for about 2 h. The resulting solution was treated with

NH₄Cl sat. sol. (10 ml) and concentrated under reduced

pressure. The residue was diluted with water and

extracted with AcOEt. Chromatography with PE/Et₂O

3:7Et₂O then AcOEt gave pure 6e (1.72 g, 99%) as a

2714

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

white foam. R_f0.26 (PE/Et₂O 1:9, A, B). [h]_D=+59.7

(c 2.18, CHCl₃). IR: w_max3518, 3000, 2958, 1729, 1589,

1447, 1065. GC–MS: 6e decomposed in the column.

¹H NMR: 2.50 [1H, broad s, –OH]; 3.62 [2H, d,

–CH₂O–, J=6.2]; 3.98 [1H, quintuplet, –CH(CH₂O–)₂,

J=5.9]; 4.02–4.18 [2H, m, –CH₂O–]; 7.13–7.41 [16H,

m, H₃and aromatics of Tr]; 7.53 [1H, ddd, H₆, J=

1.2, 7.0, 8.4]; 7.68 [1H, ddd, H₇, J=1.4, 7.0, 8.4]; 7.95

[1H, dd, H₅, J=0.8, 8.4]; 8.08 [1H, dd, H₈, J=1.2,

8.4]; 8.74 [1H, d, H₂, J=4.6]. ¹³C NMR: 42.30

[–CH(CH₂O–)₂]; 64.45 and 65.20 [2C, –CH(CH₂O–)₂];

87.26 [–CPh₃]; 119.07 [C₃]; 123.00 [C₅]; 126.50 [C₆];

127.11 [3C, C para of Tr]; 127.37 [C_4a]; 127.85 and

128.50 [12C, C ortho and meta of Tr]; 129.05 and

130.05 [2C, C₇and C₈]; 143.56 [3C, C ipso of Tr];

146.40 [C₄]; 148.07 [C_8a]; 149.67 [C₂].

ics of Tr]; 7.53 [1H, ddd, H₆, J=1.4, 7.0, 8.4]; 7.71

[1H, ddd, H₇, J=1.3, 7.0, 8.4]; 7.99 [1H, d, H₅, J=

8.8]; 8.13 [1H, dd, H₈, J=1.0, 8.4]; 8.81 [1H, d, H₂,

J=4.4]. ¹³C NMR: 40.05 [–CH(CH₂O–)₂]; 55.63

[–OCH₃]; 62.07 and 68.44 [2C, –CH(CH₂O–)₂]; 86.84

[–CPh₃]; 114.57 [2C, C ortho to –OMe]; 115.56 [2C, C

meta to –OMe]; 119.48 [C₃]; 122.97 [C₅]; 126.45 [C₆];

126.96 [3C, C para of Tr]; 127.42 [C_4a]; 127.71 and

128.52 [12C, C ortho and meta of Tr]; 128.94 and

130.26 [2C, C₇and C₈]; 143.65 [3C, C ipso of Tr];

146.18 [C₄]; 148.28 [C_8a]; 149.80 [C₂]; 152.62 and

153.98 [2C, C quat. of p-anisyl].

4.13. Preparation of commercially unavailable alkynes

4.13.1. Prop-2-ynyloxymethylbenzene (used for the

preparation of 8,9k). A suspension of NaH (60% in

mineral oil, 672 mg, 1.68 mmol) in dry DMF (10 ml)

was cooled to 0°C; then benzyl alcohol (1.65 g, 15.28

mmol) was added through an addition funnel during a

period of 10 min. The funnel was washed with addi-

tional DMF (3 ml) and the mixture was vigorously

stirred for 25 min at 0°C. Propargyl bromide (80%,

1.87 ml, 1.68 mmol) was added dropwise via the addi-

tion funnel during 5 min. The mixture was allowed to

react at 0°C for 2.5 h and 30 min at rt. Additional 122

mg of NaH and overnight stirring at rt were necessary

in order to complete the reaction. After cooling again

at 0°C, the reaction was quenched with NH₄Cl sat.

sol. and extracted with Et₂O (1:1). Chromatography

with PE/Et₂O 95:59:1 gave pure alkyne as a yellow

oil (2.03 g, 91%). R_f0.76 (PE/Et₂O 8:2, A, B). GC–

MS: R_t2.77; m/z 146 (M⁺, 2.8), 145 (8.4), 118 (5.7),

117 (17), 116 (47), 115 (24), 107 (29), 106 (5.0), 105

(4.1), 92 (65), 91 (100), 89 (10), 79 (56), 78 (14), 77

(58), 65 (28), 63 (9.7), 52 (6.4), 51 (30), 50 (12), 40

4.11. (S)-4-{1-[(Triethylsilyl)oxymethyl]-2-(trityloxy)-

ethyl}quinoline, 6f

A solution of 6e (523 mg, 1.17 mmol) in dry CH₂Cl₂

(10 ml) was cooled to 0°C and treated with 2,6-

lutidine (232 ml, 2.00 mmol) and triethylsilyl triﬂate

(319 ml, 1.41 mmol). After about 2 h at the same

temperature, the solution was partitioned between

water and Et₂O. After the addition of aqueous

NaHCO₃until pH 8 of the aqueous layer, an usual

extraction was performed. After solvent evaporation,

2,6-lutidine was azeotropically removed with n-octane.

Chromatography with PE/Et₂O 6:44:6 gave 6f as a

yellow oil. R_f0.77 (PE/Et₂O 1:9, A, B). [h]_D=+15.6 (c

2.06, CHCl₃). IR: w_max2948, 2872, 1590, 1447, 1193,

1094, 1002. GC–MS: 6f decomposed in the column.

¹H NMR: 0.46 [6H, dq, –Si(CH₂CH₃)₃, J=1.2, 7.8];

0.82 [9H, t, –Si(CH₂CH₃)₃, J=7.4]; 3.48 and 3.65 [2H,

AB part of ABX system, –CH₂O–, J_AB=8.8, J_AXand

1

J_BX=5.6, 5.8]; 3.50 [1H, quintuplet, –CH(CH₂O–)₂,

(8.7), 39 (53), 38 (8.7). H NMR: 2.48 [1H, t, –CꢀCH,

J=5.7]; 3.98–4.04 [2H, m, –CH₂O–]; 7.13–7.34 [16H,

m, H₃and aromatics of Tr]; 7.54 [1H, ddd, H₆, J=

1.0, 7.0, 8.4]; 7.70 [1H, ddd, H₇, J=1.0, 6.6, 8.0]; 8.08

[1H, d, H₅or H₈, J=8.8]; 8.12 [1H, d, H₅or H₈,

J=8.4]; 8.78 [1H, d, H₂, J=4.8]. ¹³C NMR: 4.26 [3C,

–Si(CH₂CH₃)₃]; 6.66 [3C, –Si(CH₂CH₃)₃]; 42.58

[–CH(CH₂O–)₂]; 63.33 and 63.81 [2C, –CH(CH₂O–)₂];

86.67 [–CPh₃]; 119.46 [C₃]; 123.33 [C₅]; 126.21 [C₆];

126.89 [3C, C para of Tr]; 127.66 and 128.60 [12C, C

ortho and meta of Tr]; 127.82 [C_4a]; 128.81 and 130.25

[2C, C₇and C₈]; 143.86 [3C, C ipso of Tr]; 147.28 [C₄];

148.35 [C_8a]; 149.76 [C₂].

J=2.4]; 4.18 [2H, d, –CH₂CꢀCH, J=2.2]; 4.62 [2H, s,

–CH₂Ph]; 7.26–7.38 [5H, m, aromatics].

4.13.2. 1-Methoxy-4-prop-2-ynyloxymethylbenzene (used

for the preparation of 8,9l). The same procedure

described above was followed, performing the reaction

on 80.2 mmol of 4-methoxybenzyl alcohol. The reac-

tion was completed over 2.5 h at 0°C and 30 min at

rt. After cooling again at 0°C, quenching with 50 ml

of a 0.65 M aqueous solution of K₂CO₃was per-

formed. After extraction with Et₂O, chromatography

with PE/Et₂O 95:19:1 gave pure alkyne as a yellow

oil (10.75 g, 76%). R_f0.62 (PE/Et₂O 7:3, A, B). GC–

MS: R_t4.75; m/z 176 (M⁺, 24), 175 (8.4), 146 (9.2),

145 (5.7), 137 (7.1), 136 (50), 135 (61), 131 (5.2), 122

(17), 121 (100), 109 (14), 108 (6.5), 107 (8.2), 94 (12),

92 (9.5), 91 (14), 89 (7.7), 78 (20), 77 (46), 65 (11), 64

(7.7), 63 (9.4), 53 (5.5), 52 (8.3), 51 (16), 50 (7.6), 40

4.12. (S)-4-[1-(p-Methoxyphenoxymethyl)-2-(trityloxy)-

ethyl]quinoline, 6g

The same procedure employed for the preparation of

5f,g from 5a was followed, starting from 6e to give 6g

in 72% yield as a white foam. R_f0.56 (PE/Et₂O 1:9, A,

B). [h]_D=−13.0 (c 2.00, CHCl₃). IR: w_max2955, 1730,

1590, 1464, 1444, 1250, 1067. GC–MS: 6g decomposed

1

(6.4), 39 (40), 37 (6.6). H NMR: 2.46 [1H, t, –CꢀCH,

J=2.4]; 3.80 [3H, s, –OCH₃]; 4.14 [2H, d, –CH₂CꢀCH,

J=2.5]; 4.54 [2H, s, –CH₂Ar]; 6.85–6.89 [2H, m, H

ortho to OMe]; 7.26–7.32 [2H, m, H meta to OMe].

¹³C NMR: 55.27 [–OCH₃]; 56.68 [–CH₂CꢀCH]; 71.14

[–CH₂OAr]; 74.44 [–CꢀCH]; 79.81 [–CꢀCH]; 113.81

[2C, C ortho to OMe]; 129.31 [C para to OMe]; 129.68

[2C, C meta to OMe]; 159.34 [COMe].

1

in the column. H NMR: 3.60 and 3.69 [2H, AB part

of ABX system, –CH₂O–, J_AB=9.0, J_AXand J_BX=5.8,

5.9]; 3.79 [3H, s, –OCH₃]; 4.20 [1H, center of m,

>CHCH₂O–]; 4.34–4.46 [2H, m, –CH₂O–]; 6.75–6.86

[4H, m, p-anisyl]; 7.17–7.36 [16H, m, H₃and aromat-

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2715

4.14. General procedure for the addition of acetylides

5.54 (8g) and 4.50 (9g). 8,9h: GLC [RSL-150 column,

inj. temp. 300°C, det. temp. 250°C, oven temp. 280°C,

carrier (He) press. 1.60 kg/cm²]; R_t10.43 (8h) and 11.51

(9h). 8,9i: HPLC (hexane/Et₂O 8:2, ﬂow 1.2 ml/min); R_t

7.30 (8i) and 10.17 (9i). 8,9j: HPLC (hexane/Et₂O 95:5,

ﬂow 1.5 ml/min); R_t12.02 (8j) and 14.28 (9j).

to 5a–h and 6a–g

Preparation of magnesium acetylide: a solution of the

desired alkyne (4.44 mmol) in dry THF (6.03 ml, when

EtMgBr was used, 5.36 ml when i-PrMgCl was used)

was cooled to −15°C, before EtMgBr (1.33 ml of a 3 M

solution in Et₂O, 4.0 mmol) or i-PrMgCl (2 ml of a 2

M solution in Et₂O) was added. The resulting red–

brown solution was stirred at rt for 1 h to give a 0.5 M

solution of acetylide.

4.14.2. 4-{(S*)-[2-(tert-Butyldimethylsilyloxy)-1-methyl]-

ethyl}-2-{(R*)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-

carboxylic acid benzyl ester 8a and its epimer, 9a.

Preparative thin layer chromatography was performed

with PE/Et₂O (9:1) to give 8a and 9a as pale yellow oils.

R_f0.55 (8a) and 0.44 (9a) (PE/Et₂O 9:1, A, B). Charac-

terization of 8a: IR: w_max2929, 2858, 2168, 2091, 1696,

1391, 1288, 1247. GC–MS: (usual conditions, but with

ﬁn. temp. 290°C) R_t12.25; m/z 398 (M⁺−135, 9.6), 316

(6.4), 266 (14), 245 (55), 244 (26), 238 (5.6), 92 (7.1), 91

Preparation and employment of cerous acetylide: a sus-

pension of anhydrous CeCl₃, [previously dried by

known procedure⁴⁶from CeCl₃·6H₂O (494.6 mg 1.40

mmol)] in dry THF (1 ml) was cooled to −30°C and

treated with an equimolecular amount of lithium

1

trimethylsilyl acetylide [0.5

M

solution in THF,

(100), 75 (7.3), 73 (47). H NMR: −0.09 and −0.07 [6H,

obtained by treatment of ethynyl trimethyl silane at

−30°C with a 1 M solution in THF of LiN(SiMe₃)₂].

The temperature was then allowed to raise to rt, before

quinoline 5b (105 mg, 350 mmol) and phenyl chlorofor-

mate (176 ml, 1.40 mmol) are added. Work-up followed

the same protocol described later in the general

procedure.

2 s, >Si(CH₃)₂]; 0.02 [9H, s, –Si(CH₃)₃]; 0.82 [9H, s,

–C(CH)₃]; 1.26 [3H, d, >CHCH₃, J=6.6]; 3.04 [1H,

center of m, >CHCH₃]; 3.30 and 3.64 [2H, AB part of

ABX system, >CHCH₂O–, J_AB=9.6, J_AXand J_BX=4.1,

7.8]; 5.22 and 5.30 [2H, AB system, –CH₂Ph, J_AB

12.4]; 5.83 and 5.83 [2H, AB system, H₂and H₃,

_AB=6.9]; 7.14 [1H, dt, H₆or H₇, J=1.5, 7.4]; 7.24 [1H,

=

J

dt, H₆or H₇, J=1.5, 7.8]; 7.31–7.44 [6H, m, H₅and

Ph]; 7.64 [1H, broad d, H₈, J=8.2]. ¹³C NMR: −5.45

and −5.37 [2C, >Si(CH₃)₂]; −0.13 [3C, –Si(CH₃)₃]; 15.88

[>CHCH₃]; 18.28 [–C(CH₃)₃]; 25.90 [3C, –C(CH₃)₃];

36.11 [>CHCH₃]; 44.81 [C₂]; 67.32 and 67.89 [2C,

–CH₂O–]; 88.08 and 101.99 [2C, –CꢀC–TMS]; 121.22

[C₈]; 122.99, 124.36, 124.85 and 127.25 [4C, C₃, C₅, C₆,

C₇]; 127.94 and 128.49 [4C, C ortho and meta of Ph];

128.10 [C para of Ph]; 127.78 [C_4a]; 134.52 [C₄]; 136.05

[C ipso of Ph]; 137.09 [C_8a], 153.20 [CO]. Characteriza-

tion of 9a: IR: w_max2956, 2928, 2169, 1696, 1391, 1247,

1095, 1025. GC–MS: (usual conditions, but with ﬁn.

temp. 290°C) R_t12.60; m/z 398 (M⁺−135, 12), 316 (5.0),

266 (13), 244 (10), 238 (6.1), 155 (8.2), 92 (8.7), 91

Addition reaction (conditions of Table 2): a solution of

quinoline (the screening was performed on about 100

mg of derivative) in dry THF (5 ml) was cooled to

−78°C. The acetylide solution was added (3 molar

equiv.), followed by phenyl chloroformate (3 molar

equiv.). The resulting solution was allowed to react at

the reported temperature until complete (3–15 h). After

quenching with NH₄Cl sat. sol., the mixture was

extracted as usual with Et₂O. Chromatography was

performed with the appropriate PE/Et₂O mixture. With

the exception of 8,9d, the mixture of puriﬁed

diastereoisomers was obtained. They were further sepa-

rated, with the exceptions reported below, by prepara-

tive thin layer chromatography, as reported for every

addition mixture. The yields are reported in Tables 1

and 2. For preparative purposes the same procedure

was followed, reducing THF quantities (about 2 ml/

mmol of substrate) and acetylide or chloroformate, as

reported in the Tables 1 and 2.

1

(100), 89 (7.3), 75 (6.6), 73 (46). H NMR: 0.02 [9H, s,

–Si(CH₃)₃]; 0.04 and 0.06 [6H, 2 s, >Si(CH₃)₂]; 0.90 [9H,

s, –C(CH)₃]; 1.09 [3H, d, >CHCH₃, J=6.9]; 2.98 [1H,

sextuplet, >CHCH₃, J=6.7]; 3.63 and 3.81 [2H, AB

part of ABX system, >CHCH₂O–, J_AB=9.8, J_AXand

J_BX=5.9, 6.8]; 5.24 and 5.30 [2H, AB system, –CH₂Ph,

J_AB=12.5]; 5.83 and 5.83 [2H, AB system, H₂and H₃,

J_AB=7.2]; 7.14 [1H, dt, H₆or H₇, J=1.4, 7.5]; 7.24 [1H,

4.14.1. Determination of d.r. by chromatographic meth-

ods (compounds 8,9a–j). 8,9a: GC–MS (usual conditions

but with ﬁnal temperature 290°C); R_t12.25 (8a) and

12.60 (9a). 8,9b: GLC [SE-54 column, inj. temp. 300°C,

det. temp. 300°C, oven temp. 250°C, carrier (He) press.

1.60 kg/cm²]; R_t3.42 (8b) and 3.87 (9b). 8,9c: GLC

[RSL-150 column, inj. temp. 300°C, det. temp. 250°C,

oven temp. 250°C, carrier (He) press. 1.60 kg/cm²]; R_t

8.90 (8c) and 10.70 (9c) or GC–MS (usual conditions

but with ﬁnal temperature 290°C) R_t11.89 (8c) and

12.21 (9c). 8,9d: HPLC (hexane/Et₂O 4:6, ﬂow 1.5

ml/min); R_t21.55 (8d) and 11.90 (9d). 8,9e: HPLC

(hexane/CH₂Cl₂/Et₂O 95:3:2, ﬂow 1.5 ml/min); R_t13.20

(8e) and 16.40 (9e). 8,9f: GLC [SE-54 column, inj.

temp. 300°C, det. temp. 300°C, oven temp. 250°C,

carrier (He) press. 1.60 kg/cm²]; R_t5.77 (8f) and 6.06

(9f). 8,9g: HPLC (hexane/Et₂O 8:2, ﬂow 1.2 ml/min); R_t

dt, H₆or H₇, J=1.5, 7.7]; 7.32–7.44 [6H, m, H₅and

Ph]; 7.64 [1H, broad d, H₈, J=7.5]. ¹³C NMR: −5.24

[2C, >Si(CH₃)₂]; −0.12 [3C, –Si(CH₃)₃]; 17.47

[>CHCH₃]; 18.35 [–C(CH₃)₃]; 26.00 [3C, –C(CH₃)₃];

36.11 [>CHCH₃]; 44.62 [C₂]; 67.43 and 67.89 [2C,

–CH₂O–]; 87.92 and 102.02 [2C, –CꢀC–TMS]; 120.22

[C₈]; 123.17, 124.34, 124.66 and 127.16 [4C, C₃, C₅, C₆,

C₇]; 127.86 and 128.48 [4C, C ortho and meta of Ph];

128.08 [C para of Ph]; 128.55 [C_4a]; 134.41 [C₄]; 136.05

[C ipso of Ph]; 137.95 [C_8a], 153.29 [CO].

4.14.3. 4-{(S*)-[2-(tert-Butyldimethylsilyloxy)-1-methyl]-

ethyl}-2-{(R*)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-

carboxylic acid methyl ester 8b and its epimer, 9b.

Preparative thin layer chromatography was performed

with PE/Et₂O (9:2) to give 8b and 9b as pale yellow oils.

2716

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

R_f0.62 (8b) and 0.53 (9b) (PE/Et₂O 8:2, A, B). Charac-

terization of 8b: IR: w_max2954, 2927, 2169, 2089, 1702,

1381, 1332, 1096, 1035. GC–MS: (usual conditions, but

with ﬁn. temp. 290°C) R_t10.21; m/z 457 (M⁺, 0.39), 400

(7.1), 284 (17), 180 (6.3), 155 (11), 89 (35), 75 (17), 74

H₈, J=8.0]. ¹³C NMR: −5.38 [2C, >Si(CH₃)₂]; −0.13

[3C, –Si(CH₃)₃]; 15.90 [>CHCH₃]; 18.31 [–C(CH₃)₃];

25.93 [3C, –C(CH₃)₃]; 36.14 [>CHCH₃]; 45.17 [C₂];

67.31 [–CH₂O–]; 88.49 and 101.54 [2C, –CꢀC–TMS];

121.61 [2C, C ortho of Ph]; 121.33 [C₈]; 123.14, 124.79,

125.62 and 127.40 [4C, C₃, C₅, C₆, C₇]; 125.66 [C para

of Ph]; 128.05 [C_4a]; 129.30 [2C, C meta of Ph]; 134.24

[C₄]; 137.28 [C_8a]; 151.00 [C ipso of Ph]; 151.77 [CO].

Characterization of 9c: IR: w_max2954, 2927, 2169, 1714,

1381, 1327, 1304, 1246, 1190. GC–MS: (usual condi-

tions, but with ﬁn. temp. 290°C) R_t12.40; m/z 398

(M⁺−121, 2.4), 347 (6.5), 346 (22), 338 (6.1), 266 (8.1),

180 (7.5), 156 (5.4), 155 (13), 151 (20), 115 (5.3), 89

1

(8.8), 73 (100), 59 (22), 45 (6.6). H NMR: −0.07 and

−0.05 [6H, 2 s, >Si(CH₃)₂]; 0.01 [9H, s, –Si(CH₃)₃]; 0.84

[9H, s, –C(CH)₃]; 1.26 [3H, d, >CHCH₃, J=6.6]; 3.04

[1H, center of m, >CHCH₃]; 3.28 and 3.64 [2H, AB

part of ABX system, >CHCH₂O–, J_AB=9.7, J_AXand

J_BX=4.1, 7.9]; 3.80 [3H, s, –OCH₃]; 5.80 and 5.86 [2H,

AB system, H₂and H₃, J_AB=6.8]; 7.15 [1H, dt, H₆or

H₇, J=1.4, 7.5]; 7.26 [1H, dt, H₆or H₇, J=1.6, 7.6];

7.40 [1H, dd, H₅, J=1.6, 7.6]; 7.58 [1H, broad d, H₈,

J=7.0]. ¹³C NMR: −5.56 and −5.44 [2C, >Si(CH₃)₂];

−0.20 [3C, –Si(CH₃)₃]; 15.81 [>CHCH₃]; 18.22

[–C(CH₃)₃]; 25.84 [3C, –C(CH₃)₃]; 36.08 [>CHCH₃];

44.64 [C₂]; 53.18 [–OCH₃]; 67.28 [–CH₂O–]; 87.99 and

101.93 [2C, –CꢀC–TMS]; 121.45 [C₈]; 123.00, 124.43,

124.96 and 127.25 [4C, C₃, C₅, C₆, C₇]; 127.87 [C_4a];

134.56 [C₄]; 137.08 [C_8a], 153.90 [CO]. Characterization

of 9b: IR: w_max2927, 2855, 1697, 1440, 1380, 1094, 1036.

GC–MS: (usual conditions, but with ﬁn. temp. 290°C)

R_t10.01; m/z 457 (M⁺, 2.9), 443 (11), 442 (30), 402 (12),

401 (32), 400 (100), 370 (5.9), 339 (6.3), 338 (21), 310

(8.4), 285 (14), 284 (60), 180 (6.0), 278 (6.5), 268 (5.3),

266 (18), 252 (7.5), 194 (5.5), 192 (6.2), 180 (8.7), 89

(24), 75 (9.5), 73 (50), 59 (9.7). ¹H NMR: −0.005 [9H, s,

–Si(CH₃)₃]; 0.04 and 0.07 [6H, 2 s, >Si(CH₃)₂]; 0.89 [9H,

s, –C(CH)₃]; 1.09 [3H, d, >CHCH₃, J=6.9]; 2.97 [1H,

sextuplet, >CHCH₃, J=6.6]; 3.62 and 3.81 [2H, AB

part of ABX system, >CHCH₂O–, J_AB=9.8, J_AXand

1

(34), 77 (14), 75 (14), 74 (7.5), 73 (100), 59 (8.0). H

NMR: 0.04 [9H, s, –Si(CH₃)₃]; 0.08 and 0.06 [6H, 2 s,

>Si(CH₃)₂]; 0.91 [9H, s, –C(CH)₃]; 1.14 [3H, d,

>CHCH₃, J=6.9]; 3.02 [1H, sextuplet, >CHCH₃, J=

6.6]; 3.67 and 3.85 [2H, AB part of ABX system,

>CHCH₂O–, J_AB=9.5, J_AXand J_BX=5.7, 6.7]; 5.92

[2H, apparent s, H₂and H₃]; 7.14–7.49 [8H, m, H₅, H₆,

H₇, Ph]; 7.72 [1H, broad d, H₈, J=7.0]. ¹³C NMR:

−5.25 and −5.21 [2C, >Si(CH₃)₂]; −0.13 [3C,

–Si(CH₃)₃]; 17.52 [>CHCH₃]; 18.36 [–C(CH₃)₃]; 26.02

[3C, –C(CH₃)₃]; 36.22 [>CHCH₃]; 44.97 [C₂]; 67.49

[–CH₂O–]; 88.33 and 101.57 [2C, –CꢀC–TMS]; 120.43

[C₈]; 121.64 [2C, C ortho of Ph]; 123.33, 124.80, 127.32

and 129.54 [4C, C₃, C₅, C₆, C₇]; 125.64 [C para of Ph];

128.36 [C_4a]; 129.31 [2C, C meta of Ph]; 134.16 [C₄];

138.16 [C_8a]; 151.00 [C ipso of Ph]; 151.90 [CO].

4.14.5.

4-{(S*)-[2-Hydroxy-1-methyl]ethyl}-2-{(R*)-

[(trimethylsilyl)ethynyl]}-2H-quinoline-1-carboxylic acid

phenyl ester, 8d and its epimer, 9d. Pure 8d and 9d have

been isolated by chromatography with PE/Et₂O (4:6) as

solids. Both have been crystallized from Et₂O/PE to

give white solids. R_f0.39 (8d) and 0.47 (9d) (PE/Et₂O

6:4, A, B). Characterization of 8d: Mp 109.3–110.7°C

(Et₂O/PE). IR: w_max3621, 2961, 2929, 2169, 1715, 1383,

1191, 1024. GC–MS: R_t11.62; m/z 406 (9.5), 405 (M⁺,

28), 404 (10), 374 (11), 360 (8.2), 348 (9.7), 347 (30), 346

(100), 329 (12), 328 (53), 313 (5.7), 312 (26), 284 (12),

267 (5.5), 254 (14), 253 (6.5), 252 (15), 238 (7.9), 226

(12), 222 (5.2), 208 (9.9), 194 (11), 180 (19), 156 (5.6),

J_BX=6.0, 6.8]; 3.81 [3H, s, –OCH₃]; 5.81 and 5.83 [2H,

AB system, H₂and H₃, J_AB=7.0]; 7.14 [1H, dt, H₆or

H₇, J=1.4, 7.4]; 7.25 [1H, dt, H₆or H₇, J=1.7, 8.1];

7.42 [1H, dd, H₅, J=1.8, 7.8]; 7.58 [1H, broad d, H₈,

J=8.2]. ¹³C NMR: −5.34 and −5.29 [2C, >Si(CH₃)₂];

−0.19 [3C, –Si(CH₃)₃]; 17.44 [>CHCH₃]; 18.30

[–C(CH₃)₃]; 25.96 [3C, –C(CH₃)₃]; 36.12 [>CHCH₃];

44.46 [C₂]; 53.25 [–OCH₃]; 67.50 [–CH₂O–]; 87.88 and

102.00 [2C, –CꢀC–TMS]; 120.45 [C₈]; 123.22, 124.43,

124.78 and 127.18 [4C, C₃, C₅, C₆, C₇]; 128.21 [C_4a];

134.48 [C₄]; 138.05 [C_8a], 154.02 [CO].

1

77 (22), 75 (12), 74 (5.5), 73 (57). H NMR: 0.04 [9H, s,

–Si(CH₃)₃]; 1.34 [3H, d, >CHCH₃, J=6.8]; 3.16 [1H,

sextuplet, >CHCH₃, J=6.6]; 3.64 [2H, m, became an

AB part of ABX system at 3.54 and 3.72 after exchange

with D₂O, >CHCH₂O–, J_AB=10.7, J_AXand J_BX=4.8,

4.14.4. 4-{(S*)-[2-(tert-Butyldimethylsilyloxy)-1-methyl]-

ethyl}-2-{(R*)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-

carboxylic acid phenyl ester, 8c and its epimer, 9c.

Preparative thin layer chromatography was performed

with PE/Et₂O (9:1) to give 8c and 9c as pale yellow oils.

R_f0.77 (8c) and 0.72 (9c) (PE/Et₂O 8:2, A, B). Charac-

terization of 8c: IR: w_max2955, 2171, 1715, 1382, 1328,

1289, 1243. GC–MS: (usual conditions, but with ﬁn.

temp. 290°C) R_t12.06; m/z 398 (M⁺−121, 2.8), 347

(8.7), 346 (28), 338 (8.3), 278 (6.0), 266 (12), 252 (5.5),

222 (5.3), 180 (8.6), 151 (25), 115 (6.0), 89 (30), 77 (12),

6.2]; 5.94 and 5.98 [2H, AB system, H₂and H₃, J_AB

=

7.0]; 7.16–7.46 [8H, m, H₅, H₆, H₇, Ph]; 7.76 [1H, broad

d, H₈, J=8.2]. ¹³C NMR: −0.22 [3C, –Si(CH₃)₃]; 15.81

[>CHCH₃]; 36.02 [>CHCH₃]; 45.15 [C₂]; 66.40

[–CH₂O–]; 88.72 and 101.26 [2C, –CꢀC–TMS]; 121.52

[2C, C ortho of Ph]; 121.53 [C₈]; 123.05, 124.84 [most

likely 2C] and 127.66 [4C, C₃, C₅, C₆, C₇]; 125.63 [C

para of Ph]; 127.46 [C_4a]; 129.27 [2C, C meta of Ph];

134.32 [C₄]; 136.69 [C_8a]; 150.88 [C ipso of Ph]; 151.76

[CO]. Characterization of 9d: Mp 112.3–113.0°C (Et₂O/

PE). IR: w_max3611, 2963, 2929, 2393, 1715, 1484, 1300,

1207, 1024. GC–MS: R_t11.66; m/z 406 (7.5), 405 (M⁺,

24), 404 (8.4), 374 (9.8), 348 (7.5), 347 (28), 346 (100),

330 (5.0), 329 (12), 328 (49), 313 (5.9), 312 (25), 284

(12), 282 (10), 268 (5.1), 266 (19), 254 (14), 253 (7.7),

1

75 (15), 74 (9.0), 73 (100), 59 (7.6). H NMR: −0.038

and −0.028 [6H, 2 s, >Si(CH₃)₂]; 0.04 [9H, s, –Si(CH₃)₃];

0.86 [9H, s, –C(CH)₃]; 1.30 [3H, d, >CHCH₃, J=6.7];

3.09 [1H, center of m, >CHCH₃]; 3.37 and 3.69 [2H,

AB part of ABX system, >CHCH₂O–, J_AB=9.7, J_AX

and J_BX=4.2, 7.5]; 5.91 [2H, apparent s, H₂and H₃];

7.14–7.46 [8H, m, H₅, H₆, H₇, Ph]; 7.73 [1H, broad d,

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2717

252 (18), 238 (9.3), 236 (5.6), 226 (12), 208 (8.9), 194

(10), 180 (17), 151 (6.4), 77 (20), 75 (9.3), 73 (53). H

4.14.7.

4-{(S*)-[2-Methoxy-1-methyl]ethyl}-2-{(R*)-

1

[(trimethylsilyl)ethynyl]}-2H-quinoline-1-carboxylic acid

phenyl ester, 8f and its epimer, 9f. Preparative thin layer

chromatography was performed with PE/Et₂O (7:3) to

give 8f and 9f as pale yellow oils. R_f0.68 (8f) and 0.72

(9f) (PE/Et₂O 6:4, A, B). Characterization of 8f: IR: w_max

2965, 2168, 1713, 1383, 1329, 1304, 1099. GC–MS: R_t

10.86; m/z 419 (M⁺, 6.8), 347 (7.8), 346 (28), 342 (16),

326 (6.7), 298 (5.1), 254 (5.4), 252 (5.0), 226 (5.1), 222

(5.5), 194 (11), 180 (14), 77 (28), 75 (5.0), 74 (5.4), 73

NMR: 0.04 [9H, s, –Si(CH₃)₃]; 1.19 [3H, d, >CHCH₃,

J=7.0]; 4.13 [1H, sextuplet, >CHCH₃, J=6.5]; 3.77

and 3.89 [2H, AB part of ABX system, >CHCH₂O–,

J_AB=10.7, J_AXand J_BX=6.0, 6.3]; 5.95 and 5.98 [2H,

AB system, H₂and H₃, J_AB=6.8]; 7.17–7.48 [8H, m,

H₅, H₆, H₇, Ph]; 7.75 [1H, broad d, H₈, J=7.7]. ¹³C

NMR: −0.23 [3C, –Si(CH₃)₃]; 17.14 [>CHCH₃]; 36.03

[>CHCH₃]; 44.81 [C₂]; 66.61 [–CH₂O–]; 88.76 and

101.60 [2C, –CꢀC–TMS]; 120.64 [C₈]; 121.49 [2C, C

ortho of Ph]; 122.96, 123.07 and 124.87 [most likely 2C]

[4C, C₃, C₅, C₆, C₇]; 125.74 [C para of Ph]; 127.62 [C_4a];

129.25 [2C, C meta of Ph]; 134.23 [C₄]; 137.44 [C_8a];

150.86 [C ipso of Ph]; 151.77 [CO].

1

(62). 59 (7.8), 51 (5.5), 45 (100). H NMR: 0.04 [9H, s,

–Si(CH₃)₃]; 1.34 [3H, d, >CHCH₃, J=6.2]; 3.11–3.23

(2H) and 3.45–3.56 (1H) [3H, 2 m, >CHCH₂O–]; 3.32

[3H, s, –OCH₃]; 5.92 and 5.96 [2H, AB system, H₂and

H₃, J_AB=6.8]; 7.17–7.47 [8H, m, H₅, H₆, H₇, Ph]; 7.75

[1H, broad d, H₈, J=7.2]. ¹³C NMR: −0.25 [3C,

–Si(CH₃)₃]; 16.33 [>CHCH₃]; 33.87 [>CHCH₃]; 45.10

[C₂]; 58.84 [–OCH₃]; 77.00 [–CH₂O–]; 88.57 and 101.36

[2C, –CꢀC–TMS]; 121.29 [C₈]; 121.59 [2C, C ortho of

Ph]; 122.95, 124.89 [most likely 2C] and 127.54 [4C, C₃,

C₅, C₆, C₇]; 125.65 [C para of Ph]; 127.66 [C_4a]; 129.31

[2C, C meta of Ph]; 134.30 [C₄]; 136.96 [C_8a]; 150.95 [C

ipso of Ph]; 151.82 [CO]. Characterization of 9f: IR:

w_max2966, 2394, 1715, 1197, 1081, 1033. GC–MS: R_t

10.99; m/z 419 (M⁺, 6.0), 347 (6.3), 346 (22), 342 (15),

326 (6.3), 254 (5.2), 226 (5.4), 222 (5.7), 194 (11), 180

(13), 77 (28), 75 (5.1), 74 (5.6), 73 (64). 59 (7.8), 51

4.14.6. 4-{(S*)-[2-(tert-Butyldiphenylsilyloxy)-1-methyl]-

ethyl}-2-{(R*)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-

carboxylic acid phenyl ester, 8e and its epimer, 9e.

Preparative thin layer chromatography was performed

with PE/Et₂O (95:5) to give 8e and 9e as pale yellow

oils. R_f0.48 (8e) and 0.44 (9e) (PE/CH₂Cl₂/Et₂O 85:7:8,

A, B). Characterization of 8e: IR: w_max2927, 2895, 2857,

2170, 1711, 1378, 1327, 1302, 1191, 1110. GC–MS:

unsuitable for this analysis. ¹H NMR: 0.04 [9H, s,

–Si(CH₃)₃]; 1.00 [9H, s, –C(CH)₃]; 1.38 [3H, d,

>CHCH₃, J=7.1]; 3.12 [1H, center of m, >CHCH₃];

3.51 and 3.71 [2H, AB part of ABX system,

>CHCH₂O–, J_AB=9.7, J_AXand J_BX=4.2, 7.0]; 5.91

and 5.91 [2H, AB system, H₂and H₃, J=7.5]; 7.04 [1H,

dt, H₆, J=1.2, 8.1]; 7.07–7.75 [18H, m, aromatics]. ¹³C

NMR: −0.18 [3C, –Si(CH₃)₃]; 15.80 [>CHCH₃]; 19.26

[–C(CH₃)₃]; 26.78 [3C, –C(CH₃)₃]; 35.93 [>CHCH₃];

45.15 [C₂]; 67.54 [–CH₂O–]; 88.43 and 101.62 [2C,

–CꢀC–TMS]; 120.76 [C₈]; 121.85 [2C, C ortho of –OPh];

123.12, 124.81 [most likely 2C], and 127.33 [4C, C₃, C₅,

C₆, C₇]; 125.59 [C para of –OPh]; 127.60 and 127.70

[5C, C meta to Si and, most likely, C_4a]; 129.28 [2C, C

meta of –OPh]; 129.53 and 129.62 [2C, C para to Si];

133.82 [C₄]; 135.53 and 135.61 [4C, C ortho to Si];

135.70 and 135.80 [2C, C quat. of PhSi]; 137.00 [C_8a];

151.02 [C ipso of –OPh]; 151.79 [CO]. Characterization

of 9e: IR: w_max2953, 2926, 2854, 2170, 1724, 1378, 1326,

1304, 1233, 1107. GC–MS: unsuitable for this analysis.

¹H NMR: 0.02 [9H, s, –Si(CH₃)₃]; 1.08 [9H, s,

–C(CH)₃]; 1.19 [3H, d, >CHCH₃, J=7.0]; 3.05 [1H,

sextuplet, >CHCH₃, J=6.7]; 3.73 and 3.90 [2H, AB

part of ABX system, >CHCH₂O–, J_AB=10.0, J_AXand

1

(5.4), 45 (100). H NMR: 0.04 [9H, s, –Si(CH₃)₃]; 1.19

[3H, d, >CHCH₃, J=6.9]; 3.11 [1H, center of m,

>CHCH₃]; 3.42 [3H, s, –OCH₃]; 3.46 and 3.66 [2H, AB

part of ABX system, >CHCH₂O–, J_AB=9.2, J_AXand

J_BX=5.0, 7.4]; 5.91 [2H, apparent s, H₂and H₃]; 7.16–

7.46 [8H, m, H₅, H₆, H₇, Ph]; 7.73 [1H, broad d, H₈,

J=6.8]. ¹³C NMR: −0.24 [3C, –Si(CH₃)₃]; 17.69

[>CHCH₃]; 33.88 [>CHCH₃]; 44.88 [C₂]; 59.05

[–OCH₃]; 77.02 [–CH₂O–]; 88.55 and 101.52 [2C,

–CꢀC–TMS]; 120.44 [C₈]; 121.63 [2C, C ortho of Ph];

123.10, 124.89 [most likely 2C] and 127.49 [4C, C₃, C₅,

C₆, C₇]; 125.67 [C para of Ph]; 128.82 [C_4a]; 129.34 [2C,

C meta of Ph]; 134.30 [C₄]; 137.86 [C_8a]; 151.00 [C ipso

of Ph]; 151.89 [CO].

4.14.8.

4-{(S*)-[2-Acetoxy-1-methyl]ethyl}-2-{(R*)-

[(trimethylsilyl)ethynyl]}-2H-quinoline-1-carboxylic acid

phenyl ester, 8g and its epimer, 9g. Preparative thin

layer chromatography was performed with PE/Et₂O

(8:2) to give 8g and 9g as pale yellow oils. R_f0.29 (8g)

and 0.33 (9g) (PE/Et₂O 8:2, A, B). Characterization of

8g: IR: w_max2957, 2173, 1725, 1377, 1196. GC–MS: R_t

11.99; m/z 447 (M⁺, 8.1), 371 (7.2), 370 (28), 348 (6.7),

347 (28), 346 (100), 294 (17), 280 (5.1), 279 (9.5), 278

(17), 266 (19), 252 (9.7), 250 (9.7), 226 (10), 220 (5.9),

208 (7.0), 194 (17), 180 (20), 151 (6.6), 117 (12), 77 (25),

J_BX=6.0, 7.1]; 5.93 [2H, s, H₂and H₃]; 7.10 [1H, dt, H₆,

J=1.2, 6.9]; 7.17–7.77 [18H, m, aromatics]. ¹³C NMR:

−0.21 [3C, –Si(CH₃)₃]; 17.43 [>CHCH₃]; 19.25

[–C(CH₃)₃]; 26.93 [3C, –C(CH₃)₃]; 36.28 [>CHCH₃];

44.95 [C₂]; 67.84 [>CH₂O–]; 88.37 and 101.47 [2C,

–CꢀC–TMS]; 120.77 [C₈]; 121.66 [2C, C ortho of –OPh];

123.22, 124.85 [most likely 2C], and 127.32 [4C, C₃, C₅,

C₆, C₇]; 125.66 [C para of –OPh]; 127.71 and 127.76

[4C, C meta to Si]; 128.32 [C_4a]; 129.35 [2C, C meta of

–OPh]; 129.62 and 129.72 [2C, C para to Si]; 133.67

[C₄]; 135.52 and 135.60 [2C, C quat. of PhSi]; 135.70

and 135.80 [4C, C ortho to Si]; 137.79 [C_8a]; 151.04 [C

ipso of –OPh]; 151.91 [CO].

1

75 (20), 74 (5.9), 73 (64), 59 (5.2), 43 (52). H NMR:

0.04 [9H, s, –Si(CH₃)₃]; 1.33 [3H, d, >CHCH₃, J=6.7];

2.00 [3H, –COCH₃]; 3.30 [1H, sextuplet, >CHCH₃,

J=6.5]; 3.87 and 4.22 [2H, AB part of ABX system,

>CHCH₂O–, J_AB=10.8, J_AXand J_BX=5.0, 8.2]; 5.94

and 5.99 [2H, AB system, H₂and H₃, J_AB=6.8]; 7.00–

7.50 [8H, m, H₅, H₆, H₇, Ph]; 7.74 [1H, broad d, H₈,

J=6.8]. ¹³C NMR: −0.19 [3C, –Si(CH₃)₃]; 15.98

[>CHCH₃]; 20.83 [–COCH₃]; 32.93 [>CHCH₃]; 45.05

[C₂]; 68.16 [–CH₂O–]; 88.74 and 101.21 [2C, –CꢀC–

2718

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

TMS]; 121.58 [2C, C ortho of Ph]; 121.83 [C₈];

123.01, 124.97, 125.14 and 127.69 [4C, C₃, C₅, C₆,

C₇]; 125.64 [C para of Ph]; 127.53 [C_4a]; 129.30 [2C,

C meta of Ph]; 134.33 [C₄]; 136.43 [C_8a]; 150.99 [C

ipso of Ph]; 151.81 [–OCOPh]; 170.91 [–COCH₃].

Characterization of 9g: IR: w_max2956, 2168, 1723,

1376, 1285, 1243. GC–MS: R_t12.28; m/z 447 (M⁺,

9.7), 371 (7.0), 370 (24), 347 (15), 346 (50), 295 (5.0),

294 (22), 280 (5.3), 279 (9.0), 278 (18), 266 (18), 252

(9.9), 250 (9.5), 236 (6.0), 226 (11), 220 (6.3), 208

(9.8), 194 (19), 193 (6.2), 180 (21), 156 (5.2), 154

(6.1), 151 (7.2), 117 (23), 97 (5.3), 77 (43), 75 (33), 73

acterization of 9h: IR: w_max3002, 2958, 2168, 1714,

1379, 1324, 1287, 1013. GC–MS: (usual conditions,

but with ﬁn. temp. 290°C) R_t15.06; m/z 511 (M⁺,

16), 435 (13); 434 (35), 418 (11), 390 (10), 388 (8.7),

374 (9.8), 347 (22), 346 (98), 294 (9.7), 266 (19), 252

(15), 250 (9.9), 226 (9.9), 222 (9.4), 204 (8.4), 194

(35), 180 (21), 179 (8.7), 170 (13), 151 (2), 137 (26),

124 (22), 123 (14), 109 (27), 107 (31), 94 (12), 92

1

(9.3), 77 (56), 75 (8.5), 74 (8.4), 73 (100), 43 (9.1). H

NMR: 0.05 [9H, s, –Si(CH₃)₃]; 1.38 [3H, d, >CHCH₃,

J=7.0]; 3.33 [1H, sextuplet, >CHCH₃, J=6.6]; 3.78

[3H, –OCH₃]; 3.99 and 4.18 [2H, AB part of ABX

system, >CHCH₂O–, J_AB=9.0 J_AXand J_BX=5.8, 7.2];

5.94 and 5.97 [2H, AB system, H₂and H₃, J_AB=6.0];

6.80–6.93 [4H, m, p-anisyl]; 7.16–7.48 [8H, m, H₅, H₆,

H₇, Ph]; 7.75 [1H, broad d, H₈, J=8.2]. ¹³C NMR:

−0.17 [3C, –Si(CH₃)₃]; 17.69 [>CHCH₃]; 33.65

[>CHCH₃]; 44.95 [C₂]; 55.71 [–OCH₃]; 72.56 [–CH₂O–];

88.66 and 101.42 [2C, –CꢀC–TMS]; 114.65 [2C, C

ortho to –OMe]; 115.79 [2C, C meta to –OMe];

120.79 [C₈]; 121.59 [2C, C ortho of Ph]; 123.03,

124.91 [most likely 2C] and 127.56 [4C, C₃, C₅, C₆,

C₇]; 125.66 [C para of Ph]; 129.30 [3C, C meta of Ph

and, most likely, C_4a]; 134.32 [C₄]; 136.59 [C_8a];

150.91 [C ipso of Ph]; 151.79 [CO]; 153.06 and 153.96

[2C quat. of p-anisyl].

1

(100), 65 (5.9), 59 (7.6), 51 (5.8), 45 (7.6), 43 (87). H

NMR: 0.04 [9H, s, –Si(CH₃)₃]; 1.20 [3H, d, >CHCH₃,

J=7.0]; 2.09 [3H, –COCH₃]; 3.24 [1H, sextuplet,

>CHCH₃, J=6.9]; 3.87 and 4.22 [2H, AB part of

ABX system, >CHCH₂O–, J_AB=10.8, J_AXand J_BX

5.0, 8.2]; 5.94 and 5.99 [2H, AB system, H₂and H₃,

_AB=6.8]; 7.00–7.50 [8H, m, H₅, H₆, H₇, Ph]; 7.74

=

J

[1H, broad d, H₈, J=6.8]. ¹³C NMR: −0.18 [3C,

–Si(CH₃)₃]; 17.49 [>CHCH₃]; 20.95 [–COCH₃]; 32.94

[>CHCH₃]; 44.92 [C₂]; 67.81 [–CH₂O–]; 88.76 and

101.24 [2C, –CꢀC–TMS]; 120.96 [C₈]; 121.58 [2C, C

ortho of Ph]; 122.96, 124.98 [most likely 2C] and

127.70 [4C, C₃, C₅, C₆, C₇]; 125.68 [C para of Ph];

127.54 [C_4a]; 129.32 [2C, C meta of Ph]; 134.33 [C₄];

136.88 [C_8a]; 150.98 [C ipso of Ph]; 151.84 [–OCOPh];

170.95 [–COCH₃].

4.14.10. 4-{(S*)-[1-Methyl-2-(p-nitrophenoxy)]ethyl}-2-

{(R*) - [(trimethylsilyl)ethynyl]} - 2H - quinoline - 1 - car-

boxylic acid phenyl ester, 8i and its epimer, 9i.

Preparative thin layer chromatography was performed

with PE/Et₂O (8:2) to give 8i and 9i as pale yellow

oils. R_f0.42 (8i) and 0.34 (9i) (PE/Et₂O 7:3, A, B).

Characterization of 8i: IR: w_max2956, 2171, 1721,

1592, 1379, 1332, 1216, 1111, 986, 840. GC–MS:

unsuitable for this analysis. ¹H NMR: 0.05 [9H, s,

–Si(CH₃)₃]; 1.47 [3H, d, >CHCH₃, J=6.6]; 3.37–3.55

[1H, m, >CHCH₃]; 3.79 [1H, t, >CHCHHO–, J=

8.7]; 4.15 [1H, dd, >CHCHHO–, J=3.9, 8.9]; 5.96

and 6.07 [2H, AB system, H₂and H₃, J_AB=6.8]; 6.90

[2H, dt, H meta to –NO₂, J=2.8, 9.3]; 7.15–7.48 [8H,

m, H₅, H₆, H₇, Ph]; 7.78 [1H, broad d, H₈, J=7.7];

8.16 [2H, dt, H ortho to –NO₂, J=2.8, 9.3]. ¹³C

NMR: −0.18 [3C, –Si(CH₃)₃]; 16.09 [>CHCH₃]; 33.52

[>CHCH₃]; 45.08 [C₂]; 72.70 [–CH₂O–]; 88.98 and

100.91 [2C, –CꢀC–TMS]; 114.49 [2C, C meta to

–NO₂]; 121.50 [2C, C ortho of Ph]; 122.35 [C₈];

122.73, 125.07, 125.21 and 127.95 [4C, C₃, C₅, C₆, C₇];

125.78 [C para of Ph]; 125.83 [2C, C ortho to NO₂];

127.24 [C_4a]; 129.36 [2C, C meta of Ph]; 134.36 [C₄];

135.92 [C_8a]; 141.50 [CNO₂]; 150.84 [C ipso of Ph];

151.78 [CO]; 163.81 [C para to –NO₂]. Characteriza-

tion of 9i: IR: w_max3002, 2177, 1717, 1593, 1342, 1257. GC–

4.14.9. 4-{(S*)-[2-(p-Methoxyphenoxy)-1-methyl]ethyl}-

2-{(R*)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-car-

boxylic acid phenyl ester, 8h and its epimer, 9h. Both

components of the mixture 8,9h, as a pale yellow oil,

could not be separated. R_f0.39 (8h and 9h) (PE/Et₂O

8:2, A, B). Both compounds have however been char-

acterized separately, by protection of 8d and 9d (see

text and experimental below). Characterization of 8h:

IR: w_max3014, 2956, 2169, 1713, 1380, 1301, 1014.

GC–MS: (usual conditions, but with ﬁn. temp. 290°C)

R_t14.62; m/z 512 (8.2), 511 (M⁺, 20), 435 (14); 434

(48), 418 (14), 390 (14), 388 (7.4), 386 (6.6), 374 (8.6),

348 (7.6), 347 (30), 346 (100), 294 (8.1), 280 (6.1), 266

(12), 264 (6.4), 254 (6.2), 252 (14), 250 (8.1), 226 (11),

222 (8.0), 220 (6.1), 194 (28), 193 (6.2), 181 (6.1), 180

(19), 170 (10), 154 (6.8), 151 (11), 137 (20), 124 (15),

123 (14), 109 (18), 107 (19), 97 (6.8), 95 (6.5), 94

1

(6.6), 92 (7.9), 77 (52), 75 (6.7), 74 (6.7), 73 (73). H

NMR: 0.05 [9H, s, –Si(CH₃)₃]; 1.44 [3H, d, >CHCH₃,

J=6.5]; 3.38 [1H, center of m, >CHCH₃]; 3.63 [1H, t,

>CHCHHO–, J=8.8]; 3.75 [3H, –OCH₃]; 4.04 [1H,

dd, >CHCHHO–, J=3.9, 9.0]; 5.94 and 6.03 [2H, AB

system, H₂and H₃, J_AB=6.7]; 6.80 [4H, s, p-anisyl];

7.15–7.48 [8H, m, H₅, H₆, H₇, Ph]; 7.76 [1H, broad d,

H₈, J=7.8]. ¹³C NMR: −0.17 [3C, –Si(CH₃)₃]; 16.28

[>CHCH₃]; 33.79 [>CHCH₃]; 45.14 [C₂]; 55.71

[–OCH₃]; 72.85 [–CH₂O–]; 88.72 and 101.24 [2C,

–CꢀC–TMS]; 114.58 [2C, C ortho to –OMe]; 115.65

[2C, C meta to –OMe]; 121.59 [2C, C ortho of Ph];

121.79 [C₈]; 122.95, 124.96 [most likely 2C] and

127.66 [4C, C₃, C₅, C₆, C₇]; 125.66 [C para of Ph];

129.30 [3C, C meta of Ph and, most likely, C_4a];

134.32 [C₄]; 136.59 [C_8a]; 150.91 [C ipso of Ph]; 151.79

[CO]; 152.99 and 153.83 [2C quat. of p-anisyl]. Char-

1

MS: unsuitable for this analysis. H NMR: 0.07 [9H,

s, –Si(CH₃)₃]; 1.33 [3H, d, >CHCH₃, J=6.9]; 3.42

[1H, sextuplet, >CHCH₃, J=6.6]; 4.14 and 4.31 [2H,

AB part of ABX system, >CHCH₂O–, J_AB=9.0, J_AX

and J_BX=5.6, 7.1]; 5.97 [2H, apparent s, H₂and H₃];

6.96–7.04 [2H, H meta to –NO₂]; 7.18–7.48 [8H, m,

H₅, H₆, H₇, Ph]; 7.70 [1H, broad d, H₈, J=7.9]; 8.15–

8.26 [2H, m, H ortho to –NO₂]. ¹³C NMR: −0.20 [3C,

–Si(CH₃)₃]; 17.62 [>CHCH₃]; 33.52 [>CHCH₃]; 44.91

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2719

[C₂]; 72.47 [–CH₂O–]; 88.95 and 101.22 [2C, –CꢀC–

TMS]; 114.55 [2C, C meta to –NO₂]; 121.14 [C₈]; 121.56

[2C, C ortho of Ph]; 122.84, 124.97, 125.15 and 127.88

[4C, C₃, C₅, C₆, C₇]; 125.75 [C para of Ph]; 125.92 [2C,

C ortho to NO₂]; 127.36 [C_4a]; 129.36 [2C, C meta of

Ph]; 134.44 [C₄]; 136.86 [C_8a]; 141.71 [CNO₂]; 150.96 [C

ipso of Ph]; 151.84 [CO]; 163.85 [C para to –NO₂].

[2H, d, –OCH₂CꢀC– (8k), J=1.5]; 4.27 [2H, s,

–OCH₂Ph (9k)]; 4.39 [2H, s, –OCH₂Ph (8k)]; 5.84–6.12

[2H, m, H₂and H₃(8,9k)]; 6.93 [1H, broad s, H₆

(8,9k)]; 7.08–7.48 [27H, m, H₅, H₆, H₇, –OPh, Ph, Tr

(8,9k)]; 7.75 [1H, broad d, H₈, J=7.7 (8,9k)].

4.14.13. 2-{(R*)-[3-(4-Methoxybenzyloxy)prop-1-ynyl]}-

4-{(S*)-[1-methyl-2-trityloxy]ethyl}-2H-quinoline-1-car-

boxylic acid phenyl ester 8l and its epimer 9l. Both

puriﬁed components of the mixture 8,9k, together with

a small amount of the excess of the starting alkyne, as

an ivory foam, could not be separated. Thus only a

partial characterization of them was possible. The two

diastereoisomers were however separated and fully

characterized after trityl and 4-methoxybenzyl removal

to give 26 and 27, respectively (see experimental below).

R_f0.50 (8l and 9l) (PE/Et₂O 6:4, A, B). Characterization

4.14.11.

4-{(S*)-[1-Methyl-2-trityloxy]ethyl}-2-{(R*)-

[(trimethylsilyl)ethynyl]}-2H-quinoline-1-carboxylic acid

phenyl ester, 8j and its epimer, 9j. Both components of

the mixture 8,9j, as a white foam, could not be sepa-

rated. By crystallization with Et₂O/PE nearly pure 8j

(containing only 1% of 9j by HPLC) was obtained. Mp

126.9–125.7°C (Et₂O/PE). R_f0.35 (8j and 9j) (PE/Et₂O

9:1, A, B). Characterization of 8j: IR: w_max2977, 1712,

1383, 1111, 1071. GC–MS: unsuitable for this analysis.

¹H NMR: 0.13 [9H, s, –Si(CH₃)₃]; 1.44 [3H, d,

>CHCH₃, J=6.5]; 3.07–3.13 [1H, m, >CHCH₃]; 3.25–

3.36 [2H, m, >CHCH₂O–]; 6.03 [2H, apparent s, H₂and

H₃]; 7.03 [1H, broad s, H₆]; 7.17–7.47 [22H, m, H₅, H₇,

Ph, Tr]; 7.83 [1H, broad d, H₈, J=7.8]. ¹³C NMR:

−0.14 [3C, –Si(CH₃)₃]; 16.39 [>CHCH₃]; 34.25

[>CHCH₃]; 45.15 [C₂]; 67.26 [–CH₂O–]; 86.24 [–CPh₃];

88.43 and 101.64 [2C, –CꢀC–TMS]; 121.38 [C₈]; 121.63

[2C, C ortho of Ph]; 123.25, 124.81, 125.04 and 127.26

[4C, C₃, C₅, C₆, C₇]; 125.47 [C para of Ph]; 126.74 [3C,

C para of Tr]; 127.65 and 128.61 [12C, C ortho and

meta of Tr]; 128.22 [C_4a]; 129.15 [2C, C meta of Ph];

134.29 [C₄]; 137.72 [C_8a]; 144.13 [3C, C ipso of Tr];

150.93 [C ipso of Ph]; 151.80 [CO]. Characterization of

9j (this compound was obtained pure after reduction of

30, see experimental below): IR: w_max2955, 2922, 1708,

1377, 1305, 1190, 1066, 1017. GC–MS: unsuitable for

1

of 8,9l: GC–MS: unsuitable for this analysis. H NMR:

1.18 [3H, d, >CHCH₃(9l), J=6.6]; 1.35 [3H, d,

>CHCH₃(8l), J=6.6]; 2.95–3.35 [3H, m, >CHCH₂O–

(8,9l)]; 3.78 [3H, s, –OCH₃(9l)]; 3.79 [3H, s, –OCH₃

(8l)]; 3.87 [2H, broad s, –OCH₂CꢀC– (9l)]; 3.98 [2H, d,

–OCH₂CꢀC– (8l), J=1.5]; 4.18 [2H, s, –OCH₂Ar (9l)];

4.28 [2H, s, –OCH₂Ar (8l)]; 5.84–6.08 [2H, m, H₂and

H₃(8,9l)]; 6.75–7.48 [27H, m, H₅, H₆, H₇, –OPh,

p-OMeC₆H₄, Tr (8,9l)]; 7.73 [1H, broad d, H₈, J=7.5

(8,9l)].

4.14.14. 4-{(S)-[1-(Acetoxy)methyl-2-trityloxy]ethyl}-2-

{(R)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-carboxylic

acid phenyl ester, 8m and its epimer, 9m. Diastereoiso-

mers 8,9m were in part separated by chromatography

with PE/Et₂O 95:56:4 both as white foams. R_f0.36

(8m) and 0.26 (9m) (PE/Et₂O 8:2, A, B). Characteriza-

tion of 8m: [h]_D=+115.1 (c 1.08, CHCl₃). IR: w_max2962,

2168, 1726, 1382, 1325, 1239, 1074, 1023. GC–MS:

unsuitable for this analysis. ¹H NMR: 0.005 [9H, s,

–Si(CH₃)₃]; 1.94 [3H, s, –COCH₃]; 3.21 [2H, apparent

d, –CH₂OTr, J=4.8]; 3.38 [1H, quintuplet,

–CH(CH₂O–)₂, J=5.7]; 4.45 and 4.92 [2H, AB part of

ABX system, –CH₂OAc, J_AB=11.0, J_AXand J_BX=6.1,

6.7]; 5.93 [2H, apparent s, H₂and H₃]; 6.91 [1H, broad

d, H₆, J=7.2]; 7.08–7.34 [22H, m, H₅, H₇, Ph, Tr]; 7.73

[1H, broad d, H₈, J=7.5]. ¹³C NMR: −0.26 [3C,

–Si(CH₃)₃]; 20.81 [–COCH₃]; 38.75 [–CH(CH₂O–)₂];

44.81 [C₂]; 62.07 and 63.59 [2C, –CH(CH₂O–)₂]; 86.38

[–CPh₃]; 88.64 and 101.05 [2C, –CꢀC–TMS]; 115.28,

122.56, 123.03, 124.99 and 125.19 [5C, C₃, C₅, C₆, C₇,

C₈]; 121.62 [2C, C ortho of Ph]; 125.62 [C para of Ph];

126.90 [3C, C para of Tr]; 127.69 [C_4a]; 127.76 and

128.51 [12C, C ortho and meta of Tr]; 129.23 [2C, C

meta of Ph]; 133.41 and 134.41 [2C, C₄and C_8a]; 143.74

[3C, C ipso of Tr]; 150.83 [C ipso of Ph]; 151.82

[–OCOPh]; 170.92 [–COCH₃]. Characterization of 9m:

[h]_D=−83.1 (c 0.79, CHCl₃). IR: w_max2959, 2169, 1715,

1

this analysis. H NMR: 0.07 [9H, s, –Si(CH₃)₃]; 1.19

[3H, d, >CHCH₃, J=6.6]; 3.08–3.36 [3H, m,

>CHCH₂O–]; 5.82 and 5.89 [2H, AB system, H₂and

H₃, J_AB=7.0]; 7.10–7.50 [23H, m, H₅, H₆, H₇, Ph, Tr];

7.72 [1H, broad d, H₈, J=7.8]. ¹³C NMR: −0.32 [3C,

–Si(CH₃)₃]; 18.06 [>CHCH₃]; 34.46 [>CHCH₃]; 44.92

[C₂]; 67.33 [–CH₂O–]; 86.50 [–CPh₃]; 88.48 and 101.30

[2C, –CꢀC–TMS]; 120.85 [C₈]; 121.66 [2C, C ortho of

Ph]; 123.39, 124.84 [most likely 2C] and 127.36 [4C, C₃,

C₅, C₆, C₇]; 125.67 [C para of Ph]; 126.87 [3C, C para of

Tr]; 127.76 and 128.85 [12C, C ortho and meta of Tr];

128.36 [C_4a]; 129.34 [2C, C meta of Ph]; 134.16 [C₄];

138.02 [C_8a]; 144.15 [3C, C ipso of Tr]; 151.00 [C ipso of

Ph]; 151.92 [CO].

4.14.12. 2-{(R*)-[3-(Benzyloxy)prop-1-ynyl]}-4-{(S*)-[1-

methyl-2-trityloxy]ethyl}-2H-quinoline-1-carboxylic acid

phenyl ester, 8k and its epimer, 9k. Both components of

the mixture 8,9k, together with the excess of the start-

ing alkyne, as a white foam, could not be separated.

Thus only a partial characterization of them was possi-

ble. The two diastereoisomers were however separated

and fully characterized after trityl and benzyl removal

to give 26 and 27, respectively (see experimental below).

R_f0.64 (8k and 9k) (PE/Et₂O 6:4, A, B). Characteriza-

1

1380, 1240. GC–MS: unsuitable for this analysis. H

NMR: 0.00 [9H, s, –Si(CH₃)₃]; 2.01 [3H, s, –COCH₃];

3.34–3.65 [3H, m, >CHCH₂OTr]; 4.31–4.46 [2H, m,

–CH₂OAc]; 6.04 and 6.07 [2H, AB system, H₂and H₃,

1

tion of 8,9k: GC–MS: unsuitable for this analysis. H

NMR: 1.19 [3H, d, >CHCH₃(9k), J=6.7]; 1.34 [3H, d,

>CHCH₃(8k), J=6.6]; 2.99–3.35 [3H, m, >CHCH₂O–

(8,9k)]; 3.89 [2H, d, –OCH₂CꢀC– (9k), J=1.3]; 4.02

J_AB=7.0]; 6.90–7.34 [23H, m, H₅, H₆, H₇, Ph, Tr]; 7.72

[1H, broad d, H₈, J=7.2]. ¹³C NMR: −0.37 [3C,

–Si(CH₃)₃]; 20.81 [–COCH₃]; 39.18 [–CH(CH₂O–)₂];

2720

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

meta to –OMe]; 133.35 and 134.24 [2C, C₄and C_8a];

135.55 [C para to –OMe]; 144.25 and 144.37 [2C, C ipso

of MMTr]; 150.98 [C ipso of Ph]; 151.92 [–OCOPh];

158.53 [COMe of MMTr]; 170.87 [–COCH₃].

44.85 [C₂]; 62.43 and 64.14 [2C, –CH(CH₂O–)₂]; 86.77

[–CPh₃]; 88.79 and 101.74 [2C, –CꢀC–TMS]; 121.63

[2C, C ortho of Ph]; 122.92, 123.07, 125.01 [most likely

2C] [4C, CH of 1,2-dihydroquinoline]; 125.62 [C para

of Ph]; 126.97 [3C, C para of Tr]; [C_4a: overlapped with

other signals]; 127.82 and 128.78 [12C, C ortho and

meta of Tr]; 129.37 [2C, C meta of Ph]; 133.26 and

134.21 [2C, C₄and C_8a]; 143.80 [3C, C ipso of Tr];

150.96 [C ipso of Ph]; 151.90 [–OCOPh]; 170.84

[–COCH₃].

4.14.16. 4-{(S)-[1-(Triethylsilyloxy)methyl-2-trityloxy]-

ethyl}-2-{(R)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-

carboxylic acid phenyl ester, 8o and its epimer, 9o. Both

components of the mixture 8,9o, as a yellow oil, could

not be separated. R_f0.85 (8o and 9o) (PE/Et₂O 6:4, A,

B). Characterization of 8,9o: IR: w_max2950, 2313, 2170,

1712, 1594, 1447, 1380, 1304, 1084. GC–MS: unsuitable

for this analysis. ¹H NMR: −0.14 [9H, s, –Si(CH₃)₃

(9o)]; 0.02 [9H, s, –Si(CH₃)₃(8o)]; 0.50 [6H, broad q,

–Si(CH₂CH₃)₃, J=8.0 (9o)]; 0.56 [6H, broad q,

–Si(CH₂CH₃)₃, J=8.0 (8o)]; 0.83 [9H, t, –Si(CH₂CH₃)₃,

J=7.9 (9o)]; 0.91 [9H, t, –Si(CH₂CH₃)₃, J=7.9 (8o)];

3.12–3.38 [2H, m, –CH₂OTr (8,9o)]; 3.53–3.81 [1H, m,

–CH(CH₂O–)₂(8,9o)]; 3.90–4.04 [2H, m, –CH₂OTES];

5.86 and 5.89 [2H, AB system, H₂and H₃, J_AB=6.8

(9o)]; 5.93 and 5.93 [2H, AB system, H₂and H₃,

4.14.15. 4-{(S)-[1-(Acetoxy)methyl-2-(p-methoxyphenyl)-

diphenylmethoxy]ethyl}-2-{(R)-[(trimethylsilyl)ethynyl]}-

2H-quinoline-1-carboxylic acid phenyl ester, 8n and its

epimer, 9n. Diastereoisomers 8,9n were in part sepa-

rated by chromatography with PE/Et₂O 7:33:7 both

as yellow foams. R_f0.49 (8n) and 0.41 (9n) (PE/Et₂O

6:4, A, B). Characterization of 8n: [h]_D=+207.9 (c 1.46,

CHCl₃). IR: w_max3006, 2393, 1722, 1379, 1189. GC–

1

MS: unsuitable for this analysis. H NMR: 0.03 [9H, s,

–Si(CH₃)₃]; 1.97 [3H, s, –COCH₃]; 3.16–3.28 [2H, m,

–CH₂OMMTr]; 3.39 [1H, quintuplet, –CH(CH₂O–)₂,

J=5.7]; 3.72 [3H, s, –OCH₃]; 4.47 and 4.52 [2H, AB

part of ABX system, –CH₂OAc, J_AB=10.8, J_AXand

J_AB=6.4 (8o)]; 6.90 [1H, broad d, H₆, J=6.6 (8,9o)];

7.08–7.49 [22H, m, H₅, H₇, Ph, Tr (8,9o)]; 7.73 [1H,

broad d, H₈, J=7.0 (8,9o)]. ¹³C NMR: −0.37 [3C,

–Si(CH₃)₃(9o)]; −0.24 [3C, –Si(CH₃)₃(8o)]; 4.31 [3C,

–Si(CH₂CH₃)₃(9o)]; 4.40 [3C, –Si(CH₂CH₃)₃(8o)]; 6.75

[3C, –Si(CH₂CH₃)₃(9o)]; 6.88 [3C, –Si(CH₂CH₃)₃(8o)];

42.38 [–CH(CH₂O–)₂(8o)]; 42.55 [–CH(CH₂O–)₂(9o)];

44.86 [C₂(8o)]; 44.98 [C₂(9o)]; 62.49, 62.82 and 62.98

[4C, –CH(CH₂O–)₂(8,9o)]; 86.22 [–CPh₃(9o)]; 86.55

[–CPh₃(8o)]; 88.24 and 101.44 [2C, –CꢀC–TMS (8o)];

88.55 and 101.05 [2C, –CꢀC–TMS (9o)]; 121.61 [2C, C

ortho of Ph (9o)]; 121.67 [2C, C ortho of Ph (8o)];

122.03, 123.33, 124.85, 127.30 and 128.88 [5C, C₃, C₅,

C₆, C₇, C₈(8o)]; 122.03, 123.45, 125.30, 127.46 and

128.88 [5C, C₃, C₅, C₆, C₇, C₈(9o)]; 125.53 [C para of

Ph (8o)]; 125.64 [C para of Ph (9o)]; 126.76 [3C, C para

of Tr (8,9o)]; 127.66, 127.69 and 128.63 [12C, C ortho

and meta of Tr (8,9o)]; 129.33 [2C, C meta of Ph (8o)];

129.45 [2C, C meta of Ph (9o)]; 134.21 and 134.86 [2C,

C₄and C_8a(9o)]; 134.26 and 134.50 [2C, C₄and C_8a

(8o)]; 144.02 [3C, C ipso of Tr (8o)]; 144.11 [3C, C ipso

of Tr (9o)]; 150.89 [C ipso of Ph (8o)], 151.00 [C ipso of

Ph (9o)]; 151.86 [CO (8,9o)].

J_BX=6.1, 6.7]; 5.95 [2H, s, H₂and H₃]; 6.74 [2H,

apparent d, H ortho to –OMe, J=8.8]; 6.95 [1H, broad

d, H₆, J=7.0]; 7.11–7.43 [19H, m, H₅, H₇, Ph, 2 Ph of

MMTr and H meta to –OMe]; 7.74 [1H, broad d, H₈,

J=8.0]. ¹³C NMR: −0.24 [3C, –Si(CH₃)₃]; 20.84

[–COCH₃]; 38.79 [–CH(CH₂O–)₂]; 44.84 [C₂]; 55.15

[–OCH₃]; 62.03 and 63.67 [2C, –CH(CH₂O–)₂]; 86.11

[–CPh₂Ar]; 88.66 and 101.08 [2C, –CꢀC–TMS]; 113.05

[2C, C ortho to –OMe]; 115.29, 122.54, 123.05, 124.98

and 125.20 [5C, C₃, C₅, C₆, C₇, C₈]; 121.65 [2C, C ortho

of Ph]; 125.64 [C para of Ph]; 126.77 [2C, C para of Ph

of MMTr]; 127.67 [C_4a]; 127.78, 128.23 and 128.28 [8C,

C ortho and meta of Ph of MMTr]; 129.25 [2C, C meta

of Ph]; 130.21 [2C, C meta to –OMe]; 133.44 and 134.43

[2C, C₄and C_8a]; 135.43 [C para to –OMe]; 144.25 and

144.32 [2C, C ipso of MMTr]; 150.86 [C ipso of Ph];

151.83 [–OCOPh]; 158.44 [COMe of MMTr]; 170.94

[–COCH₃]. Characterization of 9n: [h]_D=−179.3 (c 0.44,

CHCl₃). IR: w_max2928, 2854, 2171, 1725, 1377, 1248,

1

1068, 1018. GC–MS: unsuitable for this analysis. H

NMR: −0.11 [9H, s, –Si(CH₃)₃]; 1.90 [3H, s, –COCH₃];

3.32–3.50 [3H, m, >CHCH₂OMMTr]; 3.78 [3H, s,

–OCH₃]; 4.26 and 4.26 [2H, AB part of ABX system,

–CH₂OAc, J_AB=11.6, J_AXand J_BX=6.6, 6.6]; 5.92 and

5.95 [2H, AB system, H₂and H₃J_AB=7.0]; 6.81 [2H,

dt, H ortho to –OMe, J=8.8]; 7.13–7.48 [20H, m, H₅,

H₆, H₇, Ph, 2 Ph of MMTr and H meta to –OMe]; 7.30

[1H, broad d, H₈, J=7.0]. ¹³C NMR: −0.33 [3C,

–Si(CH₃)₃]; 20.83 [–COCH₃]; 39.26 [–CH(CH₂O–)₂];

44.87 [C₂]; 55.19 [–OCH₃]; 62.39 and 64.22 [2C,

–CH(CH₂O–)₂]; 86.52 [–CPh₂Ar]; 88.80 and 101.82 [2C,

–CꢀC–TMS]; 113.09 [2C, C ortho to –OMe]; 121.66

[2C, C ortho of Ph]; 122.97, 123.11, 125.01 [most likely

2C] [4C, CH of 1,2-dihydroquinoline]; 125.75 [C para

of Ph]; 126.85 [2C, C para of Ph of MMTr]; 127.67

[C_4a]; 127.82, and 128.53 [8C, C ortho and meta of Ph

of MMTr]; 129.38 [2C, C meta of Ph]; 130.48 [2C, C

4.15. (2S*,3S*,4R*)-3,4-Epoxy-4-{(S*)-[1-methyl-2-

trityloxy]ethyl}-2-[(trimethylsilyl)ethynyl]-3,4-dihydro-

2H-quinoline-1-carboxylic acid phenyl ester, 11 and its

epimer, 12

A solution of 8 or 9j (324 mg, 500 mmol) in dry CH₂Cl₂

(10 ml) was cooled to 0°C and treated with mCPBA

(1.0 mmol). After stirring until complete (about 3 h) the

reaction was quenched with Me₂S (86 ml, 1.17 mmol)

and stirred at rt in the presence of NaHCO₃sat. sol. for

an additional 15 min. Usual extraction with Et₂O was

followed by chromatography with PE/Et₂O (85:15) to

give 11 (92% yield) as a white solid, which was crystal-

lized from PE/Et₂O, and 12 (90% yield) as a pale yellow

oil. Characterization of 11: Mp: 151.5–151.9°C (PE/

Et₂O). R_f0.41 (PE/Et₂O 8:2, A, B). IR: w_max2963, 2928,

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2721

J=2.5, 10.9, after exchange with D₂O, –CHHOH];

3.98–4.10 [2H, m; became at 4.00, J=9.6,

2176, 1721, 1488, 1191. GC–MS: unsuitable for this

analysis. H NMR: −0.02 [9H, s, –Si(CH₃)₃]; 1.27 [3H,

1

a

t

–CHHOH and a d at 4.02, J=9.4, H₃, after exchange

with D₂O]; 4.96 [1H, d, H₂, J=9.4]; 5.97 [1H, broad s,

–OH]; 7.16–7.42 [8H, m, H₅, H₆, H₇and Ph]; 7.72 [1H,

broad d, H₈, J=7.3]. ¹³C NMR: −0.01 [3C, –Si(CH₃)₃];

13.69 [>CHCH₃]; 38.45 [>CHCH₃]; 50.55 [–OCH₃];

52.03 [C₂]; 63.62 [–CH₂O–]; 74.32 [C₃]; 80.71 [C₄]; 87.62

and 104.59 [2C, –CꢀC–TMS]; 121.58 [2C, C ortho of

Ph]; 124.82, 125.46, 126.02, and 127.38 [4C, C₅, C₆, C₇,

C₈]; 125.71 [C para of Ph]; 129.34 [2C, C meta of Ph];

133.07 and 134.40 [2C, C_4aand C_8a]; 151.14 [C ipso of

Ph]; 152.56 [CO]. Characterization of 14: R_f0.39 (PE/

Et₂O 4:6, A, B). IR: w_max3302, 2170, 1725, 1365, 1088.

GC–MS: R_t13.52; m/z 404 (M⁺−49, 6.1), 394 (13), 378

(8.4), 377 (27), 376 (100), 334 (9.2), 301 (5.3), 300 (18),

256 (19), 244 (5.4), 242 (6.8), 240 (5.3), 226 (5.6), 216

(6.1), 210 (6.8), 202 (13), 190 (6.9), 170 (6.7), 169 (6.8),

168 (49), 162 (8.1), 160 (5.8), 158 (14), 146 (16), 144

(6.7), 140 (5.9), 132 (5.9), 130 (23), 115 (5.5), 97 (8.6),

95 (7.6), 94 (29), 91 (5.3), 90 (5.2), 89 (8.6), 83 (7.5), 77

(30), 75 (15), 74 (7.6), 73 (89), 66 (6.0), 65 (7.6), 59 (11),

d, >CHCH₃, J=6.2]; 2.94–3.06 and 3.43–3.53 [3H, m,

>CHCH₂O–]; 3.88 [1H, d, H₃, J=3.2]; 5.71 [1H, d, H₂,

J=3.0]; 7.08–7.50 [24H, m, aromatics]. ¹³C NMR:

−0.44 [3C, –Si(CH₃)₃]; 15.25 [>CHCH₃]; 33.02

[>CHCH₃]; 44.75 [C₂]; 58.65 [C₄]; 63.82 [C₃]; 64.01

[–CH₂O–]; 86.92 [–CPh₃]; 91.71 and 99.22 [2C, –CꢀC–

TMS]; 121.55 [2C, C ortho of Ph]; 125.49, 125.55,

127.29, 128.08 and 128.76 [5C, C₅, C₆, C₇, C₈, C para of

Ph]; 127.00 [3C, C para of Tr]; 127.49 [C_4a]; 127.73 and

128.85 [12C, C ortho and meta of Tr]; 129.24 [2C, C

meta of Ph]; 135.54 [C_8a]; 144.20 [3C, C ipso of Tr];

151.20 [C ipso of Ph]; 153.43 [CO]. Characterization of

12: R_f0.41 (PE/Et₂O 8:2, A, B). IR: w_max3005, 2396,

1716, 1379, 1323, 1190, 1065. GC–MS: unsuitable for

1

this analysis. H NMR: −0.01 [9H, s, –Si(CH₃)₃]; 1.16

[3H, d, >CHCH₃, J=6.8]; 2.81–2.91 [1H, m,

>CHCH₂O–]; 3.16 and 3.30 [2H, AB part of ABX

system, >CHCH₂O–, J_AB=9.7, J_AXand J_BX=5.5, 7.2];

3.85 [1H, d, H₃, J=3.1]; 5.72 [1H, d, H₂, J=2.9];

7.05–7.49 [24H, m, aromatics]. ¹³C NMR: −0.49 [3C,

–Si(CH₃)₃]; 12.76 [>CHCH₃]; 33.84 [>CHCH₃]; 44.80

[C₂]; 57.18 [C₄]; 63.52 [C₃]; 64.82 [–CH₂O–]; 86.88

[–CPh₃]; 91.35 and 98.97 [2C, –CꢀC–TMS]; 121.58 [2C,

C ortho of Ph]; 125.57 [most likely 2C], 127.02, and

127.27 [4C, 3C (between C₅, C₆, C₇, C₈, while one is

overlapped with other signals), C para of Ph]; 127.50

[C_4a]; 127.86 [3C, C para of Tr]; 127.94 and 128.71

[12C, C ortho and meta of Tr]; 129.26 [2C, C meta of

Ph]; 135.44 [C_8a]; 144.12 [3C, C ipso of Tr]; 146.88 [C

ipso of Ph]; 151.11 [CO].

1

55 (5.2), 45 (7.5), 43 (6.4), 39 (5.9). H NMR: 0.13 [9H,

s, –Si(CH₃)₃]; 1.15 [3H, d, >CHCH₃, J=7.3]; 2.15 [1H,

center of m, >CHCH₂O–]; 2.87 [1H, broad s, –OH];

3.36 [3H, s, –OCH₃]; 3.32–3.43 [1H, m; became a dd at

3.38, J=5.5, 11.1, after exchange with D₂O,

–CHHOH]; 3.82 [1H, broad d, J=10.7; became a dd,

J=2.6, 11.1, after exchange with D₂O, –CHHOH]; 4.05

[1H, broad s, –OH]; 4.21–4.25 [1H, m, became a d at

4.23, J=7.6, after exchange with D₂O, H₃]; 5.07 [1H, d,

H₂, J=7.7]; 7.14–7.43 [8H, m, H₅, H₆, H₇and Ph]; 7.75

[1H, broad d, H₈, J=8.3]. ¹³C NMR: −0.16 [3C,

–Si(CH₃)₃]; 12.63 [>CHCH₃]; 41.09 [>CHCH₃]; 50.80

[–OCH₃]; 52.66 [C₂]; 64.79 [–CH₂O–]; 75.36 [C₃]; 81.86

[C₄]; 88.98 and 103.82 [2C, –CꢀC–TMS]; 121.57 [2C, C

ortho of Ph]; 124.91, 125.58, 125.72 [most likely 2C] and

127.80, [5C, C₅, C₆, C₇, C₈, C para of Ph]; 129.35 [2C,

C meta of Ph]; 131.12 and 135.58 [2C, C_4aand C_8a];

151.15 [C ipso of Ph]; 152.42 [CO].

4.16. (2S*,3S*,4S*)-3-Hydroxy-4-{(R*)-[2-hydroxy-1-

methyl]ethyl}-4-methoxy-2-[(trimethylsilyl)ethynyl]-3,4-

dihydro-2H-quinoline-1-carboxylic acid phenyl ester, 13

and its epimer, 14

A suspension of 11 or 12 (122 mg, 184 mmol) in dry

methanol (5 ml) was cooled to 0°C and treated with

pTSA (35 mg, 184 mmol). After 5 min the reaction ﬂask

was allowed to stir at rt for 2 h and gradually a pale

yellow solution was obtained. Neutralization with solid

NaHCO₃(16 mg, 184 mmol) was followed by careful

evaporation of methanol under reduced pressure at

:15°C. The residue was partitioned between water and

Et₂O and extracted as usual. Chromatography with

PE/Et₂O (1:1) gave the corresponding diols 13 (50 mg,

60% yield) or 14 (42 mg, 51% yield) as pale yellow oils.

Characterization of 13: R_f0.36 (PE/Et₂O 1:1, A, B). IR:

w_max3309, 2964, 2174, 1723, 1368, 1324, 1098. GC–MS:

R_t13.48; m/z 404 (M⁺−49, 5.6), 394 (5.3), 377 (8.5), 376

(30), 300 (14), 256 (7.5), 216 (6.1), 202 (13), 190 (6.6),

170 (5.6), 169 (6.6), 168 (44), 162 (7.8), 160 (5.1), 158

(15), 146 (14), 144 (5.5), 140 (5.6), 132 (6.5), 130 (24),

97 (9.8), 95 (8.0), 94 (28), 89 (8.2), 83 (7.7), 77 (31), 75

(16), 74 (9.1), 73 (100), 66 (5.2), 65 (7.7), 59 (12), 51

4.17. (2S*,3S*,4S*)-2-Ethynyl-3-hydroxy-4-{(R*)-[2-

hydroxy-1-methyl]ethyl}-4-methoxy-3,4-dihydro-2H-

quinoline-1-carboxylic acid methyl ester, 15

The oxirane opening was performed under the same

conditions described for the preparation of 13 and 14,

starting from 301 mg (453 mmol) of 11. Crude product

(or either chromatographed as previously reported),

obtained after solvent removal, was dissolved in dry

methanol (5 ml) and heated at 40°C for 3 h, after solid

NaHCO₃(241 mg, 2.87 mmol) has been added. The

mixture was concentrated under reduced pressure, par-

titioned between water and Et₂O and extracted as

usual. Chromatography with PE/Et₂O 1:1Et₂O gave,

as prevailing product, 15 (70 mg, 50% from 11) as a

pale yellow oil. R_f0.14 (PE/Et₂O 4:6, A, B). IR: w_max

3303, 2955, 1702, 1440, 1337, 1192, 1097. GC–MS: R_t

9.48; m/z 319 (M⁺, 3.6), 271 (5.0), 270 (28), 261 (15),

260 (92), 258 (10), 243 (13), 242 (84), 232 (5.8), 228 (24),

1

(5.4), 45 (8.7), 43 (7.3), 39 (6.1). H NMR: 0.17 [9H, s,

–Si(CH₃)₃]; 0.68 [3H, d, >CHCH₃, J=7.0]; 2.01 [1H,

center of m, >CHCH₂O–]; 2.04 [1H, s, –OH]; 3.44 [3H,

s, –OCH₃]; 3.50–3.88 [1H, m; became a dd at 3.52,

2722

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

4.19. (2S*,3S*,4S*)-3-Acetoxy-4-{(R*)-[2-acetoxy-1-

methyl]ethyl}-4-methoxy]-2-[(trimethylsilyl)ethynyl]-3,4-

dihydro-2H-quinoline-1-carboxylic acid phenyl ester, 17

209 (6.9), 202 (14), 201 (16), 200 (100), 192 (11), 187

(6.6), 186 (8.8), 185 (23), 184 (7.4), 177 (5.6), 174

(6.3), 172 (6.2), 170 (8.4), 169 (5.7), 168 (17), 167

(8.9), 162 (5.5), 158 (7.4), 156 (8.3), 154 (10), 146

(25), 144 (9.7), 143 (11), 142 (7.1), 141 (18), 140 (7.4),

132 (11), 130 (17), 129 (11), 128 (12), 117 (6.8), 116

A solution of 13 (16 mg, 35 mmol) in dry CH₂Cl₂(3 ml)

was treated, at 0°C, with triethylamine (15 ml, 106

mmol), 4-dimethylaminopyridine (1.0 mg, 8.2 mmol) and

acetic anhydride (10 ml, 106 mmol). After 5 min, the

solution was stirred at rt until the reaction was com-

plete (about 3 h), and then partitioned between water

and Et₂O and ﬁnally extracted with the same solvent.

Chromatography with PE/Et₂O (7:3) gave pure 17 (12

mg, 63%) as a pale yellow oil. R_f0.57 (PE/Et₂O 1:1, A,

B). IR: w_max3015, 2962, 2177, 1728, 1374, 1323, 1194,

1030. GC–MS: R_t13.57; m/z 446 (M⁺−91, 2.5), 376

(100), 268 (6.9), 210 (5.2), 202 (12), 170 (6.0), 117 (6.4),

1

(5.9), 115 (18), 91 (5.1), 77 (7.2), 59 (10). H NMR:

0.66 [3H, d, >CHCH₃, J=7.1]; 1.90 [1H, broad s,

–OH]; 1.93 [1H, center of m, >CHCH₂O–]; 2.41 [1H,

d, –CꢀCH, J=2.0]; 3.41 [3H, s, –OCH₃]; 3.58 [1H,

dd, –CHHOH, J=2.9, 10.8]; 3.82 [3H, s, –CO₂CH₃];

3.90–4.10 [2H, m; became a d at 4.02, J=9.5, H₃and

a t at 4.65, J=9.7, –CHHOH, after exchange with

D₂O]; 4.81 [1H, dd, H₂, J=1.7, 9.5]; 6.13 [1H, broad

s, –OH]; 7.14–7.38 [3H, m, H₅, H₆, H₇]; 7.59 [1H,

broad d, H₈, J=7.7]. ¹³C NMR: 13.56 [>CHCH₃];

38.14 [>CHCH₃]; 50.45 [–OCH₃]; 50.85 [C₂]; 53.44

[–CO₂CH₃]; 63.41 [–CH₂O–]; 70.51 [–CꢀCH]; 74.27

[C₃]; 80.43 [C₄]; 83.45 [–CꢀCH]; 124.58, 125.41,

125.90 and 127.27, [4C, C₅, C₆, C₇, C₈]; 132.78 and

134.28 [2C, C_4aand C_8a]; 154.68 [CO].

1

77 (14), 75 (10), 73 (30), 43 (5.2). H NMR: 0.07 [9H, s,

–Si(CH₃)₃]; 0.90 [3H, d, >CHCH₃, J=6.9]; 2.03 and

2.19 [6H, 2 s, –COCH₃]; 2.28–2.45 [1H, m, >CHCH₂O–];

3.24 [3H, s, –OCH₃]; 3.87 [1H, dd, –CHHOAc, J=9.3,

10.9]; 4.68 [1H, dd, –CHHOAc, J=3.7, 11.0]; 5.30 [1H,

d, H₃, J=6.4]; 5.61 [1H, d, H₂, J=6.4]; 7.17–7.43 [8H,

m, H₅, H₆, H₇and Ph]; 7.72 [1H, broad d, H₈, J=8.0].

4.18. (6R*,6aS*,11R*,11aS*)-6-Ethynyl-11a-methoxy-

8,8,11-trimethyl-6a,10,11,11a-tetrahydro-6H-7,9-dioxa-

5-aza-cyclohepta[a]naphthalene-5-carboxylic acid methyl

ester, 16

4.20. (1S*,3aS*,4S*,9bS*)-9b-Methoxy-1-methyl-2-

oxo-4-[(trimethylsilyl)ethynyl]-1,3a,4,9b-tetrahydro-2H-

furo[2,3-c]quinoline-5-carboxylic acid phenyl ester, 18

and its epimer, 19

A solution of 15 (54 mg, 170 mmol) in dry CH₂Cl₂(4

ml) was cooled to 0°C and treated with 2-

methoxypropene (33 ml, 341 mmol) and p-TSA (34

mml of a 0.1 M sol. in THF). After 10 min the solu-

tion was diluted with 5% aq NaHCO₃and extracted

with Et₂O. Chromatography with PE/Et₂O 7:3 fur-

nished pure 16 as a pale yellow oil. R_f0.14 (PE/Et₂O

4:6, A, B). IR: w_max3303, 2991, 2955, 2124, 1709,

1439, 1383, 1329, 1133, 1046. GC–MS: R_t8.94; m/z

359 (M⁺, 29), 301 (9.8), 286 (10), 273 (17), 272 (77),

258 (10), 242 (23), 240 (20), 234 (58), 232 (16), 231

(12), 230 (83), 229 (10), 218 (21), 215 (12), 212 (16),

205 (59), 202 (45), 198 (14), 192 (16), 187 (9.6), 184

(16), 182 (18), 181 (16), 180 (22), 174 (9.6), 172 (9.7),

170 (21), 168 (14), 167 (26), 160 (11), 156 (12), 154

(15), 146 (27), 144 (9.6), 143 (12), 142 (9.6), 141 (10),

140 (11), 130 (14), 129 (12), 128 (19), 127 (10), 115

(21), 101 (12), 91 (13), 90 (13), 77 (24), 73 (14), 69

(22), 59 (100), 51 (15), 45 (17), 43 (62), 42 (12), 41

(34), 39 (27). ¹H NMR: 0.59 [3H, d, >CHCH₃, J=

6.8]; 1.45 and 1.43 [6H, 2 s, >C(CH₃)₂]; 2.17 [1H, d,

–CꢀCH, J=2.5]; 2.37 [1H, center of m, >CHCH₂O–];

3.30 [3H, s, –OCH₃]; 3.65 and 3.67 [2H, AB part of

ABX system, –CH₂O–, J_AB=12.0, J_AXand J_BX=3.9,

13.2]; 3.83 [3H, s, –CO₂CH₃]; 4.48 [1H, d, H_6a, J=

3.0]; 5.44 [1H, t, H₆, J=2.7]; 7.15 [1H, dt, H₂, J=1.4,

7.4]; 7.24–7.34 [2H, m, H₁, H₃]; 7.53 [1H, broad d,

H₄, J=8.5]. ¹³C NMR: 12.64 [>CHCH₃]; 24.97 and

25.40 [2C, >C(CH₃)₂]; 39.82 [>CHCH₃]; 50.56 [C₆];

51.46 [–OCH₃]; 53.14 [–CO₂CH₃]; 66.06 [–CH₂O–];

73.21 [–CꢀCH]; 77.24 [C_6a]; 79.70 [C_11a]; 80.74

[–CꢀCH]; 101.87 [>C(CH₃)₂]; 123.57, 125.01, 127.42

and 128.20, [4C, C₁, C₂, C₃, C₄]; 130.66 and 136.59

[2C, C_4aand C_11b]; 154.43 [CO].

A solution of 13 or 14 (35 mg, 77 mmol) in dry CH₂Cl₂

(2 ml) was stirred for 5 min at rt in the presence of

,

powdered 4 A molecular sieves (10 mg). Then 4-methyl-

morpholine-N-oxide (25 ml, 232 mmol) and tetra-

propylammonium perruthenate (2.7 mg, 7.7 mmol) were

added and the resulting mixture was stirred for 30 min.

After concentration under reduced pressure, direct

chromatography with PE/Et₂O (8:2) gave 18 (22 mg,

62% yield) or 19 (21 mg, 61% yield) as pale yellow oils.

Characterization of 18: R_f0.41 (PE/Et₂O 7:3, A, B). IR:

w_max2960, 2180, 1784, 1727, 1381, 1327, 1246, 1045.

GC–MS: R_t12.90; m/z 449 (M⁺, 18), 357 (13), 356 (48),

322 (13), 321 (37), 300 (24), 268 (8.8), 228 (11), 196 (19),

190 (18), 180 (9.5), 173 (11), 172 (8.2), 168 (9.1), 167

(14), 158 (8.2), 157 (7.7), 146 (40), 142 (9.7), 141 (29),

130 (11), 97 (58), 90 (9.1), 89 (15), 83 (12), 77 (47), 75

(13), 74 (8.6), 73 (100), 69 (7.3), 65 (9.6), 59 (19), 55

(8.1), 51 (8.3), 45 (9.0), 43 (13), 39 (8.2). ¹H NMR:

−0.06 [9H, s, –Si(CH₃)₃]; 1.21 [3H, d, >CHCH₃, J=7.4];

2.52 [1H, q, >CHCH₃, J=7.4]; 3.38 [3H, s, –OCH₃];

5.10 [1H, s, H_3a]; 5.73 [1H, s, H₄]; 7.13–7.47 [8H, m, H₇,

H₈, H₉and Ph]; 7.66 [1H, broad d, H₆, J=7.4]. ¹³C

NMR: −0.65 [3C, –Si(CH₃)₃]; 7.20 [>CHCH₃]; 47.58

[>CHCH₃]; 50.82 [C₄]; 52.24 [–OCH₃]; 79.74 [C_9b];

85.93 [C_3a]; 93.71 and 99.16 [2C, –CꢀC–TMS]; 121.49

[2C, C ortho of Ph]; 124.43, 125.87, 125.97, 126.17 and

128.26 [5C, C₆, C₇, C₈, C₉, C para of Ph]; 129.46 [2C, C

meta of Ph]; 131.68 and 135.27 [2C, C_5aand C_9a];

151.14 [C ipso of Ph]; 152.56 [CO]; 176.12 [CO of

lactone]. Characterization of 19: R_f0.38 (PE/Et₂O 6:4,

A, B). IR: w_max2425, 2182, 1784, 1727, 1381, 1330,

1314, 1250, 1053. GC–MS (this lactone, unlike 18,

partially epimerizes in the column): R_t13.07; m/z 449

(M⁺, 17), 357 (11), 356 (41), 324 (12), 321 (21), 300 (18),

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2723

268 (8.0), 228 (11), 196 (18), 190 (18), 180 (11), 173

4.24. 8,9h by protection of 8,9d

(8.4), 172 (6.8), 168 (9.8), 167 (12), 158 (8.2), 146 (35),

142 (8.2), 141 (28), 130 (9.5), 97 (50), 90 (9.0), 89 (13),

83 (13), 77 (42), 75 (12), 74 (8.1), 73 (100), 65 (7.9), 59

The same procedure reported for the preparation of 5f

was followed starting from pure 8d or 9d and the

corresponding 8h and 9h were obtained in 67–68%

yield.

1

(18), 50 (9.4), 45 (8.8), 43 (10). H NMR: −0.05 [9H, s,

–Si(CH₃)₃]; 0.77 [3H, d, >CHCH₃, J=7.8]; 3.15 [1H, q,

>CHCH₃, J=7.8]; 3.35 [3H, s, –OCH₃]; 5.12 [1H, d,

H_3a, J=1.5]; 5.73 [1H, d, H₄, J=1.5]; 7.12–7.42 [8H, m,

H₇, H₈, H₉and Ph]; 7.65 [1H, broad d, H₆, J=7.7]. ¹³C

NMR: −0.72 [3C, –Si(CH₃)₃]; 12.68 [>CHCH₃]; 48.03

[>CHCH₃]; 49.69 [C₄]; 52.80 [–OCH₃]; 82.56 [C_9b];

85.67 [C_3a]; 93.61 and 99.03 [2C, –CꢀC–TMS]; 121.63

[2C, C ortho of Ph]; 125.58, 125.90, 126.10, 127.00 and

128.65 [5C, C₆, C₇, C₈, C₉, C para of Ph]; 129.44 [2C, C

meta of Ph]; 127.62 and 136.60 [2C, C_5aand C_9a];

150.88 [C ipso of Ph]; 152.04 [CO]; 175.86 [CO of

lactone].

4.25. 2-[(R*)-Ethynyl]-4-{(S*)-[1-methyl-2-trityloxy]-

ethyl}-2H-quinoline-1-carboxylic acid phenyl ester, 20

A solution of 8,9j (with a 82:18 d.r.) (247 mg, 381

mmol) in dry MeOH (4 ml) was treated with NaHCO₃

(128 mg, 1.52 mmol) and heated at 40°C for 2.5 h.

After addition of water, the mixture was extracted with

Et₂O. Chromatography with PE/Et₂O 9:17:3 gave

desired product (199 mg, 91%) as a white foam. Crys-

tallization from Et₂O/PE gave diastereomerically pure

20 as a white solid. Mp 160.7–161.6°C (Et₂O/PE). R_f

0.34 (PE/Et₂O 8:2, A, B). IR: w_max3303, 2962, 2037,

1712, 1447, 1377, 1302, 1067. GC–MS: unsuitable for

4.21. 8,9d by deprotection of 8,9c, 8,9e and 8,9j

From 8,9c and 8,9e: protective group has been removed

in both cases on 8c,e and 9c,e. A solution of substrate

(100 mmol) in acetonitrile (1 ml) was cooled to −20°C

and treated with :11% HF in acetonitrile. After 1.5 h

a stoichiometric amount of solid NaHCO₃with respect

to HF was added and the mixture was diluted with

water and extracted with Et₂O. Chromatography with

PE/Et₂O (1:1) gave the corresponding alcohol 8d or 9d

(yields, in the range 73–74% for both stereoisomers and

whatever the starting silyl ether, have been improved up

to 91%, performing the reaction on a 10 mmol scale of

8,9c mixture).

1

this analysis. H NMR: 1.34 [3H, d, >CHCH₃, J=6.5];

2.19 [1H, d, –CꢀCH, J=1.8]; 2.97–3.06 [1H, m,

>CHCH₃]; 3.13–3.29 [2H, m, >CHCH₂O–]; 5.93–6.01

[2H, m, H₂and H₃]; 6.92 [1H, broad s, H₆]; 7.09–7.38

[22H, m, H₅, H₇, Ph, Tr]; 7.74 [1H, broad d, H₈,

J=8.4]. ¹³C NMR 16.28 [>CHCH₃]; 34.15 [>CHCH₃];

44.09 [C₂]; 67.14 [–CH₂O–]; 71.55 [–CꢀCH]; 80.20

[–CꢀCH]; 86.19 [–CPh₃]; 120.82 [C₈]; 123.44, 125.08

[most likely 2C] and 127.60 [4C, C₃, C₅, C₆, C₇]; 121.60

[2C, C ortho of Ph]; 125.63 [C para of Ph]; 126.73 [3C,

C para of Tr]; 127.70 and 128.58 [12C, C ortho and

meta of Tr]; 128.83 [C_4a]; 129.24 [2C, C meta of Ph];

134.11 [C₄]; 138.28 [C_8a]; 144.10 [3C, C ipso of Tr];

150.83 [C ipso of Ph], 151.83 [CO].

From 8,9j: A solution of 8,9j (65 mg, 100 mmol) in dry

methanol (2 ml) was cooled to 0°C and treated with

pTSA (19 mg, 100 mmol), then, after 5 min, the solution

was allowed to stir at rt for 1.5 h. A stoichiometric

amount of solid NaHCO₃with respect to pTSA was

added and the mixture was carefully concentrated

under reduced pressure at :15°C. Then it was diluted

with water and extracted with Et₂O. Chromatography

with PE/Et₂O (1:1) gave the corresponding alcohols 8d

or 9d with an overall 99% yield.

4.26. 2-{(R*)-[3-(Benzyloxy)prop-1-ynyl]}-4-{(S*)-[(2-

hydroxy-1-methyl)ethyl]}-2H-quinoline-1-carboxylic acid

phenyl ester 22 and its epimer 23 and 4-{(S*)-[(2-

hydroxy-1-methyl)ethyl]}-2-{(R*)-[3-(p-methoxybenzyl-

oxy)prop-1-ynyl]}-2H-quinoline-1-carboxylic acid phenyl

ester, 24 and its epimer, 25

4.22. 8f by protection of 8d

By reaction with p-TSA: the same procedure used for

the transformation of 8,9j into 8,9d, but working at rt,

was employed for the preparation of 22,23 and 24,25,

starting from 8,9k and 8,9l, respectively. Chromatogra-

phy with the appropriate eluent based on PE/Et₂O gave

the corresponding products as pale yellow oils and as

inseparable diastereoisomeric mixtures (22,23 in 63%

yield and 24,25 in 78% yield). By reaction with EtSH

and boron triﬂuoride: a solution of 8,9k or 8,9l (500

mmol) in dry CH₂Cl₂(10 ml) was cooled to 0°C and

treated with EtSH (185 ml, 2.5 mmol) and BF₃·Et₂O

(127 ml, 1.0 mmol). After 1 h the reaction is usually

complete. Quenching with NH₄Cl sat. sol. and extrac-

tion with Et₂O was followed by chromatography with

PE/Et₂O to give the inseparable diastereoisomeric mix-

tures 22,23 in 89% yield from 8,9k. When the reaction

was performed on 8,9l the 4-methoxybenzyl ether was

also cleaved and 26,27 were isolated in 66% overall

A solution of 8d (15 mg, 37 mmol) in chloroform (2 ml)

was treated with 10 mg of powdered 4 A molecular

,

sieves, 2,6-di-tbutyl-4-methylpyridine (61 mg, 296

mmol) and methyl triﬂate (17 ml, 148 mmol) and then

heated at 60°C for 48 h (a second addition of an

equivalent amount of both reagents was performed

after 24 h). After dilution with water, the mixture was

extracted with Et₂O and crude product was chro-

matographed with PE/Et₂O (6:4) to give 8f (11 mg, 73%

yield).

4.23. 8g by protection of 8d

The same procedure reported for the preparation of 5e

was followed starting from pure 8d and the correspond-

ing 8g was obtained in 87% yield.

2724

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

yield. Characterization of 22,23: R_f0.31 (22,23) (PE/

Et₂O 4:6, A, B). IR (22,23): w_max3472, 2400, 1712, 1380,

1327, 1304, 1068. GC–MS: unsuitable for this analysis.

¹H NMR: 1.19 [3H, d, >CHCH₃, J=7.0 (23)]; 1.34 [3H,

d, >CHCH₃, J=6.8 (22)]; 3.15 [1H, sextuplet,

>CHCH₂O–, J=6.8 (23)]; 3.16 [1H, sextuplet,

>CHCH₂O–, J=6.6 (22)]; 3.50–3.94 [2H, m, –CHCH₂O–

(22,23)]; 4.03 [2H, s, –OCH₂CꢀC– (23)]; 4.04 [2H, s,

–OCH₂CꢀC– (22)]; 4.27 [2H, s, –OCH₂Ph (22,23)]; 6.02

[2H, apparent s, H₂and H₃(22,23)]; 7.14–7.49 [13H, m,

H₅, H₆, H₇, –OPh, Ph (22,23)]; 7.79 [1H, broad d, H₈,

J=7.8 (22,23)]. ¹³C NMR: 15.91 [>CHCH₃, (22)]; 17.25

[>CHCH₃, (23)]; 36.08 [>CHCH₃, (22)]; 36.22

[>CHCH₃, (23)]; 44.25 [C₂(23)]; 44.56 [C₂(22)]; 57.13

[–CH₂CꢀC– (22,23)]; 66.51 [–CH₂OH (22,23)]; 71.04

[–OCH₂Ph (22,23)]; 79.62 and 82.90 [2C, –CꢀC–

(22,23)]; 121.58 [2C, C ortho of Ph (carbamate) (22,23)];

123.27, 124.96, 125.07, 127.83, 127.92 and 127.98 [5C,

aromatics (22,23)]; 125.78 [C para of Ph (carbamate)

(22,23)]; 127.56 [C_4a(22,23)]; 128.23 and 128.35 [4C, C

ortho and meta of Ph (Bn) (22,23)]; 129.40 [2C, C meta

of Ph (carbamate) (22,23)]; 134.50 [C₄(22,23)]; 137.13

and 137.22 [C_8aand C ipso of Ph (Bn) (22,23)]; 150.98

[C ipso of Ph (carbamate) (22,23)]; 151.83 [CO (22,23)].

Characterization of 24,25: R_f0.30 (24,25) (PE/Et₂O 2:8,

A, B). IR (24,25): w_max3008, 2411, 1714, 1384, 1303,

paraformaldehyde the reaction was reﬂuxed for 22 h.

Quenching with NH₄Cl sat. sol. was followed by extrac-

tion with Et₂O. (b) Transformation of 21 into 26. Crude

mixture was treated with p-TSA in methanol as

described for the transformation of 8,9j into 8,9d.

Chromatography with PE/Et₂O (1:9) furnished 26 (11

mg) in 14% overall yield from 20.

From 22,23 or 24,25: the same procedure described in

the previous paragraph, using EtSH and BF₃·Et₂O was

followed, performing the reaction at reﬂux (22,23) or at

0°C (24,25). The diols 26,27, that have been separated,

have been obtained in an overall yield of 50 and 99%,

respectively, as pale yellow oils. Characterization of 26:

R_f0.47 (Et₂O 4:6, A, B). IR: w_max3461, 2960, 2391,

1713, 1328, 1303. GC–MS (analysis performed on the

diastereomeric mixture 26,27): (usual conditions, but

with ﬁn. temp. 290°C). R_t12.05; m/z 363 (M⁺, 9.8), 345

(15), 305 (11), 304 (52), 288 (12), 286 (14), 242 (11), 222

(25), 212 (12), 210 (14), 196 (11), 195 (10), 194 (46), 193

(12), 192 (13), 184 (20), 183 (8.8), 182 (17), 181 (9.9),

180 (25), 179 (11), 178 (15), 168 (12), 167 (31), 166 (40),

165 (17), 156 (18), 155 (7.0), 154 (22), 153 (9.1), 152

(18), 144 (10), 132 (14), 130 (11), 129 (9.3), 128 (22), 127

(14), 115 (19), 94 (20), 91 (9.5), 78 (10), 77 (100), 65

(25), 55 (11), 51 (24), 44 (16), 43 (10), 41 (10), 39 (25).

¹H NMR: 1.33 [3H, d, >CHCH₃, J=6.8] 3.11 [1H,

sextuplet, >CHCH₂O–, J=6.2]; 3.48 and 3.69 [2H, AB

part of ABX system, –CHCH₂OH, J_AB=9.8, J_AXand

1

1234, 1071. GC–MS: unsuitable for this analysis. H

NMR: 1.20 [3H, d, >CHCH₃, J=7.0 (25)]; 1.35 [3H, d,

>CHCH₃, J=6.7 (24)]; 3.07–3.25 [1H, m, >CHCH₂O–

(24,25)]; 3.52–3.77 [2H, m, –CHCH₂O– (24,25)]; 3.79

[3H, s, –OCH₃(24,25)]; 4.01 [2H, s, –OCH₂CꢀC–

(24,25)]; 4.31 [2H, s, –OCH₂Ar (24,25)]; 6.02 [2H,

apparent s, H₂and H₃(24,25)]; 6.82 [2H, dt, H ortho to

–OMe, J=2.4, 8.6 (24,25)]; 7.09 [2H, dt, H meta to

–OMe, J=2.6, 8.7 (24,25)]; 7.18–7.48 [8H, m, H₅, H₆,

H₇, –OPh (24,25)]; 7.80 [1H, broad d, H₈, J=6.6

(24,25)]. ¹³C NMR: 15.89 [>CHCH₃, (24)]; 17.26

[>CHCH₃, (25)]; 35.99 [>CHCH₃, (24)]; 36.14

[>CHCH₃, (25)]; 44.16 [C₂(25)]; 44.48 [C₂(24)]; 55.24

[–OCH₃(24,25)]; 56.65 [–CH₂CꢀC– (24,25)]; 66.37

[–CH₂OH (24,25)]; 70.55 [–OCH₂Ar (24,25)]; 79.58

(25), 79.65 (24), 82.72 (24) and 82.96 (25) [2C, –CꢀC–];

113.68 [2C, C ortho to –OMe (24,25)]; 121.53 [2C, C

ortho of Ph (24,25)]; 123.21, 124.86, 125.02, 127.82 (24)

and 127.89 (25) [4C, aromatics (24,25)]; 125.74 [C para

of Ph (24,25)]; 127.45 []CCH₂CꢀC– (24,25)]; 129.03

[C_4a(25)]; 129.07 [C_4a(24)]; 129.34 [2C, C meta of Ph

(24,25)]; 129.85 [2C, C meta to –OMe (24,25)]; 134.33

[C₄(24,25)]; 136.93 [C_8a(24)]; 137.73 [C_8a(25)]; 150.78

[C ipso of Ph (24,25)]; 151.76 [CO (24,25)]; 159.25

[]C-OMe (24,25)].

J_BX=6.1, 6.9]; 4.09 [2H, d, –OCH₂CꢀC–, J=1.6]; 5.93

[1H, d, H₃, J=6.4]; 5.99 [1H, dt, H₂, J=1.4, 6.6];

7.15–7.44 [8H, m, H₅, H₆, H₇, Ph]; 7.75 [1H, broad d,

H₈, J=7.6]. ¹³C NMR: 15.71 [>CHCH₃]; 35.92

[>CHCH₃]; 44.42 [C₂]; 50.97 [–CH₂CꢀC–]; 66.35

[–CH₂OH]; 81.56 and 81.89 [2C, –CꢀC–]; 121.40 [C₈];

123.26, 124.87, 125.06 and 127.93 [4C, C₃, C₅, C₆, C₇];

121.55 [2C, C ortho of Ph]; 125.82 [C para of Ph];

127.32 [C_4a]; 129.39 [2C, C meta of Ph]; 134.18 [C₄];

136.80 [C_8a]; 150.81 [C ipso of Ph]; 151.96 [CO]. Char-

acterization of 27: R_f0.36 (Et₂O 4:6, A, B). IR: w_max

3426, 2398, 1713, 1380, 1303, 1188, 1135. GC–MS: see

compound 26. ¹H NMR: 1.17 [3H, d, >CHCH₃, J=6.8]

3.11 [1H, sextuplet, >CHCH₂O–, J=6.6]; 3.77 and 3.88

[2H, AB part of ABX system, –CHCH₂OH, J_AB=10.8,

J_AXand J_BX=5.8, 6.2]; 4.12 [2H, d, –OCH₂CꢀC–,

J=1.8]; 5.95 [1H, d, H₃, J=6.6]; 6.02 [1H, dt, H₂,

J=1.7, 6.6]; 7.18–7.55 [8H, m, H₅, H₆, H₇, Ph]; 7.76

[1H, broad d, H₈, J=6.1]. ¹³C NMR: 17.25 [>CHCH₃];

36.03 [>CHCH₃]; 44.14 [C₂]; 51.07 [–CH₂CꢀC–]; 66.62

[–CH₂OH]; 81.86 and 81.97 [2C, –CꢀC–]; 120.34 [C₈];

123.19, 124.93, 125.11 and 127.92 [4C, C₃, C₅, C₆, C₇];

121.60 [2C, C ortho of Ph]; 125.84 [C para of Ph];

127.68 [C_4a]; 129.42 [2C, C meta of Ph]; 134.22 [C₄];

137.66 [C_8a]; 150.90 [C ipso of Ph]; 152.00 [CO].

4.27. 4-{(S*)-[(2-Hydroxy-1-methyl)ethyl]}-2-[(R*)-3-

hydroxyprop-1-ynyl]-2H-quinoline-1-carboxylic acid

phenyl ester, 26 and its epimer, 27

4.28. 4-{(R)-[1-Hydroxymethyl-2-trityloxy]ethyl}-2-

{(R)-[(trimethylsilyl)ethynyl]}-2H-quinoline-1-carboxylic

acid phenyl ester, 28 and its epimer at C-2, 29

From 20: (a) Transformation of 20 into 21. A solution of

20 (124 mg, 215 mmol) in dry THF (5 ml) was cooled to

0°C and treated with tBuMgCl (2 M sol in Et₂O, 107

ml). After 45 min the solution was stirred for additional

15 min at rt. Then paraformaldehyde (39 mg, 1.29 mg)

was added and the slurry was stirred at rt for 17 h; after

the addition of an equivalent amount of tBuMgCl and

Triethylsilyl ether was removed under the same condi-

tions used for the transformation of 8c and 8e into 8d,

starting from the diastereomeric mixture 8,9o. After

chromatography with PE/Et₂O 7:34:6 the two

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

2725

epimeric alcohols 28 and 29 were separated and

obtained in 97% overall yield as white foams. Charac-

terization of 28: R_f0.43 (PE/Et₂O 1:1, A, B). [h]_D=

+255.0 (c 1.75, CHCl₃). IR: w_max3023, 2995, 2954, 2170,

1708, 1447, 1376, 1190, 1008. GC–MS: unsuitable for

NMR: 0.13 [9H, s, –Si(CH₃)₃]; 2.36 [3H, s, –CH₃]; 3.27

[1H, quintuplet, –CHCH₂OTr, J=5.7]; 3.27 and 3.43

[2H, AB part of ABX system, >CHCH₂OTr, J_AB=9.0,

J_AXand J_BX=5.0, 6.8]; 4.18 and 4.24 [2H, AB part of

ABX system, >CHCH₂OTs, J_AB=9.6, J_AXand J_BX

5.0, 5.9]; 5.77 and 5.84 [2H, AB system, H₂and H₃,

_AB=6.8]; 7.06–7.42 [25H, m, H₅, H₆, H₇, Ph, Tr, H

=

1

this analysis. H NMR: 0.02 [9H, s, –Si(CH₃)₃]; 2.45

[1H, broad s, –CH₂OH]; 3.29–3.43 [3H, m,

>CHCH₂OTr]; 4.00 [2H, apparent s; became a broad d,

J=4.0, after exchange with D₂O, –CH₂OH]; 5.88 and

5.88 [2H, AB system, H₂and H₃, J_AB=6.9]; 7.02 [1H,

broad d, H₆, J=7.6]; 7.13–7.41 [22H, m, H₅, H₇, Ph,

Tr]; 7.74 [1H, broad d, H₈, J=7.8]. ¹³C NMR: −0.27

[3C, –Si(CH₃)₃]; 41.55 [–CH(CH₂O–)₂]; 44.72 [C₂];

64.78 and 65.17 [2C, –CH(CH₂O–)₂]; 87.16 [–CPh₃];

88.90 and 101.20 [2C, –CꢀC–TMS]; 121.62 [2C, C ortho

of Ph]; 122.35 [C₈]; 123.06, 125.04 [most likely 2C]; and

127.83 [4C, C₃, C₅, C₆, C₇]; 125.68 [C para of Ph];

127.20 [3C, C para of Tr]; 127.48 [C_4a]; 127.96 and

128.50 [12C, C ortho and meta of Tr]; 129.28 [2C, C

meta of Ph]; 133.69 [C₄]; 134.34 [C_8a]; 144.61 [3C, C

ipso of Tr]; 150.85 [C ipso of Ph], 151.80 [CO]. Charac-

terization of 29: R_f0.29 (PE/Et₂O 2:8, A, B). [h]_D=

−227.8 (c 1.16, CHCl₃). IR: w_max3044, 2981, 2305, 1714,

1379, 1327, 1255. GC–MS: unsuitable for this analysis.

¹H NMR: 0.08 [9H, s, –Si(CH₃)₃]; 2.22 [1H, broad s,

–CH₂OH]; 3.27 [1H, quintuplet, >CHCH₂OTr, J=6.0];

3.51 and 3.57 [2H, AB part of ABX system,

–CHCH₂OTr, J_AB=9.2, J_AXand J_BX=5.0, 8.1]; 3.77–

3.84 [2H, m, –CH₂OH]; 5.82 and 5.88 [2H, AB system,

H₂and H₃, J_AB=6.6]; 7.08–7.51 [23H, m, H₅, H₆, H₇,

Ph, Tr]; 7.73 [1H, broad d, H₈, J=7.7]. ¹³C NMR:

−0.37 [3C, –Si(CH₃)₃]; 41.92 [–CH(CH₂O–)₂]; 44.85

[C₂]; 64.46 and 64.90 [2C, –CH(CH₂O–)₂]; 87.29

[–CPh₃]; 87.29 and 101.90 [2C, –CꢀC–TMS]; 121.58 [2C,

C ortho of Ph]; 122.46 [C₈]; 123.12, 124.94 [most likely

2C]; and 127.78 [4C, C₃, C₅, C₆, C₇]; 125.71 [C para of

Ph]; 127.11 [3C, C para of Tr]; 127.54 [C_4a]; 127.94 and

128.68 [12C, C ortho and meta of Tr]; 129.33 [2C, C

meta of Ph]; 133.49 [C₄]; 134.20 [C_8a]; 144.68 [3C, C

ipso of Tr]; 150.87 [C ipso of Ph], 151.83 [CO].

J

ortho to –SO₂–]; 7.64 [2H, apparent d, H ortho to

–SO₂–, J=8.4]; 7.72 [1H, broad d, H₈, J=8.2]. ¹³C

NMR: −0.41 [3C, –Si(CH₃)₃]; 39.37 [–CH(CH₂O–)₂];

44.76 [C₂]; 62.11 and 69.18 [2C, –CH(CH₂O–)₂]; 86.96

[–CPh₃]; 88.94 and 100.48 [2C, –CꢀC–TMS]; 121.61

[2C, C ortho of Ph]; 122.69, 123.30, and 124.87 [most

likely 2C] [4C, 4C (between C₃, C₅, C₆, C₇, C₈, while

one is overlapped with another signal)]; 125.77 [C para

of Ph]; 127.05 [3C, C para of Tr]; 127.79 [2C, C ortho to

–SO₂–]; 127.85 and 128.69 [12C, C ortho and meta of

Tr]; 128.47 [C_4a]; 129.38 [2C, C meta of Ph]; 129.80 [2C,

C meta to –SO₂–]; 131.87 [C₄]; 132.50 [–CSO₂–]; 134.16

[C_8a]; 143.58 [3C, C ipso of Tr]; 144.73 [–CMe of Ts];

150.88 [C ipso of Ph], 151.78 [CO].

4.31. 9j by reduction of 30

A solution of 30 (48 mg, 59 mmol) in dry THF (3 ml)

was treated with NaI (198 mg, 132 mmol) and AIBN

[2,2%-azobis(2-methylpropionitrile)] (2.5 mg, 15 mmol).

Then nBu₃SnH (24 ml, 89 mmol) was added via syringe

and the resulting mixture was heated at 85°C in a

sealed tube for 19 h. After diluting with water, an

extraction was performed with Et₂O. Chromatography

with PE/Et₂O 9:16:4 gave 9j as a pale yellow oil [11

mg, 29% yield (39% on unrecovered starting material)].

4.32. NOE difference experiments on 16, 18, 19

The samples were prepared (20 mg/ml) using CDCl₃

,

previously dried on 3 A molecular sieves, and freshly

passed through alumina. The tubes were placed under

nitrogen and kept for 30 min in an ultrasound bath, in

order to remove oxygen. NOEDIF spectra were

acquired at 200 MHz, using a delay of 3.9 s and 256

transients. A decoupling power so that gH₂=3–4 Hz

was used. The NOEs were calculated on the basis of the

integrals for the ‘normal’ spectrum and the decoupled

one. Compound 16: irradiation of OMe gave, at 49%

saturation, NOEs of 5.5, 2.5 and 1.0 for H_6a, ꢀCꢁH and

H₁, respectively, corresponding to effective NOEs of

11.2, 5.2 and 2.1. Compound 18: (a) irradiation of OMe

gave, at 44% saturation, NOEs of 8.0, 3.4 and 0.8 for

H_3a, H₉, and CH₃CHCO, respectively, corresponding to

effective NOEs of 18.3, 7.8 and 1.8; (b) Irradiation of

CH₃CHCO gave, at 31 saturation, NOEs of 1.3, 0.7

and 0.6 for H₉, H_3aand OCH₃, respectively, corre-

sponding to effective NOEs of 4.2, 2.2 and 1.8; (c)

Irradiation of CH₃CHCO gave, at 43 saturation, NOEs

of 0.9, 0.5 and 0.5 for H₉, H₄and H_3a, respectively,

corresponding to effective NOEs of 2.0, 1.2 and 1.1.

Compound 19: (a) irradiation of OMe gave, at 50%

saturation, NOEs of 8.6, and 3.8 for H_3aand H₉,

respectively, corresponding to effective NOEs of 17.1

and 7.6; (b) Irradiation of CH₃CHCO gave, at 73

saturation, a NOE of 4.5 for H₉, corresponding to an

4.29. 8m by acetylation of 29

The same procedure reported for the preparation of 5f

was followed starting from 29 and the corresponding

8m was obtained in 82% yield.

4.30. 4-{(S)-[1-(Toluene-4-sulfonyloxymethyl)-2-trityl-

oxy]ethyl}-2-{(S)-[(trimethylsilyl)ethynyl]}-2H-quinoline-

1-carboxylic acid phenyl ester, 30

A solution of 29 (202 mg, 304 mmol) in dry CH₂Cl₂(3

ml) was cooled a t 0°C and treated with 4-dimethyl-

aminopyridine (4 mg, 33 mmol), triethylamine (148 ml,

106 mmol) and freshly distilled p-TsCl (87 mg, 456

mmol). After 5 min the reaction was stirred at rt for 7 h.

After addition of 5% aq NH₄H₂PO₄, the reaction was

extracted as usual with Et₂O. Chromatography with

PE/Et₂O 8:27:3 gave pure 30 (176 mg, 71% yield) as

a white foam. R_f0.44 (PE/Et₂O 6:4, A, B). [h]_D=−60.5

(c 1.32, CHCl₃). IR: w_max2954, 2170, 1720, 1377, 1326,

1

1291, 1174. GC–MS: unsuitable for this analysis. H

2726

G. Guanti et al. / Tetrahedron: Asymmetry 13 (2002) 2703–2726

effective NOE of 6.2; (c) Irradiation of CH₃CHCO

gave, at 73 saturation, NOEs of 5.3 and 1.9 for H_3aand

H₉, respectively, corresponding to effective NOEs of 7.3

and 2.6.

20. Guanti, G.; Narisano, E.; Riva, R. Tetrahedron: Asym-

metry 1997, 8, 2175–2187.

21. Banﬁ, L.; Guanti, G.; Mugnoli, A.; Riva, R. Tetrahedron:

Asymmetry 1998, 9, 2481–2492.

22. Greene, T. W.; Wuts, P. G. M. Protective Groups in

Organic Synthesis; J. Wiley: New York, 1999.

23. Guanti, G.; Banﬁ, L.; Riva, R.; Zannetti, M. T. Tetra-

hedron Lett. 1993, 34, 5483–5486.

24. Magnus, P.; Fairhurst, R. A. J. Chem. Soc., Chem.

Commun. 1994, 1541–1542.

25. Wender, P. A.; Zercher, C. K. J. Am. Chem. Soc. 1991,

113, 2311–2313.

26. Wender, P. A.; Beckham, S.; O’Leary, J. G. Synthesis

1994, 1278–1282.

Acknowledgements

The authors gratefully thank Novo Nordisk for a gen-

erous gift of lipase from Candida antarctica, CNR, the

University of Genova and MURST (COFIN 00) for

ﬁnancial support and Ms. Laura Bondanza and Dina

Cavallo for their help in this work.

27. Elbaum, D.; Porco, J. A.; Stout, T. J.; Clardy, J.;

Schreiber, S. L. J. Am. Chem. Soc. 1995, 117, 221–225.

28. Takahashi, T.; Sakamoto, Y.; Yamada, H.; Usui, S.;

Fukazawa, Y. Angew. Chem., Int. Ed. Engl. 1995, 34,

1345–1348.

29. Nicolaou, K. C.; Dai, W.-M. J. Am. Chem. Soc. 1992,

114, 8908–8921.

30. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.;

Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509–

9525.

References

1. Alvarez, M.; Salas, M.; Joule, J. A. Heterocycles 1991,

32, 759–794.

2. Michael, J. P. J. Nat. Prod. Rep. 1995, 12, 77–89.

3. Michael, J. P. J. Nat. Prod. Rep. 1995, 12, 465–475.

4. Chauhan, P. M. S.; Srivastava, S. K. Curr. Med. Chem.

2001, 8, 1535–1542.

5. Goya, P.; Jagerovic, N. Expert Opin. Ther. Pat. 2000, 10,

1529–1538.

31. Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.;

Madar, D. J. J. Am. Chem. Soc. 1997, 119, 6072–6094.

32. Rezgui, F.; Mangeney, P.; Alexakis, A. Tetrahedron Lett.

1999, 40, 6241–6244.

33. Nishikawa, T.; Yoshikai, M.; Obi, K.; Kawai, T.; Unno,

R.; Jomori, T.; Isobe, M. Tetrahedron 1995, 51, 9339–

9352 and references cited therein.

6. Giardina, G. A. M.; Raveglia, L. F.; Grugni, M.; Sarau,

H. M.; Farina, C.; Medhurst, A. D.; Graziani, D.;

Schmidt, D. B.; Rigolio, R.; Luttmann, M.; Cavagnera,

S.; Foley, J. J.; Vecchietti, V.; Hay, D. W. P. J. Med.

Chem. 1999, 42, 1053–1065.

7. Madsen, P.; Brand, C. L.; Holst, J. J.; Knudsen, L. B.

Curr. Pharm. Design 1999, 5, 683–691.

8. Akendengue, B.; Ngou Milama, E.; Laurens, A.; Hoc-

quemiller, R. Parasite—J. Soc. Fr. Parasitol. 1999, 6, 3–8.

9. Das, B.; Madhusudhan, P.; Reddy, P. V.; Anitha, Y.

Indian J. Chem. B 2001, 40, 453–464 and references cited

therein.

10. Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed.

Engl. 1991, 30, 1387–1416.

11. Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.;

Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H. J.

Antibiot. 1989, 42, 1449–1452.

12. Porco, J. A.; Schoenen, F. J.; Stout, T. J.; Clardy, J.;

Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410–7411.

13. Myers, A. G.; Fraley, M. E.; Tom, N. J. J. Am. Chem.

Soc. 1994, 116, 11556–11557.

14. Shair, M. D.; Yoon, T. Y.; Danishefsky, S. J. Angew.

Chem., Int. Ed. Engl. 1995, 34, 1721–1723.

15. Maier, M. E.; Bosse, F.; Niestroj, A. Eur. J. Org. Chem.

1999, 1–13.

16. Banﬁ, L.; Guanti, G. Tetrahedron Lett. 2002, 43, 7427–

7429 and references cited therein.

34. Fraenkel, G.; Cooper, J. W.; Fink, C. M. Angew. Chem.,

Int. Ed. Engl. 1970, 9, 523.

35. Thomas, E. J. J. Chem. Soc., Chem. Commun. 1997,

411–418.

36. Nishikawa, T.; Yoshikai, M.; Obi, K.; Isobe, M. Tetra-

hedron Lett. 1994, 35, 7997–8000.

37. Guanti, G.; Riva, R. Tetrahedron: Asymmetry 2001, 12,

1185–1200.

38. Nishikawa, T.; Ino, A.; Isobe, M. Tetrahedron 1994, 50,

1449–1468.

39. Bloch, R.; Brillet, C. Synlett 1991, 829–830.

40. Ohno, K.; Nishiyama, H.; Nagase, H. Tetrahedron Lett.

1979, 45, 4405–4406.

41. Finch, N.; Fitt, J. J.; Hsu, I. H. S. J. Org. Chem. 1975,

40, 206–215.

42. Walba, D. M.; Thurmes, W. N.; Haltiwanger, R. C. J.

Org. Chem. 1988, 53, 1046–1056.

43. Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J. Org.

Chem. 1979, 44, 1661–1664.

44. Ueno, Y.; Tanaka, C.; Okawara, M. Chem. Lett. 1983,

795–796.

45. Guanti, G.; Riva, R. J. Chem. Soc., Chem. Commun.

2000, 1171–1172.

46. Imamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron

Lett. 1985, 26, 4763–4766.

17. Guanti, G.; Perrozzi, S.; Riva, R. Tetrahedron: Asymme-

try 1998, 9, 3923–3927.

18. Schering-Kahlbaum, A.-G. British Patent No. 283,577, 14

January 1927; C.A. 1928, 22, 4132.

19. Zo¨llner, C. US Patent No. 1,804,045, 12 May 1930; C.A.

1931, 25, 3668.

Article Doi

O-Protecting groups as long-range stereocontrolling elements in the addition of acetylides to 4-substituted quinolines

DOI: 10.1016/S0957-4166(02)00711-5

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0957-4166(02)00711-5

Full text of DOI:10.1016/S0957-4166(02)00711-5

Products guided by the article

R&D Labs maybe for 526203-37-2

Relevant to this article

Hot Product